A Chemotherapy-Free Approach to Hairy Cell Leukemia

CURE: What is the zanubrutinib and sonrotoclax trial for hairy cell leukemia testing?

Francesco Forconi: I am a Professor of Hematology at the University of Southampton, practicing at Southampton General Hospital. I lead a group of investigators studying how cancerous B cells behave, focusing on one specific structure of the B cell: the B cell receptor.

Our trial tests the hypothesis that by blocking two of the three essential drivers of hairy cell leukemia, we can reduce the tumor burden, ideally to a level where hairy cells are no longer detectable for a long time.

The trial also aims to move beyond treatment options in the UK that are rather outdated. Today we use treatments based on a chemotherapy drug called cladribine, with or without anti-CD20 antibodies. But we know from the work of the Hairy Cell Leukemia Foundation and the investigators it supports that there are new options. And we know from our own work how essential the B cell receptor and anti-apoptotic (anti-cell-death) mechanisms are.

So we are testing a non-chemotherapy approach using two drugs: zanubrutinib, a B cell receptor pathway (BTK) inhibitor, and sonrotoclax, a BCL2 inhibitor.

Why do patients with hairy cell leukemia need an alternative to chemotherapy?

Currently, at least in the UK, the approach to hairy cell leukemia is essentially to throw a bomb into the body to kill the tumor cells. This can be quite effective at, at the very least, parking the remaining tumor cells in a corner so they don't cause problems for a long time. But it has both short-term and long-term side effects.

In the short term, drugs like cladribine cause high rates of infection, so patients in the induction phase often experience complications.

In the long term, we are giving a genotoxic drug. It damages the DNA of the hairy cells, as intended, but potentially also the DNA of other cells. We don't know whether this contributes to some of the common complications seen in patients with hairy cell leukemia, such as second cancers.

We want to avoid this approach and use something mechanistically more precise, targeting B cell receptor signaling and the BCL2-driven anti-apoptotic (anti-death) mechanisms.

Why combine a BTK inhibitor and a BCL2 inhibitor for hairy cell leukemia?

Three main mechanisms govern hairy cell leukemia:

1. The BRAF mutation: This genetic change is very important, but on its own it is not enough to cause the disease. BRAF inhibitors are effective, but as soon as we stop them, the disease comes back. So there is something more.
2. BCL2 overexpression: BCL2 is a molecule that prevents hairy cells from dying. In other cancers we understand why BCL2 is overexpressed; in hairy cell leukemia we don't yet know why. But among all B cell cancers, hairy cell leukemia is one where we find it most highly expressed, so it is clearly a target. We explored this with a first-in-class BCL2 inhibitor, venetoclax, in work published in the New England Journal of Medicine. It showed that long-term BCL2 inhibition could eradicate the disease, but it required a long duration of treatment.
3. B cell receptor signaling: Hairy cells express multiple B cell receptor isotypes on their surface, one of my early findings at the University of Southampton. Excellent trials have shown that B cell receptor inhibitors can keep the disease under control, but again, not eradicate it.

At the mechanistic level, we know that B cell receptor signaling and BCL2 cooperate within the cell: B cell receptor signaling switches on anti-apoptotic mechanisms. Blocking both at once suppresses that signal, while the second drug, the BCL2 inhibitor, takes down whatever anti-apoptotic protection remains. That is the rationale for combining a B cell receptor inhibitor with a BCL2 inhibitor.

Could zanubrutinib and sonrotoclax cure hairy cell leukemia?

It is always every doctor's wish to rid every patient of their medical problems. The goal of our trial is to see whether, within a finite treatment duration, we can reduce the disease below detectable levels. This is called undetectable minimal residual disease (uMRD). Whether that means full eradication is another story, but it is definitely the goal.

We believe we can achieve it, so we also want to learn if and when we get there. Patients will have serial response assessments, two or three times over 18 months, to see whether we can remove the tumor burden to undetectable levels earlier in the treatment.

What are the side effects of zanubrutinib and sonrotoclax?

I think patients want to know what we know about this combination: whether it has been used in other trials or other conditions.

The combination of a BCL2 inhibitor with a B cell receptor inhibitor has been used for several years in other conditions. In chronic lymphocytic leukemia (CLL), the most common leukemia, treatment is now built around these two pillars. First-in-class drugs were combined first, and now the same combination of zanubrutinib plus sonrotoclax is causing very limited toxicity, at least compared with chemotherapy.

The possibility of long-term toxicity, which is not established, we aim to eliminate or minimize by giving a finite course of treatment rather than continuous treatment.

So my message to patients is that we strongly believe this combination is not expected to be toxic, because it has not been toxic in other patients who have benefited from it, sometimes with a slightly different strategy and for longer. In those other cancers it was extremely effective and well tolerated. That has also been my personal experience with the patients I have treated this way.

When will the hairy cell leukemia trial open, and where?

The trial is in development. We are working daily with the Southampton Clinical Trials Unit, led by Professor Griffith, to complete the regulatory processes needed to activate it. The protocol is written, and we hope to recruit the first patient in the first quarter of 2027.

Unfortunately, the trial is limited to 20 patients, which is what our funding allows, and it is currently based in the UK. Five centers will operate as hubs, so we cover all of England and make the trial accessible to patients:

• Southampton (lead center)
• The Royal Marsden, London
• Leicester
• Leeds
• Birmingham

What else should patients with hairy cell leukemia know?

Because hairy cell leukemia is so rare, it is difficult to understand at its core, at least compared with what we know about more common B cell cancers. So any effort to foster research in this rare but quite tricky condition, as the Hairy Cell Leukemia Foundation is doing, is a major message we all want to deliver.

Even in advanced, Western countries, there is a strong need to establish standards of care that are not obsolete, so supporting clinical trials is essential. My personal belief is that combining a BCL2 inhibitor with a B cell receptor inhibitor is likely to translate from other conditions to hairy cell leukemia. Any support for investigating how hairy cell leukemia operates through these two pathways deserves deep investigation.

What is there to be hopeful about, and what's next for hairy cell leukemia?

What we have to be hopeful for is that this trial is successful. If the combination of zanubrutinib and sonrotoclax works, it will make a major change. It will put every patient with hairy cell leukemia in a completely different mindset, where hopefully the condition is no longer seen in those living with it.

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