ISSN 1866-8836
Клеточная терапия и трансплантация

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G. Complications in hematology (infections, haemostasis abnormalities, fertility)

Hemostasis in patients with acute myeloblastic leukemia (AML) manifestation

Valentina V. Cherepanova, Sofia G. Vladimirova, Lyudmila N. Tarassova, Gulzada N. Mustafina, Natalia N. Silina

Correlations between reactivation of herpesviruses and common complications of allo-HSCT

Olga S. Pankratova, Alexey B. Chukhlovin, Ludmila S. Zubarovskaya, Boris V. Afanasyev

Management of resistant or recurrent CMV infection following allogeneic SCT

Petr Sedlacek1, Ladislav Krol1, Petr Hubacek1, David Boutolleau2, Tomas Kalina1

C-reactive protein (CRP) concentration in patients with acute myeloblastic leukemia (AML) manifestation

Sofia G. Vladimirova, Lyudmila N. Tarassova, Gulzada N. Mustafina, Valentina V. Cherepanova

Epidemiology of bacterial infections and antibiotic resistance in BMT clinic: single center experience

Vladimir N. Vavilov1, Olga B. Ponomarenko1, Marina O. Popova1, Svetlana S. Emelyanova2, Maria Yu. Averjanova1, Oleg V. Goloschapov1, Ludmila S. Zubarovskaya1, Boris V. Afanasyev1

Invasive fungal disease (IFD) in patients after allogeneic hematopoietic stem cell transplantation: single center experience

Natalia I. Zubarovskaya1, Yulia G. Vasilieva1, Natalia V. Stancheva1, Elena V. Semenova1, Vladimir N. Vavilov1, Svetlana Emelyanova2, Nikolay N. Klimko3, Boris V. Afanasyev1

G. Complications in hematology (infections, haemostasis abnormalities, fertility)

Hemostasis in patients with acute myeloblastic leukemia (AML) manifestation

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Valentina V. Cherepanova, Sofia G. Vladimirova, Lyudmila N. Tarassova, Gulzada N. Mustafina, Natalia N. Silina

Kirov Research Institute of Hematology and Blood Transfusion, Kirov, Russia

Bleeding and infections in acute leukemia (AL) are the most frequent and dangerous complications. Autopsy results of 65 patients treated in our clinic from 1992 to 2000 testify the importance of studying blood coagulation disorders in AL: hemorrhages are cited as the cause of death in 28.6% of cases, thrombosis in 10.8% of cases. The aim was to estimate the hemostasis in patients with AML manifestation. A total of 74 patients with AML manifestation were observed (39 males and 35 females, aged 16–77 years, median age of 42). FAB classification variants of AML were as follows: М1 – 18, М2 – 39, М4 – 8, and М5 – 9. Of the 74 patients, 67 had complications, 27 of them infectious, and 46 hemorrhagic. Type I hemorrhagic syndrome was observed in 10%, II in 28%, III in 9% and IV in 20% (classification of Dabberha Nafa, 1992). A mild degree of thrombocytopenia was noticed in 25% of patients, moderate in 34% and deep in 11% (classification of Agranenko VA, 1998). The mean of APTT corresponded to the norm, but was prolonged in 17.6% of patients. Fibrinogen concentration was increased. Its decrease is revealed only in 13.5% of patients. Increase of intravascular coagulation markers was observed, such as soluble fibrin monomer by o-phenanthroline (25.7%), by ethanol tests (74.3%), and D-dimers (9.5%). There was plasminogen activation in all patients. Hageman-dependent euglobulin clot lysis on average was considerably prolonged, that in the case of hypofibrinogenemia did not exclude fibrinolysis activation. It is confirmed not only by literature data but also by our patients: in 7 patients its shortening was noted. Simultaneous antithrombin III activation and protein C consumption were established. Thus, in patients with AML manifestation high frequency of hemorrhagic complications was revealed. The complications are related not only to thrombocytopenia but also to changes in plasma coagulation.

Keywords

acute myeloblastic leukemia, AML, hemostasis, bleeding complications, hemorrhagic syndrome

G. Complications in hematology (infections, haemostasis abnormalities, fertility)

Risk factors of invasive candidiasis in children with leukemia

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Elmira G. Boichenko, Alexey S. Kolbin

City Children's Hospital № 1, St. Petersburg, Russia

Methods

512 children with leukemia were analysed: acute lymphoblastic leukemia (ALL) – 310, acute myeloid leukemia (AML) – 76, relapse of leukemia – 126 children. The median age was 7 years. There were 341 boys (67%) and 171 girls (34%).

To determine a statistical significance of risk factors of IC development the following computing methods and  importance of distinctions criteria were applied: odds ratio (OR), a confidential interval (CI), criterion р, median (Ме).

Results

The frequency of IC was 4.9% (25 patients). The statistically significant risk factors of IC development were the following: relapse of leukemia (OR 0.24, 95% CI 0.06–0.89, p <0.001), treatment of relapse (OR 0.24, 95% CI 0.06–0.91, p <0.001), duration of neutropenia (< 0.5x109/l) more than 14 days (OR 0.35, 95% CI 0.08–1.51, p=0.008), use of carbapenems (OR 0.18, 95% CI 0.06–0.59, p=0.002) and vancomycin (OR 0.23, 95% CI 0.07–0.72, p=0.014).

Conclusions

1. Risk factors of IC development in children with leukemia were the following: relapse of leukemia, treatment of the relapse, duration of neutropenia more than 14 days, the use of carbapenems and vancomycin for the antibacterial treatment. 2. Patients with risk factors of IC should receive systemic antifungal prophylaxis to prevent the development of life-threatening infection.

Keywords

leukemia, children, invasive candidiasis, risk factors

G. Complications in hematology (infections, haemostasis abnormalities, fertility)

Correlations between reactivation of herpesviruses and common complications of allo-HSCT

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Olga S. Pankratova, Alexey B. Chukhlovin, Ludmila S. Zubarovskaya, Boris V. Afanasyev

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

Patients and methods

We studied 145 patients with different hematological malignancies, including ALL (n=51), AML (n=37), CML (n=15), lymphomas (n=9), and MDS (n=6). They underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). The patients received bone marrow (35%), or peripheral blood stem cells (65%). Allo-HSCT from an unrelated donor occurred in 64% of cases. CMV-, HSV-, and EBV-specific DNA in leukocytes was detected weekly – with commercial PCR kits – up to 100 days after allo-HSCT. Cases of pneumonia, neurological signs, herpetic rushes, gut mucositis, hemorrhagic cystitis, and aGVHD grade were registered.

Results

HSV-, EBV-, and CMV-specific DNAs in post-HSCT blood samples revealed rates of 51%, 57%, and 45%, respectively (2.3 to 2.5-fold exceeding pretransplant rates). Types of underlying malignancy and gender did not influence these ratios. Following myeloablative versus reduced conditioning regimens, HSV positivity (>2 positive findings) was found in 36% and 21% of cases (p=0.02), respectively. Similar differences with CMV and EBV positivity were expressed only as tendencies.

Meanwhile, the incidence of HSV and CMV findings was age-dependent, i.e., minimal frequencies of PCR positivity were observed from 1–4 years of age, followed by increased viral reactivation from the age of 10–20 years. Among young patients (<21 years old), a correlation was found between neurological symptoms and multiple HSV positivity (p=0.002). Similarly, mucositis severity was associated with the persistence of either HSV, or CMV (p values, 0.02 and 0.008, respectively). Risk of intestinal aGVHD proved to correlate with EBV positivity (p=0.008). Similarly, a risk for posttransplant cystitis was dependent on EBV reactivation (p=0.01).

Conclusion

The study suggests that there is a correlation between repeated positivity of HSV, EBV, CMV, and some common complications after allo-HSCT. The significance of herpesvirus infection after allo-HSCT may be tested in further studies.

Keywords

hemopoietic cells, transplantation, complications, herpesviruses, reinfection

G. Complications in hematology (infections, haemostasis abnormalities, fertility)

Management of resistant or recurrent CMV infection following allogeneic SCT

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Petr Sedlacek1, Ladislav Krol1, Petr Hubacek1, David Boutolleau2, Tomas Kalina1

1Department of Pediatric Hematology and Oncology, HSCT Unit, Prague, Czech Republic; 2UPMC University Paris and Service de Virologie, GH Pitié-Salpêtrière, Paris, France

Despite the strategy of preemptive treatment of CMV infections, CMV disease is still a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Patients who failed to respond to ganciclovir (GCV) may be rescued by other virostatics or by cellular therapy. Conversely, by using preemptive strategies a lot of patients might be unnecessarily overtreated. Other tools have to be exploited in order to improve post-transplant management of CMV infection.  

We monitor CMV quantity in whole blood using real-time PCR technology. If resistance to GCV is suspected, we change the therapy and we indicate PCR detection of the most frequent CMV resistant strains. Detection of CMV-specific immune response is based on a polychromatic flow cytometry cytokine staining method. We evaluate the ability of CD4+ and CD8+ T-cells to produce interferon-γ and interleukin-2, to express activation marker CD40L, and/or to mobilize degranulation marker CD107a in response to CMV antigens.

In almost half of about 200 pediatric patients we detected CMV DNA in the sample; about 30% of them were indicated for preemptive therapy. Despite preemptive therapy CMV disease developed in 10 children (8 deceased). Clinical suspicion for CMV resistant strains was observed in 22 children and known resistance mutation was proved in 4 of them. 

Implementation of methods that allow CMV-specific T-cell reconstitution monitoring may allow us to define a subgroup of patients who are able to resolve a CMV infection without virostatics. These patients could be spared from virostatic toxicity. Inefficient reconstitution of immunity, infection with ganciclovir resistant CMV strains, and inadequate intensity of therapy are factors responsible for treatment failure.

Acknowledgements

Supported by GAUK-47807/2007, IGA ČR -NS/9996-4 and NR/9418-3.

Keywords

CMV disease, allogeneic stem cell transplantation, resistance, reconstitution of immunity, PCR monitoring

G. Complications in hematology (infections, haemostasis abnormalities, fertility)

C-reactive protein (CRP) concentration in patients with acute myeloblastic leukemia (AML) manifestation

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Sofia G. Vladimirova, Lyudmila N. Tarassova, Gulzada N. Mustafina, Valentina V. Cherepanova

Kirov Research Institute of Hematology and Blood Transfusion, Russia

Correspondence
Sofia G. Vladimirova, Kirov Research Institute of Hematology and Blood Transfusion, Krasnoarmeyskaya str., 72, Kirov, 610027, Russia, Phone: +7 (8332) 54-51-83, Phone/Fax: +7(8332) 54-97-31
E-mail: vlsg@mail.ru

The aim of the study was to estimate the dependence of CRP concentration from the presence of an infection and the amount of leukocytes and blasts in patients with AML manifestation. We observed 24 patients with AML at the stage of diagnosis of the disease (12 male, 12 female; aged 20–76 years; median age, 49).  FAB classification variants of AML were: М0–2, М1–2, М2–14, М4–5 and М5–1. CRP concentration was measured by immunoturbidimetric assay. The statistical difference between groups was assessed by Dann’s test. Spearman’s rank correlation coefficient was calculated to measure the degree of association between CRP concentration and the amount of leukocytes and blasts. All patients were divided into 3 groups: 1 – patients without fever and infection (n=10); 2 – patients with fever and infection focal (n=7); 3 – patients with fever but without the visible focal of infection (n=7).  CRP levels in group 1 ranged from 0 to 0.043g/l (median – 0.000g/l); in group 2, from 0.007 to 0.383g/l (median – 0.044g/l); and in group 3, from 0.015 to 0.260g/l (median – 0.160g/l). When comparing groups 1 vs. 2 and 1 vs. 3, differences were significant (р<0.05); between groups 2 and 3, difference was absent (p>0.05). The correlation between CRP concentration and the amount of leukocytes and blasts was observed in the patients in group 1 (rs 0.718 and 0.676 accordingly; р<0.05). These parameters did not correlate in the patients with infectious complications (groups 2 and 3). Thus, in patients with AML manifestation the increase in the number of leukocytes and blasts in peripheral blood influences CRP production in patients with AML manifestation. Its concentration increases even more with the presence of an infection. The results enable us to consider this parameter as a marker of infection during AML manifestation.

Keywords

acute myeloblastic leukemia, AML, C-reactive protein, CRP, infection complications

G. Complications in hematology (infections, haemostasis abnormalities, fertility)

Epidemiology of bacterial infections and antibiotic resistance in BMT clinic: single center experience

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Vladimir N. Vavilov1, Olga B. Ponomarenko1, Marina O. Popova1, Svetlana S. Emelyanova2, Maria Yu. Averjanova1, Oleg V. Goloschapov1, Ludmila S. Zubarovskaya1, Boris V. Afanasyev1

1Memorial R.M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University,
St. Petersburg, Russia; 2Petersburg Nuclear Physics Institute, Russian Academy of Science, St. Petersburg, Russia

Correspondence
Vladimir Vavilov, Memorial R.M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, St. Petersburg, Russia
E-mail: vladimir_vavilov@mail.ru 

Background

High-dose chemotherapy, hematopoietic stem cell transplantation (HSCT) and “graft-versus-host” disease treatment are associated with greatly increasing the risk of the most frequent and most life–threatening infectious complications.

Aim

The aim of this single-center study was to evaluate the epidemiology and antibiotic resistance of bacterial infections in oncohematological and HSCT patients.

Patients and methods

Three hundred consecutive, positive cultures were sampled from 79 high-risk patients. Cultures were provided with BacT/Alert® and Vitek® technologies.

Results

The organisms that most commonly caused infectious complications were
S. epidermidis, E. faecalis, E. faecium, S. aureus, K. pneumoniae,
Enterobacter spp., Acinetobacter spp.,
and P. aeruginosa.

The agents that most commonly caused bacteremia were S. epidermidis,
K. pneumoniae, P. aeruginosa, E. coli,
and E. faecalis. Compared with causes of bacteremia in 2006–2007, the study of 2008–2009 shows the superior but decreasing role of Gram-positive cocci and increasing rates of bacteremia episodes caused by Gram-negative agents.

Analysis of antibiotic resistance shows high efficacy of vancomycin and linezolid, cefoperazone/sulbactam and piperacillin, and moderate efficacy of carbapenems, quinolones, and aminoglycosides. In contrast, increasing resistance to some third generation cephalosporins (only ceftriaxone and ceftazidime) was observed.

We observed increasing rates of multiresistant strains of K. pneumoniae,
P. aeruginosa
and Acinetobacter spp. At the same time there is no increasing rates of Gram-positive cocci: only 12.5% of S. aureus were resistant to oxacillin (ORSA). Low rates of vancomycin resistant enterococci (VRE) infections were observed.

Conclusions

Our study shows the emerging role of Gram-negative bacteria with increasing rates of multiresistant strains. Analysis of antibiotic sensitivity shows that the principles of antimicrobial agents use in patients with hematological and oncological diseases treated in BMT clinics should be changed.

Keywords

stem cell transplantation, acute leukemia, infectious complications, antibiotic resistance

G. Complications in hematology (infections, haemostasis abnormalities, fertility)

Invasive fungal disease (IFD) in patients after allogeneic hematopoietic stem cell transplantation: single center experience

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Natalia I. Zubarovskaya1, Yulia G. Vasilieva1, Natalia V. Stancheva1, Elena V. Semenova1, Vladimir N. Vavilov1, Svetlana Emelyanova2, Nikolay N. Klimko3, Boris V. Afanasyev1

1Memorial R.M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University,
St. Petersburg, Russia; 2Petersburg Nuclear Physics Institute, Russian Academy of Science, St. Petersburg, Russia; 3Academy of postgraduate education, 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: bmt@spmu.rssi.ru

Aim

The objective was to evaluate the incidence of IFD, to determine risk factors of IFD, and to study its influence on OS in patients undergoing allo-HSCT.

Patients and methods

The study included 221 post-allo-HSCT patients (pts) between October 2000 and July 2008. The age range was 1–66 years old (median 21 y.o.) There were 150 AL pts; 27 CML, CMF and CLL pts; 11 AA pts; 8 congenital disorder pts; 17 NHL/HD pts; 6 MDS pts; and 3 solid tumor pts. Eighty-six pts underwent myeloablative conditioning, while 135 pts underwent non–myeloablative conditioning (RIC) followed by allo-HSCT. At the time of allo-HSCT, 134 pts were in CR, and 87 in relapse. Types of donor: 77 MRD pts, 135 MUD pts, and 9 haploidentical pts. Sources of HSC: 142 PBSC pts, 67 BM pts, and 12 BM+PBSC pts. Median: CD34+- 8 х106/kg. Acute GVHD prophylaxis was standard.

Results

The incidence of IFD until D+100 was 27%; after D+100, 36%. Possible IFDs were detected in 27 pts, probable IFDs in 37 pts, and proven IFDs in 2 pts. The onset of IFD was on D+1-940 (median D+86). In a multivariable analyses the following risk factors were revealed: age older than 10 years (RR=1.2; 95%CI, 1.01–1.6), usage of ATG in conditioning in pts older than 21 y.o. (RR=0.7; 95% CI, 0.59–0.88, Р<0.05), mucositis I–IV (RR=2.1; 95% CI, 1.2–3.8), chGVHD extensive form in patients younger than 21 y.o. (RR= 2.1; 95% CI, 1.3–3.4, Р<0.05). Conditioning, time of engraftment, stage of disease, and source of HSC were not independent risk factors for IFD. In pts younger than 21 y.o., synergistic effect of the following factors was detected: relapse, myeloablative conditioning, and BM as a source of HSC (RR=0.4; 95% CI, 0.21–0, 76, Р<0.05). In pts older than 21 y.o. with MRD after RIC and a source of HCS PBSC, the incidence of IFI was lower (RR=1.59; 95% CI, 1.01–2.51, Р<0.05). Overall survival (OS) in pts undergoing HSCT with IFD versus without IFD is 25% vs 53% (p<0.005).

Conclusion

The rates of IFD after HSCT remain high and impair OS.

Keywords

related allo-HSCT, unrelated allo-HSCT, allo-HSCT invasive fungal disease