targeted therapy

Efficacy and Safety of Midostaurin Combined with Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia with FLT3 Mutation

AUTOIMMUNE THROMBOCYTOPENIA ,

SN Bondarenko1, AG Smirnova1, BI Ayubova1, EV Karyagina2, OS Uspenskaya3, YuS Neredko4, AP Kochergina5, IA Samorodova6, EA Pashneva7, YuS Chernykh8, YuA Dunaev9, NB Esef’eva10, RK Il’yasov11, TI Brazhkina12, IA Novokreshchenova13, ZK Simavonyan14, EI Kuzub15, VI Bakhtina16, TI Olkhovich17, MV Burundukova18, EV Babenko1, YuD Oleinikova1, IM Barkhatov1, TL Gindina1, IS Moiseev1, AD Kulagin1

1 RM Gorbacheva Scientific Research Institute of Pediatric Oncology, Hematology and Transplantation; IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo ul., Saint Petersburg, Russian Federation, 197022

2 Municipal Hospital No. 15, 4 Avangardnaya ul., Saint Petersburg, Russian Federation, 198205

3 Leningrad Regional Clinical Hospital, 45 korp. 2A Lunacharskogo pr-t, Saint Petersburg, Russian Federation, 194291

4 Stavropol Krai Clinical Oncology Dispensary, 182a Oktyabrskaya ul., Stavropol, Russian Federation, 355047

5 Krai Clinical Hospital, 1 Lyapidevskogo ul., Barnaul, Russian Federation, 656024

6 Municipal Clinical Hospital No. 31, 3 Dinamo pr-t, Saint Petersburg, Russian Federation, 197110

7 Volgograd Regional Clinical Oncology Dispensary, 78 Zemlyachki ul., Volgograd, Russian Federation, 400138

8 MF Vladimirskii Moscow Regional Research Clinical Institute, 61/2 Shchepkina ul., Moscow, Russian Federation, 129110

9 Arkhangelsk Regional Clinical Hospital, 292 Lomonosova pr-t, Arkhangelsk, Russian Federation, 163045

10 Ulyanovsk Regional Clinical Hospital, 7 III Internatsionala ul., Ulyanovsk, Russian Federation, 432017

11 VM Efetov Crimea Republican Clinical Oncology Dispensary, 49A Bespalova ul., Simferopol, Russian Federation, 295007

12 Ivanovo Regional Clinical Hospital, 1 Lyubimova ul., Ivanovo, Russian Federation, 153040

13 RZhD-Meditsina Clinical Hospital, 15 1-i Krasnoflotskii per., Smolensk, Russian Federation, 214025

14 AI Burnazyan Federal Medical Biophysical Center, 23 Marshala Novikova ul., Moscow, Russian Federation, 123098

15 Rostov State Medical University Hospital, 29 Nakhichevanskii per., Rostov-on-Don, Russian Federation, 344022

16 Krasnoyarsk Krai Clinical Hospital, 3A Partizana Zheleznyaka ul., Krasnoyarsk, Russian Federation, 660022

17 Krasnoyarsk Interdistrict Clinical Hospital No. 7, 4 Akademika Pavlova ul., Krasnoyarsk, Russian Federation, 660003

18 Municipal Clinical Hospital No. 2, 21 Polzunova ul., Novosibirsk, Russian Federation, 630051

For correspondence: Sergei Nikolaevich Bondarenko, MD, PhD, 6/8 L’va Tolstogo ul., Saint Petersburg, Russian Federation, 197022; Tel.: +7(921)994-35-70; e-mail: dr.sergeybondarenko@gmail.com

For citation: Bondarenko SN, Smirnova AG, Ayubova BI, et al. Efficacy and Safety of Midostaurin Combined with Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia with FLT3 Mutation. Clinical oncohematology. 2022;15(2):167–75. (In Russ).

DOI: 10.21320/2500-2139-2022-15-2-167-175

ABSTRACT

Background. The detection of FLT3-ITD mutation in acute myeloid leukemia (AML) patients is associated with poor prognosis and is an indication for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the first remission. Midostaurin is the first FLT3 inhibitor approved for the treatment of AML patients with FLT3 mutation in the Russian Federation in November 2019. This study deals with the initial experiences of using midostaurin in several centers for hematology in the Russian Federation.

Aim. To analyze the initial experiences of using midostaurin at different AML stages.

Materials & Methods. The study enrolled 42 patients with newly diagnosed AML with FLT3 mutation, who were treated with midostaurin combined with chemotherapy. Allo-HSCT was performed in 11 patients.

Results. The 2-year overall survival (OS) was 51 %, and the 2-year event-free survival (EFS) was 45 %. After achieving remission, the 2-year disease-free survival (DFS) was 58 %. The 1-year DFS of allo-HSCT recipients was 86 % (95% confidence interval [95% CI] 60–100 %) vs. 66 % in patients treated with chemotherapy without allo-HSCT (95% CI 34–98 %), respectively (p = 0.5). Hyperleukocytosis at disease onset was associated with high relapse risk. Midostaurin had to be discontinued in 5 % of cases due to atrial fibrillation and QTc prolongation.

Conclusion. The present study demonstrates the safety and importance of including midostaurin in the regimens for treating AML with FLT3 mutation. Midostaurin assignment for maintenance therapy, after allo-HSCT as well as without performing it, can result in considerable improvement of OS and DFS.

Keywords: acute myeloid leukemias, FLT3 mutations, targeted therapy, midostaurin.

Received: December 27, 2021

Accepted: March 20, 2022

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Treatment of Mastocytosis: A Literature Review

AUTOIMMUNE THROMBOCYTOPENIA , ,

KM Chernavina1, AS Orlova1, EA Nikitin2

1 IM Sechenov First Moscow State Medical University, 8 bld. 2 Trubetskaya str., Moscow, Russian Federation, 119991

2 Russian Medical Academy of Postgraduate Education, 2/1 Barrikadnaya str., Moscow, Russian Federation, 125993

For correspondence: Karina Maksimovna Chernavina, 8 bld. 2 Trubetskaya str., Moscow, Russian Federation, 119992; e-mail: Shkyrlak@gmail.com

For citation: Chernavina KM, Orlova AS, Nikitin EA. Treatment of Mastocytosis: A Literature Review. Clinical oncohematology. 2021;14(3):361–9. (In Russ).

DOI: 10.21320/2500-2139-2021-14-3-361-369

ABSTRACT

The term “mastocytosis” refers to a group of rare heterogeneous disorders resulting from proliferation and accumulation of neoplastic mast cells in various organs. The World Health Organization (WHO) classifies these diseases into three types: cutaneous mastocytosis, systemic mastocytosis (SM), and mast cell sarcoma (MCS). Depending on the degree of aggressiveness SM can be indolent, smoldering, aggressive (ASM), or associated with another proliferative hematological disease of non-mast cell line (SM-AHD). SM also includes mast cell leukemia (MCL). Numerous studies confirm the prognostic value of the WHO classification. All mastocytosis patients require treatment aimed at reducing the symptoms of mast cell activation. In case of prognostically unfavorable types of mastocytosis, such as ASM, SM-AHD, MCL, and MCS, more intensive treatment methods should come into consideration, which include allogeneic hematopoietic stem cell transplantation, cytoreductive therapy with tyrosine kinase inhibitors (TKI), interferon-α, and cladribine. In the pathogenesis of mastocytosis, mutations in different KIT gene exons have a dominating role. Most common is KITD816V activating mutation (80–90 % of SM cases). Some of TKIs (imatinib mesylate and midostaurin) had been successfully used in clinical trials and were approved for treating prognostically unfavorable mastocytosis. However, in some patients exclusive TKI treatment does not result in long-lasting remission due to therapy resistance induced by KIT activating mutations as well as other additional somatic mutations and molecular changes. For the purpose of comparative analysis, the review provides the results of major clinical trials dealing with various methods of mastocytosis treatment.

Keywords: mast cells, mastocytosis, KITD816V mutation, targeted therapy, tyrosine kinase inhibitors, imatinib, midostaurin.

Received: March 12, 2021

Accepted: June 10, 2021

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Статистика Plumx английский

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Paroxysmal Nocturnal Hemoglobinuria in Patients with Aplastic Anemia: Challenges, Characteristics, and Analysis of Clinical Experience

RARE HEMATOLOGICAL TUMORS AND SYNDROMES , , , , ,

ER Shilova1, TV Glazanova1, ZhV Chubukina1, OE Rozanova1, MN Zenina1, AV Seltser1, VI Rugal1, VA Balashova1, VA Kobilyanskaya1, II Krobinets1, VYu Udal’eva1, II Zotova1, LV Stelmashenko1, NA Romanenko1, TB Zamotina1, IV Khorsheva1, SV Voloshin1,2,3

1 Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

2 SM Kirov Military Medical Academy, 6 Akademika Lebedeva str., Saint Petersburg, Russian Federation, 194044

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

For correspondence: Elena Romanovna Shilova, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel.: +7(981)129-09-77; e-mail: rniiht@mail.ru

For citation: Shilova ER, Glazanova TV, Chubukina ZhV, et al. Paroxysmal Nocturnal Hemoglobinuria in Patients with Aplastic Anemia: Challenges, Characteristics, and Analysis of Clinical Experience. Clinical oncohematology. 2019;12(3):319–28 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-319-328

ABSTRACT

Background & Aims. Paroxysmal nocturnal hemoglobinuria (PNH) is a disease caused by an acquired clonal disorder of hematopoietic stem cells with clone cell membrane hypersensitivity to the complement. PNH can exist as an independent disease and can also be associated with other pathological conditions characterized by bone marrow deficiency, first of all with aplastic anemia (AA). In PNH-associated AA (AA/PNH) pathological clones may be initially of different size. In some patients a gradual growth of PNH clone is observed together with occurring signs of intravascular hemolysis and transformation into classical hemolytic PNH. In this case it is important to assess the clinical situation and determine eligibility for complement inhibitor therapy. During targeted therapy it is necessary to assess the efficacy of treatment based on monitoring of complement-mediated hemolysis and to identify probable reasons for insufficient effect.

Materials & Methods. The paper deals with 1 clinical case. A female patient born in 1964, with initial diagnosis of AA was followed-up from 1989 till present at the Russian Research Institute of Hematology and Transfusiology. Her treatment included blood-component therapy, the use of antilymphocyte immunoglobulin, cyclosporine, plasmapheresis, eculizumab, and symptom-relieving drugs.

Results. The study deals with the case of transformation of non-severe AA with remission after immune-suppressive therapy into classical hemolytic PNH. The case report describes the characteristic features, AA/PNH diagnosis and treatment issues at different stages of the disease, and the reasons for incomplete effect of targeted therapy.

Conclusion. The case under discussion confirms the relevance of current methods of detecting PNH clone at early stages of AA diagnosis and dynamic follow-up with respect to a probable growth of clone with PNH phenotype, especially at the stage of hematopoietic recovery. Determination of PNH clone size and lactate dehydrogenase serum level is required for timely amendment of treatment strategy with a switch to long-term targeted monitoring of hemolysis which allows to prevent irreversible visceral changes and severe complications. In case of insufficient effect of targeted therapy with ongoing anemia Coombs test is recommended because of probability of C3-mediated extravascular hemolysis.

Keywords: aplastic anemia, paroxysmal nocturnal hemoglobinuria, PNH phenotype, PNH clone, targeted therapy, C3-mediated hemolysis.

Received: December 24, 2018

Accepted: May 29, 2019

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Intermediate Results of Prospective Observational Study: The 2-year Experience of Ibrutinib Therapy in Relapsed/Refractory Mantle Cell Lymphoma in Clinical Practice

LYMPHOID TUMORS , , ,

VI Vorob’ev, VA Zherebtsova, EI Dubrovin, LA Bychenkova, YuB Kochkareva, LA Mukha, VL Ivanova, NK Khuazheva, VV Ptushkin

SP Botkin Municipal Clinical Hospital, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284

For correspondence: Vladimir Ivanovich Vorob’ev, MD, PhD, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284; e-mail: morela@mail.ru

For citation: Vorob’ev VI, Zherebtsova VA, Dubrovin EI, et al. Intermediate Results of Prospective Observational Study: The 2-year Experience of Ibrutinib Therapy in Relapsed/Refractory Mantle Cell Lymphoma in Clinical Practice. Clinical oncohematology. 2019;12(2):165-72.

DOI: 10.21320/2500-2139-2019-12-2-165-172

ABSTRACT

Aim. To assess efficacy and toxicity of ibrutinib monotherapy in patients with relapsed/refractory mantle cell lymphoma (MCL).

Materials & Methods. In this group of patients ibrutinib has been used since April 2016. Ibrutinib administration criteria were the age > 18 years and the confirmed MCL diagnosis with nuclear hyperexpression of cyclin D1 and t(11;14)(q13;q32) translocation. Poor physical status, pancytopenia, infectious complications (except for life-threatening conditions), blastoid variant, and the number of previous treatment lines were not regarded as contraindications to ibrutinib therapy. Oral ibrutinib was administered once a day at a dose of 560 mg before progression and until intolerable toxicity was observed.

Results. From April 20, 2016 to April 6, 2018 ibrutinib therapy was provided to 42 patients with relapsed/refractory MCL. The median age was 69 years (range 40–81); 64 % of patients were men; ECOG > 2 was registered in 14 % of patients; 38 % of patients had blastoid variant; the median number of previous treatment lines was 2 (range 1–11). The overall response rate was 85 % (35 % were in complete remission); 57 % (24/42) of patients remain on ibrutinib treatment for the period of 4–667 days. The median event-free survival (EFS) was 365 days (95% confidence interval was 31–698 days). The median overall survival was not achieved. In blastoid variant the median EFS was 92 days, in the alternative group the median was not achieved and EFS was 76 % for 12 months (p < 0.001). In the majority of cases ibrutinib was well tolerated by patients. The most common complications were myalgia and muscle cramps (57 % cases), diarrhea (46 %, and grade 3 in 5 % cases), hemorrhagic complications (63 %, all of them of grade 1–2), and arrhythmia (7 %). Infectious complications were reported in 31 % of patients. In one case the start of ibrutinib treatment appeared to be problematic due to neutropenia of grade 4. Relative dose intensity was > 98 % (range 91.6–100 %). In 10 (24 %) patients ibrutinib treatment had to be adjusted (dose reduction or treatment interruption) due to toxicity and planned surgeries. None of ibrutinib recipients had to completely discontinue ibrutinib therapy due to complications.

Conclusion. These data on the use of ibrutinib in actual clinical practice are comparable with the results of international multicenter studies (PCYC-1104, SPARK, and RAY). Reduced toxicity profile and rather high speed of antitumor response allow for ibrutinib administration in cases of poor physical status, low blood count, and even infectious complications. However, some adverse effects are manifested not earlier than after 6-month treatment, which calls for continuous monitoring, especially when preparing for surgeries.

Keywords: mantle cell lymphoma, ibrutinib, relapse, refractory course, targeted therapy.

Received: November 4, 2018

Accepted: February 11, 2019

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    [Vorob’ev VI, Kravchenko SK, Gemdzhian EG, et al. Mantle cell lymphoma: program therapy for untreated patients under 65 years. Klinicheskaya onkogematologiya. 2013;6(3):274–81. (In Russ)]

  10. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. 2013;381(9873):1203–10. doi: 10.1016/s0140-6736(12)61763-2.

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Blinatumomab in the Treatment of Acute Lymphoblastic Leukemia: Russian Multicenter Clinical Trial

LYMPHOID TUMORS ,

SN Bondarenko1, EN Parovichnikova2, AA Maschan3, OYu Baranova4, TV Shelekhova5, VA Doronin6, VYa Mel’nichenko7, KD Kaplanov8, OS Uspenskaya9, AN Sokolov2, NV Myakova3, IS Moiseev1, IV Markova1, EI Darskaya1, AG Smirnova1, TA Bykova1, BI Ayubova1, IA Samorodova1, EV Babenko1, IM Barkhatov1, TL Gindina1, AD Kulagin1, BV Afanas’ev1

1 RM Gorbacheva Scientific Research Institute of Pediatric Oncology, Hematology and Transplantation; IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

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

3 Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, 1 Samory Mashela str., Moscow, Russian Federation, 117997

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

5 VI Razumovskii Saratov State Medical University, 112 Bol’shaya Kazach’ya str., Saratov, Russian Federation, 410012

6 Municipal Clinical Hospital No. 40, 7 Kasatkina str., Moscow, Russian Federation, 129301

7 NI Pirogov Russian National Medical Center of Surgery, 70 Nizhnyaya Pervomaiskaya str., Moscow, Russian Federation, 105203

8 Volgograd Regional Clinical Oncologic Dispensary, 78 Zemlyachki str., Volgograd, Russian Federation, 400138

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

For correspondence: Sergei Nikolaevich Bondarenko, MD, PhD, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel.: +7(812)338-62-72; e-mail: dr.sergeybondarenko@gmail.com

For citation: Bondarenko SN, Parovichnikova EN, Maschan AA, et al. Blinatumomab in the Treatment of Acute Lymphoblastic Leukemia: Russian Multicenter Clinical Trial. Clinical oncohematology. 2019;12(2):145–53.

DOI: 10.21320/2500-2139-2019-12-2-145-153

ABSTRACT

Background. Recent advances in the treatment of relapsed/refractory acute lymphoblastic leukemia (R/R ALL) are attributed to the implementation of immunotherapy methods which include blinatumomab, the bispecific engager of a patient’s endogenous T-cells (Blincyto™, Amgen®) (BC).

Aim. To assess BC efficacy and toxicity in the treatment of R/R ALL patients with persistence of minimal tumor clone before and after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Materials & Methods. The trial included 66 B-ALL patients with CD19+ aged 18 to 72 years, 23 (35 %) of them with measurable minimal residual disease (MRD+) and 43 (65 %) with R/R ALL. In 18 (27 %) patients BC was administered after prior allo-HSCT.

Results. In the overall group 2-year overall survival (OS) and disease-free survival (DFS) in patients with response to BC treatment were 53 % and 38 % respectively. In the R/R ALL group complete remission (CR) was achieved in 29 (67 %) patients including 24 (83 %) patients with negative MRD. CR rate was higher in standard cytogenetic risk group (73 %) in comparison with high-risk group (59 %). In patients with more or less than 50 % blast cells in bone marrow CR rate was 85 % and 61 %, respectively. When BC was administered after prior allo-HSCT and without it CR rate was 80 % and 60 %, respectively. In R/R ALL patients with response to BC 2-year OS and DFS were 40 % and 26 %, respectively, in the MRD+ group of ALL patients they were 66 % and 51 %, respectively. Relapse rate was lower in the group with allo-HSCT than in the group without it, i.e. 21 % vs. 55 %. Adverse events of grade 3–4 were observed in 25 (38 %) patients. In 11 (16 %) patients BC therapy had to be discontinued, in 5 (7 %) patients it was terminated prior to the scheduled date.

Conclusion. BC efficacy is higher in the MRD+ group and in R/R ALL patients with smaller tumor mass. BC treatment after allo-HSCT yields remissions in most patients and can be combined with immune-adoptive therapy.

Keywords: acute lymphoblastic leukemia, targeted therapy, blinatumomab.

Received: August 22, 2018

Accepted: January 18, 2019

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REFERENCES

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  9. Klinger M, Brandl C, Zugmaier G, et al. Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell–engaging CD19/CD3-bispecific BiTE antibody blinatumomab. Blood. 2012;119(26):6226–33. doi: 10.1182/blood-2012-01-400515.

  10. Topp MS, Gokbuget N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015;16(1):57–66. doi: 10.1016/s1470-2045(14)71170-2.

  11. Gokbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;131(14):1522–31. doi: 10.1182/blood-2017-08-798322.

  12. Kantarjian H, Stein AS, Gokbuget N, et al. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. N Engl J Med. 2017;376(9):836–47. doi: 10.1056/NEJMoa1609783.

  13. Zugmaier G, Gokbuget N, Klinger M, et al. Long-term survival and T-cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment. Blood. 2015;126(24):2578–84. doi: 10.1182/blood-2015-06-649111.

Current Issues in Carcinogenesis

REVIEWS , , , , , ,

IV Vysotskaya1, VP Letyagin2, MA Shabanov2, VYu Kirsanov1, EA Kim1, NV Levkina1

1 IM Sechenov First Moscow State Medical University, 8 bld. 2 Trubetskaya str., Moscow, Russian Federation, 119991

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

For correspondence: Prof. Irina Viktorovna Vysotskaya, MD, PhD, 8 bld. 2 Trubetskaya str., Moscow, Russian Federation, 119991; e-mail: vysotskaya.irina@mail.ru

For citation: Vysotskaya IV, Letyagin VP, Shabanov MA, et al. Current Issues in Carcinogenesis. Clinical oncohematology. 2019;12(1):101–6.

DOI: 10.21320/2500-2139-2019-12-1-101-106

ABSTRACT

The review presents current data on the major pathogenetic mechanisms underlying uncontrolled growth and dissemination of tumor and its resistance to conventional treatment. Cell genetic instability associated with accumulation of mutations in genes controlling cell growth and differentiation is a key factor in tumor proliferation. Due understanding and detailed analysis of carcinogenesis processes provide the basis for creation of new anticancer drugs which in turn enables optimization and individualization of cancer treatment.

Keywords: carcinogenesis, initiation, promotion, repair, proto-oncogenes, suppressor genes, Ras, TP53, targeted therapy.

Received: June 27, 2018

Accepted: December 20, 2018

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Tyrosine Kinase Inhibitor Resistance in Patients with Chronic Myeloid Leukemia: A 10-Year Study of BCR-ABL Gene Mutation Profile in Russia (2006–2016)

MYELOID TUMORS , , ,

VV Tikhonova1,2, MA Isakov3, VA Misyurin1, YuP Finashutina1,2, LA Kesaeva1,2, NA Lyzhko 1, IN Soldatova2, NN Kasatkina1, EN Misyurina4, AV Misyurin1,2

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

2 GenoTekhnologiya, 104 Profsoyuznaya str., Moscow, Russian Federation, 117485

3 Aston Consulting, 31g Shabolovka str., Moscow, Russian Federation, 115162

4 Municipal Clinical Hospital No. 52, 3 Pekhotnaya str., Moscow, Russian Federation, 123182

For correspondence: Vera Vyacheslavovna Tikhonova, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(967)008-02-84; e-mail: brilfor@mail.ru

For citation: Tikhonova VV, Isakov MA, Misyurin VA, et al. Tyrosine Kinase Inhibitor Resistance in Patients with Chronic Myeloid Leukemia: A 10-Year Study of BCR-ABL Gene Mutation Profile in Russia (2006–2016). Clinical oncohematology. 2018;11(3):227–33.

DOI: 10.21320/2500-2139-2018-11-3-227-233

ABSTRACT

Background. Kinase domain mutations of BCR-ABL gene is the most common cause of tyrosine kinase inhibitor resistance.

Aim. To present the data on prognostic value of BCR-ABL mutation burden in Russian patients over the last 10 years.

Materials & Methods. The study included 1885 chronic myeloid leukemia (CML) patients with tyrosine kinase inhibitor resistance who were followed up from 2006 to 2016. BCR-ABL point mutations in mRNA samples were analyzed by means of polymerase chain reaction and subsequent Sanger sequencing.

Results. In 1257 CML patients with signs of tyrosine kinase inhibitor resistance BCR-ABL expression level was > 1 %. BCR–ABL mutations were detected in 31.8 % of patients. Total mutation count was 467 (70 mutation types). Total count of patients with mutation-associated tyrosine kinase inhibitor resistance decreased from 36.6 % (2006–2008) to 24.95 % (2013–2016) and to marked decrease of 23.12 % in 2014. Detection rate of imatinib-resistant mutations and F359V mutation was shown to decrease within the period from 2010–2011 to 2014–2015. F317L level, which is responsible for dasatinib resistance, considerably increased in 2015. T315I frequency was the highest in 2014, afterwards it was gradually decreasing. Mutation-associated resistance rates varied by region of the Russian Federation.

Conclusion. The analysis of trends of mutation incidence in patients with CML can be of extreme significance in long-term prognosis of resistance development and in improvement of treatment planning.

Keywords: chronic myeloid leukemia, kinase domain mutations of BCR-ABL gene, targeted therapy, resistance.

Received: January 22, 2018

Accepted: April 16, 2018

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  6. Elnahass YH, Mahmoud HK, Ali FT, et al. Abl Kinase Domain Mutations in Imatinib-treated Egyptian Patients with Chronic Myeloid Leukemia. J Leuk. 2013;1(1):106. doi: 10.4172/2329-6917.1000106.
  7. Awidi A, Ababneh N, Magablah A, et al. ABL Kinase Domain Mutations in Patients with Chronic Myeloid Leukemia in Jordan. Genet Test Mol Biomark. 2012;16(11):1317–21. doi: 10.1089/gtmb.2012.0147.
  8. Elias MH, Baba AA, Husin A, et al. Contribution of BCR-ABL kinase domain mutations to imatinib mesylate resistance in Philadelphia chromosome positive Malaysian chronic myeloid leukemia patients. Hematol Rep. 2012;4(4):e23. doi: 10.4081/hr.2012.e23.
  9. Vaidya S, Vundinti BR, Shanmukhaiah C, et al. Evolution of BCR/ABL Gene Mutation in CML Is Time Dependent and Dependent on the Pressure Exerted by Tyrosine Kinase Inhibitor. PLoS One. 2015;10(1):e0114828. doi: 10.1371/journal.pone.0114828.
  10. Челышева Е.Ю., Шухов О.А., Лазарева О.В., Туркина А.Г. Мутации киназного домена гена BCR-ABL при хроническом миелолейкозе. Клиническая онкогематология. 2012;5(1):13–21.[Chelysheva EYu, Shukhov OA, Lazareva OV, Turkina AG. Kinase domain mutations of BCR-ABL gene in patients with chronic myeloid leukemia. Klinicheskaya onkogematologiya. 2012;5(1):13–21. (In Russ)]
  11. Kimura S, Ando T, Kojima K. BCR-ABL Point Mutations and TKI Treatment in CML Patients. J Hematol Transfus. 2014;2(3):1022.
  12. Soverini S, de Benedittis C, Mancini M, Martinelli G. Mutations in the BCR-ABL1 Kinase Domain and Elsewhere in Chronic Myeloid Leukemia. Clin Lymph Myel Leuk. 2015;15(Suppl):S120–8. doi: 10.1016/j.clml.2015.02.035.
  13. Soverini S, De Benedittis C, Papayannidis C, et al. Drug resistance and BCR-ABL kinase domain mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia from the imatinib to the second-generation tyrosine kinase inhibitor era: The main changes are in the type of mutations, but not in the frequency of mutation involvement. 2014;120(7):1002–9. doi: 10.1002/cncr.28522.
  14. Мисюрин А.В., Мисюрина Е.Н., Тихонова В.В. и др. Частота встречаемости мутаций киназного домена гена BCR-ABL у больных хроническим миелолейкозом, резистентных к терапии иматинибом. Российский биотерапевтический журнал. 2016;15(4):102–9. doi: 10.17650/1726-9784-2016-15-4-102-109.[Misyurin AV, Misyurina EN, Tikhonova VV, et al. BCR-ABL gene kinase domain mutation frequency in imatinib resistant chronic myeloid leukemia patients. Rossiiskii bioterapevticheskii zhurnal. 2016;15(4):102–9. doi: 10.17650/1726-9784-2016-15-4-102-109. (In Russ)]
  15. Hughes TP, Saglio G, Quintas-Cardama A, et al. BCR-ABL1 mutation development during first-line treatment with dasatinib or imatinib for chronic myeloid leukemia in chronic phase. Leukemia. 2015;29(9):1832–8. doi: 10.1038/leu.2015.168.
  16. Абдулкадыров К.М., Шуваев В.А., Фоминых М.С. Дженерики иматиниба: мифы и реальность (обзор литературы и собственные данные). Клиническая онкогематология. 2014;7(3):311–6.[Abdulkadyrov KM, Shuvaev VA, Fominykh MS. Imatinib Generics: Myths and Reality (Literature Review and Our Experience). Klinicheskaya onkogematologiya. 2014;7(3):311–6. (In Russ)]
  17. Валиев Т.Т., Левашов А.С., Сенжапова Э.Р. Таргетные препараты в детской онкологии. Онкопедиатрия. 2016;3(1):8–15. doi: 10.15690/onco.v3i1.1524.[Valiev TT, Levashov AS, Senzhapova ER. Targeted Drugs in Pediatric Oncology. Onkopediatriya. 2016;3(1):8–15. doi: 10.15690/onco.v3i1.1524. (In Russ)]

The Use of Brentuximab Vedotin in Relapsed/Refractory Hodgkin’s Lymphoma in the Kransnodar Region

NOVEL DRUGS , , ,

OD Serdyuk, DA Yaskul’skii

Clinical Oncology Dispensary No. 1 of the Krasnodar region, 146 Dimitrova str., Krasnodar, Russian Federation, 350040

For correspondence: Ol’ga Dmitrievna Serdyuk, 146 Dimitrova str., Krasnodar, Russian Federation, 350040; Tel.: +7(918)441-08-33; e-mail: 7-18@mail.ru

For citation: Serdyuk OD, Yaskul’skii DA. The Use of Brentuximab Vedotin in Relapsed/Refractory Hodgkin’s Lymphoma in the Kransnodar Region. Clinical oncohematology. 2018;11(1):50-3.

DOI: 10.21320/2500-2139-2018-11-1-50-53

ABSTRACT

The treatment of relapsed/refractory Hodgkin’s lymphoma (HL) remains to be a challenging issue. The morbidity of HL is reported to increase in the Krasnodar region. While considerable progress in the treatment of HL has been achieved, the relapse rate still remains high. The standard second-line treatment allows for the disease control in only half of cases of relapsed HL. Until recently, however, relapses after autologous hematopoietic stem cell transplantation (autoHSCT) could be treated only by polychemotherapy aimed at slowing the tumor growth. The use of anti-CD30 conjugated monoclonal antibodies and cytotoxic agent was shown to control the relapsed disease after high dose chemotherapy followed by autoHSCT. The present study provides pharmacological characteristics of brentuximab vedotin, its antineoplastic mechanism as well as the author’s own clinical experience in the management of a female patient with HL after autoHSCT.

Keywords: Hodgkin’s lymphoma, brentuximab vedotin, targeted therapy, relapse.

Received: November 25, 2017

Accepted: January 8, 2018

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REFERENCES

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  8. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183–9. doi: 10.1200/jco.2011.38.0410.
  9. Gopal AK, Chen R, Smith SE, et al. Durable remissions in a pivotal phase 2 study of brentuximab vedotin in relapsed or refractory Hodgkin lymphoma. Blood. 2015;125(8):1236–43. doi: 10.1182/blood-2014-08-595801.

Targeted Therapy of Myelofibrosis

MYELOID TUMORS , , , , ,

OYu Vinogradova1,3,4, VA Shuvaev2, IS Martynkevich2, MM Pankrashkina1,3, MS Fominykh2, EV Efremova2, KYu Krutikova2, LB Polushkina2, NN Sharkunov1, SV Voloshin2, AV Chechetkin2

1SP Botkin Municipal Clinical Hospital, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284

2Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

3Dmitrii Rogachev National Medical Pediatric Hematology, Oncology and Immunology Research Center, 1 Samory Mashela str., Moscow, Russian Federation, 117198

4NI Pirogov Russian National Research Medical University, 1 Ostrovityanova str., Moscow, Russian Federation, 117997

For correspondence: Ol’ga Yur’evna Vinogradova, MD, PhD, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284; Tel.: 8(495)945-97-61; e-mail: olgavinz@mail.ru.

For citation: Vinogradova OYu, Shuvaev VA, Martynkevich IS, et al. Targeted Therapy of Myelofibrosis. Clinical oncohematology. 2017;10(4):471–8 (In Russ).

DOI: 10.21320/2500-2139-2017-10-4-471-478

ABSTRACT

Background. Myelofibrosis (primary myelofibrosis, post-essential trombocythemia myelofibrosis, post-polycythemia myelofibrosis) is the most complex and pressing problem among all Ph-negative myeloproliferative diseases. The present article summarizes the author’s experience of using new Janus kinase inhibitors in routine clinical practice, and compares the data with the results of other clinical research.

Aim. To evaluate the use of ruxolitinib in patients with myelofibrosis.

Materials & Methods. Our analysis includes 48 patients (21 men and 27 women) with histologically verified myelofibrosis (primary myelofibrosis in 36 cases, post-essential trombocythemia myelofibrosis in 10 cases, and post-polycythemia myelofibrosis in 2 cases) in a chronic stage. All patients received ruxolitinib. Median age at the start of therapy was 60 years (range from 35 to 79). Massive splenomegaly (≥ 10 cm below the costal margin) was found in 34 (71 %) of 48 patients. The initial dose of ruxolitinib was determined by the platelet level. The efficacy of the therapy was evaluated in accordance with ELN 2013 criteria.

Results. Median duration of treatment was 18 months (range from 1 to 50 months). Symptoms of intoxication were relieved in 33 of 37 patients (89 %). The spleen size decreased in 64 % of patients. In 33 % of cases spleen size did not change, whereas an increase was observed in 3 % of patients. In the majority of patients hemoglobin level remained stable through the course of treatment. Three of 14 transfusion dependent patients did not require blood transfusions after 3 months of therapy. In patients with high thrombocyte levels prior to ruxolitinib therapy the mean level was approaching normal by the end of the 1st month of treatment. The median JAK2V617F mutant allele burden at the beginning treatment was 56.5 % (n = 20; 22.5–126.1 %). After 6 moths of treatment it accounted for 62.3 % (n = 11; 25.4–79.7 %) and in 12 months accounted for 47.4 % (n = 12; 14.2–102.2 %). By the time of the analysis 42 of 48 patients continued the ruxolitinib treatment (88 %). Death occurred in 4 patients. Overall 1-year (92 %) and 2-year (87 %) survival corresponds to the data of COMFORT-I, COMFORT-II and JUMP clinical trials.

Conclusion. Ruxolitinib showed to be an effective treatment for myelofibrosis. The most pronounced and rapid effect ruxolitinib had on the spleen size and the symptoms of intoxication. The tolerability of ruxolitinib was satisfactory in the majority of patients. According to the author’s data, ruxolitinib had a small impact on the JAK2V617F mutant allele burden. The overall survival rate in patients with myelofibrosis, receiving ruxolitinib in the clinical setting was similar to that of in the clinical trials.

Keywords: primary myelofibrosis, post-essential trombocythemia myelofibrosis, post-polycythemia myelofibrosis, JAK2V617F, ruxolitinib, clinical practice, targeted therapy.

Received: February 11, 2017

Accepted: May 22, 2017

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REFERENCES

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  12. Vannucchi AM, Rotunno G, Pascutto C, Pardanani A. Mutation-Enhanced International Prognostic Scoring System (MIPSS) for Primary Myelofibrosis: An AGIMM & IWG-MRT Project. (56th ASH Annual Meeting and Exposition, San-Francisco, December 6–9, 2014) Blood. 2014;2014:P405.
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  14. Harrison CN, Vannucchi AM, Kiladjian JJ, et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016;30(8):1701–7. doi: 10.1038/leu.2016.148.
  15. Verstovsek S, Mesa RA, Gotlib J, et al. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol. 2017;10(1):55. doi: 10.1186/s13045-017-0417-z.
  16. Al-Ali HK, Griesshammer M, le Coutre P, et al. Safety and efficacy of ruxolitinib in an open-label, multicenter, single-arm phase 3b expanded-access study in patients with myelofibrosis: a snapshot of 1144 patients in the JUMP trial. Haematologica. 2016;101(9):1065–73. doi: 10.3324/haematol.2016.143677.

Cardiovascular complications of chronic myeloid leukemia treated with tyrosine kinase inhibitors

COMPLICATIONS OF ANTITUMOR TREATMENT , , ,

G.E. Gendlin, L.M. Makeeva, E.I. Emelina, K.V. Shuikova, G.I. Storozhakov

 FGEI HPE RNRMU named after N.I. Pirogov of Russian MoH, Moscow, Russian Federation

ABSTRACT

The achieved nowadays success in oncohematology patients’ treatment is primarily associated with the development of targeted therapy, including invention of specific tyrosine kinase inhibitors for chronic myeloid leukemia treatment (imatinib, nilotinib and dasatinib,). However, along with the high efficacy, these medicines have certain toxicities. Cardiovascular complications of tyrosine kinase inhibitors therapy of chronic myeloid leukemia are described in this review article. Taking onto consideration the fact that therapy with these medicines can cause rear but serious side effects. It is necessary to consider the probability of cardiotoxicity, arterial occlusion of various diameter and pulmonary hypertension development before prescription. In order to minimize side effects patients examination is recommended before treatment initiation for recognition of initial cardiovascular diseases, as well as thorough control of cardiovascular condition throughout the treatment.

Keywords: chronic myeloid leukemia, tyrosine kinase inhibitors, cardiac toxicity, targeted therapy

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