Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: updated results of a randomized phase <scp>III</scp> trial

Knauf, Wolfgang; Lissitchkov, Toshko; Aldaoud, Ali; Liberati, A. M.; Loscertales, Javier; Herbrecht, Raoul; Juliusson, Gunnar; Postner, Gerhard; Gercheva-Kyuchukova, Liana; Goranov, S; Becker, Martin; Fricke, Hans; Huguet, Françoise; Giudice, Ilaria Del; Klein, Peter; Merkle, K; Montillo, Marco

doi:10.1111/bjh.12000

Cited by 100 publications

(69 citation statements)

References 17 publications

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“…Beside the documentation of cytogenetic high-risk features and unmutated IGHV status in all enrolled patients, the clinical behavior was unequivocally aggressive, with refractoriness to standard treatments (including 31% fludarabine refractory) and/or responses to previous therapies lasting <24 months. Bendamustine, in combination with rituximab, is a treatment of choice in older patients with CLL [13], but its efficacy in patients with high-risk disease (i.e., 17p deletion) was quite low [16]. In a recent trial in the relapsed/refractory setting, rituximab and bendamustine (RB, at a dose of 70 mg/m 2 combined with rituximab at standard doses) achieved an OR of 59% in a cohort of 72 patients.…”

Section: Discussionmentioning

confidence: 99%

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The combination of rituximab, bendamustine, and cytarabine for heavily pretreated relapsed/refractory cytogenetically high‐risk patients with chronic lymphocytic leukemia

et al. 2013

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Treatment of patients with B-cell chronic lymphocytic leukemia (CLL) relapsed/refractory (R/R) to conventional treatments is particularly challenging. The combination of bendamustine and cytarabine has demonstrated distinct and synergistic mechanisms of action in preclinical studies on cell lines and primary tumor cells of several B-cell lymphomas, including 17p deleted or TP53 mutated CLL. The efficacy of rituximab (375 mg/m 2 , Day 1), plus bendamustine (70 mg/m 2 , days 1-2), and cytarabine (800 mg/m 2 , Day 1-3; R-BAC), every 28 days for up to four courses, was evaluated in a pilot trial enrolling 13 patients with very selected high-risk R/R CLL. All patients (median age 60 years, range 53-74) had symptomatic Binet stage B or C active disease requiring treatment, were characterized by adverse cytogenetics (17p deletion, 11q deletion, or both), unmutated immunoglobulin heavy-chain variable region, and were heavily pretreated (1-5, median three previous lines). Overall, R-BAC was well tolerated with limited non-hematological toxicity. Major toxicities were transient Grade 3/4 neutropenia and thrombocytopenia in 84% and 85% of patients, respectively. Overall response rate (OR) was 84%, including complete and partial response in 38% and 46% of patients, respectively. Patients with 17p deletion had an OR of 78%. After a median follow-up of 17 months, median progression-free survival was 16 months while median overall survival (OS) was not reached (1-year OS: 75 6 13%). R-BAC is an active regimen in R/R heavily pretreated high-risk patients with CLL, representing an option for the treatment of patients that are usually refractory to standard therapy. Am. J.

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Section: Discussionmentioning

confidence: 99%

“…Bendamustine is an alkylating agent that has purine analogue properties and exhibits considerable activity in indolent lymphomas and CLL [13,14]. It has been reported that bendamustine exerts a cytotoxic effect in CLL cell lines, involving both p53-dependent and p53-independent mechanisms [15].…”

Section: Introductionmentioning

confidence: 99%

The combination of rituximab, bendamustine, and cytarabine for heavily pretreated relapsed/refractory cytogenetically high‐risk patients with chronic lymphocytic leukemia

et al. 2013

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“…As both age and mutation status are prognostic indicators and potential treatment-effect-modifiers in CLL [6], analyses were conducted, where data permitted, on the subgroups of patients aged ≥65 years, those with unmutated IgVH, those with del11q mutation and those without del17p mutation. Some or all outcomes of interest for the four subgroups were available from four RCTs: RESONATE-2 [13], CLL11 [12], COMPLEMENT1 [19] and Knauf et al [23]. Pairwise comparisons were conducted for ibrutinib versus Obi-Chl, R-Chl, Ofa-Chl and bendamustine, respectively, and effects were tested in the subgroups for which data were available.…”

Section: Regression Analyses For Survival Outcomes Using Chlorambucilmentioning

confidence: 99%

Front-line treatment of patients with chronic lymphocytic leukemia: a systematic review and network meta-analysis

Fahrbach

Dorman

et al. 2018

J. Comp. Eff. Res.

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Aim:A systematic literature review and network meta-analysis were conducted to determine the relative efficacy and safety of interventions for treatment-naive chronic lymphocytic leukemia patients, as comparative evidence is scarce. Materials & methods: Relative treatment effects of progression-free survival, overall survival and safety outcomes were estimated via network meta-analysis based on data identified via systematic literature review. Results: Ibrutinib was superior in all pairwise comparisons for progressionfree survival (probability to be better [P] range: overall population: 69-100%; fludarabine-ineligible population: 69-100%) and overall survival (P range: overall: 89-100%; fludarabine-ineligible: 91-100%) and had the highest probability of being best for all outcomes. Conclusion: Ibrutinib provides superior benefit in survival and safety compared with other front-line treatments of chronic lymphocytic leukemia. Chronic lymphocytic leukemia (CLL) is the most common hematologic malignancy in western countries and occurs mainly in older people. Overall, 4.2 per 100,000 population per year develop the condition, a figure that rises to over 30 per 100,000 per year among those aged over 80 years [1]. The overall 5-year survival rate for people with CLL is 83%, although survival varies widely according to disease stage [2]. Treatment for CLL has evolved rapidly over the past two decades, with the addition of CD20-targeted antibodies, B-cell lymphoma-2 (BCL-2)-targeted treatment and B-cell receptor-targeted treatment resulting in improved outcomes [3][4].As indicated by both the European Society for Medical Oncology (ESMO) and the National Comprehensive Cancer Network [1,5], there are various management options for CLL, and treatment choices must account for key patient and disease characteristics known to affect therapeutic outcomes. These include patient age [6], fitness/comorbidities [7] and molecular cytogenetics [6,8]. Generally, for fit patients with advanced, symptomatic disease, the so-called 'full-dose fludarabine-based' regimen of fludarabine + cyclophosphamide + rituximab (FCR) is recommended [1]. However, for elderly patients and/or those with significant comorbidities, FCR is associated with significant risk of myelosuppression and severe infection [9]. Options are further limited if these individuals also have cytogenetic characteristics associated with poor outcomes from current treatments (such as 17p or 11q deletion, or absence of IgVH mutation). For these patients, ESMO and National Comprehensive Cancer Network guidelines recommend ibrutinib monotherapy [1,5,9].Given the range of CLL treatment options for people with differing levels of fitness, and the dearth of head-tohead clinical trials comparing front-line treatments, there remains considerable uncertainty regarding the optimal regimen for each patient group. The objectives of the presented systematic literature review (SLR) and network meta-analyses (NMAs) were therefore to determine the relative efficacy and safety of intervention...

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“…Single agent therapy with chlorambucil, cyclophosphamide or with fludarabine, lenalidomide, bendamustine was tested in different clinical trials in the past and is no longer considered as the standard therapeutic modality in CLL but is used in resource poor countries due to its low cost. In randomized trials, single agent fludarabine or bendamustine have shown significant improvement over chlorambucil alone [57,58]. Combination of fludarabine with cyclophosphamide (FC) or cladribine with cyclophosphamide (CC) has shown improvement in the overall response rate (ORR) and progression free survival (PFS) compared to single agent therapy [59][60][61].…”

Section: Evolution Of Treatment Of Cll (Then and Now In 2016)mentioning

confidence: 99%

Chronic lymphocytic leukemia (CLL)—Then and now

Kanti

Jain²

2016

American J Hematol

134

108

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The field of chronic lymphocytic leukemia (CLL) has witnessed considerable change since the time clinical staging was introduced in clinical practice in 1975. Over the years, the prognostication in CLL has expanded with the addition in late 90s of mutational status of variable region of immunoglobulin heavy chain (IGHV), and chromosomal analyses using fluorescent in situ hybridization (FISH). More recently, stereotypy of BCR (B cell receptor) and whole exome sequencing (WES) based discovery of specific mutations such as NOTCH1, TP53, SF3B1, XPO-1, BIRC3, ATM, and RPS15 further refined the current prognostication system in CLL. In therapy, the field of CLL has seen major changes from oral chlorambucil and steroids prior to 1980s, to chemo-immunotherapy (CIT) with fludarabine, cyclophosphamide, rituximab (FCR) to the orally administered targeted therapeutic agents inhibiting kinases in the B cell receptor (BCR) signaling pathway such as Ibrutinib (BTK inhibitor) and Idelalisib (p110 PI3Kd inhibitor) and novel anti-CD20 mAb's (monoclonal antibodies) such as obinutuzumab. This progress is continuing and other targeted therapeutics such as Bcl2 antagonists (Venetoclax or ABT-199) and finally chimeric antigen receptor against T cells (CART) are in the process of being developed. This review is an attempt to summarize the major benchmarks in the prognostication and in the therapy of CLL. The topic allocated to us by Dr Ayalew Tefferi and Dr Carlo Brugnara is very appropriate to reminisce what our understanding of chronic lymphocytic leukemia (CLL) was in 1976 and how rapidly have the advances occurring in this field affected the patients with CLL. It is a disease of progressive accumulation of lymphocytes. CLL lymphocytes are morphologically indistinguishable from a normal mature lymphocyte CLL lymphocytes are functionally inert and perhaps as a direct consequence, their life-span is longer than of normal lymphocytes. It was also believed that CLL lymphocytes are not rapidly proliferating. CLL is a disease of elderly population In some cases, chronic lymphocytic leukemia (CLL) closely resembled leukemic Brill Symmers disease (leukemic form of follicular lymphoma). In an elegant study on 88 patients, the temporal profile of the clinical course of CLL was described by Galton et al.[1] Disease progression was assessed in relation to lymphadenopathy, splenomegaly and bone marrow infiltration. CLL was considered as an immunoproliferative disorder with low immunoglobulin levels, striking response to therapy with steroids and exaggerated skin reaction to arthropod bites. Management of CLL (then in 1976)Most clinicians recognized that at the time of initial diagnosis, patients with CLL, generally, were free of disease-related symptoms. Therefore, virtually all patients were followed on a wait-and-watch regimen, withholding any cytotoxic therapy. When, on clinical grounds, initiation of any therapy was considered appropriate, oral alkylating agents such as chlorambucil with/without steroids [3,4] or cyclophosphamide [5] with or...

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Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: updated results of a randomized phase III trial

Cited by 100 publications

References 17 publications

The combination of rituximab, bendamustine, and cytarabine for heavily pretreated relapsed/refractory cytogenetically high‐risk patients with chronic lymphocytic leukemia

The combination of rituximab, bendamustine, and cytarabine for heavily pretreated relapsed/refractory cytogenetically high‐risk patients with chronic lymphocytic leukemia

Front-line treatment of patients with chronic lymphocytic leukemia: a systematic review and network meta-analysis

Chronic lymphocytic leukemia (CLL)—Then and now

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