Non-chemotherapy Treatment vs Standard Chemotherapy for HCL Patients

Dr. Jae Park is an attending physician and professor at Memorial Sloan Kettering Cancer Center (MSK) in New York City. He treats leukemia and specializes in Hairy Cell Leukemia. During a webinar hosted by the Hairy Cell Leukemia Foundation in April 2025, Dr. Park presented a detailed overview of a game-changing clinical trial he is conducting at MSK that could help bring non-chemotherapy treatment to the frontline for more patients.

 What is Hairy Cell Leukemia?

Hairy cell leukemia (HCL) gets its name because, under a microscope, the cancer cells have projections that look like hair. This disease is quite rare, with only about 600 to 800 new cases diagnosed each year in the United States, compared to approximately 300,000 new cases of breast cancer every year.

 HCL has three main features to look out for:

1.Splenomegaly, which means having an enlarged spleen.

2.Changes in blood counts, which can show up as anemia (having low hemoglobin), thrombocytopenia (low platelet count), and neutropenia (low number of neutrophils, a type of white blood cell).

3.The third feature is the presence of fibrosis in the bone marrow.

In addition, 90% of people with classic HCL have a specific mutation in their hairy cells called the BRAF V600-E mutation. Knowing about these features and the mutation helps scientists develop treatments that target HCL.

 Standard Chemotherapy-Based Treatment, Advantages and Limitations

For over 20 years, the main treatments for newly diagnosed HCL patients have been Cladribine or Pentostatin. Both drugs are forms of chemotherapy given through an IV. These treatments help about 60% to 80% of patients achieve complete remission, meaning their spleen and blood counts return to normal, and no hairy cells are found in the bone marrow. In about 10% to 20% of cases, patients experience partial remission, which means blood counts and spleen size are normal, but hairy cells are still present in the bone marrow. If a bone marrow biopsy isn’t done, doctors refer to it as clinical or hematological remission since it's unclear if hairy cells still exist.

However, Cladribine and Pentostatin are not cures. About 30% of patients might see their disease return, as these treatments improve blood counts but don’t fully remove hairy cell leukemia from the bone marrow. This leftover disease is called measurable residual disease (MRD), and in about 30% of patients, these cells can grow back, leading to lower healthy blood counts.

Another treatment being looked at is a combination of Cladribine and Rituximab, an antibody that targets CD20 (a cell marker). This combo has shown to improve complete remission rates and lower recurrence rates to around 5%.

Keep in mind that these treatments are still forms of chemotherapy, which can weaken the immune system. Usually, blood counts drop at first, putting patients at a higher risk for infections during this time known as the neutropenic or thrombocytopenic phase. Some patients may need to be hospitalized or receive blood transfusions, especially if their blood counts were low to start with. Chemotherapy may cause other cancers, and past chemotherapy might not work again.

Knowing that chemotherapy doesn’t stop the disease from coming back, doctors like Dr. Jae Park are exploring treatments that don’t rely on chemotherapy. One area of research focuses on BRAF mutations, which are found in about 90% of classic Hairy Cell Leukemia cases. This mutation was discovered by Italian researchers Enrico Tiacci and Bruno Falini in 2011. It has been confirmed by various research centers, including Dr. Park’s.

Importantly, the BRAF mutation isn’t just seen in Hairy Cell Leukemia; it’s also present in other types of cancer, such as melanoma. There’s a medication approved by the FDA for melanoma called Vemurafenib, which is being studied extensively and used by doctors off label in hairy cell leukemia.

Initial Clinical Trial using Vemurafenib Alone

A clinical trial was conducted in Italy and at MSK, where patients with a relapse of hairy cell leukemia (HCL) received Vemurafenib, an oral medication. To join the trial, patients had to have more than two relapses. They also needed to show that they didn't respond well to Cladribine during their second relapse. Additionally, participants had to have signs of serious disease, like low levels of neutrophils, hemoglobin, or platelets.

For the trial, HCL patients took the same dose as melanoma patients, which was 960 milligrams twice a day. A total of 49 patients were involved - 24 from the US and 25 from Italy. All patients in the US responded to the treatment. Among them, 42% achieved a complete response, while about 58-60% had a partial response, meaning some HCL cells were still found in their bone marrow. Some patients had recurrent disease, but Vemurafenib is far less toxic than chemotherapy, making it a suitable option for older patients. The oldest participant was 80 years old.

Despite being less toxic than chemotherapy, Vemurafenib does have side effects. The most common ones are a rash and joint pain. Some patients also experienced hair thinning and sensitivity to sunlight. Side effects are classified on a scale from 1 to 5, with lower numbers indicating milder effects. First and second-grade side effects can usually be managed with over-the-counter medications like Tylenol or Motrin. Grade three side effects are more severe and may need treatment with steroids or topical creams. Most patients had low-grade rashes or joint pain, and severe side effects rarely went above grade three. Even though the drug was successful in treating HCL, it didn't completely remove the disease from the bone marrow.

Combining Vemurafenib with Rituximab

Rituximab is an important type of treatment that targets a protein called CD20 on the surface of the cells. Previous studies have shown that when Rituximab is used with Cladribine, it can significantly lower the chances of the disease coming back.

This led Dr. Park and his colleagues to the question of whether combining Rituximab with Vemurafenib could create a treatment option that doesn't involve chemotherapy. In 2021, Dr. Tiacci in Italy looked into this possibility for patients with hard-to-treat conditions. In the study, patients took 960 milligrams of Vemurafenib twice a day for eight weeks, which is about two months. Rituximab was given every two weeks for a total of eight doses, making the overall treatment last for 18 weeks. Amazingly, about 87% of the patients had a complete response to the treatment, and around 90% of these responses showed no minimal residual disease (MRD), meaning there was a lower chance of the disease coming back since it was more completely eliminated.

Vemurafenib with Obinutuzumab as Frontline Treatment

The earlier studies focused on people who had already experienced two or more relapses. But, what about patients who have just been diagnosed?

Dr. Park began studying Vemurafenib combined with Obinutuzumab, instead of Rituximab. Obinutuzumab is in the same category of drugs as Rituximab but is a bit stronger and more effective. Dr. Park aimed to achieve the best possible outcome with deeper remissions, fewer relapses, and, hopefully, a cure.

This study, which the Hairy Cell Foundation supported, was the first to test a treatment plan without chemotherapy for newly diagnosed HCL patients. Patients took Vemurafenib twice a day at a dose of 960 milligrams for about four months. Obinutuzumab was introduced in the second month and given for three months, totaling five doses. Three medical centers were involved in this study: MSK, Dana-Farber, and Yale.

Out of 30 patients, 27 responded well to the treatment. The others left the study because of side effects. Of the 27 responders, 96% showed no signs of HCL in their bone marrow. Among patients with the BRAF mutation, 100% showed no signs of it after treatment.

Since this treatment doesn’t involve chemotherapy, patients didn’t experience a drop in blood counts or harm to normal red blood cells, platelets, or neutrophils. Most patients could be treated on an outpatient basis. Two patients with other health issues needed to be treated in the hospital, but they also completed the regimen successfully.

So far, none of the patients have shown signs of the disease coming back, but since it's only been seven years, monitoring is still important, as recurrences can happen 10 to 15 years later. Some medications, like low-dose prednisone (10 or 20 milligrams), were used to manage side effects, and those issues went away once the treatment ended. Neutropenia, which is a decrease in white blood cells, was seen in 7% of patients in this study, compared to 40% in earlier studies.

It’s important to keep in mind that they used a higher dose of 960 milligrams for this study, like what is used for melanoma. Other studies have used lower doses of Vemurafenib, which seemed to be just as effective but led to more manageable side effects.

Vemurafenib + Obinutuzumab vs. Cladribine + Rituximab

Dr. Park is currently directing a clinical trial in its second phase. This trial is studying Vemurafenib used along with Obinutuzumab in previously untreated patients. It is a randomized study, meaning that half of the participants will receive a treatment that does not include chemotherapy (Vemurafenib used along with Obinutuzumab), while the other half will get the usual treatment of Cladribine and Rituximab. The study is being conducted at multiple locations and is actively looking for newly diagnosed patients to join. Dr. Park and his team believe that combining Vemurafenib with Obinutuzumab will work as well as Cladribine and Rituximab, but will have better safety and fewer side effects.

Learn more about Dr. Park’s research in non-chemotherapy HCL treatment >>

Author Information

We gratefully acknowledge the work of Vivian Lin, 2025 Communications Intern. Vivian is studying Biochemistry and Public Health at Northeastern University.