Chemotherapy-Free Combination Heads to Trial in Hairy Cell Leukemia

Dr. Francesco Forconi, professor of hematology at the University of Southampton in the United Kingdom, is leading a trial that will test a treatment approach without chemotherapy for patients with hairy cell leukemia, a rare B-cell cancer.

In the UK, treatment for hairy cell leukemia currently relies on the chemotherapy cladribine, with or without anti-CD20 therapy. Forconi described these options as “rather obsolete.” Patients who receive cladribine have high rates of infection early in treatment, he explained. Cladribine also damages DNA in healthy cells as well as cancer cells. It is not yet known whether that damage contributes to complications such as second cancers.

The new trial will combine Brukinsa (zanubrutinib), a B-cell receptor inhibitor, with sonrotoclax, a BCL2 inhibitor. Forconi noted that three mechanisms drive hairy cell leukemia:

• a BRAF mutation
• B-cell receptor signaling
• high levels of BCL2, a molecule that keeps cancer cells from dying

Earlier studies have tested drugs against each pathway separately. B-cell receptor inhibitors controlled hairy cell leukemia but could not eradicate it. BCL2 inhibition required a long course of treatment. The two pathways work together inside the cell, so blocking both at once may be more effective, he added.

The goal is to reduce hairy cell leukemia to levels that tests can no longer detect, known as undetectable minimal residual disease (uMRD), within a set treatment period. Each patient’s response will be checked two to three times over 18 months.

The same type of combination is already established in chronic lymphocytic leukemia, the most common leukemia. There it has caused limited side effects compared with chemotherapy, Forconi noted. Giving the combination for a set period rather than continuously aims to keep the risk of long-term side effects as low as possible.

The trial is in development, and the first patient is expected to enroll in the first quarter of 2027. Funding limits enrollment to 20 patients at five centers in England: Southampton, the Royal Marsden in London, Leicester, Leeds and Birmingham.

“It will make a major change,” Forconi said of the combination if the trial succeeds. “It will set any patient with hairy cell leukemia in a completely different mindset.”

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