ANTINEOPLASTIC THERAPY COMPLICATIONS

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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Role of Biochemical Inflammatory Markers in Patients with Chemotherapy-Induced Neutropenia

ANTINEOPLASTIC THERAPY COMPLICATIONS , , , , , ,

YuN Dubinina1, VO Sarzhevskii2, VYa Melnichenko2

1 Oncology and Hematology Outpatient Clinic, 2 bld. 1 Molodogvardeiskaya str., Moscow, Russian Federation, 121467

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

For correspondence: Yuliya Nikolaevna Dubinina, 2 bld. 1 Molodogvardeiskaya str., Moscow, Russian Federation, 121467; Tel.: +7(499)112-25-04; e-mail: medicinemsc@gmail.com

For citation: Dubinina YuN, Sarzhevskii VO, Melnichenko VYa. Role of Biochemical Inflammatory Markers in Patients with Chemotherapy-Induced Neutropenia. Clinical oncohematology. 2019;12(4):461–7 (In Russ).

DOI: 10.21320/2500-2139-2019-12-4-461-467

ABSTRACT

The growing number of autologous and allogeneic transplantations of bone marrow and hematopoietic stem cells as well as their technological effectiveness give rise to drug antineoplastic therapies with increased toxicity leading to development of complications. The most serious among this sort of complications are infections. Probability of infections in patients with chemotherapy-induced neutropenia reaches 90 %. In this context the search for an optimal marker of infectious complications becomes more and more important. The present review deals with basic biochemical inflammatory markers and the analysis of trials assessing diagnostic and prognostic value of C-reactive protein, procalcitonin, and presepsin.

Keywords: sepsis, autologous bone marrow transplantation, allogeneic bone marrow transplantation, chemotherapy, infection, procalcitonin, presepsin, C-reactive protein.

Received: May 7, 2019

Accepted: September 11, 2019

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Infectious Complications in Multiple Myeloma Patients Receiving Various Antitumor Regimens

ANTINEOPLASTIC THERAPY COMPLICATIONS , ,

AA Novikova, GA Klyasova, EO Gribanova, VV Ryzhko, TA Tupoleva, LP Mendeleeva, VG Savchenko

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

For correspondence: Anna Aleksandrovna Novikova, 4a Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(916)873-15-72; e-mail: annanovikova11@mail.ru

For citation: Novikova AA, Klyasova GA, Gribanova EO, et al. Infectious Complications in Multiple Myeloma Patients Receiving Various Antitumor Regimens. Clinical oncohematology. 2019;12(2):231–9.

DOI: 10.21320/2500-2139-2019-12-2-231-239

ABSTRACT

Aim. To study infectious complications and factors attributable to them as reported in multiple myeloma (MM) patients in the framework of state-of-the-art anticancer therapy.

Materials & Methods. The study included MM patients who received regimens based on bortezomib, lenalidomide, and bendamustine from January 2013 to August 2018. The regimens including thalidomide, melphalan, and aggressive antitumor treatment constituted the group of “others”.

Results. The study enrolled 174 patients (82 men and 92 women with median age of 61 years) with newly diagnosed MM (with median follow-up of 5.6 months). A total of 1362 courses of antitumor treatment were administered: 895 bortezomib (n = 174), 306 lenalidomide (n = 68), and 63 bendamustine (n = 22) regimens. The category of “others” included 98 treatment courses (n = 34). Infectious complications were reported in 129 (74.1 %) MM patients throughout the period of 344 (25.3 %) courses of antitumor treatment. Infection incidence on bortezomib (24.4 %), lenalidomide (20.3 %), and bendamustine (27 %) therapies was similar, and fell clearly below the infection incidence registered on the regimens constituting the group of “others” (48 %; р < 0.01). The most common infectious complications were pneumonias (54.9 %), urinary (24.7 %), and herpesviral infections (22.9 %). Herpesviral infections were predominantly associated with bortezomib treatment (29.8 %; p < 0.05). Significant factors (р < 0.05) associated with infection development were leukopenia, the presence of central venous catheter (CVC), need for blood transfusion, MM progression or relapse.

Conclusion. Infection incidence in MM patients receiving bortezomib, lenalidomide, and bendamustine anticancer therapy appeared to be similar, but considerably lower than in patients who received antitumor regimens belonging to category “others”. The prevalent type of infectious complications was pneumonia. Herpesviral infections were most common on bortezomib regimens. Factors related to infection development throughout all therapies were leukopenia, the presence of CVC, need for blood transfusion, MM progression or relapse.

Keywords: multiple myeloma, infectious complications, risk factors.

Received: January 26, 2019

Accepted: March 29, 2019

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REFERENCES

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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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Antibiotic Treatment of Febrile Neutropenia in Patients with Acute Leukemia

ANTINEOPLASTIC THERAPY COMPLICATIONS , , , , , ,

VA Okhmat, GA Klyasova, EN Parovichnikova, VV Troitskaya, EO Gribanova, VG Savchenko

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

For correspondence: Vladimir Aleksandrovich Okhmat, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)614-92-72; e-mail: okhmatvladimir@mail.ru

For citation: Okhmat VA, Klyasova GA, Parovichnikova EN, et al. Antibiotic Treatment of Febrile Neutropenia in Patients with Acute Leukemia. Clinical oncohematology. 2018;11(1):100-9.

DOI: 10.21320/2500-2139-2018-11-1-100-109

ABSTRACT

Aim. To estimate the efficacy of antibiotic treatment of febrile neutropenia in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

Materials & Methods. The prospective study (2013 to 2015) included 66 AML and 44 ALL patients receiving 480 chemotherapy cycles within the period of 6 months.

Results. Febrile neutropenia was registered during 242 (50 %) chemotherapy cycles occurring more frequently in AML than in ALL patients (93 % vs. 18 %, p < 0.0001). In AML patients infections were more common during induction and consolidation (98 and 89 %) phases compared to ALL patients who most commonly had infection during induction phase (55 %). Compared to ALL patients, AML patients had lower recovery rates after first-line antibiotic monotherapy (24 % vs. 57 %, p < 0.0001), compared to combination therapy (37 % vs. 18 %, p = 0.01). The use of beta-lactam antibiotics in ALL patients was associated with lower recovery rates during the induction phase compared to consolidation phase (47 % vs. 72 %, p = 0.0004). In cases of granulocytopaenia longer that 14 days the clinical recovery rate with administration of the first-line antibiotics and carbapenems accounted for 23–24 % compared to 47 % with other antimicrobials, more commonly with antifungal (21 %) administration. In patients with fever of unknown origin the monotherapy with first-line antibiotics proved to be successful (45 %). In patients with clinically and microbiologically defined infections the best results were achieved by the combined treatment with the beta-lactam antibiotics and other drugs (43 %).

Conclusion. Antibiotic escalation has proved to be the optimal strategy in treatment of ALL patients and in cases of fever of unknown origin. The efficacy of the beta-lactam antibiotic monotherapy was lower in AML patients during the induction phase as well as in cases of continuous neutropenia (> 14 days) and clinically and microbiologically diagnosed infections. The adding of other antimicrobial administration resulted in the recovery in 37–48 % of cases.

Keywords: acute leukemia, AML, ALL, febrile neutropenia, fever of unknown origin, clinically and microbiologically defined infections, antibiotics.

Received: July 2, 2017

Accepted: October 20, 2017

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REFERENCES

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Thrombotic and Hemorrhagic Complications in the Treatment of Acute Lymphoblastic Leukemia with L-Asparaginase

ANTINEOPLASTIC THERAPY COMPLICATIONS , , , , , ,

GM Galstyan, OA Polevodova, AV Bazhenov, VV Troitskaya, OA Gavrilina, DG Gitel’zon, AE Vasil’ev, EN Parovichnikova

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

For correspondence: Gennadii Martinovich Galstyan, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(916)488-50-73; e-mail: gengalst@gmail.com

For citation: Galstyan GM, Polevodova OA, Bazhenov AV, et al. Thrombotic and Hemorrhagic Complications in the Treatment of Acute Lymphoblastic Leukemia with L-Asparaginase. Clinical oncohematology. 2018;11(1):89-99.

DOI: 10.21320/2500-2139-2018-11-1-89-99

ABSTRACT

The article provides a literature review on the use of the L-asparaginase (ASP) in acute lymphoblastic leukemia (ALL) and describes two clinical cases. During the treatment with ASP as part of remission induction therapy thrombotic and hemorrhagic complications in the central nervous system were registered. In both cases these complications were associated with reduced plasma levels of antithrombin III (АТ), hypofibrinogenemia and thrombocytopenia. The risk factors for thrombohemorrhagic complications in ALL patients during ASP treatment are reviewed including combined ASP + anthracycline therapy, oral contraceptives, glucocorticosteroids, thrombophilia and the presence of central venous catheter (CVC). Possible mechanisms of thrombosis as well as the timing of its occurrence and possible localisation are discussed. The article considers different strategies for prevention and treatment of thrombotic and hemorrhagic complications in ALL patients receiving ASP. In all ALL patients receiving ASP plasma levels of fibrinogen and AT should be assessed before treatment initiation, on day 3 after the injection and further every 5 to 7 days within a period of 3 weeks after the injection. Novel oral anticoagulants are not dependent on blood AT levels and may be used for prevention and treatment of thrombotic and hemorrhagic complications associated with ASP intake. Finally, recommendations for the correction of AT levels and hypofibrinogenemia are given.

Keywords: L-asparaginase, thrombosis, thromboelastography, antithrombin III, hypofibrinogenemia, thrombocytopenia, novel oral anticoagulants.

Received: August 16, 2017

Accepted: October 27, 2017

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