The Shifting Therapeutic Spectrum for Chronic Lymphocytic Leukemia

Published: Monday, Jul 08, 2019
blood cellsDOver the past several years, the treatment landscape for chronic lymphocytic leukemia (CLL) has changed significantly. For patients with CLL, including those with high-risk disease, the availability of novel targeted therapies and monoclonal antibodies offers an increased potential for improved outcomes.1,2 Several agents that inhibit CD20 have been developed because of the role of CD20 in the process of differentiation and growth of B cells3; obinutuzumab, ofatumumab, and rituximab have subsequently been approved.1 Additionally, several agents targeting the B-cell receptor pathway have achieved FDA approval,4 including the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, the phosphatidylinositol 3-kinase inhibitors idelalisib and duvelisib, and the B-cell lymphoma 2 inhibitor venetoclax.1 Initially, several of these agents were approved by the FDA in combination with other approved agents, such as idelalisib plus rituximab, obinutuzumab plus chlorambucil, and ofatumumab plus chlorambucil. The Table includes a list of FDA-approved agents.5-13

Positive results from clinical trials that explored additional combination regimens have led to expanded indications for agents already approved by the FDA, including ofatumumab plus fludarabine and cyclophosphamide, and ibrutinib plus obinutuzumab. Importantly, indications range among the various approved monotherapies and combination regimens. Despite the availability of several agents in multiple drug classes, therapeutic selection for optimized regimens can be challenging, particularly because new evidence continues to emerge that further elucidates the clinical profile of FDA approved therapies. In particular, 3 studies presented at the 2018 American Society of Hematology (ASH) meeting showed promising results for the role of ibrutinib in the frontline treatment landscape of CLL: the Alliance North American Intergroup Study A041202 (ALLIANCE A041202),14 the E1912 trial of the ECOG-ACRIN Cancer Research Group (ECOG E1912),15 and the iLLUMINATE trial.16 The published results of these trials have already impacted the 2019 National Comprehensive Cancer Network guidelines for the patient populations who were evaluated in these trials.17 This article reviews these key findings.


The phase III ALLIANCE trial ( identifier: NCT01886872) evaluated the efficacy of ibrutinib treatment alone and in combination with the anti-CD20 monoclonal antibody rituximab against the standard-of-care chemoimmunotherapy in older patients with CLL: bendamustine (an alkylating agent) plus rituximab.14,17 Sponsored by the National Cancer Institute of the National Institutes of Health,14 ALLIANCE is the first head-to-head trial to compare ibrutinib against bendamustine/rituximab.18 Additionally, the benefit of adding rituximab to ibrutinib has not been established in previous trials. ALLIANCE is the second trial to investigate ibrutinib treatment alone or in combination with rituximab in CLL; the first trial was done in previously treated patients with CLL and results showed no difference in progression-free survival (PFS) or overall survival (OS) outcomes between treatment arms.19

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