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Routine Use of Bendamustine in Patients with Chronic Lymphocytic Leukemia: an Observational Study

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Routine Use of Bendamustine in Patients with Chronic Lymphocytic Leukemia: an Observational Study ANTICANCER RESEARCH 35: 5129-5140 (2015) Routine Use of Bendamustine in Patients with Chronic Lymphocytic Leukemia: An Observational Study MARIJANA NINKOVIC1, MICHAEL FIEGL1, MICHAEL MIAN2, PATRIZIA MONDELLO3, FLORIAN KOCHER1, CHRISTIAN WALDTHALER1, IRMGARD VERDORFER4, MICHAEL STEURER1, GÜNTHER GASTL1 and ANDREAS PIRCHER1 1Department of Internal Medicine V, Hematology and Oncology, Medical University of Innsbruck, Innsbruck, Austria; 2Department of Hematology and CBMT, Hospital of Bolzano, Bolzano, Italy; 3Department of Human Pathology, University of Messina, Messina, Italy; 4Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria Abstract. Bendamustine is an established treatment option Chronic lymphocytic leukemia (CLL) is the most common in chronic lymphocytic leukemia (CLL) and frequently used type of adult leukemia in industrialized countries (1, 2). in Austria and Italy. Therefore, we analyzed 100 unselected, Despite the advent of new drugs (3, 4), it still remains an consecutive patients with CLL (treatment-naïve and incurable disease, except for the few patients who are able to relapsed/refractory) receiving bendamustine in a real-life undergo allogeneic stem-cell transplantation (5-8). Only setting. Most patients were treated with bendamustine in recently, bendamustine, first synthesized in the early 1960s, combination with rituximab (BR). However, bendamustine was to become an efficient treatment for hematological monotherapy was additionally evaluated. Patients treated malignancies and it was approved for rituximab-refractory with BR had a significantly higher overall response rate of indolent lymphoma (9), CLL (10) and multiple myeloma (11). 76% (complete response=22%) when compared to those Up until now, the use of bendamustine in CLL was mainly treated solely with bendamustine (overall response investigated in clinical trials in combination with rituximab rate=50%; complete response=13%). Overall survival (OS) (12). Current guidelines recommend a bendamustine-based and progression -ree survival (PFS) were significantly lower therapy in patients with Binet stage C or Binet stage A and B in the bendamustine-treated group (OS=14.3 months; with symptomatic disease and notably physically non-fit PFS=8.3 months) compared to the BR group (OS=42.7; patients (11, 13, 14). Only a few real-life CLL populations, PFS=22.5 months; both p<0.001). In multivariate analysis, which were either treated with bendamustine monotherapy or patients with a good cytogenetic risk and those receiving BR in combination with rituximab, have been analyzed had a significantly better OS. Grade 3/4 hematological retrospectively (2, 13). Therefore, we herein present data on the complications were seen in 32% of the patients. Hence, toxicity and therapeutic efficacy in 100 unselected, consecutive bendamustine, especially in combination with rituximab, is patients with treatment-naïve or relapsed/refractory CLL an effective therapy with manageable toxicity for non- treated with bendamustine-based therapy. selected patients with CLL including those pre-treated with The objectives of the present study were to provide a fludarabine and the elderly. descriptive analysis of a CLL population who received bendamustine-based therapy to evaluate patients’ characteristics, including the spectrum of bendamustine- based therapy combinations used, and efficacy in terms of response and survival; as well as to determine toxicity in routine clinical use. Correspondence to: Marijana Ninkovic, MD, Department of Internal Medicine V/Hematology and Oncology, Medical Patients and Methods University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria. Tel: +43 512-50480761, Fax: +43 51250422602, e-mail: We retrospectively assessed 100 unselected, consecutive patients [email protected] with CLL who received bendamustine either as monotherapy (n=24) or in combination with rituximab (n=76). The study was conducted Key Words: Bendamustine, rituximab, chronic lymphocytic leukemia according to the rules of the Medical University of Innsbruck Ethics (CLL), chemotherapy, immunotherapy Committee, as reported in other studies (15-17). 0250-7005/2015 $2.00+.40 5129 ANTICANCER RESEARCH 35: 5129-5140 (2015) Figure 1. Progression-free survival according to treatment modality. a: The median PFS for patients treated with bendamustine and rituximab (BR) was 22.5 months (n=76) compared to 8.3 months for patients treated with bendamustine monotherapy (n=24; p<0.001). b: The median PFS for treatment-naïve patients on BR was 27.3 months (n=21) and for pre-treated patients was 17.7 months (n=55), while that of patients on bendamustine monotherapy was 8.3 months (n=24). When comparing all groups together the p-value was 0.001 (bendamustine vs. BR pre-treated [p=0.010], bendamustine vs. BR not pre-treated [p=0.001], BR pre-treated vs. BR not pre-treated [p=0.120]). Data concerning the therapeutic regimen, efficacy, toxicity and and April 2013. Detailed patient characteristics are shown in follow-up were obtained directly from the clinical charts and from Table I. The administered bendamustine dose ranged between primary physicians. Data for 26 patients from a previous evaluation 60 mg/m2 and 120 mg/m2 body surface area on day 1 and 2 were updated and included in the study (18). The final data update every 4 weeks. Rituximab was usually administered on day one was in September 2013. All analyses were performed using SPSS 2 software version 20 (IBM Corp. Armonk, NY, USA). of each cycle, mostly at the recommended dose of 500 mg/m . Complete remission (CR), partial remission (PR), stable disease The median number of cycles administered was 5 in the BR (SD) and progressive disease (PD) were classified according to the group and 3.5 cycles in the bendamustine-treated group. current International Work Group on Chronic Lymphocytic Bendamustine was administered as monotherapy (n=24, Leukemia guidelines for CLL (iWCLL) (7). Treatment-related 24%) or in combination with rituximab (n=76, 76%). A total adverse events were classified according to the Common Toxicity of 64 patients were male (64%). The median age was 73 Criteria (CTC v.4) (19). Survival curves were plotted according to years (range=41-88 years). The majority of the cases were the Kaplan–Meier method. Progression-free survival (PFS) was defined as the time from the initiation of bendamustine-based therapy treated in a higher therapy line (76%) and presented with Rai until disease progression (PD) or death, whichever occurred first. stages III and IV (27% and 40%, respectively), and were Patients, who were lost to follow-up without any sign of progression, characterized by CIRS scores over 6 [n=32/41 evaluable or were alive at the final data update, were censored at the time of patients (78%), median CIRS = 9]. last observation. Overall survival (OS) was measured from start of Cytogenetic status, by fluorescence in situ hybridization bendamustine-based therapy. Univariate survival comparisons (FISH) was available in 81 patients. According to the between categorical variables were evaluated with the log-rank test. algorithm of Döhner et al. (21), 44% of patients were high- All parameters with a p-value of 0.05 or less in univariate analyses were included in a Cox proportional hazard model. The p-value of risk, harboring 11q deletion (n=15) or 17p deletion (n=20), 0.05 or less was considered as significant in two-sided tests. meaning that patients with these cytogenetic aberrations A subset of 41 patients’ assessments of co-morbidity according to usually respond very poorly to conventional chemotherapy the cumulative illness rating scale (CIRS) was available. The patient and have inferior survival. Most of the patients had a WHO fitness groups according to CIRS were defined by the Alberta performance status of 0-1 (87%) and presented without B- Health Services clinical practice guideline LYHE-007 (20). symptoms (61%) at the beginning of the treatment. Forty- three patients with CLL (43%) had previously received Results fludarabine, of whom seven (16%) had fludarabine-refractory disease according to the criteria proposed by Keating et al. Patients’ characteristics and mode of therapy. Forty-five patients (22). Bendamustine alone or in association with rituximab (45%) were treated in Tyrol (Austria), and 31 (31%) and 24 was administered in first, second and higher line of therapy (24%) in Bolzano and Messina (Italy), respectively. in 24 (24%), 27 (27%) and 49 (49%) patients, with a median Bendamustine-based therapy was initiated between August 2007 of one (range=0-7) previous therapy. 5130 Ninkovic et al: Bendamustine in CLL Figure 2. Overall survival (OS) according to treatment modality. a: The median OS in patients treated with bendamustine and rituximab (BR) was 42.7 months (n=76), compared to 14.3 months for those treated with bendamustine monotherapy (n=24; p<0.001). b: The median OS for treatment- naïve patients on BR was not reached (n=21) and for pre-treated patients on BR was 35.8 months (n=55), while that for patients on bendamustine monotherapy was 14.3 months (n=24). When comparing all groups together the p-value was lower than 0.001 (bendamustine vs. BR pre-treated [p=0.001], bendamustine vs. BR not pre-treated [p<0.001], BR pre-treated vs. BR not pre-treated [p=0.050]). Response to therapy. Sufficient data for response assessment Progression-free survival. The overall median PFS was 17.7 information were available for 87 patients. In 13 patients, months. For the whole cohort, PFS was influenced by clinical response was not evaluable due to premature death (n=6), characteristics and therapy-related factors, namely the FISH therapy switch (n=1), premature discontinuation due to karyotype risk-group (p<0.001), type of bendamustine toxicity (n=2), or due to loss to follow-up (n=4) (as shown therapy (p<0.001), quality of response (p<0.001) and in Table II). A response according to iWCLL criteria was cumulative dose of applied bendamustine (p=0.005). The achieved in 70 patients (ORR=70%) with CR in 20 (20%) cohort treated with BR regimen reached a median PFS of and PR in 50 (50%).
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