Project Term
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Francesco Forconi, MD, PhD, DM, FRCPath
University of Southampton
Southampton,
United Kingdom
Project Summary
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.
Lay Abstract
Hairy cell leukemia (HCL) is a rare blood cancer that affects a type of blood cell called a “B cell”. Around 1100 new cases of HCL are diagnosed every 5 years in the UK. HCL mostly occurs in men during their working life. The disease is named after the “hairy” appearance of the cancer cells under the microscope.
Scientists know that HCL develops and persists because of three key changes in the cancer cells:
1. A mutation called BRAF V600E, which contributes to cancer cell survival and gives them their “hairy” appearance;
2. Too much of a survival protein called BCL2, which prevents the cancer cells from dying when they should;
3. The expression of an immune receptor, called B-cell receptor (BCR), is needed for both healthy and cancerous B-cells to survive and grow. A protein called BTK helps pass these signals inside the cell.
Despite this understanding, current standard treatments for HCL are still based on the use of older chemotherapy drugs, called purine analogs, such as cladribine and pentostatin. These are given through injections or infusions at a hospital, and, while they effectively kill cancerous cells, they also kill healthy cells. This leads to significant side effects, including prolonged immune suppression and bone marrow toxicity.
When the leukemia returns or doesn’t respond to these drugs, treatment options are very limited. Because HCL is rare, there are few clinical trials to test new therapies. Many patients end up receiving the same chemotherapy drugs again, which eventually results in lower response rates and shorter durations of remission.
Recently, targeted oral drugs that block specific survival signals in cancer cells, such as BCL2is and BTKis, have worked well in related blood cancers. These drugs are easier to take and cause fewer side effects. However, when used alone in HCL and other leukemias, they take a long time to clear the disease completely.
This clinical trial will test whether combining a BTKi and a BCL2i can achieve deeper, longer-lasting remissions, potentially eliminating the disease. The aim is to see if a time-limited course of this combination treatment can lead to “curative” results, rather than requiring patients to receive therapy indefinitely. We will also assess the impact of treatment on quality of life.
Researchers will also study how the bone marrow and immune system respond and recover during and after treatment, using both standard blood tests and advanced techniques to look at individual immune cells. Sample and data collections will be shared with other researchers working in the field of HCL to maximize opportunities to accelerate scientific progress.
Ultimately, this study aims to develop a targeted, effective, and shorter treatment for HCL that targets its main disease pathways. These treatments would be easier to take, reduce the risk of side effects, and reduce the impact of treatment on the lives of individuals living with HCL from a health, social, and psychological perspective.
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