AUTOIMMUNE THROMBOCYTOPENIA

Clinical Efficacy of Daratumumab in Monotherapy of Relapsed/Refractory Multiple Myeloma

AUTOIMMUNE THROMBOCYTOPENIA , ,

SS Bessmeltsev1, EV Karyagina2, EYu Ilyushkina2, ZhL Stolypina2, RR Miftakhova1, II Kostroma1, TL Shelkovskaya2

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

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

For correspondence: Prof. Stanislav Semenovich Bessmeltsev, MD, PhD, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel.: +7(812)717-67-80, +7(911)228-18-01; e-mail: bsshem@hotmail.com, bessmeltsev@yandex.ru

For citation: Bessmeltsev SS, Karyagina EV, Ilyushkina EYu, et al. Clinical Efficacy of Daratumumab in Monotherapy of Relapsed/Refractory Multiple Myeloma. Clinical oncohematology. 2020;13(1):25–32. (In Russ).

DOI: 10.21320/2500-2139-2020-13-1-25-32

ABSTRACT

Background. Daratumumab is IgG1-κ humanized anti-CD38 monoclonal antibody. It has a direct impact on tumor and immunomodulatory effect.

Aim. To assess the efficacy of daratumumab monotherapy in patients with progressive, and relapsed/refractory multiple myeloma (MM), as well as to find out the degree of toxicity and safety of this drug.

Materials & Methods. The trial included 10 MM patients (3 men and 7 women) aged 51–74 years (median 57 years). Stage 3 (according to Durie-Salmon system) was determined in all patients, in 2 of them stage 3B with creatinine clearance < 30 mL/min was reported. According to ISS (International Staging System) criteria, stage 2 and stage 3 were identified in 6 and 4 patients, respectively. All the patients had been previously treated with bortezomib and lenalidomide with further double refractoriness in 4 out of 10 patients. Bendamustine and carfilzomib were administered to one patient each, both in combined regimens. The number of previous therapy lines was 3–6 (median 5).

Results. Overall response was 50 % including 2 (20 %) patients with very good partial remission. In 1 (10 %) patient complete remission was achieved. During the follow-up of 6–32 months (median 15 months) median overall survival was not achieved. Median progression-free survival was 17.8 months. Daratumumab is characterized by favorable safety profile. In 20 % of patients infusion-induced reactions with severity grades 1–2 were observed. Among other adverse events the following should be pointed out: weakness (30 %), nausea (10 %), headache (10 %), anorexia (10 %), thrombocytopenia (20 %), and neutropenia (30 %). No serious complications were reported.

Conclusion. Daratumumab treatment is a safe and effective method of anticancer drug therapy in relapsed/refractory MM.

Keywords: daratumumab, multiple myeloma, complete remission, overall response, survival, double refractoriness.

Received: August 22, 2019

Accepted: December 10, 2019

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    [Semochkin SV, Salogub GN, Bessmeltsev SS, Kaplanov KD. Practical Aspects of the Use of Carfilzomib in Multiple Myeloma. Clinical oncohematology. 2019;12(1):21–31. doi: 10.21320/2500-2139-2019-12-1-21-31. (In Russ)]

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Primary Bone Lymphomas: 18F-FDG PET and PET-CT as Methods of Diagnosis and Efficacy Estimation of Antitumor Treatment

AUTOIMMUNE THROMBOCYTOPENIA , , ,

AK Smol’yaninova1, ER Moskalets2, GA Yatsyk1, IE Kostina1, AS Bogolyubskaya3, NG Gabeeva1, EG Gemdzhian1, SA Tatarnikova1, DS Badmadzhapova1, EE Zvonkov1

1 National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

2 European Medical Center, 35 Shchepkina str., Moscow, Russian Federation, 129090

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

For correspondence: Anna Konstantinovna Smol’yaninova, MD, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(926)912-31-16; e-mail: annmo8@mail.ru

For citation: Smol’yaninova AK, Moskalets ER, Yatsyk GA, et al. Primary Bone Lymphomas: 18F-FDG PET and PET-CT as Methods of Diagnosis and Efficacy Estimation of Antitumor Treatment. Clinical oncohematology. 2020;13(1):33–49 (In Russ).

DOI: 10.21320/2500-2139-2020-13-1-33-49

ABSTRACT

Background. Primary bone lymphoma (PBL) is a rare malignant tumor. Initial examination aimed at detecting all primary lesions is an indispensable prerequisite for the choice of optimal antitumor treatment. Standard methods of diagnosis (X-ray, CT, and MRI) are not always adequate to measure the real tumor mass. Another well-known characteristic feature of PBL is a challenge in evaluating the effect of its treatment because of residual changes in the bones of most patients. However, the data on using 18F-FDG PET, another method of metabolic imaging, in PBL are rather rare in accessible literature.

Aim. To study the specific use of PET with 18F-FDG at initial examination and efficacy estimation of PBL treatment.

Materials & Methods. The trial included 21 PBL patients who received PET with 18F-FDG at initial examination and a month after the end of treatment. The results of 18F-FDG PET imaging were compared with the data obtained by means of structural diagnostic methods (CT and MRI) and the analysis of biopsy samples with pathologic lesions.

Results. Intensive uptake of 18F-FDG (SUVmax 8.6–40.1, mean SUVmax 23.5), according to PET data, was reported in all patients in those tumor lesions which were identified by the structural diagnostic methods and confirmed by biopsies. Besides, each of 21 cases showed pathologic infiltration of adjacent soft tissues with high metabolic activity. In PET-CT with 18F-FDG 13 further tumor localizations were revealed in 8 (38 %) patients. On completing the therapy, according to CT and MRI data, residual changes were observed in all (n = 21, 100 %) patients. The residual metabolic activity in the involved bones was identified in 13 (62 %) patients (SUVmax 2.91–8.7, mean SUVmax 4.2). In 4 of them the residual lesions were subjected to biopsy. None of 4 cases was reported to show tumors. Only in 1 out of 13 patients with residual metabolic changes a tumor relapse was detected. Overall 10-year survival in the groups of patients with and without FDG+ residual changes was 91 % and 100 %, respectively, with insignificant differences (p = 0.39).

Conclusion. PET-CT with 18F-FDG is a highly sensitive technique for evaluating the primary lesion volumes in PBL patients. In 100 % of bone and soft tissue lesions an intensive uptake of 18F-FDG was observed. At the same time our study showed persistent metabolic activity on completing antitumor treatment in more than a half of patients, and in most of them it was not caused by tumor. Therefore, in our view, ongoing residual metabolic activity in PBL cannot always be regarded as an indication for continued treatment or consolidation radiotherapy.

Keywords: primary bone lymphoma, survival, positron emission tomography, diagnosis, efficacy estimation of antitumor treatment.

Received: August 2, 2019

Accepted: December 5, 2019

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Characteristics of Hematopoiesis in Follicular Lymphoma Patients

AUTOIMMUNE THROMBOCYTOPENIA

MA Frenkel, AV Mozhenkova, NA Kupryshina, NA Falaleeva, NN Tupitsyn

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

For correspondence: Prof. Marina Abramovna Frenkel, MD, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-45-60; e-mail: marinafren@yandex.ru

For citation: Frenkel MA, Mozhenkova AV, Kupryshina NA, et al. Characteristics of Hematopoiesis in Follicular Lymphoma Patients. Clinical oncohematology. 2020;13(1):50–57 (In Russ).

DOI: 10.21320/2500-2139-2020-13-1-50-57

ABSTRACT

Aim. To assess hematopoiesis in follicular lymphoma (FL) patients at different disease stages with different morphologic structures of tumor and bone marrow microenvironment.

Materials & Methods. The trial included 152 FL patients treated from 2006 to 2016. In all of them the diagnosis was based on immunohistochemical analysis of extramedullar tumor as well as the analysis of bone marrow aspirates and core biopsy samples. In cases of bone marrow lesions (n = 33) a detailed morpho-immunophenotypic evaluation of tumor cells was carried out by means of flow cytometry, and lymphocyte subset panel evaluation was performed.

Results. Anemia, thrombocytopenia, and monocytosis in blood of FL patients are not associated with bone marrow lesions. In the absence of signs of these lesions anemia was detected in 23 (19 %) patients, thrombocytopenia was identified in 8 (7 %) patients, and 11 (9.1 %) patients showed monocytosis. Among patients with bone marrow lesions 9 (27.2 %) anemia, 11 (33.8 %) thrombocytopenia, and 7 (21 %) monocytosis cases were reported. Depth of cytopenia was determined by the degree of bone marrow tumor infiltration. Based on lymphocyte subset panel evaluation the following types of tumor cells in bone marrow aspirates were characterized: elements with blastic structure of nuclear chromatin, atypical lymphoid cells, and those similar to normal lymphocytes. Immunophenotypic heterogeneity of tumor cells in bone marrow was demonstrated. The trial showed that hemoglobin level, the count of blood thrombocytes and monocytes as well as the count of bone marrow T-cells are not associated with types of tumor cells.

Conclusion. Arrest of hematopoiesis and increasing number of monocytes in blood correlate with the degree of bone marrow tumor infiltration and are not affected by morphoimmunological characteristics of FL tumor cells.

Keywords: follicular lymphoma, centrocyte, centroblast, aspirate, core biopsy sample, immunophenotype.

Received: February 8, 2019

Accepted: December 2, 2019

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REFERENCES

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  3. Тумян Г.С., Леонтьева А.А., Фалалеева Н.А. и др. Фолликулярная лимфома: 10 лет терапии. Клиническая онкогематология. 2012;5(3):204–13.

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    [Frenkel MA, Chigrinova EV, Kupryshina NA, Pavlovskaya AI. Diagnostic value of the analysis of bone marrow core biopsy imprints in peripheral non-Hodgkin’s lymphomas. Klinicheskaya laboratornaya diagnostika. 2007;1:44–7. (In Russ)]

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Overt and Masked Polycythemia Vera Within the Scope of Ph-Negative Myeloproliferative Diseases

AUTOIMMUNE THROMBOCYTOPENIA

ZhV Tratsevskaya, AM Kovrigina, DI Chebotarev, AL Melikyan, AO Abdullaev, AB Sudarikov

National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Prof. Alla Mikhailovna Kovrigina, PhD in Biology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-61-12; e-mail: kovrigina.alla@gmail.com

For citation: Tratsevskaya ZhV, Kovrigina AM, Chebotarev DI, et al. Overt and Masked Polycythemia Vera Within the Scope of Ph-negative Myeloproliferative Diseases. Clinical oncohematology. 2020;13(1):58–66 (In Russ).

DOI: 10.21320/2500-2139-2020-13-1-58-66

ABSTRACT

Aim. To study the structure of Ph-negative myeloproliferative diseases (Ph– MPD) and to identify morphological markers for diagnosing masked polycythemia vera (PV).

Materials & Methods. Bone marrow core biopsy samples from the database of pathology department of National Research Center for Hematology within the period from January 2014 to June 2017 provided the basis for analyzing the diagnosed Ph– MPD cases. The trial included the bone marrow core biopsy samples of the patients treated and followed-up not only at the National Research Center for Hematology but also at other medical centers in the Russian Federation in the context of clinical, laboratory and molecular data.

Results. In 1611 Ph– MPD patients PV prevailed corresponding to 40.6 % of all cases. In the PV group the masked form was diagnosed in 29 % of patients. Primary myelofibrosis (PMF) was diagnosed in 26.6 % of all patients including 10 % of cases with pre-fibrosis/early stage. The 3d most frequent disorder was essential thrombocythemia (ET) which corresponded to 16 %. JAK2 driver mutation was identified in all 654 PV patients. In 4 cases out of them exon 12 mutation was detected. A similar mutation was found out in PMF (53 %) and ET (60 %). In 36 % of PMF patients and 27 % of ET patients CALR mutation was detected. MPL mutation was identified in 4 % of PMF cases and was not discovered in ET. Triple negative patients were identified in 7 % of PMF and 13 % of ET cases. The designation of “myeloproliferative disease unclassifiable” can be applied to 16.8 % of cases. The trial deals with morphological criteria for diagnosing masked PV during examination of bone marrow core biopsy samples. In 30 % of patients with masked PV (according to the 2017 WHO classification) and splenomegaly (> 14 cm) portal vein thrombosis was identified.

Conclusion. In the Ph– MPD group PV diagnosis prevailed (40.6 %). The histological analysis of bone marrow core biopsy samples of the patients with the masked PV accounting for 29 % of all PV cases, revealed morphological features typical of overt PV. Histological analysis of bone marrow is a reliable method for diagnosing overt and masked PV. Among morphological characteristics of the bone marrow of patients with masked PV and portal vein thrombosis special attention should be paid to the MF-1 grade of reticulin fibrosis (29 % of cases) and loose clusters of megakaryocytes (71.4 %).

Keywords: Ph-negative myeloproliferative disease/neoplasms, masked polycythemia vera, pathomorphology, bone marrow core biopsy.

Received: September 14, 2019

Accepted: December 12, 2019

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REFERENCES

  1. Swerdlow SH, Campo E, Harris NL, et al. (eds). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (Revised 4th edition). Lyon: IARC Press; 2017. 585 p.

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  3. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379–90. doi: 10.1056/NEJMoa1311347.

  4. Pietra D, Rumi E, Ferretti VV, et al. Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms. Leukemia. 2016;30(2):431–8. doi: 10.1038/leu.2015.277.

  5. Tefferi A, Lasho TL, Finke CM, et al. CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia. 2014;28(7):1472–7. doi: 10.1038/leu.2014.3.

  6. Zamora L, Xicoy B, Cabezon M, et al. Co-existence of JAK2 V617F and CALR mutations in primary myelofibrosis. Leuk Lymphoma. 2015;56(10):2973–4. doi: 10.3109/10428194.2015.1015124.

  7. Lin Y, Liu E, Sun Q, et al. The prevalence of JAK2, MPL, and CALR mutations in Chinese patients with BCR-ABL1-negative myeloproliferative neoplasms. Am J Clin Path. 2015;144(1):165–71. doi: 10.1309/AJCPALP51XDIXDDV.

  8. Ahmed RZ, Rashid M, Ahmed N, et al. Coexisting JAK2V617F and CALR Exon 9 Mutations in Myeloproliferative Neoplasms – Do They Designate a New Subtype? Asian Pacif J Cancer Prevent. 2016;17(3):923–6. doi: 10.7314/apjcp.2016.17.3.923.

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  12. Gianelli U, Iurlo A, Vener C, et al. The Significance of Bone Marrow Biopsy and JAK2V617F Mutation in the Differential Diagnosis Between the “Early” Prepolycythemic Phase of Polycythemia Vera and Essential Thrombocythemia. Am J Clin Pathol. 2008;130(3):336–42. doi: 10.1309/6BQ5K8LHVYAKUAF4.

  13. Thiele J, Kvasnicka HM, Zankovich R, Diehl V. The value of bone marrow histology in differentiating between early stage polycythemia vera and secondary (reactive) polycythemias. Haematologica. 2001;86(4):368–74.

  14. Barbui T, Thiele J, Vannucchi AM, et al. Rethinking the diagnostic criteria of polycythemia vera. Leukemia. 2013;28(6):1191–5. doi: 10.1038/leu.2013.380.

  15. Thiele J, Kvasnicka HM, Diehl V. Initial (latent) polycythemia vera with thrombocytosis mimicking essential thrombocythemia. Acta Haematol. 2005;113(4):213–9. doi: 10.1159/000084673.

  16. Barbui T, Thiele J, Carobbio A, et al. Masked polycythemia vera diagnosed according to WHO and BCSH classification. Am J Hematol. 2014;89(2):199–202. doi: 10.1002/ajh.23617.

  17. Kvasnicka HM, Orazi A, Thiele J, et al. European LeukemiaNet study on the reproducibility of bone marrow features in masked polycythemia vera and differentiation from essential thrombocythemia. Am J Hematol. 2017;92(10):1062–7. doi 10.1002/ajh.24837.

  18. Ковригина А.М., Байков В.В. Истинная полицитемия: новая концепция диагностики и клинические формы. Клиническая онкогематология. 2016;9(2):115–22. doi: 10.21320/2500-2139-2016-9-2-115-122.

    [Kovrigina AM, Baikov VV. Polycythemia Vera: New Diagnostic Concept and Its Types. Clinical oncohematology. 2016;9(2):115–22. doi: 10.21320/2500-2139-2016-9-2-115-122. (In Russ)]

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  22. Murphy S. Diagnostic criteria and prognosis in polycythemia vera and essential thrombocythemia. Semin Hematol. 1999;36(1 Suppl 2):9–13.

  23. Lussana F, Carobbio A, Randi ML, et al. A lower intensity of treatment may underlie the increased risk of thrombosis in young patients with masked polycythaemia Vera. Br J Haematol. 2014;167(4):541–6. doi: 10.1111/bjh.13080.

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    [Melikyan AL, Turkina AG, Kovrigina AM, et al. Clinical recommendations for diagnosis and therapy of Ph-negative myeloproliferative neoplasms (polycythemia vera, essential thrombocythemia, primary myelofibrosis) (edition 2016). Gematologiya i transfuziologiya. 2017;62(1 Suppl 1):25–60. doi: 10.18821/0234-5730-2017-62-1-S1-1-60. (In Russ)]

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    [Subortseva IN, Kolosheinova TI, Pustovaya EI, et al. Polycythemia Vera: Literature Review and Own Data. Clinical oncohematology. 2015;8(4):397–412. doi: 10.21320/2500-2139-2015-8-4-397-412. (In Russ)]

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Gemtuzumab Ozogamicin in the Treatment of Critical Patients with Refractory Acute Myeloid Leukemia (3 Case Reports)

AUTOIMMUNE THROMBOCYTOPENIA

DV Zaitsev, LL Girshova, VV Ivanov, IG Budaeva, DV Motorin, RSh Badaev, KV Bogdanov, YuV Mirolyubova, TS Nikulina, KA Zagorodnikova, NA Zhukova, SV Efremova, TV Chitanava, YuA Alekseeva, AY Zaritskey

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

For correspondence: Daniil Vladislavovich Zaitsev, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; Tel.: +7(981)727-16-74; e-mail: zaicev_daniil@mail.ru

For citation: Zaitsev DV, Girshova LL, Ivanov VV, et al. Gemtuzumab Ozogamicin in the Treatment of Critical Patients with Refractory Acute Myeloid Leukemia (3 Case Reports). Clinical oncohematology. 2020;13(1):67–74 (In Russ).

DOI: 10.21320/2500-2139-2020-13-1-67-74

ABSTRACT

The treatment of refractory acute myeloid leukemia (AML) patients presents considerable challenges. They are often critically ill. The critical conditions of these patients are mainly associated with severe infectious complications resulting in sepsis as well as with the extramedullary lesions with organ dysfunctions. So far, the obtained data demonstrated the successful use of gemtuzumab ozogamicin, the mechanism of which is likely to be based not only on depletion of CD33-positive tumor cells but also on its immunomodulatory effect. The present article focuses on the fast-effect mechanisms of gemtuzumab ozogamicin and deals with clinical experience of successful use of this drug combined with hypomethylating agents in patients with refractory AML whose condition is critical by the time therapy begins. The use of this drug combination results in fast stabilization of health status, recovery of internal organs, and apyrexia with the decreasing systemic inflammatory response within the first days of therapy. All this together with significantly lower blast count in blood and in bone marrow can bring critically ill patients to recovery.

Keywords: acute myeloid leukemia, critically ill patients, gemtuzumab ozogamicin, refractory course.

Received: August 15, 2019

Accepted: December 16, 2019

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Crucial Role of BAALC-Expressing Progenitor Cells in Emergence and Development of Post-Transplantation Relapses in Patients with Acute Myeloid Leukemia

AUTOIMMUNE THROMBOCYTOPENIA

NN Mamaev, AI Shakirova, IM Barkhatov, YaV Gudozhnikova, TL Gindina, OV Paina, LS Zubarovskaya, BV Afanas’ev

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

For correspondence: Prof. Nikolai Nikolaevich Mamaev, MD, PhD, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; e-mail: nikmamaev524@gmail.com

For citation: Mamaev NN, Shakirova AI, Barkhatov IM, et al. Crucial Role of BAALC–Expressing Progenitor Cells in Emergence and Development of Post-Transplantation Relapses in Patients with Acute Myeloid Leukemia. Clinical oncohematology. 2020;13(1):75–88 (In Russ).

DOI: 10.21320/2500-2139-2020-13-1-75-88

ABSTRACT

This article presents data demonstrating frequent BAALC hyperexpression, also in combination with WT1 hyperexpression, in children and adults with acute myeloid leukemia (AML). Treatment included allogeneic hematopoietic stem cell transplantation. The analysis of serial measurements of BAALC and WT1 expression level in 50 AML patients (37 adults and 13 children) showed that the increased BAALC expression is more common in patients with M1, M2, M4, and M5 FAB variants of AML with equal frequency in adults and children. Furthermore, the increased BAALC expression was rather common in combination with the increased WT1 expression, which predicted poorer prognosis. Since BAALC expression level in AML patients is closely related to AML-producing progenitor cells of leukemia hematopoiesis, a serial study of this phenomenon offers insights into the role of these cells in emergence and development of post-transplantation relapses, which is of both theoretical and practical importance.

Keywords: acute myeloid leukemia, BAALC and WT1 genes, synchronous hyperexpression, post-transplantation relapses, BAALC–producing progenitor cells, prognosis.

Received: June 30, 2019

Accepted: December 1, 2019

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Risk Factors for Rehospitalizations after Allogeneic Hematopoietic Stem Cell Transplantation

AUTOIMMUNE THROMBOCYTOPENIA

MYu Drokov, AA Dmitrova, LA Kuzmina, VA Vasil’eva, ED Mikhaltsova, OM Koroleva, EV Usikova, EN Parovichnikova, VG Savchenko

National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Mikhail Yur’evich Drokov, MD, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)614-90-42; e-mail: mdrokov@gmail.com

For citation: Drokov MYu, Dmitrova AA, Kuzmina LA, et al. Risk Factors for Rehospitalization after Allogeneic Hematopoietic Stem Cell Transplantation. Clinical oncohematology. 2020;13(1):89–94 (In Russ).

DOI: 10.21320/2500-2139-2020-13-1-89-94

ABSTRACT

Aim. To assess the rehospitalization data of patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT), to determine possible risk factors for rehospitalization, and to work out a strategy of post-transplantation follow-up for this category of patients.

Materials & Methods. From 2009 to 2019 at the National Research Center for Hematology 418 patients received allo-HSCT. The final analysis included 374 patients who were discharged from hospital after allo-HSCT. The reasons for rehospitalizations of patients with allo-HSCT within 30 days after their hospital discharge were subjected to analysis. Independent risk factors for rehospitalizations were identified by the Cox model. Risk density was visually estimated within 365 days after hospital discharge with the purpose of working out the optimal strategy of post-transplantation follow-up for this category of patients.

Results. The probability of rehospitalization within 30 days after hospital discharge was 30.7 % for all patients with allo-HSCT. The data assessment showed that the majority of rehospitalizations (55.7 %) were associated with infectious complications. Acute graft-versus-host disease (GVHD) during the first hospitalization, i.e. immediately after allo-HSCT during the hospital stay, proved to enhance the probability of rehospitalizations within 30 days after hospital discharge by 1.7 times compared with the patients without acute GVHD.

Conclusion. The leading cause of rehospitalizations of patients with allo-HSCT within 30 days after hospital discharge was acute GVHD which occurred before, i.e. during the first hospital stay. The data obtained demonstrate the necessity of close monitoring of a patient’s status within the first 120 days after discharge from the hospital where allo-HSCT was performed.

Keywords: allogeneic hematopoietic stem cell transplantation, rehospitalizations, graft-versus-host disease.

Received: July 16, 2019

Accepted: December 17, 2019

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Primary Gastric Lymphomas

AUTOIMMUNE THROMBOCYTOPENIA

AA Danilenko, SV Shakhtarina, NA Falaleeva

AF Tsyb Medical Research Center for Radiology, Division of National Medical Radiology Research Center, 4 Koroleva str., Kaluga Region, Obninsk, Russian Federation, 249036

For correspondence: Anatolii Aleksandrovich Danilenko, MD, PhD, 4 Koroleva str., Kaluga Region, Obninsk, Russian Federation, 249036; Tel.: +7(909)250-18-10; e-mail: danilenkoanatol@mail.ru

For citation: Danilenko AA, Shakhtarina SV, Falaleeva NA. Primary Gastric Lymphomas. Clinical oncohematology. 2020;13(1):95–103 (In Russ).

DOI: 10.21320/2500-2139-2020-13-1-95-103

ABSTRACT

Primary gastric lymphomas (PGL) are more common than lymphomas with involvement of other organs and cover a wide spectrum of immunomorphological variants: from indolent marginal zone lymphoma to aggressive diffuse large B-cell lymphoma. PGLs are not characterized with any specific clinical manifestations, which sometimes leads to misdiagnosis. Due to the rareness of the disease many PLG-related issues remain unresolved, this provided the background for the present review.

Keywords: primary gastric lymphomas, diffuse large B-cell lymphoma, MALT lymphoma, Helicobacter pylori.

Received: July 29, 2019

Accepted: December 5, 2019

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Comparative Analysis of Cardiovascular Disorders in Patients with Chronic Myeloid Leukemia on Tyrosine Kinase Inhibitor Therapy

AUTOIMMUNE THROMBOCYTOPENIA ,

LM Makeeva1, EI Emelina1, AV Bykova2, GE Gendlin1, GA Gusarova2, IG Nikitin1, EYu Chelysheva2, OYu Vinogradova1,3,4, IE Lazarev3, EG Arshanskaya3, AG Turkina2

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

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

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

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

For correspondence: Prof. Gennadii Efimovich Gendlin, MD, PhD, 1 Ostrovityanova str., Moscow, Russian Federation, 117997; e-mail: rgmugt2@mail.ru

For citation: Makeeva LM, Emelina EI, Bykova AV, et al. Comparative Analysis of Cardiovascular Disorders in Patients with Chronic Myeloid Leukemia on Tyrosine Kinase Inhibitor Therapy. Clinical oncohematology. 2020;13(1):104–111 (In Russ).

DOI: 10.21320/2500-2139-2020-13-1-104-111

ABSTRACT

Aim. To analyze adverse cardiovascular events in chronic myeloid leukemia (CML) patients who received various tyrosine kinase inhibitors (TKI).

Materials & Methods. The trial included 97 CML patients with nilotinib, dasatinib or imatinib indications. By the time of examination the patients had undergone TKI therapy for 1–138 months. The three of them were sequentially treated with 2 drugs over the monitoring period. All CML patients were aged 22–79 years (median 53.5 years): 55 women were aged 22–71 years (median 53.5 years) and 42 men were aged 24–79 years (median 53 years).

Results. The comparative analysis demonstrated significantly higher impact of nilotinib on QTc duration compared with other TKIs. The patients who received nilotinib (n = 15) throughout 38 months had QTc of 0.47 s (interquartile range [IQR] 0.46–0.47 s), in imatinib group (n = 17) QTc was 0.43 s (IQR 0.43–0.44 s), and in dasatinib group (n = 4) QTc was 0.43 s (IQR 0.42–0.44 s) (p = 0.0008). Among all patients treated with nilotinib there were 62 % (31/50) with QTc > 0.46 s, in imatinib (6/41) and dasatinib (2/18) groups it was detected in 14.6 % and 11.1 % of patients, respectively (p = 0.0008). Five patients had QTc > 0.48 s, which is the criterion for discontinuation of treatment or dose reduction. In two patients the identified changes of QTc duration required TKI temporary suspension. After nilotinib dose reduction or discontinuation QTc duration normalized in all cases within 2 weeks. Decreased ankle-brachial index (ABI) < 0.9 without pronounced clinical symptoms was identified in two patients who received nilotinib. Afterwards they showed peripheral occlusive disease of lower extremities, and nilotinib treatment was discontinued. In patients treated with other TKIs no occlusive vascular lesions were observed. A case of chronic heart failure with reduced left ventricular ejection fraction developing on nilotinib therapy was revealed and described.

Conclusion. Despite high specificity for BCR-ABL tyrosine kinase, new TKIs can, although rarely, induce cardiovascular adverse events. Prior to TKI treatment assignment CML patients should be examined with ECG and EchoCG with systolic function evaluation, and the measurement of pulmonary artery pressure as well as ABI. The examination should be repeated in the end of the 1st year TKI treatment if there is no reason for extra examinations. It is recommended to hold 24-hour ECG monitoring with QTc max measurement prior to nilotinib assignment, then once a year within 2 years of nilotinib treatment, and once in 6 months after 3 years of therapy.

Keywords: imatinib, dasatinib, nilotinib, chronic myeloid leukemia, QTc prolongation, sudden cardiac death, peripheral occlusive disease of lower extremities, chronic heart failure, cardiomyopathy, pulmonary arterial hypertension.

Received: September 8, 2019

Accepted: December 21, 2019

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Challenges in the Treatment of Primary Refractory and Relapsed Diffuse Large B-cell Lymphoma in the Russian Federation. What will the future hold?

AUTOIMMUNE THROMBOCYTOPENIA

УЧАСТНИКИ КОНСУЛЬТАЦИОННОГО СОВЕТА:

  1. Ирина Владимировна Поддубная — д-р мед. наук, профессор, академик РАН, заведующая кафедрой онкологии и паллиативной медицины, проректор по международному сотрудничеству ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» МЗ РФ (РМАНПО МЗ РФ), председатель Российского общества онкогематологов.
  2. Вадим Вадимович Птушкин — д-р мед. наук, профессор кафедры онкологии, гематологии и лучевой терапии РНИМУ им. Н.И. Пирогова, заместитель главного врача по гематологии ГБУЗ «Городская клиническая больница им. С.П. Боткина», главный внештатный гематолог г. Москвы, заведующий отделом инновационных методов лечения подростков и взрослых ГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева», член правления Российского общества онкогематологов.
  3. Гаяне Сергеевна Тумян — д-р мед. наук, ведущий научный сотрудник отделения химиотерапии гемобластозов ФГБУ «НМИЦ онкологии им. Н.Н. Блохина», профессор кафедры онкологии и паллиативной медицины ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» МЗ РФ, член правления Российского общества онкогематологов.
  4. Евгений Александрович Османов — д-р мед. наук, профессор кафедры онкологии 1-го Московского государственного медицинского университета им. И.М. Сеченова, заведующий отделом гематологии и трансплантации костного мозга ФГБУ «НМИЦ онкологии им. Н.Н. Блохина» МЗ РФ, главный консультант экспертного совета «Лаборатории Гемотест», главный редактор журнала «Клиническая онкогематология. Фундаментальные исследования и клиническая практика».
  5. Лали Галимовна Бабичева — канд. мед. наук, доцент кафедры онкологии и паллиативной медицины ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» МЗ РФ, доцент кафедры общей терапии ФДПО РНИМУ им. Н.И. Пирогова.
  6. Елена Александровна Барях — канд. мед. наук, доцент кафедры общей терапии ФДПО РНИМУ им Н.И. Пирогова, заведующая отделением гематологии и химиотерапии ГБУЗ «Городская клиническая больница № 52» ДЗМ.
  7. Камиль Даниялович Капланов — канд. мед. наук, заведующий отделением гематологии ГБУЗ «Волгоградский областной клинический онкологический диспансер», главный специалист-гематолог комитета по здравоохранению Администрации Волгоградской области, ассистент кафедры онкологии с курсом онкологии и гематологии ФУВ Волгоградского государственного медицинского университета.
  8. Сергей Владимирович Волошин — канд. мед. наук, доцент, руководитель клинического отделения химиотерапии гемобластозов, депрессий кроветворения и трансплантации костного мозга ФГБУ РосНИИГТ ФМБА России.
  9. Ольга Сергеевна Самойлова — канд. мед. наук, заведующая отделением гематологии НОКБ им. Н.А. Семашко, главный внештатный специалист гематолог-трансфузиолог Приволжского федерального округа.
  10. Татьяна Ивановна Поспелова — д-р мед. наук, профессор, проректор по научной работе, заведующая кафедрой терапии, гематологии и трансфузиологии Новосибирского государственного медицинского университета, руководитель Городского гематологического центра, главный гематолог и трансфузиолог МЗ РФ по Сибирскому федеральному округу, главный гематолог МЗ НСО.
  11. Сергей Кириллович Кравченко — канд. мед. наук, доцент, заведующий отделением интенсивной высокодозной химиотерапии гемобластозов с круглосуточным и дневным стационарами ФГБУ «НМИЦ гематологии» МЗ РФ.
  12. Алексей Юрьевич Кувшинов — канд. мед. наук, врач-гематолог отделения химиотерапии гемобластозов, депрессий кроветворения и трансплантации костного мозга ФГБУ РосНИИГТ ФМБА России.
  13. Hervé Tilly — д-р мед. наук, профессор, Le Centre Henri-Becquerel de Lutte Contre le Cancer (CLCC), г. Руан, Франция.
  14. Владимир Иванович Воробьев — канд. мед. наук, врач-гематолог гематологического отделения ГБУЗ «Городская клиническая больница им. С.П. Боткина» ДЗМ.

РЕЗОЛЮЦИЯ

Диффузная В-крупноклеточная лимфома (ДВКЛ) является наиболее распространенным вариантом агрессивных лимфопролиферативных заболеваний взрослых. В 2016 г. в США зарегистрировано 27 650 новых случаев ДВКЛ, в Европе ежегодно выявляется 3–4 случая на 100 000 населения [1, 2]. В Российской Федерации на долю ДВКЛ приходится примерно 30–40 % (56 % по данным регистра Российского общества онкогематологов) всех неходжкинских лимфом [3]. Заболеваемость составляет в среднем 4–5 случаев на 100 000 населения [4], в 2017 г. в России было зарегистрировано примерно 3000 новых случаев ДВКЛ [5]. В возрасте до 18 лет частота этого варианта В-клеточной опухоли не превышает 10 %, при этом число больных значительно увеличивается в возрасте после 50 лет.

ДВКЛ объединяет целый спектр опухолей, различающихся по своим клиническим, морфологическим, иммунологическим и молекулярно-биологическим характеристикам. Заболевание отличается чрезвычайным клиническим разнообразием: первичный очаг опухолевого роста может локализоваться как в лимфатических узлах, так и экстранодально (40 %) [4].

Гетерогенность опухоли объясняется разным профилем экспрессии генов (gene expression profiling, GEP), что, несомненно, имеет клиническое значение и связано с прогнозом заболевания. На основании данных исследования были идентифицированы основные молекулярные подгруппы ДВКЛ: лимфома из В-клеток герминативного центра (germinal center В-cell like type, GCB) и лимфома из активированных В-клеток (activated В-cell like type, ABC, non-GCB) [6].

Основой лечения ДВКЛ независимо от морфологического варианта, иммуногистохимического профиля и клинического подтипа опухоли остаются схема CHOP и различные ее модификации. Главным достижением последних десятилетий, существенно улучшившим непосредственные и отдаленные результаты лечения пациентов, стало добавление к схеме CHOP моноклональных (анти-СD20) антител — ритуксимаба [6].

В то же время в зависимости от числа неблагоприятных прогностических факторов согласно международному прогностическому индексу (IPI) у 20–50 % больных ДВКЛ развиваются рефрактерность к режиму R-CHOP или рецидивы после достижения полного ответа на терапию [7]. Таким образом, возможности иммунохимиотерапии R-CHOP признаются неудовлетворительными, а использование опций, предполагающих увеличение дозоинтенсивности лечения или включение трансплантации аутологичных гемопоэтических стволовых клеток (аутоТГСК) в первую линию, не подкреплено результатами контролируемых исследований [8]. Попытки улучшить режим R-CHOP в широкой популяции ДВКЛ до настоящего времени не увенчались успехом [9–11].

После первого рецидива ДВКЛ лечение пациентов строится в зависимости от того, можно ли пациенту провести аутоТГСК или нет. В реальной клинической практике нашей страны высокодозная химиотерапия (ВДХТ) с аутоТГСК на этапе консолидации выполняется лишь у небольшого числа пациентов в возрастной группе до 60 лет. Принятие решения о выборе терапии второй линии у пожилых больных осложняется большим числом сопутствующих заболеваний, которые ограничивают применение программ, имеющих значимую миело- и экстрамедуллярную токсичность [8]. В целом рецидивирующие/рефрактерные варианты ДВКЛ имеют ограниченные опции лечения и плохой прогноз с медианой общей выживаемости около 6 мес. [7].

Согласно результатам зарубежных наблюдений, только 30–40 % пациентов отвечают на терапию «спасения» (salvage) с последующим использованием ВДХТ и аутоТГСК [12]. Даже среди пациентов, которые ответили на терапию «спасения» с дальнейшей аутоТГСК, примерно у 50 % в конечном итоге будет диагностирован рецидив заболевания. В итоге большинство пациентов с рефрактерной ДВКЛ не имеют эффективных вариантов лечения [13].

Таким образом, в настоящее время остаются серьезные нерешенные проблемы в терапии ДВКЛ: недостаточная эффективность первой линии лечения у 30–50 % пациентов, в т. ч. первичная резистентность опухоли у 10–15 % и ранние рецидивы у 20–25 %. Инновационные предложения эффективных лечебных воздействий, способных кардинально изменить течение болезни как в первой линии, так и при рецидиве, отсутствуют.

Особое место среди препаратов, исследуемых в терапии рецидивирующей/рефрактерной ДВКЛ, занимает первый в своем классе конъюгат моноклонального антитела к CD79b и химиотерапевтического агента — полатузумаб ведотин. В исследовании II фазы GO29365 сравнивалась терапия полатузумабом ведотином в комбинации с бендамустином и ритуксимабом (BR) с режимом BR у 80 пациентов с рецидивирующей/рефрактерной ДВКЛ. По результатам исследования терапия с полатузумабом ведотином более чем в 2 раза улучшила показатели ответа, выживаемости без прогрессирования (ВБП) и общей выживаемости (ОВ), при этом преимущество терапии полатузумабом наблюдалось во всех подгруппах вне зависимости от количества предыдущих линий лечения, рефрактерности и молекулярных подгрупп (ABC, GCB). Показатель полного ответа у пациентов с рецидивирующей/рефрактерной ДВКЛ в группе полатузумаба ведотина составил 40 % (18 % в группе сравнения), медиана ОВ — 12,4 мес. (4,7 мес. в группе сравнения) [13], медиана длительности ответа — 10,3 мес. (4,1 мес. в группе сравнения). Показатель 2-летней ВБП у 31,4 % пациентов говорит о долгосрочном контроле над заболеванием в группе полатузумаба ведотина. На период наблюдения 45,9 мес. в полной ремиссии остается 22 % пациентов, получавших терапию с полатузумабом [14]. Преимущество в эффективности сочеталось с прогнозируемым и легко управляемым профилем безопасности терапии полатузумабом ведотином.

Полатузумаб ведотин получил статус «прорыв в терапии» (breakthrough therapy designation, BTD) в Управлении по контролю за качеством пищевых продуктов и лекарственных средств США (FDA) и статус «приоритетные лекарственные средства» (priority medicines, PRIME) в Европейском агентстве по лекарственным средствам (EMA) при лечении пациентов с рецидивирующей/рефрактерной ДВКЛ [15]. Первая в мире регистрация полатузумаба ведотина для терапии рецидивирующей/рефрактерной ДВКЛ произошла в июне 2019 г. в США [15].

Учитывая высокую потребность в новых эффективных опциях терапии ДВКЛ и результаты исследования GO29365, своевременное включение полатузумаба ведотина в Российские клинические рекомендации и дальнейшее внедрение препарата в стандартную терапию у пациентов с рецидивирующей/рефрактерной ДВКЛ позволят улучшить результаты лечения и прогноз у этой категории пациентов.

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