Research we fund

This collaborative program investigates why Hairy Cell Leukemia (HCL) and its variant often relapse despite effective therapies and why bone-marrow fibrosis frequently persists after treatment. This proposal examines fibrosis as both a biomarker and a biological driver of disease. Project 1 determines whether persistent scarring predicts relapse and uses human bone-marrow organoid cultures to test how leukemia and stromal cells interact. Together, these studies connect patient data and experimental systems to reveal how fibrosis contributes to disease persistence in HCL and HCL-v.

Hairy Cell Leukemia (HCL) is a rare blood cancer that affects white blood cells. The usual first treatment is with drugs called purine analogs (PAs). While PAs work well initially, their efficacy decreases with each treatment round, they cause long-lasting immune suppression and increase the likelihood of developing serious infections.

Therefore, safer treatments that can control or even eliminate the disease, and allow the immune system to recover are urgently needed. New targeted oral therapies offer a promising alternative to chemotherapy, and those that induce apoptosis (BCL2 inhibitors) or inhibit B-cell receptor signaling (BTK inhibitors) have shown single-agent activity and excellent tolerability in HCL patients. However, alone, they often result in incomplete responses and require long-term administration. We will test if combining a BTK inhibitor (zanubrutinib) with a BCL2 inhibitor (sonrotoclax) can achieve deeper, longer-lasting remissions and allow treatment to stop after a fixed period rather than continuing indefinitely.

We will examine responses after 6, 12, and 18 cycles (a cycle is 28 days) to assess how quickly the disease resolves and how deep the response is. We will monitor immune recovery using blood tests and advanced techniques to investigate how the treatment affects any remaining leukemia cells.

The ultimate goal is to determine if this drug combination can eliminate HCL and how long treatment needs to continue to achieve this result.

Patients with B cell malignancies who do not fall into a distinct pathological disease category pose a challenge for patient care, and patient classification has been exacerbated by the recent emergence of two separate classification systems. Genome-wide DNA methylation is a stable and information-rich biomarker that has been successfully used to classify other cancer types, however remains understudied in hairy cell leukemia and related splenic B cell lymphoma and leukemia. In this proposal we will investigate the utility of DNA methylation to establish a novel, unbiased, biologically-based classification paradigm for hairy cell leukemia, with a focus on the variant subtype, and investigate novel mechanisms and etiology underlying these rare leukemia patients.

We aim to determine if rigorous assessment of quality of life (QOL) can help with treatment decisions for hairy cell leukemia (HCL). We will first analyze a robust HCL patient database to understand QOL trajectories among patients before they need initial treatment or relapse, as well as among specific subgroups such as those who are younger (75), and those who or working. We will then then utilize a patient-driven consensus process to determine which QOL instruments most accurately reflect experiences when facing treatment or re-treatment. Finally, we will engage 30 HCL patients nearing treatment or re-treatment, measure QOL, and provide results for discussion with providers, measuring feasibility and preliminary impact of this approach.

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.

Most of the Hairy Cell Leukemia variant patients do not respond to conventional therapies. They develop resistance to the chemotherapy drugs and we will investigate why this happens. Our data shows that a protein called BAFF is playing a key role in providing additional survival advantages to these patient cells to resist therapies. We will develop new treatment methods by targeting this protein in order to make these patients sensitive to therapy and to improve clinical outcome.

We have long standing experience in the field of HCL research. The aim of this research proposal is to characterize HCL on single cell level across multiple layers to uncover interactions of HCL with its microenvironment, which supports HCL cell survival. We will further explore metabolic and functional dependencies of primary HCL cells, and we hypothesize that their attenuation compromises HCL cell survival. Finally, we aim to pharmacologically disrupt these pro-survival pathways in HCL cells.

Hairy cell leukemia (HCL) is very sensitive to chemotherapy, whose toxicity to the bone marrow and the immune system is however concerning. We have established vemurafenib plus rituximab as a very effective chemotherapy-free regimen in relapsed/refractory HCL (NEJM, in press). Here, we will test it in a clinical trial against a chemotherapy-based standard of care represented by cladribine plus rituximab, aiming at lower toxicity and similar efficacy.

In this proposal, we have combined clinical and research expertise in HCL across Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, the University of Pennsylvania, and Yale University to develop newer targeted therapeutics for every stage and subtype of hairy cell leukemia. Capitalizing on this combined expertise, our proposal stands to significantly advance treatment strategies for hairy cell leukemia through the following aims: to test BRAF inhibition for initial treatment of classical hairy cell leukemia, test new oral inhibitors of the MAP kinase signaling pathway known as ERK inhibitors in both classical and variant hairy cell leukemia, evaluate totally new treatments that degrade BRAF, and develop T-cell immunotherapies for the first time in hairy cell leukemia.