title: Bendamustine for patients with indolent B cell lymphoid malignancies including chronic lymphocytic leukaemia.
abstract: BACKGROUND
  Indolent B cell lymphoid malignancies include follicular lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, lymphoplasmacytic lymphoma and marginal zone lymphomas. Chronic lymphocytic leukaemia (CLL) is a lymphoid malignancy similar to small lymphocytic lymphoma (SLL) in its leukaemic phase.Indolent lymphoid malignancies including CLL are characterised by slow growth, a high initial response rate and a relapsing and progressive disease course. Advanced-stage indolent B cell lymphoid malignancies are often incurable. If symptoms or progressive disease occur, chemotherapy plus rituximab is indicated. No chemotherapy regimen has been shown to improve overall survival compared to a different regimen.Bendamustine is efficacious in the treatment of patients with indolent B cell lymphoid malignancies. A number of randomised controlled trials have examined the effect of bendamustine compared to other chemotherapy regimens in these patients. Improved disease control with no survival benefit is shown.
  
  
  OBJECTIVE
  To evaluate the efficacy of bendamustine therapy for patients with indolent B cell lymphoid malignancies including CLL.
  
  
  METHODS
  We electronically searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 2), MEDLINE (1966 to May 2012), EMBASE (1974 to November 2011), LILACS (1982 to May 2012), databases of ongoing trials (accessed 30 April 2012) and relevant conference proceedings. We searched references of identified trials and contacted the first author of each included trial.
  
  
  METHODS
  Randomised controlled trials that compared a bendamustine-containing regimen to other chemotherapy with or without immunotherapy.
  
  
  METHODS
  Two authors independently appraised the quality of each trial and extracted data from included trials. We estimated and pooled hazard ratios (HR) and risk ratios (RR) with 95% confidence intervals (CI).
  
  
  RESULTS
  We included five trials randomising 1343 adult patients in the systematic review. Allocation and blinding were unclear in three trials and adequate in two. Incomplete outcome data and selective reporting were adequate in all trials. Trials varied in the type of lymphoid malignancy, bendamustine regimen and the comparator regimen. In the three trials that included patients with follicular lymphoma, mantle cell lymphoma and other indolent lymphomas the comparator treatment was cyclophosphamide, a combination of cyclophosphamide, vincristine, doxorubicin and prednisone, and fludarabine. Two trials included only patients with CLL and compared bendamustine to chlorambucil, and to fludarabine. We did not conduct a meta-analysis due to the clinical heterogeneity among trials. Bendamustine had no statistically significant effect on the overall survival of patients with indolent B cell lymphoid malignancies in any of the included trials (trials of moderate quality). Progression-free survival was statistically significantly improved with bendamustine treatment compared to other chemotherapy in three of the four trials that reported on it. One trial demonstrated a non statistically significant improvement of PFS. The risk of grade 3 or 4 adverse events was similar when bendamustine was compared to CHOP and fludarabine, and higher when compared to chlorambucil. Compared to chlorambucil quality of life was unaffected by bendamustine treatment (one trial, no meta-analysis).
  
  
  CONCLUSIONS
  As none of the currently available chemotherapeutic protocols for induction therapy in indolent B cell lymphoid malignancies confer a survival benefit and due to the improved progression-free survival in each of the included trials, and a similar rate of grade 3 or 4 adverse events, bendamustine may be considered for the treatment of patients with indolent B cell lymphoid malignancies. However, the unclear effect on survival and the higher rate of adverse events compared to chlorambucil in patients with CLL/SLL does not support the use of bendamustine for these patients.The effect of bendamustine combined with rituximab should be evaluated in randomised clinical trials with more homogenous populations and outcomes for specific subgroups of patients by type of lymphoma should be reported. Any future trial should evaluate the effect of bendamustine on quality of life.
authors.affiliation: Department of Medicine E, Beilinson Hospital, Rabin Medical Center, Petah Tikva, Israel. vidallit@yahoo.com.
authors.forename: Liat
authors.initials: L
authors.lastname: Vidal
authors.forename: Anat
authors.initials: A
authors.lastname: Gafter-Gvili
authors.forename: Ronit
authors.initials: R
authors.lastname: Gurion
authors.forename: Pia
authors.initials: P
authors.lastname: Raanani
authors.forename: Martin
authors.initials: M
authors.lastname: Dreyling
authors.forename: Ofer
authors.initials: O
authors.lastname: Shpilberg
mesh_terms: D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use; D000069461:Bendamustine Hydrochloride; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000627:therapeutic use; D004317:Doxorubicin / Q000008:administration & dosage; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000401:mortality; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000401:mortality; D008224:Lymphoma, Follicular / Q000188:drug therapy / Q000401:mortality; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000401:mortality; D009588:Nitrogen Mustard Compounds / Q000627:therapeutic use*; D011241:Prednisone / Q000008:administration & dosage; D012008:Recurrence; D014750:Vincristine / Q000008:administration & dosage; D008258:Waldenstrom Macroglobulinemia / Q000188:drug therapy / Q000401:mortality
chemical_list: D018906:Antineoplastic Agents, Alkylating; D009588:Nitrogen Mustard Compounds; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D000069461:Bendamustine Hydrochloride; D011241:Prednisone