Making Advances in First-Line Chronic Lymphocytic Leukemia Treatment

Abstract

Bendamustine was developed in East Germany as a potent alkylating agent. Bendamustine monotherapy was US Food and Drug Administration approved for both first-line and salvage treatment of patients with chronic lymphocytic leukemia (CLL) as a result of superior progression-free survival (PFS) compared with that seen with chlorambucil monotherapy in first-line treatment of CLL. Although CD20 monoclonal antibody (mAB) monotherapy has limited activity in CLL, the German CLL Study Group (GCLLSG) confirmed in their CLL8 trial that the addition of rituximab to chemotherapy significantly advanced treatment for CLL, with improved PFS and overall survival (OS). On the basis of these data and data from the REACH (Rituximab in the Study of Relapsed Chronic Lymphocytic Leukemia) trial, rituximab was US Food and Drug Administration approved in combination with fludarabine and cyclophosphamide (FC) for firstline and previously treated CLL. The GCLLSG reported results of a phase II trial of bendamustine combined with rituximab (BR) for relapsed and refractory CLL, and in the article that accompanies this editorial, Fischer et al, on behalf of the GCLLSG, report results of a first-line, multicenter phase II clinical trial of BR for CLL. They report an overall response rate of 88%, complete remission (CR) rate of 23%, and estimated median PFS of 34 months for 117 previously untreated patients with CLL. Grade 3 or 4 neutropenia, thrombocytopenia, and anemia occurred in 20%, 22%, and 20% of patients, respectively. Randomized first-line phase III clinical trials that evaluated chlorambucil versus fludarabine, then fludarabine versus FC, and most recently, FC versus FC plus rituximab (FCR), established FCR as a standard chemoimmunotherapy (CIT) regimen that provides excellent PFS and OS. Other agents have been evaluated in phase III trials as monotherapy compared with chlorambucil, such as alemtuzumab and bendamustine, and have garnered US Food and Drug Administration approval on the basis of superior PFS, but hardly represent significant therapeutic advances. Several phase II trials have aimed to improve outcomes by modifying FCR, but without obvious success. Examples include increasing the dose of rituximab, adding mitoxantrone, adding alemtuzumab, or adding a granulocytemacrophage colony-stimulating factor to the FCR regimen. These first-line phase II BR trial results can be compared with standard first-line CD20 mAb–containing CIT regimens like FCR, FR, or pentostatin, cyclophosphamide, and rituximab (Table 1). The difficulty in comparing outcomes between clinical trials is that