acute myeloid leukemia

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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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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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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Efficacy of platelet transfusions during standard induction chemotherapy in patients with acute myeloid leukemia

SUPPORTIVE THERAPY , ,

Davaasambuu1, S.V. Gritsayev2, T.V. Glazanova2, S.A. Tiranova2, N.A. Potikhonova2, I.S. Martynkevtch2, and A.V. Chechetkin2

1 I.I. Mechnikov Northwest State Medical University, RF Ministry of Health, Saint Petersburg, Russian Federation

2 Russian Research Institute of Hematology and Transfusiology, RF FMBA, Saint Petersburg, Russian Federation

ABSTRACT

The efficacy of platelet transfusions that is mainly determined by the immunological mechanisms still depends on the non-immunological factors causing the low platelet count increment after transfusions. The objective of the study was to identify clinical and hematological parameters that were associated with the efficacy of the platelet transfusions during induction chemotherapy according to “7+3” regimen in the patients with acute myeloid leukemias (AML) The data on 41 patients (median age: 42) were analyzed. The platelet transfusion was considered efficacious when the 24-corrected platelet count increment was ³ 4.5 ´ 109/L. The patients were divided into 2 groups according to the efficacy ³ 50 % or < 50 %, respectively. The groups showed no significant difference with respect to the age, AML variants according to the WHO classification and ELN prognostic scale, the response to chemotherapy, or the median of overall survival (OS). At the same time, the portion of the patients with the bone marrow (BM) blasts of myeloid origin (M1 and M2 variants of AML according to FAB classification) was greater in the group with the platelet transfusion efficacy of ³ 50 %. In the group of < 50 % platelet transfusion efficacy, there was the greater portion of patients with BM blasts of monocytic origin (M4 and M5 variants according to FAB classification (p =.001). Also, the trend towards the decreased median of OS was noted in the patients with the pre-transfusion platelet count below 10 ´ 109/L (p =0.049).

Keywords: acute myeloid leukemia, “7+3” induction chemotherapy, platelet transfusion.

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Acute myeloid leukemias with t(7;21)(p22;q22) translocation, 5q- deletion, CD56 expression, and hemophagocytosis: case report and literature review

CLINICAL PRESENTATION, DIAGNOSIS, AND MANAGEMENT OF MYELOID MALIGNANCIES , , , ,

N.N. Mamayev1, T.L. Gindina1, E.G. Boychenko2, A.V. Gorbunova1, V.M. Kravtsova1, N.V. Stancheva1, P.V. Kozhokar1, O.V. Paina1, L.S. Zubarovskaya1, and B.V. Afanasyev1

1 R.M. Gorbacheva Institute of Pediatric Oncology, Hematology and Transplantology, I.P. Pavlov Saint Petersburg State Medical University, Saint Petersburg, Russian Federation

2 Children’s City Hospital #1, Saint Petersburg, Russian Federation

ABSTRACT

We present the clinical and laboratory data on a 13-year old patient with the recently described variant of CD56-positive acute myeloid leukemia with criptic t(7;21)(p22;q22) translocation involving rearrangements of RUNX1 and USP42 genes, 5q deletion, and hemophagocytosis. According to the literature, this rare recently described AML subvariant mostly occurs in males, is resistant to chemotherapy, and can be successfully treated using allogeneic hematopoietic stem cell transplantation.

Keywords: acute myeloid leukemia, t(7;21)(p22;q22), 5q-, CD56+, resistance to chemotherapy, erythrophagocytosis, alloHSCT.

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REFERENCES

  1. Paulsson K., Bekassy A.N., Olofsson T. et al. A novel and cytogenetically cryptic t(7;21)(p22;q22) in acute myeloid leukemia results in fusion of RUNX1 with the ubiquting-specific protease gene USP42. Leukemia 2006; 20(2): 224–9.
  2. Hock A.K., Vigneron A.M., Carter S., Ludwig R.L., Vousden K.H. Regulation of p53 stability and function by the deubiquitinating enzyme USP42. EMBO J. 2011; 30(24): 4921–30.
  3. Foster N., Paulsson K., Sales M. et al. Molecular characterization of a recurrent, semi-cryptic RUBX1 translocation t(7;21) in myelodysplastic syndrome and acute myeloid leukemia. Br. J. Haematol. 2010; 148(6): 938–43.
  4. Giguere A., Hebert J. Microhomologies and topoisomerase II consensus sequences identified near the breakpoint junctions of the recurrent t(7;21)(p22;q22) translocation in acute myeloid leukemia. Gen. Chrom. Cancer 2011; 50(4): 228–38.
  5. Jeandidier E., Gervais C., Radford-Weiss I. et al. A cytogenetic study of 397 consecutive acute myeloid leukemia cases identified three with a t(7;21) associated with 5q abnormalities and exhibiting similar clinical and biological features, suggesting a new, rare acute myeloid leukemia entity. Cancer Genet. 2012; 205(7–8): 365–72.
  6. Panagopoulos J., Gorunova L., Brandel P. et al. Myeloid leukemia with t(7;21)(p22;q22) and 5q deletion. Onсol. Rep. 2013; 30(4): 1549–52.
  7. Gindina T., Barkhatov I., Boichenko E. et al. A new case of acute myeloid leukemia with semi-cryptic t(7;21)(p22;q22). Atlas Genet. Cytogenet. Oncol. Haematol. 2012; 16(9): 689–91.
  8. Park J.E., Park I.J., Lim Y.A. et al. Hemophagocytosis by leukemic blasts in B lymphoblastic leukemia with t(12;21)(p13;q22); TEL-AML1 (ETV6-RUNX1): a case report. Ann. Clin. Lab. Sci. 2013; 43(2): 186–9.

Stable donor hematopoiesis reconstitution after post-transplantation relapse of acute myeloid leukemia in patient with inv(3)(q21q26), –7 and EVI1 oncogene overexpression treated by donor lymphocyte infusions and hypomethylating agents

BONE MARROW TRANSPLANTATION , , , , , ,

N.N. Mamaev, A.V. Gorbunova, T.L. Gindina, O.A. Slesarchuk, V.N. Ovechkina, S.N. Bondarenko, O.V. Goloshchapov, V.M. Kravtsova, and B.V. Afanasev

I.P. Pavlov Saint Petersburg State Medical University, R.M. Gorbacheva Institute of Pediatric Oncology, Hematology and Transplantology, Saint Petersburg, Russian Federation

ABSTRACT

We present the case of successful treatment of post-transplantation relapse of prognostically unfavorable AML with inv(3)(q21q26), –7 and EVI1 oncogene overexpression, when stable donor hematopoiesis reconstitution was achieved due to one high-dose cytarabine course, DLI, and hypomethylating agents (decitabine, 5-azacitidine). Possible molecular mechanisms of this effect are discussed with respect to the new approaches to management of such patients.

Keywords: acute myeloid leukemia, inv(3)(q21q26), EVI1 high expression, hematopoietic stem cell transplantation, relapse, treatment, donor lymphocyte infusions, hypomethylating agents.

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REFERENCES

  1. Мамаев Н.Н., Горбунова А.В., Гиндина Т.Л. и др. Лейкозы и миелодис- пластические синдромы с высокой экспрессией гена EVI1: теоретические и клинические аспекты. Клин. онкогематол. 2012; 5(4): 361–4.[Mamayev N.N., Gorbunova A.V., Gindina T.L. et al. Leukemias and myelodisplastic syndromes with high EVI1 gene expression: theoretical and clinical aspects. Klin. onkogematol. 2012; 5(4): 361–4. (In Russ.)].
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  5. Pavletic S.Z., Kumar S., Mohty M. et al. NCI First International Workshop on the biology, prevention, and treatment of relapse after allogeneic hematopoietic stem cell transplantation: Report from the Committee on the Epidemiology and Natural History of Relapse following Allogeneic Cell Transplantation. Biol. Blood Marrow Transplant. 2010; 16: 871–90.
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Clinico-hematological and molecular genetic variability of acute myeloid leukemia with CD7 expression on blasts cells

CLINICAL PRESENTATION, DIAGNOSIS, AND MANAGEMENT OF MYELOID MALIGNANCIES , , , ,

S.V. Gritsayev1, Z.V. Chubukina1, I.S. Martynkevich1, I.I. Kostroma1, T.V. Glazanova1, Ye.V. Petrova1, L.S. Martynenko1, S.A. Tiranova1, N.A. Potikhonova1, I.S. Zyuzgin2, L.N. Bubnova1, and K.M. Abdulkadyrov1

1 Russian Research Institute of Hematology and Transfusiology, FMBA, Saint Petersburg, Russian Federation

2 Leningrad Regional Hospital, Saint Petersburg, Russian Federation

ABSTRACT

The objective of the study was to evaluate the heterogeneity of patients with acute myeloid leukemia with CD7 aberrant expression. The retrospective analysis of 31 AML patients’ laboratory and clinical data was performed. Marked morphological, cytogenetic, and molecular heterogeneity of AML with CD7 coexpression was established. Also, it was found that these patients could be stratified into groups by overall survival. Four patients with t(8;21) or t(15;17) translocations or inv(16) inversion were followed-up for 53, 33, 11, and 10 months, respectively. The median of OS was not reached among the patients with t(8;21), t(15;15), and inv(16). The median OS among 10 patients with normal karyotype with no FLT3-ITD mutation was 17 months. The median OS among 17 patients with other genetic abnormalities including 7 patients with normal karyotype and FLT3-ITD mutation was 8 months; p = 0.033. We conclude that CD7 expression on AML blast cells is not an independent prognostic factor.

Keywords: acute myeloid leukemia, myeloblasts, CD7 coexpression, karyotype, FLT3-ITD mutation.

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