atrial fibrillation

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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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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Ibrutinib in the Treatment of Refractory Chronic Lymphocytic Leukemia

NOVEL DRUGS , , , ,

EA Nikitin1, EA Dmitrieva1, MA Panteleev2, EI Emelina3, VL Ivanova1, YuB Kochkareva1, EG Arshanskaya1, IE Lazarev1, EE Markova1, LA Mukha1, NG Novitskaya1, MM Pankrashkina1, VV Glazunova1, AV Shubina1, SA Chernysh1, NK Khuazheva1, EV Naumova4, SA Lugovskaya4, ME Pochtar’4, TN Obukhova5, OYu Vinogradova1, GE Gendlin3, VV Ptushkin1

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

2 Dmitrii Rogachev Federal Scientific Clinical Centre of Pediatric Hematology, Oncology and Immunology, 1 Samory Mashela str., Moscow, Russian Federation, 117198

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

4 Department of Clinical Laboratory Diagnostics, Russian Medical Academy of Postgraduate Education, 7 bld. 2 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284

5 Hematology Research Center, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

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

For citation: Nikitin EA, Dmitrieva EA, Panteleev MA, et al. Ibrutinib in the Treatment of Refractory Chronic Lymphocytic Leukemia. Clinical oncohematology. 2017;10(3):271–81 (In Russ).

DOI: 10.21320/2500-2139-2017-10-3-271-281

ABSTRACT

Background & Aims. This paper presents the results of the observational study of ibrutinib in patients with chronic lymphocytic leukemia (CLL), conducted in SP Botkin Municipal Clinical Hospital. The main objective was the analysis of complications of ibrutinib and identification of factors, influencing the dosage regimen; the secondary objective was the estimation of the total response to treatment, event-free and overall survival.

Materials & Methods. The study included 96 patients with CLL with indications for ibrutinib therapy. The median age was 64,9 years (range 32–91 years), the study population consisted of 69 (72 %) men and 27 (28 %) women. The condition of 25 (26 %) patients according to the ECOG scale was of > 3 points. The disease of stage C were diagnosed in 36 (37 %) patients . Deletion of 17p/TP53 mutations were detected in 29 (33 %) of 87 patients. Seventy patients had refractory CLL. The median of the number of the lines of the previous therapy was 3 (range 1–9). Adverse events were assessed in accordance with the CTCAE criteria, version 4.0; the bleeding severity was evaluated using ITP-specific bleeding score; hematological complications were classified according to the recommendations of IWCLL-2008.

Results. Ibrutinib was administered at a dosage of 420 mg per day daily until progression or intolerable toxicity. The median duration of ibrutinib therapy was 10.3 months. Ibrutinib was shown to have moderate toxicity, mostly of grade I or II. The bleeding was the most frequent complication. Of the hematological complications, thrombocytopenia was the most common (35 %); neutropenia < 1 × 109/L was observed in 4 patients. GIT complications were identified in 51 (53 %) patients. Atrial fibrillation was registered in 5 patients, who initially had sinus rhythm. The total of 144 infections were diagnosed in 64 (66 %) patients. Severe infections (> grade III) developed in 26 % of patients. The treatment response was assessed in 92 patients. The overall response to treatment was 89 %. Complete remission, partial remission and partial remission with lymphocytosis were achieved in 4 (4 %), 57 (62 %), and 21 (23 %) patients, respectively. The event-free survival and overall survival by the month 10 was 90 % and 91 %, respectively. For this observation period, ECOG status and the number of the lines of therapy prior to ibrutinib had the prognostic value.

Conclusion. Ibrutinib was shown to have high efficiency in relapsed/refractory forms of CLL. The nature of the ibrutinib toxicity is fundamentally different from that of the conventional chemotherapy. The frequency of ibrutinib therapy complications and patients’ non-compliance depends on the intensity of the previous treatment of CLL. Despite a short observation period, it can be concluded that ibrutinib had the greatest impact on the patient’s quality of life when administered for the first relapse. The low toxicity of ibrutinib is likely to allow the combination with other antitumor agents.

Keywords: chronic lymphocytic leukemia, del 17p, TP53, refractory CLL, ibrutinib, bleeding, atrial fibrillation.

Received: March 14, 2017

Accepted: April 14, 2017

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