Targeted Therapy vs. Chemo in Hairy Cell Leukemia

Dr. Seema Bhat is a hematologist in the Division of Hematology at The Ohio State University Comprehensive Cancer Center, where she specializes in chronic lymphocytic leukemia (CLL) and hairy cell leukemia (HCL). She is leading an NCI-sponsored trial of tovorafenib plus rituximab, which will compare that combination head to head with standard cladribine plus rituximab in newly diagnosed patients. We spoke with her about the trial, quality of life, and how patients can take an active role in their care.

This interview has been edited for length and clarity.

CURE: Why specialize in CLL and a rare cancer like hairy cell leukemia?

Dr. Bhat: My areas of expertise are chronic lymphocytic leukemia and hairy cell leukemia. There was a lot happening in CLL when I started practicing. New drugs were being developed, and treatment was shifting from chemoimmunotherapy to targeted therapy. Patients were doing much better, with fewer toxic side effects. It was exciting to be part of a complete paradigm shift.

Hairy cell leukemia is very rare. Fewer than 1,000 people are diagnosed in the United States each year. When I was a fellow, I saw a patient with my mentor, and he told me to go through the history very carefully, because I might see only one or two cases in my whole career. That's how rare it is.

A general oncologist or hematologist in the community may not see many cases, which means there are knowledge gaps. They may not be up to date on the latest treatments or research. That drew me to this disease. Cladribine and other purine analogs have long been the mainstay of treatment, but we are moving toward targeted therapy. Combining a targeted agent with an anti-CD20 antibody lets us avoid the toxicity of purine analogs while keeping the strong responses. I think we are at that same paradigm shift in HCL now.

What is the tovorafenib and rituximab trial for hairy cell leukemia?

I'm working with a compound called tovorafenib. It was approved recently for a different disease, pediatric low-grade glioma, where it was very effective.

In classic hairy cell leukemia, we see the BRAF V600E mutation. There is excellent data on vemurafenib, including vemurafenib with obinutuzumab, with stellar response rates. But vemurafenib comes with its own problems: skin toxicity and rashes, arthritis and joint pain that affect quality of life, a risk of second cancers, especially skin cancers, and liver toxicity. We always say a targeted agent is better than chemotherapy for side effects, but it has its own side effect profile. In the frontline study published in the New England Journal of Medicine, 97% of patients needed a dose reduction because of toxicity.

Tovorafenib is a pan-RAF inhibitor, so it acts against BRAF V600E. Based on the studies so far, especially in pediatric low-grade glioma, its toxicity profile looks very favorable.

There's another reason. Even though vemurafenib is in the guidelines, it isn't approved for hairy cell leukemia. We still have to go through the hoops of insurance approval, and sometimes it's denied and we have to justify why we want to use it. We want a targeted agent that is approved specifically for HCL.

The study, sponsored by the National Cancer Institute, has two parts. The first is a phase 1 study in relapsed or refractory patients, combining tovorafenib with rituximab. Its main aim is safety, though we also want early efficacy data.

Once that part is complete, we move to the frontline setting, and I'm really excited about that because it's randomized. Patients who have never been treated and need treatment will be randomized to tovorafenib plus rituximab or cladribine plus rituximab, so we can compare them head to head. We've already treated one patient at our institution. I'm hoping we open the trial at more sites so enrollment moves faster and we can complete the study.

How can patients maintain quality of life with hairy cell leukemia?

Quality of life is paramount in both diseases I treat. Both are chronic, relapsing leukemias. They aren't curable, so patients with CLL and hairy cell go through multiple treatments over their journey. Treatments have improved, but they still have side effects.

We want our patients to live well with their leukemia, and living well isn't just controlling the disease. It means living like you and I do. If they're employed, they keep their jobs. If they're retired, they enjoy the things they love and have a good time with family. Targeted agents have gotten us to the point where many side effects are reduced.

We also want to limit drug exposure, using treatments for as short a time as possible. That means finding more effective combinations: a couple of months of treatment for hairy cell, or a year for CLL. Patients go into a very deep remission and go back to living their lives.

Quality of life also means preventing infections, which are a big risk for patients with both HCL and CLL. I'm very invested in improving vaccine responses, and I have an ongoing CLL study on improving responses to the pneumococcal vaccine.

Fatigue is another major issue in my clinic. Whether patients are untreated or on treatment, they bring it up again and again, and it keeps them from enjoying life. There are studies on supplements and on exercise, and we're looking into all of these approaches to improve fatigue.

How do doctors choose a hairy cell leukemia treatment?

Knowledge is power. It is a tool in the hands of the patient. Know your disease, know your options, and come prepared to ask questions when you sit down with your physician. What fits one patient may not fit another, based on their other health conditions or how they approach treatment. Some of my hairy cell patients simply don't want chemotherapy and would rather go with targeted therapy.

My role is to guide them to the right treatment. We now have two effective treatments. Hopefully we'll have head-to-head data in the coming years from our study and from one at Memorial Sloan Kettering. Until then, I look at the patient's preferences and other health conditions, and we make a shared decision on the most appropriate treatment.

The Hairy Cell Leukemia Foundation is a very important resource. It has a lot of information, and it connects patients with peers who have similar conditions and can share what their journey was like.

How should patients prepare for a hairy cell leukemia appointment?

Patients often travel long distances to see their physician, so that investment should be worth it.

1. Bring someone with you. The first appointment can be overwhelming. Patients are already anxious, and they get flooded with information. Another set of ears helps. The patient may forget something, but a caregiver or family member can remember what was or wasn't discussed.
2. Know your disease and come prepared. Bring your symptoms and what's bothering you. If treatment has been discussed, ask about the different options.
3. Ask about resources. Targeted therapies are not getting cheaper. Ask what help is available. We have copay assistance programs and grants we can apply for to help with costs. Asking these questions lets us know your needs so we can address them.

How do language and culture affect coping with a cancer diagnosis?

Besides English, I speak Kashmiri and Urdu. I haven't yet had a patient in my clinic who shares those languages with me. But we have many Spanish-speaking patients and physicians who speak Spanish, and there is a real connection when you speak in the patient's language. If I have a Spanish-speaking patient, I may bring a Spanish-speaking staff member with me so we can overcome any barrier.

Having something in common creates a connection. When there's no shared language, I find other ways, like shared interests. If a patient loves gardening, we connect on gardening. One of my colleagues connects with patients over pets. We're in Ohio, so we're big football fans and connect over games.

At the end of the day, we're talking about a serious disease, and patients can arrive very anxious. My job is to keep them as relaxed as possible, because the more relaxed they are, the more receptive they are to information. That human touch is very important in our clinics.

Is there a cure for hairy cell leukemia?

The goal is always better care for our patients. This trial is not going to be a cure. Until we cure cancer, I don't think any oncologist or researcher is done, and the goal of research should always be to eventually cure the disease.

My goal with tovorafenib and rituximab is better quality of life: treatment that isn't as harsh, without compromising on efficacy. Getting to a cure someday will remain an ongoing aspiration for most researchers.

What new hairy cell leukemia treatments are being studied?

The afternoon session will be very interesting. We just finished a session on CAR T-cell therapy. Beyond purine analogs and BRAF inhibitors, other treatments are being studied, including CAR T and combinations of BRAF inhibitors with other agents. For example, one study being presented combines a BRAF inhibitor with a BCL-2 inhibitor. These concepts need further development, and hopefully we can use them someday for patients with hairy cell leukemia.

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