Clinical Value of miR-3151 Overexpression in Synergistic Interaction with BAALC Host Gene in Patients with Acute Myeloid Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

AI Shakirova, IM Barkhatov, AI Churkina, NN Mamaev, LS Zubarovskaya, BV Afanas’ev

RM Gorbacheva Scientific Research Institute of Pediatric Oncology, Hematology and Transplantation; IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Alena Igorevna Shakirova, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel.: +7(812)338-62-72; e-mail: alyona.i.shakirova@gmail.com

For citation: Shakirova AI, Barkhatov IM, Churkina AI, et al. Clinical Value of miR-3151 Overexpression in Synergistic Interaction with BAALC Host Gene in Patients with Acute Myeloid Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation. Clinical oncohematology. 2019;12(3):303–8 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-303-308


ABSTRACT

Background. Among a multitude of molecular genetic changes underlying acute myeloid leukemia (AML) disordered epigenetic regulation is of special importance. It includes expression change in miR-3151 gene forming a part of BAALC gene on chromosome 8 in q22.3 locus. At present BAALC gene overexpression is observed in a half of AML patients. A considerable part of them shows a combination of it with an increased transcriptional activity of miR-3151 gene, which is associated with the poorest AML prognosis.

Aim. To assess the prognostic value of miR-3151 overexpression in synergistic interaction with BAALC host gene in AML patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Materials & Methods. The trial included bone marrow samples taken from 10 healthy SCT donors and 29 AML patients after receiving allo-HSCT. Relative miR-3151 expression level and relative BAALC copy number were measured by quantitative real-time polymerase chain reaction.

Results. The analysis yielded a poor correlation between miR-3151 expression level and blast cell count in bone marrow (r = 0.330; = 0.005) as well as between the expression levels of miR-3151 and BAALC (r = 0.273; = 0.020). In addition, a great prognostic value of miR-315 overexpression in post-transplantation period was confirmed (= 0.005). Patients with miR-315 and BAALC co-expression in post-transplantation period have also the poorest prognosis than the control group with regard to both disease-free survival and relapse risks within 2 years after allo-HSCT.

Conclusion. Monitoring expression level of miR-3151 and its host gene BAALC in AML patients after receiving allo-HSCT seems to be important not only in AML prognosis but also in therapy efficacy evaluation.

Keywords: acute myeloid leukemia, miR-3151, BAALC, prognosis, allogeneic hematopoietic stem cell transplantation.

Received: October 22, 2018

Accepted: June 7, 2019

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Prediction of FLAG ± Ida Regimen Efficacy in Patients with Relapsed/Refractory Acute Myeloid Leukemia

IG Budaeva, EG Ovsyannikova, EN Goryunova, OV Kulemina, DV Zaitsev, DV Motorin, RSh Badaev, DB Zammoeva, VV Ivanov, KV Bogdanov, OS Pisotskaya, YuV Mirolyubova, TS Nikulina, YuA Alekseeva, AYu Zaritskey, LL Girshova

VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

For correspondence: Irina Garmaevna Budaeva, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; Tel.: +7(931)351-07-06; e-mail: irina2005179@mail.ru

For citation: Budaeva IG, Ovsyannikova EG, Goryunova EN, et al. Prediction of FLAG ± Ida Regimen Efficacy in Patients with Relapsed/Refractory Acute Myeloid Leukemia. Clinical oncohematology. 2019;12(3):289-96 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-289-296


ABSTRACT

Aim. To assess the efficacy of FLAG/FLAG-Ida regimen and to identify factors that influence remission, duration of disease-free survival (DFS) and overall survival (OS) of patients with relapsed/refractory acute myeloid leukemia (AML).

Materials & Methods. The trial included 54 patients (28 men and 26 women), median age was 37 years (range 18–70 years). 27 (50 %) out of 54 patients had refractory AML and 27 (50 %) patients had relapsed AML. FLAG and FLAG-Ida regimens were administered as induction therapy. 37 (68.5 %) patients received bone marrow transplantation. Molecular genetic and cytogenetic examinations were performed prior to therapy and on the 28th day after the start of treatment. WT1 gene expression was evaluated on the 14th–16th day of treatment.

Results. Complete remission (CR) was achieved in 42 (77.8 %) out of 54 patients. Refractoriness to therapy was observed in 9 (16.7 %) out of 54 patients, mortality was 5.5 % (3/54). Remission rate was higher in patients with relapsed AML compared with refractory AML: 85.2 % (23/27) and 70.4 % (19/27), respectively. On the 14th–16th day of treatment patients with blast cell count ≥ 10 % in bone marrow (BM) showed significantly lower CR rate (60 %) compared with the group of patients with < 10 % blast cells in BM (89.6 %; = 0.024) and shorter DFS (median 7.6 vs. 17.6 months, respectively; = 0.03). Median DFS in patients with WT1 expression reduction to < 1 log on the 14th–16th day was 5 vs. 18 months in patients without WT1 expression reduction (= 0.01). DFS varied in groups of patients with blast cell count < 10 % in BM on the 14th–16th day of treatment based on the level of WT1 expression reduction (= 0.04). MRD-negative patients (57.1 %) showed significantly longer DFS and OS compared with MRD-positive patients (median DFS was 17.6 vs. 5.2 months, respectively, = 0.02; median OS was 19 vs. 6.9 months, = 0.0002). Median DFS and OS were different only in ELN low- and high-risk groups (median not reached vs. 5.2 months, respectively, = 0.039; median not reached vs. 10.2 months, = 0.039).

Conclusion. FLAG and FLAG-Ida are effective and safe regimens in the treatment of relapsed/refractory AML. Achieving remission depends on neither the risk group nor the time of relapse occurrence. The blast cell count in BM on the 14th–16th day of FLAG/FLAG-Ida treatment is a prognostic factor determining achievement and duration of remission. WT1 expression level in the early post-induction period is a sensitive DFS marker. MRD status and molecular genetic risk (ELN) group affiliation are essential prognostic factors determining DFS and OS.

Keywords: acute myeloid leukemia, relapse, refractoriness, FLAG and FLAG-Ida regimens.

Received: November 2, 2018

Accepted: May 28, 2019

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Preventive Use of Azacitidine in Patients with Acute Myeloid Leukemia after Haploidentical Allo-BMT

RSh Badaev, DB Zammoeva, LL Girshova, DV Babenetskaya, NA Il’ina, YuA Alekseeva, AYu Zaritskey, DV Motorin

VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

For correspondence: Dmitrii Vasil’evich Motorin, MD, PhD, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; e-mail: almazov-bmt@mail.ru

For citation: Badaev RSh, Zammoeva DB, Girshova LL, et al. Preventive Use of Azacitidine in Patients with Acute Myeloid Leukemia after Haploidentical Allo-BMT. Clinical oncohematology. 2019;12(1):37–42.

DOI: 10.21320/2500-2139-2019-12-1-37-42


ABSTRACT

Background. Haploidentical bone marrow transplantation (BMT) can be a reliable alternative if a fully matched donor is not available. The main challenges after BMT are a relapse of major disease, graft-versus-host disease (GVHD), and infections. Azacitidine possesses antileukemic effect together with immunomodulating properties and being administered soon after BMT can significantly improve the outcome.

Aim. To study azacitidine effect on the outcome of haploidentical BMT in patients with acute myeloid leukemia (AML) in the early post-transplantation period.

Materials & Methods. The trial included 18 AML patients who received haploidentical BMT at VA Almazov National Medical Research Center. In all patients MRD-negative remission was achieved on the 30th day after BMT. Azacitidine therapy was initiated not earlier than 2 months after BMT with a complete engraftment of transplant and no GVHD. Azacitidine 100 mg/day was administered on D1–D5 every 28 days within a year after BMT. When a molecular relapse was detected, donor lymphocytes were additionally infused during every other cycle of therapy.

Results. Eleven patients received preventive azacitidine treatment, 7 patients were included in control group. Median onset of azacitidine treatment after haploidentical BMT was 4 months (range 2–10 months), median number of azacitidine courses was 3.5 (range 1–9). During azacitidine treatment acute GVHD was identified in 5 (45.4 %) patients. In 4 of them an exacerbation of earlier GVHD was detected (3 with cutaneous form and 1 with intestinal form), and only in 1 patient de novo acute intestinal GVHD was discovered.

Conclusion. Azacitidine treatment of AML patients after haploidentical allo-BMT is safe and well tolerated. Preventive azacitidine treatment after haploidentical BMT improves overall survival of AML patients.

Keywords: haploidentical allogeneic bone marrow transplantation, azacitidine, acute myeloid leukemia.

Received: June 22, 2018

Accepted: December 11, 2018

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Results of Molecular Monitoring in Posttransplant Period by Means of Series Investigation of WT1 Gene Expression in Patients with Acute Myeloid Leukemia

YaV Gudozhnikova, NN Mamaev, IM Barkhatov, VA Katerina, TL Gindina, AI Shakirova, SN Bondarenko, OA Slesarchuk, EI Darskaya, OV Paina, LS Zubarovskaya, BV Afanas’ev

RM Gorbacheva Scientific Research Institute of Pediatric Oncology, Hematology and Transplantation; IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Prof. Nikolai Nikolaevich Mamaev, MD, PhD, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel.: +7(812)233-12-43; e-mail: nikmamaev524@gmail.com

For citation: Gudozhnikova YaV, Mamaev NN, Barkhatov IM, et al. Results of Molecular Monitoring in Posttransplant Period by Means of Series Investigation of WT1 Gene Expression in Patients with Acute Myeloid Leukemia. Clinical oncohematology. 2018;11(3):241–51.

DOI: 10.21320/2500-2139-2018-11-3-241-251


ABSTRACT

Aim. To demonstrate diagnostic and prognostic significance of series measurement of WT1 expression in patients with acute myeloid leukemia (AML) after allogenic hematopoietic stem cell transplantation (allo-HSCT).

Materials & Methods. The clinical trial included 88 AML patients (38 females (43 %) and 50 males (57 %) aged 2–68, median 30 years). All the patients received allo-HSCT. Bone marrow was aspirated before (D0) and after HSCT (D+30, D+60, and D+100).

Results. The univariate analysis showed statistically significant differences in 2-year overall survival with respect to the following factors: with and without remission at the moment of HSCT (< 0.001), with and without chronic graft vs. host disease (cGVHD) (= 0.002), primary or secondary (MDS) AML (= 0,028), WT1 gene expression < and > 250 copies before HSCT (< 0.001) and at time points D+60 (= 0.012), and D+100 (< 0.001). Multivariate analysis revealed similar statistical significance of differences among patients transplanted in remission (= 0.041) and with cGVHD (= 0.03). In univariate analysis statistically significant differences in 2-year event-free survival (EFS) were found: a) in patients with allo-HSCT, either in remission or not (< 0.001); b) using HSC, but not bone marrow, as transplant source (p < 0.026); c) with normal or high WT1 expression at the stage of HSCT (< 0.001) and at time point D+100 (< 0.001); d) using HSC from related or unrelated donor (= 0.006); e) in patients with cGVHD (= 0.05). In multivariate analysis independent positive effect on EFS was observed only in patients with normal WT1 expression at D+100 (= 0.011) and with cGVHD (= 0.038). Cumulative incidence of posttransplant relapse (PTR) in AML patients with normal or high WT1 expression at the stage of HSCT within the 2-year follow-up was significantly different (28.2 vs. 58.9 %; = 0.002), also in measurements of this parameter at D+60 and D+100 (= 0.015 and < 0.001, respectively). In 1/4 of patients cytological relapses (cPTR) appeared considerably later than molecular relapses (mPTR), i.e. 13–489 days later (median 35 days), which is accounted for by early preventive therapy aimed at cPTR prophylaxis against the background of already recorded mPTR. According to our data, GVHD plays a crucial role in cPTR management.

Conclusion. Phenomenon of WT1 expression normalization after allo-HSCT in AML patients proves to have a high diagnostic and prognostic significance. Introduction of this approach into clinical practice seems highly advisable for national oncohematological centers.

Keywords: acute myeloid leukemia, allo-HSCT, posttransplant relapse, diagnostics and treatment with molecular monitoring of WT1 expression, graft vs. host disease.

Received: January 20, 2018

Accepted: April 18, 2018

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The Role of Hypomethylating Agents Prior to Allogeneic Hematopoietic Stem Cells Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome

VN Ovechkina1, SN Bondarenko1, EV Morozova1, IS Moiseev1, AA Osipova1, TL Gindina1, AI Shakirova1, TA Bykova1, AD Kulagin1, IA Samorodova2, EV Karyakina3, EA Ukrainchenko4, LS Zubarovskaya1, BV Afanas’ev1

1 RM Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

2 Municipal Clinical Hospital No. 31, 3 Dinamo pr-t, Saint Petersburg, Russian Federation, 197110

3 Municipal Hospital No. 15, 4 Avangardnaya str., Saint Petersburg, Russian Federation, 198205

4 Aleksandrov Hospital, 4 Solidarnosti pr-t, Saint Petersburg, Russian Federation, 193312

For correspondence: Varvara Nikolaevna Ovechkina, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel.: +7(812)338-62-72; e-mail ovetchkina@gmail.com

For citation: Ovechkina VN, Bondarenko SN, Morozova EV, et al. The Role of Hypomethylating Agents Prior to Allogeneic Hematopoietic Stem Cells Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome. Clinical oncohematology. 2017;10(3):351–7 (In Russ).

DOI: 10.21320/2500-2139-2017-10-3-351-357


ABSTRACT

Background & Aims. The aim of the study was to evaluate the efficacy and safety of azacytidine and decitabine prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia.

Materials & Methods. The research included 62 patients who received hypomethylating agents (HMA) prior to allo-HSCT. The median age was 28 years (range from 1 to 68 years), the study population consisted of 27 (43.5 %) women and 35 (56.5 %) men.

Results. The overall response (complete + partial remission) was observed in 42 % (n = 26) of cases. At the time of allo-HSCT no disease progression was observed in 41 (66 %) patients. The multivariant analysis showed the overall survival (OS) statistically significantly increased with the graft retention (hazard ratio [HR] 0.002; 95% confidence interval [95% CI] 0.001–0.74; p = 0.03), and also with the administration of HMA after allo-HSCT (HR 0.24; 95% CI 0.08–0.67; p = 0.007). The response (stabilisation, partial or complete remission) due to HMA administration prior to allo-HSCT (HR 6.4; 95% CI 0.75–54.0; p = 0.08) was associated with improved OS. The event-free survival (EFS) was significantly higher with the response to azacytidine and decitabine at the time of allo-HSCT (HR 38.9; 95% CI 1.3–1198.0; p = 0.03) and with the graft retention (HR 0.02; 95% CI 0.005–0.1; p = 0.001). In patients with MDS compared with AML (HR 2.3; 95% CI 0.9–22.0; p = 0.08), there was a tendency to EFS improvement. Progression-free survival rates were higher in patients with a number of blast cells in the bone marrow less than 31 % at the time of diagnosis (HR 1.1; 95% CI 1.1–9.9; p = 0.01).

Conclusion. The use of azacytidine and decitabine prior to allo-HSCT allows to safely control the tumor mass in patients with MDS and to maintain the achieved remission with AML. In patients with a response to HMA, the best OS and EFS values are seen after allo-HSCT.

Keywords: acute myeloid leukemia, myelodysplastic syndrome, allogeneic hematopoietic stem cell transplantation, hypomethylating agents, azacitidine, decitabine.

Received: December 19, 2016

Accepted: March 9, 2017

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Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemias with Hyperdiploid Karyotype

TL Gindina, NN Mamaev, ES Nikolaeva, SN Bondarenko, OA Slesarchuk, AS Borovkova, SV Razumova, OV Pirogova, AL Alyanskii, LS Zubarovskaya, BV Afanas’ev

RM Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Academician IP Pavlov First St. Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Tat’yana Leonidovna Gindina, PhD, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel: + 7(812)233-12-43; e-mail: cytogenetics.bmt.lab@gmail.com

For citation: Gindina TL, Mamaev NN, Nikolaeva ES, et al. Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemias with Hyperdiploid Karyotype. Clinical oncohematology. 2016;9(4):383–90 (In Russ).

DOI: 10.21320/2500-2139-2016-9-4-383-390


ABSTRACT

Aim. To evaluate the prognostic impact of the different cytogenetic characteristics, including the modal number, the number of chromosomal aberrations in a complex karyotype, and adverse chromosomal abnormalities (ACA) (–7/7q–, –5/5q–, –17/17p–, t(6;9)(p22;q34)) on the results of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with hyperdiploid acute myeloid leukemia (H-AML).

Methods. Forty seven H-AML patients (21 women and 26 men, aged from 1 to 58 years, median — 23.9 years) were examined. The analysis of overall (OS) and event-free survival (EFS) predictors after allo-HSCT in patients with different clinical, transplant and cytogenetic characteristics was performed.

Results. The modal number of chromosomes (MN) of 47–48 was the most common one in the karyotype which was observed in 31 (66 %) patients. High hyperdiploidy with the modal number of 49–65 was identified in 13 (28 %) patients, near-triploid and near-tetraploid karyotypes were found in 3 (6 %) patients. Quantitative chromosomal abnormalities were nonrandom. Chromosome 8 (50 %), 21 (32 %), 13 (16 %) и 22 (16 %) trisomy was the most common one. Structural chromosomal abnormalities were detected in 22 (47 %) patients, at that, ACA were found in 7 (19 %) patients. In univariate analysis, the OS and EFS after allo-HSCT differed in patients with different clinical status (remission vs. active disease; = 0.003 and = 0.002, respectively), different chromosomal abnormalities in hyperdiploid karyotype (ACA– vs. ACA+; = 0.001 and = 0.03, respectively). An additional analysis of selected patients group with a structurally complex karyotype (n = 19) showed, that patients without ACA had a higher OS than patients with ACA (= 0.03). In multivariate analysis, the disease status (relapse) at allo-HSCT was an independent predictor of decreased OS and EFS (= 0.004 и = 0.006, respectively), as well as the presence of the ACA (= 0.002 only for OS).

Conclusion. ACA were high-risk factors in H-AML patients received allo-HSCT. Therefore, the patients with formal criteria of a complex karyotype should not be automatically included in the cytogenetic unfavorable risk group.


Keywords: hyperdiploid and complex karyotypes, acute myeloid leukemia, allogeneic hematopoietic stem cell transplantation, prognosis.

Received: April 17, 2016

Accepted: May 5, 2016

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REFERENCES

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Genetic Mutations in Acute Myeloid Leukemia

OV Blau

Charite Clinic, Berlin Medical University, 30 Hindenburgdamm, Berlin, Germany, 12200

For correspondence: Ol’ga Vladimirovna Blau, DSci, Department of Hematology, Oncology and Tumorimmunology, Charite University School of Medicine, Hindenburgdamm 30, 12200, Berlin, Germany; e-mail: olga.blau@charite.de.

For citation: Blau OV. Genetic Mutations in Acute Myeloid Leukemia. Clinical oncohematology. 2016;9(3):245-56 (In Russ).

DOI: 10.21320/2500-2139-2016-9-3-245-256


ABSTRACT

Acute myeloid leukemia (AML) is a clonal malignancy characterized by ineffective hematopoiesis. Most AML patients present different cytogenetic and molecular defects associated with certain biologic and clinical features of the disease. Approximately 50–60 % of de novo AML and 80–95 % of secondary AML patients demonstrate chromosomal aberrations. Structural chromosomal aberrations are the most common cytogenetic abnormalities in about of 40 % of de novo AML patients. A relatively large group of intermediate risk patients with cytogenetically normal (CN) AML demonstrates a variety of outcomes. Current AML prognostic classifications include only some mutations with known prognostic value, namely NPM1, FLT3 and C/EBPa. Patients with NPM1 mutation, but without FLT3-ITD or C/EBPa mutations have a favorable prognosis, whereas patients with FLT3-ITD mutation have a poor prognosis. A new class of mutations affecting genes responsible for epigenetic mechanisms of genome regulations, namely for DNA methylation and histone modification, was found recently. Among them, mutations in genes DNMT3A, IDH1/2, TET2 and some others are the most well-studied mutations to date. A number of studies demonstrated an unfavorable prognostic effect of the DNMT3A mutation in AML. The prognostic significance of the IDH1/2 gene is still unclear. The prognosis is affected by a number of biological factors, including those associated with cytogenetic aberrations and other mutations, especially FLT3 and NPM1. The number of studies of genetic mutations in AML keeps growing. The data on genetic aberrations in AML obtained to date confirm their role in the onset and development of the disease.


Keywords: acute myeloid leukemia, AML, karyotype, cytogenetic aberrations, gene mutation, prognosis.

Received: January 23, 2016

Accepted: April 4, 2016

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Low Dose Cytarabine and Cladribine for Treatment of Relapsed or Refractory Acute Myeloid Leukemia: Clinical Experience

SV Gritsaev, II Kostroma, AA Kuzyaeva, IM Zapreeva, EV Litvinskaya, LV Stelmashenko, SA Tiranova, IS Martynkevich, NA Potikhonova, KM Abdulkadyrov

Russian Scientific Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

For correspondence: Sergei Vasil’evich Gritsaev, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel.: +7(812)717-54-68; e-mail: gritsaevsv@mail.ru

For citation: Gritsaev SV, Kostroma II, Kuzyaeva AA, et al. Low Dose Cytarabine and Cladribine for Treatment of Relapsed or Refractory Acute Myeloid Leukemia: Clinical Experience. Clinical oncohematology. 2016;9(1):48–53 (In Russ).

DOI: 10.21320/2500-2139-2016-9-1-48-53


ABSTRACT                                      

Aim. The aim of this paper is to evaluate the effectiveness of low dose cytarabine (Ara-C) combined with cladribine for the treatment of relapsed or refractory acute myeloid leukemia (AML) and to determine clinical and lab factors associated with response to the therapy.

Methods. Data of 10 patients aged 26–58 years (median 48 years) were analyzed. The diagnoses were de novo AML (7 patients), secondary AML (sAML) (2 patients) and refractory anemia with excess of blasts (RAEB-2) (1 patient). Four patients had primary refractory AML. Relapse was diagnosed in 3 patients. The induction scheme 7+3 was ineffective in patient with RAEB-2. There was no response to any kind of therapy in sAML patients. The treatment scheme under trial consisted of Ara-C 10–15 mg/m2 subcutaneously twice a day for 1–14 days and cladribine 5 mg/m2 intravenously once a day for 1–5 days. The course was repeated in case of at least two-fold decrease in bone marrow blasts level in a punctate versus baseline. Medical examination and maintenance therapy were performed in accordance with protocols approved by the clinic.

Results. According to the protocol, the patients received 1–2 courses. Response was achieved in 5 patients: 2 patients achieved complete response (CR) and 3 achieved partial response (PR). The most common complication was hematologic toxicity. All patients received transfusions of blood components. No lethal outcomes were observed within 8 weeks. The duration of the response was 2 to 3 months. During this period of time, allogeneic stem cell transplantation was performed in 2 patients with CR; however, in one patient, the conditioning regimen began at the same time with the increase in blast cell count in the bone marrow. The search for unrelated donors of hematopoietic stem cells for 2 patients with CR was begun. The distinct features of all patients with CR and PR were the following factors: de novo AML, absence of FLT3 or c-KIT mutations and the course duration was not less than 10 days.

Conclusion. Low dose Ara-C in combination with cladribine may be considered a treatment option for some patients with relapsed or refractory de novo AML.


Keywords: acute myeloid leukemia, relapse, refractory, chemotherapy, low dose cytarabine, cladribine.

Received: June 4, 2015

Accepted: October 8, 2015

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Hematological Improvement is a Favorable Response to Azacitidine in Patients with Acute Myeloid Leukemias and Myelodysplastic Syndromes

I.I. Kostroma1, S.V. Gritsaev1, E.V. Karyagina2, A.S. Nizamutdinova3, I.S. Martynkevich1, K.M. Abdulkadyrov1

1 Russian Scientific Research Institute of Hematology and Transfusiology under the Federal Medico-Biological Agency, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

2 Municipal Hospital No. 15, 4 Avangardnaya str., Saint Petersburg, Russian Federation, 198205

3 Alexandrovskaya Municipal Hospital No. 17, 4 pr-t Solidarnosti, Saint Petersburg, Russian Federation, 193312

For correspondence: Ivan Ivanovich Kostroma, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel.: +7(812)717-58-57; e-mail: obex@rambler.ru

For citation: Kostroma II, Gritsaev SV, Karyagina EV, et al. Hematological Improvement is a Favorable Response to Azacitidine in Patients with Acute Myeloid Leukemias and Myelodysplastic Syndromes. Clinical oncohematology. 2015;8(4):413–419 (In Russ).

DOI: 10.21320/2500-2139-2015-8-4-413-419


ABSTRACT

Aim. To evaluate types of response to azacitidine associated with improvement of overall survival (OS) rates of patients with acute myeloid leukemias (AML) and myelodysplastic syndromes (MDS).

Methods. A retrospective analyses of medical records of 14 AML patients and 13 MDS patients at the age of 39 to 84 treated with azacitidine at a dose of 75 mg/m2 subcutaneously for 7 subsequent days every 28 days was performed. The therapy effectiveness was evaluated according to modified 2006 IWG criteria. The OS was calculated beginning with the date of initiation of the azacitidine therapy.

Results. From 2 to 25 azacitidine cycles was performed. Complete remission (CR) was achieved in 6 patients (22.2 %) including 4 AML and 2 MDS patients. Bone marrow remission (mCR) was diagnosed in 1 MDS patient (3.7 %). Hematological improvement was obtained in 11 patients (40.7 %) including 5 AML and 6 MDS patients. The overall response was 66.7 % (18 to 27 patients). There was no correlation between the therapy effectiveness and patients’ age, disease type, duration of the previous period, baseline hemoglobin, leukocytes, and platelets levels, and dependence on transfusions of erythrocyte suspension and thromboconcentrate. The therapy was considered ineffective in 9 patients (33.3 %). Stabilization with retained requirements of blood component transfusion was observed in 4 AML and 3 MDS patients. 2 patients presented gradual increase of the blast cell count in the bone marrow. The follow-up period was 2–29 months. The median OS of all patients was 11.5 months. The median OS of patients with CR, mCR and hematological improvement was significantly greater than that in the group of patients with stable disease and progression: 15.9 versus 7.4 months, respectively (= 0,010).

Conclusion. Reduction of transfusion requirement and/or stable improvement of peripheral blood levels due to azacitidine administration are associated with improved OS rates of AML and MDS patients.


Keywords: acute myeloid leukemia, myelodysplastic syndromes, azacitidine, hematological improvement, overall survival.

Received: April 6, 2015

Accepted: October 22, 2015

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Acute Myeloid Leukemias: 10-Year Therapy Experience

О.Yu. Baranova1, A.S. Antipova1, O.D. Zakharov2, N.A. Falaleeva1, G.I. Kaletin1, A.D. Shirin1, G.R. Arakelyan1, N.N. Tupitsyn1, M.A. Frenkel’1, N.A. Kupryshina1, T.N. Obukhova3, E.V. Domracheva3, V.B. Larionova1, E.V. Ogorodnikova1, E.A. Osmanov1

1 N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

2 Municipal Outpatient’s Hospital No. 11 under the Department of Healthcare of Moscow, 14 Kravchenko str., Moscow, Russian Federation, 119331

3 Hematology Research Center under the Ministry of Health of the Russian Federation, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Ol’ga Yur’evna Baranova, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-28-64; e-mail: baranova-crc@mail.ru

For citation: Baranova OYu, Antipova AC, Zakharov OD, et al. Acute Myeloid Leukemias: 10-Year Therapy Experience. Clinical oncohematology. 2015;8(3):287–301 (In Russ).


ABSTRACT

Objective. To assess treatment outcomes of 132 patients with acute myeloid leukemia (AML) treated in hematology department of the N.N. Blokhin Russian Cancer Research Center over the period from January, 2003, till November, 2014.

Methods. 106 patients with primary AML and 26 patients with secondary AML and AML arising from MDS were enrolled in this study. Median age was 43.5 years (varied from 15 to 82). The study design provided 1 cycle of remission induction according to the 3+7+7 scheme (idarubicin 12 mg/m2 on days 1–3, cytarabine 100 mg/m2 every 12 h on days 1–7, etoposide 75 mg/m2 on days 1–7), 2 cycles of consolidation according to the HAI scheme (cytarabine 3 g/m2 on days 1, 3, 5; idarubicin 10 mg/m2 on days 2, 4), and 6 cycles of maintenance treatment according the 1+5+5 scheme for patients younger than 60 years (cytarabine 100 mg/m2 every 12 h on days 1–5, idarubicin 15 mg/m2 on day 1, etoposide 75 mg/m2 on days 1–5). The treatment protocol for patients aged 60–65 did not include etoposide, and the cytarabine dose was reduced to 1 g/m2 at the remission consolidation stage.

Results. The analysis of treatment efficacy in 71 patients younger than 60 years with primary AML demonstrated that the percentage of complete remissions (CR) was 77.5 %. In 41 (74.5 %) patients the CR was achieved after the 1st induction cycle. The 5-year overall survival (OS) and relapse-free survival (RFS) rates were 43 % and 52 %, respectively. In the favorable cytogenetic risk group, the CR rate was 90 %, 5-year ОS and RFS were 65 % and 100 %, respectively; in the intermediate cytogenetic risk group these parameters were 90.5 %, 45 %, and 48 %, respectively. In the high risk group, CR was achieved in 36.4 % patients achieved; the resistant disease was observed in 63.6 % of cases, 2-years ОS and DFS rates were 16 % and 0 %, respectively. Among patients aged 60–65 years receiving intensified consolidation therapy, the CR rate was 61.5 %, the resistant disease was observed in 23.1 % of cases. The early mortality rate was 15.4 %, and the 3-year ОS and DFS rates were 14 % and 50 %, respectively.

Conclusion. The treatment program with intensified consolidation demonstrated high long-term survival rates in patients with primary AML younger than 60 years. The best results were obtained in the favorable cytogenetic risk group. Management of patients over 60 years of age and patients with AML in high-risk cytogenetic group is still a challenge.


Keywords: acute myeloid leukemia, high doses cytarabine.

Received: April 2, 2015

Accepted: May 31, 2015

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