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Introduction

Previous studies have shown heterogeneity of leukemia-producing cell populations in the patients with acute myeloid leukemia (AML) [1]. In model experiments with human leukemic cells transplanted into immunodeficient mice, the earlier CD34+CD38- human stem cells were responsible for leukemia induction and, moreover, were able to express a pan-specific Brain And Acute Leukemia Cytoplasmic (BAALC) gene [2, 3]. Moreover, similar experiments with acute promyelocytic leukemia (APL) cells revealed more mature leukemia-initiating precursors [4 Patel et al, 2012], which, along with blast cells, according to our hypothesis, might express WT1, another pan-specific gene [5-7]. Since mRNA of the both genes may be detected with quantitative real-time PCR (RT-qPCR), we attempted to evaluate the genes of interest by means of this standard approach [5-7]. Our works have yielded the following results: a) important role of BAALC expressing stem-cells in post-transplant relapses (PTR) of AML [5-6]; b) proven clinical effect of a targeted drug (Mylotarg) upon the levels of leukemic stem cells and precursors [7]; and c) possible presence of leukemic hematopoietic regulators causing transition from some immature stem cells in AML to more mature precursors [5, 7] as well as in APL [6]. To support this hypothesis, we have recently studied leukemic hematopoiesis in a mixed group of adult and pediatric patients with EVI1-positive AML. Chromosome aberrations at the 3q26 locus are considered common in adult patients, however, being virtually absent in pediatric cases. Meanwhile, EVI1-positive AML with presumable rearrangements of KMT2A gene was found in one-fourth of pediatric patients [8-10], thus also presenting essential age-dependent differences in responses to therapy and HSCT. At the same time, an excellent response to retinoid treatment has been recently revealed in all types of EVI1-positive AML [11], which seems to be associated with their direct action upon functional activity of stem cells [12].

The aim of our work was to test BAALC/WT1 molecular panel in the mixed pediatric and adult cohort of patients with of AML variants which are generally resistant to intensive therapy and HSCT.

Patients and methods

1.1. Patient cohort

Our retrospective study presents the data on BAALC and WT1 gene expression levels measured in parallel in the course of serial bone marrow sampling from fourteen EVI1-positive patients with different AML FAB-variants, who underwent allogeneic HSCT at R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation (St. Petersburg) from 2010 to 2016 years. This group included 8 pediatric patients under 18 years and 6 adults with AML. In all the patients, BAALC and WT1 gene expression changes, as well as blast cell counts were serially monitored in the same bone marrow aspirates. Written informed consent was obtained from all patients, following the Declaration of Helsinki Recommendations.

1.2. Analysis of BAALC and WT1 gene expression levels

Total mRNA was extracted from fresh bone marrow samples, its reverse transcription and estimation of the BAALC gene expression level were performed by quantitative real-time PCR (RT-qPCR) as elsewhere described [13]. In brief, BAALC transcript copy numbers (CN) were determined by means of BAALC RQ-Kit (Inogene, Russia), including plasmid standards for plotting appropriate calibration curves for BAALC and ABL1 reference gene. Basic control time points for the bone marrow examination were as follows: at diagnosis (e.g., D-80), prior to conditioning (D0), and, as obligatory diagnostics, in post-transplant relapses (PTR). A median follow-up time after HSCT was 7 months (range, 0.6 to 52.5 months). Relative BAALC expression level was calculated as a ratio of CN_BAALC to CN_ABL1 and expressed as a percent value. The expression level of 31% was chosen as a common cut-off value to study clinical significance of BAALC gene overexpression before and after HSCT. This value was shown to exceed maximal BAALC expression levels in the patients with pre-transplant cytological remission without any signs of the disease progression.

In parallel, the WT1 gene expression levels were determined in each sample at the same time points. The copy numbers of WT1 transcripts were evaluated by the similar RT-qPCR method, according to Recommendations of European LeukemiaNet Group [14]. The basal WT1 expression level of 250 copies per 10⁴ copies of ABL1 reference gene was used to discriminate between low and high WT1 expression rates. Similarly, the 10 per cent expression level was considered a cut-off value when studying clinical significance of EVI1 overexpression.

1.3. Statistical analysis

Due to small numbers of patients in the tested groups, full-scale statistical analysis was not carried out. The data with asymmetric distribution were presented as extreme ranges and median values. Overall survival (OS) and relapse free-survival (RFS) were measured from D0 until the date of death, regardless of cause, or until the term of documented relapse, or last contact date. STATISTICA software was used for calculations. P< 0.05 was considered the statistically significant difference level, having been determined in every case.

Results

Basic clinical and laboratory data are presented in Table 1. They concern eight pediatric (lower 18 y. o.) and six adult patients. The common levels of EVI1 expression ranged from 0.3% to 130%, being the highest in 26 year-old female with M1 FAB-variant (#11) with complex karyotype. One should note that the cytogenetic changes in pediatric patients were not related to specific 3q26 locus, whereas this pattern of chromosome aberrations was found in 5 of 6 adult patients (83%). At the same time, one of pediatric patients (#5) showed KMT2A rearrangements which are more typical to this type of childhood AML. In general, the cytogenetic aberrations ranged from chromothripsis (#1) and highly complex karyotype to single reciprocal translocations (#8) or deletions (#6). Normal karyotype was registered only in one child (#3).

Table 1. Clinical and laboratory parameters of pediatric (#1-8) and adult (#9-14) variants of EVI1-positive acute myeloid leukemia, treated with hematopoietic stem cell transplantation

*, deceased patients; n/d, no data; rel, related; n/rel, nonrelated; haplo, haploidentical; overexpressed levels of BAALC expression and higher meanings of OV in children are noted by red and green colours, respectively

One should comment that primary diagnosis in most patients was assessed at regional hospitals, where precise molecular diagnostics was not available. Therefore, molecular markers at the early stages of disease are lacking in these patients.

Despite this drawback, elevated BAALC expression in EVI1-positive AML at primary diagnosis was demonstrated both in pediatric (#7) and adult (#9, 11) patients, being higher in adults.

Before HSCT, overexpression of BAALC was seen in three pediatric patients (#1, 6, 7), as well as in two adults (#9, 14) who, along with increased blast counts, showed insufficient response of these leukemic cells to pretransplant therapy. This pattern of response is also confirmed by common elevation of WT1 level expression prior to HSCT (6/13; 46%). Finally, upon emergence of post-transplant relapse (PTR) in 5/6 adult patients and 5/8 pediatric ones, the elevated BAALC expression was revealed in five cases (#4, 6, 9, 11 and 13), being the highest (389%) in a young female with secondary (from MDS) M4-FAB-variant of AML (# 9). WT1 gene expression at diagnosis, was enhanced in patients #7, #9 and #11 (11753, 867 and 10493 copies, respectively), with appropriate increase of blast numbers in bone marrow (resp., 88%, 17%, and 84%). At pre-transplant stage, the levels of WT1 expression were increased in the patients #3, #6, #8, #9 and #14 (up to 3693, 2048. 2957. 2025 and 2671 copies, respectively), showing only weak correlation with blast counts in their bone marrow samples (13.4, 7.2, 21, 38 and 7.6, respectively.) Comparison of these data argues for our earlier concept presuming an active participation of other cell populations in WT1 gene expression, for instance, of more mature precursors recently found in successful xenograft of APL samples in immunodeficient NOD/shi-SCID IL2Ry-/- mice [4].

Finally, at stage of PTR, increased WT1 expression levels were found in patients #1, 3, 4, 6, 8, 9, 11, 12, and 13 (respectively, 3315, 1049, 436. 120239. 32684, 1165, 6500, 4542 and 18872 copies) that also weakly correlated with number of blasts in tested bone marrows (60.4, 20.8, 29.8, 30.4, 24.4, 31.5, 51.2, 21, and 26%, respectively).

In conclusion, one should notice that the patients with M3 (#8) and M7 (#1 and 3) had lower levels of BAALC expression at all studied stages, which is explained simply by basic role in hematopoiesis with more mature precursors than BAALC-expressing stem cells. Further, one may conclude on opportunity for different variants of emerging PTR. Thus, in several cases (#4, 6, 9, 11, and 13), PTR were associated with activation of both BAALC-expressing stem cells and WT1-expressing mature precrsors. Meanwhile, PTR in patients with M3 (#8), M7 ( # 1 , 3 and single presenters of M5 (#12) FAB-variants were accompanied by WT1 expressing precursors only.

Discussion

Hence, despite different biological and cytogenetic characteristics of pediatric and adult EVI1-positive AML, they revealed relatively higher levels of BAALC-expressing precursors at diagnosis, as well as at pre- and posttransplant stages, which, in turn, may be related with great difficulties in preparative regimens for HSCT. The real difference between the age groups consisted only in more often relapse-free course of leukemia in children (n=3), than that was among adults (n=1). Therefore, median of overall survival in pediatric patients was longer than that in adults (999 vs 317 days, respectively) which is statistically significant (p<0.05). Presence of cases with AML FAB-variants of M7 (n=2) and M3 (n=1) in pediatric group among these patients may be another reason for absence of expected difference in OS. These patients, generally, do not show higher levels of BAALC expression, due to alternative nature of hematopoiesis precursors.

Conclusion

To reveal the expected difference in BAALC-expressing precursors between pediatric and adult EVI1-positive AML, further studies should be performed in larger cohorts of carefully chosen patients, with omission of M7 and M3 FAB- variants.

Our simultaneous measurements of BAALC and WT1-expressiong leukemic precursors by means of standardized RT-qPCR supported crucial role of BAALC-expressing stem cells in pathogenesis of EVI1-positive AML and relapses evolving in both tested groups.

Conflict of interest

None reported.

References

1. Walter R, Appelbaum F, Estey E, Bernstein I. Acute myeloid leukemia stem cells and CD33-targeted immunotherapy. Blood 2012; 119: 6198-6208. doi: 10.1182/ blood-2011-11-325050
2. Lapidot T, Siratd C, Vormoor J, et al. Z Cell initiating human acute myeloid leukemia after transplantation into SCID mice, Nature 1994;367(6464):645-8. doi: 10.1038/367645a0
3. Morita R, Masamotyo Y, Kataoka K, Koya J, Kagoya Y, Yashiroda H, Sato T, Murata S, Kurokawa M. BAALC potentiates oncogenic ERK pathway through interactions with MEKK1 and KLF4. Leukemia 2015; 29(11): 2248-2256. doi: 10.1038/leu.2015.137
4. Patel S, Zhang Y, Cassinat B, Zassadowski F, Ferré N, Cuccuini W, Cayuela JM, Fenaux P, Bonnet D, Chomienne C, Louache F. Successful xenografts of AML3 samples in immunodeficient NOD/shi-SCID IL2Rγ–/– mice. Leukemia 2012; 26(11):2432-2435. doi: 10.1038/leu.2012.154
5. Mamaev NN, Shakirova AI, Barkhatov IM, et al. New opportunities for assay of leukemia initiating cells (LICs) participating in post-transplant relapse development in the patients with acute myeloid leukemia. 3rd Annual IACH Meeting, 1-3 October, 2020, Paris, report #12.
6. Mamaev NN, Shakirova AI, Barkhatov IM, Gudozhnikova YV, Gindina TL, Kanunnikov MM, Kravtsova VM, Rakhmanova ZZ, Paina OV, Zubarovskaya LS. Crucial role of BAALC-expressing leukemic precursors in origin and development of posttransplant relapses in patients with acute myeloid leukemias. Int J Hematol 2020; 8(6): 127-131. doi: 10.15406/htij.2020.08.00240
7. Mamaev NN, Shakirova AI, Gindina TL, Bondarenko SN, Ayubova BI, Barkhatov IM, Gudozhnikova YaV, Kravtsova VM, Kanunnikov MM, Paina OV, Rakhmanova ZZ, Gracheva TYu, Zubarovskaya LS. Quantitative study of BAALC- and WT1-expressing cell precursors in the patients with different cytogenetic and molecular AML variants treated with Gemtuzumab ozogamycin and hematopoietic stem cell transplantation. Cell Ther Transplant 2021; 10(1)):55-62. doi: 10.18620/ctt-1866-8836-2021-10-1-55-62
8. Balgobind BV, Lugthart S, Hollink IH, Arentsen-Peters STJCM, van Wering ER, de Graaf SSN, et al. EVI1 overexpression in distinct subtypes of pediatric acute myeloid leukemia. Leukemia 2010;24:942-949. doi:10.1038/leu.2010.47
9. Ho PA, Alonzo TA, Gerbing RB, Pollard JA, Hirsch B, Raimondi SC, Cooper T, Gamis AS, Meshinchi S. High EVI1 expression is associated with MLL rearrangements and predicts decreased survival in pediatric acute myeloid leukemia: a report from the children’s oncology group. Br J Haematol 2013;162(5): 670-677. doi: 10.1111/bjh.12444
10. Sadaghian MH, Dezaki ZR. Prognostic value of EVI1 expression in pediatric acute myeloid leukemia: A systematic review. Iran J Pathol. 2018; 13(3):294-300. PMID: 30636951
11. Pauebelle E, Piesa A, Hayette S, et al. Efficacy of ALL-TRANS-RETINOIC ACID in high riskacute myeloid leukemia with overexpression of EVI1. Oncol Ther 2019; 7(2): 121-130. doi: 10.1007/s40487-019-0095-9
12. Mamaev NN, Shakirova AI, Morozova EV, Gindina TL. EVI1-Positive Leukemias and Myelodysplastic Syndromes: Theoretical and Practical Aspects (Literature Review). Clinical Oncohematol 2021;14(1): 103-117 (In Russian). doi: 10.21320/2500-2139-2021-14-1-103-117
13. Shakirova A, Barkhatov I, Churkina A, Moiseev IS, Gindina TL, Bondarenko SN, Afanasyev BV. Prognostic significance of BAALC overexpression in patients with AML during the posttransplant period. Cell Ther Transplant 2018; 7(2):54-63. doi: 10.18620/ctt-1866-8836-2018-7-2-54-63
14. Cilloni D, Renneville A, Hermitte F, Hills R, Daly S, Jovanovic J, Gottardi E, Fava M, Schnittger S, Weiss T, Izzo B, Nomdedeu J, van den Heijden A, van der Reijden B, Jansen J, van der Verlden V, Ommen H, Preudhomme C, Saglio G, Grimwade D. et al. Real-time quantitative polymerase chain reaction detection of minimal residual disease by standardized WT1 assay to enhance risk stratification in acute myeloid leukemia: a European LeukemiaNet study. J Clin Oncol 2009; 27(31): 5195-5201. doi: 10.1200/JCO.2009.22.4865

" ["~DETAIL_TEXT"]=> string(17863) "

Introduction

Previous studies have shown heterogeneity of leukemia-producing cell populations in the patients with acute myeloid leukemia (AML) [1]. In model experiments with human leukemic cells transplanted into immunodeficient mice, the earlier CD34+CD38- human stem cells were responsible for leukemia induction and, moreover, were able to express a pan-specific Brain And Acute Leukemia Cytoplasmic (BAALC) gene [2, 3]. Moreover, similar experiments with acute promyelocytic leukemia (APL) cells revealed more mature leukemia-initiating precursors [4 Patel et al, 2012], which, along with blast cells, according to our hypothesis, might express WT1, another pan-specific gene [5-7]. Since mRNA of the both genes may be detected with quantitative real-time PCR (RT-qPCR), we attempted to evaluate the genes of interest by means of this standard approach [5-7]. Our works have yielded the following results: a) important role of BAALC expressing stem-cells in post-transplant relapses (PTR) of AML [5-6]; b) proven clinical effect of a targeted drug (Mylotarg) upon the levels of leukemic stem cells and precursors [7]; and c) possible presence of leukemic hematopoietic regulators causing transition from some immature stem cells in AML to more mature precursors [5, 7] as well as in APL [6]. To support this hypothesis, we have recently studied leukemic hematopoiesis in a mixed group of adult and pediatric patients with EVI1-positive AML. Chromosome aberrations at the 3q26 locus are considered common in adult patients, however, being virtually absent in pediatric cases. Meanwhile, EVI1-positive AML with presumable rearrangements of KMT2A gene was found in one-fourth of pediatric patients [8-10], thus also presenting essential age-dependent differences in responses to therapy and HSCT. At the same time, an excellent response to retinoid treatment has been recently revealed in all types of EVI1-positive AML [11], which seems to be associated with their direct action upon functional activity of stem cells [12].

The aim of our work was to test BAALC/WT1 molecular panel in the mixed pediatric and adult cohort of patients with of AML variants which are generally resistant to intensive therapy and HSCT.

Patients and methods

1.1. Patient cohort

Our retrospective study presents the data on BAALC and WT1 gene expression levels measured in parallel in the course of serial bone marrow sampling from fourteen EVI1-positive patients with different AML FAB-variants, who underwent allogeneic HSCT at R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation (St. Petersburg) from 2010 to 2016 years. This group included 8 pediatric patients under 18 years and 6 adults with AML. In all the patients, BAALC and WT1 gene expression changes, as well as blast cell counts were serially monitored in the same bone marrow aspirates. Written informed consent was obtained from all patients, following the Declaration of Helsinki Recommendations.

1.2. Analysis of BAALC and WT1 gene expression levels

Total mRNA was extracted from fresh bone marrow samples, its reverse transcription and estimation of the BAALC gene expression level were performed by quantitative real-time PCR (RT-qPCR) as elsewhere described [13]. In brief, BAALC transcript copy numbers (CN) were determined by means of BAALC RQ-Kit (Inogene, Russia), including plasmid standards for plotting appropriate calibration curves for BAALC and ABL1 reference gene. Basic control time points for the bone marrow examination were as follows: at diagnosis (e.g., D-80), prior to conditioning (D0), and, as obligatory diagnostics, in post-transplant relapses (PTR). A median follow-up time after HSCT was 7 months (range, 0.6 to 52.5 months). Relative BAALC expression level was calculated as a ratio of CN_BAALC to CN_ABL1 and expressed as a percent value. The expression level of 31% was chosen as a common cut-off value to study clinical significance of BAALC gene overexpression before and after HSCT. This value was shown to exceed maximal BAALC expression levels in the patients with pre-transplant cytological remission without any signs of the disease progression.

In parallel, the WT1 gene expression levels were determined in each sample at the same time points. The copy numbers of WT1 transcripts were evaluated by the similar RT-qPCR method, according to Recommendations of European LeukemiaNet Group [14]. The basal WT1 expression level of 250 copies per 10⁴ copies of ABL1 reference gene was used to discriminate between low and high WT1 expression rates. Similarly, the 10 per cent expression level was considered a cut-off value when studying clinical significance of EVI1 overexpression.

1.3. Statistical analysis

Due to small numbers of patients in the tested groups, full-scale statistical analysis was not carried out. The data with asymmetric distribution were presented as extreme ranges and median values. Overall survival (OS) and relapse free-survival (RFS) were measured from D0 until the date of death, regardless of cause, or until the term of documented relapse, or last contact date. STATISTICA software was used for calculations. P< 0.05 was considered the statistically significant difference level, having been determined in every case.

Results

Basic clinical and laboratory data are presented in Table 1. They concern eight pediatric (lower 18 y. o.) and six adult patients. The common levels of EVI1 expression ranged from 0.3% to 130%, being the highest in 26 year-old female with M1 FAB-variant (#11) with complex karyotype. One should note that the cytogenetic changes in pediatric patients were not related to specific 3q26 locus, whereas this pattern of chromosome aberrations was found in 5 of 6 adult patients (83%). At the same time, one of pediatric patients (#5) showed KMT2A rearrangements which are more typical to this type of childhood AML. In general, the cytogenetic aberrations ranged from chromothripsis (#1) and highly complex karyotype to single reciprocal translocations (#8) or deletions (#6). Normal karyotype was registered only in one child (#3).

Table 1. Clinical and laboratory parameters of pediatric (#1-8) and adult (#9-14) variants of EVI1-positive acute myeloid leukemia, treated with hematopoietic stem cell transplantation

*, deceased patients; n/d, no data; rel, related; n/rel, nonrelated; haplo, haploidentical; overexpressed levels of BAALC expression and higher meanings of OV in children are noted by red and green colours, respectively

One should comment that primary diagnosis in most patients was assessed at regional hospitals, where precise molecular diagnostics was not available. Therefore, molecular markers at the early stages of disease are lacking in these patients.

Despite this drawback, elevated BAALC expression in EVI1-positive AML at primary diagnosis was demonstrated both in pediatric (#7) and adult (#9, 11) patients, being higher in adults.

Before HSCT, overexpression of BAALC was seen in three pediatric patients (#1, 6, 7), as well as in two adults (#9, 14) who, along with increased blast counts, showed insufficient response of these leukemic cells to pretransplant therapy. This pattern of response is also confirmed by common elevation of WT1 level expression prior to HSCT (6/13; 46%). Finally, upon emergence of post-transplant relapse (PTR) in 5/6 adult patients and 5/8 pediatric ones, the elevated BAALC expression was revealed in five cases (#4, 6, 9, 11 and 13), being the highest (389%) in a young female with secondary (from MDS) M4-FAB-variant of AML (# 9). WT1 gene expression at diagnosis, was enhanced in patients #7, #9 and #11 (11753, 867 and 10493 copies, respectively), with appropriate increase of blast numbers in bone marrow (resp., 88%, 17%, and 84%). At pre-transplant stage, the levels of WT1 expression were increased in the patients #3, #6, #8, #9 and #14 (up to 3693, 2048. 2957. 2025 and 2671 copies, respectively), showing only weak correlation with blast counts in their bone marrow samples (13.4, 7.2, 21, 38 and 7.6, respectively.) Comparison of these data argues for our earlier concept presuming an active participation of other cell populations in WT1 gene expression, for instance, of more mature precursors recently found in successful xenograft of APL samples in immunodeficient NOD/shi-SCID IL2Ry-/- mice [4].

Finally, at stage of PTR, increased WT1 expression levels were found in patients #1, 3, 4, 6, 8, 9, 11, 12, and 13 (respectively, 3315, 1049, 436. 120239. 32684, 1165, 6500, 4542 and 18872 copies) that also weakly correlated with number of blasts in tested bone marrows (60.4, 20.8, 29.8, 30.4, 24.4, 31.5, 51.2, 21, and 26%, respectively).

In conclusion, one should notice that the patients with M3 (#8) and M7 (#1 and 3) had lower levels of BAALC expression at all studied stages, which is explained simply by basic role in hematopoiesis with more mature precursors than BAALC-expressing stem cells. Further, one may conclude on opportunity for different variants of emerging PTR. Thus, in several cases (#4, 6, 9, 11, and 13), PTR were associated with activation of both BAALC-expressing stem cells and WT1-expressing mature precrsors. Meanwhile, PTR in patients with M3 (#8), M7 ( # 1 , 3 and single presenters of M5 (#12) FAB-variants were accompanied by WT1 expressing precursors only.

Discussion

Hence, despite different biological and cytogenetic characteristics of pediatric and adult EVI1-positive AML, they revealed relatively higher levels of BAALC-expressing precursors at diagnosis, as well as at pre- and posttransplant stages, which, in turn, may be related with great difficulties in preparative regimens for HSCT. The real difference between the age groups consisted only in more often relapse-free course of leukemia in children (n=3), than that was among adults (n=1). Therefore, median of overall survival in pediatric patients was longer than that in adults (999 vs 317 days, respectively) which is statistically significant (p<0.05). Presence of cases with AML FAB-variants of M7 (n=2) and M3 (n=1) in pediatric group among these patients may be another reason for absence of expected difference in OS. These patients, generally, do not show higher levels of BAALC expression, due to alternative nature of hematopoiesis precursors.

Conclusion

To reveal the expected difference in BAALC-expressing precursors between pediatric and adult EVI1-positive AML, further studies should be performed in larger cohorts of carefully chosen patients, with omission of M7 and M3 FAB- variants.

Our simultaneous measurements of BAALC and WT1-expressiong leukemic precursors by means of standardized RT-qPCR supported crucial role of BAALC-expressing stem cells in pathogenesis of EVI1-positive AML and relapses evolving in both tested groups.

Conflict of interest

None reported.

References

1. Walter R, Appelbaum F, Estey E, Bernstein I. Acute myeloid leukemia stem cells and CD33-targeted immunotherapy. Blood 2012; 119: 6198-6208. doi: 10.1182/ blood-2011-11-325050
2. Lapidot T, Siratd C, Vormoor J, et al. Z Cell initiating human acute myeloid leukemia after transplantation into SCID mice, Nature 1994;367(6464):645-8. doi: 10.1038/367645a0
3. Morita R, Masamotyo Y, Kataoka K, Koya J, Kagoya Y, Yashiroda H, Sato T, Murata S, Kurokawa M. BAALC potentiates oncogenic ERK pathway through interactions with MEKK1 and KLF4. Leukemia 2015; 29(11): 2248-2256. doi: 10.1038/leu.2015.137
4. Patel S, Zhang Y, Cassinat B, Zassadowski F, Ferré N, Cuccuini W, Cayuela JM, Fenaux P, Bonnet D, Chomienne C, Louache F. Successful xenografts of AML3 samples in immunodeficient NOD/shi-SCID IL2Rγ–/– mice. Leukemia 2012; 26(11):2432-2435. doi: 10.1038/leu.2012.154
5. Mamaev NN, Shakirova AI, Barkhatov IM, et al. New opportunities for assay of leukemia initiating cells (LICs) participating in post-transplant relapse development in the patients with acute myeloid leukemia. 3rd Annual IACH Meeting, 1-3 October, 2020, Paris, report #12.
6. Mamaev NN, Shakirova AI, Barkhatov IM, Gudozhnikova YV, Gindina TL, Kanunnikov MM, Kravtsova VM, Rakhmanova ZZ, Paina OV, Zubarovskaya LS. Crucial role of BAALC-expressing leukemic precursors in origin and development of posttransplant relapses in patients with acute myeloid leukemias. Int J Hematol 2020; 8(6): 127-131. doi: 10.15406/htij.2020.08.00240
7. Mamaev NN, Shakirova AI, Gindina TL, Bondarenko SN, Ayubova BI, Barkhatov IM, Gudozhnikova YaV, Kravtsova VM, Kanunnikov MM, Paina OV, Rakhmanova ZZ, Gracheva TYu, Zubarovskaya LS. Quantitative study of BAALC- and WT1-expressing cell precursors in the patients with different cytogenetic and molecular AML variants treated with Gemtuzumab ozogamycin and hematopoietic stem cell transplantation. Cell Ther Transplant 2021; 10(1)):55-62. doi: 10.18620/ctt-1866-8836-2021-10-1-55-62
8. Balgobind BV, Lugthart S, Hollink IH, Arentsen-Peters STJCM, van Wering ER, de Graaf SSN, et al. EVI1 overexpression in distinct subtypes of pediatric acute myeloid leukemia. Leukemia 2010;24:942-949. doi:10.1038/leu.2010.47
9. Ho PA, Alonzo TA, Gerbing RB, Pollard JA, Hirsch B, Raimondi SC, Cooper T, Gamis AS, Meshinchi S. High EVI1 expression is associated with MLL rearrangements and predicts decreased survival in pediatric acute myeloid leukemia: a report from the children’s oncology group. Br J Haematol 2013;162(5): 670-677. doi: 10.1111/bjh.12444
10. Sadaghian MH, Dezaki ZR. Prognostic value of EVI1 expression in pediatric acute myeloid leukemia: A systematic review. Iran J Pathol. 2018; 13(3):294-300. PMID: 30636951
11. Pauebelle E, Piesa A, Hayette S, et al. Efficacy of ALL-TRANS-RETINOIC ACID in high riskacute myeloid leukemia with overexpression of EVI1. Oncol Ther 2019; 7(2): 121-130. doi: 10.1007/s40487-019-0095-9
12. Mamaev NN, Shakirova AI, Morozova EV, Gindina TL. EVI1-Positive Leukemias and Myelodysplastic Syndromes: Theoretical and Practical Aspects (Literature Review). Clinical Oncohematol 2021;14(1): 103-117 (In Russian). doi: 10.21320/2500-2139-2021-14-1-103-117
13. Shakirova A, Barkhatov I, Churkina A, Moiseev IS, Gindina TL, Bondarenko SN, Afanasyev BV. Prognostic significance of BAALC overexpression in patients with AML during the posttransplant period. Cell Ther Transplant 2018; 7(2):54-63. doi: 10.18620/ctt-1866-8836-2018-7-2-54-63
14. Cilloni D, Renneville A, Hermitte F, Hills R, Daly S, Jovanovic J, Gottardi E, Fava M, Schnittger S, Weiss T, Izzo B, Nomdedeu J, van den Heijden A, van der Reijden B, Jansen J, van der Verlden V, Ommen H, Preudhomme C, Saglio G, Grimwade D. et al. Real-time quantitative polymerase chain reaction detection of minimal residual disease by standardized WT1 assay to enhance risk stratification in acute myeloid leukemia: a European LeukemiaNet study. J Clin Oncol 2009; 27(31): 5195-5201. doi: 10.1200/JCO.2009.22.4865

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Таким образом, можно ожидать и различную патогенетическую роль лейкозных клеток-предшественников при данных вариантах ОМЛ. Нашей целью была проверка этой возможности, и мы количественно определяли экспрессию мРНК лейкозными клетками-предшественниками с применением недавно предложенной молекулярной модели оценки <i>ВAALC/WT1</i>. Уровни экспрессии генов <i>BAALC, WT1</i> и <i>EVI1</i> определяли параллельно в образцах костного мозга у 8 пациентов детского возраста и 6 взрослых с <i>EVI1⁺</i> ОМЛ с помощью количественной ПЦР в реальном режиме времени (РТ-кПЦР) в конкретные сроки: а) при первичной диагностике, б) перед ТГСК и в) на фоне посттрансплантационного рецидива (ПТР). Подсчет бластных форм проводили в этих же образцах костного мозга. Наши результаты показали наличие гиперэкспрессии гена <i>BAALC </i>в обеих группах на всех этапах исследования. Гиперэкспрессия <i>BAALC</i> перед проведением ТГСК выявлялась у 6 из 14 пациентов, что может быть связано с реальными сложностями химиотерапии для последующей ТГСК в этой категории больных. Кроме того, поскольку гиперэкспрессия <i>BAALC </i>или <i>BAALC/WT1</i> была обнаружена у большинства пациентов с рецидивом после ТГСК, можно предполагать о ключевой роли <i>BAALC</i>-экспрессирующих предшественников в развитии рецидива. </p> <p style="text-align: justify;"> Надо отметить, что гиперэкспрессия <i>BAALC</i> не выявлялась во всех исследованных этапах при M3- и M7-вариантах ОМЛ, возможно, благодаря большему уровню дифференцировки соответствующих клеток-предшественников. В целом, определение <i>BAALC-</i> и <i>WT1</i>-экспрессирующих предшественников посредством РТ-кПЦР представляется перспективным подходом к исследованиям конкретных патогенетических механизмов при различных вариантах ОМЛ, а также при диагностике возникающих рецидивов и может быть весьма важным для клинической практики. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> Острый миелобластный лейкоз, <i>EVI1</i>-позитивный, дети, взрослые, трансплантация гемопоэтических стволовых клеток, рецидивы, экспрессия <i>BAALC</i>, экспрессия <i>WT1</i>, экспрессия <i>EVI1</i>, предшественники лейкозных клеток, количественная ПЦР. </p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(351) "Оценка BAALC- и WT1-экспрессирующих лейкозных клеток-предшественников у детей и взрослых с EVI1-позитивным острым миелобластным лейкозом посредством количественной ПЦР в режиме реального времени" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(351) "Оценка BAALC- и WT1-экспрессирующих лейкозных 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Мамаев, Алена И. Шакирова, Ильдар М. Бархатов, Михаил М. Канунников, Татьяна Л. Гиндина, Джамал Ж. Рахманова, Олеся В. Паина, Мария В. Латыпова, Татьяна Ю. Грачева, Людмила С. Зубаровская </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(357) "

Николай Н. Мамаев, Алена И. Шакирова, Ильдар М. Бархатов, Михаил М. Канунников, Татьяна Л. Гиндина, Джамал Ж. Рахманова, Олеся В. Паина, Мария В. Латыпова, Татьяна Ю. Грачева, Людмила С. Зубаровская

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НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

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Показано, что ряд основных биологических и цитогенетических характеристик лейкозных клеток при EVI1-позитивном (EVI1⁺) остром миелобластном лейкозе (ОМЛ) различен у пациентов детского возраста и взрослых, как и их ответ на химиотерапию и трансплантацию гемопоэтических стволовых клеток (ТГСК). Таким образом, можно ожидать и различную патогенетическую роль лейкозных клеток-предшественников при данных вариантах ОМЛ. Нашей целью была проверка этой возможности, и мы количественно определяли экспрессию мРНК лейкозными клетками-предшественниками с применением недавно предложенной молекулярной модели оценки ВAALC/WT1. Уровни экспрессии генов BAALC, WT1 и EVI1 определяли параллельно в образцах костного мозга у 8 пациентов детского возраста и 6 взрослых с EVI1⁺ ОМЛ с помощью количественной ПЦР в реальном режиме времени (РТ-кПЦР) в конкретные сроки: а) при первичной диагностике, б) перед ТГСК и в) на фоне посттрансплантационного рецидива (ПТР). Подсчет бластных форм проводили в этих же образцах костного мозга. Наши результаты показали наличие гиперэкспрессии гена BAALC в обеих группах на всех этапах исследования. Гиперэкспрессия BAALC перед проведением ТГСК выявлялась у 6 из 14 пациентов, что может быть связано с реальными сложностями химиотерапии для последующей ТГСК в этой категории больных. Кроме того, поскольку гиперэкспрессия BAALC или BAALC/WT1 была обнаружена у большинства пациентов с рецидивом после ТГСК, можно предполагать о ключевой роли BAALC-экспрессирующих предшественников в развитии рецидива.

Надо отметить, что гиперэкспрессия BAALC не выявлялась во всех исследованных этапах при M3- и M7-вариантах ОМЛ, возможно, благодаря большему уровню дифференцировки соответствующих клеток-предшественников. В целом, определение BAALC- и WT1-экспрессирующих предшественников посредством РТ-кПЦР представляется перспективным подходом к исследованиям конкретных патогенетических механизмов при различных вариантах ОМЛ, а также при диагностике возникающих рецидивов и может быть весьма важным для клинической практики.

Ключевые слова

Острый миелобластный лейкоз, EVI1-позитивный, дети, взрослые, трансплантация гемопоэтических стволовых клеток, рецидивы, экспрессия BAALC, экспрессия WT1, экспрессия EVI1, предшественники лейкозных клеток, количественная ПЦР.

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Nikolay N. Mamaev, Alyena I. Shakirova, Ildar M. Barkhatov, Mikhail M. Kanunnikov, Tatiana L. Gindina, Zhamal Z. Rakhmanova, Olesya V. Paina, Maria V. Latypova, Tatiana Yu. Gracheva, Ludmila S. Zubarovskaya

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia

Correspondence
Prof. Nikolay N. Mamaev, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, 12 Roentgen St, 197022, St. Petersburg, Russia
Phone: +7 (911) 760 5086
E-mail: nikmamaev524@gmail.com

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Some basic biological and cytogenetic characteristics of leukemic cells in EVI1-positive (EVI1⁺) acute myeloid leukemia (AML) are shown to be different for pediatric and adult patients, like as their response to chemotherapy and hematopoietic stem cell transplantation (HSCT). Hence, one may also expect different pathogenetic roles of leukemic precursors in these AML variants. Our aim was to check this opportunity, and we have quantitatively assessed mRNA expression by leukemic precursors using a recently proposed BAALC/WT1 molecular panel. The levels of BAALC, WT1 and EVI1 gene expression were determined simultaneously in bone marrow samples from 8 pediatric and 6 adult patients with EVI1⁺ AML by means of quantitative real-time polymerase reaction (RT-qPCR) at specified time-points: a) upon primary diagnosis, b) prior to HSCT, and c) during post-transplant relapse (PTR). Blast cell counts were also provided for these bone marrow samples. Our study showed BAALC gene overexpression in both groups at all the tested stages. Before hematopoietic stem cell transplantation (HSCT) BAALC overexpression was revealed in 6 of 14 patients which could be associated with real difficulties for chemotherapy preparation for HSCT in this category of patients. Moreover, BAALC, or combined BAALC/WT1 overexpression were revealed in most patients with posttransplant relapse (PTR), thus suggesting a crucial role of BAALC-expressing precursors for the emerging relapses. Worth of note, BAALC overexpression was absent at all the tested stages of M3 and M7 FAB-variants, probably, due to more mature nature of appropriate precursor cells. In general, determination of BAALC- and WT1-expressing precursors by means of RT-qPCR seems to be a promising approach to the studies of precise pathogenetic mechanisms in different AML variants, as well as to diagnostics of emerging relapses and, thus, it may be quite important for clinical practice.

Keywords

Acute myeloid leukemia, EVI1-positive, pediatric, adults, hematopoietic stem cell transplantation, relapses, BAALC expression, WT1 expression, EVI1 expression, leukemic cell precursors, quantitative PCR.

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Mamaev, Alyena I. Shakirova, Ildar M. Barkhatov, Mikhail M. Kanunnikov, Tatiana L. Gindina, Zhamal Z. Rakhmanova, Olesya V. Paina, Maria V. Latypova, Tatiana Yu. Gracheva, Ludmila S. Zubarovskaya</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(214) "

Nikolay N. Mamaev, Alyena I. Shakirova, Ildar M. Barkhatov, Mikhail M. Kanunnikov, Tatiana L. Gindina, Zhamal Z. Rakhmanova, Olesya V. Paina, Maria V. Latypova, Tatiana Yu. Gracheva, Ludmila S. Zubarovskaya

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Nikolay N. Mamaev, Alyena I. Shakirova, Ildar M. Barkhatov, Mikhail M. Kanunnikov, Tatiana L. Gindina, Zhamal Z. Rakhmanova, Olesya V. Paina, Maria V. Latypova, Tatiana Yu. Gracheva, Ludmila S. Zubarovskaya

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Some basic biological and cytogenetic characteristics of leukemic cells in EVI1-positive (EVI1⁺) acute myeloid leukemia (AML) are shown to be different for pediatric and adult patients, like as their response to chemotherapy and hematopoietic stem cell transplantation (HSCT). Hence, one may also expect different pathogenetic roles of leukemic precursors in these AML variants. Our aim was to check this opportunity, and we have quantitatively assessed mRNA expression by leukemic precursors using a recently proposed BAALC/WT1 molecular panel. The levels of BAALC, WT1 and EVI1 gene expression were determined simultaneously in bone marrow samples from 8 pediatric and 6 adult patients with EVI1⁺ AML by means of quantitative real-time polymerase reaction (RT-qPCR) at specified time-points: a) upon primary diagnosis, b) prior to HSCT, and c) during post-transplant relapse (PTR). Blast cell counts were also provided for these bone marrow samples. Our study showed BAALC gene overexpression in both groups at all the tested stages. Before hematopoietic stem cell transplantation (HSCT) BAALC overexpression was revealed in 6 of 14 patients which could be associated with real difficulties for chemotherapy preparation for HSCT in this category of patients. Moreover, BAALC, or combined BAALC/WT1 overexpression were revealed in most patients with posttransplant relapse (PTR), thus suggesting a crucial role of BAALC-expressing precursors for the emerging relapses. Worth of note, BAALC overexpression was absent at all the tested stages of M3 and M7 FAB-variants, probably, due to more mature nature of appropriate precursor cells. In general, determination of BAALC- and WT1-expressing precursors by means of RT-qPCR seems to be a promising approach to the studies of precise pathogenetic mechanisms in different AML variants, as well as to diagnostics of emerging relapses and, thus, it may be quite important for clinical practice.

Keywords

Acute myeloid leukemia, EVI1-positive, pediatric, adults, hematopoietic stem cell transplantation, relapses, BAALC expression, WT1 expression, EVI1 expression, leukemic cell precursors, quantitative PCR.

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Some basic biological and cytogenetic characteristics of leukemic cells in EVI1-positive (EVI1⁺) acute myeloid leukemia (AML) are shown to be different for pediatric and adult patients, like as their response to chemotherapy and hematopoietic stem cell transplantation (HSCT). Hence, one may also expect different pathogenetic roles of leukemic precursors in these AML variants. Our aim was to check this opportunity, and we have quantitatively assessed mRNA expression by leukemic precursors using a recently proposed BAALC/WT1 molecular panel. The levels of BAALC, WT1 and EVI1 gene expression were determined simultaneously in bone marrow samples from 8 pediatric and 6 adult patients with EVI1⁺ AML by means of quantitative real-time polymerase reaction (RT-qPCR) at specified time-points: a) upon primary diagnosis, b) prior to HSCT, and c) during post-transplant relapse (PTR). Blast cell counts were also provided for these bone marrow samples. Our study showed BAALC gene overexpression in both groups at all the tested stages. Before hematopoietic stem cell transplantation (HSCT) BAALC overexpression was revealed in 6 of 14 patients which could be associated with real difficulties for chemotherapy preparation for HSCT in this category of patients. Moreover, BAALC, or combined BAALC/WT1 overexpression were revealed in most patients with posttransplant relapse (PTR), thus suggesting a crucial role of BAALC-expressing precursors for the emerging relapses. Worth of note, BAALC overexpression was absent at all the tested stages of M3 and M7 FAB-variants, probably, due to more mature nature of appropriate precursor cells. In general, determination of BAALC- and WT1-expressing precursors by means of RT-qPCR seems to be a promising approach to the studies of precise pathogenetic mechanisms in different AML variants, as well as to diagnostics of emerging relapses and, thus, it may be quite important for clinical practice.

Keywords

Acute myeloid leukemia, EVI1-positive, pediatric, adults, hematopoietic stem cell transplantation, relapses, BAALC expression, WT1 expression, EVI1 expression, leukemic cell precursors, quantitative PCR.

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia

Correspondence
Prof. Nikolay N. Mamaev, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, 12 Roentgen St, 197022, St. Petersburg, Russia
Phone: +7 (911) 760 5086
E-mail: nikmamaev524@gmail.com

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia

Correspondence
Prof. Nikolay N. Mamaev, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, 12 Roentgen St, 197022, St. Petersburg, Russia
Phone: +7 (911) 760 5086
E-mail: nikmamaev524@gmail.com

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Николай Н. Мамаев, Алена И. Шакирова, Ильдар М. Бархатов, Михаил М. Канунников, Татьяна Л. Гиндина, Джамал Ж. Рахманова, Олеся В. Паина, Мария В. Латыпова, Татьяна Ю. Грачева, Людмила С. Зубаровская

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Николай Н. Мамаев, Алена И. Шакирова, Ильдар М. Бархатов, Михаил М. Канунников, Татьяна Л. Гиндина, Джамал Ж. Рахманова, Олеся В. Паина, Мария В. Латыпова, Татьяна Ю. Грачева, Людмила С. Зубаровская

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Таким образом, можно ожидать и различную патогенетическую роль лейкозных клеток-предшественников при данных вариантах ОМЛ. Нашей целью была проверка этой возможности, и мы количественно определяли экспрессию мРНК лейкозными клетками-предшественниками с применением недавно предложенной молекулярной модели оценки <i>ВAALC/WT1</i>. Уровни экспрессии генов <i>BAALC, WT1</i> и <i>EVI1</i> определяли параллельно в образцах костного мозга у 8 пациентов детского возраста и 6 взрослых с <i>EVI1⁺</i> ОМЛ с помощью количественной ПЦР в реальном режиме времени (РТ-кПЦР) в конкретные сроки: а) при первичной диагностике, б) перед ТГСК и в) на фоне посттрансплантационного рецидива (ПТР). Подсчет бластных форм проводили в этих же образцах костного мозга. Наши результаты показали наличие гиперэкспрессии гена <i>BAALC </i>в обеих группах на всех этапах исследования. Гиперэкспрессия <i>BAALC</i> перед проведением ТГСК выявлялась у 6 из 14 пациентов, что может быть связано с реальными сложностями химиотерапии для последующей ТГСК в этой категории больных. Кроме того, поскольку гиперэкспрессия <i>BAALC </i>или <i>BAALC/WT1</i> была обнаружена у большинства пациентов с рецидивом после ТГСК, можно предполагать о ключевой роли <i>BAALC</i>-экспрессирующих предшественников в развитии рецидива. </p> <p style="text-align: justify;"> Надо отметить, что гиперэкспрессия <i>BAALC</i> не выявлялась во всех исследованных этапах при M3- и M7-вариантах ОМЛ, возможно, благодаря большему уровню дифференцировки соответствующих клеток-предшественников. В целом, определение <i>BAALC-</i> и <i>WT1</i>-экспрессирующих предшественников посредством РТ-кПЦР представляется перспективным подходом к исследованиям конкретных патогенетических механизмов при различных вариантах ОМЛ, а также при диагностике возникающих рецидивов и может быть весьма важным для клинической практики. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> Острый миелобластный лейкоз, <i>EVI1</i>-позитивный, дети, взрослые, трансплантация гемопоэтических стволовых клеток, рецидивы, экспрессия <i>BAALC</i>, экспрессия <i>WT1</i>, экспрессия <i>EVI1</i>, предшественники лейкозных клеток, количественная ПЦР. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4392) "

Показано, что ряд основных биологических и цитогенетических характеристик лейкозных клеток при EVI1-позитивном (EVI1⁺) остром миелобластном лейкозе (ОМЛ) различен у пациентов детского возраста и взрослых, как и их ответ на химиотерапию и трансплантацию гемопоэтических стволовых клеток (ТГСК). Таким образом, можно ожидать и различную патогенетическую роль лейкозных клеток-предшественников при данных вариантах ОМЛ. Нашей целью была проверка этой возможности, и мы количественно определяли экспрессию мРНК лейкозными клетками-предшественниками с применением недавно предложенной молекулярной модели оценки ВAALC/WT1. Уровни экспрессии генов BAALC, WT1 и EVI1 определяли параллельно в образцах костного мозга у 8 пациентов детского возраста и 6 взрослых с EVI1⁺ ОМЛ с помощью количественной ПЦР в реальном режиме времени (РТ-кПЦР) в конкретные сроки: а) при первичной диагностике, б) перед ТГСК и в) на фоне посттрансплантационного рецидива (ПТР). Подсчет бластных форм проводили в этих же образцах костного мозга. Наши результаты показали наличие гиперэкспрессии гена BAALC в обеих группах на всех этапах исследования. Гиперэкспрессия BAALC перед проведением ТГСК выявлялась у 6 из 14 пациентов, что может быть связано с реальными сложностями химиотерапии для последующей ТГСК в этой категории больных. Кроме того, поскольку гиперэкспрессия BAALC или BAALC/WT1 была обнаружена у большинства пациентов с рецидивом после ТГСК, можно предполагать о ключевой роли BAALC-экспрессирующих предшественников в развитии рецидива.

Надо отметить, что гиперэкспрессия BAALC не выявлялась во всех исследованных этапах при M3- и M7-вариантах ОМЛ, возможно, благодаря большему уровню дифференцировки соответствующих клеток-предшественников. В целом, определение BAALC- и WT1-экспрессирующих предшественников посредством РТ-кПЦР представляется перспективным подходом к исследованиям конкретных патогенетических механизмов при различных вариантах ОМЛ, а также при диагностике возникающих рецидивов и может быть весьма важным для клинической практики.

Ключевые слова

Острый миелобластный лейкоз, EVI1-позитивный, дети, взрослые, трансплантация гемопоэтических стволовых клеток, рецидивы, экспрессия BAALC, экспрессия WT1, экспрессия EVI1, предшественники лейкозных клеток, количественная ПЦР.

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Показано, что ряд основных биологических и цитогенетических характеристик лейкозных клеток при EVI1-позитивном (EVI1⁺) остром миелобластном лейкозе (ОМЛ) различен у пациентов детского возраста и взрослых, как и их ответ на химиотерапию и трансплантацию гемопоэтических стволовых клеток (ТГСК). Таким образом, можно ожидать и различную патогенетическую роль лейкозных клеток-предшественников при данных вариантах ОМЛ. Нашей целью была проверка этой возможности, и мы количественно определяли экспрессию мРНК лейкозными клетками-предшественниками с применением недавно предложенной молекулярной модели оценки ВAALC/WT1. Уровни экспрессии генов BAALC, WT1 и EVI1 определяли параллельно в образцах костного мозга у 8 пациентов детского возраста и 6 взрослых с EVI1⁺ ОМЛ с помощью количественной ПЦР в реальном режиме времени (РТ-кПЦР) в конкретные сроки: а) при первичной диагностике, б) перед ТГСК и в) на фоне посттрансплантационного рецидива (ПТР). Подсчет бластных форм проводили в этих же образцах костного мозга. Наши результаты показали наличие гиперэкспрессии гена BAALC в обеих группах на всех этапах исследования. Гиперэкспрессия BAALC перед проведением ТГСК выявлялась у 6 из 14 пациентов, что может быть связано с реальными сложностями химиотерапии для последующей ТГСК в этой категории больных. Кроме того, поскольку гиперэкспрессия BAALC или BAALC/WT1 была обнаружена у большинства пациентов с рецидивом после ТГСК, можно предполагать о ключевой роли BAALC-экспрессирующих предшественников в развитии рецидива.

Надо отметить, что гиперэкспрессия BAALC не выявлялась во всех исследованных этапах при M3- и M7-вариантах ОМЛ, возможно, благодаря большему уровню дифференцировки соответствующих клеток-предшественников. В целом, определение BAALC- и WT1-экспрессирующих предшественников посредством РТ-кПЦР представляется перспективным подходом к исследованиям конкретных патогенетических механизмов при различных вариантах ОМЛ, а также при диагностике возникающих рецидивов и может быть весьма важным для клинической практики.

Ключевые слова

Острый миелобластный лейкоз, EVI1-позитивный, дети, взрослые, трансплантация гемопоэтических стволовых клеток, рецидивы, экспрессия BAALC, экспрессия WT1, экспрессия EVI1, предшественники лейкозных клеток, количественная ПЦР.

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НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

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НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

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Introduction

Multiple sclerosis (MS) is a severe inflammatory and demyelinating autoimmune disease of the central nervous system (CNS), which affects mainly young people and leads to progressive quality of life (QoL) deterioration due to progressive disability [1, 2]. Relapsing remitting MS (RRMS) evolves into secondary progressive disease in 70-80% of cases during 10-15 years [3, 4]. Hence, this relatively favorable variant of MS seems to be a very difficult condition with high risk of disability. Thus, the goal of treatment is to prevent MS progression and disability, to provide better control of the symptoms and to improve patient’s QoL [5]. Conventional DMT (Disease Modifying Therapies) does not provide satisfactory control of MS, due to inability to eradicate self-aggressive T- and B-cell clones. Immunosuppressive treatment including monoclonal antibodies, which are usually used as a second-line therapy, also have only partial beneficial effect [6, 7].

At present, high-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation (AHSCT) has been used with increasing frequency as a therapeutic option for MS patients [8-14]. The rationale for this method presumes that ablation of the impaired immune system followed by reconstitution of the new immune cell populations may alter the characteristics of the T – and B-cell responses and other immunological properties which can improve clinical course of MS [15, 16]. Previous studies demonstrated that AHSCT was associated with improvement in neurological disability and QoL in RRMS patients [17-21].

At the same time, in spite of promising clinical results, there are still several questions to be clarified before recommending AHSCT as a treatment choice for MS patients, especially for those with relapsing-remitting disease. For example, effectiveness and safety of different conditioning regimens (intermediate and low-intensity) should be analyzed carefully. Several clinical studies have addressed the issue of safety and effectiveness of AHSCT with BEAM as intermediate-intensity conditioning regimen in MS with certain promising results [22-25]. On the other side, it was shown recently, that low-intensity regimens (BEAM-like or Cyclophosphamide based) are associated with similar outcome results and less toxicity profile to compare with more intensive conditioning. Patients’ selection for AHSCT is another core issue [26, 27]. Additionally, comprehensive treatment outcomes assessment is very important in all variants of AHSCT [28, 29]. Both disease-free period and improvement of patient’s QoL are recognized as important treatment outcomes. Also, one of the key issues is the long-term follow-up and assessment of clinical and patient-reported outcomes [29-31].

Thus, we aimed to evaluate the effect of AHSCT with low-intensity conditioning regimens in patients with RRMS, in terms of clinical and patient-reported outcomes.

Patients and methods

All the patients underwent AHSCT in the Transplantation Unit, Department of Haematology and Cellular Therapy, Pirogov National Medical and Surgical Centre (Moscow) from October 2006 to October 2018. The study was conducted according to the principles of Helsinki Declaration, and was approved by the Institute Research Board and local Ethics Committee before initiation. All the patients had given their written informed consent. The patients were eligible if they were >15 years old and met the Poser and McDonald criteria for clinically defined MS [32]. Other criteria for patients’ selection included normal mental status and absence of severe concomitant diseases. The vast majority of patients was refractory to 2-4 different lines of conventional treatment including interferons, copaxone, mitoxantrone, cladribine, monoclonal antibodies therapy, azathioprine, intravenous immunoglobulin, glucocorticosteroids etc.

Hematopoietic stem cells were mobilized with granulocyte colony-stimulating factor (G-CSF, 10 µg/kg) during 4-5 days. The mobilized cells were collected by apheresis after 4 days of stimulation until a yield of at least 2.0×10⁶ CD34+ cells/kg.

Three low-intensity conditioning regimens were applied in the patients. Two regimens were based on reduced BEAM protocol: (1) BM schedule (BCNU 300 mg/m², Melphalan 100 mg/m² + horse ATG at the dose of 30 mg/kg on days 1 and 2 for in vivo T cell-depletion); (2) BEAM-like regimen (BCNU 300 mg/m², Etoposide 100 mg/m², Ara-C 100 mg/m², Melphalan 100 mg/m² + horse ATG at the dose of 30 mg/kg on days 1 and 2 for in vivo T cell-depletion). The third conditioning regimen included high-dose cyclophosphamide (200 mg/kg) + Rituximab (500 mg/m²) on D+11-12 (one infusion).

G-CSF (5 µg/kg) was administered on D+1 to D+2 until granulocyte recovery. For infection prophylaxis, oral levofloxacin, fluconazole, co-trimoxazole and acyclovir were used.

Toxicity of treatment was evaluated in accordance with National Cancer Institute Common Toxicity Criteria (version 2) [33]. The terms of posttransplant neutrophil engraftment were defined since the first day when absolute neutrophil count was >500 cells/mL. Platelet engraftment was registered since the first day when the platelet count was >20,000 platelets/mL (without platelet transfusions). Transplant-related mortality (TRM) included every death occurring within 100 days of transplantation [34].

The primary end point was disability level defined by the EDSS score [35]. Other studied end-points included safety, relapse-free survival (no acute relapses) and quality of life (QoL) changes. To evaluate clinical outcomes, neurological assessment and MRI scans were performed. Neurological assessment using EDSS was performed at baseline, at discharge, at 3, 6, and 12 months after transplantation, every 6 months thereafter up to 48 months, and, later, at the annual basis. EDSS decrease of 1.0 or more was considered a significant improvement, and an increase of 1.0 or greater was viewed as significant worsening. MRI scans of brain and cervical spinal cord with gadolinium enhancement were performed at baseline, at 3, 6, and 12 months after transplantation, every 6 months up to 48 months, and then at yearly intervals. QoL was assessed using RAND SF-36 [36], common symptoms, by CSP-MS-42 [37]. The SF-36 is generic tool for QoL assessment widely used in patients with chronic diseases, including MS [38, 39]. The Comprehensive Symptom Profile-MS-42 (CSP-MS-42) was developed in 2007 by New Jersey Center for Quality of Life and Health Outcome Research (USA) and Multinational Center for QoL Research (Russia) to assess the severity of 42 symptoms which are common and most disturbing for MS patients. It consists of numerical analogous scales, scored from "0" (no symptom) to "10" (most expressed symptom). The measurements were conducted before AHSCT, at 6 and 12 months after AHSCT, then every 6 months during 2 years after AHSCT and every 12 months after 2 years during 5 years after AHSCT.

For statistical evaluation, paired t-test, Wilcoxon test and ANOVA were used. Progression-free survival (PFS) and relapse-free survival (RFS) after AHSCT were evaluated using Kaplan-Meyer method. To compare survival rates, log-rank criterion and Tarone-Ware criterion were applied. Mc-Nemar’s test was used in order to compare the proportions of patients according to symptom prevalence before AHSCT and 12 months following transplant. P values of <0.05 will be used as a cut-off point for statistical significance, and all statistical tests will be two-sided.

Results

General characteristics

A total of 258 patients with RRMS were enrolled in the study. Mean age was 36.5 years old; male/female ratio, 73/185. Median EDSS value before transplantation was 2.0 (range 1.5-6.5). Mean duration of the disease was 4.9 years (median 3.0, range 0.5-24). Patients’ characteristics are shown in Table 1.

Safety

The procedure of autologous HSCT was well tolerated by the patients. There were no cases of transplantation-related mortality. Mobilization was successful in all cases with median number of 2.1×10⁶/kg (range 2-10.9×10⁶/kg) collected CD34+cells; no major clinical adverse events were observed during this phase.

The mean time of neutropenia (grade 4) was 8.0 days. The mean time of thrombocytopenia (grade 3-4) was 7.0 days. Neutrophil engraftment was registered on D+8- D+11. No differences in hematological toxicity between the three conditioning regimens were found (P>0.05).

Common adverse effects after AHSCT were as follows: hepatic toxicity (grade 2 and 3) – 20.5%; mucositis (grade 2), 1.6%; temporary neurological worsening, 6.4%; neutropenic fever, 27%; local infection, 6.2%; anemia (grade 3), 1.9%; allergic reactions, 2.3%. No differences in toxicity were observed among the patients who received different conditioning regimens. No deaths were registered throughout the entire follow-up period.

Сlinical outcomes

Median follow-up after AHSCT was 30 months (3.7-110.9). The vast majority of patients (99%) responded to treatment. The decrease of EDSS score from median 2.0 to 1.5 was observed at 12 months after AHSCT, and it remained at this level during the follow-up of more than 60 months (Fig. 1). The EDSS score improved significantly for the entire group (P <0.001) at all the time intervals, as compared with base-line. EDSS changes in patients with RRMS prior to and at different time-points after AHSCT are presented in Table 2. The proportion of patients with change of >1.0 in EDSS score was 36% (86 patients) with index of improvement at 12 months, and 0.4% (1 patient) with an index of the disease progression. At 2 years post-transplant, 47 (32%) patients showed improvement, 1 patient (0.7%) became worse, and others presented with stable disease. At 3 years posttransplant, improvement was observed in 23 (25%) patients, worsening – in 1 (1.1%) patient, the others were in stable clinical state. At 4 years posttransplant, the majority (83.1%) of patients were stable, there was no further worsening, and 10 patients (16.9%) exhibited improvement. Hence, the vast majority of patients was stable during the continuous follow-up; clinical deterioration took place in 6% of patients.

Table 2. EDSS changes in patients with RRMS before and at different time-points after AHSCT

After AHSCT, the vast majority of patients with RRMS were relapse-free (245 out of 258). The mean term until relapse was 30.4 months (95% CI 18.24-42.52). Estimated relapse-free survival (RFS) at the median follow-up of 29.5 months was 95% (95% CI: 92.3-97.7) (Fig. 2A).

Estimated RFS at the follow-up of 36 months was 95.6% (95% CI: 92.4-98.8), at the follow-up of 60 months, 88.2% (95% CI: 80.2-96.2); at the follow-up of 84 months, 83.3% (95% CI: 71.3-95.3). Estimated progression-free survival (PFS) at the follow-up of 36 months was 98% (95% CI: 95.6-100.0), at the follow-up of 60 months, 91.2% (95% CI: 81.9-100.0), at the follow-up of 84 months, 86.2% (95% CI: 73.1-99.3), as seen from Fig. 2B.

Figure 2. Relapse-free (a) and progression free (b) survival Kaplan-Meyer curves in RRMS patients after AHSCT

Separate analysis of RFS probability in the groups of patients with different conditioning regimen was also performed.Comparison was made between the conditioning regimens based on BEAM-like and Cyclophosphamide+Rituximab protocols. Previously, it was shown that the outcomes for mini-BEAM and BM were similar [24]. Thus, the BEAM-like group included mini-BEAM and BM conditioning regimens. No differences in RFS were found between patients who received BEAM-like and these who received high-dose cyclophosphamide+Rituximab (log-rank, P=0.92), as shown in Fig. 3.

Patient-reported outcomes

Mean QoL values in RRMS patients before AHSCT and 12 months after AHSCT (n=78) are presented in Table 3. QoL changes (Δ) of scores according to all the SF-36 scales in 12 mo after AHSCT were compared to the baseline levels (Fig. 4).

We have also performed analysis of QoL changes at long-term follow-up after AHSCT (≥18 months) as compared to baseline values (n=41). Median follow-up was 22.9 months (interquartile range: 16.8-35.7 mo; mean±SD, 23.9±5.05 mo;95% CI: 22.3 to 25.5 mo). The mean QoL values in RRMS patients before AHSCT and in the course of long-term follow-up after AHSCT are presented in Table 4. QoL changes (Δ) of scores for all SF-36 scales over long-term follow-up after AHSCT were compared to baseline scores (Fig. 5).

Table 3. Quality of life mean values in RRMS patients at baseline and 12 months after AHSCT

Table 4. Mean values for QoL indexes in RRMS patients at baseline and in long-term follow-up after AHSCT

Prevalence of the most common symptoms by CSP-MS42 in RRMS patients at 12 mo after ASCT against appropriate baseline values is shown in Fig. 6. Before AHSCT, the ten most common symptoms were present in more than half of the patients. Such symptoms as constant tiredness feeling, early exhaustion after physical activity, decreased energy, fatigue, heaviness in legs, loss of balance, lack of working coordination, difficulty walking and poor tolerance of hot water were reported by the vast majority of patients. As seen from the Fig. 6, their prevalence decreased 12 months post-transplant. The number of patients who experienced these symptoms except of heaviness in legs was significantly less after AHSCT as compared with baseline prevalence (P<0.05). The severity of all these symptoms also decreased after AHSCT (P<0.05).

Figure 6. Prevalence of common MS symptoms before and at 12 months posttransplant

AHSCT was accompanied by a significant improvement in patient’s QoL and decrease of symptom burden. Improved QoL was preserved during the entire period of follow-up. AHSCT is beneficial in unfavorable group of MS patients, those with progressive MS, with high disability and long lasting disease.

Discussion

We have analyzed a cohort of 258 patients with RRMS undergoing AHSCT, with a median follow-up of 30 months. Low-intensity conditioning regimens based on BEAM and cyclophosphamide were applied. Outcomes of AHSCT were evaluated both from physician’s and patient’s perspective. Transplantation procedure was well tolerated by the patients. There were no cases of transplantation-related mortality. In our cohort, the vast majority of patients responded to treatment and exhibited clinical improvement, or were stable during the entire period of follow-up. Significant decrease of EDSS score was observed after transplantation; the EDSS score improved (decreased by ≥1.0 point), with 32% and 17% of patients demonstrating improvement at 2 years and 4 years, respectively. In our cohort, relapse-free survival and progression-free survival at 7-year follow-up were 83% and 86%, respectively. These results are in line with previously published data by R. Burt [18, 19].

Moreover, AHSCT was accompanied by significant improvement in patient’s QoL. The analysis of QoL demonstrated benefits of AHSCT with low-intensity conditioning regimens in this patient population. QoL is an important outcome of MS treatment and its assessment provides the patient’s perspective on the overall effect of treatment and allows evaluating patient benefits. Our results definitely show that AHSCT resulted in significant and sustained improvement of patient’s QoL. Also, prevalence and severity of common symptoms of MS decreased after transplantation. Thus, noticeble decrease of symptom burden after AHSCT was demonstrated.

For the first time to our knowledge, we report the AHSCT outcomes in MS patients after different low-intensity conditioning regimens and long-term follow-up. We did not find any differences in RFS between the patients who received BM/BEAM-like+ATG, and those who received high-dose cyclophosphamide+Rituximab. These data are in line with the results we have published previously [29]. Our study also demonstrated that RFS did not differ between various age groups, and between the groups with different duration of the disease.

On the contrary, disability status was an important factor influencing the outcomes of transplantation: RFS was dramatically better in patients with EDSS<4 as compared to patients with EDSS=4-6.5. This finding supports the idea that AHSCT is beneficial for patients with highly active relapsing-remitting MS and moderate disability.

This study has several important limitations. Firstly, the study was conducted at a single academic institution, which may introduce some bias. However, all patients had clinical continuity and were monitored for in terms of relapses or need for additional treatment. Secondly, a large number of patients were treated on a compassionate basis rather than within a study protocol. Thirdly, a long-term follow-up (i.e, for ≥4 years) was not available for a substantial proportion of patients. Fourth, this was an observational cohort lacking a control group. Therefore, any inferences about causal effects of AHSCT can’t be made.

Thus, the risk/benefit ratio of AHSCT with low-intensity conditioning regimens in our population of RRMS patients is rather favorable. The consistency of our clinical and QoL results, together with persistent improvement suggest clinical efficacy of AHSCT strategy in RRMS patients. In general, the results of our study support the feasibility of AHSCT with low-intensity conditioning in RRMS patients. To optimize the mentioned treatment protocols of AHSCT in RRMS, multicenter cooperative studies are necessary in future.

Conflicts of interest

None reported.

References

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Introduction

Multiple sclerosis (MS) is a severe inflammatory and demyelinating autoimmune disease of the central nervous system (CNS), which affects mainly young people and leads to progressive quality of life (QoL) deterioration due to progressive disability [1, 2]. Relapsing remitting MS (RRMS) evolves into secondary progressive disease in 70-80% of cases during 10-15 years [3, 4]. Hence, this relatively favorable variant of MS seems to be a very difficult condition with high risk of disability. Thus, the goal of treatment is to prevent MS progression and disability, to provide better control of the symptoms and to improve patient’s QoL [5]. Conventional DMT (Disease Modifying Therapies) does not provide satisfactory control of MS, due to inability to eradicate self-aggressive T- and B-cell clones. Immunosuppressive treatment including monoclonal antibodies, which are usually used as a second-line therapy, also have only partial beneficial effect [6, 7].

At present, high-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation (AHSCT) has been used with increasing frequency as a therapeutic option for MS patients [8-14]. The rationale for this method presumes that ablation of the impaired immune system followed by reconstitution of the new immune cell populations may alter the characteristics of the T – and B-cell responses and other immunological properties which can improve clinical course of MS [15, 16]. Previous studies demonstrated that AHSCT was associated with improvement in neurological disability and QoL in RRMS patients [17-21].

At the same time, in spite of promising clinical results, there are still several questions to be clarified before recommending AHSCT as a treatment choice for MS patients, especially for those with relapsing-remitting disease. For example, effectiveness and safety of different conditioning regimens (intermediate and low-intensity) should be analyzed carefully. Several clinical studies have addressed the issue of safety and effectiveness of AHSCT with BEAM as intermediate-intensity conditioning regimen in MS with certain promising results [22-25]. On the other side, it was shown recently, that low-intensity regimens (BEAM-like or Cyclophosphamide based) are associated with similar outcome results and less toxicity profile to compare with more intensive conditioning. Patients’ selection for AHSCT is another core issue [26, 27]. Additionally, comprehensive treatment outcomes assessment is very important in all variants of AHSCT [28, 29]. Both disease-free period and improvement of patient’s QoL are recognized as important treatment outcomes. Also, one of the key issues is the long-term follow-up and assessment of clinical and patient-reported outcomes [29-31].

Thus, we aimed to evaluate the effect of AHSCT with low-intensity conditioning regimens in patients with RRMS, in terms of clinical and patient-reported outcomes.

Patients and methods

All the patients underwent AHSCT in the Transplantation Unit, Department of Haematology and Cellular Therapy, Pirogov National Medical and Surgical Centre (Moscow) from October 2006 to October 2018. The study was conducted according to the principles of Helsinki Declaration, and was approved by the Institute Research Board and local Ethics Committee before initiation. All the patients had given their written informed consent. The patients were eligible if they were >15 years old and met the Poser and McDonald criteria for clinically defined MS [32]. Other criteria for patients’ selection included normal mental status and absence of severe concomitant diseases. The vast majority of patients was refractory to 2-4 different lines of conventional treatment including interferons, copaxone, mitoxantrone, cladribine, monoclonal antibodies therapy, azathioprine, intravenous immunoglobulin, glucocorticosteroids etc.

Hematopoietic stem cells were mobilized with granulocyte colony-stimulating factor (G-CSF, 10 µg/kg) during 4-5 days. The mobilized cells were collected by apheresis after 4 days of stimulation until a yield of at least 2.0×10⁶ CD34+ cells/kg.

Three low-intensity conditioning regimens were applied in the patients. Two regimens were based on reduced BEAM protocol: (1) BM schedule (BCNU 300 mg/m², Melphalan 100 mg/m² + horse ATG at the dose of 30 mg/kg on days 1 and 2 for in vivo T cell-depletion); (2) BEAM-like regimen (BCNU 300 mg/m², Etoposide 100 mg/m², Ara-C 100 mg/m², Melphalan 100 mg/m² + horse ATG at the dose of 30 mg/kg on days 1 and 2 for in vivo T cell-depletion). The third conditioning regimen included high-dose cyclophosphamide (200 mg/kg) + Rituximab (500 mg/m²) on D+11-12 (one infusion).

G-CSF (5 µg/kg) was administered on D+1 to D+2 until granulocyte recovery. For infection prophylaxis, oral levofloxacin, fluconazole, co-trimoxazole and acyclovir were used.

Toxicity of treatment was evaluated in accordance with National Cancer Institute Common Toxicity Criteria (version 2) [33]. The terms of posttransplant neutrophil engraftment were defined since the first day when absolute neutrophil count was >500 cells/mL. Platelet engraftment was registered since the first day when the platelet count was >20,000 platelets/mL (without platelet transfusions). Transplant-related mortality (TRM) included every death occurring within 100 days of transplantation [34].

The primary end point was disability level defined by the EDSS score [35]. Other studied end-points included safety, relapse-free survival (no acute relapses) and quality of life (QoL) changes. To evaluate clinical outcomes, neurological assessment and MRI scans were performed. Neurological assessment using EDSS was performed at baseline, at discharge, at 3, 6, and 12 months after transplantation, every 6 months thereafter up to 48 months, and, later, at the annual basis. EDSS decrease of 1.0 or more was considered a significant improvement, and an increase of 1.0 or greater was viewed as significant worsening. MRI scans of brain and cervical spinal cord with gadolinium enhancement were performed at baseline, at 3, 6, and 12 months after transplantation, every 6 months up to 48 months, and then at yearly intervals. QoL was assessed using RAND SF-36 [36], common symptoms, by CSP-MS-42 [37]. The SF-36 is generic tool for QoL assessment widely used in patients with chronic diseases, including MS [38, 39]. The Comprehensive Symptom Profile-MS-42 (CSP-MS-42) was developed in 2007 by New Jersey Center for Quality of Life and Health Outcome Research (USA) and Multinational Center for QoL Research (Russia) to assess the severity of 42 symptoms which are common and most disturbing for MS patients. It consists of numerical analogous scales, scored from "0" (no symptom) to "10" (most expressed symptom). The measurements were conducted before AHSCT, at 6 and 12 months after AHSCT, then every 6 months during 2 years after AHSCT and every 12 months after 2 years during 5 years after AHSCT.

For statistical evaluation, paired t-test, Wilcoxon test and ANOVA were used. Progression-free survival (PFS) and relapse-free survival (RFS) after AHSCT were evaluated using Kaplan-Meyer method. To compare survival rates, log-rank criterion and Tarone-Ware criterion were applied. Mc-Nemar’s test was used in order to compare the proportions of patients according to symptom prevalence before AHSCT and 12 months following transplant. P values of <0.05 will be used as a cut-off point for statistical significance, and all statistical tests will be two-sided.

Results

General characteristics

A total of 258 patients with RRMS were enrolled in the study. Mean age was 36.5 years old; male/female ratio, 73/185. Median EDSS value before transplantation was 2.0 (range 1.5-6.5). Mean duration of the disease was 4.9 years (median 3.0, range 0.5-24). Patients’ characteristics are shown in Table 1.

Safety

The procedure of autologous HSCT was well tolerated by the patients. There were no cases of transplantation-related mortality. Mobilization was successful in all cases with median number of 2.1×10⁶/kg (range 2-10.9×10⁶/kg) collected CD34+cells; no major clinical adverse events were observed during this phase.

The mean time of neutropenia (grade 4) was 8.0 days. The mean time of thrombocytopenia (grade 3-4) was 7.0 days. Neutrophil engraftment was registered on D+8- D+11. No differences in hematological toxicity between the three conditioning regimens were found (P>0.05).

Common adverse effects after AHSCT were as follows: hepatic toxicity (grade 2 and 3) – 20.5%; mucositis (grade 2), 1.6%; temporary neurological worsening, 6.4%; neutropenic fever, 27%; local infection, 6.2%; anemia (grade 3), 1.9%; allergic reactions, 2.3%. No differences in toxicity were observed among the patients who received different conditioning regimens. No deaths were registered throughout the entire follow-up period.

Сlinical outcomes

Median follow-up after AHSCT was 30 months (3.7-110.9). The vast majority of patients (99%) responded to treatment. The decrease of EDSS score from median 2.0 to 1.5 was observed at 12 months after AHSCT, and it remained at this level during the follow-up of more than 60 months (Fig. 1). The EDSS score improved significantly for the entire group (P <0.001) at all the time intervals, as compared with base-line. EDSS changes in patients with RRMS prior to and at different time-points after AHSCT are presented in Table 2. The proportion of patients with change of >1.0 in EDSS score was 36% (86 patients) with index of improvement at 12 months, and 0.4% (1 patient) with an index of the disease progression. At 2 years post-transplant, 47 (32%) patients showed improvement, 1 patient (0.7%) became worse, and others presented with stable disease. At 3 years posttransplant, improvement was observed in 23 (25%) patients, worsening – in 1 (1.1%) patient, the others were in stable clinical state. At 4 years posttransplant, the majority (83.1%) of patients were stable, there was no further worsening, and 10 patients (16.9%) exhibited improvement. Hence, the vast majority of patients was stable during the continuous follow-up; clinical deterioration took place in 6% of patients.

Table 2. EDSS changes in patients with RRMS before and at different time-points after AHSCT

After AHSCT, the vast majority of patients with RRMS were relapse-free (245 out of 258). The mean term until relapse was 30.4 months (95% CI 18.24-42.52). Estimated relapse-free survival (RFS) at the median follow-up of 29.5 months was 95% (95% CI: 92.3-97.7) (Fig. 2A).

Estimated RFS at the follow-up of 36 months was 95.6% (95% CI: 92.4-98.8), at the follow-up of 60 months, 88.2% (95% CI: 80.2-96.2); at the follow-up of 84 months, 83.3% (95% CI: 71.3-95.3). Estimated progression-free survival (PFS) at the follow-up of 36 months was 98% (95% CI: 95.6-100.0), at the follow-up of 60 months, 91.2% (95% CI: 81.9-100.0), at the follow-up of 84 months, 86.2% (95% CI: 73.1-99.3), as seen from Fig. 2B.

Figure 2. Relapse-free (a) and progression free (b) survival Kaplan-Meyer curves in RRMS patients after AHSCT

Separate analysis of RFS probability in the groups of patients with different conditioning regimen was also performed.Comparison was made between the conditioning regimens based on BEAM-like and Cyclophosphamide+Rituximab protocols. Previously, it was shown that the outcomes for mini-BEAM and BM were similar [24]. Thus, the BEAM-like group included mini-BEAM and BM conditioning regimens. No differences in RFS were found between patients who received BEAM-like and these who received high-dose cyclophosphamide+Rituximab (log-rank, P=0.92), as shown in Fig. 3.

Patient-reported outcomes

Mean QoL values in RRMS patients before AHSCT and 12 months after AHSCT (n=78) are presented in Table 3. QoL changes (Δ) of scores according to all the SF-36 scales in 12 mo after AHSCT were compared to the baseline levels (Fig. 4).

We have also performed analysis of QoL changes at long-term follow-up after AHSCT (≥18 months) as compared to baseline values (n=41). Median follow-up was 22.9 months (interquartile range: 16.8-35.7 mo; mean±SD, 23.9±5.05 mo;95% CI: 22.3 to 25.5 mo). The mean QoL values in RRMS patients before AHSCT and in the course of long-term follow-up after AHSCT are presented in Table 4. QoL changes (Δ) of scores for all SF-36 scales over long-term follow-up after AHSCT were compared to baseline scores (Fig. 5).

Table 3. Quality of life mean values in RRMS patients at baseline and 12 months after AHSCT

Table 4. Mean values for QoL indexes in RRMS patients at baseline and in long-term follow-up after AHSCT

Prevalence of the most common symptoms by CSP-MS42 in RRMS patients at 12 mo after ASCT against appropriate baseline values is shown in Fig. 6. Before AHSCT, the ten most common symptoms were present in more than half of the patients. Such symptoms as constant tiredness feeling, early exhaustion after physical activity, decreased energy, fatigue, heaviness in legs, loss of balance, lack of working coordination, difficulty walking and poor tolerance of hot water were reported by the vast majority of patients. As seen from the Fig. 6, their prevalence decreased 12 months post-transplant. The number of patients who experienced these symptoms except of heaviness in legs was significantly less after AHSCT as compared with baseline prevalence (P<0.05). The severity of all these symptoms also decreased after AHSCT (P<0.05).

Figure 6. Prevalence of common MS symptoms before and at 12 months posttransplant

AHSCT was accompanied by a significant improvement in patient’s QoL and decrease of symptom burden. Improved QoL was preserved during the entire period of follow-up. AHSCT is beneficial in unfavorable group of MS patients, those with progressive MS, with high disability and long lasting disease.

Discussion

We have analyzed a cohort of 258 patients with RRMS undergoing AHSCT, with a median follow-up of 30 months. Low-intensity conditioning regimens based on BEAM and cyclophosphamide were applied. Outcomes of AHSCT were evaluated both from physician’s and patient’s perspective. Transplantation procedure was well tolerated by the patients. There were no cases of transplantation-related mortality. In our cohort, the vast majority of patients responded to treatment and exhibited clinical improvement, or were stable during the entire period of follow-up. Significant decrease of EDSS score was observed after transplantation; the EDSS score improved (decreased by ≥1.0 point), with 32% and 17% of patients demonstrating improvement at 2 years and 4 years, respectively. In our cohort, relapse-free survival and progression-free survival at 7-year follow-up were 83% and 86%, respectively. These results are in line with previously published data by R. Burt [18, 19].

Moreover, AHSCT was accompanied by significant improvement in patient’s QoL. The analysis of QoL demonstrated benefits of AHSCT with low-intensity conditioning regimens in this patient population. QoL is an important outcome of MS treatment and its assessment provides the patient’s perspective on the overall effect of treatment and allows evaluating patient benefits. Our results definitely show that AHSCT resulted in significant and sustained improvement of patient’s QoL. Also, prevalence and severity of common symptoms of MS decreased after transplantation. Thus, noticeble decrease of symptom burden after AHSCT was demonstrated.

For the first time to our knowledge, we report the AHSCT outcomes in MS patients after different low-intensity conditioning regimens and long-term follow-up. We did not find any differences in RFS between the patients who received BM/BEAM-like+ATG, and those who received high-dose cyclophosphamide+Rituximab. These data are in line with the results we have published previously [29]. Our study also demonstrated that RFS did not differ between various age groups, and between the groups with different duration of the disease.

On the contrary, disability status was an important factor influencing the outcomes of transplantation: RFS was dramatically better in patients with EDSS<4 as compared to patients with EDSS=4-6.5. This finding supports the idea that AHSCT is beneficial for patients with highly active relapsing-remitting MS and moderate disability.

This study has several important limitations. Firstly, the study was conducted at a single academic institution, which may introduce some bias. However, all patients had clinical continuity and were monitored for in terms of relapses or need for additional treatment. Secondly, a large number of patients were treated on a compassionate basis rather than within a study protocol. Thirdly, a long-term follow-up (i.e, for ≥4 years) was not available for a substantial proportion of patients. Fourth, this was an observational cohort lacking a control group. Therefore, any inferences about causal effects of AHSCT can’t be made.

Thus, the risk/benefit ratio of AHSCT with low-intensity conditioning regimens in our population of RRMS patients is rather favorable. The consistency of our clinical and QoL results, together with persistent improvement suggest clinical efficacy of AHSCT strategy in RRMS patients. In general, the results of our study support the feasibility of AHSCT with low-intensity conditioning in RRMS patients. To optimize the mentioned treatment protocols of AHSCT in RRMS, multicenter cooperative studies are necessary in future.

Conflicts of interest

None reported.

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В данной публикации представлены результаты комплексной оценки клинической эффективности и оценок, данных пациентом, у больных с ремиттирующим вариантом течения РС до и в разные сроки после ВИСТ+ТГСК с использованием режимов кондиционирования сниженной интенсивности (две программы на основе BEAM и одна на основе циклофосфамида). В исследование включены 258 пациентов, средний возраст – 36,5 лет, мужчины/женщины – 71/185. Медиана индекса инвалидизации по шкале EDSS до трансплантации – 2,0 балла. Средняя длительность периода наблюдения составила 4,9 года. Для оценки клинической эффективности использовались динамика индекс EDSS и данные МРТ. Также проводился анализ безрецидивной выживаемости и выживаемости без прогрессирования заболевания. Для оценки качества жизни использовали общий опросник RAND SF-36 и опросник оценки симптомов CSP-MS-42. Процедура мобилизации и трансплантации хорошо переносилась больными. Безрецидивная выживаемость и выживаемость без прогрессирования заболевания составила 83% и 86%, соответственно, в течение 7 лет после ТГСК.</p> <p style="text-align: justify;">В результате исследования не было выявлено различий в эффективности и токсичности при применении режимов кондиционирования сниженной интенсивности на основе BEAM с АТГ и циклофосфамида с ритуксимабом. После ТГСК отмечено значительное улучшение параметров качества жизни и снижение выраженности симптомов у подавляющего большинства пациентов. Таким образом, с помощью оценки клинического ответа и параметров качества жизни, продемонстрирована высокая эффективность и безопасность режимов кондиционирования сниженной интенсивности у пациентов с ремиттирующим РС.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Аутологичная трансплантация гемопоэтических стволовых клеток, режим кондиционирования, рассеянный склероз, клинический ответ, качество жизни. </p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(334) "Аутологичная трансплантация гемопоэтических стволовых клеток с режимом сниженной интенсивности при ремиттирующем рассеянном склерозе: клиническая эффективность и качество жизни" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(334) "Аутологичная трансплантация гемопоэтических стволовых клеток с режимом сниженной интенсивности при ремиттирующем рассеянном склерозе: клиническая эффективность и качество жизни" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(334) "Аутологичная трансплантация гемопоэтических стволовых 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Мельниченко¹, Денис А. Федоренко¹, Татьяна П. Никитина², Наталья М. Порфирьева³, Илья С. Николаев¹, Татьяна И. Ионова²</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(299) "

Владимир Я. Мельниченко¹, Денис А. Федоренко¹, Татьяна П. Никитина², Наталья М. Порфирьева³, Илья С. Николаев¹, Татьяна И. Ионова²

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27607" ["VALUE"]=> array(2) { ["TEXT"]=> string(667) "<p>¹ Национальный медико-хирургический центр им. Н. И. Пирогова Минздрава РФ, Москва, Россия<br> ² Санкт-Петербургский государственный университет, Клиника высоких медицинских технологий им. Н. И. Пирогова, <br>Санкт-Петербург, Россия<br> ³ Межнациональный центр исследования качества жизни, Санкт-Петербург, Россия</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(601) "

¹ Национальный медико-хирургический центр им. Н. И. Пирогова Минздрава РФ, Москва, Россия
² Санкт-Петербургский государственный университет, Клиника высоких медицинских технологий им. Н. И. Пирогова,
Санкт-Петербург, Россия
³ Межнациональный центр исследования качества жизни, Санкт-Петербург, Россия

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27608" ["VALUE"]=> array(2) { ["TEXT"]=> string(3788) "<p style="text-align: justify;">Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией гемопоэтических стволовых клеток (ВИСТ+ТГСК) – новый эффективный метод лечения рассеянного склероза (РС). В данной публикации представлены результаты комплексной оценки клинической эффективности и оценок, данных пациентом, у больных с ремиттирующим вариантом течения РС до и в разные сроки после ВИСТ+ТГСК с использованием режимов кондиционирования сниженной интенсивности (две программы на основе BEAM и одна на основе циклофосфамида). В исследование включены 258 пациентов, средний возраст – 36,5 лет, мужчины/женщины – 71/185. Медиана индекса инвалидизации по шкале EDSS до трансплантации – 2,0 балла. Средняя длительность периода наблюдения составила 4,9 года. Для оценки клинической эффективности использовались динамика индекс EDSS и данные МРТ. Также проводился анализ безрецидивной выживаемости и выживаемости без прогрессирования заболевания. Для оценки качества жизни использовали общий опросник RAND SF-36 и опросник оценки симптомов CSP-MS-42. Процедура мобилизации и трансплантации хорошо переносилась больными. Безрецидивная выживаемость и выживаемость без прогрессирования заболевания составила 83% и 86%, соответственно, в течение 7 лет после ТГСК.</p> <p style="text-align: justify;">В результате исследования не было выявлено различий в эффективности и токсичности при применении режимов кондиционирования сниженной интенсивности на основе BEAM с АТГ и циклофосфамида с ритуксимабом. После ТГСК отмечено значительное улучшение параметров качества жизни и снижение выраженности симптомов у подавляющего большинства пациентов. Таким образом, с помощью оценки клинического ответа и параметров качества жизни, продемонстрирована высокая эффективность и безопасность режимов кондиционирования сниженной интенсивности у пациентов с ремиттирующим РС.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Аутологичная трансплантация гемопоэтических стволовых клеток, режим кондиционирования, рассеянный склероз, клинический ответ, качество жизни. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3710) "

Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией гемопоэтических стволовых клеток (ВИСТ+ТГСК) – новый эффективный метод лечения рассеянного склероза (РС). В данной публикации представлены результаты комплексной оценки клинической эффективности и оценок, данных пациентом, у больных с ремиттирующим вариантом течения РС до и в разные сроки после ВИСТ+ТГСК с использованием режимов кондиционирования сниженной интенсивности (две программы на основе BEAM и одна на основе циклофосфамида). В исследование включены 258 пациентов, средний возраст – 36,5 лет, мужчины/женщины – 71/185. Медиана индекса инвалидизации по шкале EDSS до трансплантации – 2,0 балла. Средняя длительность периода наблюдения составила 4,9 года. Для оценки клинической эффективности использовались динамика индекс EDSS и данные МРТ. Также проводился анализ безрецидивной выживаемости и выживаемости без прогрессирования заболевания. Для оценки качества жизни использовали общий опросник RAND SF-36 и опросник оценки симптомов CSP-MS-42. Процедура мобилизации и трансплантации хорошо переносилась больными. Безрецидивная выживаемость и выживаемость без прогрессирования заболевания составила 83% и 86%, соответственно, в течение 7 лет после ТГСК.

В результате исследования не было выявлено различий в эффективности и токсичности при применении режимов кондиционирования сниженной интенсивности на основе BEAM с АТГ и циклофосфамида с ритуксимабом. После ТГСК отмечено значительное улучшение параметров качества жизни и снижение выраженности симптомов у подавляющего большинства пациентов. Таким образом, с помощью оценки клинического ответа и параметров качества жизни, продемонстрирована высокая эффективность и безопасность режимов кондиционирования сниженной интенсивности у пациентов с ремиттирующим РС.

Ключевые слова

Аутологичная трансплантация гемопоэтических стволовых клеток, режим кондиционирования, рассеянный склероз, клинический ответ, качество жизни.

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Vladimir Y. Melnichenko¹, Denis A. Fedorenko¹, Tatiana P. Nikitina², Natalia M. Porfirieva³, Ilya S. Nikolaev¹, Tatiana I. Ionova²

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¹ Pirogov National Medical and Surgical Center of The Ministry of Healthcare of Russian Federation, Moscow, Russia
² Saint Petersburg State University Hospital, St. Petersburg, Russia
³ Multinational Center for Quality of Life Research, St. Petersburg, Russia

Correspondence
Professor Tatyana I. Ionova, Saint Petersburg State University Hospital, 154 Fontanka embankment, 190103, St. Petersburg, Russia
Phone: +7 (962) 710-17-11
E-mail: tation16@gmail.com

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The effect of autologous hematopoietic stem cell transplantation (AHSCT) with low-intensity conditioning regimens, in terms of clinical and patient-reported outcomes, was studied in patients with relapsing-remitting multiple sclerosis (RRMS). In total, 258 RRMS patients were enrolled in a single-center study. The median follow-up duration was 30 months. Low-intensity conditioning regimens (two based on reduced BEAM and one on cyclophosphamide) were applied. Outcomes of AHSCT were evaluated from both the physicians’ and patients’ perspectives. Reversal of the disability progression, relapse-free survival (RFS), progression-free survival (PFS), as well as changes in quality of life (QoL), and severity of symptoms were analyzed. Transplantation procedure was well tolerated by the patients, and there were no cases of transplantation-related mortality. In addition, no deaths were registered throughout the follow-up period.

The vast majority of patients exhibited clinical improvement, or were in stable condition during the entire follow-up period. The estimated proportions of RFS and PFS were 83% and 86%, respectively, at 7 years after AHSCT. No differences in RFS were found between the patients who received reduced BEAM±ATG and high-dose cyclophosphamide+rituximab conditioning regimens. AHSCT resulted in significant and sustained QoL improvement, as well as decrease of symptom burden.The results of our study support feasibility of autologous HSCT with low-intensity conditioning regimens in RRMS. Multicentre cooperative studies should be done to optimize the treatment protocol of mini-AHSCT.

Keywords

Autologous hematopoietic stem cell transplantation, conditioning regimen, multiple sclerosis, clinical outcomes, quality of life.

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"HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(80) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(72) "Название (для очень длинных заголовков)" ["~DEFAULT_VALUE"]=> array(2) { ["TYPE"]=> string(4) "HTML" ["TEXT"]=> string(0) "" } } } ["DISPLAY_PROPERTIES"]=> array(10) { ["AUTHOR_EN"]=> array(37) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> 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Melnichenko¹, Denis A. Fedorenko¹, Tatiana P. Nikitina², Natalia M. Porfirieva³, Ilya S. Nikolaev¹, Tatiana I. Ionova²</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(204) "

Vladimir Y. Melnichenko¹, Denis A. Fedorenko¹, Tatiana P. Nikitina², Natalia M. Porfirieva³, Ilya S. Nikolaev¹, Tatiana I. Ionova²

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Vladimir Y. Melnichenko¹, Denis A. Fedorenko¹, Tatiana P. Nikitina², Natalia M. Porfirieva³, Ilya S. Nikolaev¹, Tatiana I. Ionova²

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The effect of autologous hematopoietic stem cell transplantation (AHSCT) with low-intensity conditioning regimens, in terms of clinical and patient-reported outcomes, was studied in patients with relapsing-remitting multiple sclerosis (RRMS). In total, 258 RRMS patients were enrolled in a single-center study. The median follow-up duration was 30 months. Low-intensity conditioning regimens (two based on reduced BEAM and one on cyclophosphamide) were applied. Outcomes of AHSCT were evaluated from both the physicians’ and patients’ perspectives. Reversal of the disability progression, relapse-free survival (RFS), progression-free survival (PFS), as well as changes in quality of life (QoL), and severity of symptoms were analyzed. Transplantation procedure was well tolerated by the patients, and there were no cases of transplantation-related mortality. In addition, no deaths were registered throughout the follow-up period.

The vast majority of patients exhibited clinical improvement, or were in stable condition during the entire follow-up period. The estimated proportions of RFS and PFS were 83% and 86%, respectively, at 7 years after AHSCT. No differences in RFS were found between the patients who received reduced BEAM±ATG and high-dose cyclophosphamide+rituximab conditioning regimens. AHSCT resulted in significant and sustained QoL improvement, as well as decrease of symptom burden.The results of our study support feasibility of autologous HSCT with low-intensity conditioning regimens in RRMS. Multicentre cooperative studies should be done to optimize the treatment protocol of mini-AHSCT.

Keywords

Autologous hematopoietic stem cell transplantation, conditioning regimen, multiple sclerosis, clinical outcomes, quality of life.

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The effect of autologous hematopoietic stem cell transplantation (AHSCT) with low-intensity conditioning regimens, in terms of clinical and patient-reported outcomes, was studied in patients with relapsing-remitting multiple sclerosis (RRMS). In total, 258 RRMS patients were enrolled in a single-center study. The median follow-up duration was 30 months. Low-intensity conditioning regimens (two based on reduced BEAM and one on cyclophosphamide) were applied. Outcomes of AHSCT were evaluated from both the physicians’ and patients’ perspectives. Reversal of the disability progression, relapse-free survival (RFS), progression-free survival (PFS), as well as changes in quality of life (QoL), and severity of symptoms were analyzed. Transplantation procedure was well tolerated by the patients, and there were no cases of transplantation-related mortality. In addition, no deaths were registered throughout the follow-up period.

The vast majority of patients exhibited clinical improvement, or were in stable condition during the entire follow-up period. The estimated proportions of RFS and PFS were 83% and 86%, respectively, at 7 years after AHSCT. No differences in RFS were found between the patients who received reduced BEAM±ATG and high-dose cyclophosphamide+rituximab conditioning regimens. AHSCT resulted in significant and sustained QoL improvement, as well as decrease of symptom burden.The results of our study support feasibility of autologous HSCT with low-intensity conditioning regimens in RRMS. Multicentre cooperative studies should be done to optimize the treatment protocol of mini-AHSCT.

Keywords

Autologous hematopoietic stem cell transplantation, conditioning regimen, multiple sclerosis, clinical outcomes, quality of life.

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¹ Pirogov National Medical and Surgical Center of The Ministry of Healthcare of Russian Federation, Moscow, Russia
² Saint Petersburg State University Hospital, St. Petersburg, Russia
³ Multinational Center for Quality of Life Research, St. Petersburg, Russia

Correspondence
Professor Tatyana I. Ionova, Saint Petersburg State University Hospital, 154 Fontanka embankment, 190103, St. Petersburg, Russia
Phone: +7 (962) 710-17-11
E-mail: tation16@gmail.com

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¹ Pirogov National Medical and Surgical Center of The Ministry of Healthcare of Russian Federation, Moscow, Russia
² Saint Petersburg State University Hospital, St. Petersburg, Russia
³ Multinational Center for Quality of Life Research, St. Petersburg, Russia

Correspondence
Professor Tatyana I. Ionova, Saint Petersburg State University Hospital, 154 Fontanka embankment, 190103, St. Petersburg, Russia
Phone: +7 (962) 710-17-11
E-mail: tation16@gmail.com

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Владимир Я. Мельниченко¹, Денис А. Федоренко¹, Татьяна П. Никитина², Наталья М. Порфирьева³, Илья С. Николаев¹, Татьяна И. Ионова²

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Владимир Я. Мельниченко¹, Денис А. Федоренко¹, Татьяна П. Никитина², Наталья М. Порфирьева³, Илья С. Николаев¹, Татьяна И. Ионова²

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В данной публикации представлены результаты комплексной оценки клинической эффективности и оценок, данных пациентом, у больных с ремиттирующим вариантом течения РС до и в разные сроки после ВИСТ+ТГСК с использованием режимов кондиционирования сниженной интенсивности (две программы на основе BEAM и одна на основе циклофосфамида). В исследование включены 258 пациентов, средний возраст – 36,5 лет, мужчины/женщины – 71/185. Медиана индекса инвалидизации по шкале EDSS до трансплантации – 2,0 балла. Средняя длительность периода наблюдения составила 4,9 года. Для оценки клинической эффективности использовались динамика индекс EDSS и данные МРТ. Также проводился анализ безрецидивной выживаемости и выживаемости без прогрессирования заболевания. Для оценки качества жизни использовали общий опросник RAND SF-36 и опросник оценки симптомов CSP-MS-42. Процедура мобилизации и трансплантации хорошо переносилась больными. Безрецидивная выживаемость и выживаемость без прогрессирования заболевания составила 83% и 86%, соответственно, в течение 7 лет после ТГСК.</p> <p style="text-align: justify;">В результате исследования не было выявлено различий в эффективности и токсичности при применении режимов кондиционирования сниженной интенсивности на основе BEAM с АТГ и циклофосфамида с ритуксимабом. После ТГСК отмечено значительное улучшение параметров качества жизни и снижение выраженности симптомов у подавляющего большинства пациентов. Таким образом, с помощью оценки клинического ответа и параметров качества жизни, продемонстрирована высокая эффективность и безопасность режимов кондиционирования сниженной интенсивности у пациентов с ремиттирующим РС.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Аутологичная трансплантация гемопоэтических стволовых клеток, режим кондиционирования, рассеянный склероз, клинический ответ, качество жизни. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3710) "

Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией гемопоэтических стволовых клеток (ВИСТ+ТГСК) – новый эффективный метод лечения рассеянного склероза (РС). В данной публикации представлены результаты комплексной оценки клинической эффективности и оценок, данных пациентом, у больных с ремиттирующим вариантом течения РС до и в разные сроки после ВИСТ+ТГСК с использованием режимов кондиционирования сниженной интенсивности (две программы на основе BEAM и одна на основе циклофосфамида). В исследование включены 258 пациентов, средний возраст – 36,5 лет, мужчины/женщины – 71/185. Медиана индекса инвалидизации по шкале EDSS до трансплантации – 2,0 балла. Средняя длительность периода наблюдения составила 4,9 года. Для оценки клинической эффективности использовались динамика индекс EDSS и данные МРТ. Также проводился анализ безрецидивной выживаемости и выживаемости без прогрессирования заболевания. Для оценки качества жизни использовали общий опросник RAND SF-36 и опросник оценки симптомов CSP-MS-42. Процедура мобилизации и трансплантации хорошо переносилась больными. Безрецидивная выживаемость и выживаемость без прогрессирования заболевания составила 83% и 86%, соответственно, в течение 7 лет после ТГСК.

В результате исследования не было выявлено различий в эффективности и токсичности при применении режимов кондиционирования сниженной интенсивности на основе BEAM с АТГ и циклофосфамида с ритуксимабом. После ТГСК отмечено значительное улучшение параметров качества жизни и снижение выраженности симптомов у подавляющего большинства пациентов. Таким образом, с помощью оценки клинического ответа и параметров качества жизни, продемонстрирована высокая эффективность и безопасность режимов кондиционирования сниженной интенсивности у пациентов с ремиттирующим РС.

Ключевые слова

Аутологичная трансплантация гемопоэтических стволовых клеток, режим кондиционирования, рассеянный склероз, клинический ответ, качество жизни.

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Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией гемопоэтических стволовых клеток (ВИСТ+ТГСК) – новый эффективный метод лечения рассеянного склероза (РС). В данной публикации представлены результаты комплексной оценки клинической эффективности и оценок, данных пациентом, у больных с ремиттирующим вариантом течения РС до и в разные сроки после ВИСТ+ТГСК с использованием режимов кондиционирования сниженной интенсивности (две программы на основе BEAM и одна на основе циклофосфамида). В исследование включены 258 пациентов, средний возраст – 36,5 лет, мужчины/женщины – 71/185. Медиана индекса инвалидизации по шкале EDSS до трансплантации – 2,0 балла. Средняя длительность периода наблюдения составила 4,9 года. Для оценки клинической эффективности использовались динамика индекс EDSS и данные МРТ. Также проводился анализ безрецидивной выживаемости и выживаемости без прогрессирования заболевания. Для оценки качества жизни использовали общий опросник RAND SF-36 и опросник оценки симптомов CSP-MS-42. Процедура мобилизации и трансплантации хорошо переносилась больными. Безрецидивная выживаемость и выживаемость без прогрессирования заболевания составила 83% и 86%, соответственно, в течение 7 лет после ТГСК.

В результате исследования не было выявлено различий в эффективности и токсичности при применении режимов кондиционирования сниженной интенсивности на основе BEAM с АТГ и циклофосфамида с ритуксимабом. После ТГСК отмечено значительное улучшение параметров качества жизни и снижение выраженности симптомов у подавляющего большинства пациентов. Таким образом, с помощью оценки клинического ответа и параметров качества жизни, продемонстрирована высокая эффективность и безопасность режимов кондиционирования сниженной интенсивности у пациентов с ремиттирующим РС.

Ключевые слова

Аутологичная трансплантация гемопоэтических стволовых клеток, режим кондиционирования, рассеянный склероз, клинический ответ, качество жизни.

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¹ Национальный медико-хирургический центр им. Н. И. Пирогова Минздрава РФ, Москва, Россия
² Санкт-Петербургский государственный университет, Клиника высоких медицинских технологий им. Н. И. Пирогова,
Санкт-Петербург, Россия
³ Межнациональный центр исследования качества жизни, Санкт-Петербург, Россия

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¹ Национальный медико-хирургический центр им. Н. И. Пирогова Минздрава РФ, Москва, Россия
² Санкт-Петербургский государственный университет, Клиника высоких медицинских технологий им. Н. И. Пирогова,
Санкт-Петербург, Россия
³ Межнациональный центр исследования качества жизни, Санкт-Петербург, Россия

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Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only potentially curative treatment for the patients with acute myeloid leukemia (AML). Over last decades, the number of allo-HSCTs is substantially increased, including those performed in Russian Federation. Fully HLA-compatible sibling is the optimal marrow donor for allo-HSCT. However, a matched related donor (MRD) is available only for 30% of the patients [1, 2]. HSCT from unrelated donor is associated with some problems, e.g., longer terms of donor activation and higher financial costs [3]. In this respect, allogeneic HSCT from haploidentical related donors with 50% HLA compatibility seems to be a possible alternative. Implementation of posttransplant cyclophosphamide (PTCy) prophylaxis significantly decreased frequency of graft-versus-host disease (GVHD) and primary graft failure [4]. Over last years, clinical efficiency of haploidentical HSCT (haplo-HSCT) approached the results of allogeneic MRD-HSCTs [5, 6]. This permitted us to include haplo-HSCT into management standards of the patients with hematooncological diseases, e.g., at earlier stages of the disorder [7].

Patients and methods

The study included 68 patients with AML subjected to allogeneic HSCT at the V.A.Almazov Research Medical Center from 2011 to 2019. A total of 21 compatible related stem cell transplants and 57 haploidentical HSCTs were performed (Table 1). Both groups had comparable number of subjects with active disease at the time of transplantation (Haplo-HSCT, 32.7%; MRD-HSCT, 31.6%). Myeloablative conditioning was used more often in MRD-HSCT. In the patients with active disease and high numbers of blast cells at the moment of HSCT, the conditioning protocols with prior cytoreduction were used. The proportion of myeloablative, nonmyeloablative, and protocols with preceding cytoreduction was, respectively, 0%, 80.7%, 19.3%; in haplo-HSCT versus 57.1%, 23.8%, 19.1% when transplanting from MRD. When performing haplo-HSCT, most patients received the following GVHD prophylaxis: posttransplant cyclophosphamide combined with calcineurin inhibitors and mycophenolate mofetil (94.7%). In MRD-HSCT group a combination of calcineurin inhibitors with methotrexate was applied in most cases (76.2%). Peripheral blood was more often used as a source of hematopoietic stem cells in both groups (89.5% in haplo-HSCT; 76.2% in MRD-HSCT). In the patients with high risk of posttransplant disease progression and absence of counterindications, prophylactic targeted therapy with low dosed Azacitidine was performed (53.8% in haplo-HSCT, and 31.6% in MRD-HSCT). Also 4 patients after haplo-HSCT (8.2%) received prophylactic donor lymphocyte infusion. By evaluating cytokine reactions, the patients with proven infections were excluded from the study. The patients were administered antibacterial drugs if it was not possible to make differential diagnostic between bacterial infections and cytokine reactions.

Table 1. Clinical features of the patients subjected to matched related HSCT (MRD-HSCT) and haploidendital familial transplant (haplo-HSCT)

Primary endpoints of the study were relapse-free survival (RFS) and overall survival (OS). Death for any cause was considered an event, and the surviving patients were censored by the date of last contact. Relapse was determined as bone marrow recurrence of disease or extramedullary lesions. The date of hematopoietic recovery was referred as the first of three subsequent days with absolute neutrophil number of >0.5×10⁹/L, and thrombocyte recovery was referred as the first of seven subsequent days platelet numbers >50×10⁹/L, without blood transfusion requirements.

Difference between the two groups upon evaluation of categorial factors was performed with coupling tables and Fisher criterion. Probability of relapse-free and overall survival (respectively, RFS and OS) was calculated with Kaplan-Meier analysis. Probability of granulo- and thrombocytopoiesis recovery, development of acute and chronic GVHD, relapses was calculated by the cumulative frequency method. Multifactorial analysis was performed using Cox regression. Influence of the following factors upon HSCT outcomes was tested: age and gender of patient and donor, disease status. Evaluation of chronic GVHD was carried out among the patients who survived for more than 90 days after HSCT.

Results

Patient characteristics

The patients subjected to haplo-HSCT were comparable by their age, gender, active disease rates at the time of HSCT and usage of posttransplant prophylaxis. Medians of age in haplo-HSCT and MRD-HSCT patients were, respectively, 40 years (18-61) and 32 years (18-61). Gender distribution was similar in both groups (ca. 50%). A total of 10 repeated HSCTs were performed, due to AML relapse (n=5) and graft rejection (n=5).

Engraftment was achieved in 84.4% of cases (95% CI 74.9-96.0) in haplo-HSCT versus 100% (95% CI 100-100%, p=0.742) in MRD-HSCT (Fig. 1). Ten patients died within early terms after haplo-HSCT, before the engraftment was registered. Primary engraftment was more common in haplo-HSCT, however, being statistically insignificant (10.6% versus 0%, р=0.31). For the granulocyte recovery, there was no significant timing difference, i.e., the medians of 17 days and 18 days in haplo-HSCT and MRD-HSCT settings, respectively. Cumulative frequency of thrombocyte recovery by the D+100 was sufficiently worse in haplo-HSCT 65.2% (95% CI 52.4-81.3) and 100% (95% CI 100-100%, р=0.00013). Similarly, recovery of thrombocyte numbers was also longer in haplo-HSCT setting than in MRD-HSCT, with median values of, respectively, 30 days and 21 days (р=0.015). When performing haplo-HSCT, a cytokine reaction to hematopoietic stem cell infusion was observed in 85.7% of the cases (n=42), however, without detectable severe responses.

Figure 1. Hematopoiesis recovery in haploidentical and matched related HSCT

Abbreviations: Haplo-HSCT, Haploidentical stem cell transplantation; SCT, stem cells transplantation; MRD-HSCT, matched related donor hematopoietic stem cell transplantation.

GVHD and relapse rates

A trend for higher frequency of acute GVHD (grade 2-4) at 6 months was observed in haplo-HSCT group, i.e., 45.3% (95% CI 31.7-64.6) and 36.3% (95% CI 20.0-65.6%, p=0.173), as seen from Fig. 2. There were no differences observed for severe acute GVHD (grade 3-4) between the two mentioned groups: 16.1% (95% CI 7.6-34.4) in haplo-HSCT versus 25.6% (95% CI 12.0-54.7%) in MRD-HSCT (p=0.5). A tendency for higher rate of different stages of chronic GVHD (at 1 year) was observed in MRD-HSCT: 22.9% (95% CI 11.3-62.6) as compared with 9.0% in haplo-HSCT (95% CI 3.6-64.6, p=0.07) (Fig. 3).

The median observation period was 294 days for the entire group (95% CI 210-51), and 1299 days for the surviving patients (95% CI 916-1798). A trend for increased relapse rate was found in the MRD-HSCT subgroup (40.7%; 95% CI 22.8-72.5) as compared to haplo-HSCT (16.6%; 95% CI 7.3-37.7%, p=0.151) as seen from Fig. 4. The median terms for relapses did not differ significantly: 256 days for MRD-HSCT, and 114 days for haplo-HSCT setting (р=0.104). Moreover, the results of 1-year relapse-free survival did not differ between the both groups, i.e., 40.8% for haplo-HSCT versus 52.4% for MRD-HSCT (р=0.44).

Survival

An increase in 30- and 100-day mortality was revealed in haplo-HSCT against MRD-HSCT: 21.1% vs 0% (р=0.001); 41.5% vs 9.5% (p=0.011), respectively. However, the one-year OS rates did not show a significant difference (haplo-HSCT, 42.9% vs MRD-HSCT, 61.9%; р=0.19). Similarly, the data on relapse-free and overall survival did not differ for these groups (respectively, p=0.401 and p=0.206, Fig. 5).

The OS values were not influenced by the acute GVHD (p=0.292); severe acute GVHD stage 3-4 (p=0.168) and by evolving chronic GVHD (р=0.174).

Meanwhile, the best results were obtained when performing HSCT in first remission. E.g., RFS value was 47.2% when transplanted in 1^st remission; 33.3% with HSCT in 2^nd or next remission, and 17.4% after HSCT in active phase of disease. The OS rates were as follows: 48.6% after HSCT in 1^st remission; 36.4% following HSCT in >2^nd remission, and 18.2% after HSCT in active state of disease. Of note, these differences were not statistically significant, both for RFS and OS after HSCT at 1^st and next remissions (p>0.05, Fig. 6).

Survival analysis following haplo-HSCT

We have made a separate data analysis in the group of haplo-HSCT patients, with similar results. Like in the total group of AML patients, overall survival rates were not affec- ted by acute GVHD stage 2-4 (p=0.095), acute GVHD stage 3-4 (p=0.297) and chronic GVHD (p=0.255).

Presence of remission at the time of HSCT was again the sole factor, which led to significant worsening of RFS, i.e., 47.1% if treated in remission vs 6.3% after HSCT in active disease (p=0.001). The same differences were registered for OS rates, e.g., 48.5% for HSCT in remission vs 6.3% for the patients transplanted in active disease (p=0.001) (Fig. 7). In multifactorial analysis active disease also was the only factor, influencing on OS (p=0.008).

Figure 7. Effect of the disease status upon the AML patient survival after haploidentical HSCT

Abbreviations: RFS, relapse-free survival; OS, overall survival; CR, complete remission; SCT, stem cells transplantation.

To assign causes of death after haplo-HSCT, appropriate sub-analysis was performed for this group. We have revealed, that among the patients, treated at the active stage of disease, compared to patients in CR at the moment of transplantation, a sufficient increase of 30-d mortality was observed, i.e., 47.6% vs 10.0% (р=0.002). The most frequent causes of death in early period after haplo-HSCT were: infection (75%, N=9), stroke (16.7%, N=2) and progression (8.3%, N=1).

Survival analysis in long-living haplo-HSCT patients

Due to sufficient early-mortality among haplo-HSCT patients, we performed a sub-analysis for the patients who survived >28 days after SCT. A trend for improvement of RFS results was retained (p=0.065), as well as OS data (p=0.067) when haplo-HSCT was carried out in remission of the disease, however, without statistical significance. The only factor which sufficiently influenced the results of haplo-HSCT in this group of patients was development of acute GVHD stage 3-4, causing a decrease of relapse-free survival, i.e. 0% in case of severe GVHD vs 53.1% in its absence (p=0.014), with similar effects on OS rates (severe GVHD 0% versus 54.8% in its absence (p=0.012)), as shown in Fig. 8.

Discussion

Proper choice for HLA-compatible donor is a prior task when performing allogeneic HSCT. Meanwhile, the aim of present study was to assess the results of haploidentical HSCT in AML patients and to compare them with outcomes of familial HLA-compatible HSCT. Due to low probability of finding HLA-compatible donors among siblings and in donor registries, the number of haploidentical HSCTs in our BMT Center was sufficiently increased and takes leading position at the present time.

When comparing time course of engraftment, we have observed high rates of primary graft failure, along with worse recovery of thrombocytopoiesis. This, however, provided an opportunity for repeated haplo-HSCT. Decreased rate of platelet reconstitution after HSCT may be connected with more pronounced immunological differences between patient and donor in haploidentical HSCT, as well as higher frequency of viral infections, e.g. cytomegalovirus. The results of survival analysis were comparable in the both groups. Therefore, our clinics now perform haplo-HSCT at broader basis, including the cases of relapse after MRD-HSCT.

ccording to our data, haplo-HSCT is associated with tendency for higher frequency of acute GVHD stage 2-4, thus being in agreement with other studies [8, 9]. Meanwhile, frequency of severe acute GVHD (stage 3-4) in these patients did not differ from MRD-HSCT. However, frequency of chronic GHVD tended to be higher in MRD-HSCT. It may be connected with usage of posttransplant cyclophosphamide HSCT group, and, therefore, more pronounced immune suppression achieved with this schedule.

Of interest, AML relapses were more common in the patients subjected to MRD-HSCT, despite myeloablative conditioning applied in most patients of this group. It could be attributed to potent antileukemic action of allo-HSCT (graft-versus-leukemia effect) which seems to be more pronounced with haploidentical transplant [10]. Moreover, one may note, that majority of the patients who underwent haplo-HSCT received prophylactic targeted chemotherapy with low-dose Azacitidine, if no contraindications existed. Meanwhile, less than 1/3 of the patients after MRD-HSCT received prophylactic therapy with Azacitidine +/- DLI only in cases of molecular relapse or evidence of active disease at the time of HSCT. Two patients in haploidentical and 2 patients in MRD groups received prophylactic donor lymphocyte infusions.

When evaluating overall survival, we did not see any difference between haploidentical and MRD-HSCT. Nonetheless, we saw certain features during posttransplant period in the both groups. We have revealed higher level of early mortality in the patients following haplo-HSCT on D+30 and D+100, with active malignant disease at HSCT, being among the main causes, increasing rate of early death post-transplant. Higher graft failure rates could also contribute to this early mortality. However, precise evaluation of engraftment was not feasible in these patients. Increased frequency of acute GVHD (grade 2-4) was also noted here.

Moreover, there are some data on longer reconstitution of immunity in haplo-HSCT [11]. Some workers suggest that it may lead to higher incidence of infectious complications, in particular, cytomegalovirus (CMV) reactivation [12]. Since all the patients with haplo-HSCT received non-myeloablative conditioning regimens, it seems that early mortality not to be associated with chemotherapeutic toxicity.

Active disease was associated with significantly poorer outcome after haplo-HSCT, being confirmed by the multifactorial analysis. The median survival in this group was only 25 days. The best results were obtained upon haploidentical HSCT performed in the 1st complete remission.

We have observed a sufficient proportion of the patients who deceased due to early (transplant-related) mortality within 1 month after transplantation. Meanwhile, the causes of death at later stages after transplantation significantly differ. A sub-analysis performed for the patients, who survived for >28 days post-HSCT, had shown, that OS in this long-living group was mainly influenced by acute GVHD (stage 3-4) whereas activity of primary disease prior to HSCT showed much lesser effect upon their survival.

Conclusion

1. Haploidentical HSCT is a plausible alternative for AML patients if HLA-compatible donor is not available.

2. Best results are obtained when haplo-HSCT is performed in the 1st complete remission.

3. Antileukemic effect of haplo-HSCT may be enhanced during posttransplant period by application of maintenance therapy with Azacitidine and donor lymphocyte infusions.

Conflict of interest

The authors report no conflicts of interest.

Acknowledgement

This study was financially supported by the Ministry of Science and Higher Education of the Russian Federation (Contract No. 075-15-2020-901).

References

1. Singh AK, McGuirk JP. Allogeneic Stem Cell Transplantation: A Historical and Scientific Overview. Cancer Res. 2016; 76(22):6445-6451. doi: 10.1158/0008-5472.CAN-16-1311
2. Tiercy JM. How to select the best available related or unrelated donor of hematopoietic stem cells? Haematologica. 2016; 101(6):680-687. doi: 10.3324/haematol.2015.141119
3. Afanasyev BV, Zubarovskaya LS, Borovkova AS, Kuzmich EV, Bykova TA, Deev RV,Isaev AA. Donor selection in allogeneic hematopoietic stem cell transplantation. Russian Journal of Pediatric Hematology and Oncology. 2016; 3(3):30-36 (In Russian). doi: 10.17650/2311-1267-2016-3-3-30-36
4. Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, Gooley TA, Piantadosi S, Kaup M, Ambinder RF, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008; 14(6):641-650. doi: 10.1016/j.bbmt.2008.03.005
5. Ciurea SO, Zhang MJ, Bacigalupo AA, Bashey A, Appelbaum FR, Aljitawi OS, Armand P, Antin JH, Chen J, Devine SM, Fowler DH, Luznik L, et al. Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia. Blood. 2015;126(8):1033-1040. doi: 10.1182/blood-2015-04-639831
6. Gu Z, Wang L, Yuan L, Huang W, Li M, Guan L, Wang Q, Gao Z, Zhao S, Luo L, et al. Similar outcomes after haploidentical transplantation with post-transplant cyclophosphamide versus HLA-matched transplantation: a meta-analysis of case-control studies. Oncotarget. 2017; 8(38):63574-63586. doi: 10.18632/oncotarget.18862
7. Passweg JR, Baldomero H, Bader P, Bonini C, Duarte RF, Dufour C, Gennery A, Kröger N, Kuball J, Lanza F, et al. Use of haploidentical stem cell transplantation continues to increase: the 2015 European Society for Blood and Marrow Transplant activity survey report. Bone Marrow Transplant. 2017; 52(6):811-817. doi: 10.1038/bmt.2017.34
8. Wang Y, Liu QF, Xu LP, Liu KY, Zhang XH, Ma X, Fan ZP, Wu DP, Huang XJ. Haploidentical vs identical-sibling transplant for AML in remission: a multicenter, prospective study. Blood. 2015; 125(25):396-62. doi: 10.1182/blood-2015-02-627786
9. Kunacheewa C. et al. Comparative efficacy and clinical outcomes of haploidentical stem cell transplantation to other stem sources for treatment in acute myeloid leukemia and myelodysplastic syndrome patients: a systematic review and meta-analysis. Cell transplantation. 2020; 29: 0963689720904965.
10. Chang YJ. et al. Haplo-SCT mediates stronger GVL effect than HLA-matched sibling allograft by significantly reducing leukemia burden. Blood. 2018. 132: 2186. doi: 10.1182/blood-2018-99-118409
11. McCurdy SR, Luznik L. Immune reconstitution after T-cell replete HLA-haploidentical transplantation. Semin Hematol. 2019;56(3):221-226. doi: 10.1053/j.seminhematol.2019.03.005
12. Lin CH, Su YJ, Hsu CY, Wang PN, Teng CJ. Haploidentical allogeneic hematopoietic stem cell transplantation increases the risk of cytomegalovirus infection in adult patients with acute leukemia. Transpl Infect Dis. 2019; 21(4):e13096. doi: 10.1111/tid.13096

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Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only potentially curative treatment for the patients with acute myeloid leukemia (AML). Over last decades, the number of allo-HSCTs is substantially increased, including those performed in Russian Federation. Fully HLA-compatible sibling is the optimal marrow donor for allo-HSCT. However, a matched related donor (MRD) is available only for 30% of the patients [1, 2]. HSCT from unrelated donor is associated with some problems, e.g., longer terms of donor activation and higher financial costs [3]. In this respect, allogeneic HSCT from haploidentical related donors with 50% HLA compatibility seems to be a possible alternative. Implementation of posttransplant cyclophosphamide (PTCy) prophylaxis significantly decreased frequency of graft-versus-host disease (GVHD) and primary graft failure [4]. Over last years, clinical efficiency of haploidentical HSCT (haplo-HSCT) approached the results of allogeneic MRD-HSCTs [5, 6]. This permitted us to include haplo-HSCT into management standards of the patients with hematooncological diseases, e.g., at earlier stages of the disorder [7].

Patients and methods

The study included 68 patients with AML subjected to allogeneic HSCT at the V.A.Almazov Research Medical Center from 2011 to 2019. A total of 21 compatible related stem cell transplants and 57 haploidentical HSCTs were performed (Table 1). Both groups had comparable number of subjects with active disease at the time of transplantation (Haplo-HSCT, 32.7%; MRD-HSCT, 31.6%). Myeloablative conditioning was used more often in MRD-HSCT. In the patients with active disease and high numbers of blast cells at the moment of HSCT, the conditioning protocols with prior cytoreduction were used. The proportion of myeloablative, nonmyeloablative, and protocols with preceding cytoreduction was, respectively, 0%, 80.7%, 19.3%; in haplo-HSCT versus 57.1%, 23.8%, 19.1% when transplanting from MRD. When performing haplo-HSCT, most patients received the following GVHD prophylaxis: posttransplant cyclophosphamide combined with calcineurin inhibitors and mycophenolate mofetil (94.7%). In MRD-HSCT group a combination of calcineurin inhibitors with methotrexate was applied in most cases (76.2%). Peripheral blood was more often used as a source of hematopoietic stem cells in both groups (89.5% in haplo-HSCT; 76.2% in MRD-HSCT). In the patients with high risk of posttransplant disease progression and absence of counterindications, prophylactic targeted therapy with low dosed Azacitidine was performed (53.8% in haplo-HSCT, and 31.6% in MRD-HSCT). Also 4 patients after haplo-HSCT (8.2%) received prophylactic donor lymphocyte infusion. By evaluating cytokine reactions, the patients with proven infections were excluded from the study. The patients were administered antibacterial drugs if it was not possible to make differential diagnostic between bacterial infections and cytokine reactions.

Table 1. Clinical features of the patients subjected to matched related HSCT (MRD-HSCT) and haploidendital familial transplant (haplo-HSCT)

Primary endpoints of the study were relapse-free survival (RFS) and overall survival (OS). Death for any cause was considered an event, and the surviving patients were censored by the date of last contact. Relapse was determined as bone marrow recurrence of disease or extramedullary lesions. The date of hematopoietic recovery was referred as the first of three subsequent days with absolute neutrophil number of >0.5×10⁹/L, and thrombocyte recovery was referred as the first of seven subsequent days platelet numbers >50×10⁹/L, without blood transfusion requirements.

Difference between the two groups upon evaluation of categorial factors was performed with coupling tables and Fisher criterion. Probability of relapse-free and overall survival (respectively, RFS and OS) was calculated with Kaplan-Meier analysis. Probability of granulo- and thrombocytopoiesis recovery, development of acute and chronic GVHD, relapses was calculated by the cumulative frequency method. Multifactorial analysis was performed using Cox regression. Influence of the following factors upon HSCT outcomes was tested: age and gender of patient and donor, disease status. Evaluation of chronic GVHD was carried out among the patients who survived for more than 90 days after HSCT.

Results

Patient characteristics

The patients subjected to haplo-HSCT were comparable by their age, gender, active disease rates at the time of HSCT and usage of posttransplant prophylaxis. Medians of age in haplo-HSCT and MRD-HSCT patients were, respectively, 40 years (18-61) and 32 years (18-61). Gender distribution was similar in both groups (ca. 50%). A total of 10 repeated HSCTs were performed, due to AML relapse (n=5) and graft rejection (n=5).

Engraftment was achieved in 84.4% of cases (95% CI 74.9-96.0) in haplo-HSCT versus 100% (95% CI 100-100%, p=0.742) in MRD-HSCT (Fig. 1). Ten patients died within early terms after haplo-HSCT, before the engraftment was registered. Primary engraftment was more common in haplo-HSCT, however, being statistically insignificant (10.6% versus 0%, р=0.31). For the granulocyte recovery, there was no significant timing difference, i.e., the medians of 17 days and 18 days in haplo-HSCT and MRD-HSCT settings, respectively. Cumulative frequency of thrombocyte recovery by the D+100 was sufficiently worse in haplo-HSCT 65.2% (95% CI 52.4-81.3) and 100% (95% CI 100-100%, р=0.00013). Similarly, recovery of thrombocyte numbers was also longer in haplo-HSCT setting than in MRD-HSCT, with median values of, respectively, 30 days and 21 days (р=0.015). When performing haplo-HSCT, a cytokine reaction to hematopoietic stem cell infusion was observed in 85.7% of the cases (n=42), however, without detectable severe responses.

Figure 1. Hematopoiesis recovery in haploidentical and matched related HSCT

Abbreviations: Haplo-HSCT, Haploidentical stem cell transplantation; SCT, stem cells transplantation; MRD-HSCT, matched related donor hematopoietic stem cell transplantation.

GVHD and relapse rates

A trend for higher frequency of acute GVHD (grade 2-4) at 6 months was observed in haplo-HSCT group, i.e., 45.3% (95% CI 31.7-64.6) and 36.3% (95% CI 20.0-65.6%, p=0.173), as seen from Fig. 2. There were no differences observed for severe acute GVHD (grade 3-4) between the two mentioned groups: 16.1% (95% CI 7.6-34.4) in haplo-HSCT versus 25.6% (95% CI 12.0-54.7%) in MRD-HSCT (p=0.5). A tendency for higher rate of different stages of chronic GVHD (at 1 year) was observed in MRD-HSCT: 22.9% (95% CI 11.3-62.6) as compared with 9.0% in haplo-HSCT (95% CI 3.6-64.6, p=0.07) (Fig. 3).

The median observation period was 294 days for the entire group (95% CI 210-51), and 1299 days for the surviving patients (95% CI 916-1798). A trend for increased relapse rate was found in the MRD-HSCT subgroup (40.7%; 95% CI 22.8-72.5) as compared to haplo-HSCT (16.6%; 95% CI 7.3-37.7%, p=0.151) as seen from Fig. 4. The median terms for relapses did not differ significantly: 256 days for MRD-HSCT, and 114 days for haplo-HSCT setting (р=0.104). Moreover, the results of 1-year relapse-free survival did not differ between the both groups, i.e., 40.8% for haplo-HSCT versus 52.4% for MRD-HSCT (р=0.44).

Survival

An increase in 30- and 100-day mortality was revealed in haplo-HSCT against MRD-HSCT: 21.1% vs 0% (р=0.001); 41.5% vs 9.5% (p=0.011), respectively. However, the one-year OS rates did not show a significant difference (haplo-HSCT, 42.9% vs MRD-HSCT, 61.9%; р=0.19). Similarly, the data on relapse-free and overall survival did not differ for these groups (respectively, p=0.401 and p=0.206, Fig. 5).

The OS values were not influenced by the acute GVHD (p=0.292); severe acute GVHD stage 3-4 (p=0.168) and by evolving chronic GVHD (р=0.174).

Meanwhile, the best results were obtained when performing HSCT in first remission. E.g., RFS value was 47.2% when transplanted in 1^st remission; 33.3% with HSCT in 2^nd or next remission, and 17.4% after HSCT in active phase of disease. The OS rates were as follows: 48.6% after HSCT in 1^st remission; 36.4% following HSCT in >2^nd remission, and 18.2% after HSCT in active state of disease. Of note, these differences were not statistically significant, both for RFS and OS after HSCT at 1^st and next remissions (p>0.05, Fig. 6).

Survival analysis following haplo-HSCT

We have made a separate data analysis in the group of haplo-HSCT patients, with similar results. Like in the total group of AML patients, overall survival rates were not affec- ted by acute GVHD stage 2-4 (p=0.095), acute GVHD stage 3-4 (p=0.297) and chronic GVHD (p=0.255).

Presence of remission at the time of HSCT was again the sole factor, which led to significant worsening of RFS, i.e., 47.1% if treated in remission vs 6.3% after HSCT in active disease (p=0.001). The same differences were registered for OS rates, e.g., 48.5% for HSCT in remission vs 6.3% for the patients transplanted in active disease (p=0.001) (Fig. 7). In multifactorial analysis active disease also was the only factor, influencing on OS (p=0.008).

Figure 7. Effect of the disease status upon the AML patient survival after haploidentical HSCT

Abbreviations: RFS, relapse-free survival; OS, overall survival; CR, complete remission; SCT, stem cells transplantation.

To assign causes of death after haplo-HSCT, appropriate sub-analysis was performed for this group. We have revealed, that among the patients, treated at the active stage of disease, compared to patients in CR at the moment of transplantation, a sufficient increase of 30-d mortality was observed, i.e., 47.6% vs 10.0% (р=0.002). The most frequent causes of death in early period after haplo-HSCT were: infection (75%, N=9), stroke (16.7%, N=2) and progression (8.3%, N=1).

Survival analysis in long-living haplo-HSCT patients

Due to sufficient early-mortality among haplo-HSCT patients, we performed a sub-analysis for the patients who survived >28 days after SCT. A trend for improvement of RFS results was retained (p=0.065), as well as OS data (p=0.067) when haplo-HSCT was carried out in remission of the disease, however, without statistical significance. The only factor which sufficiently influenced the results of haplo-HSCT in this group of patients was development of acute GVHD stage 3-4, causing a decrease of relapse-free survival, i.e. 0% in case of severe GVHD vs 53.1% in its absence (p=0.014), with similar effects on OS rates (severe GVHD 0% versus 54.8% in its absence (p=0.012)), as shown in Fig. 8.

Discussion

Proper choice for HLA-compatible donor is a prior task when performing allogeneic HSCT. Meanwhile, the aim of present study was to assess the results of haploidentical HSCT in AML patients and to compare them with outcomes of familial HLA-compatible HSCT. Due to low probability of finding HLA-compatible donors among siblings and in donor registries, the number of haploidentical HSCTs in our BMT Center was sufficiently increased and takes leading position at the present time.

When comparing time course of engraftment, we have observed high rates of primary graft failure, along with worse recovery of thrombocytopoiesis. This, however, provided an opportunity for repeated haplo-HSCT. Decreased rate of platelet reconstitution after HSCT may be connected with more pronounced immunological differences between patient and donor in haploidentical HSCT, as well as higher frequency of viral infections, e.g. cytomegalovirus. The results of survival analysis were comparable in the both groups. Therefore, our clinics now perform haplo-HSCT at broader basis, including the cases of relapse after MRD-HSCT.

ccording to our data, haplo-HSCT is associated with tendency for higher frequency of acute GVHD stage 2-4, thus being in agreement with other studies [8, 9]. Meanwhile, frequency of severe acute GVHD (stage 3-4) in these patients did not differ from MRD-HSCT. However, frequency of chronic GHVD tended to be higher in MRD-HSCT. It may be connected with usage of posttransplant cyclophosphamide HSCT group, and, therefore, more pronounced immune suppression achieved with this schedule.

Of interest, AML relapses were more common in the patients subjected to MRD-HSCT, despite myeloablative conditioning applied in most patients of this group. It could be attributed to potent antileukemic action of allo-HSCT (graft-versus-leukemia effect) which seems to be more pronounced with haploidentical transplant [10]. Moreover, one may note, that majority of the patients who underwent haplo-HSCT received prophylactic targeted chemotherapy with low-dose Azacitidine, if no contraindications existed. Meanwhile, less than 1/3 of the patients after MRD-HSCT received prophylactic therapy with Azacitidine +/- DLI only in cases of molecular relapse or evidence of active disease at the time of HSCT. Two patients in haploidentical and 2 patients in MRD groups received prophylactic donor lymphocyte infusions.

When evaluating overall survival, we did not see any difference between haploidentical and MRD-HSCT. Nonetheless, we saw certain features during posttransplant period in the both groups. We have revealed higher level of early mortality in the patients following haplo-HSCT on D+30 and D+100, with active malignant disease at HSCT, being among the main causes, increasing rate of early death post-transplant. Higher graft failure rates could also contribute to this early mortality. However, precise evaluation of engraftment was not feasible in these patients. Increased frequency of acute GVHD (grade 2-4) was also noted here.

Moreover, there are some data on longer reconstitution of immunity in haplo-HSCT [11]. Some workers suggest that it may lead to higher incidence of infectious complications, in particular, cytomegalovirus (CMV) reactivation [12]. Since all the patients with haplo-HSCT received non-myeloablative conditioning regimens, it seems that early mortality not to be associated with chemotherapeutic toxicity.

Active disease was associated with significantly poorer outcome after haplo-HSCT, being confirmed by the multifactorial analysis. The median survival in this group was only 25 days. The best results were obtained upon haploidentical HSCT performed in the 1st complete remission.

We have observed a sufficient proportion of the patients who deceased due to early (transplant-related) mortality within 1 month after transplantation. Meanwhile, the causes of death at later stages after transplantation significantly differ. A sub-analysis performed for the patients, who survived for >28 days post-HSCT, had shown, that OS in this long-living group was mainly influenced by acute GVHD (stage 3-4) whereas activity of primary disease prior to HSCT showed much lesser effect upon their survival.

Conclusion

1. Haploidentical HSCT is a plausible alternative for AML patients if HLA-compatible donor is not available.

2. Best results are obtained when haplo-HSCT is performed in the 1st complete remission.

3. Antileukemic effect of haplo-HSCT may be enhanced during posttransplant period by application of maintenance therapy with Azacitidine and donor lymphocyte infusions.

Conflict of interest

The authors report no conflicts of interest.

Acknowledgement

This study was financially supported by the Ministry of Science and Higher Education of the Russian Federation (Contract No. 075-15-2020-901).

References

1. Singh AK, McGuirk JP. Allogeneic Stem Cell Transplantation: A Historical and Scientific Overview. Cancer Res. 2016; 76(22):6445-6451. doi: 10.1158/0008-5472.CAN-16-1311
2. Tiercy JM. How to select the best available related or unrelated donor of hematopoietic stem cells? Haematologica. 2016; 101(6):680-687. doi: 10.3324/haematol.2015.141119
3. Afanasyev BV, Zubarovskaya LS, Borovkova AS, Kuzmich EV, Bykova TA, Deev RV,Isaev AA. Donor selection in allogeneic hematopoietic stem cell transplantation. Russian Journal of Pediatric Hematology and Oncology. 2016; 3(3):30-36 (In Russian). doi: 10.17650/2311-1267-2016-3-3-30-36
4. Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, Gooley TA, Piantadosi S, Kaup M, Ambinder RF, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008; 14(6):641-650. doi: 10.1016/j.bbmt.2008.03.005
5. Ciurea SO, Zhang MJ, Bacigalupo AA, Bashey A, Appelbaum FR, Aljitawi OS, Armand P, Antin JH, Chen J, Devine SM, Fowler DH, Luznik L, et al. Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia. Blood. 2015;126(8):1033-1040. doi: 10.1182/blood-2015-04-639831
6. Gu Z, Wang L, Yuan L, Huang W, Li M, Guan L, Wang Q, Gao Z, Zhao S, Luo L, et al. Similar outcomes after haploidentical transplantation with post-transplant cyclophosphamide versus HLA-matched transplantation: a meta-analysis of case-control studies. Oncotarget. 2017; 8(38):63574-63586. doi: 10.18632/oncotarget.18862
7. Passweg JR, Baldomero H, Bader P, Bonini C, Duarte RF, Dufour C, Gennery A, Kröger N, Kuball J, Lanza F, et al. Use of haploidentical stem cell transplantation continues to increase: the 2015 European Society for Blood and Marrow Transplant activity survey report. Bone Marrow Transplant. 2017; 52(6):811-817. doi: 10.1038/bmt.2017.34
8. Wang Y, Liu QF, Xu LP, Liu KY, Zhang XH, Ma X, Fan ZP, Wu DP, Huang XJ. Haploidentical vs identical-sibling transplant for AML in remission: a multicenter, prospective study. Blood. 2015; 125(25):396-62. doi: 10.1182/blood-2015-02-627786
9. Kunacheewa C. et al. Comparative efficacy and clinical outcomes of haploidentical stem cell transplantation to other stem sources for treatment in acute myeloid leukemia and myelodysplastic syndrome patients: a systematic review and meta-analysis. Cell transplantation. 2020; 29: 0963689720904965.
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12. Lin CH, Su YJ, Hsu CY, Wang PN, Teng CJ. Haploidentical allogeneic hematopoietic stem cell transplantation increases the risk of cytomegalovirus infection in adult patients with acute leukemia. Transpl Infect Dis. 2019; 21(4):e13096. doi: 10.1111/tid.13096

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В настоящем исследовании проведена оценка результатов 57 гаплоидентичных (гапло-ТКМ) и 21 совместимой родственной ТКМ (СР-ТКМ) у пациентов с острым миелоидным лейкозом. Целью нашей работы было сравнение клинической эффективности, частоты осложнений и исходов терапии у больных, трансплантированных от гаплоидентичных и HLA-совместимых родственных доноров. Частота первичного неприживления трансплантата была незначительно чаще при гапло-ТКМ (10,6% и 0%, р=0,31) и кумулятивная частота восстановления тромбоцитопоэза значимо ниже при гапло-ТКМ (65,2% и 100%, р=0,00013). При этом сроки восстановления гранулоцитопоэза и тромбоцитопоэза значимо не отличались. Час- тота острой РТПХ значимо не отличалась. При СР-ТКМ имелась тенденция к увеличению частоты хронической РТПХ (9,0% и 22,9%, p=0,07) и рецидива ОМЛ (40,7% и 16,6%, p=0,151). Результаты безрецидивной и общей выживаемости были сопоставимы при обоих видах ТКМ. Значимо ухудшало результаты проведение ТКМ на фоне прогрессии заболевания. 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Бадаев, Дарина Б. Заммоева, Диана В. Бабенецкая, Наталья А. Ильина, Анастасия И. Решетова, Лариса Л. Гиршова, Ирина Г. Будаева, Елена Н. Точеная, Раиса И. Вабищевич, Алексей В. Петров, Юлия А. Алексеева, Андрей Ю. Зарицкий, Дмитрий В. Моторин</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(446) "

Ренат Ш. Бадаев, Дарина Б. Заммоева, Диана В. Бабенецкая, Наталья А. Ильина, Анастасия И. Решетова, Лариса Л. Гиршова, Ирина Г. Будаева, Елена Н. Точеная, Раиса И. Вабищевич, Алексей В. Петров, Юлия А. Алексеева, Андрей Ю. Зарицкий, Дмитрий В. Моторин

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ФГБУ «Национальный медицинский исследовательский центр им. В. А. Алмазова, Санкт-Петербург, Россия

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27596" ["VALUE"]=> array(2) { ["TEXT"]=> string(3276) "<p style="text-align: justify;">Выбор гаплоидентичного донора является подходящей альтернативой в случае отсутствия HLA-совместимого сиблинга у пациентов с острым миелоидным лейкозом (ОМЛ). В настоящем исследовании проведена оценка результатов 57 гаплоидентичных (гапло-ТКМ) и 21 совместимой родственной ТКМ (СР-ТКМ) у пациентов с острым миелоидным лейкозом. Целью нашей работы было сравнение клинической эффективности, частоты осложнений и исходов терапии у больных, трансплантированных от гаплоидентичных и HLA-совместимых родственных доноров. Частота первичного неприживления трансплантата была незначительно чаще при гапло-ТКМ (10,6% и 0%, р=0,31) и кумулятивная частота восстановления тромбоцитопоэза значимо ниже при гапло-ТКМ (65,2% и 100%, р=0,00013). При этом сроки восстановления гранулоцитопоэза и тромбоцитопоэза значимо не отличались. Час- тота острой РТПХ значимо не отличалась. При СР-ТКМ имелась тенденция к увеличению частоты хронической РТПХ (9,0% и 22,9%, p=0,07) и рецидива ОМЛ (40,7% и 16,6%, p=0,151). Результаты безрецидивной и общей выживаемости были сопоставимы при обоих видах ТКМ. Значимо ухудшало результаты проведение ТКМ на фоне прогрессии заболевания. При гапло-ТКМ была значимо выше частота 30-дневной (р=0,001) и 100-дневной (р=0,011). В группе пациентов после гапло-ТКМ без ранней летальности, развитие острой РТПХ 3-4 ст. значимо ухудшало результаты. Таким образом, гаплоидентичная ТГСК является пригодной альтернативой для пациентов с ОМЛ при отсутствии HLA-совместимого родственного донора. В частности, лучшие результаты достигаются при гапло-ТГСК, выполненной в первой полной клинической ремиссии.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Острый миелоидный лейкоз, трансплантация гемопоэтических стволовых клеток, родственная, гаплоидентичный донор, HLA-совместимый донор.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3220) "

Выбор гаплоидентичного донора является подходящей альтернативой в случае отсутствия HLA-совместимого сиблинга у пациентов с острым миелоидным лейкозом (ОМЛ). В настоящем исследовании проведена оценка результатов 57 гаплоидентичных (гапло-ТКМ) и 21 совместимой родственной ТКМ (СР-ТКМ) у пациентов с острым миелоидным лейкозом. Целью нашей работы было сравнение клинической эффективности, частоты осложнений и исходов терапии у больных, трансплантированных от гаплоидентичных и HLA-совместимых родственных доноров. Частота первичного неприживления трансплантата была незначительно чаще при гапло-ТКМ (10,6% и 0%, р=0,31) и кумулятивная частота восстановления тромбоцитопоэза значимо ниже при гапло-ТКМ (65,2% и 100%, р=0,00013). При этом сроки восстановления гранулоцитопоэза и тромбоцитопоэза значимо не отличались. Час- тота острой РТПХ значимо не отличалась. При СР-ТКМ имелась тенденция к увеличению частоты хронической РТПХ (9,0% и 22,9%, p=0,07) и рецидива ОМЛ (40,7% и 16,6%, p=0,151). Результаты безрецидивной и общей выживаемости были сопоставимы при обоих видах ТКМ. Значимо ухудшало результаты проведение ТКМ на фоне прогрессии заболевания. При гапло-ТКМ была значимо выше частота 30-дневной (р=0,001) и 100-дневной (р=0,011). В группе пациентов после гапло-ТКМ без ранней летальности, развитие острой РТПХ 3-4 ст. значимо ухудшало результаты. Таким образом, гаплоидентичная ТГСК является пригодной альтернативой для пациентов с ОМЛ при отсутствии HLA-совместимого родственного донора. В частности, лучшие результаты достигаются при гапло-ТГСК, выполненной в первой полной клинической ремиссии.

Ключевые слова

Острый миелоидный лейкоз, трансплантация гемопоэтических стволовых клеток, родственная, гаплоидентичный донор, HLA-совместимый донор.

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Renat S. Badaev, Darina B. Zammoeva, Diana V. Babenetskaya, Natalia A. Il’ina, Anastasia I. Reshetova, Larisa L. Girshova, Irina G. Budaeva, Elena N. Tochenaya, Raisa I. Vabishchevich, Alexey V. Petrov, Yulia A. Alexeeva, Andrey Yu. Zaritskey, Dmitry V. Motorin

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V. A. Almazov National Medical Research Center, St. Petersburg, Russia

Correspondence
Dr. Dmitry V. Motorin, V. A. Almazov National Medical Research Center, 2 Akkuratova St, St. Petersburg, Russia
E-mail: dmotorin@mail.ru

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Haploidentical SCT is an appropriate alternative for patients with acute myeloid leukemia (AML) in absence of compatible familial donor. Results of 57 haplo-SCT and 21 matched related donor SCT of patients with AML were assessed in the present study. Our aim was to compare clinical efficiency, complication rates and outcomes in the patients transplanted from related haploidentical donors versus HLA-compatible related donors. The rate of graft failure proved to be higher in haplo-SCT (10.6% and 0%, р=0.31) and cumulative frequency of platelet recovery was much lesser in haplo-SCT group (65.2% and 100%, р=0.00013). However, the time before recovery of granulocytopoiesis and thrombocytopoiesis was similar. Frequencies of acute GVHD, RFS and OS were comparable. In MRD-HSCT group was tendency for higher rate of chronic GVHD (9.0% and 22.9%, p=0.07) and relapse (40.7% and 16.6%, p=0.15).

Active disease was the only factor with negative influence on results of SCT. Haplo-SCT was associated with higher rate of D+30 (р=0.001) and 100-d (р=0.011) mortality. In the group of patients after haplo-SCT without early mortality, GVHD grade 3-4 had negative influence on results of SCT. Hence, haploidentical HSCT is a plausible alternative for AML patients if HLA-compatible donor is not available. In particular, best results are obtained when haplo-HSCT is performed in the 1^st complete clinical remission.

Keywords

Acute myeloid leukemia, hematopoietic stem cell transplantation, related, haploidentical donor, HLA-compatible donor.

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["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27598" ["VALUE"]=> array(2) { ["TEXT"]=> string(283) "<p>Renat S. Badaev, Darina B. Zammoeva, Diana V. Babenetskaya, Natalia A. Il’ina, Anastasia I. Reshetova, Larisa L. Girshova, Irina G. Budaeva, Elena N. Tochenaya, Raisa I. Vabishchevich, Alexey V. Petrov, Yulia A. Alexeeva, Andrey Yu. Zaritskey, Dmitry V. Motorin</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(271) "

Renat S. Badaev, Darina B. Zammoeva, Diana V. Babenetskaya, Natalia A. Il’ina, Anastasia I. Reshetova, Larisa L. Girshova, Irina G. Budaeva, Elena N. Tochenaya, Raisa I. Vabishchevich, Alexey V. Petrov, Yulia A. Alexeeva, Andrey Yu. Zaritskey, Dmitry V. Motorin

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Renat S. Badaev, Darina B. Zammoeva, Diana V. Babenetskaya, Natalia A. Il’ina, Anastasia I. Reshetova, Larisa L. Girshova, Irina G. Budaeva, Elena N. Tochenaya, Raisa I. Vabishchevich, Alexey V. Petrov, Yulia A. Alexeeva, Andrey Yu. Zaritskey, Dmitry V. Motorin

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Haploidentical SCT is an appropriate alternative for patients with acute myeloid leukemia (AML) in absence of compatible familial donor. Results of 57 haplo-SCT and 21 matched related donor SCT of patients with AML were assessed in the present study. Our aim was to compare clinical efficiency, complication rates and outcomes in the patients transplanted from related haploidentical donors versus HLA-compatible related donors. The rate of graft failure proved to be higher in haplo-SCT (10.6% and 0%, р=0.31) and cumulative frequency of platelet recovery was much lesser in haplo-SCT group (65.2% and 100%, р=0.00013). However, the time before recovery of granulocytopoiesis and thrombocytopoiesis was similar. Frequencies of acute GVHD, RFS and OS were comparable. In MRD-HSCT group was tendency for higher rate of chronic GVHD (9.0% and 22.9%, p=0.07) and relapse (40.7% and 16.6%, p=0.15).

Active disease was the only factor with negative influence on results of SCT. Haplo-SCT was associated with higher rate of D+30 (р=0.001) and 100-d (р=0.011) mortality. In the group of patients after haplo-SCT without early mortality, GVHD grade 3-4 had negative influence on results of SCT. Hence, haploidentical HSCT is a plausible alternative for AML patients if HLA-compatible donor is not available. In particular, best results are obtained when haplo-HSCT is performed in the 1^st complete clinical remission.

Keywords

Acute myeloid leukemia, hematopoietic stem cell transplantation, related, haploidentical donor, HLA-compatible donor.

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Haploidentical SCT is an appropriate alternative for patients with acute myeloid leukemia (AML) in absence of compatible familial donor. Results of 57 haplo-SCT and 21 matched related donor SCT of patients with AML were assessed in the present study. Our aim was to compare clinical efficiency, complication rates and outcomes in the patients transplanted from related haploidentical donors versus HLA-compatible related donors. The rate of graft failure proved to be higher in haplo-SCT (10.6% and 0%, р=0.31) and cumulative frequency of platelet recovery was much lesser in haplo-SCT group (65.2% and 100%, р=0.00013). However, the time before recovery of granulocytopoiesis and thrombocytopoiesis was similar. Frequencies of acute GVHD, RFS and OS were comparable. In MRD-HSCT group was tendency for higher rate of chronic GVHD (9.0% and 22.9%, p=0.07) and relapse (40.7% and 16.6%, p=0.15).

Active disease was the only factor with negative influence on results of SCT. Haplo-SCT was associated with higher rate of D+30 (р=0.001) and 100-d (р=0.011) mortality. In the group of patients after haplo-SCT without early mortality, GVHD grade 3-4 had negative influence on results of SCT. Hence, haploidentical HSCT is a plausible alternative for AML patients if HLA-compatible donor is not available. In particular, best results are obtained when haplo-HSCT is performed in the 1^st complete clinical remission.

Keywords

Acute myeloid leukemia, hematopoietic stem cell transplantation, related, haploidentical donor, HLA-compatible donor.

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V. A. Almazov National Medical Research Center, St. Petersburg, Russia

Correspondence
Dr. Dmitry V. Motorin, V. A. Almazov National Medical Research Center, 2 Akkuratova St, St. Petersburg, Russia
E-mail: dmotorin@mail.ru

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V. A. Almazov National Medical Research Center, St. Petersburg, Russia

Correspondence
Dr. Dmitry V. Motorin, V. A. Almazov National Medical Research Center, 2 Akkuratova St, St. Petersburg, Russia
E-mail: dmotorin@mail.ru

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Ренат Ш. Бадаев, Дарина Б. Заммоева, Диана В. Бабенецкая, Наталья А. Ильина, Анастасия И. Решетова, Лариса Л. Гиршова, Ирина Г. Будаева, Елена Н. Точеная, Раиса И. Вабищевич, Алексей В. Петров, Юлия А. Алексеева, Андрей Ю. Зарицкий, Дмитрий В. Моторин

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В настоящем исследовании проведена оценка результатов 57 гаплоидентичных (гапло-ТКМ) и 21 совместимой родственной ТКМ (СР-ТКМ) у пациентов с острым миелоидным лейкозом. Целью нашей работы было сравнение клинической эффективности, частоты осложнений и исходов терапии у больных, трансплантированных от гаплоидентичных и HLA-совместимых родственных доноров. Частота первичного неприживления трансплантата была незначительно чаще при гапло-ТКМ (10,6% и 0%, р=0,31) и кумулятивная частота восстановления тромбоцитопоэза значимо ниже при гапло-ТКМ (65,2% и 100%, р=0,00013). При этом сроки восстановления гранулоцитопоэза и тромбоцитопоэза значимо не отличались. Час- тота острой РТПХ значимо не отличалась. При СР-ТКМ имелась тенденция к увеличению частоты хронической РТПХ (9,0% и 22,9%, p=0,07) и рецидива ОМЛ (40,7% и 16,6%, p=0,151). Результаты безрецидивной и общей выживаемости были сопоставимы при обоих видах ТКМ. Значимо ухудшало результаты проведение ТКМ на фоне прогрессии заболевания. При гапло-ТКМ была значимо выше частота 30-дневной (р=0,001) и 100-дневной (р=0,011). В группе пациентов после гапло-ТКМ без ранней летальности, развитие острой РТПХ 3-4 ст. значимо ухудшало результаты. Таким образом, гаплоидентичная ТГСК является пригодной альтернативой для пациентов с ОМЛ при отсутствии HLA-совместимого родственного донора. В частности, лучшие результаты достигаются при гапло-ТГСК, выполненной в первой полной клинической ремиссии.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Острый миелоидный лейкоз, трансплантация гемопоэтических стволовых клеток, родственная, гаплоидентичный донор, HLA-совместимый донор.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3220) "

Выбор гаплоидентичного донора является подходящей альтернативой в случае отсутствия HLA-совместимого сиблинга у пациентов с острым миелоидным лейкозом (ОМЛ). В настоящем исследовании проведена оценка результатов 57 гаплоидентичных (гапло-ТКМ) и 21 совместимой родственной ТКМ (СР-ТКМ) у пациентов с острым миелоидным лейкозом. Целью нашей работы было сравнение клинической эффективности, частоты осложнений и исходов терапии у больных, трансплантированных от гаплоидентичных и HLA-совместимых родственных доноров. Частота первичного неприживления трансплантата была незначительно чаще при гапло-ТКМ (10,6% и 0%, р=0,31) и кумулятивная частота восстановления тромбоцитопоэза значимо ниже при гапло-ТКМ (65,2% и 100%, р=0,00013). При этом сроки восстановления гранулоцитопоэза и тромбоцитопоэза значимо не отличались. Час- тота острой РТПХ значимо не отличалась. При СР-ТКМ имелась тенденция к увеличению частоты хронической РТПХ (9,0% и 22,9%, p=0,07) и рецидива ОМЛ (40,7% и 16,6%, p=0,151). Результаты безрецидивной и общей выживаемости были сопоставимы при обоих видах ТКМ. Значимо ухудшало результаты проведение ТКМ на фоне прогрессии заболевания. При гапло-ТКМ была значимо выше частота 30-дневной (р=0,001) и 100-дневной (р=0,011). В группе пациентов после гапло-ТКМ без ранней летальности, развитие острой РТПХ 3-4 ст. значимо ухудшало результаты. Таким образом, гаплоидентичная ТГСК является пригодной альтернативой для пациентов с ОМЛ при отсутствии HLA-совместимого родственного донора. В частности, лучшие результаты достигаются при гапло-ТГСК, выполненной в первой полной клинической ремиссии.

Ключевые слова

Острый миелоидный лейкоз, трансплантация гемопоэтических стволовых клеток, родственная, гаплоидентичный донор, HLA-совместимый донор.

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Выбор гаплоидентичного донора является подходящей альтернативой в случае отсутствия HLA-совместимого сиблинга у пациентов с острым миелоидным лейкозом (ОМЛ). В настоящем исследовании проведена оценка результатов 57 гаплоидентичных (гапло-ТКМ) и 21 совместимой родственной ТКМ (СР-ТКМ) у пациентов с острым миелоидным лейкозом. Целью нашей работы было сравнение клинической эффективности, частоты осложнений и исходов терапии у больных, трансплантированных от гаплоидентичных и HLA-совместимых родственных доноров. Частота первичного неприживления трансплантата была незначительно чаще при гапло-ТКМ (10,6% и 0%, р=0,31) и кумулятивная частота восстановления тромбоцитопоэза значимо ниже при гапло-ТКМ (65,2% и 100%, р=0,00013). При этом сроки восстановления гранулоцитопоэза и тромбоцитопоэза значимо не отличались. Час- тота острой РТПХ значимо не отличалась. При СР-ТКМ имелась тенденция к увеличению частоты хронической РТПХ (9,0% и 22,9%, p=0,07) и рецидива ОМЛ (40,7% и 16,6%, p=0,151). Результаты безрецидивной и общей выживаемости были сопоставимы при обоих видах ТКМ. Значимо ухудшало результаты проведение ТКМ на фоне прогрессии заболевания. При гапло-ТКМ была значимо выше частота 30-дневной (р=0,001) и 100-дневной (р=0,011). В группе пациентов после гапло-ТКМ без ранней летальности, развитие острой РТПХ 3-4 ст. значимо ухудшало результаты. Таким образом, гаплоидентичная ТГСК является пригодной альтернативой для пациентов с ОМЛ при отсутствии HLA-совместимого родственного донора. В частности, лучшие результаты достигаются при гапло-ТГСК, выполненной в первой полной клинической ремиссии.

Ключевые слова

Острый миелоидный лейкоз, трансплантация гемопоэтических стволовых клеток, родственная, гаплоидентичный донор, HLA-совместимый донор.

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ФГБУ «Национальный медицинский исследовательский центр им. В. А. Алмазова, Санкт-Петербург, Россия

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ФГБУ «Национальный медицинский исследовательский центр им. В. А. Алмазова, Санкт-Петербург, Россия

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	 Показано, что ряд основных биологических и цитогенетических характеристик лейкозных клеток при <i>EVI1</i>-позитивном (<i>EVI1<sup>+</sup></i>) остром миелобластном лейкозе (ОМЛ) различен у пациентов детского возраста и взрослых, как и их ответ на химиотерапию и трансплантацию гемопоэтических стволовых клеток (ТГСК). Таким образом, можно ожидать и различную патогенетическую роль лейкозных клеток-предшественников при данных вариантах ОМЛ. Нашей целью была проверка этой возможности, и мы количественно определяли экспрессию мРНК лейкозными клетками-предшественниками с применением недавно предложенной молекулярной модели оценки <i>ВAALC/WT1</i>. Уровни экспрессии генов <i>BAALC, WT1</i> и <i>EVI1</i> определяли параллельно в образцах костного мозга у 8 пациентов детского возраста и 6 взрослых с <i>EVI1<sup>+</sup></i> ОМЛ с помощью количественной ПЦР в реальном режиме времени (РТ-кПЦР) в конкретные сроки: а) при первичной диагностике, б) перед ТГСК и в) на фоне посттрансплантационного рецидива (ПТР). Подсчет бластных форм проводили в этих же образцах костного мозга. Наши результаты показали наличие гиперэкспрессии гена <i>BAALC </i>в обеих группах на всех этапах исследования. Гиперэкспрессия <i>BAALC</i> перед проведением ТГСК выявлялась у 6 из 14 пациентов, что может быть связано с реальными сложностями химиотерапии для последующей ТГСК в этой категории больных. Кроме того, поскольку гиперэкспрессия <i>BAALC </i>или <i>BAALC/WT1</i> была обнаружена у большинства пациентов с рецидивом после ТГСК, можно предполагать о ключевой роли <i>BAALC</i>-экспрессирующих предшественников в развитии рецидива.
</p>
<p style="text-align: justify;">
	 Надо отметить, что гиперэкспрессия <i>BAALC</i> не выявлялась во всех исследованных этапах при M3- и M7-вариантах ОМЛ, возможно, благодаря большему уровню дифференцировки соответствующих клеток-предшественников. В целом, определение <i>BAALC-</i> и <i>WT1</i>-экспрессирующих предшественников посредством РТ-кПЦР представляется перспективным подходом к исследованиям конкретных патогенетических механизмов при различных вариантах ОМЛ, а также при диагностике возникающих рецидивов и может быть весьма важным для клинической практики.
</p>
<h2>Ключевые слова</h2>
<p style="text-align: justify;">
	Острый миелобластный лейкоз, <i>EVI1</i>-позитивный, дети, взрослые, трансплантация гемопоэтических стволовых клеток, рецидивы, экспрессия <i>BAALC</i>, экспрессия <i>WT1</i>, экспрессия <i>EVI1</i>, предшественники лейкозных клеток, количественная ПЦР.
</p>
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	 Показано, что ряд основных биологических и цитогенетических характеристик лейкозных клеток при EVI1-позитивном (EVI1+) остром миелобластном лейкозе (ОМЛ) различен у пациентов детского возраста и взрослых, как и их ответ на химиотерапию и трансплантацию гемопоэтических стволовых клеток (ТГСК). Таким образом, можно ожидать и различную патогенетическую роль лейкозных клеток-предшественников при данных вариантах ОМЛ. Нашей целью была проверка этой возможности, и мы количественно определяли экспрессию мРНК лейкозными клетками-предшественниками с применением недавно предложенной молекулярной модели оценки ВAALC/WT1. Уровни экспрессии генов BAALC, WT1 и EVI1 определяли параллельно в образцах костного мозга у 8 пациентов детского возраста и 6 взрослых с EVI1+ ОМЛ с помощью количественной ПЦР в реальном режиме времени (РТ-кПЦР) в конкретные сроки: а) при первичной диагностике, б) перед ТГСК и в) на фоне посттрансплантационного рецидива (ПТР). Подсчет бластных форм проводили в этих же образцах костного мозга. Наши результаты показали наличие гиперэкспрессии гена BAALC в обеих группах на всех этапах исследования. Гиперэкспрессия BAALC перед проведением ТГСК выявлялась у 6 из 14 пациентов, что может быть связано с реальными сложностями химиотерапии для последующей ТГСК в этой категории больных. Кроме того, поскольку гиперэкспрессия BAALC или BAALC/WT1 была обнаружена у большинства пациентов с рецидивом после ТГСК, можно предполагать о ключевой роли BAALC-экспрессирующих предшественников в развитии рецидива.


	 Надо отметить, что гиперэкспрессия BAALC не выявлялась во всех исследованных этапах при M3- и M7-вариантах ОМЛ, возможно, благодаря большему уровню дифференцировки соответствующих клеток-предшественников. В целом, определение BAALC- и WT1-экспрессирующих предшественников посредством РТ-кПЦР представляется перспективным подходом к исследованиям конкретных патогенетических механизмов при различных вариантах ОМЛ, а также при диагностике возникающих рецидивов и может быть весьма важным для клинической практики.

Ключевые слова

	Острый миелобластный лейкоз, EVI1-позитивный, дети, взрослые, трансплантация гемопоэтических стволовых клеток, рецидивы, экспрессия BAALC, экспрессия WT1, экспрессия EVI1, предшественники лейкозных клеток, количественная ПЦР.

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Zhamal Z. Rakhmanova, Olesya V. Paina, Maria V. Latypova, Tatiana Yu. Gracheva, Ludmila S. Zubarovskaya</p>
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Nikolay N. Mamaev, Alyena I. Shakirova, Ildar M. Barkhatov, Mikhail M. Kanunnikov, Tatiana L. Gindina,
Zhamal Z. Rakhmanova, Olesya V. Paina, Maria V. Latypova, Tatiana Yu. Gracheva, Ludmila S. Zubarovskaya
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                    [TEXT] => <p>RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia</p><br>
<p><b>Correspondence</b><br>
Prof. Nikolay N. Mamaev, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, 12 Roentgen St, 197022, St. Petersburg, Russia<br>
Phone: +7 (911) 760 5086<br>
E-mail: nikmamaev524@gmail.com</p>
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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia


Correspondence

Prof. Nikolay N. Mamaev, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, 12 Roentgen St, 197022, St. Petersburg, Russia

Phone: +7 (911) 760 5086

E-mail: nikmamaev524@gmail.com
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	 Some basic biological and cytogenetic characteristics of leukemic cells in <i>EVI1</i>-positive (<i>EVI1<sup>+</sup></i>) acute myeloid leukemia (AML) are shown to be different for pediatric and adult patients, like as their response to chemotherapy and hematopoietic stem cell transplantation (HSCT). Hence, one may also expect different pathogenetic roles of leukemic precursors in these AML variants. Our aim was to check this opportunity, and we have quantitatively assessed mRNA expression by leukemic precursors using a recently proposed <i>BAALC/WT1</i> molecular panel. The levels of <i>BAALC, WT1</i> and <i>EVI1</i> gene expression were determined simultaneously in bone marrow samples from 8 pediatric and 6 adult patients with <i>EVI1<sup>+</sup></i> AML by means of quantitative real-time polymerase reaction (RT-qPCR) at specified time-points: a) upon primary diagnosis, b) prior to HSCT, and c) during post-transplant relapse (PTR). Blast cell counts were also provided for these bone marrow samples. Our study showed <i>BAALC </i>gene overexpression in both groups at all the tested stages. Before hematopoietic stem cell transplantation (HSCT) <i>BAALC </i>overexpression was revealed in 6 of 14 patients which could be associated with real difficulties for chemotherapy preparation for HSCT in this category of patients. Moreover, <i>BAALC</i>, or combined <i>BAALC/WT1</i> overexpression were revealed in most patients with posttransplant relapse (PTR), thus suggesting a crucial role of <i>BAALC</i>-expressing precursors for the emerging relapses. Worth of note, <i>BAALC</i> overexpression was absent at all the tested stages of M3 and M7 FAB-variants, probably, due to more mature nature of appropriate precursor cells. In general, determination of <i>BAALC</i>- and <i>WT1</i>-expressing precursors by means of RT-qPCR seems to be a promising approach to the studies of precise pathogenetic mechanisms in different AML variants, as well as to diagnostics of emerging relapses and, thus, it may be quite important for clinical practice.
</p>
<h2>
Keywords </h2>
<p style="text-align: justify;">
	 Acute myeloid leukemia, <i>EVI1</i>-positive, pediatric, adults, hematopoietic stem cell transplantation, relapses, <i>BAALC</i> expression, <i>WT1</i> expression, <i>EVI1</i> expression, leukemic cell precursors, quantitative PCR.
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	 Some basic biological and cytogenetic characteristics of leukemic cells in EVI1-positive (EVI1+) acute myeloid leukemia (AML) are shown to be different for pediatric and adult patients, like as their response to chemotherapy and hematopoietic stem cell transplantation (HSCT). Hence, one may also expect different pathogenetic roles of leukemic precursors in these AML variants. Our aim was to check this opportunity, and we have quantitatively assessed mRNA expression by leukemic precursors using a recently proposed BAALC/WT1 molecular panel. The levels of BAALC, WT1 and EVI1 gene expression were determined simultaneously in bone marrow samples from 8 pediatric and 6 adult patients with EVI1+ AML by means of quantitative real-time polymerase reaction (RT-qPCR) at specified time-points: a) upon primary diagnosis, b) prior to HSCT, and c) during post-transplant relapse (PTR). Blast cell counts were also provided for these bone marrow samples. Our study showed BAALC gene overexpression in both groups at all the tested stages. Before hematopoietic stem cell transplantation (HSCT) BAALC overexpression was revealed in 6 of 14 patients which could be associated with real difficulties for chemotherapy preparation for HSCT in this category of patients. Moreover, BAALC, or combined BAALC/WT1 overexpression were revealed in most patients with posttransplant relapse (PTR), thus suggesting a crucial role of BAALC-expressing precursors for the emerging relapses. Worth of note, BAALC overexpression was absent at all the tested stages of M3 and M7 FAB-variants, probably, due to more mature nature of appropriate precursor cells. In general, determination of BAALC- and WT1-expressing precursors by means of RT-qPCR seems to be a promising approach to the studies of precise pathogenetic mechanisms in different AML variants, as well as to diagnostics of emerging relapses and, thus, it may be quite important for clinical practice.


Keywords 

	 Acute myeloid leukemia, EVI1-positive, pediatric, adults, hematopoietic stem cell transplantation, relapses, BAALC expression, WT1 expression, EVI1 expression, leukemic cell precursors, quantitative PCR.

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<sup>2</sup> Санкт-Петербургский государственный университет, Клиника высоких медицинских технологий им. Н. И. Пирогова, <br>Санкт-Петербург, Россия<br>
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1 Национальный медико-хирургический центр им. Н. И. Пирогова Минздрава РФ, Москва, Россия

2 Санкт-Петербургский государственный университет, Клиника высоких медицинских технологий им. Н. И. Пирогова, 
Санкт-Петербург, Россия

3 Межнациональный центр исследования качества жизни, Санкт-Петербург, Россия
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                    [TEXT] => <p style="text-align: justify;">Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией гемопоэтических стволовых клеток (ВИСТ+ТГСК) – новый эффективный метод лечения рассеянного склероза (РС).
В данной публикации представлены результаты комплексной оценки клинической эффективности и оценок, данных пациентом, у больных с ремиттирующим вариантом течения РС до и в разные сроки после ВИСТ+ТГСК с использованием режимов кондиционирования сниженной интенсивности (две программы на основе BEAM и одна на основе циклофосфамида). В исследование включены 258 пациентов, средний возраст – 36,5 лет, мужчины/женщины – 71/185. Медиана индекса инвалидизации по шкале EDSS до трансплантации – 2,0 балла. Средняя длительность периода наблюдения составила 4,9 года. Для оценки клинической эффективности использовались динамика индекс EDSS и данные МРТ. Также проводился анализ безрецидивной выживаемости и выживаемости без прогрессирования заболевания. Для оценки качества жизни использовали общий опросник RAND SF-36 и опросник оценки симптомов CSP-MS-42. Процедура мобилизации и трансплантации хорошо переносилась больными. Безрецидивная выживаемость и выживаемость без прогрессирования заболевания составила 83% и 86%, соответственно, в течение 7 лет после ТГСК.</p>
<p style="text-align: justify;">В результате исследования не было выявлено различий в эффективности и токсичности при применении режимов кондиционирования сниженной интенсивности на основе BEAM с АТГ и циклофосфамида с ритуксимабом. После ТГСК отмечено значительное улучшение параметров качества жизни и снижение выраженности симптомов у подавляющего большинства пациентов. Таким образом, с помощью оценки клинического ответа и параметров качества жизни, продемонстрирована высокая эффективность и безопасность режимов кондиционирования сниженной интенсивности у пациентов с ремиттирующим РС.</p>
<h2>Ключевые слова</h2>
<p style="text-align: justify;">Аутологичная трансплантация гемопоэтических стволовых клеток, режим кондиционирования, рассеянный склероз, клинический ответ, качество
жизни. </p>
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Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией гемопоэтических стволовых клеток (ВИСТ+ТГСК) – новый эффективный метод лечения рассеянного склероза (РС).
В данной публикации представлены результаты комплексной оценки клинической эффективности и оценок, данных пациентом, у больных с ремиттирующим вариантом течения РС до и в разные сроки после ВИСТ+ТГСК с использованием режимов кондиционирования сниженной интенсивности (две программы на основе BEAM и одна на основе циклофосфамида). В исследование включены 258 пациентов, средний возраст – 36,5 лет, мужчины/женщины – 71/185. Медиана индекса инвалидизации по шкале EDSS до трансплантации – 2,0 балла. Средняя длительность периода наблюдения составила 4,9 года. Для оценки клинической эффективности использовались динамика индекс EDSS и данные МРТ. Также проводился анализ безрецидивной выживаемости и выживаемости без прогрессирования заболевания. Для оценки качества жизни использовали общий опросник RAND SF-36 и опросник оценки симптомов CSP-MS-42. Процедура мобилизации и трансплантации хорошо переносилась больными. Безрецидивная выживаемость и выживаемость без прогрессирования заболевания составила 83% и 86%, соответственно, в течение 7 лет после ТГСК.
В результате исследования не было выявлено различий в эффективности и токсичности при применении режимов кондиционирования сниженной интенсивности на основе BEAM с АТГ и циклофосфамида с ритуксимабом. После ТГСК отмечено значительное улучшение параметров качества жизни и снижение выраженности симптомов у подавляющего большинства пациентов. Таким образом, с помощью оценки клинического ответа и параметров качества жизни, продемонстрирована высокая эффективность и безопасность режимов кондиционирования сниженной интенсивности у пациентов с ремиттирующим РС.
Ключевые слова
Аутологичная трансплантация гемопоэтических стволовых клеток, режим кондиционирования, рассеянный склероз, клинический ответ, качество
жизни. 
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                    [TEXT] => <p>Vladimir Y. Melnichenko<sup>1</sup>, Denis A. Fedorenko<sup>1</sup>, Tatiana P. Nikitina<sup>2</sup>, Natalia M. Porfirieva<sup>3</sup>, Ilya S. Nikolaev<sup>1</sup>,
Tatiana I. Ionova<sup>2</sup></p>
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Vladimir Y. Melnichenko1, Denis A. Fedorenko1, Tatiana P. Nikitina2, Natalia M. Porfirieva3, Ilya S. Nikolaev1,
Tatiana I. Ionova2
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                    [TEXT] => <p><sup>1</sup> Pirogov National Medical and Surgical Center of The Ministry of Healthcare of Russian Federation, Moscow, Russia<br>
<sup>2</sup> Saint Petersburg State University Hospital, St. Petersburg, Russia<br> 
<sup>3</sup> Multinational Center for Quality of Life Research, St. Petersburg, Russia</p><br>
<p><b>Correspondence</b><br>
Professor Tatyana I. Ionova, Saint Petersburg State University Hospital, 154 Fontanka embankment, 190103,
St. Petersburg, Russia<br>
Phone: +7 (962) 710-17-11<br>
E-mail: tation16@gmail.com</p>
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1 Pirogov National Medical and Surgical Center of The Ministry of Healthcare of Russian Federation, Moscow, Russia

2 Saint Petersburg State University Hospital, St. Petersburg, Russia
 
3 Multinational Center for Quality of Life Research, St. Petersburg, Russia


Correspondence

Professor Tatyana I. Ionova, Saint Petersburg State University Hospital, 154 Fontanka embankment, 190103,
St. Petersburg, Russia

Phone: +7 (962) 710-17-11

E-mail: tation16@gmail.com
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                    [TEXT] => <p style="text-align: justify;">The effect of autologous hematopoietic stem cell transplantation (AHSCT) with low-intensity conditioning regimens, in terms of clinical and patient-reported outcomes, was studied in patients with relapsing-remitting multiple sclerosis (RRMS). In total, 258 RRMS patients were enrolled in a single-center study. The median follow-up duration was 30 months. Low-intensity conditioning regimens (two based on reduced BEAM and one on cyclophosphamide) were applied. Outcomes of AHSCT were evaluated from both the physicians’ and patients’ perspectives. Reversal of the disability progression, relapse-free survival (RFS), progression-free survival (PFS), as well as changes in quality of life (QoL), and severity of symptoms were analyzed. Transplantation procedure was well tolerated by the patients, and there were no cases of transplantation-related mortality. In addition, no deaths were registered throughout the follow-up period.</p>
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<h2>Keywords</h2>
<p style="text-align: justify;">Autologous hematopoietic stem cell transplantation, conditioning regimen, multiple sclerosis, clinical outcomes, quality of life.</p>
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The effect of autologous hematopoietic stem cell transplantation (AHSCT) with low-intensity conditioning regimens, in terms of clinical and patient-reported outcomes, was studied in patients with relapsing-remitting multiple sclerosis (RRMS). In total, 258 RRMS patients were enrolled in a single-center study. The median follow-up duration was 30 months. Low-intensity conditioning regimens (two based on reduced BEAM and one on cyclophosphamide) were applied. Outcomes of AHSCT were evaluated from both the physicians’ and patients’ perspectives. Reversal of the disability progression, relapse-free survival (RFS), progression-free survival (PFS), as well as changes in quality of life (QoL), and severity of symptoms were analyzed. Transplantation procedure was well tolerated by the patients, and there were no cases of transplantation-related mortality. In addition, no deaths were registered throughout the follow-up period.
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Keywords
Autologous hematopoietic stem cell transplantation, conditioning regimen, multiple sclerosis, clinical outcomes, quality of life.
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                    [TEXT] => <p style="text-align: justify;">Выбор гаплоидентичного донора является подходящей альтернативой в случае отсутствия HLA-совместимого сиблинга у пациентов с острым миелоидным лейкозом (ОМЛ). В настоящем исследовании проведена оценка результатов 57 гаплоидентичных (гапло-ТКМ) и 21 совместимой родственной ТКМ (СР-ТКМ) у пациентов с острым миелоидным лейкозом. Целью нашей работы было сравнение клинической эффективности, частоты осложнений и исходов терапии у больных, трансплантированных от гаплоидентичных и HLA-совместимых родственных доноров. Частота первичного неприживления трансплантата была незначительно чаще при гапло-ТКМ (10,6% и 0%, р=0,31) и кумулятивная частота восстановления тромбоцитопоэза значимо ниже при гапло-ТКМ (65,2% и 100%, р=0,00013). При этом сроки восстановления гранулоцитопоэза и тромбоцитопоэза значимо не отличались. Час-
тота острой РТПХ значимо не отличалась. При СР-ТКМ имелась тенденция к увеличению частоты
хронической РТПХ (9,0% и 22,9%, p=0,07) и рецидива ОМЛ (40,7% и 16,6%, p=0,151). Результаты безрецидивной и общей выживаемости были сопоставимы при обоих видах ТКМ. Значимо ухудшало результаты проведение ТКМ на фоне прогрессии заболевания. При гапло-ТКМ была значимо выше частота 30-дневной (р=0,001) и 100-дневной (р=0,011). В группе пациентов после гапло-ТКМ без ранней летальности, развитие острой РТПХ 3-4 ст. значимо ухудшало результаты. Таким образом, гаплоидентичная ТГСК является пригодной альтернативой для пациентов с ОМЛ при отсутствии HLA-совместимого родственного донора. В частности, лучшие результаты достигаются при гапло-ТГСК, выполненной в первой полной клинической ремиссии.</p>
<h2>Ключевые слова</h2>
<p style="text-align: justify;">Острый миелоидный лейкоз, трансплантация гемопоэтических стволовых клеток, родственная, гаплоидентичный донор, HLA-совместимый донор.</p>
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Выбор гаплоидентичного донора является подходящей альтернативой в случае отсутствия HLA-совместимого сиблинга у пациентов с острым миелоидным лейкозом (ОМЛ). В настоящем исследовании проведена оценка результатов 57 гаплоидентичных (гапло-ТКМ) и 21 совместимой родственной ТКМ (СР-ТКМ) у пациентов с острым миелоидным лейкозом. Целью нашей работы было сравнение клинической эффективности, частоты осложнений и исходов терапии у больных, трансплантированных от гаплоидентичных и HLA-совместимых родственных доноров. Частота первичного неприживления трансплантата была незначительно чаще при гапло-ТКМ (10,6% и 0%, р=0,31) и кумулятивная частота восстановления тромбоцитопоэза значимо ниже при гапло-ТКМ (65,2% и 100%, р=0,00013). При этом сроки восстановления гранулоцитопоэза и тромбоцитопоэза значимо не отличались. Час-
тота острой РТПХ значимо не отличалась. При СР-ТКМ имелась тенденция к увеличению частоты
хронической РТПХ (9,0% и 22,9%, p=0,07) и рецидива ОМЛ (40,7% и 16,6%, p=0,151). Результаты безрецидивной и общей выживаемости были сопоставимы при обоих видах ТКМ. Значимо ухудшало результаты проведение ТКМ на фоне прогрессии заболевания. При гапло-ТКМ была значимо выше частота 30-дневной (р=0,001) и 100-дневной (р=0,011). В группе пациентов после гапло-ТКМ без ранней летальности, развитие острой РТПХ 3-4 ст. значимо ухудшало результаты. Таким образом, гаплоидентичная ТГСК является пригодной альтернативой для пациентов с ОМЛ при отсутствии HLA-совместимого родственного донора. В частности, лучшие результаты достигаются при гапло-ТГСК, выполненной в первой полной клинической ремиссии.
Ключевые слова
Острый миелоидный лейкоз, трансплантация гемопоэтических стволовых клеток, родственная, гаплоидентичный донор, HLA-совместимый донор.
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                    [TEXT] => <p>Renat S. Badaev, Darina B. Zammoeva, Diana V. Babenetskaya, Natalia A. Il’ina, Anastasia I. Reshetova, Larisa L. Girshova, Irina G. Budaeva, Elena N. Tochenaya, Raisa I. Vabishchevich, Alexey V. Petrov, Yulia A. Alexeeva, Andrey Yu. Zaritskey,
Dmitry V. Motorin</p>
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Renat S. Badaev, Darina B. Zammoeva, Diana V. Babenetskaya, Natalia A. Il’ina, Anastasia I. Reshetova, Larisa L. Girshova, Irina G. Budaeva, Elena N. Tochenaya, Raisa I. Vabishchevich, Alexey V. Petrov, Yulia A. Alexeeva, Andrey Yu. Zaritskey,
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                    [TEXT] => <p>V. A. Almazov National Medical Research Center, St. Petersburg, Russia</p><br>
<p><b>Correspondence</b><br>
Dr. Dmitry V. Motorin, V. A. Almazov National Medical
Research Center, 2 Akkuratova St, St. Petersburg, Russia<br> E-mail: dmotorin@mail.ru</p>
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V. A. Almazov National Medical Research Center, St. Petersburg, Russia


Correspondence

Dr. Dmitry V. Motorin, V. A. Almazov National Medical
Research Center, 2 Akkuratova St, St. Petersburg, Russia
 E-mail: dmotorin@mail.ru
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                    [TEXT] => <p style="text-align: justify;">Haploidentical SCT is an appropriate alternative for patients with acute myeloid leukemia (AML) in absence of compatible familial donor. Results of 57 haplo-SCT and 21 matched related donor SCT of patients with AML were assessed in the present study. Our aim was to compare clinical efficiency, complication rates and outcomes in the patients transplanted from related haploidentical donors versus HLA-compatible related donors. The rate of graft failure proved to be higher in haplo-SCT (10.6% and 0%, р=0.31) and cumulative frequency of platelet recovery was much lesser in haplo-SCT group (65.2% and 100%, р=0.00013). However, the time before recovery of granulocytopoiesis and thrombocytopoiesis was similar. Frequencies of acute GVHD, RFS and OS were comparable. In MRD-HSCT group was tendency for higher rate of chronic GVHD (9.0% and 22.9%, p=0.07) and relapse (40.7% and 16.6%, p=0.15).</p>
<p style="text-align: justify;">Active disease was the only factor with negative influence on results of SCT. Haplo-SCT was associated with higher rate of D+30 (р=0.001) and 100-d (р=0.011) mortality. In the group of patients after haplo-SCT without early mortality, GVHD grade 3-4 had negative influence on results of SCT. Hence, haploidentical HSCT is a plausible alternative for AML patients if HLA-compatible donor is not available. In particular, best results are obtained when haplo-HSCT is performed in the 1<sup>st</sup> complete clinical remission. </p>
<h2>Keywords</h2>
<p style="text-align: justify;">Acute myeloid leukemia, hematopoietic stem cell transplantation, related, haploidentical donor, HLA-compatible donor.</p>
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Haploidentical SCT is an appropriate alternative for patients with acute myeloid leukemia (AML) in absence of compatible familial donor. Results of 57 haplo-SCT and 21 matched related donor SCT of patients with AML were assessed in the present study. Our aim was to compare clinical efficiency, complication rates and outcomes in the patients transplanted from related haploidentical donors versus HLA-compatible related donors. The rate of graft failure proved to be higher in haplo-SCT (10.6% and 0%, р=0.31) and cumulative frequency of platelet recovery was much lesser in haplo-SCT group (65.2% and 100%, р=0.00013). However, the time before recovery of granulocytopoiesis and thrombocytopoiesis was similar. Frequencies of acute GVHD, RFS and OS were comparable. In MRD-HSCT group was tendency for higher rate of chronic GVHD (9.0% and 22.9%, p=0.07) and relapse (40.7% and 16.6%, p=0.15).
Active disease was the only factor with negative influence on results of SCT. Haplo-SCT was associated with higher rate of D+30 (р=0.001) and 100-d (р=0.011) mortality. In the group of patients after haplo-SCT without early mortality, GVHD grade 3-4 had negative influence on results of SCT. Hence, haploidentical HSCT is a plausible alternative for AML patients if HLA-compatible donor is not available. In particular, best results are obtained when haplo-HSCT is performed in the 1st complete clinical remission. 
Keywords
Acute myeloid leukemia, hematopoietic stem cell transplantation, related, haploidentical donor, HLA-compatible donor.
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