Project Term
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Project Summary
We will test the first fully oral, chemotherapy-free drug combination that simultaneously blocks two different key survival mechanisms in hairy cell leukemia. First, it blocks the genetic cause of the disease, i.e. the BRAF mutant gene, using the BRAF inhibitor drug vemurafenib. Second, it deprives leukemic cells of their intrinsic ability of resisting natural cell death (apoptosis) by blocking the apoptosis inhibitor BCL2 with the drug venetoclax. We have already tested in patients either drug alone, and found that both have some efficacy and each one has its distinct limitations. By combining them for a short period of time, we aim to develop an overall more effective treatment. Importantly, this approach is designed with patients in mind to also preserve their quality of life and lessen treatment-related social disruption.
Lay Abstract
Hairy cell leukemia (HCL) is a rare chronic hematologic malignancy characterized by progressive decrease of blood counts (hemoglobin, platelets and white blood cells) and enlargement of the spleen, which require treatment with chemotherapy. Our group discovered its genetic cause (i.e., BRAF gene mutation) and additional mechanisms used by the leukemic cells to escape cell death (apoptosis), namely overexpression of the apoptosis inhibitor BCL2. These advances in knowledge led to new therapeutic options, including intelligent oral drugs that specifically target such disease vulnerabilities, in particular vemurafenib that blocks mutant BRAF, and venetoclax that blocks BCL2. We have already tested each of these two drugs alone (as monotherapy) in patients not responding to, or relapsing multiple times after, chemotherapy, and showed that they have good (but incomplete) efficacy, a favorable tolerability profile, and different toxicities, making their combination a rational strategy to improve patient outcomes.
Hence, our goal is to conduct a clinical trial on approximately 25 patients with relapsed or refractory HCL to evaluate this first, entirely oral, chemotherapy-free combination regimen that simultaneously blocks two different key mechanisms driving leukemic cell growth and survival. The treatment schema will include an initial first cycle (1 cycle=28 days) of vemurafenib monotherapy, followed by three cycles of combination therapy with stepwise dose escalation of both drugs, to mitigate venetoclax toxicity on blood counts while ensuring its safe co-administration with vemurafenib. In case of a still suboptimal response, a subsequent brief immunotherapy with the monoclonal antibody rituximab will be administered to achieve a deeper remission and prolong response duration. To ensure that patients’ needs and views are taken into due account, this project entails a patient involvement plan at each stage of the research, and patients enrolled in the clinical trial will also complete questionnaires before, during, and after treatment to gather insights into their reported quality of life, including also treatment-related social disruption. Furthermore, participants will collaborate to interpret the trial results in ways that are relevant and meaningful to their broader community. Finally, patient contributions will be acknowledged in publications and presentations of the trial results, maximizing their real-world value and impact.
The Hairy Cell Leukemia Foundation (HCLF) and Blood Cancer United have joined forces to create the Hairy Cell Leukemia Research Initiative program to support targeted research to build a more comprehensive foundational understanding of the molecular basis of hairy cell leukemia (HCL), develop additional therapies, and optimize outcomes for patients with this disease.
Program
