MYELOID TUMORS

Myelofibrosis Models: Literature Review and Own Data

MYELOID TUMORS , , ,

AA Silyutina, II Gin, NM Matyukhina, EN Balayan, PA Butylin

VA Almazov Federal North-West Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

For correspondence: Pavel Andreevich Butylin, PhD, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; e-mail: butylinp@gmail.com

For citation: Silyutina AA, Gin II, Matyukhina NM, et al. Myelofibrosis Models: Literature Review and Own Data. Clinical oncohematology. 2017;10(1):75–84 (In Russ).

DOI: 10.21320/2500-2139-2017-10-1-75-84

ABSTRACT

Background & Aims. Chronic myeloproliferative disorders typically develop during a long latent period, and it complicates the study of the mechanism of its pathogenesis. Observations from the clinical practice should be confirmed by experiments. The mechanisms of oncological transformation related to mutations associated with chronic myeloproliferative diseases were confirmed in transgene animal models. Biological models permitted to determine a complex nature of myelofibrosis. However, studies of the cellular mechanisms of myelofibrosis require new models. This paper presents a review of published models of myeloproliferative disorders, mainly, primary myelofibrosis, and results of studies of a new cell line with expression of JAK2 V617F. The aim of this study is to create a new cell line with expression of transforming JAK2 V617F mutation in acute monocytic leukemia THP-1 cells.

Methods. Transgenic cell lines were created on the basis of monocytic leukemia THP-1 cell line that can differentiate into macrophages. Direct mutagenesis was used to cause V617F mutation. Two cell lines were created: one with JAK2 expression with V617F mutation, the other with wild type JAK2.

Results. Both transgenic lines were characterized by increased JAK2 expression as compared to non-modified cells. In routine cultivation, transgenic THP-1 cells retained the morphology of monocytes. After treatment with phorbol ester, THP-1 differentiated into macrophages and become adherent to culture plastic. Adherent cells demonstrated the variety of shapes: some of them were spherical, the other ones had pseudopodia. No significant differences in viability of cells were observed. However, macrophages expressing mutant JAK2 and overexpressing the wild type JAK2 demonstrated a tendency to decreased amount unlivable cells during cultivation.

Conclusion. The obtained cell model can be used for estimating the influence of JAK2 V617F mutation on pro- and antifibrotic potential of macrophages that can help to investigate the pathogenetic role of macrophages in myelofibrosis development. In addition, this model can help to develop novel methods of therapy and diagnostics of primary and secondary myelofibrosis.

Keywords: Ph-negative chronic myeloproliferative disorders, primary myelofibrosis, JAK2 V617F, transgenic animals.

Received: September 15, 2016

Accepted: December 13, 2016

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Clinical and Hematological Characteristics of Patients with Chronic Myeloid Leukemia under Present-Day Conditions: Results of the Russian Part of International Multi-Center Prospective EUTOS Population-Based CML Study

MYELOID TUMORS , ,

OV Lazareva1, AG Turkina1, EYu Chelysheva1, IA Tishchenko1, MA Galaiko2, OM Senderova3, VM Pepelyaeva4, SV Meresii5, AS Luchinin6, GI Milyutina7, LV Gavrilova8, LB Avdeeva9, OYu Vinogradova10, SM Kulikov1

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

2 NA Semahko Central Clinical Hospital No. 2 under the JSC RZD, 43 Losinoostrovskaya str., Moscow, Russian Federation, 107150

3 Irkutsk Order of the Badge of Honor District Clinical Hospital, 100 Yubileinyi microdistrict, Irkutsk, Russian Federation, 664049

4 Perm Order of the Badge of Honor District Clinical Hospital, 85 Pushkina str., Perm, Russian Federation, 614990

5 Clinical Medical Unit No. 1, 68 Gagarina b-r, Perm, Russian Federation, 614077

6 Kirov District Clinical Hospital, 42 Vorovskogo str., Kirov, Russian Federation, 610027

7 District Clinical Hospital No. 1, 86 Stanke Dmitrova pr-t, Bryansk, Russian Federation, 241033

8 Republican Clinical Hospital No. 4 under the Ministry of Health of Russia, 32 Yl’yanova str., Saransk, Russian Federation, 430032

9 District Clinical Hospital, 7 Kokhanskogo str., Chita, Russian Federation, 672038

10 Dmitrii Rogachev Federal Scientific Clinical Centre of Pediatric Hematology, Oncology and Immunology under the Ministry of Health of the Russian Federation, 1 Samory Mashela str., Moscow, Russian Federation, 117997

For correspondence: Ol’ga Veniaminovna Lazareva, PhD, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel: +7(495)612-48-60; e-mail: stakhino@gmail.com

For citation: Lazareva OV, Turkina AG, Chelysheva EYu, et al. Clinical and Hematological Characteristics of Patients with Chronic Myeloid Leukemia under Present-Day Conditions: Results of the Russian Part of International Multi-Center Prospective EUTOS Population-Based CML Study. Clinical oncohematology. 2017;10(1):65–74(In Russ).

DOI: 10.21320/2500-2139-2017-10-1-65-74

ABSTRACT

Background. Much attention has been paid to molecule-genetic diagnostics of chronic myeloid leukemia (CML) and its treatment using new highly effective methods of therapy. The baseline characteristics of patients at primary CML diagnosis are hardly discussed in literature.

Aim. To provide clinical, hematological, molecular genetic and demographic characteristics of patients obtained at primary diagnosis of CML.

Patients & Methods. Characteristics of CML patients are based on data gathered by the Russian Investigational Group for CML within the international project European Treatment and Outcome Study of CML in Europe (EUTOS, the European Treatment and Outcomes Study). The study included 197 patients with newly diagnosed CML in 6 regions of the Russian Federation (Mordovia, Kirov, Perm (2 sites), Bryansk, Irkutsk, and Chita) over the period from 2009 till 2012.

Results. The study demonstrated that 94 % of CML cases were diagnosed in the chronic phase (CP) and 6 % of cases in the acceleration phase (AP) and the blast crisis phase (BC). In 40 % of patients there were no clinical symptoms, and CML was suspected only due to changes in the CBC test. Fatigue was the main subjective complaint presented by 77 % of patients in the CP and 100 % of patients with the AP and BC. Peripheral blood leukocytosis, left shift to immature myeloid cells and increased granulocytic lineage in bone marrow were typical for the patients. In all patients, the CML diagnosis was confirmed by cytogenetic or molecular tests. The social and demographic characteristics of CML patients and comorbidities at diagnosis were analyzed.

Conclusion. Based on the results of the study, a modern «portrait of a CML patient» was obtained. The study demonstrated that cytogenetic and molecular methods allow to diagnose CML in most patients at early stages of the disease in the absence of clinical signs of progression. The data on comorbidities require a special attention while choosing a therapy considering its duration. Demographic and social characteristics of CML patients demonstrate that they are socially active, particularly interested in retaining the working capacity and quality of life.

Keywords: chronic myeloid leukemia, clinical and hematological characteristics, population-based study.

Received: August 2, 2016

Accepted: December 7, 2016

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Molecular Monitoring of RUNX1-RUNX1T1 Transcript Level in Acute Myeloblastic Leukemias on Treatment

MYELOID TUMORS , ,

LL Girshova, EG Ovsyannikova, SO Kuzin, EN Goryunova, RI Vabishchevich, AV Petrov, DV Motorin, DV Babenetskaya, VV Ivanov, KV Bogdanov, IV Kholopova, TS Nikulina, YuV Mirolyubova, YuA Alekseeva, AYu Zaritskii

VA Almazov Federal North-West Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

For correspondence: Ekaterina Gennad’evna Ovsyannikova, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; Tel: +7(921)313-68-35; e-mail: katrin51297@mail.ru

For citation: Girshova LL, Ovsyannikova EG, Kuzin SO, et al. Molecular Monitoring of RUNX1-RUNX1T1 Transcript Level in Acute Myeloblastic Leukemias on Treatment. Clinical oncohematology. 2016;9(4):456–64 (In Russ).

DOI: 10.21320/2500-2139-2016-9-4-456-464

ABSTRACT

Background. The current approach to treatment of acute myeloblastic leukemia (AML) includes the achievement of maximum tumor reduction and, therefore, eradication of a leukemic clone. The goal of the therapy is to achieve undetectable levels of the target gene, except an isolated molecular rearrangement of RUNX1-RUNX1T1.

Aim. To estimate the dynamics of the RUNX1-RUNX1T1 level and relevant clinical manifestations during the monitoring of various stages of the program therapy and after its completion.

Methods. The article presents a description of 10 cases of AML with isolated RUNX1-RUNX1T1 expression (n = 4) and the expression in combination with different molecular and cytogenetic abnormalities (n = 6). In addition, a long-term monitoring of the gene expression by quantitative determination of RUNX1-RUNX1T1 using a real-time PCR was presented.

Results. The incidence of relapses in a group with a decreased RUNX1-RUNX1T1 expression level of >2 log is 75 % as compared to patients with a less significant reduction of the transcript level (with the relapse incidence equal to 0 %) (p = 0.05). The increase of the RUNX1-RUNX1T1 level against the background of bone marrow remission by more than 1 log coincided with a bone marrow relapse within 5–18 weeks. In addition, long-term persistence of a certain transcript level after the completion of a program therapy without relapse is possible.

Conclusion. The study analyzed possible molecular background of different clinical outcomes of long-term persistence of the RUNX1-RUNX1T1 transcript that might lead to an individualized approach to AML patients.

Keywords: acute myeloblastic leukemia, AML, RUNX1-RUNX1T1, molecular monitoring.

Received: April 5, 2016

Accepted: April 18, 2016

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Rearrangement of 11q23 Chromosome Region in Acute Myeloid Leukemias in Children

MYELOID TUMORS , ,

EV Fleishman1, OI Sokova1, AV Popa1, GA Tsaur2,3,4, LN Konstantinova1, OM Plekhanova2, MV Strigaleva2, ES Nokhrina2, VS Nemirovchenko1, OR Arakaev2,3

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

2 District Children’s Hospital No. 1, 32 S. Deryabinoy str., Yekaterinburg, Russia, 620149

3 Research Institute of Medical Cell Technologies, 22a Karla Marksa str., Yekaterinburg, Russia, 620026

4 The First President of Russia BN Yeltsin Ural Federal University, 19 Mira str., Yekaterinburg, Russia, 620002

For correspondence: Elena Vol’fovna Fleishman, DSci, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel: +7(499)323-57-22; e-mail: flesok@yandex.ru

For citation: Fleishman EV, Sokova OI, Popa AV, et al. Rearrangement of 11q23 Chromosome Region in Acute Myeloid Leukemias in Children. Clinical oncohematology. 2016;9(4):446–55 (In Russ).

DOI: 10.21320/2500-2139-2016-9-4-446-455

ABSTRACT

Aim. To study characteristics of 11q23 involvement, age-specific differences in the incidence of these chromosomal markers in acute myeloid leukemias (AML) in children, and to determine their prognostic significance in patients treated according to the protocols applied in leading Russian pediatric hematological clinics.

Methods. The chromosomal analysis of bone marrow and peripheral blood cells has been performed prior to initiation of treatment in 395 children with primary AML aged from 0 to 16 years. The patients were treated in pediatric hematological clinics of Moscow and Moscow Region and in Yekaterinburg District Children’s Hospital No. 1. Clinical outcomes of 300 followed-up pediatric patients treated with similar modern therapy protocols were analyzed to evaluate the prognostic impact of 11q23/MLL abnormalities. To determine the incidence of 11q23/MLL rearrangements in AML of different age groups, we examined not only children, but also adult patients (n = 212).

Results. In AML, the frequency of changes in the 11q23 region exceeded 40 % in children aged from 0 to 2 years. The frequency decrease with age and in patients over 40 years it was only 2 %. Significant heterogeneity of changes in karyotypes with 11q23/MLL rearrangements was observed: both various translocations with different regions of other chromosomes, and 11q23 deletions were detected. In addition, a great variability of numerical and structural additional chromosomal abnormalities was observed. The 10-year relapse-free survival rates (30.4 ± 6.7 %) and overall survival rates (35.1 ± 7.0 %) in AML with changes in the 11q23 region (n = 61) were significantly lower than those in patients from the intermediate risk group (n = 103): 48.9 ± 5.8 % and 43.8 ± 7.5 %, respectively (p = 0.035). The data are close to those in the high-risk group (n = 44): 35.9 ± 8.1 % and 38.3 ± 7.6 %, respectively. The study failed to confirm the published data that t(9;11) is a more favorable prognostic factor, and that t(6;11) and t(10;11) are less favorable ones than all other 11q23 translocations. Our results did not confirm a negative prognostic effect of additional chromosome abnormalities associated with 11q23 rearrangements.

Conclusion. Pediatric AML patients with 11q23 abnormalities should be included in a high-risk group if therapy is performed according protocols applied in leading hematological centers of Russia.

Keywords: pediatric acute myeloid leukemias, 11q23/MLL rearrangements, risk groups.

Received: May 12, 2016

Accepted: June 15, 2016

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Biology of Myeloproliferative Malignancies

MYELOID TUMORS , , , , , , ,

AL Melikyan, IN Subortseva

Hematology Research Center, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Irina Nikolaevna Subortseva, PhD, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-44-71; e-mail: soubortseva@yandex.ru

For citation: Melikyan AL, Subortseva IN. Biology of Myeloproliferative Malignancies. Clinical oncohematology. 2016;9(3):326-35 (In Russ).

DOI: 10.21320/2500-2139-2016-9-3-314-325

ABSTRACT

Chronic myeloproliferative diseases (WHO, 2001), or myeloproliferative neoplasms/malignancies (MPN) (WHO, 2008), are clonal diseases characterized by proliferation of one or more myelopoietic cell line in the bone marrow with signs of unimpaired terminal differentiation and is normally associated with changes in peripheral blood characteristics. The group of classical Ph-negative MPNs consists of polycythemia vera, essential thrombocythemia, primary myelofibrosis and unclassified MPNs. Acquired somatic mutations contributing to the pathogenesis of Ph-negative MPNs include JAK2 (V617F, exon 12), MPL, CALR gene mutations found in about 90 % of patients. However, these molecular events are not unique in the pathogenesis of the diseases. Mutations of other genes (ТЕТ2, ASXL1, CBL, IDH1/IDH2, IKZF1, DNMT3A, SOCS, EZH2, TP53, RUNX1, and HMGA2) are involved in formation of the disease phenotype. This review describes current concepts concerning the molecular biology of MPNs.

Keywords: chronic myeloproliferative diseases, myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, primary myelofibrosis, genes JAK2, CALR, and MPL.

Received: April 11, 2016

Accepted: April 11, 2016

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New Сytogenetic Approaches in Patients with Primary Myelofibrosis

MYELOID TUMORS , ,

TL Gindina, NN Mamaev, VV Baikov, MV Barabanshchikova, EN Nikolaeva, IA Petrova, IS Moiseev, OV Pirogova, YuYu Vlasova, MO Ivanova, EV Morozova, SN Bondarenko, BV Afanas’ev

R.M. Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Academician I.P. 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, Baikov VV, et al. New Сytogenetic Approaches in Patients with Primary Myelofibrosis. Clinical oncohematology. 2016;9(1):61–9 (In Russ).

DOI: 10.21320/2500-2139-2016-9-1-61-69

ABSTRACT

Aim. To evaluate the potential of a new cytogenetic technique in patients with primary myelofibrosis (PMF).

Materials and methods. 48-hour blood cell cultures (according to Singh et al., 2013) were used for cytogenetic study in 11 PMF patients (5 female, 6 men, aged 32–60 years; median 48.6 years). GTG-banding and different types of fluorescence in situ hybridization (FISH) techniques were used for identification of chromosomal aberrations.

Results. The incidence of abnormal karyotypes in blood cultures was significantly higher than that in standard bone marrow cultures (82 vs 27 %; p < 0.01). The polyploid clones were found in blood cultures of 45 % of patients. Structural chromosomal aberrations were found in chromosomes 6, 1, 3, as well as 16 and 17 (in 2 and 1 patients with each aberration, respectively). In all but one patients these abnormalities in diploid and polyploid metaphases were identical. Partial 1q trisomy resulted from adding of additional (1q21–1q44) material translocated to the short arm of chromosome 5 to the material of 2 normal homologue of chromosome 1. It seems that 1q+, i(17q) and some others chromosomal abnormalities were secondary, whereas 6p21 locus involvement may be a primary defect in PMF. The t(3;6)(q25;p21) translocation described for the first time and confirmed by FISH should be considered a variant of well-known translocation t(1;6). Allo-HSCT in 2 patients with 1q+ was successful, whereas there were problems with engraftment in a female patient with prognostically unfavorable t(3;3)(q21;q26) translocation associated with the EVI1 gene overexpression.

Conclusion. Cytogenetic examinations in blood cultures provide important additional information about PMF patients.

Keywords: primary myelofibrosis, 48-hour peripheral blood cell culture, cytogenetics.

Received: July 14, 2015

Accepted: November 1, 2015

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  35. Vaidya R, Caramazza D, Begna KH, et al. Monosomal karyotype in primary myelofibrosis is detrimental to both overall and leukemia-free survival. Blood. 2011;117(21):5612–5. doi: 10.1182/blood-2010-11-320002.
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Chronic Myeloid Leukemia: Long-Term Experience of Target Therapy

MYELOID TUMORS , , , ,

KM Abdulkadyrov, VA Shuvaev, IS Martynkevich, MS Fominykh, NA Potikhonova, II Zotova, VYu Udal’eva, RA Golovchenko, NV Shakhvorostova, DI Shikhbabaeva, MN Zenina, SA Tiranova, SA Kudryashova, LS Martynenko, MP Ivanova, NYu Tsybakova, EV Petrova, LB Polushkina, EV Kleina

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

For correspondence: Vasilii Anatol’evich Shuvaev, PhD, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel.: +7(921)636-54-72; e-mail: shuvaev77@mail.ru

For citation: Abdulkadyrov KM, Shuvaev VA, Martynkevich IS, et al. Chronic Myeloid Leukemia: Long-Term Experience of Target Therapy. Clinical oncohematology. 2016;9(1):54–60 (In Russ).

DOI: 10.21320/2500-2139-2016-9-1-54-60

ABSTRACT

Background & Aims. Interpretation of key aspects of pathogenesis of chronic myeloid leukemia (CML) and development and introduction of target therapy have changed the prognosis of this once fatal disease dramatically. Results of numerous clinical trials demonstrated substantial superiority of tyrosine kinase inhibitors over previous therapy techniques. At the same time, clinical trials had limitations in patient enrollment, as well as treatment conditions and duration. The analysis of our clinical experience in CML target therapy (over the period from 2003 till 2015) is an important argument for introduction of novel drugs into routine clinical practice. The aim of the study is to analyze our own experience in CML target therapy and to compare our results with clinical trials data.

Methods. Outpatient’s cards and case histories of CML patients treated in the Russian Scientific Research Institute of Hematology and Transfusiology over last 12 years were analyzed in this work. Published results of multi-center clinical trials evaluating the use of tyrosine kinase inhibitors in CML were used for a comparative analysis. The primary morbidity rate and the prevalence of CML, results of first and subsequent treatment lines were studied with assessment of survival rates, adverse events, and the nature of the response (hematologic, cytogenetic and molecular).

Results. The experience in treatment of 208 CML patients was analyzed. The use of imatinib led to clinical and hematological remission (complete hematologic response) was achieved in 95 % of patients. The frequency of complete cytogenetic responses (CCyR) was 69 %, and that of major molecular responses (MMR) was 58 %. The overall 5-year survival (OS) was 86.4 %, the 10-years OS was 67.5 %. The use of nilotinib during the second line permitted to achieve CCyR in 61 % of patients, and the MMR in 55 % of cases. The two-year OS was 96 % and the 5-year OS was 68 %. CCyR and MMR were achieved in 50 % patients treated with dasatinib during the second line. As for the third line, CCyR was achieved in 50 % of patients and MMR in 25 %. In case of previous imatinib and nilotinib resistance, CCyR was observed only in 36 % of patients and MMR in 18 % of cases. During second-line dasatinib treatment, the 2-year OS was 85 %, and the 5-year OS was 51 %; as for the third line, the results were 75 % and 50 %, respectively. The range and rates of adverse events of the therapy, in general, corresponded to results of clinical trials.

Conclusion. The use of tyrosine kinase inhibitors in treatment of CML permits to prolong patient’s life span and quality of life significantly. The use of nilotinib and dazatinib (in case of nilotinib intolerance and/or resistance) could be effective in most patients.

Keywords: chronic myeloid leukemia, target therapy, tyrosine kinase inhibitors, imatinib, nilotinib, dasatinib, clinical practice.

Received: September 10, 2015

Accepted: October 20, 2015

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

MYELOID TUMORS , , , , ,

SV Gritsaev, II Kostroma, AA Kuzyaeva, IM Zapreeva, EV Litvinskaya, LV Stel’mashenko, 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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REFERENCES

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

MYELOID TUMORS , , , ,

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 (p = 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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  3. Грицаев С.В., Мартынкевич И.С., Абдулкадыров К.М. и др. Комплексный кариотип — маркер крайне неблагоприятного прогноза у больных острыми миелоидными лейкозами и развернутыми вариантами миелодиспластического синдрома старше 70 лет с высоким индексом коморбидности. Терапевтический архив. 2012;7:16–21.
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Polycythemia Vera: Literature Review and Own Data

MYELOID TUMORS , ,

I.N. Subortseva, T.I. Kolosheinova, E.I. Pustovaya, E.K. Egorova, A.M. Kovrigina, Yu.V. Pliskunova, T.V. Makarik, A.O. Abdullaev, A.L. Melikyan

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

For correspondence: Irina Nikolaevna Subortseva, PhD, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-44-72; e-mail: soubortseva@yandex.ru

For citation: Subortseva IN, Kolosheinova TI, Pustovaya EI, et al. Polycythemia Vera: Literature Review and Own Data. Clinical oncohematology. 2015;8(4):397–412 (In Russ).

DOI: 10.21320/2500-2139-2015-8-4-397-412

ABSTRACT

Background & Aims. Polycythemia vera (PV) refers to a group of classic Ph-negative myeloproliferative neoplasms characterized by panmyelosis, pancytosis, high risk of thrombotic and hemorrhagic complications, poor quality of life due to symptoms of tumor proliferation. Low-dose acetylsalicylic acid and phlebotomy/erythrocytapheresis are recommended for patients at low risk of complications, while the cytoreductive therapy (hydroxyurea or interferon alpha) is recommended for patients at high risk of thrombotic and hemorrhagic complications. At present, much attention is paid to the problems of diagnosis and treatment PV.

Methods. The article presents a brief description of the condition, a review of modern methods of treatment, results of observation over 100 PV patients who have been treated in the outpatient department of the Hematology Research Center. The observation period ranged from 6 to 262 months (median follow-up is 14 months).

Results. Patients’ age ranged from 23 to 80 years (median 56 years); 67 % of them were women, and 33 % were men. PV was diagnosed according to 2008 WHO guidelines. JAK2V617F mutation was detected in 100 % of cases. Splenomegaly was found in 70 % of patients. Plethoric symptoms (such as facial and hand hyperemia, and scleral injection) were found in 65 % of patients. All patients complained of headaches and dizziness, and 25 % of patients complained of itching. All patients received symptomatic therapy, antiaggregants, medications improving microcirculation, or antihypoxants. Patients were treated according to clinical guidelines: 49 % of them received hydroxyurea, 14 % IFN a-2b, 14 % a combination therapy (hydroxyurea and phlebotomy or IFN a-2b and phlebotomy), and 23 % of patients phlebotomy alone. Response to treatment was evaluated according to 2009 European LeukemiaNet criteria. Among all patients, the frequency of complete remission was 48 %, the partial response rate was 41 %, and no effect was achieved in 11 % of patients regardless they received therapy or not. The therapy was changed, if the treatment had proved to be ineffective, or in case of intolerance or complications. Complete remission was not achieved after switching treatment from one method to another.

Conclusion. Treatment of PV is mainly symptomatic. The effectiveness of first line therapy (complete remission) ranged from 14.5 to 71 %. It is necessary to conduct clinical trials designed to evaluate the effectiveness and safety of new targeted therapies.

Keywords: myeloproliferative neoplasms, polycythemia vera, JAK2V617F, target therapy.

Received: June 30, 2015

Accepted: November 5, 2015

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