Chronic lymphocytic leukemia: where are we and where are we going?

For decades, chlorambucil was the mainstay of therapy for chronic lymphocytic leukemia. However, based, in part, on the impressive data published by Rai et al. in 2000 [1], fludarabine has replaced chlorambucil as the backbone of front-line regimens. Over the past several years much of the efforts in CLL have been spent identifying the best fludarabine-based regimen. The CALGB compared sequential fludarabine and rituximab (FR) to concurrent FR and found that, although the quality of response was better with concurrent therapy, there was no difference in survival [2]. Keating et al. published impressive results with the addition of cyclophosphamide (C), resulting in the popular FCR regimen [3]. Subsequently, the GCLLSG compared FCR to FC, demonstrating the benefit of the monoclonal antibody by achieving a survival advantage with FCR [4].

Despite its efficacy, fludarabine is associated with considerable toxicity, particularly in the elderly population. Common adverse events include significant myelosuppression and serious opportunistic infections. Less frequently, autoimmune hemolytic anemia and secondary malignancies such as acute myeloid leukemia and myelodysplastic syndrome are encountered. Thus, other effective and less toxic agents are needed.

Bendamustine is a bifunctional alkylating agent with demonstrated activity in CLL. Chang and Kahl have provided us with a thorough review of its emergence as a valuable treatment option in this disease [5]. Bendamustine was approved by the FDA for CLL based on the results of the randomized Phase-III trial by Knauf et al. Bendamustine proved to be superior to chlorambucil in terms of complete and overall response rate, progression-free survival, as well as exhibiting a more favorable toxicity profile [6]. The GCLLSG showed that the combination of BR in previously untreated patients produced impressive response rates, even in poor risk cytogenetic groups [7]. We are awaiting the results of the GCLLSG CLL-10 trial which will determine whether BR has comparable efficacy to FCR while being more tolerable in previously untreated patients.

Perhaps the most significant breakthrough in lymphoid malignancies was the development of the monoclonal antibody, Rituximab. Over the past few years there have been several attempts to further expand the role of immunotherapy. These include the development of newer antibodies against a various B-cell surface markers as well as antibody-related molecules. Ofatumumab, a CD20 antibody with a slightly different mechanism of action profile than Rituximab, is approved for patients with disease that is refractory to fludarabine and alemtuzumab [8]. Other antibodies being studied include GA101 which also targets CD20 and Medi-551 which is directed against CD19. Drug-antibody conjugates including the anti-CD22, DCDT2980S, are also in Phase-I clinical trials.

Lenalidomide has provided promising data both in the relapsed and refractory and upfront settings [9,10]. Lenalidomide is an immunomodulatory agent that has a number of actions, including targeting NF-κB, inhibiting angiogenesis, and manipulating the tumor microenvironment. In a single-arm Phase-II study lenalidomide consolidation improved the complete response rate after FR induction [11]. We are awaiting the results of the Phase-III intergroup study in which previously untreated patients are randomized to FR induction alone, FR induction followed by lenalidomide consolidation, or FCR induction. All patients with the deletion 11q abnormality will be switched to FCR induction after cycle 1 followed by lenalidomide consolidation, addressing the need for alkylating therapy in this subgroup.

The most current excitement in CLL has been generated by novel small molecules that target various intracellular pathways of the malignant B-cell. Bruton tyrosine kinase (BTK) is a down-stream mediator of B-cell antigen receptor (BCR) signaling which is essential for the initiation and maintenance of B-cell malignancies. Ibrutinib is a BTK inhibitor that produces impressive responses in relapsed and refractory CLL with minimal toxicity [12]. Phase-II studies of ibrutinib in combination with Ofatumumab, FCR, and BR in CLL are ongoing. Similarly, GS-1101, formerly known as CAL-101, is an inhibitor of phosphatidylinositol 3-kinase p110δ (PI3K-δ). PI3K-δ is overexpressed in B-cell malignancies and plays a key role in cancer cell proliferation and survival. By targeting this pathway, GS-1101 has demonstrated notable responses in relapsed and refractory CLL [13]. GS-1101 is now in phase III investigation in combination with Rituximab and BR in previously treated CLL.

Allogeneic stem cell transplantation remains the only possibility of cure in CLL. It continues to have a role in certain high-risk situations, such as young patients with del 17p, but is not an option for the majority of patients with CLL. With the arrival of these new agents we must reconsider our current treatment algorithms. Is fludarabine still the correct choice in previously untreated patients? As more patients are treated with bendamustine-based therapy up-front, what is the appropriate therapy in the second-line setting? How do we incorporate these newer targeted agents? Given the otherwise incurable nature of this disease, are we able to postpone the need for cytotoxic chemotherapy, particularly in the elderly with comorbidities and poor performance status? Will combinations of these small molecule inhibitors and immunotherapy be sufficient enough of a regimen, or do we need to combine them with chemotherapy for maximum benefit? Can unique combinations of these novel agents be developed to benefit patients with high-risk cytogenetics or multi-drug resistance disease? The results of ongoing and upcoming trials may well answer these questions in the near future. Correlative studies including gene expression profiling, evaluation of protein expression, and examination of downstream signaling pathways are being performed in conjunction with these trials in order to determine which patients will benefit the most from each of these therapies. A better comprehension of the biology of these diseases should allow us to replace conventional chemotherapy with the proper combination of these various targeted agents, to individualize therapy, to prolong patient survival, and, hopefully, lead to the elusive goal of cure.

Declaration of interest

BD Cheson has received funding from Genentech, Teva, Celgene, Pharmacyclics and Gilead. C Ujjani declares no conflict of interest.