ISSN 1866-8836
Клеточная терапия и трансплантация
Изменить отображение страницы на: только анонсы
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Since my 1st Raisa Gorbacheva Memorial Lecture 2 years ago things have changed in part whereas other things remain unchanged and appear more and more consistent.

Unchanged are the data from the numerous international multicenter trials published since 1981 covering both younger and older patients. The extract from these trials shows an increase of the mean complete remission rates between the 1980s and thereafter from 66% to 72% in younger and from 42 to 51% in older patients. Similarly, the rate of continuous complete remissions has increased over time from 17 to 34% in younger and 11 to 15% in older patients. During this period of time we also learnt about the effects of different treatment options. Thus, in our 1978 pilot study we made the observation that patients receiving any type of post-remission chemotherapy achieved some long-term remission rate, whereas patients not receiving post-remission chemotherapy all relapsed: mostly within the 1st year (Fig.1) [1].

Figure 1. Implementation of immunotherapeutic strategies into the treatment of high-risk childhood leukemia

CTT-2-5-2009-en-Buchner-Figure-1_small.PNG

Patients receiving post-remission consolidation and were randomized to receive prolonged maintenance chemotherapy showed a significantly longer relapse-free survival than those randomized to no further treatment [1]. A similar randomization between prolonged maintenance and high-dose AraC consolidation groups resulted again in a significantly superior relapse-free survival in the maintenance arm [2]. In the current AMLCG trial patients were randomized upfront between double induction with standard dose and high-dose (TAD–HAM) chemotherapy versus two courses of high-dose chemotherapy (HAM–HAM). This big difference did not translate into a difference in the overall survival or in the relapse rate of either younger or older patients [3]. The effect of autologous stem cell transplantation versus prolonged maintenance chemotherapy has also been investigated using upfront randomization. There was no difference in outcome neither by intention-to-treat nor by analysis as treated [3]. In an attempt to possibly enhance the anti-leukemic potential of chemotherapy, patients assigned by upfront randomization received G-CSF priming before and together with all chemotherapy courses during the first year. This modulation failed to change the outcome [4].

A large-scale comparison between different treatment strategies became possible through a network of 4 multicenter randomized AML trials in Germany (AML Intergroup). The different trials were connected with each other by a common standard treatment arm containing 10% of patients from each trial recruited via a general upfront randomization [5]. There were fundamental differences in the designs of the trials, which used chemotherapy of differing intensity, and different assignment to treatment alternatives either via a randomization process or according to risk factors (Fig.2), and also different preferences for allogeneic stem cell transplantation. Nevertheless, the long term overall survival in the 2784 patients under 60 years of age shows an almost identical 40–45% projected to 4 years (Fig. 3). A similar concordance is found in the relapse-free survival.

Figure 2. Study network of the German AML Intergroup: 4 independent and different AML trials are combined by the uniform standard arm and the general up-front randomization

CTT-2-5-2009-en-Buchner-Figure-2_small.PNG

Figure 3. Overall survival in the 4 trials and the standard arm: Update from the AML Intergroup

CTT-2-5-2009-en-Buchner-Figure-3_small.PNG

In a summary of the multiple international trials, the series of trials by the AML Cooperative Group, and finally the updates from the AML Intergroup, the anti-leukemic potential of chemotherapy as administered so far remains limited and may not be further improved by intensification. In contrast, the potential of chemotherapy appears to be exhausted.

The way forward might be more differentiated and distinctive. The direction is given by genetic classification of the individual AML. This is provided by the established chromosomal abnormalities that are found in only about half of the patients. More recently the other half exhibiting normal cytogenetics can be classified via gene mutations, the most prognostic of which are mutations of the NPM1 gene and internal tandem duplications of the FLT3 gene. Their combination allows identification of a rather favorable and a rather unfavorable prognostic group of patients [6]. In the meantime many different mutations and their combinations have been described with marked influences on the outcome, such as the CEBPαgene mutation. The mutations and combinations other than NPM1/FLT3 contribute prognostic factors for only small groups of patients. The vast majority of AML patients can be prognostically classified on the basis of 3 factors: Age (younger versus older than 60 years), abnormal karyotype favorable versus intermediate versus unfavorable, and normal karyotype with isolated NPM1 mutation versus FLT3- ITD (Fig. 4).

Figure 4. AML risk groups defined by age, karyotype, and NPM1/FLT3 mutation status

CTT-2-5-2009-en-Buchner-Figure-4_small.PNG

Now what about the role of allogeneic stem cell transplantation in AML? Allo SCT certainly represents a leading treatment option for AML. This becomes obvious when we look at the effect of allo SCT both from related and unrelated donors in patients carrying the most unfavorable genetic marker of a complex karyotype abnormality. And what about the general use of this option in the case of 1st complete remission? A large meta-analysis of European trials came to the result that patients younger than 35 with no favorable cytogenetics benefit from a superior relapse-free survival and even overall survival when analyzed on the basis of donor versus no-donor. Before we can accept this as a treatment of choice we should also ask for a similar donor versus no-donor analysis restricted to tissue-typed patients and siblings. This kind of analysis may be under way in the meantime. We must be aware that comparative studies on the effect of allo SCT in 1st remission are difficult and subject to bias. As a useful compromise our group prefers to compare patients who underwent allo SCT with chemotherapy patients who are pairwise comparable in major risk factors such as cytogenetics, age, de-novo/secondary AML, type of induction treatment and follow-up time. Using this matched pair analysis in 135 transplanted patients we see a highly significant superior relapse-free survival, whereas the overall survival is not significantly different as an effect of the substantial non-relapse mortality in the transplant group. More recently the transplant-related mortality may be overcome through the use of a reduced intensity conditioning such as TBI 8 instead of 12Gy together with fludarabine and ATG, resulting in a high plateau even for the overall survival, equally in the transplants from siblings and unrelated donors when transplanted in 1st or 2nd complete remission [7]. Gratwohl [8] has shown that in high numbers of European allo SCT patients the transplant-related mortality appears significantly decreased over time, also in AML. As mentioned before the benefit from allogeneic SCT may depend on the risk classification. As shown by the AMLSG, a benefit in the relapse-free survival seems to be restricted to patients with unfavorable gene mutations and not to be seen in patients with favorable mutations [9]. Mutations may even provide an algorithm for prioritized treatments. This algorithm includes FLT3 and NPM1 mutations and hyper-expressions of the BAALC gene [10]. We can also learn from the experiences of the pediatricians on risk-oriented allo SCT. I am grateful to my colleague Jörg Ritter for providing me with some data. The German BFM Group (Berlin, Frankfurt, Münster) restricted allo SCT to high-risk AML and available family donors. In their donor versus no-donor analysis there is some trend toward longer overall survival in the donor group, but this is not significant [11].

In summary of the conflicting data on allo SCT in AML we can conclude at the moment that there is good justification for allo SCT if a family donor is available, and that there is a clear indication for allo SCT even from an unrelated donor in adult high-risk AML. In an attempt to further define the role of allo SCT in AML we are about to start a strictly prospective multicenter trial where patients are randomized between allo SCT from related or unrelated donors in 1st remission versus after relapse. We strongly feel that this question can only be addressed in a randomized fashion.

Apart from allo SCT, novel targeted treatments will increasingly be integrated into the armamentarium against AML. Among a few examples, Rolf Mesters and his group [12] could demonstrate a complete response to a tyrosin kinase inhibitor with neutrophil and platelet recovery in a refractory AML. Alan Burnett and the MRC Group randomized their patients between chemotherapy alone or additional Gemtuzumab Ozogamicin (Mylotarg), and found a superior disease-free survival and reduced relapse rate in the Mylotarg group with no advantage so far in the overall survival. In the meantime there is a long list of targets and targeted agents (Table 1).

Table 1. Novel Approaches in AML

Targets Approach
GvL target Allo SCT (MRD, MUD)
RARA ATRA
PML Arsenic trioxide
BCR/ABL, c-kit Imatinib, Dasatinib, Nilotinib
FLT3 (wild type and mutated) Sorafenib, Midostaurin
Tyrosin Kinase SU5416
Farnesyl-Transferase Tipifarnib
DNA synthesis Clofarabine
Histone deacetylation (HDAC) Valproic acid
Hypermethylation (DNMT) 5-azacytidine, Decitabine
CD33 GO (Mylotarg)

The most popular ones are All Trans Retinoic Acid and Arsenic Trioxide, which have been successfully applied in APL; some inhibitors of FLT3 like Sorafenib and Midostaurin are being currently investigated in randomized trials [13], and agents like decitabine and 5-Azacytidine are targeting the hypermethylation of histone in AML [14]. The novel targeted agents are particularly indicated in older age AML per se representing an own risk factor across all AML subgroups [15]. In another year we should know a little more about the novel approaches in AML using allo SCT and targeted treatment. We will follow with great interest the further developments at the Raisa Gorbacheva Memorial Institute here in St. Petersburg.

References

1. Büchner T, Urbanitz D, Hiddemann W, et al. Intensified induction and consolidation with or without maintenence chemotherapy for acute myeloid leukemia (AML): two multicenter studies of the German AML Cooperatice Group. J Clin Oncol. 1985;3:1583-89.

2. Büchner T, Hiddemann W, Berdel WE, et al. 6-Thioguanine, cytarabine, and daunorubicin (TAD) and high-dose cytarabine and mitoxantrone (HAM) for induction, TAD for consolidation, and either prolonged maintenance by reduced monthly TAD or TAD-HAM-TAD and one course of intensive consolidation by sequential HAM in adult patients at all ages with de novo acute myeloid leukemia (AML): a randomized trial of the German AML Cooperative Group. J Clin Oncol. 2003;21:4496-504.

3. Büchner T, Berdel WE, Schoch C, et al. Double induction containing either two courses or one course of high-dose cytarabine plus mitoxantrone and postremission therapy by either autologous stem-cell transplantation or by prolonged maintenance for acute myeloid leukemia. J Clin Oncol. 2006;24:2480-9. doi: 10.1200/JCO.2005.04.5013.

4. Büchner T, Berdel WE. Priming with granulocyte colony-stimulating factor – relation to high-dose cytarabine in acute myeloid leukemia. N Engl J Med. 2004;350:2215-16.

5. Büchner T, Döhner H, Ehninger G, et al. Up-front randomization and common standard arm: a proposal for comparing AML treatment strategies between different studies. Leuk Res. 2002;26:1073-75.

6. Schnittger S, Schoch C, Kern W, et al. Nucleophosmin gene mutation are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood. 2005;106:3733-39. doi: 10.1182/blood-2005-06-2248.

7. Stelljes M, Bornhauser M, Kroger M, et al. Cooperative German Transplant Study Group. Conditioning with 8-Gy total body irradiation and fludarabine for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia. Blood. 2005;106:3314-21. doi:10.1182/blood-2005-04-1377.

8. Gratwohl A, personal communication.

9. Schlenk RF, Döhner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358:1909-18.

10. Mrózek K, Marcucci G, Paschka P, et al. Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? Blood. 2007;109:431-48. doi: 10.1182/blood-2006-06-001149.

11. Creutzig U, personal communication.

12. Mesters RM, Padró T, Bieker R, et al. Stable remission after administration of the receptor tyrosine kinase inhibitor SU5416 in a patient with refractory acute myeloid leukemia. Blood. 2001;98:241-3.

13. Kottaridis PD, Gale RE, Frew ME, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001;98:1752-9.

14. Lübbert M, Müller-Tidow C, Hofmann WK, Koeffler HP. Advances in the treatment of acute myeloid leukemia: from chromosomal aberrations to biologically targeted therapy. J Cell Biochem. 2008;104:2059-70.

15. Büchner T, Berdel WE, Haferlach C, et al. Age related risk profile and chemotherapy dose response in acute myeloid leukemia (AML). J Clin Oncol. 2009;27:61-9.

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Since my 1st Raisa Gorbacheva Memorial Lecture 2 years ago things have changed in part whereas other things remain unchanged and appear more and more consistent.

Unchanged are the data from the numerous international multicenter trials published since 1981 covering both younger and older patients. The extract from these trials shows an increase of the mean complete remission rates between the 1980s and thereafter from 66% to 72% in younger and from 42 to 51% in older patients. Similarly, the rate of continuous complete remissions has increased over time from 17 to 34% in younger and 11 to 15% in older patients. During this period of time we also learnt about the effects of different treatment options. Thus, in our 1978 pilot study we made the observation that patients receiving any type of post-remission chemotherapy achieved some long-term remission rate, whereas patients not receiving post-remission chemotherapy all relapsed: mostly within the 1st year (Fig.1) [1].

Figure 1. Implementation of immunotherapeutic strategies into the treatment of high-risk childhood leukemia

CTT-2-5-2009-en-Buchner-Figure-1_small.PNG

Patients receiving post-remission consolidation and were randomized to receive prolonged maintenance chemotherapy showed a significantly longer relapse-free survival than those randomized to no further treatment [1]. A similar randomization between prolonged maintenance and high-dose AraC consolidation groups resulted again in a significantly superior relapse-free survival in the maintenance arm [2]. In the current AMLCG trial patients were randomized upfront between double induction with standard dose and high-dose (TAD–HAM) chemotherapy versus two courses of high-dose chemotherapy (HAM–HAM). This big difference did not translate into a difference in the overall survival or in the relapse rate of either younger or older patients [3]. The effect of autologous stem cell transplantation versus prolonged maintenance chemotherapy has also been investigated using upfront randomization. There was no difference in outcome neither by intention-to-treat nor by analysis as treated [3]. In an attempt to possibly enhance the anti-leukemic potential of chemotherapy, patients assigned by upfront randomization received G-CSF priming before and together with all chemotherapy courses during the first year. This modulation failed to change the outcome [4].

A large-scale comparison between different treatment strategies became possible through a network of 4 multicenter randomized AML trials in Germany (AML Intergroup). The different trials were connected with each other by a common standard treatment arm containing 10% of patients from each trial recruited via a general upfront randomization [5]. There were fundamental differences in the designs of the trials, which used chemotherapy of differing intensity, and different assignment to treatment alternatives either via a randomization process or according to risk factors (Fig.2), and also different preferences for allogeneic stem cell transplantation. Nevertheless, the long term overall survival in the 2784 patients under 60 years of age shows an almost identical 40–45% projected to 4 years (Fig. 3). A similar concordance is found in the relapse-free survival.

Figure 2. Study network of the German AML Intergroup: 4 independent and different AML trials are combined by the uniform standard arm and the general up-front randomization

CTT-2-5-2009-en-Buchner-Figure-2_small.PNG

Figure 3. Overall survival in the 4 trials and the standard arm: Update from the AML Intergroup

CTT-2-5-2009-en-Buchner-Figure-3_small.PNG

In a summary of the multiple international trials, the series of trials by the AML Cooperative Group, and finally the updates from the AML Intergroup, the anti-leukemic potential of chemotherapy as administered so far remains limited and may not be further improved by intensification. In contrast, the potential of chemotherapy appears to be exhausted.

The way forward might be more differentiated and distinctive. The direction is given by genetic classification of the individual AML. This is provided by the established chromosomal abnormalities that are found in only about half of the patients. More recently the other half exhibiting normal cytogenetics can be classified via gene mutations, the most prognostic of which are mutations of the NPM1 gene and internal tandem duplications of the FLT3 gene. Their combination allows identification of a rather favorable and a rather unfavorable prognostic group of patients [6]. In the meantime many different mutations and their combinations have been described with marked influences on the outcome, such as the CEBPαgene mutation. The mutations and combinations other than NPM1/FLT3 contribute prognostic factors for only small groups of patients. The vast majority of AML patients can be prognostically classified on the basis of 3 factors: Age (younger versus older than 60 years), abnormal karyotype favorable versus intermediate versus unfavorable, and normal karyotype with isolated NPM1 mutation versus FLT3- ITD (Fig. 4).

Figure 4. AML risk groups defined by age, karyotype, and NPM1/FLT3 mutation status

CTT-2-5-2009-en-Buchner-Figure-4_small.PNG

Now what about the role of allogeneic stem cell transplantation in AML? Allo SCT certainly represents a leading treatment option for AML. This becomes obvious when we look at the effect of allo SCT both from related and unrelated donors in patients carrying the most unfavorable genetic marker of a complex karyotype abnormality. And what about the general use of this option in the case of 1st complete remission? A large meta-analysis of European trials came to the result that patients younger than 35 with no favorable cytogenetics benefit from a superior relapse-free survival and even overall survival when analyzed on the basis of donor versus no-donor. Before we can accept this as a treatment of choice we should also ask for a similar donor versus no-donor analysis restricted to tissue-typed patients and siblings. This kind of analysis may be under way in the meantime. We must be aware that comparative studies on the effect of allo SCT in 1st remission are difficult and subject to bias. As a useful compromise our group prefers to compare patients who underwent allo SCT with chemotherapy patients who are pairwise comparable in major risk factors such as cytogenetics, age, de-novo/secondary AML, type of induction treatment and follow-up time. Using this matched pair analysis in 135 transplanted patients we see a highly significant superior relapse-free survival, whereas the overall survival is not significantly different as an effect of the substantial non-relapse mortality in the transplant group. More recently the transplant-related mortality may be overcome through the use of a reduced intensity conditioning such as TBI 8 instead of 12Gy together with fludarabine and ATG, resulting in a high plateau even for the overall survival, equally in the transplants from siblings and unrelated donors when transplanted in 1st or 2nd complete remission [7]. Gratwohl [8] has shown that in high numbers of European allo SCT patients the transplant-related mortality appears significantly decreased over time, also in AML. As mentioned before the benefit from allogeneic SCT may depend on the risk classification. As shown by the AMLSG, a benefit in the relapse-free survival seems to be restricted to patients with unfavorable gene mutations and not to be seen in patients with favorable mutations [9]. Mutations may even provide an algorithm for prioritized treatments. This algorithm includes FLT3 and NPM1 mutations and hyper-expressions of the BAALC gene [10]. We can also learn from the experiences of the pediatricians on risk-oriented allo SCT. I am grateful to my colleague Jörg Ritter for providing me with some data. The German BFM Group (Berlin, Frankfurt, Münster) restricted allo SCT to high-risk AML and available family donors. In their donor versus no-donor analysis there is some trend toward longer overall survival in the donor group, but this is not significant [11].

In summary of the conflicting data on allo SCT in AML we can conclude at the moment that there is good justification for allo SCT if a family donor is available, and that there is a clear indication for allo SCT even from an unrelated donor in adult high-risk AML. In an attempt to further define the role of allo SCT in AML we are about to start a strictly prospective multicenter trial where patients are randomized between allo SCT from related or unrelated donors in 1st remission versus after relapse. We strongly feel that this question can only be addressed in a randomized fashion.

Apart from allo SCT, novel targeted treatments will increasingly be integrated into the armamentarium against AML. Among a few examples, Rolf Mesters and his group [12] could demonstrate a complete response to a tyrosin kinase inhibitor with neutrophil and platelet recovery in a refractory AML. Alan Burnett and the MRC Group randomized their patients between chemotherapy alone or additional Gemtuzumab Ozogamicin (Mylotarg), and found a superior disease-free survival and reduced relapse rate in the Mylotarg group with no advantage so far in the overall survival. In the meantime there is a long list of targets and targeted agents (Table 1).

Table 1. Novel Approaches in AML

Targets Approach
GvL target Allo SCT (MRD, MUD)
RARA ATRA
PML Arsenic trioxide
BCR/ABL, c-kit Imatinib, Dasatinib, Nilotinib
FLT3 (wild type and mutated) Sorafenib, Midostaurin
Tyrosin Kinase SU5416
Farnesyl-Transferase Tipifarnib
DNA synthesis Clofarabine
Histone deacetylation (HDAC) Valproic acid
Hypermethylation (DNMT) 5-azacytidine, Decitabine
CD33 GO (Mylotarg)

The most popular ones are All Trans Retinoic Acid and Arsenic Trioxide, which have been successfully applied in APL; some inhibitors of FLT3 like Sorafenib and Midostaurin are being currently investigated in randomized trials [13], and agents like decitabine and 5-Azacytidine are targeting the hypermethylation of histone in AML [14]. The novel targeted agents are particularly indicated in older age AML per se representing an own risk factor across all AML subgroups [15]. In another year we should know a little more about the novel approaches in AML using allo SCT and targeted treatment. We will follow with great interest the further developments at the Raisa Gorbacheva Memorial Institute here in St. Petersburg.

References

1. Büchner T, Urbanitz D, Hiddemann W, et al. Intensified induction and consolidation with or without maintenence chemotherapy for acute myeloid leukemia (AML): two multicenter studies of the German AML Cooperatice Group. J Clin Oncol. 1985;3:1583-89.

2. Büchner T, Hiddemann W, Berdel WE, et al. 6-Thioguanine, cytarabine, and daunorubicin (TAD) and high-dose cytarabine and mitoxantrone (HAM) for induction, TAD for consolidation, and either prolonged maintenance by reduced monthly TAD or TAD-HAM-TAD and one course of intensive consolidation by sequential HAM in adult patients at all ages with de novo acute myeloid leukemia (AML): a randomized trial of the German AML Cooperative Group. J Clin Oncol. 2003;21:4496-504.

3. Büchner T, Berdel WE, Schoch C, et al. Double induction containing either two courses or one course of high-dose cytarabine plus mitoxantrone and postremission therapy by either autologous stem-cell transplantation or by prolonged maintenance for acute myeloid leukemia. J Clin Oncol. 2006;24:2480-9. doi: 10.1200/JCO.2005.04.5013.

4. Büchner T, Berdel WE. Priming with granulocyte colony-stimulating factor – relation to high-dose cytarabine in acute myeloid leukemia. N Engl J Med. 2004;350:2215-16.

5. Büchner T, Döhner H, Ehninger G, et al. Up-front randomization and common standard arm: a proposal for comparing AML treatment strategies between different studies. Leuk Res. 2002;26:1073-75.

6. Schnittger S, Schoch C, Kern W, et al. Nucleophosmin gene mutation are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood. 2005;106:3733-39. doi: 10.1182/blood-2005-06-2248.

7. Stelljes M, Bornhauser M, Kroger M, et al. Cooperative German Transplant Study Group. Conditioning with 8-Gy total body irradiation and fludarabine for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia. Blood. 2005;106:3314-21. doi:10.1182/blood-2005-04-1377.

8. Gratwohl A, personal communication.

9. Schlenk RF, Döhner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358:1909-18.

10. Mrózek K, Marcucci G, Paschka P, et al. Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? Blood. 2007;109:431-48. doi: 10.1182/blood-2006-06-001149.

11. Creutzig U, personal communication.

12. Mesters RM, Padró T, Bieker R, et al. Stable remission after administration of the receptor tyrosine kinase inhibitor SU5416 in a patient with refractory acute myeloid leukemia. Blood. 2001;98:241-3.

13. Kottaridis PD, Gale RE, Frew ME, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001;98:1752-9.

14. Lübbert M, Müller-Tidow C, Hofmann WK, Koeffler HP. Advances in the treatment of acute myeloid leukemia: from chromosomal aberrations to biologically targeted therapy. J Cell Biochem. 2008;104:2059-70.

15. Büchner T, Berdel WE, Haferlach C, et al. Age related risk profile and chemotherapy dose response in acute myeloid leukemia (AML). J Clin Oncol. 2009;27:61-9.

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Сводка этих испытаний указывает на повышение средних уровней достижения полной ремиссии по сравнению с 80-ми годами, как у молодых, так и у старших больных. У больных после консолидирующего лечения, получающих поддерживающую терапию, выявлена значительно более длительная безрецидивная выживаемость, нежели в ситуациях без дальнейшего лечения. Аналогичное сравнение между длительной поддерживающей терапией и высокодозным лечением Ара-С также выявило значительно лучшую безрецидивную выживаемость в группе с поддерживающей терапией. В текущем испытании AMLCG проводили рандомизацию больных после двойной индукционной терапии с химиотерапией в стандартных и высоких дозах (TAD–HAM), по сравнению с двойной высокодозной химиотерапией (HAM–HAM). Не обнаружено различий по общей выживаемости или частоте рецидивов у молодых или старших больных. Стимуляция Г-КСФ до и во время химиотерапии, а также аутологичная трансплантация стволовых клеток, по сравнению с длительной поддерживающей химиотерапией не приводят к улучшению клинических исходов. Программа, состоящая из четырех мультицентрических рандомизированных исследований ОМЛ в Германии (AML Intergroup) показала, что несмотря на использование химиотерапии разной интенсивности и различные варианты лечения, долгосрочная и безрецидивная выживаемость среди 2784 больных младше 60 лет оказывается почти идентичной (40-45%) при 4-летнем наблюдении.<br /><br />Суммируя данные многочисленных международных испытаний, антилейкозный потенциал существующей химиотерапии не может быть далее улучшен за счет ее интенсификации. Обещающим подходом может быть генетическая классификация индивидуальных случаев ОМЛ. Описаны многочисленные мутации и их сочетания со выраженными воздействиями на исход, такие, как мутация гена CEBPα. Однако мутации и их сочетания, кроме NPM1/FLT3, являются значимыми прогностическими факторами только в малых группах больных. Подавляющее большинство больных ОМЛ может быть классифицировано с прогностических позиций на основе 3 факторов: возраста (менее и более 60 лет), аномальный кариотип (благоприятный, промежуточный или неблагоприятный) и нормальный кариотип с изолированной мутацией NPM1 или FLT3- ITD. В качестве полезного компромисса, наша группа предпочитает сравнивать больных с аллотрансплантацией стволовых клеток с больными после химиотерапии, сравнимых по основным факторам риска, таким, как цитогенетические данные, возраст, первичный или вторичный ОМЛ, тип индукционной терапии и сроки наблюдения. Смертность, ассоциированная с трансплантацией, может быть снижена за счет уменьшения интенсивности кондиционирования. <br /><br />В заключение можно сделать вывод о том, что алло-ТГСК хорошо обоснована для трансплантации от родственных доноров, и даже от неродственных доноров при ОМЛ высокого риска у взрослых. Необходимо строгое проспективное многоцентровое испытание для уточнения роли алло-ТГСК при ОМЛ. Кроме алло-ТГСК теперь применяются новые методы целевого лечения, таких, как ингибиторы тирозинкиназы, Миелотарг. Наиболее популярными из этого списка являются ATRA и триоксид мышьяка, успешно применяемые при остром промиелоцитарном лейкозе, некоторые  ингибиторы FLT3, как, например, Сорафениб и Мидостаурин, которые в настоящее время изучают в рандомизированных исследованиях, а также агенты, подобные децитабину и 5-азацитидину, направленные на гиперметилирование гистонов при ОМЛ. 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Томас Бюхнер

" ["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) "14242" ["VALUE"]=> array(2) { ["TEXT"]=> string(469) "<p class="bodytext"><b>Корреспонденция:</b> <br>Томас Бюхнер, профессор медицины и гематологии, Университет Мюнстера, Германия <br>E-mail: <a href="http://www.ctt-journal.com/http://javascript:linkTo_UnCryptMailto%28%27qempxs.fyiglrvDyrm1qyirwxiv2hi%27%29;" target="_blank">buechnr@uni-muenster.de</a> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(391) "

Корреспонденция:
Томас Бюхнер, профессор медицины и гематологии, Университет Мюнстера, Германия
E-mail: buechnr@uni-muenster.de

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Сводка этих испытаний указывает на повышение средних уровней достижения полной ремиссии по сравнению с 80-ми годами, как у молодых, так и у старших больных. У больных после консолидирующего лечения, получающих поддерживающую терапию, выявлена значительно более длительная безрецидивная выживаемость, нежели в ситуациях без дальнейшего лечения. Аналогичное сравнение между длительной поддерживающей терапией и высокодозным лечением Ара-С также выявило значительно лучшую безрецидивную выживаемость в группе с поддерживающей терапией. В текущем испытании AMLCG проводили рандомизацию больных после двойной индукционной терапии с химиотерапией в стандартных и высоких дозах (TAD–HAM), по сравнению с двойной высокодозной химиотерапией (HAM–HAM). Не обнаружено различий по общей выживаемости или частоте рецидивов у молодых или старших больных. Стимуляция Г-КСФ до и во время химиотерапии, а также аутологичная трансплантация стволовых клеток, по сравнению с длительной поддерживающей химиотерапией не приводят к улучшению клинических исходов. Программа, состоящая из четырех мультицентрических рандомизированных исследований ОМЛ в Германии (AML Intergroup) показала, что несмотря на использование химиотерапии разной интенсивности и различные варианты лечения, долгосрочная и безрецидивная выживаемость среди 2784 больных младше 60 лет оказывается почти идентичной (40-45%) при 4-летнем наблюдении.<br /><br />Суммируя данные многочисленных международных испытаний, антилейкозный потенциал существующей химиотерапии не может быть далее улучшен за счет ее интенсификации. Обещающим подходом может быть генетическая классификация индивидуальных случаев ОМЛ. Описаны многочисленные мутации и их сочетания со выраженными воздействиями на исход, такие, как мутация гена CEBPα. Однако мутации и их сочетания, кроме NPM1/FLT3, являются значимыми прогностическими факторами только в малых группах больных. Подавляющее большинство больных ОМЛ может быть классифицировано с прогностических позиций на основе 3 факторов: возраста (менее и более 60 лет), аномальный кариотип (благоприятный, промежуточный или неблагоприятный) и нормальный кариотип с изолированной мутацией NPM1 или FLT3- ITD. В качестве полезного компромисса, наша группа предпочитает сравнивать больных с аллотрансплантацией стволовых клеток с больными после химиотерапии, сравнимых по основным факторам риска, таким, как цитогенетические данные, возраст, первичный или вторичный ОМЛ, тип индукционной терапии и сроки наблюдения. Смертность, ассоциированная с трансплантацией, может быть снижена за счет уменьшения интенсивности кондиционирования. <br /><br />В заключение можно сделать вывод о том, что алло-ТГСК хорошо обоснована для трансплантации от родственных доноров, и даже от неродственных доноров при ОМЛ высокого риска у взрослых. Необходимо строгое проспективное многоцентровое испытание для уточнения роли алло-ТГСК при ОМЛ. Кроме алло-ТГСК теперь применяются новые методы целевого лечения, таких, как ингибиторы тирозинкиназы, Миелотарг. Наиболее популярными из этого списка являются ATRA и триоксид мышьяка, успешно применяемые при остром промиелоцитарном лейкозе, некоторые  ингибиторы FLT3, как, например, Сорафениб и Мидостаурин, которые в настоящее время изучают в рандомизированных исследованиях, а также агенты, подобные децитабину и 5-азацитидину, направленные на гиперметилирование гистонов при ОМЛ. Такие новые целевые агенты особенно показаны в старших возрастах.</p> <h3>Ключевые слова</h3> <p>острый миелобластный лейкоз, варианты лечения, эффективность, многоцентровые испытания</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(6750) "

Многочисленные международные многоцентровые исследования по лечению острого миелобластного лейкоза (ОМЛ) публикуются с 1981 г. Сводка этих испытаний указывает на повышение средних уровней достижения полной ремиссии по сравнению с 80-ми годами, как у молодых, так и у старших больных. У больных после консолидирующего лечения, получающих поддерживающую терапию, выявлена значительно более длительная безрецидивная выживаемость, нежели в ситуациях без дальнейшего лечения. Аналогичное сравнение между длительной поддерживающей терапией и высокодозным лечением Ара-С также выявило значительно лучшую безрецидивную выживаемость в группе с поддерживающей терапией. В текущем испытании AMLCG проводили рандомизацию больных после двойной индукционной терапии с химиотерапией в стандартных и высоких дозах (TAD–HAM), по сравнению с двойной высокодозной химиотерапией (HAM–HAM). Не обнаружено различий по общей выживаемости или частоте рецидивов у молодых или старших больных. Стимуляция Г-КСФ до и во время химиотерапии, а также аутологичная трансплантация стволовых клеток, по сравнению с длительной поддерживающей химиотерапией не приводят к улучшению клинических исходов. Программа, состоящая из четырех мультицентрических рандомизированных исследований ОМЛ в Германии (AML Intergroup) показала, что несмотря на использование химиотерапии разной интенсивности и различные варианты лечения, долгосрочная и безрецидивная выживаемость среди 2784 больных младше 60 лет оказывается почти идентичной (40-45%) при 4-летнем наблюдении.

Суммируя данные многочисленных международных испытаний, антилейкозный потенциал существующей химиотерапии не может быть далее улучшен за счет ее интенсификации. Обещающим подходом может быть генетическая классификация индивидуальных случаев ОМЛ. Описаны многочисленные мутации и их сочетания со выраженными воздействиями на исход, такие, как мутация гена CEBPα. Однако мутации и их сочетания, кроме NPM1/FLT3, являются значимыми прогностическими факторами только в малых группах больных. Подавляющее большинство больных ОМЛ может быть классифицировано с прогностических позиций на основе 3 факторов: возраста (менее и более 60 лет), аномальный кариотип (благоприятный, промежуточный или неблагоприятный) и нормальный кариотип с изолированной мутацией NPM1 или FLT3- ITD. В качестве полезного компромисса, наша группа предпочитает сравнивать больных с аллотрансплантацией стволовых клеток с больными после химиотерапии, сравнимых по основным факторам риска, таким, как цитогенетические данные, возраст, первичный или вторичный ОМЛ, тип индукционной терапии и сроки наблюдения. Смертность, ассоциированная с трансплантацией, может быть снижена за счет уменьшения интенсивности кондиционирования.

В заключение можно сделать вывод о том, что алло-ТГСК хорошо обоснована для трансплантации от родственных доноров, и даже от неродственных доноров при ОМЛ высокого риска у взрослых. Необходимо строгое проспективное многоцентровое испытание для уточнения роли алло-ТГСК при ОМЛ. Кроме алло-ТГСК теперь применяются новые методы целевого лечения, таких, как ингибиторы тирозинкиназы, Миелотарг. Наиболее популярными из этого списка являются ATRA и триоксид мышьяка, успешно применяемые при остром промиелоцитарном лейкозе, некоторые  ингибиторы FLT3, как, например, Сорафениб и Мидостаурин, которые в настоящее время изучают в рандомизированных исследованиях, а также агенты, подобные децитабину и 5-азацитидину, направленные на гиперметилирование гистонов при ОМЛ. Такие новые целевые агенты особенно показаны в старших возрастах.

Ключевые слова

острый миелобластный лейкоз, варианты лечения, эффективность, многоцентровые испытания

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Thomas Büchner

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Professor of Medicine and Hematology, University of Münster, Germany


Correspondence:
Thomas Büchner MD PhD, Professor of Medicine and Hematology, University of Münster, Germany
E-mail: buechnr@spam is baduni-muenster.de

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Thomas Büchner

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Thomas Büchner

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Professor of Medicine and Hematology, University of Münster, Germany


Correspondence:
Thomas Büchner MD PhD, Professor of Medicine and Hematology, University of Münster, Germany
E-mail: buechnr@spam is baduni-muenster.de

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Professor of Medicine and Hematology, University of Münster, Germany


Correspondence:
Thomas Büchner MD PhD, Professor of Medicine and Hematology, University of Münster, Germany
E-mail: buechnr@spam is baduni-muenster.de

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Томас Бюхнер

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Томас Бюхнер

" } ["SUMMARY_RU"]=> array(37) { ["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) "14243" ["VALUE"]=> array(2) { ["TEXT"]=> string(6820) "<p class="bodytext">Многочисленные международные многоцентровые исследования по лечению острого миелобластного лейкоза (ОМЛ) публикуются с 1981 г. Сводка этих испытаний указывает на повышение средних уровней достижения полной ремиссии по сравнению с 80-ми годами, как у молодых, так и у старших больных. У больных после консолидирующего лечения, получающих поддерживающую терапию, выявлена значительно более длительная безрецидивная выживаемость, нежели в ситуациях без дальнейшего лечения. Аналогичное сравнение между длительной поддерживающей терапией и высокодозным лечением Ара-С также выявило значительно лучшую безрецидивную выживаемость в группе с поддерживающей терапией. В текущем испытании AMLCG проводили рандомизацию больных после двойной индукционной терапии с химиотерапией в стандартных и высоких дозах (TAD–HAM), по сравнению с двойной высокодозной химиотерапией (HAM–HAM). Не обнаружено различий по общей выживаемости или частоте рецидивов у молодых или старших больных. Стимуляция Г-КСФ до и во время химиотерапии, а также аутологичная трансплантация стволовых клеток, по сравнению с длительной поддерживающей химиотерапией не приводят к улучшению клинических исходов. Программа, состоящая из четырех мультицентрических рандомизированных исследований ОМЛ в Германии (AML Intergroup) показала, что несмотря на использование химиотерапии разной интенсивности и различные варианты лечения, долгосрочная и безрецидивная выживаемость среди 2784 больных младше 60 лет оказывается почти идентичной (40-45%) при 4-летнем наблюдении.<br /><br />Суммируя данные многочисленных международных испытаний, антилейкозный потенциал существующей химиотерапии не может быть далее улучшен за счет ее интенсификации. Обещающим подходом может быть генетическая классификация индивидуальных случаев ОМЛ. Описаны многочисленные мутации и их сочетания со выраженными воздействиями на исход, такие, как мутация гена CEBPα. Однако мутации и их сочетания, кроме NPM1/FLT3, являются значимыми прогностическими факторами только в малых группах больных. Подавляющее большинство больных ОМЛ может быть классифицировано с прогностических позиций на основе 3 факторов: возраста (менее и более 60 лет), аномальный кариотип (благоприятный, промежуточный или неблагоприятный) и нормальный кариотип с изолированной мутацией NPM1 или FLT3- ITD. В качестве полезного компромисса, наша группа предпочитает сравнивать больных с аллотрансплантацией стволовых клеток с больными после химиотерапии, сравнимых по основным факторам риска, таким, как цитогенетические данные, возраст, первичный или вторичный ОМЛ, тип индукционной терапии и сроки наблюдения. Смертность, ассоциированная с трансплантацией, может быть снижена за счет уменьшения интенсивности кондиционирования. <br /><br />В заключение можно сделать вывод о том, что алло-ТГСК хорошо обоснована для трансплантации от родственных доноров, и даже от неродственных доноров при ОМЛ высокого риска у взрослых. Необходимо строгое проспективное многоцентровое испытание для уточнения роли алло-ТГСК при ОМЛ. Кроме алло-ТГСК теперь применяются новые методы целевого лечения, таких, как ингибиторы тирозинкиназы, Миелотарг. Наиболее популярными из этого списка являются ATRA и триоксид мышьяка, успешно применяемые при остром промиелоцитарном лейкозе, некоторые  ингибиторы FLT3, как, например, Сорафениб и Мидостаурин, которые в настоящее время изучают в рандомизированных исследованиях, а также агенты, подобные децитабину и 5-азацитидину, направленные на гиперметилирование гистонов при ОМЛ. Такие новые целевые агенты особенно показаны в старших возрастах.</p> <h3>Ключевые слова</h3> <p>острый миелобластный лейкоз, варианты лечения, эффективность, многоцентровые испытания</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(6750) "

Многочисленные международные многоцентровые исследования по лечению острого миелобластного лейкоза (ОМЛ) публикуются с 1981 г. Сводка этих испытаний указывает на повышение средних уровней достижения полной ремиссии по сравнению с 80-ми годами, как у молодых, так и у старших больных. У больных после консолидирующего лечения, получающих поддерживающую терапию, выявлена значительно более длительная безрецидивная выживаемость, нежели в ситуациях без дальнейшего лечения. Аналогичное сравнение между длительной поддерживающей терапией и высокодозным лечением Ара-С также выявило значительно лучшую безрецидивную выживаемость в группе с поддерживающей терапией. В текущем испытании AMLCG проводили рандомизацию больных после двойной индукционной терапии с химиотерапией в стандартных и высоких дозах (TAD–HAM), по сравнению с двойной высокодозной химиотерапией (HAM–HAM). Не обнаружено различий по общей выживаемости или частоте рецидивов у молодых или старших больных. Стимуляция Г-КСФ до и во время химиотерапии, а также аутологичная трансплантация стволовых клеток, по сравнению с длительной поддерживающей химиотерапией не приводят к улучшению клинических исходов. Программа, состоящая из четырех мультицентрических рандомизированных исследований ОМЛ в Германии (AML Intergroup) показала, что несмотря на использование химиотерапии разной интенсивности и различные варианты лечения, долгосрочная и безрецидивная выживаемость среди 2784 больных младше 60 лет оказывается почти идентичной (40-45%) при 4-летнем наблюдении.

Суммируя данные многочисленных международных испытаний, антилейкозный потенциал существующей химиотерапии не может быть далее улучшен за счет ее интенсификации. Обещающим подходом может быть генетическая классификация индивидуальных случаев ОМЛ. Описаны многочисленные мутации и их сочетания со выраженными воздействиями на исход, такие, как мутация гена CEBPα. Однако мутации и их сочетания, кроме NPM1/FLT3, являются значимыми прогностическими факторами только в малых группах больных. Подавляющее большинство больных ОМЛ может быть классифицировано с прогностических позиций на основе 3 факторов: возраста (менее и более 60 лет), аномальный кариотип (благоприятный, промежуточный или неблагоприятный) и нормальный кариотип с изолированной мутацией NPM1 или FLT3- ITD. В качестве полезного компромисса, наша группа предпочитает сравнивать больных с аллотрансплантацией стволовых клеток с больными после химиотерапии, сравнимых по основным факторам риска, таким, как цитогенетические данные, возраст, первичный или вторичный ОМЛ, тип индукционной терапии и сроки наблюдения. Смертность, ассоциированная с трансплантацией, может быть снижена за счет уменьшения интенсивности кондиционирования.

В заключение можно сделать вывод о том, что алло-ТГСК хорошо обоснована для трансплантации от родственных доноров, и даже от неродственных доноров при ОМЛ высокого риска у взрослых. Необходимо строгое проспективное многоцентровое испытание для уточнения роли алло-ТГСК при ОМЛ. Кроме алло-ТГСК теперь применяются новые методы целевого лечения, таких, как ингибиторы тирозинкиназы, Миелотарг. Наиболее популярными из этого списка являются ATRA и триоксид мышьяка, успешно применяемые при остром промиелоцитарном лейкозе, некоторые  ингибиторы FLT3, как, например, Сорафениб и Мидостаурин, которые в настоящее время изучают в рандомизированных исследованиях, а также агенты, подобные децитабину и 5-азацитидину, направленные на гиперметилирование гистонов при ОМЛ. Такие новые целевые агенты особенно показаны в старших возрастах.

Ключевые слова

острый миелобластный лейкоз, варианты лечения, эффективность, многоцентровые испытания

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Многочисленные международные многоцентровые исследования по лечению острого миелобластного лейкоза (ОМЛ) публикуются с 1981 г. Сводка этих испытаний указывает на повышение средних уровней достижения полной ремиссии по сравнению с 80-ми годами, как у молодых, так и у старших больных. У больных после консолидирующего лечения, получающих поддерживающую терапию, выявлена значительно более длительная безрецидивная выживаемость, нежели в ситуациях без дальнейшего лечения. Аналогичное сравнение между длительной поддерживающей терапией и высокодозным лечением Ара-С также выявило значительно лучшую безрецидивную выживаемость в группе с поддерживающей терапией. В текущем испытании AMLCG проводили рандомизацию больных после двойной индукционной терапии с химиотерапией в стандартных и высоких дозах (TAD–HAM), по сравнению с двойной высокодозной химиотерапией (HAM–HAM). Не обнаружено различий по общей выживаемости или частоте рецидивов у молодых или старших больных. Стимуляция Г-КСФ до и во время химиотерапии, а также аутологичная трансплантация стволовых клеток, по сравнению с длительной поддерживающей химиотерапией не приводят к улучшению клинических исходов. Программа, состоящая из четырех мультицентрических рандомизированных исследований ОМЛ в Германии (AML Intergroup) показала, что несмотря на использование химиотерапии разной интенсивности и различные варианты лечения, долгосрочная и безрецидивная выживаемость среди 2784 больных младше 60 лет оказывается почти идентичной (40-45%) при 4-летнем наблюдении.

Суммируя данные многочисленных международных испытаний, антилейкозный потенциал существующей химиотерапии не может быть далее улучшен за счет ее интенсификации. Обещающим подходом может быть генетическая классификация индивидуальных случаев ОМЛ. Описаны многочисленные мутации и их сочетания со выраженными воздействиями на исход, такие, как мутация гена CEBPα. Однако мутации и их сочетания, кроме NPM1/FLT3, являются значимыми прогностическими факторами только в малых группах больных. Подавляющее большинство больных ОМЛ может быть классифицировано с прогностических позиций на основе 3 факторов: возраста (менее и более 60 лет), аномальный кариотип (благоприятный, промежуточный или неблагоприятный) и нормальный кариотип с изолированной мутацией NPM1 или FLT3- ITD. В качестве полезного компромисса, наша группа предпочитает сравнивать больных с аллотрансплантацией стволовых клеток с больными после химиотерапии, сравнимых по основным факторам риска, таким, как цитогенетические данные, возраст, первичный или вторичный ОМЛ, тип индукционной терапии и сроки наблюдения. Смертность, ассоциированная с трансплантацией, может быть снижена за счет уменьшения интенсивности кондиционирования.

В заключение можно сделать вывод о том, что алло-ТГСК хорошо обоснована для трансплантации от родственных доноров, и даже от неродственных доноров при ОМЛ высокого риска у взрослых. Необходимо строгое проспективное многоцентровое испытание для уточнения роли алло-ТГСК при ОМЛ. Кроме алло-ТГСК теперь применяются новые методы целевого лечения, таких, как ингибиторы тирозинкиназы, Миелотарг. Наиболее популярными из этого списка являются ATRA и триоксид мышьяка, успешно применяемые при остром промиелоцитарном лейкозе, некоторые  ингибиторы FLT3, как, например, Сорафениб и Мидостаурин, которые в настоящее время изучают в рандомизированных исследованиях, а также агенты, подобные децитабину и 5-азацитидину, направленные на гиперметилирование гистонов при ОМЛ. Такие новые целевые агенты особенно показаны в старших возрастах.

Ключевые слова

острый миелобластный лейкоз, варианты лечения, эффективность, многоцентровые испытания

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Корреспонденция:
Томас Бюхнер, профессор медицины и гематологии, Университет Мюнстера, Германия
E-mail: buechnr@uni-muenster.de

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Корреспонденция:
Томас Бюхнер, профессор медицины и гематологии, Университет Мюнстера, Германия
E-mail: buechnr@uni-muenster.de

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Tapani Ruutu

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Division of Hematology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland


Correspondence
Tapani Ruutu, Division of Hematology, Department of Medicine, Helsinki University Central Hospital, PO Box 340, 00029 HUS, Helsinki, Finland
E-Mail:
tapani.ruutu@hus.fi

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Allogeneic stem cell transplantation is an efficient treatment of malignant hematological disorders but considerable morbidity and mortality limit its use. To reduce complications, conditioning regimens with reduced extramedullary toxicity compared to standard regimens – but with a strong cytotoxic effect on hematopoietic cells – can be used. The combination of treosulfan (14 g/m2 x 3) and fludarabine (30 mg/m2 x 5) is such a regimen. It has been used in clinical studies as well as in routine practice in patients too fragile to be given conventional conditioning. In a phase II study in MDS, 45 patients were transplanted using this conditioning. The median age was 50 (range 22–63) years. Of the donors 33% were related and 67% unrelated (MUD). The IPSS risk groups were 7% low, 44% Int-1, 31% Int-2, and 18% high. GVHD prophylaxis was CsA+MTX, and ATG in case of MUD. The graft was PBPC in 89% and BM in 11%. The median follow-up was 25 (range 12–41) months. The median times to neutrophil (> 0.5 x 109/l) and platelet (> 20 x 109/l) engraftment were 18 and 17 days. The cumulative incidence (CI) of complete donor chimerism was 73% on day +28 and 93% on day +100. The toxicity was very modest. The CI of gr II–IV aGVHD was 24% and that of gr III–IV 16%. The CI of cGVHD at 2 years was 59% and that of extensive cGVHD 28%. The CI of non–relapse mortality was 9% at 100 days and 17% at 2 years, and that of relapse/progression 16% at 2 years. The Kaplan-Meier estimates of OS and DFS at 2 years were 71% and 67%. These data confirm the favourable safety and efficacy of treosulfan-based conditioning in MDS. Because of the modest toxicity, allogeneic transplantation using treosulfan-based conditioning can be offered to many patients considered too fragile to receive conventional conditioning.

Keywords

allogeneic stem cell transplantation, reduced-toxicity conditioning, myelodysplastic syndrome, treosulfan, fludarabine

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Tapani Ruutu

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Tapani Ruutu

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Allogeneic stem cell transplantation is an efficient treatment of malignant hematological disorders but considerable morbidity and mortality limit its use. To reduce complications, conditioning regimens with reduced extramedullary toxicity compared to standard regimens – but with a strong cytotoxic effect on hematopoietic cells – can be used. The combination of treosulfan (14 g/m2 x 3) and fludarabine (30 mg/m2 x 5) is such a regimen. It has been used in clinical studies as well as in routine practice in patients too fragile to be given conventional conditioning. In a phase II study in MDS, 45 patients were transplanted using this conditioning. The median age was 50 (range 22–63) years. Of the donors 33% were related and 67% unrelated (MUD). The IPSS risk groups were 7% low, 44% Int-1, 31% Int-2, and 18% high. GVHD prophylaxis was CsA+MTX, and ATG in case of MUD. The graft was PBPC in 89% and BM in 11%. The median follow-up was 25 (range 12–41) months. The median times to neutrophil (> 0.5 x 109/l) and platelet (> 20 x 109/l) engraftment were 18 and 17 days. The cumulative incidence (CI) of complete donor chimerism was 73% on day +28 and 93% on day +100. The toxicity was very modest. The CI of gr II–IV aGVHD was 24% and that of gr III–IV 16%. The CI of cGVHD at 2 years was 59% and that of extensive cGVHD 28%. The CI of non–relapse mortality was 9% at 100 days and 17% at 2 years, and that of relapse/progression 16% at 2 years. The Kaplan-Meier estimates of OS and DFS at 2 years were 71% and 67%. These data confirm the favourable safety and efficacy of treosulfan-based conditioning in MDS. Because of the modest toxicity, allogeneic transplantation using treosulfan-based conditioning can be offered to many patients considered too fragile to receive conventional conditioning.

Keywords

allogeneic stem cell transplantation, reduced-toxicity conditioning, myelodysplastic syndrome, treosulfan, fludarabine

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Allogeneic stem cell transplantation is an efficient treatment of malignant hematological disorders but considerable morbidity and mortality limit its use. To reduce complications, conditioning regimens with reduced extramedullary toxicity compared to standard regimens – but with a strong cytotoxic effect on hematopoietic cells – can be used. The combination of treosulfan (14 g/m2 x 3) and fludarabine (30 mg/m2 x 5) is such a regimen. It has been used in clinical studies as well as in routine practice in patients too fragile to be given conventional conditioning. In a phase II study in MDS, 45 patients were transplanted using this conditioning. The median age was 50 (range 22–63) years. Of the donors 33% were related and 67% unrelated (MUD). The IPSS risk groups were 7% low, 44% Int-1, 31% Int-2, and 18% high. GVHD prophylaxis was CsA+MTX, and ATG in case of MUD. The graft was PBPC in 89% and BM in 11%. The median follow-up was 25 (range 12–41) months. The median times to neutrophil (> 0.5 x 109/l) and platelet (> 20 x 109/l) engraftment were 18 and 17 days. The cumulative incidence (CI) of complete donor chimerism was 73% on day +28 and 93% on day +100. The toxicity was very modest. The CI of gr II–IV aGVHD was 24% and that of gr III–IV 16%. The CI of cGVHD at 2 years was 59% and that of extensive cGVHD 28%. The CI of non–relapse mortality was 9% at 100 days and 17% at 2 years, and that of relapse/progression 16% at 2 years. The Kaplan-Meier estimates of OS and DFS at 2 years were 71% and 67%. These data confirm the favourable safety and efficacy of treosulfan-based conditioning in MDS. Because of the modest toxicity, allogeneic transplantation using treosulfan-based conditioning can be offered to many patients considered too fragile to receive conventional conditioning.

Keywords

allogeneic stem cell transplantation, reduced-toxicity conditioning, myelodysplastic syndrome, treosulfan, fludarabine

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Division of Hematology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland


Correspondence
Tapani Ruutu, Division of Hematology, Department of Medicine, Helsinki University Central Hospital, PO Box 340, 00029 HUS, Helsinki, Finland
E-Mail:
tapani.ruutu@hus.fi

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Division of Hematology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland


Correspondence
Tapani Ruutu, Division of Hematology, Department of Medicine, Helsinki University Central Hospital, PO Box 340, 00029 HUS, Helsinki, Finland
E-Mail:
tapani.ruutu@hus.fi

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"<p>Maria V. Pryanishnikova, Alexandra A. Sipol, Irina S. Solomonova, Ildar M. Barkhatov, Elena V. Semenova, Liudmila S. Zubarovskaya, Boris V. Afanasyev</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(156) "

Maria V. Pryanishnikova, Alexandra A. Sipol, Irina S. Solomonova, Ildar M. Barkhatov, Elena V. Semenova, Liudmila S. Zubarovskaya, Boris V. Afanasyev

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Memorial R.M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, St. Petersburg, Russia

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Introduction

For the last 20 years allo–HSCT has been one of the most effective treatments for different hematological malignancies. Hematopoietic chimerism analysis is an important method of monitoring the post-allo-HSCT outcome.

Patients and methods

In the study we included 142 patients with different hematological malignancies allografted between October 2002 and October 2008. The chimerism status was assessed by analyzing short tandem repeat polymorphisms.

Results

Overall survival in patients with complete donor chimerism on day +28 after allo-HSCT was 55% and 17% in patients with mixed chimerism or an absence of chimerism on the same day (p=0.0124). Similar results were observed by analyzing chimerism on day +60 following allo-HSCT. There were no significant differences in overall survival depending on chimerism value on day +28 and +60 in patients with myeloablative and nonmyeloablative conditioning regimen.

Of the patients with mixed chimerism or an absence of chimerism on day +28 after allo-HSCT, 67% had disease relapse, while 33% remained in remission (p=0.023).

Conclusions

Complete donor chimerism on day +28 and day +60 after allo-HSCT is associated with better prognosis. Mixed chimerism at day +28 after allo-HSCT is associated with an increased risk of relapse.

Keywords

chimerism, allo-HSCT, relapse, outcome

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Pryanishnikova, Alexandra A. Sipol, Irina S. Solomonova, Ildar M. Barkhatov, Elena V. Semenova, Liudmila S. Zubarovskaya, Boris V. Afanasyev</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(156) "

Maria V. Pryanishnikova, Alexandra A. Sipol, Irina S. Solomonova, Ildar M. Barkhatov, Elena V. Semenova, Liudmila S. Zubarovskaya, Boris V. Afanasyev

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Maria V. Pryanishnikova, Alexandra A. Sipol, Irina S. Solomonova, Ildar M. Barkhatov, Elena V. Semenova, Liudmila S. Zubarovskaya, Boris V. Afanasyev

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Introduction

For the last 20 years allo–HSCT has been one of the most effective treatments for different hematological malignancies. Hematopoietic chimerism analysis is an important method of monitoring the post-allo-HSCT outcome.

Patients and methods

In the study we included 142 patients with different hematological malignancies allografted between October 2002 and October 2008. The chimerism status was assessed by analyzing short tandem repeat polymorphisms.

Results

Overall survival in patients with complete donor chimerism on day +28 after allo-HSCT was 55% and 17% in patients with mixed chimerism or an absence of chimerism on the same day (p=0.0124). Similar results were observed by analyzing chimerism on day +60 following allo-HSCT. There were no significant differences in overall survival depending on chimerism value on day +28 and +60 in patients with myeloablative and nonmyeloablative conditioning regimen.

Of the patients with mixed chimerism or an absence of chimerism on day +28 after allo-HSCT, 67% had disease relapse, while 33% remained in remission (p=0.023).

Conclusions

Complete donor chimerism on day +28 and day +60 after allo-HSCT is associated with better prognosis. Mixed chimerism at day +28 after allo-HSCT is associated with an increased risk of relapse.

Keywords

chimerism, allo-HSCT, relapse, outcome

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Introduction

For the last 20 years allo–HSCT has been one of the most effective treatments for different hematological malignancies. Hematopoietic chimerism analysis is an important method of monitoring the post-allo-HSCT outcome.

Patients and methods

In the study we included 142 patients with different hematological malignancies allografted between October 2002 and October 2008. The chimerism status was assessed by analyzing short tandem repeat polymorphisms.

Results

Overall survival in patients with complete donor chimerism on day +28 after allo-HSCT was 55% and 17% in patients with mixed chimerism or an absence of chimerism on the same day (p=0.0124). Similar results were observed by analyzing chimerism on day +60 following allo-HSCT. There were no significant differences in overall survival depending on chimerism value on day +28 and +60 in patients with myeloablative and nonmyeloablative conditioning regimen.

Of the patients with mixed chimerism or an absence of chimerism on day +28 after allo-HSCT, 67% had disease relapse, while 33% remained in remission (p=0.023).

Conclusions

Complete donor chimerism on day +28 and day +60 after allo-HSCT is associated with better prognosis. Mixed chimerism at day +28 after allo-HSCT is associated with an increased risk of relapse.

Keywords

chimerism, allo-HSCT, relapse, outcome

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Memorial R.M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, St. Petersburg, Russia

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Memorial R.M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, St. Petersburg, Russia

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Stancheva, Elena V. Semenova, Natalia I. Zubarovskaya, Yulia G. Vasilieva, Vladimir V. Vavilоv, Irina A. Mushchitskaya, Ludmila S. Zubarovskaya, Boris V. Afanasyev</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(182) "

Natalia V. Stancheva, Elena V. Semenova, Natalia I. Zubarovskaya, Yulia G. Vasilieva, Vladimir V. Vavilоv, Irina A. Mushchitskaya, Ludmila S. Zubarovskaya, Boris V. Afanasyev

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Memorial R. M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University,
St. Petersburg, Russia


Correspondence
Memorial R. M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, 6/8, Tolstoy str., St. Petersburg, 199044, Russia
E-mail: n.stancheva@mail.ru

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Background

Allogeneic hematopoietic stem cell transplant (allo HSCT) is a curative approach for children with hematological malignancies but is associated with high treatment-related morbidity and mortality. A conditioning regimen (CR) with reduced toxicity is a potential option used in these cases. Treosulfan is an alkylating agent with high antileukemic, myeloablative activity and low toxicity. We compared the efficacy and toxicity of two conditioning regimens in allo HSCT: treosulfan (TREO)+cyclophosphamide (CY) (first group) and busulfan (BU) +CY (second group).

Patients and methods

The first group – with a follow-up from Feb. 2004 to Nov. 2007 – had 11 patients (pts): 6 boys and 5 girls; a median age of 9 y.o.; ALL – 10 pts and AML – 1 pt;  CR: TREO 30–42 g/m2 and CY 120mg/kg; HSC donors: 2 matched related donors (MRD) and 9 matched unrelated donor (MUD). The second group – with a follow-up from Nov 2000 to Nov 2006 – had 31 pts: 19 boys and 12 girls; a median age of 12 y.o.; AML – 7 pts, ALL – 24 pts; HSC donors: 11 MRD and 20 MUD; CR: BU 16 mg/kg and CY 120mg/kg. Prophylaxis for aGVHD: CsA+MTX. Unrelated allo-HSCT pts received ATG (“Pfizer”) 60 mg/kg.

Results

First vs second group: engraftment on day +17 vs +21, primary non-engraftment 0% vs 6% (p<0.05), hemorrhagic complication 18 vs 68% (p<0.05). Common toxicity criteria (CTC) II/IV: VOD 0% vs 3% (p<0.05), mucositis 18% vs 68% (p<0.05), neurology symptoms 9% vs 23% (p<0.05), hepatic toxicity 18% vs 26%. AGVHD III/IV 36% vs 20%, relapse 27% vs 29%. Three-year overall survival (OS) 37% vs 40%, respectively.

Conclusion

A treosulfan-based conditioning regimen is well tolerable, safe, efficient, and can be used in heavily-pretreated children with severe complications after previous chemotherapy; though in comparing the efficacy of both regimens, there are no differences. 

Keywords

allo HSCT, toxicity, efficacy, treosulfan, busulfan

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Stancheva, Elena V. Semenova, Natalia I. Zubarovskaya, Yulia G. Vasilieva, Vladimir V. Vavilоv, Irina A. Mushchitskaya, Ludmila S. Zubarovskaya, Boris V. Afanasyev</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(182) "

Natalia V. Stancheva, Elena V. Semenova, Natalia I. Zubarovskaya, Yulia G. Vasilieva, Vladimir V. Vavilоv, Irina A. Mushchitskaya, Ludmila S. Zubarovskaya, Boris V. Afanasyev

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Natalia V. Stancheva, Elena V. Semenova, Natalia I. Zubarovskaya, Yulia G. Vasilieva, Vladimir V. Vavilоv, Irina A. Mushchitskaya, Ludmila S. Zubarovskaya, Boris V. Afanasyev

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Background

Allogeneic hematopoietic stem cell transplant (allo HSCT) is a curative approach for children with hematological malignancies but is associated with high treatment-related morbidity and mortality. A conditioning regimen (CR) with reduced toxicity is a potential option used in these cases. Treosulfan is an alkylating agent with high antileukemic, myeloablative activity and low toxicity. We compared the efficacy and toxicity of two conditioning regimens in allo HSCT: treosulfan (TREO)+cyclophosphamide (CY) (first group) and busulfan (BU) +CY (second group).

Patients and methods

The first group – with a follow-up from Feb. 2004 to Nov. 2007 – had 11 patients (pts): 6 boys and 5 girls; a median age of 9 y.o.; ALL – 10 pts and AML – 1 pt;  CR: TREO 30–42 g/m2 and CY 120mg/kg; HSC donors: 2 matched related donors (MRD) and 9 matched unrelated donor (MUD). The second group – with a follow-up from Nov 2000 to Nov 2006 – had 31 pts: 19 boys and 12 girls; a median age of 12 y.o.; AML – 7 pts, ALL – 24 pts; HSC donors: 11 MRD and 20 MUD; CR: BU 16 mg/kg and CY 120mg/kg. Prophylaxis for aGVHD: CsA+MTX. Unrelated allo-HSCT pts received ATG (“Pfizer”) 60 mg/kg.

Results

First vs second group: engraftment on day +17 vs +21, primary non-engraftment 0% vs 6% (p<0.05), hemorrhagic complication 18 vs 68% (p<0.05). Common toxicity criteria (CTC) II/IV: VOD 0% vs 3% (p<0.05), mucositis 18% vs 68% (p<0.05), neurology symptoms 9% vs 23% (p<0.05), hepatic toxicity 18% vs 26%. AGVHD III/IV 36% vs 20%, relapse 27% vs 29%. Three-year overall survival (OS) 37% vs 40%, respectively.

Conclusion

A treosulfan-based conditioning regimen is well tolerable, safe, efficient, and can be used in heavily-pretreated children with severe complications after previous chemotherapy; though in comparing the efficacy of both regimens, there are no differences. 

Keywords

allo HSCT, toxicity, efficacy, treosulfan, busulfan

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Background

Allogeneic hematopoietic stem cell transplant (allo HSCT) is a curative approach for children with hematological malignancies but is associated with high treatment-related morbidity and mortality. A conditioning regimen (CR) with reduced toxicity is a potential option used in these cases. Treosulfan is an alkylating agent with high antileukemic, myeloablative activity and low toxicity. We compared the efficacy and toxicity of two conditioning regimens in allo HSCT: treosulfan (TREO)+cyclophosphamide (CY) (first group) and busulfan (BU) +CY (second group).

Patients and methods

The first group – with a follow-up from Feb. 2004 to Nov. 2007 – had 11 patients (pts): 6 boys and 5 girls; a median age of 9 y.o.; ALL – 10 pts and AML – 1 pt;  CR: TREO 30–42 g/m2 and CY 120mg/kg; HSC donors: 2 matched related donors (MRD) and 9 matched unrelated donor (MUD). The second group – with a follow-up from Nov 2000 to Nov 2006 – had 31 pts: 19 boys and 12 girls; a median age of 12 y.o.; AML – 7 pts, ALL – 24 pts; HSC donors: 11 MRD and 20 MUD; CR: BU 16 mg/kg and CY 120mg/kg. Prophylaxis for aGVHD: CsA+MTX. Unrelated allo-HSCT pts received ATG (“Pfizer”) 60 mg/kg.

Results

First vs second group: engraftment on day +17 vs +21, primary non-engraftment 0% vs 6% (p<0.05), hemorrhagic complication 18 vs 68% (p<0.05). Common toxicity criteria (CTC) II/IV: VOD 0% vs 3% (p<0.05), mucositis 18% vs 68% (p<0.05), neurology symptoms 9% vs 23% (p<0.05), hepatic toxicity 18% vs 26%. AGVHD III/IV 36% vs 20%, relapse 27% vs 29%. Three-year overall survival (OS) 37% vs 40%, respectively.

Conclusion

A treosulfan-based conditioning regimen is well tolerable, safe, efficient, and can be used in heavily-pretreated children with severe complications after previous chemotherapy; though in comparing the efficacy of both regimens, there are no differences. 

Keywords

allo HSCT, toxicity, efficacy, treosulfan, busulfan

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Correspondence
Memorial R. M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, 6/8, Tolstoy str., St. Petersburg, 199044, Russia
E-mail: n.stancheva@mail.ru

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Memorial R. M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University,
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Correspondence
Memorial R. M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, 6/8, Tolstoy str., St. Petersburg, 199044, Russia
E-mail: n.stancheva@mail.ru

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Jon-Magnus Tangen1, Jorg Axel Bohl2, Yngvar Floisand3, Einar Haukaas4, Inger Anne Naess5, Tove Skjelbakken6

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1Department of hematology, Ulleval University Hospital, Oslo, Norway; 2Hematology section, Haukeland University Hospital, Bergen, Norway; 3Hematology section, Rikshospitalet, Oslo, Norway; 4Department of onco-hematology, Stavanger University Hospital, Stavanger, Norway; 5Hematology section, St.Olav University Hospital, Trondheim, Norway; 6Hematology section, University Hospital of North Norway, Tromso, Norway

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In the period 1.1.2000–31.12.2007 129 patients with ALL under 66 years who received treatment with curative intent were registered in Norway (B-ALL 103 T-ALL 26). The median age was 38,6 years (15,6–65,9 years). The majority (110 patients) were treated with a common national protocol consisting of prednisone, vincristine, asparginase, doxorubicin and cyclophosphamide as induction. Consolidation was daunorubicin, cytarabine and  thioguanine, followed by methotrexate i.v. and mercaptopurine per os. Maintenance was prednisone, vincristine and doxorubicin i.v. followed by methotrexate and mercaptopurine per os, given as part of a 3 months cycle repeatedly for 3 ½ years. CNS prophylaxis consisted of i.t. injections of methotrexate. Patients with high risk ALL were elegible for allogenous stem cell transplantation in CR 1.

In all 82,9% reached CR. For patients < 40 years and for patients ≥ 40 years CR rates were 91,4% and 72,9%, respectively. Nine patients received SCT in CR 1 and 2 patients received SCT in CR 2. Five year overall survival was 48,6% (SD 43,0%–54,2%), for patients < 40 years 54,9% (SD 47,3%–62,5%) and for patients ≥40 years 34,9% (SD 26,1%–43,7%).

Keywords

acute lymphatic leukemia, chemotherapy, stem cell transplantation, remission frequency, overall survival

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Jon-Magnus Tangen1, Jorg Axel Bohl2, Yngvar Floisand3, Einar Haukaas4, Inger Anne Naess5, Tove Skjelbakken6

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In the period 1.1.2000–31.12.2007 129 patients with ALL under 66 years who received treatment with curative intent were registered in Norway (B-ALL 103 T-ALL 26). The median age was 38,6 years (15,6–65,9 years). The majority (110 patients) were treated with a common national protocol consisting of prednisone, vincristine, asparginase, doxorubicin and cyclophosphamide as induction. Consolidation was daunorubicin, cytarabine and  thioguanine, followed by methotrexate i.v. and mercaptopurine per os. Maintenance was prednisone, vincristine and doxorubicin i.v. followed by methotrexate and mercaptopurine per os, given as part of a 3 months cycle repeatedly for 3 ½ years. CNS prophylaxis consisted of i.t. injections of methotrexate. Patients with high risk ALL were elegible for allogenous stem cell transplantation in CR 1.

In all 82,9% reached CR. For patients < 40 years and for patients ≥ 40 years CR rates were 91,4% and 72,9%, respectively. Nine patients received SCT in CR 1 and 2 patients received SCT in CR 2. Five year overall survival was 48,6% (SD 43,0%–54,2%), for patients < 40 years 54,9% (SD 47,3%–62,5%) and for patients ≥40 years 34,9% (SD 26,1%–43,7%).

Keywords

acute lymphatic leukemia, chemotherapy, stem cell transplantation, remission frequency, overall survival

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In the period 1.1.2000–31.12.2007 129 patients with ALL under 66 years who received treatment with curative intent were registered in Norway (B-ALL 103 T-ALL 26). The median age was 38,6 years (15,6–65,9 years). The majority (110 patients) were treated with a common national protocol consisting of prednisone, vincristine, asparginase, doxorubicin and cyclophosphamide as induction. Consolidation was daunorubicin, cytarabine and  thioguanine, followed by methotrexate i.v. and mercaptopurine per os. Maintenance was prednisone, vincristine and doxorubicin i.v. followed by methotrexate and mercaptopurine per os, given as part of a 3 months cycle repeatedly for 3 ½ years. CNS prophylaxis consisted of i.t. injections of methotrexate. Patients with high risk ALL were elegible for allogenous stem cell transplantation in CR 1.

In all 82,9% reached CR. For patients < 40 years and for patients ≥ 40 years CR rates were 91,4% and 72,9%, respectively. Nine patients received SCT in CR 1 and 2 patients received SCT in CR 2. Five year overall survival was 48,6% (SD 43,0%–54,2%), for patients < 40 years 54,9% (SD 47,3%–62,5%) and for patients ≥40 years 34,9% (SD 26,1%–43,7%).

Keywords

acute lymphatic leukemia, chemotherapy, stem cell transplantation, remission frequency, overall survival

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1Department of hematology, Ulleval University Hospital, Oslo, Norway; 2Hematology section, Haukeland University Hospital, Bergen, Norway; 3Hematology section, Rikshospitalet, Oslo, Norway; 4Department of onco-hematology, Stavanger University Hospital, Stavanger, Norway; 5Hematology section, St.Olav University Hospital, Trondheim, Norway; 6Hematology section, University Hospital of North Norway, Tromso, Norway

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1Department of hematology, Ulleval University Hospital, Oslo, Norway; 2Hematology section, Haukeland University Hospital, Bergen, Norway; 3Hematology section, Rikshospitalet, Oslo, Norway; 4Department of onco-hematology, Stavanger University Hospital, Stavanger, Norway; 5Hematology section, St.Olav University Hospital, Trondheim, Norway; 6Hematology section, University Hospital of North Norway, Tromso, Norway

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Zalyalov, Abdulbasir A. Ganapiev, Boris V. Afanasyev</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(67) "

Yury R. Zalyalov, Abdulbasir A. Ganapiev, Boris V. Afanasyev

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Memorial R. M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University,
St. Petersburg, Russia


Correspondence
Memorial R. M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, 6/8, Tolstoy str., St. Petersburg, 199044, Russia
E-mail: yz21@mail.ru

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Allogeneic stem cell transplantation (allo-SCT) is an important therapeutical approach for patients with different malignant and non–malignant disorders. However, the failure to find a proper donor match for all recipients restricts the procedure in most cases due to higher graft-versus-host disease (GVHD) rates. Currently, reports comparing the clinical efficacy of different antithymocyte globulin (ATG) brands regarding their post–transplant prophylaxis value after allo-SCT from HLA-mismatched donors are limited. In this report we have evaluated the outcomes of 24 patients with different hematological malignancies who underwent unrelated SCTs during a period from 2005 to 2008.

The patients’ median age was 15 years (range, 1–48). All transplants had been performed with unrelated grafts carrying one or more mismatches in HLA-А, -В, -С, -DRB1, -DQB1 loci. The post–transplant prophylactic regimens were based on a combination of either cyclosporine A with methotrexate or CellCept with tacrolimus. All transplanted patients received peripheral blood stem cells as stem cell source. The median CD34+ cell dose was 6.6 х106/kg bw (range, 1–18). Myeloablative and nonmyeloablative preparative conditioning had been used in 37% and 63% of all transplants, respectively. Depending on the brand of ATG being used, all patients were subdivided in two groups. The first group (n=7) received thymoglobulin (cum. dose 7.5 mg/kg), while the second group (n=17) ATGAM (cum. dose 60 mg/kg). Both groups were comparable concerning the sex and AB0–blood group mismatch between donor and recipient. 

Neutrophil engraftment rates were similar in both groups: day +15 (range, 13–25) in the thymoglobulin group and day +16 (range, 11–22) in the ATGAM group. All the patients had been successfully engrafted. The trend towards lower acute GVHD II–IV rate had been more noticeably observed in the thymoglobulin group compared to the ATGAM group (28% vs. 70%; p=0.06). The risk of extensive chronic GVHD was also lower in the thymoglobulin group (28% vs. 78%; p=0.05). Overall survival for 1 year (71% vs. 47%; p=0.6) and 1-year TRM (15% vs. 48%; p=0.2) seemed to be better in patients who received thymoglobulin.

In conclusion, our study suggests that the use of thymoglobulin as a post–transplant prophylaxis could be associated with lower acute and/or chronic GVHD rates as well as with better outcomes in recipients of allo-SCT from mismatched unrelated donors as compared to ATGAM.

Keywords

GVHD, thymoglobulin, ATGAM, allo-SCT

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Yury R. Zalyalov, Abdulbasir A. Ganapiev, Boris V. Afanasyev

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Allogeneic stem cell transplantation (allo-SCT) is an important therapeutical approach for patients with different malignant and non–malignant disorders. However, the failure to find a proper donor match for all recipients restricts the procedure in most cases due to higher graft-versus-host disease (GVHD) rates. Currently, reports comparing the clinical efficacy of different antithymocyte globulin (ATG) brands regarding their post–transplant prophylaxis value after allo-SCT from HLA-mismatched donors are limited. In this report we have evaluated the outcomes of 24 patients with different hematological malignancies who underwent unrelated SCTs during a period from 2005 to 2008.

The patients’ median age was 15 years (range, 1–48). All transplants had been performed with unrelated grafts carrying one or more mismatches in HLA-А, -В, -С, -DRB1, -DQB1 loci. The post–transplant prophylactic regimens were based on a combination of either cyclosporine A with methotrexate or CellCept with tacrolimus. All transplanted patients received peripheral blood stem cells as stem cell source. The median CD34+ cell dose was 6.6 х106/kg bw (range, 1–18). Myeloablative and nonmyeloablative preparative conditioning had been used in 37% and 63% of all transplants, respectively. Depending on the brand of ATG being used, all patients were subdivided in two groups. The first group (n=7) received thymoglobulin (cum. dose 7.5 mg/kg), while the second group (n=17) ATGAM (cum. dose 60 mg/kg). Both groups were comparable concerning the sex and AB0–blood group mismatch between donor and recipient. 

Neutrophil engraftment rates were similar in both groups: day +15 (range, 13–25) in the thymoglobulin group and day +16 (range, 11–22) in the ATGAM group. All the patients had been successfully engrafted. The trend towards lower acute GVHD II–IV rate had been more noticeably observed in the thymoglobulin group compared to the ATGAM group (28% vs. 70%; p=0.06). The risk of extensive chronic GVHD was also lower in the thymoglobulin group (28% vs. 78%; p=0.05). Overall survival for 1 year (71% vs. 47%; p=0.6) and 1-year TRM (15% vs. 48%; p=0.2) seemed to be better in patients who received thymoglobulin.

In conclusion, our study suggests that the use of thymoglobulin as a post–transplant prophylaxis could be associated with lower acute and/or chronic GVHD rates as well as with better outcomes in recipients of allo-SCT from mismatched unrelated donors as compared to ATGAM.

Keywords

GVHD, thymoglobulin, ATGAM, allo-SCT

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Allogeneic stem cell transplantation (allo-SCT) is an important therapeutical approach for patients with different malignant and non–malignant disorders. However, the failure to find a proper donor match for all recipients restricts the procedure in most cases due to higher graft-versus-host disease (GVHD) rates. Currently, reports comparing the clinical efficacy of different antithymocyte globulin (ATG) brands regarding their post–transplant prophylaxis value after allo-SCT from HLA-mismatched donors are limited. In this report we have evaluated the outcomes of 24 patients with different hematological malignancies who underwent unrelated SCTs during a period from 2005 to 2008.

The patients’ median age was 15 years (range, 1–48). All transplants had been performed with unrelated grafts carrying one or more mismatches in HLA-А, -В, -С, -DRB1, -DQB1 loci. The post–transplant prophylactic regimens were based on a combination of either cyclosporine A with methotrexate or CellCept with tacrolimus. All transplanted patients received peripheral blood stem cells as stem cell source. The median CD34+ cell dose was 6.6 х106/kg bw (range, 1–18). Myeloablative and nonmyeloablative preparative conditioning had been used in 37% and 63% of all transplants, respectively. Depending on the brand of ATG being used, all patients were subdivided in two groups. The first group (n=7) received thymoglobulin (cum. dose 7.5 mg/kg), while the second group (n=17) ATGAM (cum. dose 60 mg/kg). Both groups were comparable concerning the sex and AB0–blood group mismatch between donor and recipient. 

Neutrophil engraftment rates were similar in both groups: day +15 (range, 13–25) in the thymoglobulin group and day +16 (range, 11–22) in the ATGAM group. All the patients had been successfully engrafted. The trend towards lower acute GVHD II–IV rate had been more noticeably observed in the thymoglobulin group compared to the ATGAM group (28% vs. 70%; p=0.06). The risk of extensive chronic GVHD was also lower in the thymoglobulin group (28% vs. 78%; p=0.05). Overall survival for 1 year (71% vs. 47%; p=0.6) and 1-year TRM (15% vs. 48%; p=0.2) seemed to be better in patients who received thymoglobulin.

In conclusion, our study suggests that the use of thymoglobulin as a post–transplant prophylaxis could be associated with lower acute and/or chronic GVHD rates as well as with better outcomes in recipients of allo-SCT from mismatched unrelated donors as compared to ATGAM.

Keywords

GVHD, thymoglobulin, ATGAM, allo-SCT

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Memorial R. M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University,
St. Petersburg, Russia


Correspondence
Memorial R. M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, 6/8, Tolstoy str., St. Petersburg, 199044, Russia
E-mail: yz21@mail.ru

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Memorial R. M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University,
St. Petersburg, Russia


Correspondence
Memorial R. M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, 6/8, Tolstoy str., St. Petersburg, 199044, Russia
E-mail: yz21@mail.ru

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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"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "14682" ["VALUE"]=> string(31) "10.3205/ctt-2009-No5-abstract52" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(31) "10.3205/ctt-2009-No5-abstract52" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_EN"]=> array(36) { ["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"]=> string(2) "37" ["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) "14683" ["VALUE"]=> array(2) { ["TEXT"]=> string(553) "<p>Alexander V. Popa<sup>1</sup>, Elena S. Gorohova<sup>2</sup>, Elena V. Flejshman<sup>3</sup>, Larisa G. Fechina<sup>4</sup>, Vladimir V. Lebedev<sup>5</sup>, Karapet S. Aslanyan<sup>6</sup>, Evgenia V. Inyushkina<sup>2</sup>, Svetlana A. Mayakova<sup>1</sup>, Irina E. Gavrilova<sup>1</sup>, Olga P. Chlebnikova<sup>4</sup>, Elmira G. Boichenko<sup>7</sup>, George L. Mentkevich<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(397) "

Alexander V. Popa1, Elena S. Gorohova2, Elena V. Flejshman3, Larisa G. Fechina4, Vladimir V. Lebedev5, Karapet S. Aslanyan6, Evgenia V. Inyushkina2, Svetlana A. Mayakova1, Irina E. Gavrilova1, Olga P. Chlebnikova4, Elmira G. Boichenko7, George L. Mentkevich1

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_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"]=> string(2) "38" ["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) "14684" ["VALUE"]=> array(2) { ["TEXT"]=> string(761) "<p class="bodytext"><sup>1</sup>RAMS N.N. Blokhin RCRC, Pediatric Oncology and Hematology Research Institute, Hematology/Oncology Department, Russia;<sup> 2</sup>Moscow Region Oncology Hospital, Pediatric Oncology Department, Russia; <sup>3</sup>RAMS N.N. Blokhin RCRC, Institute of Cancer Genesis, Laboratory of Cytogenetic, Russia; <sup>4</sup>Ekaterinburg Region Pediatric Cancer Research Center, Russia; <sup>5</sup>Krasnodar Region Pediatric Hospital, Hematology Department, Russia; <sup>6</sup>Rostov-na-Donu Region Pediatric Hospital, Hematology/Oncology Department, Russia; <br><sup>7</sup>St. Petersburg Children’s Hospital N1, Russia</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(649) "

1RAMS N.N. Blokhin RCRC, Pediatric Oncology and Hematology Research Institute, Hematology/Oncology Department, Russia; 2Moscow Region Oncology Hospital, Pediatric Oncology Department, Russia; 3RAMS N.N. Blokhin RCRC, Institute of Cancer Genesis, Laboratory of Cytogenetic, Russia; 4Ekaterinburg Region Pediatric Cancer Research Center, Russia; 5Krasnodar Region Pediatric Hospital, Hematology Department, Russia; 6Rostov-na-Donu Region Pediatric Hospital, Hematology/Oncology Department, Russia;
7St. Petersburg Children’s Hospital N1, Russia

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Purpose

We presume that a combination of CT and epigenetic therapy (ET) might improve the results in pediatric AML.Methods: Between October 2006 and August 2008, 42 children with AML were enrolled in the study: 25 boys (59.5%) and 17 girls (40.5%); the mean age was 8.3±0.8 ys. Seven pts (16.7%) were found to be standard risk (SR), 15 (34.7%) intermediate risk (IR), and 20 (48.6%) high risk (HR). Standard cytogenetics was performed in 32 patients.

Treatment was carried out according to the NII-DOG-AML 2007 protocol. CT for SR consisted of induction (AIE), consolidation (Ara-C 75mg/m2/d 4 days N4 every week, daunomycin 30mg/m2/m N4 every week, and 6–MP 60mg/m2/d days 1–28), and two courses HAE. For pts with IR and HR, CT had 4 courses: AIE, HAM in timing as induction, and postinduction (FLAG, HAE). ET consisted of ATRA 25mg/m2/d+valproic acid (VPA) 25mg/kg/d. Children with SR got VPA during maintenance until the seventy-eighth week and ATRA for 14 days every 14 days. Pts with IR and HR got VPA during all treatment for 18 mo and ATRA during the first 45 days and for 14 days with every consecutive CT course.

Results

Response was assessed on day 15. CR (M-1) was observed in all 7 SR pts, in 14 IR pts (93.3%), and in 14 HR pts (70%); PR (M-2) was observed in 1  IR pt (6.7%). All 4 children who did not respond on day 15 were in HR. After induction, CR was seen in 39  pts (92.9%). CR was not observed in 3 pts: 1 died from invasive aspergillosis, and 2 never got into CR. The 29 mo EFS was 57.2±8.3%, median follow up 18.8±1.8 mo, DFS 67.7±8.3%, and median follow up 21.1±1.8 mo. ET did not lead to any severe complications.

Conclusion

Chemotherapy combined with epigenetic treatment lead to complete remission in 39 out of 42 pts with AML without any extra toxicity. These results allow us to go on with this study.

Keywords

childhood acute myeloid leukemia, chemotherapy, epigenetic therapy

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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) "14683" ["VALUE"]=> array(2) { ["TEXT"]=> string(553) "<p>Alexander V. Popa<sup>1</sup>, Elena S. Gorohova<sup>2</sup>, Elena V. Flejshman<sup>3</sup>, Larisa G. Fechina<sup>4</sup>, Vladimir V. Lebedev<sup>5</sup>, Karapet S. Aslanyan<sup>6</sup>, Evgenia V. Inyushkina<sup>2</sup>, Svetlana A. Mayakova<sup>1</sup>, Irina E. Gavrilova<sup>1</sup>, Olga P. Chlebnikova<sup>4</sup>, Elmira G. Boichenko<sup>7</sup>, George L. Mentkevich<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(397) "

Alexander V. Popa1, Elena S. Gorohova2, Elena V. Flejshman3, Larisa G. Fechina4, Vladimir V. Lebedev5, Karapet S. Aslanyan6, Evgenia V. Inyushkina2, Svetlana A. Mayakova1, Irina E. Gavrilova1, Olga P. Chlebnikova4, Elmira G. Boichenko7, George L. Mentkevich1

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Alexander V. Popa1, Elena S. Gorohova2, Elena V. Flejshman3, Larisa G. Fechina4, Vladimir V. Lebedev5, Karapet S. Aslanyan6, Evgenia V. Inyushkina2, Svetlana A. Mayakova1, Irina E. Gavrilova1, Olga P. Chlebnikova4, Elmira G. Boichenko7, George L. Mentkevich1

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Purpose

We presume that a combination of CT and epigenetic therapy (ET) might improve the results in pediatric AML.Methods: Between October 2006 and August 2008, 42 children with AML were enrolled in the study: 25 boys (59.5%) and 17 girls (40.5%); the mean age was 8.3±0.8 ys. Seven pts (16.7%) were found to be standard risk (SR), 15 (34.7%) intermediate risk (IR), and 20 (48.6%) high risk (HR). Standard cytogenetics was performed in 32 patients.

Treatment was carried out according to the NII-DOG-AML 2007 protocol. CT for SR consisted of induction (AIE), consolidation (Ara-C 75mg/m2/d 4 days N4 every week, daunomycin 30mg/m2/m N4 every week, and 6–MP 60mg/m2/d days 1–28), and two courses HAE. For pts with IR and HR, CT had 4 courses: AIE, HAM in timing as induction, and postinduction (FLAG, HAE). ET consisted of ATRA 25mg/m2/d+valproic acid (VPA) 25mg/kg/d. Children with SR got VPA during maintenance until the seventy-eighth week and ATRA for 14 days every 14 days. Pts with IR and HR got VPA during all treatment for 18 mo and ATRA during the first 45 days and for 14 days with every consecutive CT course.

Results

Response was assessed on day 15. CR (M-1) was observed in all 7 SR pts, in 14 IR pts (93.3%), and in 14 HR pts (70%); PR (M-2) was observed in 1  IR pt (6.7%). All 4 children who did not respond on day 15 were in HR. After induction, CR was seen in 39  pts (92.9%). CR was not observed in 3 pts: 1 died from invasive aspergillosis, and 2 never got into CR. The 29 mo EFS was 57.2±8.3%, median follow up 18.8±1.8 mo, DFS 67.7±8.3%, and median follow up 21.1±1.8 mo. ET did not lead to any severe complications.

Conclusion

Chemotherapy combined with epigenetic treatment lead to complete remission in 39 out of 42 pts with AML without any extra toxicity. These results allow us to go on with this study.

Keywords

childhood acute myeloid leukemia, chemotherapy, epigenetic therapy

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2056) "

Purpose

We presume that a combination of CT and epigenetic therapy (ET) might improve the results in pediatric AML.Methods: Between October 2006 and August 2008, 42 children with AML were enrolled in the study: 25 boys (59.5%) and 17 girls (40.5%); the mean age was 8.3±0.8 ys. Seven pts (16.7%) were found to be standard risk (SR), 15 (34.7%) intermediate risk (IR), and 20 (48.6%) high risk (HR). Standard cytogenetics was performed in 32 patients.

Treatment was carried out according to the NII-DOG-AML 2007 protocol. CT for SR consisted of induction (AIE), consolidation (Ara-C 75mg/m2/d 4 days N4 every week, daunomycin 30mg/m2/m N4 every week, and 6–MP 60mg/m2/d days 1–28), and two courses HAE. For pts with IR and HR, CT had 4 courses: AIE, HAM in timing as induction, and postinduction (FLAG, HAE). ET consisted of ATRA 25mg/m2/d+valproic acid (VPA) 25mg/kg/d. Children with SR got VPA during maintenance until the seventy-eighth week and ATRA for 14 days every 14 days. Pts with IR and HR got VPA during all treatment for 18 mo and ATRA during the first 45 days and for 14 days with every consecutive CT course.

Results

Response was assessed on day 15. CR (M-1) was observed in all 7 SR pts, in 14 IR pts (93.3%), and in 14 HR pts (70%); PR (M-2) was observed in 1  IR pt (6.7%). All 4 children who did not respond on day 15 were in HR. After induction, CR was seen in 39  pts (92.9%). CR was not observed in 3 pts: 1 died from invasive aspergillosis, and 2 never got into CR. The 29 mo EFS was 57.2±8.3%, median follow up 18.8±1.8 mo, DFS 67.7±8.3%, and median follow up 21.1±1.8 mo. ET did not lead to any severe complications.

Conclusion

Chemotherapy combined with epigenetic treatment lead to complete remission in 39 out of 42 pts with AML without any extra toxicity. These results allow us to go on with this study.

Keywords

childhood acute myeloid leukemia, chemotherapy, epigenetic therapy

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1RAMS N.N. Blokhin RCRC, Pediatric Oncology and Hematology Research Institute, Hematology/Oncology Department, Russia; 2Moscow Region Oncology Hospital, Pediatric Oncology Department, Russia; 3RAMS N.N. Blokhin RCRC, Institute of Cancer Genesis, Laboratory of Cytogenetic, Russia; 4Ekaterinburg Region Pediatric Cancer Research Center, Russia; 5Krasnodar Region Pediatric Hospital, Hematology Department, Russia; 6Rostov-na-Donu Region Pediatric Hospital, Hematology/Oncology Department, Russia;
7St. Petersburg Children’s Hospital N1, Russia

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1RAMS N.N. Blokhin RCRC, Pediatric Oncology and Hematology Research Institute, Hematology/Oncology Department, Russia; 2Moscow Region Oncology Hospital, Pediatric Oncology Department, Russia; 3RAMS N.N. Blokhin RCRC, Institute of Cancer Genesis, Laboratory of Cytogenetic, Russia; 4Ekaterinburg Region Pediatric Cancer Research Center, Russia; 5Krasnodar Region Pediatric Hospital, Hematology Department, Russia; 6Rostov-na-Donu Region Pediatric Hospital, Hematology/Oncology Department, Russia;
7St. Petersburg Children’s Hospital N1, Russia

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Table 1.

Diagnosis

N

Indications   

Treatment   

N   

CR   

Response  

3 yr OS

ALL

15 

Relapse

DLI+chemotherapy

10   

3

4 (27%)

44%

DLI

1

0

MRD

DLI

2

1

Mixed chimerism

DLI

1

0

Graft rejection

DLI

1

0

AML

14 

Relapse

DLI+chemotherapy

5

3

8 (57%)


36%

DLI

6

3

Mixed chimerism

DLI

2

2

Preemptive

DLI

1

0

" ["~DETAIL_TEXT"]=> string(3970) "

Table 1.

Diagnosis

N

Indications   

Treatment   

N   

CR   

Response  

3 yr OS

ALL

15 

Relapse

DLI+chemotherapy

10   

3

4 (27%)

44%

DLI

1

0

MRD

DLI

2

1

Mixed chimerism

DLI

1

0

Graft rejection

DLI

1

0

AML

14 

Relapse

DLI+chemotherapy

5

3

8 (57%)


36%

DLI

6

3

Mixed chimerism

DLI

2

2

Preemptive

DLI

1

0

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Slesarchuk, Elena V. Babenko, Maria A. Estrina, Ilya V. Kazantsev, Ludmila S. Zubarovskaya, Boris V. Afanasyev<p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(124) "

Olga A. Slesarchuk, Elena V. Babenko, Maria A. Estrina, Ilya V. Kazantsev, Ludmila S. Zubarovskaya, Boris V. Afanasyev

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Memorial R.M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University,
St. Petersburg, Russia


Correspondence
Olga A. Slesarchuk, Memorial R.M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, 6/8, Tolstoy str., St. Petersburg, 199044, Russia
E-mail: cadet2002@mail.ru

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To evaluate the efficacy of donor lymphocyte infusion (DLI) after allo-HSCT in patients (pts) with acute leukemia.

Patients and Methods

Data from 29 pts given allo-HSCT from HLA-matched related donors (n=12), unrelated donors (n=11), and from haploidentical family member donors (n=6) were retrospectively analyzed. The conditioning regimen was myeloablative in 13 patients and RIC in 16 patients. Underlying malignant diseases were acute myeloid leukemia (AML, n=14) and acute lymphoblastic leukemia (ALL, n=15). The indications for DLI were minimal residual disease (n=2), mixed chimerism (n=3), preemptive treatment (n=1), graft rejection (n=1), and disease relapse (n=22). Fifteen pts with disease relapse received cytoreductive chemotherapy before DLI and 7 pts received DLI alone. The total number of DLI procedures was 56. Cell dose ranged from 3х104 CD3+cells/kg to 1х108 CD3+cells/kg. Fifteen pts received DLI as a bulk dose regimen, 16 pts received an escalating dose regimen. At the moment of DLI all pts had no signs of aGVHD; however, 5 pts had cGVHD./p>

Results

Complete remission (CR) was obtained in 12 pts (41%): 4 (27%) of 15 pts with ALL and 8 (57%) of 14 pts with AML. GVHD grade I–II appeared in 2 (6.8%) pts, grade III–IV in 3 (10%) pts, and in 2 cases it was fatal. Seven pts relapsed after DLI. The duration of CR after DLI ranged from 2 to 11 months. Five pts (17%) after allo-HSCT and DLI are still alive and in CR. Although response rate was greater in AML then in ALL, the 3yr OS was similar for both groups: 5 (36%) and 6 (44%), respectively.

Conclusions

Using DLI is effective in pts with disease relapse after allo-HSCT. However, it is associated with a high risk of aGVHD. Strategies to use a combination of DLI with target agents for efficacy improvement should be investigated in patients after allo-HSCT.

Keywords

relapse post-HSCT, donor lymphocyte infusion, response, GVHD, cell dose

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Slesarchuk, Elena V. Babenko, Maria A. Estrina, Ilya V. Kazantsev, Ludmila S. Zubarovskaya, Boris V. Afanasyev<p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(124) "

Olga A. Slesarchuk, Elena V. Babenko, Maria A. Estrina, Ilya V. Kazantsev, Ludmila S. Zubarovskaya, Boris V. Afanasyev

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Olga A. Slesarchuk, Elena V. Babenko, Maria A. Estrina, Ilya V. Kazantsev, Ludmila S. Zubarovskaya, Boris V. Afanasyev

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To evaluate the efficacy of donor lymphocyte infusion (DLI) after allo-HSCT in patients (pts) with acute leukemia.

Patients and Methods

Data from 29 pts given allo-HSCT from HLA-matched related donors (n=12), unrelated donors (n=11), and from haploidentical family member donors (n=6) were retrospectively analyzed. The conditioning regimen was myeloablative in 13 patients and RIC in 16 patients. Underlying malignant diseases were acute myeloid leukemia (AML, n=14) and acute lymphoblastic leukemia (ALL, n=15). The indications for DLI were minimal residual disease (n=2), mixed chimerism (n=3), preemptive treatment (n=1), graft rejection (n=1), and disease relapse (n=22). Fifteen pts with disease relapse received cytoreductive chemotherapy before DLI and 7 pts received DLI alone. The total number of DLI procedures was 56. Cell dose ranged from 3х104 CD3+cells/kg to 1х108 CD3+cells/kg. Fifteen pts received DLI as a bulk dose regimen, 16 pts received an escalating dose regimen. At the moment of DLI all pts had no signs of aGVHD; however, 5 pts had cGVHD./p>

Results

Complete remission (CR) was obtained in 12 pts (41%): 4 (27%) of 15 pts with ALL and 8 (57%) of 14 pts with AML. GVHD grade I–II appeared in 2 (6.8%) pts, grade III–IV in 3 (10%) pts, and in 2 cases it was fatal. Seven pts relapsed after DLI. The duration of CR after DLI ranged from 2 to 11 months. Five pts (17%) after allo-HSCT and DLI are still alive and in CR. Although response rate was greater in AML then in ALL, the 3yr OS was similar for both groups: 5 (36%) and 6 (44%), respectively.

Conclusions

Using DLI is effective in pts with disease relapse after allo-HSCT. However, it is associated with a high risk of aGVHD. Strategies to use a combination of DLI with target agents for efficacy improvement should be investigated in patients after allo-HSCT.

Keywords

relapse post-HSCT, donor lymphocyte infusion, response, GVHD, cell dose

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2034) "

To evaluate the efficacy of donor lymphocyte infusion (DLI) after allo-HSCT in patients (pts) with acute leukemia.

Patients and Methods

Data from 29 pts given allo-HSCT from HLA-matched related donors (n=12), unrelated donors (n=11), and from haploidentical family member donors (n=6) were retrospectively analyzed. The conditioning regimen was myeloablative in 13 patients and RIC in 16 patients. Underlying malignant diseases were acute myeloid leukemia (AML, n=14) and acute lymphoblastic leukemia (ALL, n=15). The indications for DLI were minimal residual disease (n=2), mixed chimerism (n=3), preemptive treatment (n=1), graft rejection (n=1), and disease relapse (n=22). Fifteen pts with disease relapse received cytoreductive chemotherapy before DLI and 7 pts received DLI alone. The total number of DLI procedures was 56. Cell dose ranged from 3х104 CD3+cells/kg to 1х108 CD3+cells/kg. Fifteen pts received DLI as a bulk dose regimen, 16 pts received an escalating dose regimen. At the moment of DLI all pts had no signs of aGVHD; however, 5 pts had cGVHD./p>

Results

Complete remission (CR) was obtained in 12 pts (41%): 4 (27%) of 15 pts with ALL and 8 (57%) of 14 pts with AML. GVHD grade I–II appeared in 2 (6.8%) pts, grade III–IV in 3 (10%) pts, and in 2 cases it was fatal. Seven pts relapsed after DLI. The duration of CR after DLI ranged from 2 to 11 months. Five pts (17%) after allo-HSCT and DLI are still alive and in CR. Although response rate was greater in AML then in ALL, the 3yr OS was similar for both groups: 5 (36%) and 6 (44%), respectively.

Conclusions

Using DLI is effective in pts with disease relapse after allo-HSCT. However, it is associated with a high risk of aGVHD. Strategies to use a combination of DLI with target agents for efficacy improvement should be investigated in patients after allo-HSCT.

Keywords

relapse post-HSCT, donor lymphocyte infusion, response, GVHD, cell dose

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Memorial R.M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University,
St. Petersburg, Russia


Correspondence
Olga A. Slesarchuk, Memorial R.M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, 6/8, Tolstoy str., St. Petersburg, 199044, Russia
E-mail: cadet2002@mail.ru

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Memorial R.M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University,
St. Petersburg, Russia


Correspondence
Olga A. Slesarchuk, Memorial R.M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, 6/8, Tolstoy str., St. Petersburg, 199044, Russia
E-mail: cadet2002@mail.ru

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Boris V. Afanasyev, Elena V. Semenova

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Memorial R. M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University,
St. Petersburg, Russia (EBMT CIC 725)


Correspondence:
Memorial R.M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, 6/8, Tolstoy str., St. Petersburg, 199044, Russia
E–mail: bmt-director@spmu.rssi.ru

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In patients with high-risk acute leukemia (AL) hematopoietic stem cell transplantation (HSCT) is an essential part of the treatment strategy. Current trends in HSCT suggest the use of myeloablative conditioning in leukemia patients. However, myeloablative preparative regimens are associated with a risk of treatment-related mortality. Given that the use of reduced intensity conditioning regimens (RIC) decreases TRM rates but appear to be associated with a higher incidence of relapse than observed with more intensive regimens. Data of 109 HSCT performed in patients with acute leukemia were analyzed with purpose to compare outcomes of RIC HSCTs (55 pts) and meyloablative preparative regimens (54 pts). Disease status at the time of transplantation was 1 or 2 CR.

There was no statistically significant difference in OS between RIC HSCT and standard preparative regimen (OS after RIC was 45% versus 46% after myeloablative conditioning). Moreover, statistically significant improvement of OS was noted in patients with ALL. Seven years OS after RIC HSCT was 58% (n=22) versus 32 % (n=34) after myeloablative conditioning. In pediatric ALL 7 years OS after RIC HSCT was 64% (n=14) versus 43% (n=23) after myeloablative conditioning. However, there was no difference in EFS after HSCT performed in pediatric ALL (37% (n=14) after RIC versus 39% (n=23) after myeloablative conditioning).      
Patients after RIC HSCT showed faster engraftment, therefore had lower rate of bacterial complications and received fewer haemotransfusions.

According to our data RIC HSCT is better tolerated by patients, has more favorable short term outcomes than more intensive regimens. Analyzes of HSCT outcomes in pediatric ALL revealed significant improvement in OS after RIC, nevertheless there was no difference in term of EFS. These results encourage us to continue investigations on RIC use. Our researches focus on post HSCT relapse prophylaxis by means of immunadoptive and targeted therapy.

Keywords: acute leukemia, reduced-intensity conditioning, immunoadoptive therapy

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Boris V. Afanasyev, Elena V. Semenova

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In patients with high-risk acute leukemia (AL) hematopoietic stem cell transplantation (HSCT) is an essential part of the treatment strategy. Current trends in HSCT suggest the use of myeloablative conditioning in leukemia patients. However, myeloablative preparative regimens are associated with a risk of treatment-related mortality. Given that the use of reduced intensity conditioning regimens (RIC) decreases TRM rates but appear to be associated with a higher incidence of relapse than observed with more intensive regimens. Data of 109 HSCT performed in patients with acute leukemia were analyzed with purpose to compare outcomes of RIC HSCTs (55 pts) and meyloablative preparative regimens (54 pts). Disease status at the time of transplantation was 1 or 2 CR.

There was no statistically significant difference in OS between RIC HSCT and standard preparative regimen (OS after RIC was 45% versus 46% after myeloablative conditioning). Moreover, statistically significant improvement of OS was noted in patients with ALL. Seven years OS after RIC HSCT was 58% (n=22) versus 32 % (n=34) after myeloablative conditioning. In pediatric ALL 7 years OS after RIC HSCT was 64% (n=14) versus 43% (n=23) after myeloablative conditioning. However, there was no difference in EFS after HSCT performed in pediatric ALL (37% (n=14) after RIC versus 39% (n=23) after myeloablative conditioning).      
Patients after RIC HSCT showed faster engraftment, therefore had lower rate of bacterial complications and received fewer haemotransfusions.

According to our data RIC HSCT is better tolerated by patients, has more favorable short term outcomes than more intensive regimens. Analyzes of HSCT outcomes in pediatric ALL revealed significant improvement in OS after RIC, nevertheless there was no difference in term of EFS. These results encourage us to continue investigations on RIC use. Our researches focus on post HSCT relapse prophylaxis by means of immunadoptive and targeted therapy.

Keywords: acute leukemia, reduced-intensity conditioning, immunoadoptive therapy

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In patients with high-risk acute leukemia (AL) hematopoietic stem cell transplantation (HSCT) is an essential part of the treatment strategy. Current trends in HSCT suggest the use of myeloablative conditioning in leukemia patients. However, myeloablative preparative regimens are associated with a risk of treatment-related mortality. Given that the use of reduced intensity conditioning regimens (RIC) decreases TRM rates but appear to be associated with a higher incidence of relapse than observed with more intensive regimens. Data of 109 HSCT performed in patients with acute leukemia were analyzed with purpose to compare outcomes of RIC HSCTs (55 pts) and meyloablative preparative regimens (54 pts). Disease status at the time of transplantation was 1 or 2 CR.

There was no statistically significant difference in OS between RIC HSCT and standard preparative regimen (OS after RIC was 45% versus 46% after myeloablative conditioning). Moreover, statistically significant improvement of OS was noted in patients with ALL. Seven years OS after RIC HSCT was 58% (n=22) versus 32 % (n=34) after myeloablative conditioning. In pediatric ALL 7 years OS after RIC HSCT was 64% (n=14) versus 43% (n=23) after myeloablative conditioning. However, there was no difference in EFS after HSCT performed in pediatric ALL (37% (n=14) after RIC versus 39% (n=23) after myeloablative conditioning).      
Patients after RIC HSCT showed faster engraftment, therefore had lower rate of bacterial complications and received fewer haemotransfusions.

According to our data RIC HSCT is better tolerated by patients, has more favorable short term outcomes than more intensive regimens. Analyzes of HSCT outcomes in pediatric ALL revealed significant improvement in OS after RIC, nevertheless there was no difference in term of EFS. These results encourage us to continue investigations on RIC use. Our researches focus on post HSCT relapse prophylaxis by means of immunadoptive and targeted therapy.

Keywords: acute leukemia, reduced-intensity conditioning, immunoadoptive therapy

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Memorial R. M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University,
St. Petersburg, Russia (EBMT CIC 725)


Correspondence:
Memorial R.M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, 6/8, Tolstoy str., St. Petersburg, 199044, Russia
E–mail: bmt-director@spmu.rssi.ru

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Memorial R. M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University,
St. Petersburg, Russia (EBMT CIC 725)


Correspondence:
Memorial R.M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, 6/8, Tolstoy str., St. Petersburg, 199044, Russia
E–mail: bmt-director@spmu.rssi.ru

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Lubimova, Larisa A. Kuzmina, Elena N. Parovichnikova, Inna V. Alexeeva, Valeriy G. Savchenko</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(108) "

Lidia S. Lubimova, Larisa A. Kuzmina, Elena N. Parovichnikova, Inna V. Alexeeva, Valeriy G. Savchenko

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Hematologic Scientific Centre, Russian Academy of Medical Sciences, Moscow, Russia

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Aim

To analyze the results of SyBMT in patients (pts) with leukemia.

Materials and methods

We included 11 pts: 7 CML (6 – CP, 1 – AP) and 4 AL (3 in CR, 1 in relapse): M/F 7/4, average age 24.5 years (13–39). In all cases myeloablative conditioning (BU 16 mg/kg+Cph 120 mg/kg) was used. Morphological, cytogenetic and molecular (FISH, RT PCR) investigations were performed.

Results

Of the 7 CML pts, 4 are alive: 2 have been in complete molecular remission (CMR) for 143 and 206 mo, while a third has been in complete cytogenetic remission (CCR) for 17 mo. During the first 3 mo after BMT, the third patient had a very weak expression of the BCR/ABL gene according to an RT PCR. In 6 mo he was negative according to an RT PCR and in 13 and 16 mo BCR/ABL was determined again (0.05–0.04%) accordingly. One pt with AP CML has been in a chronic phase for 136 mo, while 3 pts relapsed and died. Of the 4 pts with AL, 3 are alive – all 3 were in CR before BMT. One pt remained in CMR and 2 pts achieved only CCR, but the persistence of inv (16) – which was detected before BMTaccording to an RT PCR – was revealed. Therefore, of the initial 11 pts, 7 (64%) are alive: 6 of who are in CCR – of which 3 are in CMR. At the same time, 3 pts with CCR – 1 CML and 2 AL – have MRD according to an RT PCR; FISH was negative in all cases.

Conclusion

After SyBMT, long survival of pts is possible in the majority of cases where CCR has been achieved. The RT PCR method was the most informative for the diagnosis of MRD, which was recognized in 3 of the 6 pts. We previously published our first encouraging results of using immunomodulatory therapy after autological BMT: the relapse rate decreased twice in treated pts. At that time a question came up: Is it necessary to treat patients after SyBMT, especially those with MRD? Recently, the use of immunomodulatory therapy after SyBMT was initiated in our clinic: IFN-α in CML and IFN-α + ATRA or IL2 in acute AL. The results will be evaluated in the future.

Keywords

syngeneic bone marrow transplantation, graft-versus-leukemia effects, GVL, acute leukemia, AL, chronic myeloid leukemia, CML, minimal residual disease, MRD

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Lubimova, Larisa A. Kuzmina, Elena N. Parovichnikova, Inna V. Alexeeva, Valeriy G. Savchenko</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(108) "

Lidia S. Lubimova, Larisa A. Kuzmina, Elena N. Parovichnikova, Inna V. Alexeeva, Valeriy G. Savchenko

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Lidia S. Lubimova, Larisa A. Kuzmina, Elena N. Parovichnikova, Inna V. Alexeeva, Valeriy G. Savchenko

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Aim

To analyze the results of SyBMT in patients (pts) with leukemia.

Materials and methods

We included 11 pts: 7 CML (6 – CP, 1 – AP) and 4 AL (3 in CR, 1 in relapse): M/F 7/4, average age 24.5 years (13–39). In all cases myeloablative conditioning (BU 16 mg/kg+Cph 120 mg/kg) was used. Morphological, cytogenetic and molecular (FISH, RT PCR) investigations were performed.

Results

Of the 7 CML pts, 4 are alive: 2 have been in complete molecular remission (CMR) for 143 and 206 mo, while a third has been in complete cytogenetic remission (CCR) for 17 mo. During the first 3 mo after BMT, the third patient had a very weak expression of the BCR/ABL gene according to an RT PCR. In 6 mo he was negative according to an RT PCR and in 13 and 16 mo BCR/ABL was determined again (0.05–0.04%) accordingly. One pt with AP CML has been in a chronic phase for 136 mo, while 3 pts relapsed and died. Of the 4 pts with AL, 3 are alive – all 3 were in CR before BMT. One pt remained in CMR and 2 pts achieved only CCR, but the persistence of inv (16) – which was detected before BMTaccording to an RT PCR – was revealed. Therefore, of the initial 11 pts, 7 (64%) are alive: 6 of who are in CCR – of which 3 are in CMR. At the same time, 3 pts with CCR – 1 CML and 2 AL – have MRD according to an RT PCR; FISH was negative in all cases.

Conclusion

After SyBMT, long survival of pts is possible in the majority of cases where CCR has been achieved. The RT PCR method was the most informative for the diagnosis of MRD, which was recognized in 3 of the 6 pts. We previously published our first encouraging results of using immunomodulatory therapy after autological BMT: the relapse rate decreased twice in treated pts. At that time a question came up: Is it necessary to treat patients after SyBMT, especially those with MRD? Recently, the use of immunomodulatory therapy after SyBMT was initiated in our clinic: IFN-α in CML and IFN-α + ATRA or IL2 in acute AL. The results will be evaluated in the future.

Keywords

syngeneic bone marrow transplantation, graft-versus-leukemia effects, GVL, acute leukemia, AL, chronic myeloid leukemia, CML, minimal residual disease, MRD

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2272) "

Aim

To analyze the results of SyBMT in patients (pts) with leukemia.

Materials and methods

We included 11 pts: 7 CML (6 – CP, 1 – AP) and 4 AL (3 in CR, 1 in relapse): M/F 7/4, average age 24.5 years (13–39). In all cases myeloablative conditioning (BU 16 mg/kg+Cph 120 mg/kg) was used. Morphological, cytogenetic and molecular (FISH, RT PCR) investigations were performed.

Results

Of the 7 CML pts, 4 are alive: 2 have been in complete molecular remission (CMR) for 143 and 206 mo, while a third has been in complete cytogenetic remission (CCR) for 17 mo. During the first 3 mo after BMT, the third patient had a very weak expression of the BCR/ABL gene according to an RT PCR. In 6 mo he was negative according to an RT PCR and in 13 and 16 mo BCR/ABL was determined again (0.05–0.04%) accordingly. One pt with AP CML has been in a chronic phase for 136 mo, while 3 pts relapsed and died. Of the 4 pts with AL, 3 are alive – all 3 were in CR before BMT. One pt remained in CMR and 2 pts achieved only CCR, but the persistence of inv (16) – which was detected before BMTaccording to an RT PCR – was revealed. Therefore, of the initial 11 pts, 7 (64%) are alive: 6 of who are in CCR – of which 3 are in CMR. At the same time, 3 pts with CCR – 1 CML and 2 AL – have MRD according to an RT PCR; FISH was negative in all cases.

Conclusion

After SyBMT, long survival of pts is possible in the majority of cases where CCR has been achieved. The RT PCR method was the most informative for the diagnosis of MRD, which was recognized in 3 of the 6 pts. We previously published our first encouraging results of using immunomodulatory therapy after autological BMT: the relapse rate decreased twice in treated pts. At that time a question came up: Is it necessary to treat patients after SyBMT, especially those with MRD? Recently, the use of immunomodulatory therapy after SyBMT was initiated in our clinic: IFN-α in CML and IFN-α + ATRA or IL2 in acute AL. The results will be evaluated in the future.

Keywords

syngeneic bone marrow transplantation, graft-versus-leukemia effects, GVL, acute leukemia, AL, chronic myeloid leukemia, CML, minimal residual disease, MRD

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Hematologic Scientific Centre, Russian Academy of Medical Sciences, Moscow, Russia

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Hematologic Scientific Centre, Russian Academy of Medical Sciences, Moscow, Russia

" } ["AUTHORS"]=> array(38) { ["ID"]=> string(2) "24" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:45:07" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "AUTHORS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "24" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> array(5) { [0]=> string(5) "14590" [1]=> string(5) "14591" [2]=> string(5) "14592" [3]=> string(5) "14593" [4]=> string(5) "14594" } ["VALUE"]=> array(5) { [0]=> string(4) "1034" [1]=> string(4) "1035" [2]=> string(4) "1036" [3]=> string(4) "1037" [4]=> string(4) "1038" } ["DESCRIPTION"]=> array(5) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" [4]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(5) { [0]=> string(4) "1034" [1]=> string(4) "1035" [2]=> string(4) "1036" [3]=> string(4) "1037" [4]=> string(4) "1038" } ["~DESCRIPTION"]=> array(5) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" [4]=> string(0) "" } ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> array(5) { [0]=> string(61) "Lidia S. Lubimova" [1]=> string(61) "Larisa A. Kuzmina" [2]=> string(67) "Elena N. Parovichnikova" [3]=> string(60) "Inna V. Alexeeva" [4]=> string(64) "Valeriy G. Savchenko" } ["LINK_ELEMENT_VALUE"]=> bool(false) } ["CONTACT"]=> array(38) { ["ID"]=> string(2) "23" ["TIMESTAMP_X"]=> string(19) "2015-09-03 14:43:05" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(14) "Контакт" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "CONTACT" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "23" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "14573" ["VALUE"]=> string(4) "1034" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(4) "1034" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(61) "Lidia S. Lubimova" ["LINK_ELEMENT_VALUE"]=> bool(false) } } } [10]=> array(49) { ["IBLOCK_SECTION_ID"]=> string(2) "51" ["~IBLOCK_SECTION_ID"]=> string(2) "51" ["ID"]=> string(4) "1009" ["~ID"]=> string(4) "1009" ["IBLOCK_ID"]=> string(1) "2" ["~IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(147) "Results of treatment of relapsed promyelocytic leukemia in children using chemotherapy and arsenic trioxide (ATO) followed by autologous SCT (ASCT)" ["~NAME"]=> string(147) "Results of treatment of relapsed promyelocytic leukemia in children using chemotherapy and arsenic trioxide (ATO) followed by autologous SCT (ASCT)" ["ACTIVE_FROM"]=> NULL ["~ACTIVE_FROM"]=> NULL ["TIMESTAMP_X"]=> string(19) "27.07.2017 16:51:51" ["~TIMESTAMP_X"]=> string(19) "27.07.2017 16:51:51" ["DETAIL_PAGE_URL"]=> string(174) "/ru/archive/tom-2-nomer-1-5/rezyume-gruppy-simpoziuma/a-lechenie-leykoza/results-of-treatment-of-relapsed-promyelocytic-leukemia-in-children-using-chemotherapy-and-arsenic-t/" ["~DETAIL_PAGE_URL"]=> string(174) "/ru/archive/tom-2-nomer-1-5/rezyume-gruppy-simpoziuma/a-lechenie-leykoza/results-of-treatment-of-relapsed-promyelocytic-leukemia-in-children-using-chemotherapy-and-arsenic-t/" ["LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["~LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["DETAIL_TEXT"]=> string(4589) "Table 1.

Case № 1 2 3 4 5 6 7
Age in years 14 13 1 14 7 12 13
WBC at Dx mm3 1.400 3.900 57.000 15.700 2.600 40.000 0.900
Rx start – relapse, mo 21 29 9 35 23 4 12
PML/RARα before maintenance + + - + - + -
Relapse site bone marrow bone marrow bone marrow bone marrow skin bone marrow bone marrow skin bone marrow
2nd remission induction АТRА АТО АТRА 7+3 АТRА HDAraC Mitox АТRА AraC, Ida АТRА АТО Mitox АТО АТО
Post 2nd remission therapy АТО 2 courses АТО 3 courses АTО 3 courses АТО 3 courses АТО 3 courses АТО GO АТО 1 course
Autо-HSCT + + + + + +  
Duration of 2nd mol remission mo + 35 + 27 + 26 + 26 + 18 + 8 + 1
" ["~DETAIL_TEXT"]=> string(4589) "Table 1.

Case № 1 2 3 4 5 6 7
Age in years 14 13 1 14 7 12 13
WBC at Dx mm3 1.400 3.900 57.000 15.700 2.600 40.000 0.900
Rx start – relapse, mo 21 29 9 35 23 4 12
PML/RARα before maintenance + + - + - + -
Relapse site bone marrow bone marrow bone marrow bone marrow skin bone marrow bone marrow skin bone marrow
2nd remission induction АТRА АТО АТRА 7+3 АТRА HDAraC Mitox АТRА AraC, Ida АТRА АТО Mitox АТО АТО
Post 2nd remission therapy АТО 2 courses АТО 3 courses АTО 3 courses АТО 3 courses АТО 3 courses АТО GO АТО 1 course
Autо-HSCT + + + + + +  
Duration of 2nd mol remission mo + 35 + 27 + 26 + 26 + 18 + 8 + 1
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Baidildina, Elena V. Samochatova, Michail A. Maschan, Alexey A. Maschan</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(86) "

Dina D. Baidildina, Elena V. Samochatova, Michail A. Maschan, Alexey A. Maschan

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On behalf of the Russian-Byelorussian Pediatric APL study group

Correspondence:
Elena V. Samochatova, Research Institute for Pediatric Hematology, 117, Leninsky prosp, Moscow, 105062, Russia
E-mail: samochatova@spam is badniidg.ru

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The Russian multicenter APL-2003 protocol for pediatric APL demonstrated a non–inferior outcome compared with the APL-93/98 studies despite a reduction of ATRA to 25 mg/m2 and cumulative anthracycline dose to 405 mg/m2: at a median follow up of 35 mo the EFS and OS were 0.79±0.6 and 0.93±0.3. Seven relapses (11.9%) occurred out of 61 patients (pts) at a median of 21 (4–35) mo. Second remission was induced with diverse therapy (Table 1) and consolidated with 14 ATO at 0.15 mg/kg per day;
in 1 pt gemtuzumab ozogamicin (GO) at 6 mg/m2 was added to ATO. All pts achieved 2nd hematological remission and PML/RARα negativity in bone marrow either after induction (3 pts) or after consolidation (4 pts). HDAraC + G–CSF were used for additional “in-vivo purging” and PBSC mobilization. Harvesting was successful in all pts: а median of CD34+ dose 17 (8–40) х 106/kg was achieved after single apheresis. In all cases, apheresis product proved to be PML/RARα negative. AHSCT was performed in 6 pts after conditioning with HDAraC + Mel180 mg/m2 in 4 pts, Bu12mg/kg + Mel 140 mg/m2 in 1 pt and Treosulfan 42 mg/m2 + Mel140 mg/m2 in 1 pt. All pts engrafted at a median of 16 (12–25) d with minimal transplant-related toxicity. Three pts received GO on day +100 after ASCT with minimal toxicity. Two pts with skin involvement received complementary electron beam skin irradiation. At a median of 26 mo 6 pts continued in molecular remission and 1 pt experienced 2nd relapse. We conclude that children with relapsed APL can be treated effectively with chemotherapy, ATO, and ASCT.

Keywords: promylocytic leukemia, arsenic trioxide, autologous hematopoietic stem cell transplantation

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Dina D. Baidildina, Elena V. Samochatova, Michail A. Maschan, Alexey A. Maschan

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Dina D. Baidildina, Elena V. Samochatova, Michail A. Maschan, Alexey A. Maschan

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The Russian multicenter APL-2003 protocol for pediatric APL demonstrated a non–inferior outcome compared with the APL-93/98 studies despite a reduction of ATRA to 25 mg/m2 and cumulative anthracycline dose to 405 mg/m2: at a median follow up of 35 mo the EFS and OS were 0.79±0.6 and 0.93±0.3. Seven relapses (11.9%) occurred out of 61 patients (pts) at a median of 21 (4–35) mo. Second remission was induced with diverse therapy (Table 1) and consolidated with 14 ATO at 0.15 mg/kg per day;
in 1 pt gemtuzumab ozogamicin (GO) at 6 mg/m2 was added to ATO. All pts achieved 2nd hematological remission and PML/RARα negativity in bone marrow either after induction (3 pts) or after consolidation (4 pts). HDAraC + G–CSF were used for additional “in-vivo purging” and PBSC mobilization. Harvesting was successful in all pts: а median of CD34+ dose 17 (8–40) х 106/kg was achieved after single apheresis. In all cases, apheresis product proved to be PML/RARα negative. AHSCT was performed in 6 pts after conditioning with HDAraC + Mel180 mg/m2 in 4 pts, Bu12mg/kg + Mel 140 mg/m2 in 1 pt and Treosulfan 42 mg/m2 + Mel140 mg/m2 in 1 pt. All pts engrafted at a median of 16 (12–25) d with minimal transplant-related toxicity. Three pts received GO on day +100 after ASCT with minimal toxicity. Two pts with skin involvement received complementary electron beam skin irradiation. At a median of 26 mo 6 pts continued in molecular remission and 1 pt experienced 2nd relapse. We conclude that children with relapsed APL can be treated effectively with chemotherapy, ATO, and ASCT.

Keywords: promylocytic leukemia, arsenic trioxide, autologous hematopoietic stem cell transplantation

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The Russian multicenter APL-2003 protocol for pediatric APL demonstrated a non–inferior outcome compared with the APL-93/98 studies despite a reduction of ATRA to 25 mg/m2 and cumulative anthracycline dose to 405 mg/m2: at a median follow up of 35 mo the EFS and OS were 0.79±0.6 and 0.93±0.3. Seven relapses (11.9%) occurred out of 61 patients (pts) at a median of 21 (4–35) mo. Second remission was induced with diverse therapy (Table 1) and consolidated with 14 ATO at 0.15 mg/kg per day;
in 1 pt gemtuzumab ozogamicin (GO) at 6 mg/m2 was added to ATO. All pts achieved 2nd hematological remission and PML/RARα negativity in bone marrow either after induction (3 pts) or after consolidation (4 pts). HDAraC + G–CSF were used for additional “in-vivo purging” and PBSC mobilization. Harvesting was successful in all pts: а median of CD34+ dose 17 (8–40) х 106/kg was achieved after single apheresis. In all cases, apheresis product proved to be PML/RARα negative. AHSCT was performed in 6 pts after conditioning with HDAraC + Mel180 mg/m2 in 4 pts, Bu12mg/kg + Mel 140 mg/m2 in 1 pt and Treosulfan 42 mg/m2 + Mel140 mg/m2 in 1 pt. All pts engrafted at a median of 16 (12–25) d with minimal transplant-related toxicity. Three pts received GO on day +100 after ASCT with minimal toxicity. Two pts with skin involvement received complementary electron beam skin irradiation. At a median of 26 mo 6 pts continued in molecular remission and 1 pt experienced 2nd relapse. We conclude that children with relapsed APL can be treated effectively with chemotherapy, ATO, and ASCT.

Keywords: promylocytic leukemia, arsenic trioxide, autologous hematopoietic stem cell transplantation

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On behalf of the Russian-Byelorussian Pediatric APL study group

Correspondence:
Elena V. Samochatova, Research Institute for Pediatric Hematology, 117, Leninsky prosp, Moscow, 105062, Russia
E-mail: samochatova@spam is badniidg.ru

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On behalf of the Russian-Byelorussian Pediatric APL study group

Correspondence:
Elena V. Samochatova, Research Institute for Pediatric Hematology, 117, Leninsky prosp, Moscow, 105062, Russia
E-mail: samochatova@spam is badniidg.ru

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Boichenko<sup>1</sup>, Margarita B. Belogurova<sup>2</sup>, Gritta Janka<sup>3</sup>, Margarita S. Livshits<sup>1</sup>, Eleonora M. Petrova<sup>1</sup>, Marina B. Ivanovskaya<sup>1</sup>, Irina A. Garbusova<sup>1</sup>, Galyna G. Radulesku<sup>2</sup>, Tatjana D. Victorovich<sup>2</sup>, Emylia D. Tchavpetsova<sup>2</sup>, Ludmila I. Shats<sup>2</sup>  </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(378) "

Elmira G. Boichenko1, Margarita B. Belogurova2, Gritta Janka3, Margarita S. Livshits1, Eleonora M. Petrova1, Marina B. Ivanovskaya1, Irina A. Garbusova1, Galyna G. Radulesku2, Tatjana D. Victorovich2, Emylia D. Tchavpetsova2, Ludmila I. Shats2 

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1City Children's Hospital 1, St. Petersburg, Russia; 2City Hospital 31, St. Petersburg, Russia; 3Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Germany" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_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"]=> string(2) "39" ["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) "14413" ["VALUE"]=> array(2) { ["TEXT"]=> string(2779) "<p class="bodytext">Between January 1999 and August 2008, a total of 272 newly diagnosed patients (pts) up to 18 years of age with ALL were treated according to the COALL-Saint-Petersburg-92 protocol (COALL-S-Pb-92). Since August 2008, the pediatric oncohemathological clinics of St. Petersburg have been affiliated with the all-Russian study Moscow-Berlin 2008. </p> <h3>Methods<h3> <p>Protocol COALL-S-Pb-92 is a modification of the German protocol COALL-92. The intensive phase of treatment lasted  5.5 months in the low risk (LR) group  and 8 months in the high risk (HR) group and consisted of 4 parts: induction, consolidation, CNS-treatment and reinduction. It was followed by maintenance treatment until 2 years from the date of diagnosis. Treatment of presymptomatic CNS disease consisted of i.th. MTX; cranial irradiation (12 Gy) was given additionally  to HR pts with T-ALL and/or primary hyperleukocytosis. <br /><br />Pts were stratified into LR (n=129, 47%) or HR (n=143, 53%) groups. The criteria for HR were: initial white blood count ≥ 25000/l, primary CNS and/or mediastinal involvement, Т-cell and pre-pre-B-cell immunophenotype, an age ≥ 10 years, Ph–chromosome positivity, and failure to achieve remission at day 28 from the beginning of treatment.</p> <h3>Results</h3> <p> 266 pts (98%) achieved complete remission. 6 HR pts died during induction (hemorrhagic and infectious complications, progression of leukemia). There was only the one late responder, no non-responders. 18 pts died of infectious complications while in remission. 47 (17.7%) patients relapsed: 12.4% in the LR group and 22.6% in the HR group. Non-lethal complications – like mucositis, hepatotoxicity, hemorrhagic and infectious complications – were more frequent and severe in HR–group pts. After an observation time of 10 years, the estimate for EFS of all 272 valuable patients is 64.8±3.4% (LR 74.7±4.4%, HR 55.9±4.9%), the estimate of probability of RFS is 75.9±3.4% (LR 82.4±4.1%, HR 69.6±4.8%) and probability of overall survival is 76.0±3.1% (LR 87.5±3.5%, HR 65.3±5.0%). </p> <h3>Conclusions</h3> <p>Treatment results based on the COALL-92 protocol have demonstrated an obvious improvement in comparison with previous results of leukemia chemotherapy in children in St. Petersburg. We are going to continue to follow up our COALL patients in order to be able to compare treatment results in different age and risk groups as well as long-term survival and treatment sequela with different treatment strategies.</p> <h3>Keywords</h3> <p> acute lymphoblastic leukemia, children, intensive chemotherapy</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2649) "

Between January 1999 and August 2008, a total of 272 newly diagnosed patients (pts) up to 18 years of age with ALL were treated according to the COALL-Saint-Petersburg-92 protocol (COALL-S-Pb-92). Since August 2008, the pediatric oncohemathological clinics of St. Petersburg have been affiliated with the all-Russian study Moscow-Berlin 2008.

Methods

Protocol COALL-S-Pb-92 is a modification of the German protocol COALL-92. The intensive phase of treatment lasted  5.5 months in the low risk (LR) group  and 8 months in the high risk (HR) group and consisted of 4 parts: induction, consolidation, CNS-treatment and reinduction. It was followed by maintenance treatment until 2 years from the date of diagnosis. Treatment of presymptomatic CNS disease consisted of i.th. MTX; cranial irradiation (12 Gy) was given additionally  to HR pts with T-ALL and/or primary hyperleukocytosis.

Pts were stratified into LR (n=129, 47%) or HR (n=143, 53%) groups. The criteria for HR were: initial white blood count ≥ 25000/l, primary CNS and/or mediastinal involvement, Т-cell and pre-pre-B-cell immunophenotype, an age ≥ 10 years, Ph–chromosome positivity, and failure to achieve remission at day 28 from the beginning of treatment.

Results

266 pts (98%) achieved complete remission. 6 HR pts died during induction (hemorrhagic and infectious complications, progression of leukemia). There was only the one late responder, no non-responders. 18 pts died of infectious complications while in remission. 47 (17.7%) patients relapsed: 12.4% in the LR group and 22.6% in the HR group. Non-lethal complications – like mucositis, hepatotoxicity, hemorrhagic and infectious complications – were more frequent and severe in HR–group pts. After an observation time of 10 years, the estimate for EFS of all 272 valuable patients is 64.8±3.4% (LR 74.7±4.4%, HR 55.9±4.9%), the estimate of probability of RFS is 75.9±3.4% (LR 82.4±4.1%, HR 69.6±4.8%) and probability of overall survival is 76.0±3.1% (LR 87.5±3.5%, HR 65.3±5.0%).

Conclusions

Treatment results based on the COALL-92 protocol have demonstrated an obvious improvement in comparison with previous results of leukemia chemotherapy in children in St. Petersburg. We are going to continue to follow up our COALL patients in order to be able to compare treatment results in different age and risk groups as well as long-term survival and treatment sequela with different treatment strategies.

Keywords

acute lymphoblastic leukemia, children, intensive chemotherapy

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Boichenko<sup>1</sup>, Margarita B. Belogurova<sup>2</sup>, Gritta Janka<sup>3</sup>, Margarita S. Livshits<sup>1</sup>, Eleonora M. Petrova<sup>1</sup>, Marina B. Ivanovskaya<sup>1</sup>, Irina A. Garbusova<sup>1</sup>, Galyna G. Radulesku<sup>2</sup>, Tatjana D. Victorovich<sup>2</sup>, Emylia D. Tchavpetsova<sup>2</sup>, Ludmila I. Shats<sup>2</sup>  </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(378) "

Elmira G. Boichenko1, Margarita B. Belogurova2, Gritta Janka3, Margarita S. Livshits1, Eleonora M. Petrova1, Marina B. Ivanovskaya1, Irina A. Garbusova1, Galyna G. Radulesku2, Tatjana D. Victorovich2, Emylia D. Tchavpetsova2, Ludmila I. Shats2 

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Elmira G. Boichenko1, Margarita B. Belogurova2, Gritta Janka3, Margarita S. Livshits1, Eleonora M. Petrova1, Marina B. Ivanovskaya1, Irina A. Garbusova1, Galyna G. Radulesku2, Tatjana D. Victorovich2, Emylia D. Tchavpetsova2, Ludmila I. Shats2 

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Between January 1999 and August 2008, a total of 272 newly diagnosed patients (pts) up to 18 years of age with ALL were treated according to the COALL-Saint-Petersburg-92 protocol (COALL-S-Pb-92). Since August 2008, the pediatric oncohemathological clinics of St. Petersburg have been affiliated with the all-Russian study Moscow-Berlin 2008.

Methods

Protocol COALL-S-Pb-92 is a modification of the German protocol COALL-92. The intensive phase of treatment lasted  5.5 months in the low risk (LR) group  and 8 months in the high risk (HR) group and consisted of 4 parts: induction, consolidation, CNS-treatment and reinduction. It was followed by maintenance treatment until 2 years from the date of diagnosis. Treatment of presymptomatic CNS disease consisted of i.th. MTX; cranial irradiation (12 Gy) was given additionally  to HR pts with T-ALL and/or primary hyperleukocytosis.

Pts were stratified into LR (n=129, 47%) or HR (n=143, 53%) groups. The criteria for HR were: initial white blood count ≥ 25000/l, primary CNS and/or mediastinal involvement, Т-cell and pre-pre-B-cell immunophenotype, an age ≥ 10 years, Ph–chromosome positivity, and failure to achieve remission at day 28 from the beginning of treatment.

Results

266 pts (98%) achieved complete remission. 6 HR pts died during induction (hemorrhagic and infectious complications, progression of leukemia). There was only the one late responder, no non-responders. 18 pts died of infectious complications while in remission. 47 (17.7%) patients relapsed: 12.4% in the LR group and 22.6% in the HR group. Non-lethal complications – like mucositis, hepatotoxicity, hemorrhagic and infectious complications – were more frequent and severe in HR–group pts. After an observation time of 10 years, the estimate for EFS of all 272 valuable patients is 64.8±3.4% (LR 74.7±4.4%, HR 55.9±4.9%), the estimate of probability of RFS is 75.9±3.4% (LR 82.4±4.1%, HR 69.6±4.8%) and probability of overall survival is 76.0±3.1% (LR 87.5±3.5%, HR 65.3±5.0%).

Conclusions

Treatment results based on the COALL-92 protocol have demonstrated an obvious improvement in comparison with previous results of leukemia chemotherapy in children in St. Petersburg. We are going to continue to follow up our COALL patients in order to be able to compare treatment results in different age and risk groups as well as long-term survival and treatment sequela with different treatment strategies.

Keywords

acute lymphoblastic leukemia, children, intensive chemotherapy

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Between January 1999 and August 2008, a total of 272 newly diagnosed patients (pts) up to 18 years of age with ALL were treated according to the COALL-Saint-Petersburg-92 protocol (COALL-S-Pb-92). Since August 2008, the pediatric oncohemathological clinics of St. Petersburg have been affiliated with the all-Russian study Moscow-Berlin 2008.

Methods

Protocol COALL-S-Pb-92 is a modification of the German protocol COALL-92. The intensive phase of treatment lasted  5.5 months in the low risk (LR) group  and 8 months in the high risk (HR) group and consisted of 4 parts: induction, consolidation, CNS-treatment and reinduction. It was followed by maintenance treatment until 2 years from the date of diagnosis. Treatment of presymptomatic CNS disease consisted of i.th. MTX; cranial irradiation (12 Gy) was given additionally  to HR pts with T-ALL and/or primary hyperleukocytosis.

Pts were stratified into LR (n=129, 47%) or HR (n=143, 53%) groups. The criteria for HR were: initial white blood count ≥ 25000/l, primary CNS and/or mediastinal involvement, Т-cell and pre-pre-B-cell immunophenotype, an age ≥ 10 years, Ph–chromosome positivity, and failure to achieve remission at day 28 from the beginning of treatment.

Results

266 pts (98%) achieved complete remission. 6 HR pts died during induction (hemorrhagic and infectious complications, progression of leukemia). There was only the one late responder, no non-responders. 18 pts died of infectious complications while in remission. 47 (17.7%) patients relapsed: 12.4% in the LR group and 22.6% in the HR group. Non-lethal complications – like mucositis, hepatotoxicity, hemorrhagic and infectious complications – were more frequent and severe in HR–group pts. After an observation time of 10 years, the estimate for EFS of all 272 valuable patients is 64.8±3.4% (LR 74.7±4.4%, HR 55.9±4.9%), the estimate of probability of RFS is 75.9±3.4% (LR 82.4±4.1%, HR 69.6±4.8%) and probability of overall survival is 76.0±3.1% (LR 87.5±3.5%, HR 65.3±5.0%).

Conclusions

Treatment results based on the COALL-92 protocol have demonstrated an obvious improvement in comparison with previous results of leukemia chemotherapy in children in St. Petersburg. We are going to continue to follow up our COALL patients in order to be able to compare treatment results in different age and risk groups as well as long-term survival and treatment sequela with different treatment strategies.

Keywords

acute lymphoblastic leukemia, children, intensive chemotherapy

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Estrina, Мurat O. Yagmourov, Dmitriy E. Pevtsov, Еvgenia A. Kochina, Natalia E. Ivanova, Alla A. Golovacheva, Alexander L. Alyanskiy, Ludmila S. Zoubarovskaya, Abdulbasir A. Ganapiev, Boris V. Afanasyev</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(220) "

Maria A. Estrina, Мurat O. Yagmourov, Dmitriy E. Pevtsov, Еvgenia A. Kochina, Natalia E. Ivanova, Alla A. Golovacheva, Alexander L. Alyanskiy, Ludmila S. Zoubarovskaya, Abdulbasir A. Ganapiev, Boris V. Afanasyev

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_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"]=> string(2) "38" ["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) "14522" ["VALUE"]=> array(2) { ["TEXT"]=> string(171) "<p>Memorial R. M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, St. Petersburg, Russia</p> " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(159) "

Memorial R. M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, St. Petersburg, Russia

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Background

ABO incompatibility between donor and recipient is currently considered one of the risk factors for immune-mediated complications, which can influence the outcome of allogeneic hematopoietic stem cell transplantation (allo-SCT).

Patients and methods

We analyzed 140 consecutive allo-HSCT recipients. 124 patients had HLA-compatible donors (39 related and 85 unrelated) and 16 patients had haploidentical donors. Fifty-nine of the donor–recipient pairs were ABO-identical, while 34 had minor incompatibility, 35 major incompatibility, and 12 bidirectional incompatibility. Seventy-eight patients received bone marrow (BM), 46 peripheral blood stem cells (PBSC), and 16 stem cells from both sources. Conventional myeloablative conditioning was used in 64 patients and non–myeloablative regimens in 78 patients. In both groups the same regimen of graft–versus–host disease (GVHD) prophylaxis was administered. In major ABO incompatibility SCT donor stem cells were depleted of RBC (6% hydroxyethyl starch sedimentation), in cases of minor incompatibility donor incompatible plasma was removed, and in cases of bidirectional incompatibility both methods were used.

Results

In all the study groups, we observed no cases of acute hemolysis after PBSC transfusion and only 2 cases after BM transfusion. Engraftment of leukocytes, neutrophils, and platelets was not altered in any of the groups (р=0.45).  Delayed RBC engraftment was more frequent in patients with ABO-incompatible SCTs (р=0.04). There were 4 cases of delayed hemolysis. Incidence and severity of GVHD was higher in the ABO-incompatible allo-SCT group (р=0.005).

Conclusions

ABO incompatibility between donor and recipient can cause acute and delayed hemolysis and it is a risk factor in the development of GVHD. It can delay RBC engraftment, but has no influence on other cell lines. Adequate prophylactic measures allow us to keep the incidence of acute hemolysis low.

Keywords

ABO incompatibility, PBSC, GVHD, engraftment

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Estrina, Мurat O. Yagmourov, Dmitriy E. Pevtsov, Еvgenia A. Kochina, Natalia E. Ivanova, Alla A. Golovacheva, Alexander L. Alyanskiy, Ludmila S. Zoubarovskaya, Abdulbasir A. Ganapiev, Boris V. Afanasyev</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(220) "

Maria A. Estrina, Мurat O. Yagmourov, Dmitriy E. Pevtsov, Еvgenia A. Kochina, Natalia E. Ivanova, Alla A. Golovacheva, Alexander L. Alyanskiy, Ludmila S. Zoubarovskaya, Abdulbasir A. Ganapiev, Boris V. Afanasyev

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Maria A. Estrina, Мurat O. Yagmourov, Dmitriy E. Pevtsov, Еvgenia A. Kochina, Natalia E. Ivanova, Alla A. Golovacheva, Alexander L. Alyanskiy, Ludmila S. Zoubarovskaya, Abdulbasir A. Ganapiev, Boris V. Afanasyev

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Background

ABO incompatibility between donor and recipient is currently considered one of the risk factors for immune-mediated complications, which can influence the outcome of allogeneic hematopoietic stem cell transplantation (allo-SCT).

Patients and methods

We analyzed 140 consecutive allo-HSCT recipients. 124 patients had HLA-compatible donors (39 related and 85 unrelated) and 16 patients had haploidentical donors. Fifty-nine of the donor–recipient pairs were ABO-identical, while 34 had minor incompatibility, 35 major incompatibility, and 12 bidirectional incompatibility. Seventy-eight patients received bone marrow (BM), 46 peripheral blood stem cells (PBSC), and 16 stem cells from both sources. Conventional myeloablative conditioning was used in 64 patients and non–myeloablative regimens in 78 patients. In both groups the same regimen of graft–versus–host disease (GVHD) prophylaxis was administered. In major ABO incompatibility SCT donor stem cells were depleted of RBC (6% hydroxyethyl starch sedimentation), in cases of minor incompatibility donor incompatible plasma was removed, and in cases of bidirectional incompatibility both methods were used.

Results

In all the study groups, we observed no cases of acute hemolysis after PBSC transfusion and only 2 cases after BM transfusion. Engraftment of leukocytes, neutrophils, and platelets was not altered in any of the groups (р=0.45).  Delayed RBC engraftment was more frequent in patients with ABO-incompatible SCTs (р=0.04). There were 4 cases of delayed hemolysis. Incidence and severity of GVHD was higher in the ABO-incompatible allo-SCT group (р=0.005).

Conclusions

ABO incompatibility between donor and recipient can cause acute and delayed hemolysis and it is a risk factor in the development of GVHD. It can delay RBC engraftment, but has no influence on other cell lines. Adequate prophylactic measures allow us to keep the incidence of acute hemolysis low.

Keywords

ABO incompatibility, PBSC, GVHD, engraftment

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Background

ABO incompatibility between donor and recipient is currently considered one of the risk factors for immune-mediated complications, which can influence the outcome of allogeneic hematopoietic stem cell transplantation (allo-SCT).

Patients and methods

We analyzed 140 consecutive allo-HSCT recipients. 124 patients had HLA-compatible donors (39 related and 85 unrelated) and 16 patients had haploidentical donors. Fifty-nine of the donor–recipient pairs were ABO-identical, while 34 had minor incompatibility, 35 major incompatibility, and 12 bidirectional incompatibility. Seventy-eight patients received bone marrow (BM), 46 peripheral blood stem cells (PBSC), and 16 stem cells from both sources. Conventional myeloablative conditioning was used in 64 patients and non–myeloablative regimens in 78 patients. In both groups the same regimen of graft–versus–host disease (GVHD) prophylaxis was administered. In major ABO incompatibility SCT donor stem cells were depleted of RBC (6% hydroxyethyl starch sedimentation), in cases of minor incompatibility donor incompatible plasma was removed, and in cases of bidirectional incompatibility both methods were used.

Results

In all the study groups, we observed no cases of acute hemolysis after PBSC transfusion and only 2 cases after BM transfusion. Engraftment of leukocytes, neutrophils, and platelets was not altered in any of the groups (р=0.45).  Delayed RBC engraftment was more frequent in patients with ABO-incompatible SCTs (р=0.04). There were 4 cases of delayed hemolysis. Incidence and severity of GVHD was higher in the ABO-incompatible allo-SCT group (р=0.005).

Conclusions

ABO incompatibility between donor and recipient can cause acute and delayed hemolysis and it is a risk factor in the development of GVHD. It can delay RBC engraftment, but has no influence on other cell lines. Adequate prophylactic measures allow us to keep the incidence of acute hemolysis low.

Keywords

ABO incompatibility, PBSC, GVHD, engraftment

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Memorial R. M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, St. Petersburg, Russia

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Memorial R. M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, St. Petersburg, Russia

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References

1. Dini G, Banov L, Dini S. EBMT Paediatric Diseases Working Party. Where should adolescents with ALL be treated? Bone Marrow Transplant. 2008 Oct;42 Suppl 2:35-9.

2. Ramanujachar R, Richards S, Hann I, Goldstone A, Mitchell C, Vora A et al.   Adolescents with Acute Lymphoblastic Leukaemia: outcome on UK National Paediatric (ALL 97) and Adult (UKALL XII/E2993) trials. Pediatric Blood Cancer. 2007;48:254-261.

3. Ramanujachar R, Richards S, Hann I, and Webb D. Adolescents with Acute Lymphoblastic Leukaemia: emerging from the shadow of paediatric and adult treatment protocols. Pediatric Blood Cancer. 2006;47:748-756.  

4. Testi AM, Valsecchi MG, Conter V, Vignetti M, Nigro LL, Locatelli F at al. Differences in outcome of adolescents with acute lymphoblastic leukaemia enrolled in paediatric (AIEOP) and adult (GIMEMA) protocols. Blood. 2004;104:539a.

5. De Bont JM, Holt B, Dekker AW, vanderDoes-vanderBerg A, Sonneveld P, Pieters R, et al. Significant difference in outcome for adolescents with acute lymphoblastic leukaemia treated on paediatric vs adult protocols in the Netherlands. Leukemia. 2004;18:2032-2035.

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References

1. Dini G, Banov L, Dini S. EBMT Paediatric Diseases Working Party. Where should adolescents with ALL be treated? Bone Marrow Transplant. 2008 Oct;42 Suppl 2:35-9.

2. Ramanujachar R, Richards S, Hann I, Goldstone A, Mitchell C, Vora A et al.   Adolescents with Acute Lymphoblastic Leukaemia: outcome on UK National Paediatric (ALL 97) and Adult (UKALL XII/E2993) trials. Pediatric Blood Cancer. 2007;48:254-261.

3. Ramanujachar R, Richards S, Hann I, and Webb D. Adolescents with Acute Lymphoblastic Leukaemia: emerging from the shadow of paediatric and adult treatment protocols. Pediatric Blood Cancer. 2006;47:748-756.  

4. Testi AM, Valsecchi MG, Conter V, Vignetti M, Nigro LL, Locatelli F at al. Differences in outcome of adolescents with acute lymphoblastic leukaemia enrolled in paediatric (AIEOP) and adult (GIMEMA) protocols. Blood. 2004;104:539a.

5. De Bont JM, Holt B, Dekker AW, vanderDoes-vanderBerg A, Sonneveld P, Pieters R, et al. Significant difference in outcome for adolescents with acute lymphoblastic leukaemia treated on paediatric vs adult protocols in the Netherlands. Leukemia. 2004;18:2032-2035.

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