Advances in Hematologic Malignancies
Issue 11, Fall 2019
— Jennifer Crombie, MD, and Matthew Davids, MD, MMSc
Several novel therapeutic agents have recently been approved for patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Although these new drugs can be effective as
single agents, complete response (CR) rates with monotherapy are typically low, and responses are not durable in many patients. Furthermore, treatment with novel agent monotherapy typically requires indefinite treatment, which is associated with a
prolonged risk of toxicity, development of resistance, and enormous cost.
To address these issues, we are conducting a multicenter, phase 1/2 trial of duvelisib, a small molecule dual inhibitor of PI3K-δ and PI3K-γ, plus venetoclax, a BCL-2 inhibitor, for patients
with relapsed/refractory (R/R) CLL or SLL. Duvelisib and venetoclax, which are FDA-approved individually for the treatment of R/R CLL/SLL, are well-tolerated therapies that target pathways fundamental to CLL biology. Additionally, these drugs
provide an all-oral regimen with a convenient treatment schedule.
In this study, we aim to determine the rates of CR and minimal residual disease (MRD) negativity with this combination. Patients who achieve MRD negative CR after at least one year of duvelisib plus venetoclax combination therapy will have the option
to discontinue treatment with close monitoring and re-initiation of therapy for recurrent disease. This strategy has the potential to be paradigm shifting in the management of CLL/SLL, with deeper responses alleviating the need for lifelong therapy,
reducing the risk of toxicity, and also possibly decreasing resistance to therapy.
In the study, we will also be evaluating the combination of duvelisib plus venetoclax in a cohort of patients with Richter’s syndrome (RS), in which CLL has transformed to diffuse large B-cell lymphoma (DLBCL). RS is associated with extremely poor outcomes
and is in urgent need of novel treatment options.
This investigator-initiated study is being supported by Verastem Oncology, which is also providing duvelisib at no charge to participants. The co-principal investigators are Matthew Davids, MD, MMSc, and Jennifer Crombie, MD, of Dana-Farber's Center for Chronic Lymphocytic Leukemia,
and the phase 2 portion of the study will be opening at several additional sites across the United States through the Blood Cancer Research Partnership,
with funding from the Leukemia Lymphoma Society.