acute myeloblastic leukemia

Efficacy, Safety, and Tolerance of Gemtuzumab Ozogamicin Combined with FLAG/FLAG-Ida or Azacitidine in Relapsed/Refractory Acute Myeloblastic Leukemia

AUTOIMMUNE THROMBOCYTOPENIA , , , , ,

IG Budaeva, DV Zaitsev, AA Shatilova, EN Tochenaya, AV Petrov, RI Vabishchevich, DV Motorin, RSh Badaev, DB Zammoeva, VV Ivanov, SV Efremova, KV Bogdanov, YuV Mirolyubova, TS Nikulina, YuA Alekseeva, AYu Zaritskey, LL Girshova

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

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

For citation: Budaeva IG, Zaitsev DV, Shatilova AA, et al. Efficacy, Safety, and Tolerance of Gemtuzumab Ozogamicin Combined with FLAG/FLAG-Ida or Azacitidine in Relapsed/Refractory Acute Myeloblastic Leukemia. Clinical oncohematology. 2021;14(3):299–307. (In Russ).

DOI: 10.21320/2500-2139-2021-14-3-299-307

ABSTRACT

Aim. To assess the efficacy, safety, and tolerance of gemtuzumab ozogamicin (GO) combined with FLAG/FLAG-Ida chemotherapy or azacitidine in patients with relapsed/refractory acute myeloblastic leukemia (AML) in clinical practice.

Materials & Methods. The study included 32 patients (16 men and 16 women). The median age was 44 years (range 23–83 years). Among them there were 15 (46.8 %) patients with refractory and 17 (53.2 %) patients with relapsed AML. GO combined with FLAG/FLAG-Ida was administered to 15 (46.8 %) patients, whereas 17 (53.2 %) patients were treated with GO and azacitidine combination. Therapy safety was assessed according to CTCAE v. 5.0.

Results. Overall response rate including complete remission (CR), CR MRD–, CR with incomplete hematologic recovery, and morphologic leukemia-free status was 59.4 % (19/32). Refractoriness was observed in 31.25 % (10/32) of patients. Early mortality was 9.4 % (3/32). Overall response was 64.7 % (11/17) in the azacitidine and 53.3 % (8/15) in the FLAG/FLAG-Ida groups. In 4 (80 %) out of 5 patients with prior to FLAG treatment refractoriness, the response was achieved after GO + azacitidine therapy. In 58.9 % (10/17) of patients who received GO + azacitidine therapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) could be performed. The incidence of GO infusion complications in the tested groups did not significantly differ (p = 0.72) and was 46.7 % (7/15) (40 % with grade 1/2 and 6.7 % with grade 3) in the GO + FLAG/FLAG-Ida group and 35.3 % (6/17) (29.4 % with grade 1/2 and 5.9 % with grade 4) in the GO + azacitidine group. In the GO + FLAG/FLAG-Ida group 5 (33.3 %) patients experienced serious adverse events (SAE) of sepsis. In the GO + azacitidine group SAEs were reported in 6 (35.3 %) patients: 4 (66.6 %) with sepsis, 1 (16.7 %) with acute cardiovascular failure, and 1 (16.7 %) with acute respiratory failure. The median (range) duration was 23 (10–39) days for neutropenia grade 4, 24 (11–38) days for neutropenia grade 3, 21 (11–41) days for thrombocytopenia grade 4, 26 (16–45) days for thrombocytopenia grade 3, and 25 (22–45) days for thrombocytopenia grade 1/2. Thrombocytopenia duration was longer in patients with GO + FLAG/FLAG-Ida therapy, however, no significant differences were identified. No cases of veno-occlusive liver disease were reported. Median overall survival (OS) for both groups (n = 32) was 31.4 months, median disease-free survival (n = 21) was 13.3 months. In the group of patients with effective treatment, the median OS was not reached. In non-responders, it was 18 months (p = 0.0442).

Conclusion. GO combined with FLAG/FLAG-Ida chemotherapy or azacitidine proved effective in relapsed/refractory AML patients. Remission did not appear to be associated with ELN risk, gender, age, CD33 expression, number of prior therapy lines, or number of relapses. GO + azacitidine combination showed efficacy, safety, and good tolerance in patients with prior high-dose chemotherapy refractoriness as well as low ECOG performance status. That allowed for the subsequent allo-HSCT administration to these patients. There was no significant difference between the groups of patients in the incidence of hematologic, non-hematologic toxicity, and time to hematologic recovery. Thrombocytopenia duration was longer in patients with GO + FLAG/FLAG-Ida therapy which is consistent with literature data. GO-based effective treatment in relapsed/refractory AML considerably improves OS: during 36 months of follow-up the median was not reached.

Keywords: acute myeloblastic leukemia, relapse, refractoriness, gemtuzumab ozogamicin, FLAG/FLAG-Ida regimens, azacitidine, efficacy, safety, toxicity.

Received: February 5, 2021

Accepted: May 15, 2021

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Статистика Plumx английский

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Aureobasidium pullulans-Associated Invasive Mycosis in a Child with Acute Myeloblastic Leukemia: A Case Report

INFECTIONS IN ONCOHEMATOLOGY ,

NS Bagirova1, AV Popa1, ТS Bogomolova2, NA Batmanova1, NV Dmitrieva1, IN Petukhova1, EN Sokolova1

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

2 II Mechnikov North-Western State Medical University, 41 Kirochnaya str., Saint Petersburg, Russian Federation, 191015

For correspondence: Nataliya Sergeevna Bagirova, MD, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: 8(499)324-18-60; e-mail: nbagirova@mail.ru

For citation: Bagirova NS, Popa AV, Bogomolova ТS, et al. Aureobasidium pullulans-Associated Invasive Mycosis in a Child with Acute Myeloblastic Leukemia: A Case Report. Clinical oncohematology. 2018;11(3):259–64.

DOI: 10.21320/2500-2139-2018-11-3-259-264

ABSTRACT

Severe mycotic infection occurring mainly in immunocompromised patients often exacerbates the progression of the primary oncohematological disease. It is the first attempt in Russian literature to present clinical and microbiological characteristics of invasive mycosis caused by Aureobasidium pullulans in a child with acute myeloblastic leukemia after receiving cytoreductive and antifungal treatment with favourable outcome.

Keywords: Aureobasidium pullulans, acute myeloblastic leukemia, invasive mycosis.

Received: January 15, 2018

Accepted: April 8, 2018

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Prognostic Value and Correlation Between WT1 Overexpression and NPM1 Mutation in Patients with Acute Myeloblastic Leukemia

MYELOID TUMORS , ,

LL Girshova, IG Budaeva, EG Ovsyannikova, SO Kuzin, DV Motorin, RSh Badaev, DB Zammoeva, VV Ivanov, KV Bogdanov, OS Pisotskaya, YuV Mirolyubova, TS Nikulina, YuA Alekseeva, AYu Zaritskii

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

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

For citation: Girshova LL, Budaeva IG, Ovsyannikova EG, et al. Prognostic Value and Correlation Between WT1 Overexpression and NPM1 Mutation in Patients with Acute Myeloblastic Leukemia. Clinical oncohematology. 2017;10(4):485–93 (In Russ).

DOI: 10.21320/2500-2139-2017-10-4-485-493

ABSTRACT

Background. Acute myeloblastic leukemia (AML) with NPM1 mutation amounts to 30 % of all AML and is characterized by good prognosis with the exception of cases with FLT3-ITD mutation. Despite the good prognosis, the likelihood of relapses in patients with NPM1 mutation may significantly differ. Thus, the estimation of the minimal residual disease (MRD) after chemotherapy and during follow-up is becoming increasingly important. This approach will make it possible to predict the sensitivity of a tumoral clone to chemotherapy.

Aim. To evaluate the prognostic value of highly specific marker (NPM1 mutation) and non-specific marker (WT1 overexpression) of MRD, as well as to identify the correlation between the levels of NPM1 and WT1 at different stages of therapy and in the follow-up period.

Materials & Methods. The research included 14 patients with AML. All patients had the NPM1 mutation and WT1 overexpression: 50 % of patients had additional molecular markers (BAALC overexpression, FLT3-ITD, DNMT3A, and MLL mutations). Real-time PCR was used for long-term monitoring of WT1 expression levels and NPM1 mutation.

Results. The median decrease of NPM1 levels after the induction therapy was 3 log. All patients had relapses, NPM1 mutation, and lower rates of OS/RFS, which significantly correlated with prognostically negative molecular markers. There were no statistically significant differences in RFS in groups with the decrease of WT1 expression level < 2 log and > 2 log on day 28 of treatment. At the same time, the decrease of WT1 expression by > 2 log was associated with significant differences in early relapses, which correlated with the decrease of NPM1 levels (> and < than 3 log) is revealed. RFS rates were higher in patients with WT1 expression level of < 100 per 104 copies ABL on day 28 and WT1 of < 250 per 104 copies ABL on day 14 of treatment. WT1 expression was significantly lower on days 14 and 28 in patients with NPM1 decrease of > 3 log on day 28. The decrease in WT1 expression of < 100 per 104 copies ABL on day 28 was more common in patients with isolated NPM1 mutation, compared to patients with additional negative molecular markers.

Conclusion. The decrease in NPM1 levels after the induction therapy may serve as reliable prognostic marker of RFS and OS rates. New correlation between the degree of NPM1 reduction and the presence of additional molecular markers was established. Highly specific (NPM1 mutation) was shown to be more specific compared to non-specific markers (WT1 overexpression). The research showed the predictive value of a lower limit level of WT1 on day 28 of treatment (100 per 104 copies ABL), and for the first time, the importance of the early assessment WT1 expression reduction on day 14 of induction therapy.

Keywords: acute myeloblastic leukemia, AML, NPM1, WT1, molecular monitoring.

Received: February 22, 2017

Accepted: May 26, 2017

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

BONE MARROW 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 %) (p = 0.001); 2-year OS was 63 % (95% CI 39–67 %) and 37 % (95% CI 26–48 %) (p = 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 (p = 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 (p = 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 %) (p = 0.001); 2-year EFS was 63 % (95% CI 39–67 %) and 37 % (95% CI 26–48 %) (p = 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 %) (p = 0.001); 2-year relapse-free and GVHR-free survival was 47 % (95% CI 32–62 %) and 27 % (95% CI 17–37 %) (p = 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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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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