refractoriness

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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Chronic Lymphocytic Leukemia in Blood Relatives: Two Case Reports of Male Siblings

AUTOIMMUNE THROMBOCYTOPENIA ,

NV Kurkina1,2, EA Repina1

1 NP Ogarev National Research Mordovia State University, 68 Bolshevistskaya str., Saransk, Russian Federation, 430005

2 Republican Clinical Hospital No. 4, 32 Ul’yanova str., Saransk, Russian Federation, 430032

For correspondence: Nadezhda Viktorovna Kurkina, MD, PhD, 32 Ul’yanova str., Saransk, Russian Federation, 430032; e-mail: nadya.kurckina@yandex.ru

For citation: Kurkina NV, Repina EA. Chronic Lymphocytic Leukemia in Blood Relatives: Two Case Reports of Male Siblings. Clinical oncohematology. 2021;14(1):69–72. (In Russ).

DOI: 10.21320/2500-2139-2021-14-1-69-72

ABSTRACT

In recent years there are more and more evidences for a hereditary factor in malignant lymphoproliferative disorders. Various lymphoid tumors are diagnosed in blood relatives. This is most frequently observed in chronic lymphocytic leukemia: 13.3 % vs. 8.8 % in non-Hodgkin’s lymphoma and 5.9 % in Hodgkin’s lymphoma. This paper presents two case reports of chronic lymphocytic leukemia in blood relatives (male siblings). Besides, in one of them the efficacy of targeted therapy with ibrutinib is estimated.

Keywords: chronic lymphocytic leukemia, heredity, ibrutinib, refractoriness, relapse.

Received: June 25, 2020

Accepted: November 6, 2020

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Prediction of FLAG ± Ida Regimen Efficacy in Patients with Relapsed/Refractory Acute Myeloid Leukemia

MYELOID TUMORS , , ,

IG Budaeva, EG Ovsyannikova, EN Goryunova, OV Kulemina, DV Zaitsev, DV Motorin, RSh Badaev, DB Zammoeva, VV Ivanov, KV Bogdanov, OS Pisotskaya, 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, Ovsyannikova EG, Goryunova EN, et al. Prediction of FLAG ± Ida Regimen Efficacy in Patients with Relapsed/Refractory Acute Myeloid Leukemia. Clinical oncohematology. 2019;12(3):289-96 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-289-296

ABSTRACT

Aim. To assess the efficacy of FLAG/FLAG-Ida regimen and to identify factors that influence remission, duration of disease-free survival (DFS) and overall survival (OS) of patients with relapsed/refractory acute myeloid leukemia (AML).

Materials & Methods. The trial included 54 patients (28 men and 26 women), median age was 37 years (range 18–70 years). 27 (50 %) out of 54 patients had refractory AML and 27 (50 %) patients had relapsed AML. FLAG and FLAG-Ida regimens were administered as induction therapy. 37 (68.5 %) patients received bone marrow transplantation. Molecular genetic and cytogenetic examinations were performed prior to therapy and on the 28th day after the start of treatment. WT1 gene expression was evaluated on the 14th–16th day of treatment.

Results. Complete remission (CR) was achieved in 42 (77.8 %) out of 54 patients. Refractoriness to therapy was observed in 9 (16.7 %) out of 54 patients, mortality was 5.5 % (3/54). Remission rate was higher in patients with relapsed AML compared with refractory AML: 85.2 % (23/27) and 70.4 % (19/27), respectively. On the 14th–16th day of treatment patients with blast cell count ≥ 10 % in bone marrow (BM) showed significantly lower CR rate (60 %) compared with the group of patients with < 10 % blast cells in BM (89.6 %; p = 0.024) and shorter DFS (median 7.6 vs. 17.6 months, respectively; p = 0.03). Median DFS in patients with WT1 expression reduction to < 1 log on the 14th–16th day was 5 vs. 18 months in patients without WT1 expression reduction (p = 0.01). DFS varied in groups of patients with blast cell count < 10 % in BM on the 14th–16th day of treatment based on the level of WT1 expression reduction (p = 0.04). MRD-negative patients (57.1 %) showed significantly longer DFS and OS compared with MRD-positive patients (median DFS was 17.6 vs. 5.2 months, respectively, p = 0.02; median OS was 19 vs. 6.9 months, p = 0.0002). Median DFS and OS were different only in ELN low- and high-risk groups (median not reached vs. 5.2 months, respectively, p = 0.039; median not reached vs. 10.2 months, p = 0.039).

Conclusion. FLAG and FLAG-Ida are effective and safe regimens in the treatment of relapsed/refractory AML. Achieving remission depends on neither the risk group nor the time of relapse occurrence. The blast cell count in BM on the 14th–16th day of FLAG/FLAG-Ida treatment is a prognostic factor determining achievement and duration of remission. WT1 expression level in the early post-induction period is a sensitive DFS marker. MRD status and molecular genetic risk (ELN) group affiliation are essential prognostic factors determining DFS and OS.

Keywords: acute myeloid leukemia, relapse, refractoriness, FLAG and FLAG-Ida regimens.

Received: November 2, 2018

Accepted: May 28, 2019

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The Use of Ibrutinib in Refractory Chronic Lymphocytic Leukemia and in High-Risk Patients

LYMPHOID TUMORS , , ,

NV Kurkina1,2, EA Repina1, NN Mashnina2

1 NP Ogarev Mordovia National Research State University, 68 Bol’shevistskaya str., Saransk, Republic of Mordovia, Russian Federation, 430032

2 Republican Clinical Hospital No. 4, 32 Ul’yanova str., Saransk, Republic of Mordovia, Russian Federation, 430032

For correspondence: Nadezhda Viktorovna Kurkina, MD, PhD, 68 Bol’shevistskaya str., Saransk, Republic of Mordovia, Russian Federation, 430032; e-mail: nadya.kurckina@yandex.ru

For citation: Kurkina NV, Repina EA, Mashnina NN. The Use of Ibrutinib in Refractory Chronic Lymphocytic Leukemia and in High-Risk Patients. Clinical oncohematology. 2019;12(3):278–81 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-278-281

ABSTRACT

Despite advances in chemo-immunotherapy of chronic lymphocytic leukemia, a choice of therapy is a frequent challenge in patients with a refractory form of the disease, autoimmune hemolytic complications, and also in high-risk patients with cytogenetic changes. The use of ibrutinib, one of Bruton’s tyrosine kinase inhibitors, allows to overcome the resistance to anticancer therapy without adverse effects on patients’ quality of life.

Keywords: chronic lymphocytic leukemia, chemo-immunotherapy, ibrutinib, refractoriness, relapse.

Received: January 21, 2018

Accepted: May 10, 2019

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REFERENCES

  1. Zenz T, Gribben JG, Hallek M, et al. Risk categories and refractory CLL in the era of chemoimmunotherapy. Blood. 2012;119(18):4101. doi: 10.1182/blood-2011-11-312421.

  2. Никитин Е.А., Судариков А.Б. Хронический лимфолейкоз высокого риска: история, определение, диагностика и лечение. Клиническая онкогематология. 2013;6(1):59–67.

    [Nikitin EA, Sudarikov AB. High­risk chronic lymphocytic leukemia: history, definition, diagnosis, and management. Klinicheskaya onkogematologiya. 2013;6(1):59–67. (In Russ)]

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  6. Byrd JС, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125(16):2497–506. doi: 10.1182/blood-2014-10-606038.

  7. Имбрувика® (инструкция по медицинскому применению). Джонсон & Джонсон (Россия). Доступно по: https://www.vidal.ru/drugs/imbruvica Ссылка активна на 21.01.2019.

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Bortezomib Combination Therapy of Relapsed and Refractory Acute Lymphoblastic Leukemia in Children

LYMPHOID TUMORS , ,

NA Batmanova, MA Shervashidze, AV Popa, LYu Grivtsova, IN Serebryakova, GL Mentkevich

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

For correspondence: Natal’ya Andreevna Batmanova, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(925)321-26-42; e-mail: Batmanova_nataly@mail.ru

For citation: Batmanova NА, Shervashidze MА, Popa АV, et al. Bortezomib Combination Therapy of Relapsed and Refractory Acute Lymphoblastic Leukemia in Children. Clinical oncohematology. 2017;10(3):381–9 (In Russ).

DOI: 10.21320/2500-2139-2017-10-3-381-389

ABSTRACT

Background & Aims. Despite significant success in the treatment of acute lymphoblastic leukemia (ALL) in children, relapses and drug resistance to the standard therapy remain the main cause of treatment failure. The addition of bortezomib to the combination therapy of relapsed ALL to change the sensitivity of blast cells may be a perspective approach to cure patients. The aim was to evaluate the efficacy and toxicity of the anti-relapse ALL treatment protocols REZ BFM 95/96 without bortezomib and COG AALL07P1 with bortezomib in relapsed and refractory ALL in children.

Materials & Methods. The study included 54 children with a confirmed ALL of various localizations. From 1995 to 2011, ALL REZ BFM 95/96 treatment without bortezomib was administered to 26 patients. From 2011 to 2016, 28 children received COG AALL07P1 combination treatment with bortezomib.

Results. The immediate treatment efficacy significantly higher in patients treated with bortezomib (85.7 % vs 57.6 %) after induction chemotherapy with the ALL REZ BFM 95/96. The analysis of the long-term outcomes (disease-free, event-free, overall survival) showed no significant differences between the groups. The event-free survival of patients with isolated bone marrow relapses for a period of 2 years was 20.3 ± 17.5 %. The tolerability of the program was acceptable, complications developing during myelosuppression were not associated with the administration of bortezomib.

Conclusion. The intensification of induction chemotherapy in recurrent remission according to COG AALL07P1 protocol with the addition of bortezomib allowed to increase the number of complete remissions including MRD negative ones.

Keywords: acute lymphoblastic leukemia, refractoriness, relapses, bortezomib.

Received: February 24, 2017

Accepted: May 2, 2017

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REFERENCES

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  17. Messinger YH, Gaynon PS, Sposto R, et al. Bortezomib with chemotherapy is highly active in advanced B-precursor acute lymphoblastic leukemia: Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study. Blood. 2012;120(2):285–90. doi: 10.1182/blood-2012-04-418640.

 

Treatment of Relapsed and Refractory Hodgkin’s Lymphoma in Children

LYMPHOID TUMORS , , , ,

NS Kulichkina, ES Belyaeva, GL Mentkevich, VK Boyarshinov, AS Levashov, IV Glekov, AV Popa

Scientific Research Institute of Pediatric Oncology and Hematology, N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Aleksandr Valentinovich Popa, DSci, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-55-03; e-mail: apopa@list.ru

For citation: Kulichkina NS, Belyaeva ES, Mentkevich GL, et al. Treatment of Relapsed and Refractory Hodgkin’s Lymphoma in Children. Clinical oncohematology. 2016;9(1):13–21 (In Russ).

DOI: 10.21320/2500-2139-2016-9-1-13-21

ABSTRACT

Background & Aims. Most children with Hodgkin’s lymphoma (HL) can be cured irrespective of the disease stage using modern risk adapted protocols. But 3–5 % of children develop relapse of the disease or refractoriness to the treatment performed. The aim of the study was to perform a comparative analysis of ViGePP vs ICE antitumor treatment regimens in patients with relapsed and refractory Hodgkin’s lymphoma, as well as to evaluate the need in auto-HSCT and the site for a combined chemoradiation therapy in this patient population.

Methods. From June, 2003, till December, 2014, 35 patients with relapsed (18) and refractory (17) HL received chemotherapy based on two regimes: ICE (n = 14; 40 %) and ViGePP (n = 14; 40 %). 7 (20 %) children were switched to another regimen due to a poor antitumor response to the first two courses of chemotherapy.

Results. The direct effectiveness of the therapy was significantly higher in patients on ViGePP as compared to ICE irrespective of the disease status (relapsed or refractory). A complete response was achieved more often in those children with relapse HL whose initial treatment included radiation therapy. Higher survival rates were registered in girls, as well as in children with a complete overall response to the antirelapse therapy. In case of relapses, delayed treatment effects (disease free survival and overall survival) were higher in children treated with 4 courses of ViGePP than 2 courses of ICE. High-dose chemotherapy with subsequent auto-HSCT is not able to overcome refractoriness to the chemotherapy.

Conclusion. Children with relapsed and refractory HL need an intensive antirelapse chemotherapy with subsequent HDC and auto-HSCT to achieve CR.

Keywords: Hodgkin’s lymphoma, children, relapse, refractoriness, auto-HSCT.

Received: November 9, 2015

Accepted: December 25, 2015

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