MYELOID TUMORS

Diagnostic Strategy for Detection of Typical and Atypical BCR-ABL Fusion Gene Transcripts in Chronic Myeloid Leukemia

MYELOID TUMORS , ,

OV Nikulina1,2, GA Tsaur1,2,3, TO Riger1,2, YuA Yakovleva1,2, AS Demina1,2, ER Semenikhina1, TV Spil’nik3, LI Savel’ev1,2,3, LG Fechina1,2

1 Regional Children’s Hospital No. 1, 32 Serafimy Deryabinoy str., Yekaterinburg, Russian Federation, 620149

2 Research Institute of Medical Cell Technologies, 22a K. Marksa str., Yekaterinburg, Russian Federation, 620026

3 Ural State Medical University, 3 Repina str., Yekaterinburg, Russian Federation, 620219

For correspondence: Grigorii Anatol’evich Tsaur, PhD, 32 Serafimy Deryabinoy str., Yekaterinburg, Russian Federation, 620149; Tel.: +7(343)216-25-17; e-mail: tsaur@mail.ru

For citation: Nikulina O.V., Tsaur G.A., Riger T.O., Yakovleva Yu.A., Demina A.S., Semenikhina E.R., Spil’nik T.V., Savel’ev L.I., Fechina L.G. Diagnostic Strategy for Detection of Typical and Atypical BCR-ABL Fusion Gene Transcripts in Chronic Myeloid Leukemia. Klin. Onkogematol. 22015;8(2):161–8 (In Russ.).

ABSTRACT

Background & Aims. The diagnosis of chronic myeloid leukemia (CML) is confirmed when t(9;22)(q34;q11) translocation is found by the cytogenetic test method and/or chimeric BCR-ABL transcript is detected by the reverse transcription polymerase chain reaction (RT-PCR). It is known that two most common types of chimeric BCR-ABL transcript are determined in CML patients: e13a2 (b2a2) и e14a2 (b3a2). However, rare types of chimeric BCR-ABL transcript have been described and they may be overlooked. Moreover, timely diagnosing and detection of different types of the chimeric transcript are very important, because the clinical course of the disease and efficacy of the therapy with tyrosine kinases inhibitors depend on the structure of chimeric BCR-ABL gene. Since in some cases CML may be diagnosed without the standard cytogenetic test and be confirmed by RT-PCR alone, we consider it important to develop a diagnostic algorithm which might permit to determine almost any type of chimeric BCR-ABL transcript.

Methods. Over the period from January, 2004, till December, 2013, in the laboratory of molecular biology of the department of pediatric oncology and hematology in Regional Children’s Hospital No. 1 (Yekaterinburg), the diagnosis of CML was confirmed in 1082 patients: 531 (49 %) males and 551 (51 %) females. The median age was 50 years (range 5–88 years). All patients underwent standard cytogenetic and molecular genetic tests. Primers which are complementary to nucleotide ABL gene sequence are localized in 2 and 3 ABL exons and are used for detection of all transcript types. Primers which are complementary to nucleotide BCR gene sequence are localized either in 12 and 13 exons for detection of most typical e13a2 and e14a2 (M-bcr) transcripts or in exon 1 for detection of e12a (m-bcr) transcript. While detecting amplicons which size differs from that of e13a2, e14a2, and e1a2, their direct paired-end sequencing is performed using primers (applied during the second round of RT-PCR) and a Big Dye Terminator 3.1 kit.

Results. After having analyzed 1082 patients with confirmed CML, we have developed a diagnostic algorithm for detecting common and rare types of chimeric BCR-ABL transcript in CML using RT-PCR. We detected common chimeric BCR-ABL transcripts, e14a2 and e13a2, in 62.53 % and 35.89 % of cases, respectively, using this algorithm. Rare transcripts, e13a3, e14a3, e19a2, e1a2, e3a2, e6a2, and e8a2, were detected in 1.57 % of cases.

Conclusion. Therefore, the proposed diagnostic algorithm proved to be effective for detection of common and rare types of chimeric BCR-ABL transcripts in CML patients.

Keywords: chronic myeloid leukemia, molecular diagnostics, chimeric BCR-ABL transcript.

Received: December 31, 2014

Accepted: February 4, 2015

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Complex Karyotype in Pediatric Acute Myeloid Leukemia

MYELOID TUMORS , ,

EV Fleishman1, OI Sokova1, AV Popa1, II Kalinina2, LN Konstantinova1

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

2 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: Elena Vol’fovna Fleischman, 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. Complex Karyotype in Pediatric Acute Myeloid Leukemia. Clinical oncohematology. 2015;8(2):151–60 (In Russ).

ABSTRACT

Objective. To evaluate the clinical relevance of the complex karyotype in pediatric practice.

Methods. In this study, we investigated the karyotype of 521 patients with de novo AML (299 children and 222 adults). Among them 34 pediatric patients and 25 adults had various complex karyotypes.

Results. Certain differences of complex karyotypes between pediatric and adult AML were revealed. Some peculiarities of marker sets were also found: in children, such high-risk markers as monosomy 5 and del(5q) as well as monosomy 7 and del(7q) were less frequent than in adults. Monosomal complex karyotypes were less common in children. Specific distribution of blast cell morphological types was observed in pediatric AML with complex karyotypes. Unlike AML with noncomplex karyotype, where the M2 type was found in almost a half (47.9 %) of patients, in patients with 3 and more chromosome aberrations its incidence was 11.8 % only (p = 0,000). However, incidence of M5 and rare M0 and M7 types in patients with complex karyotype was higher than in the others. RFS in patients with a complex karyotype was similar to that of remaining patients in the high-risk group: 38.4 ± 9.9 % and 30.6 ± 8.8 %, respectively. The OS rate of patients with a complex karyotype was practically identical to that of intermediate-risk group patients: 48.0 ± 10.0 % and 48.0 ± 10.0 %, respectively. There was a comparatively high 10-year survival rate (RFS and OS were higher than 30 %) in the pediatric high-risk group. Ten of 25 (40 %) patients with complex karyotype survived five years and 7 of them persisted in complete remission for more than 10 years. Five-year survival in adults from high-risk group is up to 15 %.

Conclusion. Analysis of data on survival of pediatric AML does not answer a question in which prognostic group (high or intermediate-risk) cases of AML with complex karyotypes without high-risk chromosome markers must be included.

Keywords: pediatric acute myeloid leukemia, chromosome aberrations, complex karyotype.

Received: November 26, 2014

Accepted: February 2, 2015

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Mixed-Phenotype Acute Leukemia: Clinical and Laboratory Features, and Prognosis

MYELOID TUMORS , , ,

AS Antipova1, OYu Baranova1, MA Frenkel’1, NN Tupitsyn1, NA Kupryshina1, TN Obukhova2, AD Shirin1

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

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

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

For citation: Antipova AS, Baranova OYu, Frenkel’ MA, et al. Mixed-Phenotype Acute Leukemia: Clinical and Laboratory Features, and Prognosis. Clinical oncohematology. 2015;8(2):136–50 (In Russ).

ABSTRACT

Objective. To determine clinical and laboratory features and prognosis of mixed-phenotype acute leukemia (MPAL).

Methods. Of 208 AL patients treated in the N.N. Blokhin Russian Cancer Research Center over past 14 years, MPAL was diagnosed in 5 cases (2.4 %). In total 13 patients were enrolled in this study; these patients were hospitalized in the N.N. Blokhin Russian Cancer Research Center (n = 5) and in four other hematological hospitals of Moscow (n = 8). The disease was diagnosed in accordance with the 2008 WHO classification. The median age was 48 years (ranged from 20 to 75 years).

Results. В/М-phenotype was diagnosed in most patients (n = 11) and Т/М only in 2 patients. Translocation t(9;22)(q34;q11) was the most common chromosome aberration diagnosed in 5 (55.5 %) patients. BCR-ABL chimeric gene was in 8 of 9 patients. Treatment strategy was determined by molecular biological and cytogenetic MPAL profiles. Patients with t(9;22)(q34;q11) and/or BCR-ABL chimeric gene treated with imatinib combined with ALL-regimes (n = 8). Patients with Ph-negative MPAL (n = 1) or unknown molecular biological and cytogenetic MPAL profiles (n = 4) received AML-directed therapy or combined regimes for the treatment of ALL and AML. Complete remission (CR) was obtained in most patients (83.3 %) with low rate of early mortality (8.3 %). 3-year OS was 18.2 % (median 14 months), 3-year RFS was 12.8 % (median 16 months). CRs were induced in all Ph+ MPAL patients.

Conclusion. There are no specific clinical and laboratory predictors of MPAL. Tyrosine kinase inhibitors (TKI) play the key role in the treatment of Ph+ MPAL. TKI combined with low intensity ALL regimes seem more promising. The problem of treatment of Ph-negative MPAL patients remains unsolved.

Keywords: mixed-phenotype acute leukemia, acute leukemia of ambiguous lineage, bilineage leukemia, biphenotypic leukemia.

Received: January 10, 2015

Accepted: January 29, 2015

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First Line Treatment Choice for Chronic Myelogenous Leukemia: Modeling of Clinical and Economic Factors

MYELOID TUMORS , , , ,

VA Shuvaev, KM Abdulkadyrov, IS Martynkevich, MS Fominykh

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: Shuvaev VA, Abdulkadyrov KM, Martynkevich IS, Fominykh MS. First Line Treatment Choice for Chronic Myelogenous Leukemia: Modeling of Clinical and Economic Factors.. Clinical oncohematology. 2015;8(1):78–83 (In Russ).

ABSTRACT

Background. Second generation tyrosine kinase inhibitors (nilotinib and dasatinib) have advantages over imatinib in frequency and rate of cytogenetic and molecular responses obtaining in chronic myelogenous leukemia (CML) treatment. At the same time, they produced more severe adverse effects and are more expensive than imatinib. At present, CML patients with stable deep molecular response are considered as candidates for enrollment into clinical trials studying the management of treatment-free remission. Constant growth of expenses for CML diagnosing and treatment require a pharmacoeconomic analysis in order to optimize expenses and provide cost-effectiveness data for introduction of novel highly effective drugs.

Objective. Pharmacoeconomic modeling of the choice of CML treatment using first and second generation tyrosine kinase inhibitors in first-line therapy with an analysis of sensitivity of clinico-economic factors.

Methods. Pharmacoeconomic modeling of CML diagnosing and treatment. Cost-utility analysis of first and second generation tyrosine kinase inhibitors in first-line treatment. Sensitivity analysis with identification of most important clinical and economic factors affecting treatment results. Simulation for feasibility analysis of the nationwide use of first and second generation tyrosine kinase inhibitors in first-line therapy.

Results. Sensitivity analyses of pharmacoeconomic models showed its robustness. The threshold limits for drug costs and frequency of achievement of a complete molecular response affecting economic feasibility of the choice of first and second generation tyrosine kinase inhibitors were determined.

Conclusions. These pharmacoeconomic models may be applied for improvement of diagnostic and therapeutic standards.

Keywords: chronic myeloleukemia, tyrosine kinase inhibitors, imatinib, nilotinib, dasatinib, pharmacoeconomics, cost-effectiveness.

Received: September 11, 2014

Accepted: November 7, 2014

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REFERENCES

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Complex Chromosomal Aberrations in Patients with Post-Transplantation Relapses of Acute Leukemias: Clinical and Theoretical Aspects

MYELOID TUMORS , ,

TL Gindina, NN Mamaev, SN Bondarenko, NV Semenova, EN Nikolaeva, ME Vlasova, NV Stancheva, OA Slesarchuk, VN Vavilov, EV Morozova, AL Alyanskii, BV Afanas’ev

R.M. Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Academician I.P. Pavlov First St. Petersburg State Medical University, 12 Rentgena str., Saint Petersburg, Russian Federation, 197022

For correspondence: Tat’yana Leonidovna Gindina, PhD, 12 Rentgena str., Saint Petersburg, Russian Federation, 197022; Tel.: +7(812)233-12-43; e-mail: tatgindina@gmail.com

For citation: Gindina TL, Mamaev NN, Bondarenko SN, et al. Complex Chromosomal Aberrations in Patients with Post-Transplantation Relapses of Acute Leukemias: Clinical and Theoretical Aspects. Clinical oncohematology. 2015;8(1):69–77 (In Russ).

ABSTRACT

Objective. To analyze the incidence of a complex karyotype in patients with post-transplantation relapses of acute myeloid leukemias and to evaluate preliminary treatment results before and after bone marrow transplantation in order to elaborate optimal approaches to the treatment of this disease.

Methods. Cytogenetic investigations (including fluorescent in situ hybridization [FISH]) were performed in 100 patients (53 males, 47 females aged from 1 to 60; median — 23 years) with post-transplantation relapses of acute myeloid leukemias (AML) (n = 61) and acute lymphoblastic leukemia (ALL) (n = 39).

Results. Aberrant karyotypes were found in 90 % of AML and 97 % of ALL patients. The incidence of acute leukemias (AL) with complex karyotypes (CK) was significantly higher in ALL patients than that in the AML group (67 % vs 36 %; p = 0.002). At that, the percentage of CK with 4 and more chromosome abnormalities per cell in ALL patients aged 1–18 years was also significantly higher than that in AML patients (60 % vs 30 %; p = 0.03). Besides, this difference was observed in the CK+ proportion between ALL and AML groups. Transplantation was performed during the active phase of the disease (i.e. after remission) in 75 % vs 55 %, respectively (p = 0.003).

Conclusions. Serial cytogenetic investigations showed that CKs before transplantation and in PTR are closely related, thus confirming their clonal nature. Therefore, it may be assumed that karyotype complication achieved by the PTR can be caused by both chemotherapy performed at early stages of acute leukemia and pre-transplant conditioning regimes. In this case, further increase of the chemotherapeutic intensity in order to prevent and treat expected PTRs in patients with CK+ acute leukemias seems to be unreasonable. In this connection, infusion of donor lymphocytes, administration of hypomethylating agents or medicines with target mechanism of action should be used for management of AML patients during the post-transplant period.

Keywords: acute leukemias, post-transplantation relapses, complex karyotype.

Received: September 2, 2014

Accepted: November 13, 2014

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Principles of Pathomorphological Differential Diagnosis of Myelodysplastic Syndromes

MYELOID TUMORS , , ,

AM Kovrigina1, SA Glinkina1, VV Baikov2

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

2 R.M. Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Academician I.P. Pavlov First St. Petersburg State Medical University, 12 Rentgena str., Saint Petersburg, Russian Federation, 197022

For correspondence: Alla Mikhailovna Kovrigina, PhD, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-61-12; e-mail: kovrigina.alla@gmail.com

For citation: Kovrigina AM, Glinkina SA, Baikov VV. Principles of Pathomorphological Differential Diagnosis of Myelodysplastic Syndromes. Clinical oncohematology. 2015;8(1):62–8 (In Russ).

ABSTRACT

The article dwells on the diagnosis of myelodysplastic syndromes (MDS) in bone marrow trephine biopsies. The paper describes problems of a complex approach to differential diagnostics of MDS and non-clonal/reactive changes in hematopoiesis. It is emphasized that clinical and laboratory data, as well as data on patient’s medical history should be submitted to a pathologist. The authors substantiate the algorithm for the morphological investigation of a bone marrow trephine bioptate, including evaluation of cellularity, stromal patterns, and morphological signs of dysplasia. The diagnostic value of histochemistry and immunohistochemistry is discussed.

Keywords: myelodysplastic syndrome, bone marrow trephine biopsy, pathomorphology, differential diagnostics.

Received: October 22, 2014

Accepted: November 10, 2014

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Second Generation Tyrosine Kinase Inhibitors and Their Toxicity in Treatment of Patients in Chronic Phase of Chronic Myeloid Leukemia

MYELOID TUMORS , ,

N.S. Lazorko1, E.G. Lomaia1, E.G. Romanova1, E.I. Sbityakova1, E.R. Machyulaitene2, P.A. Butylin1,3, A.Yu. Zaritskii1,2

1 Federal North-West Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russia, 197341

2 Academician I.P. Pavlov First St. Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russia, 197022

3 Saint Petersburg State University of Information Technologies, Mechanics and Optics, Institute of Translational Medicine, 49 Kronverkskii pr-t, Saint Petersburg, Russia, 197101

For correspondence: Elza Galaktionovna Lomaia, PhD, 2 Akkuratova str., Saint Petersburg, Russia, 197341; Tel.: +7(812)702-37-65; e-mail: lomelza@gmail.com

For citation: Lazorko N.S., Lomaia E.G., Romanova E.G., Sbityakova E.I., Machyulaitene E.R., Butylin P.A., Zaritskii A.Yu. Second Generation Tyrosine Kinase Inhibitors and Their Toxicity in Treatment of Patients in Chronic Phase of Chronic Myeloid Leukemia. Klin. Onkogematol. 2015;8(3):302–8. (In Russ.)

ABSTRACT

Background & Aims. Certain experience in the use of new tyrosine kinase inhibitors (TKIs) in treatment of patients with chronic myeloid leukemia has been obtained over the last years. The article summarizes literature data on toxicity obtained in international clinical trials. The aim of the study is to evaluate adverse effects of second generation TKIs in the routine clinical practice and to assess their effect on patient future life.

Methods. We analyzed our own data obtained during routine clinical practice. 76 patients (36 men and 40 women) over 18 years of age (median age was 49 years, range 26–75) with chronic myeloid leukemia were enrolled in the retrospective trial. 48 patients were treated with nilotinib, 28 patients received dazatinib during the chronic phase of the disease as a second line therapy after withdrawal of imatinib mesylate. The toxicity degree was determined according to CTCAE 4.0 criteria.

Results. III–IV degree hematologic toxicity was registered in 36.8 % of patients. No significant difference in the incidence of complications between nilotinib and dazatinib groups was observed: 39.6 % and 32.1 %, respectively. II–IV degree non-hematologic toxicity was found in 35.4 % patients on nilotinib and in 25 % of patients on dazatinib. The incidence of individual types of toxicity did not exceed 15 %. A combination of different types of non-hematologic toxicity was observed in 9.2 % of patients. No TKI2 toxicity-related lethal outcomes were registered.

Conclusion. Hematologic and/or non-hematologic toxicity related to TKI2 was registered in more than 50 % of patients. In most cases, the complications were transient and eliminated after discontinuation of TKI2 or after dose reduction. TKI2-associated complications did not affect the possibility to achieve a complete cytogenetic response and its stability.

Keywords: chronic myeloid leukemia, tyrosine kinase inhibitors, toxicity.

Received: January 29, 2015

Accepted: June 1, 2015

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Acute Myeloid Leukemias: 10-Year Therapy Experience

MYELOID TUMORS ,

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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Rationale for Maintenance Treatment of Patients with Acute Myeloid Leukemia below 65 Years of Age, According to Data of a Retrospective Analysis of Protocols AML-2000 and AML-2007

MYELOID TUMORS ,

S.V. Semochkin1,2, T.N. Tolstykh1, V.V. Lunin3, N.K. Khuazheva3, A.I. Kostin3, S.A. Chernysh3, M.E. Pochtar’3, V.L. Ivanova3

1 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

2 N.I. Pirogov Russian National Research Medical University under the Ministry of Health of the Russian Federation, 1 Ostrovityanova str., Moscow, Russian Federation, 117997

3 S.P. Botkin Municipal Clinical Hospital, 5 2-i Botkinskii pr-zd, Moscow, Russian Federation, 125284

For correspondence: S.V. Semochkin, DSci, Professor, 1 Samory Mashela str., Moscow, Russian Federation, 117997; Tel: +7(495)653-14-78; e-mail: semochkin_sv@rsmu.ru

For citation: Semochkin S.V., Tolstykh T.N., Lunin V.V., Khuazheva N.K., Kostin A.I., Chernysh S.A., Pochtar’ M.E., Ivanova V.L. Rationale for Maintenance Treatment of Patients with Acute Myeloid Leukemia below 65 Years of Age According to Data of a Retrospective Analysis of Protocols AML-2000 and AML-200. Klin. Onkogematol. 2014; 7(4): 564–572 (In Russ.).

ABSTRACT

Objective. To evaluate the efficacy of prolonged maintenance therapy versus intensified consolidation for patients with acute myeloid leukemia (AML).

Patients and methods. 198 patients with median age 43.9 years (ranging from 15 to 64) with newly diagnosed AML were enrolled in this retrospective study. Over the period from 2000 to 2009, 97 patients were assigned to receive treatment in accordance with Protocol AML-2000 which provided 2 cycles of induction according to the «7+3» scheme (the dose of daunorubicin is 45 mg/m2), 3 cycles of consolidation according to the «5+1» scheme, and 2-year maintenance treatment consisting of the same cycles. 101 patients were enrolled in the subsequent study according to Protocol AML-2007; over the period from 2007 to 2012, they received 2 cycles of induction «7+3» or «7+3» plus HAM, if the complete remission (CR) was not achieved after the first cycle. Then there were 4 cycles of treatment with high-dose cytarabine without subsequent maintenance treatment.

Results. In total, 57.1 % of patients achieved CR. 2-year overall survival (OS) was higher for Protocol AML-2000 (39.2 ± 5.0 vs 28.5 ± 4.8 %; p = 0.052). The maintenance treatment prolonged the median cumulative relapse risk from 1.2 to 2.1 years (p = 0.008). However no statistically significant difference was observed for the 5-year relapse-free survival and OS between the two trials with the median follow-up for surviving patients equal to 3.3 and 9.9 years, respectively. Age ³ 46 years (p = 0.004), baseline leukocytosis ³ 50 000/ml (p = 0.035) and secondary AML (p = 0.020) had a negative prognostic effect on the 5-year OS. Intensive consolidation according to Protocol AML-2007 was associated with higher incidence of III/IV degree adverse events, including neutropenia (100 vs 68.9 %; p < 0.001), thrombocytopenia (100 vs 55.2 %; p = 0.012), and enteropathy (29.4 vs 0 %; p = 0.001).

Conclusion. The maintenance treatment is an effective therapeutic option for AML, since it prolongs the median cumulative relapse risk.

Keywords: acute myeloid leukemia, maintenance treatment.

Accepted: September 19, 2014

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Allogeneic Hematopoietic Stem Cell Transplantation in Myelodysplastic Syndromes and Clinical Significance of WT1 Gene Overexpression

MYELOID TUMORS , , , , ,

N.N. Mamaev1, A.V. Gorbunova1, T.L. Gindina1, E.V. Morozova1, Ya.V. Gudozhnikova1, O.A. Slesarchuk1, V.N. Ovechkina1, A.A. Rats1, E.G. Boichenko2, E.A. Ukrainchenko3, V.M. Kravtsova1, A.V. Evdokimov1, I.M. Barkhatov1, S.N. Bondarenko1, B.V. Afanas’ev1

1 R.M. Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Academician I.P. Pavlov First St. Petersburg State Medical University, 12 Rentgena str., Saint Petersburg, Russian Federation, 197022

2 Municipal Children’s Hospital No. 1, 14 Avangardnaya str., Saint Petersburg, Russian Federation, 198205

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

For correspondence: N.N. Mamaev, DSci, Professor, 12 Rentgena str., Saint Petersburg, Russian Federation, 197022; Tel: +7(812)233-12-43; e-mail: nikmamaev524@gmail.com

For citation: Mamaev N.N., Gorbunova A.V., Gindina T.L., Morozova E.V., Gudozhnikova Ya.V., Slesarchuk O.A., Ovechkina V.N., Rats A.A., Boichenko E.G., Ukrainchenko E.A., Kravtsova V.M., Evdokimov A.V., Barkhatov I.M., Bondarenko S.N., Afanas’ev B.V. Allogeneic Hematopoietic Stem Cell Transplantation in Myelodysplastic Syndromes and Clinical Significance of WT1 Gene Overexpression. Klin. Onkogematol. 2014; 7(4): 551–563 (In Russ.).

ABSTRACT

The results of allogeneic hematopoietic stem cell transplantation (HSCT) in 17 patients (pts, 11 male, 6 female) with myelodysplastic syndromes (3 RA/RARS/RCMD, 5 RAEB-1, 7 RAEB-2, 2 JMML) are presented. The median age was 26 years with a range between 1 and 55 years. Serial cytogenetic investigations were carried out in all of them. Seven pts demonstrated monosomy 7, which was associated with other chromosome abnormalities in 4 cases. In addition, deletion at 11q23 (n = 3), trisomy 8 (n = 2) and 21 (n = 2), involvement into rearrangement at 3q (n = 2), t(6;9) translocation, and others more rare abnormalities were found. Prior to aHSCT, 11 of 7 received hypomethylating agents (HA) which proved to be effective in a half of them. In order to prepare for aHSCT, ablative (busulfan, cyclophosphamide) or non-ablative (fludarabine, cyclophosphamide) conditioning regimes were applied (4 and 13 respectively). Repeated aHSCT was carried out in 6 pts because of transplant rejection or post-transplant relapses. Molecular monitoring of minimal residual disease as well as early diagnosis of these relapses was performed by means of serial tests of the WT1 gene level expression and donor chimerism. Maximum WT1 values varied between 15 and 43133 copies/104 copies of ABL gene; and molecular relapses were registered in a half of them, including 5 patients with transformation into acute leukemia (AL). HA were used for prevention and treatment of relapses in 4 (24 %) patients; and HA were combined with donor lymphocyte infusions. Standard chemotherapy was applied for these purposes relatively rarely. This study demonstrated WT1 gene overexpression to be not only an important marker for diagnosis of post-transplant MDS/AL relapses, but it also can be used for evaluation of the treatment efficacy.

Keywords: myelodysplastic syndromes, allogeneic HSCT, post-transplant relapses, minimal residual disease, molecular monitoring, serial WT1 gene expression.

Accepted: September 30, 2014

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