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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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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Acute Myeloblastic Leukemia and Myelodysplastic Syndrome: Azacitidine for Prophylactic and Preventive Purposes after Allogeneic Hematopoietic Stem Cell Transplantation

VN Ovechkina1, SN Bondarenko1, EV Morozova1, IS Moiseev1, OA Slesarchuk1, AG Smirnova1, OS Uspenskaya2, YaV Gudozhnikova1, AA Osipova1, VS Sergeev1, NN Mamaev1, LS Zubarovskaya1, BV Afanas’ev1

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

2 Leningrad District Clinical Hospital, 45–49 Lunacharskogo pr-t, Saint Petersburg, Russian Federation, 194291

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. Acute Myeloblastic Leukemia and Myelodysplastic Syndrome: Azacitidine for Prophylactic and Preventive Purposes after Allogeneic Hematopoietic Stem Cell Transplantation. Clinical oncohematology. 2017;10(1):45-51 (In Russ).

DOI: 10.21320/2500-2139-2017-10-1-45-51


ABSTRACT

Aim. To evaluate the effectiveness of preventive and prophylactic post-transplantation therapy using azacitidine (5-AZA) in patients at high risk of post-transplantation relapse.

Methods. 136 patients were included in the study performed by the pairwise comparison: 68 of them received 5-AZA after allo-HSCT and 68 patients were included in the historical control group. 5-AZA was prescribed for prophylactic or preventive purposes. The results were assessed according to the OS, RR, EFS, DUM, and relapse-free and GVHR-free survival.

Results. 1-year OS was 76 % in the 5-AZA group (95% CI 60–84 %) and 44 % in the reference group (95% CI 33–55 %) (= 0.001); 2-year OS was 63 % (95% CI 39–67 %) and 37 % (95% CI 26–48 %) (= 0.007), respectively. The relapse rate (RR) in the 5-AZA group was 34 % (95% CI 22–46 %) during 1 year and 51 % (95% CI 38–64 %) in the reference group (= 0.02). 1- and 2-year disease unrelated mortality (DUM) was similar: 5 % in the 5-AZA group (95% CI 0.1–14.0 %) and 25 % (95% CI 13–37 %) in the reference group (= 0.005). 1-year EFS was 76 % in the 5-AZA group (95% CI 61–85 %) and 44 % in the reference group (95% CI 33–55 %) (= 0.001); 2-year EFS was 63 % (95% CI 39–67 %) and 37 % (95% CI 26–48 %) (= 0.01), respectively. 1-year relapse-free and GVHR-free survival was 55 % in the 5-AZA group (95% CI 41–69 %) and 28 % in the reference group (95% CI 17–39 %) (= 0.001); 2-year relapse-free and GVHR-free survival was 47 % (95% CI 32–62 %) and 27 % (95% CI 17–37 %) (= 0.002), respectively.

Conclusion. The use of 5-AZA for prophylactic and preventive purposes after allo-HSCT does not increase the risk of GVHR and DUM, does not suppress the GVL effect and can be used in combination with the donor lymphocyte infusion (DLI). The therapy with 5-AZA is safe during the early period after allo-HSCT. The drug does not suppress the GVL effect and can be used in high risk patients to prevent early post-transplantation relapse. The use of 5-AZA in combination with DLI does not increase the incidence of severe GVHR.

Keywords: acute myeloblastic leukemia, myelodysplastic syndrome, allogeneic hematopoietic stem cell transplantation, hypomethylating therapy, azacitidine.

Received: July 18, 2016

Accepted: December 17, 2016

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Hypomethylating Agents in Oncohematology

AD Shirin, OYu Baranova

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

For correspondence: Anton Dmitrievich Shirin, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-28-24; e-mail: shirin-anton@mail.ru

For citation: Shirin AD, Baranova OYu. Hypomethylating Agents in Oncohematology. Clinical oncohematology. 2016;9(4):369–82 (In Russ).

DOI: 10.21320/2500-2139-2016-9-4-369-382


ABSTRACT

The review describes epigenetic processes, including methylation of nuclear and mitochondrial DNA, as well as RNA. It dwells on mechanisms of demethylation and corresponding medicinal products. It presents detailed information on results of numerous large randomized studies intended to evaluate hypomethylating agents (azanucleosides). Special attention is paid to outcomes of azanucleoside therapy in patients with acute myeloid leukemias. The article describes several prognostic systems and treatment algorithms for myelodysplastic syndromes. Two azanucleosides have been approved in Russia to date: azacitidine (for SQ administration) and decitabine (for IV administration). International authors analyze the experience in oral and subcutaneous administration of decitabine. However, the problem of off-label use of hypomethylating agents is still open. The review gives a brief description of ongoing clinical trials with azanucleosides.


Keywords: epigenetics, acute myeloid leukemias, myelodysplastic syndromes, azacitidine, decitabine, hypomethylating agents, azanucleosides.

Received: May 10, 2016

Accepted: May 20, 2016

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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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