chronic lymphocytic leukemia

ROR-1 Expression in the Diagnosis and Monitoring of Minimal Residual Disease in Chronic Lymphocytic Leukemia

AUTOIMMUNE THROMBOCYTOPENIA

EV Pochtar1, SA Lugovskaya1, EV Naumova1, EA Dmitrieva2, VV Dolgov1

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

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

For correspondence: Evgenii Vladimirovich Pochtar, 12 apt. 53 Verkhnyaya Maslovka, Moscow, Russian Federation, 127083; Tel.: +7(917)550-06-38; e-mail: pochtar_ev@mail.ru

For citation: Pochtar EV, Lugovskaya SA, Naumova EV, et al. ROR-1 Expression in the Diagnosis and Monitoring of Minimal Residual Disease in Chronic Lymphocytic Leukemia. Clinical oncohematology. 2022;15(2):148–55. (In Russ).

DOI: 10.21320/2500-2139-2022-15-2-148-155

ABSTRACT

Background. In view of similar morphological and phenotypic characteristics of some B-cell lymphoproliferative diseases and despite the known phenotype of tumor cells, a search is currently underway for new diagnostic markers, the expression of which remains stable during chronic lymphocytic leukemia (CLL) treatment and can be used for both diagnosis and assessment of residual tumor population. One of such markers is ROR-1.

Aim. To assess the expression and feasibility of the ROR-1 marker using В-lymphocytes in minimal residual disease (MRD) dynamics and monitoring in CLL.

Materials & Methods. Hematological and immunophenotypic analyses were performed in 110 CLL patients (50 of them with newly diagnosed disease and 60 on therapy). In addition to that, 20 patients with reactive lymphocytosis and 32 donors were examined. The ROR-1 expression in В-lymphocytes were measured with FACS Canto II flow cytometer using the following monoclonal antibody panel: CD45, CD19, CD20, and ROR-1.

Results. The analysis showed that ROR-1 is essentially not expressed in normal and reactive В-lymphocytes and is detected in 100 % of CLL tumor cells both at disease onset and on therapy. The ROR-1 expression does not change during CLL treatment and can be used not only for CLL diagnosis but also for detection of MRD. Bone marrow aspirates (n = 64) and peripheral blood samples (n = 6) were analysed for MRD assessment by two methods: according to the standardized protocol, recommended by ERIC (European Research Initiative on CLL) in 2007, with FACS Canto II flow cytometer (BD Biosciences) and using DuraClone RE CLB Tube (Beckman Coulter) with Navious flow cytometer (Beckman Coulter).

Conclusion. The comparison of the two methods for MRD assessment, i.e., the standardized (ERIC) one and DuraClone RE CLB (Beckman Coulter) including ROR-1, yielded a high correlation between them (r = 0.9936.)

Keywords: ROR-1, chronic lymphocytic leukemia, minimal residual disease.

Received: December 27, 2021

Accepted: March 18, 2022

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Ibrutinib as First-Line Therapy in High-Risk Chronic Lymphocytic Leukemia: Case Reports

AUTOIMMUNE THROMBOCYTOPENIA , ,

NV Kurkina, EA Repina

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

For correspondence: Nadezhda Viktorovna Kurkina, MD, PhD, 26А Ul’yanova str., Saransk, Russian Federation, 430032; Tel.: +7(927)172-48-63; e-mail: nadya.kurckina@yandex.ru

For citation: Kurkina NV, Repina EA. Ibrutinib as First-Line Therapy in High-Risk Chronic Lymphocytic Leukemia: Case Reports. Clinical oncohematology. 2021;14(4):488–95. (In Russ).

DOI: 10.21320/2500-2139-2021-14-4-488-495

ABSTRACT

In the selection of the optimal specific therapy in chronic lymphocytic leukemia (CLL), a crucial role is played by the determination of risk groups. The CLL International Prognostic Index takes account of unfavorable del(17p), del(11q) cytogenetic abnormalities, and/or TP53 gene mutations as well as the mutation status of immunoglobulin heavy chain variable region genes (IGHV). The absence of IGHV gene mutations is often associated with such prognostically unfavorable genetic markers as del(17p), del(11q), trisomy 12, and TP53 mutation. The combinations of this kind affect the prognosis and overall survival rate. Besides, in high-risk CLL the efficacy of therapy is rather low and the development of refractoriness is possible. In such patients the use of Bruton tyrosine kinase inhibitor as first-line therapy considerably increases the probability of long-term remission. The present paper provides the analysis of clinical and hematological efficacy and tolerance of ibrutinib as first-line therapy in high-risk CLL. Ibrutinib shows high efficacy and low toxicity. The use of ibrutinib as first-line therapy effectively reduces the probability of CLL progression, which is especially critical in high-risk patients, i.e., with 17p deletion and TP53 gene mutation.

Keywords: chronic lymphocytic leukemia, high-risk group, 17p deletion, TP53 gene mutation, ibrutinib, efficacy, toxicity.

Received: March 15, 2021

Accepted: August 30, 2021

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CAR-Т Cells for the Treatment of Chronic Lymphocytic Leukemia: Literature Review

AUTOIMMUNE THROMBOCYTOPENIA

IV Gribkova, AA Zav’yalov

Research Institute of Healthcare and Medical Management, 9 Sharikopodshipnikovskaya str., Moscow, Russian Federation, 115088

For correspondence: Irina Vladimirovna Gribkova, PhD in Biology, 9 Sharikopodshipnikovskaya str., Moscow, Russian Federation, 115088; Tel.: +7(916)078-73-90; e-mail: igribkova@yandex.ru

For citation: Gribkova IV, Zav’yalov AA. CAR-Т Cells for the Treatment of Chronic Lymphocytic Leukemia: Literature Review. Clinical oncohematology. 2021;14(2):225–30. (In Russ).

DOI: 10.21320/2500-2139-2021-14-2-225-230

ABSTRACT

Chronic lymphocytic leukemia (CLL) is the most common adult malignant lymphoid disease. Despite new highly effective targeted drugs, the prognosis of relapsed and resistant form of this disease is poor. CAR-Т cell therapy using T-lymphocytes with chimeric antigen receptor (CAR) demonstrated its efficacy in the treatment of such oncohematological diseases as В-cell non-Hodgkin’s lymphomas and acute lymphoblastic leukemia. The present literature review focuses on the experience of using CAR-Т cells for CLL therapy. It presents the advantages and drawbacks of this technique as well as the challenging issues to be solved for its implementation into broad clinical practice.

Keywords: chronic lymphocytic leukemia, CAR-Т cell therapy, chimeric antigen receptor, adoptive therapy, immunotherapy.

Received: December 15, 2020

Accepted: March 10, 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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Статистика Plumx английский

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Infections in Chronic Lymphocytic Leukemia Patients Treated with Ibrutinib: Incidence and Predisposing Factors

ANTINEOPLASTIC THERAPY COMPLICATIONS ,

EA Dmitrieva1, EA Nikitin1, EE Markova1, NYu Dmitrieva2, VV Ptushkin1

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

2 Aston Consulting, 10 bld. 3 Shabolovka str., Moscow, Russian Federation, 119049

For correspondence: Evgenii Aleksandrovich Nikitin, MD, PhD, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284; Tel.: +7(916)572-06-44; e-mail: eugene_nikitin@mail.ru

For citation: Dmitrieva EA, Nikitin EA, Markova EE, et al. Infections in Chronic Lymphocytic Leukemia Patients Treated with Ibrutinib: Incidence and Predisposing Factors. Clinical oncohematology. 2019;12(4):438–48 (In Russ).

DOI: 10.21320/2500-2139-2019-12-4-438-448

ABSTRACT

Background. Infections are a common complication of chronic lymphocytic leukemia (CLL). The lack of recommendations for infection prevention in CLL patients treated with ibrutinib can be attributed by an insufficiency of data in the literature.

Aim. To assess the incidence and nature of infections in CLL patients treated with ibrutinib and to analyze predisposing factors.

Materials & Methods. The paper provides data on bacterial, viral, and fungal infections in CLL patients treated with ibrutinib for 4.2 years (November 2014 to December 2018) in a single center. Severity grade was determined according to CTCAE criteria (version 4).

Results. The trial included 240 CLL patients. Median age was 65 years (range 32–91), 86 (36 %) patients were female, and 117 (48 %) patients had Binet stage C. Ibrutinib as monotherapy was administered to 204 (85 %) patients, 36 (15 %) patients received it in combination with monoclonal anti-CD20 antibodies. Median follow-up was 14.8 months (range 1–54). Most patients (n = 224, 93 %) received ibrutinib for relapsed CLL. Median number of prior therapy lines was 3 (range 1–12). Neutropenia (specified as neutrophil level < 1000 cells/µL) before ibrutinib treatment was identified in 20 (8 %) patients. Glucocorticoid hormones (GCs) together with ibrutinib were administered to 20 patients. A total of 525 infectious episodes were registered in 183 patients. Out of them 381 (72.5 %) were bacterial/mixed, 115 (22 %) were viral, and 29 (5.5 %) were fungal infections. Among bacterial/mixed infections 121 (32 %) episodes were qualified as infection of grade 3 and 43 (11 %) episodes were qualified as grade 4. In 7 (1.8 %) patients infections were fatal. Within 12 months overall cumulative incidence of bacterial infections of grade 3/4 was 37 % (95% confidence interval [95% CI] 31–43 %), as for viral infections it was 28 % (95% CI 22–34 %), and as for fungal infections it was 8 % (95% CI 4–12 %). Higher cumulative incidence of bacterial infections of grade 3/4 was identified in patients with ≥ 3 lines of therapy before ibrutinib treatment (hazard ratio [HR] 2.0; 95% CI 1.36–2.97), with Binet stage C (HR 1.4; 95% CI 0.95–2.08), with ECOG status ≥ 2 (HR 2.4; 95% CI 1.6–3.6), baseline neutropenia (HR 1.25; 95% CI 0.73–2.13), as well as in men (HR 1.8; 95% CI 1.16–2.8; p = 0.004). Multivariate analysis showed that male sex (HR 1.89; 95% CI 0.5–3.0; p = 0.006), ECOG status ≥ 2 (HR 1.97; 95% CI 0.5–3.0), and baseline neutropenia (HR 1.76; 95% CI 0.99–3.1) were significant and independent risk factors. Cumulative incidence of any fungal infection was associated with simultaneous use of GCs (HR 6.0; 95% CI 5.85–14.7) and baseline neutropenia (HR 2.36; 95% CI 0.95–5.85). The only parameter significantly associated with viral infections was the number of prior therapy lines ≥ 3 (HR 1.74; 95% CI 1.06–2.86; p = 0.029).

Conclusion. Patients with baseline neutropenia and ECOG status ≥ 2 face the highest risk of severe bacterial infections. We believe that antibacterial prophylaxis should be considered in such patients till ECOG status becomes < 2 and neutropenia resolves. Patients receiving GCs together with ibrutinib face the risk of fungal infections at any stage of treatment. In these patients the simultaneous antifungal prophylaxis should be considered.

Keywords: chronic lymphocytic leukemia, infections, ibrutinib.

Received: March 27, 2019

Accepted: September 19, 2019

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Antithrombotic Therapy in Patients with Malignant Lymphoproliferative Disorders Treated with Ibrutinib

ANTINEOPLASTIC THERAPY COMPLICATIONS , , , , , , ,

EI Emelina, GE Gendlin, IG Nikitin

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

For correspondence: Elena Ivanovna Emelina, MD, PhD, 1 Ostrovityanova str., Moscow, Russian Federation, 117997; e-mail: eei1210@mail.ru

For citation: Emelina EI, Gendlin GE, Nikitin IG. Antithrombotic Therapy in Patients with Malignant Lymphoproliferative Disorders Treated with Ibrutinib. Clinical oncohematology. 2019;12(4):449–60 (In Russ).

DOI: 10.21320/2500-2139-2019-12-4-449-460

ABSTRACT

Background. Antithrombotic therapy in chronic lymphocytic leukemia (CLL) patients is challenging, as this category of patients is initially characterized by high risk of hemorrhagic complications. The use of ibrutinib influencing the platelet function constitutes an additional bleeding risk. A crucial task consists in risk minimization of both hemorrhagic complications and thrombosis while sticking to ibrutinib treatment.

Aim. To assess the feasibility of antithrombotic therapy in CLL patients receiving ibrutinib and having indications for this therapy, as well as the use of dual antiplatelet and dual antithrombotic therapies.

Materials & Methods. The trial included 197 patients with CLL (n = 190), mantle cell lymphoma (n = 5), and Waldenstrom macroglobulinemia (n = 2) aged 32 to 91 years (median 66 years). The number of female patients was 70, aged 39 to 83 years (median 64 years) and the number of male patients was 127, aged 32 to 91 years (median 66 years). The patients were at different stages of ibrutinib treatment within 5 to 56 months. In this work methods of nonparametric statistics were used. All data are shown in the form of median and interquartile range or absolute numbers and percentages.

Results. Antithrombotic therapy during ibrutinib administration was used in 29 (14,7 %) patients. The new oral anticoagulants (NOAC) had to be prescribed to 26 patients with atrial fibrillation (AF). Dual antiplatelet therapy was used in 3 patients who underwent percutaneous coronary intervention with subsequent revascularization. In 2 patients with AF who underwent coronary stenting the dual antithrombotic therapy instead of the triple one was administered according to the management algorithm for patients with high risk of hemorrhagic complications. In 6 patients out of those who had AF and received NOAC the drug was withdrawn because of thrombocytopenia. Hemorrhagic manifestations which were the reason of NOAC withdrawal were observed in 1 female patient in the form of gross hematuria recurring when anticoagulant treatment was switched to the minimal effective doses and also when the administered anticoagulant was replaced with another one used in the minimal dose effective for stroke prevention in patients with AF. Hemorrhagic manifestations which were the reason of anticoagulant dose reduction emerged in 4 patients, and 3 patients required another anticoagulant for the same reason. In 5 patients there was no need to change the anticoagulant treatment. In 10 NOAC recipients no hemorrhagic syndrome was observed. None of 5 patients receiving dual antithrombotic therapy showed hemorrhagic complications within 3 to 14 months. The incidence of them in women is more than twice as high as in men.

Conclusion. Hemorrhagic manifestations in patients receiving ibrutinib and antithrombotic therapy were not life threatening and, in most cases, did not require drug withdrawal. Thrombocytopenia was the main reason for NOAC withdrawal. A thorough follow-up of patients receiving ibrutinib and antithrombotic therapy allows for timely correction of it if necessary. It involves dose reduction, anticoagulant replacement, and in rare cases the withdrawal of antithrombotic therapy with subsequent consideration of the feasibility of its resumption. As a rule, the need for different variants of antithrombotic therapy is not an obstacle to either assignment or continuation of antineoplastic treatment with ibrutinib.

Keywords: ibrutinib, chronic lymphocytic leukemia, antithrombotic therapy, dual antiplatelet therapy, atrial fibrillation, coronary stenting on ibrutinib therapy, new oral anticoagulants, rivaroxaban, dabigatran, apixaban.

Received: February 25, 2019

Accepted: July 31, 2019

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REFERENCES

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  2. Mulligan SP, Ward CM, Whalley D, et al. Atrial fibrillation, anticoagulant stroke prophylaxis and bleeding risk with ibrutinib therapy for chronic lymphocytic leukaemia and lymphoproliferative disorders. Br J Haematol. 2016;175(3):359–64. doi: 10.1111/bjh.14321.

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  5. Gribben JG, Bosch F, Cymbalista F, et al. Optimising outcomes for patients with chronic lymphocytic leukaemia on ibrutinib therapy: European recommendations for clinical practice. Br J Haematol. 2018;180(5):666–79. doi: 10.1111/bjh.15080.

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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

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  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)]

  3. Byrd JС, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32–42. doi: 10.1056/nejmoa1215637.

  4. Kil LP, de Bruijn MJ, van Hulst JA, et al. Bruton’s tyrosine kinase mediated signaling enhances leukemogenesis in a mouse model for chronic lymphocytic leukemia. Am J Blood Res. 2013;3(1):71–83.

  5. Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical end points in chronic lymphocytic leukemia. J Clin Oncol. 2012;30(23):2820–2. doi: 10.1200/jco.2012.43.3748.

  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.

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Rhythm and Conduction Disorders in Patients Receiving Ibrutinib

ANTINEOPLASTIC THERAPY COMPLICATIONS , , , , , ,

EI Emelina1, GE Gendlin1, IG Nikitin1, EA Dmitrieva2, EA Nikitin2, VV Ptushkin2

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

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

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

For citation: Emelina EI, Gendlin GE, Nikitin IG, et al. Rhythm and Conduction Disorders in Patients Receiving Ibrutinib. Clinical oncohematology. 2019;12(2):220–30.

DOI: 10.21320/2500-2139-2019-12-2-220-230

ABSTRACT

Aim. Early diagnosis and treatment of rhythm and conduction disorders in patients receiving ibrutinib.

Materials & Methods. The trial included 206 patients with indications for ibrutinib, 193 of them are at different stages of treatment from 1.5 to 51 months. The trial enrolled the patients with chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom’s macroglobulinemia, aged 59 to 72 years (with median age of 66 years): 70 women aged 54 to 71 years (with median age of 64 years), and 123 men aged 60 to 72 years (with median age of 66 years). For early detection of rhythm and conduction disorders all the patients received ECG monitoring and 24-hour Holter ECG monitoring.

Results. Atrial fibrillation (AF) was identified in 21 (12 %) patients during ibrutinib therapy period of 1 to 24 months. Most often AF is registered within the first 6 months of ibrutinib therapy. Before its administration 18 (10.5 %) patients had history of prior AF. Thus, a total of 39 ibrutinib recipients with AF are followed-up. According to CHA2DS2-VASc 27 (69 %) of them have an indication for anticoagulant treatment. Severe atrioventricular block was diagnosed in 2 (1 %) patients that necessitated a pacemaker. In 2 (1 %) female patients severe supraventricular tachycardia with up to 295 BPM was registered which required ablation. In a patient with permanent atrial fibrillation rhythm pauses were identified and a pacemaker was installed.

Conclusion. The presence of AF in ibrutinib recipients is not a withdrawal criterion and does not require ibrutinib therapy to be discontinued. Anticoagulants were administered to patients with AF according to existing guidelines in compliance with CHA2DS2-VASc which had to be approached with caution and required dynamic monitoring of patients. Severe rhythm and conduction disorders in ibrutinib recipients arise in rare cases (2 %). Such patients require cardiac surgery with subsequent ibrutinib treatment without dose reduction. Timely diagnosis and the correction of rhythm and conduction allow to avoid changing of antitumor therapy plan.

Keywords: ibrutinib, chronic lymphocytic leukemia, atrial fibrillation, atrioventricular block, rhythm pauses, supraventricular tachycardia, pacemaker installation, ablation.

Received: October 30, 2018

Accepted: February 8, 2019

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REFERENCES

  1. Gribben JG, Bosch F, Cymbalista F, et al. Optimising outcomes for patients with chronic lymphocytic leukaemia on ibrutinib therapy: European recommendations for clinical practice. Br J Haematol. 2018;180(5):666–79. doi: 10.1111/bjh.15080.

  2. Zamorano JL, Lancellotti P, Munoz RD, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J. 2016;37(36):2768–801. doi: 10.1093/eurheartj/ehw211.

  3. Brown JR, Moslehi J, O’Brien S, et al. Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials. Haematologica. 2017;102(10):1796–805. doi: 10.3324/haematol.2017.171041.

  4. Gustine JN, Meid K, Dubeau TE, et al. Atrial fibrillation associated with ibrutinib in Waldenstrom macroglobulinemia. Am J Hematol. 2016;91(6):E312–3. doi: 10.1002/ajh.24366.

  5. Lee HJ, Chihara D, Wang M, et al. Ibrutinib-related atrial fibrillation in patients with mantle cell lymphoma. Leuk Lymphoma. 2016;57(12):2914–6. doi: 10.3109/10428194.2016.1169408.

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  7. Mulligan SP, Ward CM, Whalley D, et al. Atrial fibrillation, anticoagulant stroke prophylaxis and bleeding risk with ibrutinib therapy for chronic lymphocytic leukaemia and lymphoproliferative disorders. Br J Haematol. 2016;175(3):359–64. doi: 10.1111/bjh.14321.

  8. Chai KL, Rowan G, Seymour JF, et al. Practical recommendations for the choice of anticoagulants in the management of patients with atrial fibrillation on ibrutinib. Leuk Lymphoma. 2017;58(12):2811–4. doi: 10.1080/10428194.2017.1315115.

  9. Thompson PA, Levy V, Tam CS, et al. Atrial fibrillation in CLL patients treated with ibrutinib. An international retrospective study. Br J Haematol. 2016;175(3):462–6. doi: 10.1111/bjh.14324.

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  16. Lopez-Fernandez T, Canales M, Farmakis D, et al. Ibrutinib-Associated Atrial Fibrillation: A Practical Approach. Ann Hematol Oncol. 2018;5(4):1203. doi: 10.26420/annhematoloncol.2018.1203.

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Immunological Synapse in the Biology of Chronic Lymphocytic Leukemia

REVIEWS , ,

DS Badmazhapova, IV Gal’tseva, EE Zvonkov

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

For correspondence: Darima Semunkoevna Badmazhapova, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(929)562-93-41; e-mail: badmazhapova-darima@mail.ru

For citation: Badmazhapova DS, Gal’tseva IV, Zvonkov EE. Immunological Synapse in the Biology of Chronic Lymphocytic Leukemia. Clinical oncohematology. 2018;11(4):313–8.

DOI: 10.21320/2500-2139-2018-11-4-313-318

ABSTRACT

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disease manifested by accumulation of tumor B-cells with characteristic immunophenotype (CD19+CD5+CD23+) in bone marrow, peripheral blood and secondary lymphoid organs. The clinical course of CLL is heterogeneous. This is the most prevalent leukemia among older-aged patients. Despite the use of novel drugs refractory forms of disease remain. The latest discoveries in immunology enabled understanding of some mechanisms of tumor evasion from immune surveillance. The interaction of immune system cells occurs due to the development of immunological synapse that predominantly depends on the family of CD28/В7 molecules, the so-called immune checkpoints able to control the activating and inhibiting mechanisms of cells. The acquisition of tumor phenotype is a multistage process, in which cells obtain unique biological properties including the ability of being invisible to the immune system. As opposed to solid tumors in lymphoproliferative diseases tumor B-cells are able to express major histocompatibility complex class II and CD80 and CD86 co-stimulatory molecules. It proves their ability to present antigens to T-cells. Co-inhibitory molecules on the surface of tumor cells is a factor contributing to the inhibition of immune response. The present paper reviews current conceptions of biological properties and immunological interactions of CLL cells with the microenvironmental cells.

Keywords: chronic lymphocytic leukemia, immunological synapse, immune system.

Received: March 15, 2018

Accepted: June 29, 2018

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Minimal Residual Disease and IGHV-Genes Mutational Status as the Main Predictors of Response to Bendamustine-Rituximab Therapy in Previously Untreated Chronic Lymphocytic Leukemia

LYMPHOID TUMORS , , , , , ,

YuV Mirolyubova, EA Stadnik, VV Strugov, TO Andreeva, TS Nikulina, YuV Virts, PA Butylin, AG Rumyantsev, AYu Zaritskey

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

For correspondence: Yuliya Vladimirovna Mirolyubova, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; e-mail: juli9702@yandex.ru

For citation: Mirolyubova YuV, Stadnik EA, Strugov VV, et al. Minimal Residual Disease and IGHV-Genes Mutational Status as the Main Predictors of Response to Bendamustine-Rituximab Therapy in Previously Untreated Chronic Lymphocytic Leukemia. Clinical oncohematology. 2018;11(2):167–74.

DOI: 10.21320/2500-2139-2018-11-2-167-174

ABSTRACT

Background. In patients with chronic lymphocytic leukemia (CLL) the eradication of minimal residual disease (MRD) is a prognostic factor of overall survival (OS) and progression-free survival (PFS). IGHV mutational status has also independent prognostic value.

Aim. To analyse the impact of mutational status and MRD eradication in CLL patients after first-line standard BR (bendamustine + rituximab) immunochemotherapy.

Materials & Methods. The prospective study included patients with immunophenotypically confirmed CLL who had not previously received anticancer therapy. All patients were treated by BR combination from 2012 to 2015. MRD level was determined in 109 patients after completing the 3rd and the 6th treatment courses. IGHV mutational status data were available for 98 patients. IGHV mutational status was evaluated in accordance with ERIC recommendations. MRD was assessed by standardized method of 4-color flow cytometry.

Results. MRD negativity was achieved in 37 (34 %) out of 109 patients. MRD eradication correlated with the best PFS (p = 0.04). IGHV mutational status had a statistically significant impact on PFS (p = 0.02). In patients with MRD-negative response and IGHV mutation no unfavorable events occurred during the period of monitoring. Conversely, PFS rates in MRD-negative patients having no IGHV mutation and in MRD-positive patients with mutation were significantly worse. MRD eradication resulted in statistically significant improvement of PFS rates after completing 3 treatment courses, compared with the cases with MRD persistence regardless of residual malignant clone level (p = 0.01).

Conclusion. BR therapy as first-line treatment statistically improved PFS in patients who achieved MRD-negative remission after completing the 3rd treatment course. PFS was significantly higher in MRD-negative patients with IGHV mutation after 6 treatment courses. MRD negativity resulting from 6 BR therapies in patients having no IGHV mutation was not accompanied by PFS improvement. It follows that by itself MRD negativity cannot be considered to be a universal prognostic factor.

Keywords: chronic lymphocytic leukemia, minimal residual disease, bendamustine, rituximab, BR, IGHV, mutational status.

Received: December 29, 2017

Accepted: February 27, 2018

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