Why Rituxan Plus Cladribine May Delay Hairy Cell Leukemia Relapse

Research from the National Institutes of Health (NIH) suggests that giving Rituxan (rituximab) at the same time as cladribine, a type of chemotherapy known as a purine analog, may lead to deeper remissions for patients newly diagnosed with classic hairy cell leukemia, a rare blood cancer that often returns years after treatment.

In an interview with CURE, Dr. Yoonhee Choi, a third-year hematology oncology fellow at the National Cancer Institute (NCI) at the NIH who conducts research with Dr. Robert Kreitman, discussed the work she presented at [EVENT], which will also be presented at the American Society of Hematology (ASH) Annual Meeting. She explained what complete remission means in hairy cell leukemia, which patients may be best suited for the combination and where research is headed next.

This interview has been edited for length and clarity.

What is the outlook for patients with classic hairy cell leukemia?

Choi: Patients with classic hairy cell leukemia have a normal life expectancy, and a lot of physicians, and people out there, think it's an indolent [slow-growing] disease that doesn't need attention anymore. However, 30% to 40% of patients relapse within 10 to 15 years and require the next line of treatment. That can lead to secondary malignancies, immune suppression, infection and all kinds of treatment-related toxicities that can impact their quality of life. So I think it's important to have a deep remission in the front-line setting that can buy them 10 to 20 years before they require another treatment.

What did NIH research on cladribine plus Rituxan in hairy cell leukemia evaluate?

Choi: The work at NIH is to see if giving rituximab concurrently with cladribine can lengthen progression-free survival [the time patients live without their cancer worsening], relapse-free survival and time to next treatment. A 2020 paper from a randomized cohort compared concurrent cladribine and rituximab versus cladribine followed by delayed rituximab if [a patient's minimal residual disease (MRD)] became positive. It showed that complete remission without MRD is much higher with the concurrent regimen than with delayed rituximab or cladribine alone. So I think it is important to give patients who are newly diagnosed both cladribine and rituximab. Rituximab is given once a week, for eight doses in total.

How does Rituxan help cladribine work against hairy cell leukemia?

Choi: Rituximab is a CD20 antibody that targets the CD20 [protein] on hairy cells, which can potentially help clear the residual disease that cladribine could not. On top of that, rituximab increases the sensitivity of hairy cell leukemia cells to purine analogs, meaning cladribine or pentostatin, which has been studied in vitro [in the lab]. Adding rituximab lowers the threshold of the mitochondrial apoptotic pathway [the process cells use to self-destruct], which essentially makes the cells more likely to die from purine analog treatment.

What does complete remission mean in hairy cell leukemia, and how is MRD different?

Choi: Classic hairy cell leukemia is characterized by low blood counts, including white cells, platelets and hemoglobin, but also splenomegaly [an enlarged spleen]. In order to be in complete remission by the 2017 guidelines, these all have to be normalized. The blood counts have to be normalized, with an ANC [absolute neutrophil count, a measure of infection-fighting white blood cells] above 1,500 and hemoglobin above 11, along with resolution of the spleen size and no morphologic evidence [visible signs of hairy cells] in the bone marrow or the peripheral blood.

MRD is looking at something that can't be captured with these methods. It's below that level, so we're trying to capture what's left in the bone marrow or the blood with sensitive methods, such as multiparameter flow cytometry and bone marrow immunohistochemistry, looking at different stains. Patients can be in complete remission but still have residual disease that a microscope cannot detect.

How do results with cladribine plus Rituxan compare with earlier hairy cell leukemia data?

Choi: It's not a direct comparison, but we do have the randomized trial data from 2020, and Royal Marsden Hospital also published their data in 2009. It's hard to compare apples to oranges, but the two had a similar follow-up time. In our data, only one patient out of 68 relapsed, whereas in the Royal Marsden series, among 90 patients, 28% relapsed, which is a much higher number. So we do believe that adding rituximab on day one can lengthen the time until the next treatment.

Why does long-term follow-up matter in hairy cell leukemia research?

Choi: Hairy cell leukemia is an indolent disease. In many of these studies, there's not much of an overall survival difference, because it's such a rare disease that it's hard to have the power to see the difference, and disease progression is usually slow. Even if you're MRD positive, it may take years before you fully relapse clinically and need another treatment. That's why it's important to follow these patients long term, and we have a great opportunity to compare with UK data that followed patients for almost 40 years. It has been a great resource.

What side effects have been seen with cladribine plus Rituxan in hairy cell leukemia?

Choi: There were multiple discussions throughout the session today about whether adding rituximab could have other side effects, which have been shown in other cancers, like infection or secondary malignancies. Those have not been reported much so far in our study. It doesn't seem like patients who received the concurrent treatment had more side effects than those who didn't. However, it was a controlled study, and these patients were newly diagnosed and otherwise healthy. In the real world, it might impact patients' immune recovery or cause secondary toxicities, so I'm going to focus my future project on that aspect, to see if they have more infections or more malignancies.

It's also important to look at real-world patients who have failed other treatments before going on to [cladribine and rituximab]. There are going to be differences in patient demographics, and the patients who come to NIH are usually very motivated, so there might be a selection bias compared with real-world patients.

Which patients with hairy cell leukemia are good candidates for cladribine plus Rituxan?

Choi: When we presented today, there was a discussion that everyone knows cladribine plus rituximab has great efficacy, but at the same time, it has its own toxicity, especially with cladribine. Cladribine can lead to severe immune suppression, and some patients end up in the hospital for a long period of time, so not all patients may be fit for this regimen. We recommend cladribine and rituximab for younger patients who are fit and don't have a lot of comorbidities [other health conditions]. With elderly, frail patients, we might have to think more about targeted therapy. But again, these patients are expected to have a normal life expectancy, so I think it's important to have longer disease control as much as possible for younger patients, and adding rituximab makes sense for them.

Why do patients with hairy cell leukemia need advocacy?

Choi: Overall, patients with hairy cell leukemia are a bit neglected compared with [patients with] other cancers, because they have better outcomes than other lymphoid malignancies. However, it's still described as an incurable disease, and they need multiple lines of treatment throughout their lives. It is important to understand patients' concerns and try to advocate for them. It's hard to get [U.S. Food and Drug Administration (FDA)] approval or attention for a new drug for patients with hairy cell leukemia because of the rarity of the disease. The NIH team will certainly try to advocate for them as much as possible through trials, research and clinical care.

What is next for hairy cell leukemia research?

Choi: Although we know about the BRAF mutation in hairy cell leukemia, there are other variants with different mutations, and we're still working on reaching a consensus about the different types. Because it's a rare disease and hard to have patients on a trial, I think it's important to work together and discuss different cases. One of the concerns brought up at this meeting was how to classify or treat [patients] differently within hairy cell leukemia variant. That's still kind of a mystery that needs to be studied in the future.

We have an exciting trial using CD22 CAR T-cell therapy [a treatment that reengineers a patient's own immune cells to attack cancer] in hairy cell leukemia and hairy cell leukemia variant that we are hoping can be a potential cure.

I think there are two things to be hopeful for. One is to find a way to cure hairy cell leukemia. Although we have great disease control, we still don't have a curative therapy, and I think cellular therapy can play a big role in that. Second is to minimize the toxicity of treatment. BRAF inhibitors [targeted drugs that block the mutated BRAF protein] work great, but at the same time, they have toxicities in the skin and joints, as well as concerns for secondary malignancies. It's important to continue to work to minimize that, and those will be our future directions.

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