Autoimmune Cytopenias in Patients with Chronic Lymphocytic Leukemia Treated with Cladribine
Authors: Blonski Jerzy Z , Robak Tadeusz , Trelinski Jacek , Chojnowski Krzysztof , Warzocha Krzysztof , Seferynska Ilona , Konopka Lech , Ceglarek Bernadetta , Calbecka Malgorzata , Kostyra Aleksandra , Stella-Holowiecka Beata , Kloczko Janusz , Dmoszynska Anna , Kowal Malgorzata , Lewandowski Krzysztof , Dwilewicz-Trojaczek Jadwiga , Wiater Elzbieta , Kuliczkowski Kazimierz , Potoczek Stanislaw , Hellmann Andrzej , Mital Andrzej , Skotnicki Aleksander B. , Nowak Wieslaw , Sulek Kazimierz , Zdunczyk Andrzej , Zawilska Krystyna 
Published: April 2020

Abstract
Autoimmune disorders like immune haemolytic anemia (AIHA) and immune thrombocytopenia (IT) represent the autoimmune haematological conditions most frequently associated with chronic lymphocytic leukemia (CLL). Recently there has been several case reports suggesting relation between occurrence of these disorders and treatment with purin analogues. The aim of this study was to compare the frequency and prognostic value of AIHA and IT in the group of CLL patients treated with chlorambucil or cladribine. Retrospective analysis of 777 patients treated in 1999–2004 years according to two randomized clinical trial protocols coordinated by Polish Adult Leukemia Group (PALG) was performed. In 104 patients chlorambucil and in 673 cladribine was applied according to NCIWG criteria. In the cladribine group 315 were given monotherapy, in 170 combination therapy with cyclophosphamide (CC) and in 188 with cyclophosphamide and mitoxantron (CMC) were used. The details of the treatment schedules were published previously. IT patients had to fulfill the following diagnostic criteria: rapid and severe fall of the platelet count, normal or augmented number of megakariocytes in bone marrow, no reaction to platelet transfusions, no palpable splenomegaly and no chemotherapy in the last 30 days. No patient had IT before enrolment to any cytotoxic treatment. Diagnosis of AIHA was based on haemoglobin &lt;100 g/l and a positive direct antiglobulin test (DAT) for either immunoglobulin or the complement fragment C3d in the absence of bleeding. For patients with negative DAT the diagnosis was based additionally on the presence of at least two indicators of haemolysis (increased indirect bilirubin, increased reticulocyte count, increased LDH concentration, low haptoglobin concentration). The occurrence of studied events was estimated among end of first and beginning of second line treatment. The results of the study are shown in Table 1.
In conclusion the application of cladribine either in monotherapy or in combination with cyclophosphamide or mitoxantron did not significantly increase the frequency of AIHA and/or IT in the studied population in comparison to chlorambucil. Although the remission rates (CR-complete and OR-overall) in patients with concomitant AIHA and IT treated with cladribine was lower than in patients without these complications no influence on and overall survival (OS) was observed.
Table.1.
Characteristic Cladribine Chlorambucil p value AIHA Yes No Yes No Total (%) 48 (7.1) 625 (92.9) 6 (5.8) 98 (94.2) 0.61 OR (%) 35 72.9 448 80.9 2 33.3 57 58.8 0.11 vs 0.22 CR (%) 10 20.8 194 35.0 0 0.0 12 12.4 0.008 vs 0.36 Death (%) 29 60.4 342 55.1 6 100.0 69 71.1 - OS (median. years) 4.226 3.247 4.843 2.614 0.16 vs 0.81 IT Yes No Yes No Total (%) 50 7.4 623 92.6 5 4.8 99 95.2 0.33 OR (%) 31 63.3 449 81.6 2 40.0 57 58.2 0.004 vs 0.42 CR (%) 5 10.2 196 35.6 1 20.0 11 11.2 0.0006 vs 0.55 Death (%) 36 72.0 335 54.1 5 100.0 70 71.4 - OS (median. years) 2.231 9.595 4.300 5.237 0.11 vs 0.23