Hairy cell leukemia (HCL) is a relatively rare type of leukemia that results when the bone marrow produces too many lymphocyte clones with specific features, including fine membrane projections visible under a light microscope. The hematologic disorder was first described in 1958,1 and the median survival remained low — about four years — for nearly three decades.2 Then, in the 1980s, the development of purine analog chemotherapy, pentostatin, and cladribine led to durable remissions among patients with HCL and a near normal lifespan for many.3
The current front-line standard of care (SOC) for patients with HCL is cladribine or pentostatin with or without concurrent rituximab, an anti-CD20 monoclonal antibody, weekly for eight doses. Cladribine is used more often because the treatment can be completed in five to seven days compared to pentostatin, which is given every two weeks for about three months.
“This is a finite therapy. Most patients do well with this combination, especially younger patients. So the argument is, why develop other drugs in this setting? However, the chemotherapy has its own side effects, particularly an increased risk of infections and prolonged immunosuppression, and some patients still do relapse as much as a decade to 15 years after this treatment,” said Jae Park, MD, a hematologist who specializes in treating leukemias, including HCL, at Memorial Sloan Kettering (MSK) Cancer Center in New York.
When one of the purine analogs is used as a monotherapy, approximately half of treated patients relapse, with some becoming refractory to these chemotherapy agents. Fewer patients relapse after treatment with the fixed-duration combination of cladribine plus rituximab, but the cladribine can be toxic, so the need for additional therapies remained.
An opportunity to test a new class of targeted therapy in HCL came in 2011 when researchers identified a key and targetable molecular driver of the disease — the BRAF kinase. Using whole-exome sequencing, researchers identified the BRAFV600E mutation in 98% of patients with HCL.4 BRAFV600E was already a known oncogenic mutation that had been identified in 60% of melanoma cases,5 and BRAF inhibitors were made available for metastatic melanoma in 2011 following the U.S. Food and Drug Administration’s approval of vemurafenib.
Initially, vemurafenib was shown to be effective as a finite course of therapy among patients with relapsed or refractory HCL in phase II trials in Italy and the U.S.6
More recently, in 2023, Dr. Park and his colleagues published the results of their phase II clinical trial testing the combination of vemurafenib plus obinutuzumab, a second-generation anti-CD20 monoclonal antibody, in patients with previously untreated HCL.7
“This was an excellent paper and a very provocative study that, for the first time, showed, in the front-line setting, the effectiveness of the first chemotherapy-free regimen for the initial treatment of HCL,” said Robert J. Kreitman, MD, a senior investigator and medical oncologist at the Center for Cancer Research at the National Institutes of Health in Bethesda, Maryland, who specializes in the treatment of HCL and who was not involved in the clinical trial.
ASH Clinical News spoke with Dr. Park, Dr. Kreitman, and other experts about the diagnosis and treatment of HCL, including the new chemotherapy-free combination option of vemurafenib plus obinutuzumab for newly diagnosed patients.
Diagnosis and Workup
“HCL is quite rare, and the number of these patients at any one oncology practice is limited. In Canada and the U.S., besides a few experts, most physicians have limited experience with this type of leukemia, especially in the relapsed setting,” said Versha Banerji, MD, a hematologist specializing in leukemias who is an associate professor at the University of Manitoba and a clinician scientist at the Paul Albrechtsen Research Institute at CancerCare Manitoba in Canada.
HCL is an indolent low-grade B-cell lymphoid malignancy that comprises about 2% of all leukemia cases.8 Approximately 1,300 new cases of HCL are diagnosed in the U.S. annually.9 The ratio of affected men to women is about 4:1, and the median age of diagnosis is 55 years. “The prevalence is relatively high, possibly in the tens of thousands in the U.S. as the lifespans of SOC-treated patients have a good prognosis, and many patients have residual disease,” Dr. Kreitman said.
“The age range at diagnosis is wide, with patients being diagnosed in their 30s and 40s, and even their 20s, as well as older patients. There are about four cases diagnosed per day in the U.S.,” said Dr. Kreitman, whose clinic focuses on HCL and who has 500 to 1,000 patients with HCL he continues to follow, including more than 400 who remain in remission.
Patients typically present with issues secondary to low blood counts, including bleeding, fatigue, or infection. They often have an enlarged spleen and have a characteristic bone marrow. “If you have a patient with all of these findings or at least two, you need to consider HCL,” said Richard Stone, MD, director of the adult leukemia program at Dana-Farber Cancer Institute in Boston.
“Patients also often present with atypical infections as a result of a compromised immune system. These are not the standard febrile neutropenic infections, so it also becomes difficult to treat these patients with an active infection with chemotherapy, which is why new chemotherapy-free regimens of BRAF inhibitors are so welcome. Adding obinutuzumab will help with the depth of response and the duration of remission long term,” Dr. Banerji said.
HCL may not be at the top of clinicians’ minds, so the diagnosis may take months, according to Dr. Banjeri. Patients’ blood is initially analyzed by flow cytometry, which can detect circulating B cells with cytoplasmic projections that give them a hairy appearance. Because the BRAFV600E mutation is seen in about 98% of classic HCL cases, patients’ cells should also undergo immunohistochemistry analysis or PCR sequencing to detect the mutation. Morphology, flow cytometry, and molecular testing are all necessary to come to an accurate diagnosis.
A distinct HCL variant (HCL-V) is unique from classic HCL, is more aggressive, has a poor response rate to the SOC purine analog chemotherapy, and lacks the BRAF mutation.
Indolent Disease: Deciding When to Initiate Therapy
“HCL is often indolent, and patients can be followed without therapy initially in many cases, depending on the patient’s blood cell counts,” Dr. Stone said. “There is some controversy on how low the counts must be to warrant therapy in an asymptomatic patient.”
Dr. Kreitman agreed. “I find that clinicians tend to push patients to begin therapy as soon as possible, even if their blood cell counts are not that bad. We generally follow the one, 10, and 100 rule, which is that we initiate therapy only if a patient’s platelet count is less than 100, hemoglobin count is less than 10, or the neutrophil count is less than one. Many patients jump into therapy too quickly before figuring out the molecular features of their disease and what treatment is best,” he said. For example, patients who have HCL-V will not respond well to cladribine therapy alone or to a BRAF inhibitor.
An Effective SOC Therapy for Treatment-Naïve Patients
Most hematologists agree that the current SOC for newly diagnosed patients is cladribine with or without rituximab. In a 68-patient clinical trial, at six months, cladribine plus concurrent rituximab resulted in a 100% complete response (CR) rate in patients with classic HCL who were purine analog-naïve compared to an 88% CR rate in patients who received cladribine monotherapy (p=0.11). The median patient age was 48 years. Measurable residual disease (MRD)-free CR rates were 97% compared to 24% in the combination versus monotherapy arms (p<0.0001), and blood MRD-free rates were 100% versus 50%, respectively (p<0.0001). After a median follow-up of 78 months, 94% versus 12% remained MRD free in the two arms, respectively. Overall, the delayed rituximab regimen, begun at least six months after cladribine if and when MRD was detected, achieved an acceptable rate and durability of MRD-free CR but was lower compared to the concurrent approach (67% of 21 evaluable patients; p=0.0034; p=0.0081, 0.094 hazard radio favoring the concurrent combination). These results, from a phase II randomized trial, were published in 2020.10
“We designed the trial to measure blood MRD positivity to know which patients should receive the delayed rituximab because in the real world, many patients don’t get bone marrow biopsies frequently or at all after treatment,” said Dr. Kreitman, who is the senior author and principal investigator on the trial. Patients have continued to be followed to understand whether any will need follow-up treatment.
Patients in the concurrent therapy arm experienced more grade 3-4 thrombocytopenia (59% vs. 9%; p<0.0001) and platelet transfusions without bleeding (35% vs. 0%; p=0.0002), yet higher neutrophil (p=0.017) and platelet (p=0.0015) counts compared to cladribine alone at four weeks.
“These results are extremely good. We don’t see patients relapsing with MRD long term,” Dr. Kreitman added.
“For younger patients with a longer life span especially, we favor this [concurrent] combination because of how well it works — the response rate is 90% to 100% — such that only about 80% of patients stay in remission and don’t have to get a second treatment,” Dr. Park said.
“Concurrent treatment may be advantageous for older patients as well, due to the more rapid recovery of platelets and neutrophils and the lower chance of relapse later when patients are even older and less able to handle treatment,” Dr. Kreitman noted.
An Emerging Front-Line Chemotherapy-Free Regimen
“The argument is against developing new front-line therapies. Why develop other drugs in this setting if the SOC works well?” Dr. Park said. “But the chemotherapy has side effects including immune suppression that can last for a year, and some patients require blood transfusions, and some have bleeding complications and more infections.”
Chemotherapy also comes with a risk of developing secondary cancers. “For younger patients who will likely live a long life, they are more likely to experience the long-term negative effects from the chemotherapy. So, the impetus for our study was to see if we could replace the SOC chemotherapy with a truly chemo-free regimen,” Dr. Park said.
“We had previously tested vemurafenib monotherapy in the relapsed setting and showed that it worked well,” he added.
Starting in 2018, Dr. Park and his colleagues enrolled 30 patients with previously untreated HCL at nine sites in the U.S. into their single-arm, phase II clinical trial testing a 960 mg twice-daily dose of vemurafenib in 28-day cycles for four cycles concurrently with obinutuzumab at 1,000 mg/day starting on days 1, 8, and 15 during cycle 2 and then every four weeks during cycles 3 and 4.10
Three patients discontinued the study early because of adverse events (AEs). Of the 27 patients who completed the regimen, 100% achieved a CR, and 26 patients achieved MRD-negative status. At a median follow-up of 34.9 months, no patient experienced disease relapse.
The most common AEs related to vemurafenib were rash and arthralgia. Febrile neutropenia also occurred in two patients, and two patients required blood or platelet transfusions.
“This combination doesn’t have the prolonged immunosuppression, neutropenic fever, nadir in blood counts, and hospitalizations that are associated with chemotherapy,” Dr. Park said. “The regimen is completely outpatient, while cladribine is often given inpatient, especially for those patients who present with low blood counts and infections. Because many patients with HCL present with infection, this is a good alternative to cladribine as, unlike cladribine, it can be given while the patient has an infection.
“I believe the health care cost utilization will be better for this regimen compared to cladribine because of lower rates of blood and platelet transfusions and hospitalization for neutropenic fever, although we haven’t done a formal analysis yet,” Dr. Park added.
Twenty-six of the 27 patients (96%) required a dose reduction of vemurafenib because of rash, photosensitivity, and joint pain. The 960 mg dose twice daily was initially reduced to 240 mg twice daily in 16 patients (62%) and to 480 mg twice daily in 10 patients (38%), and some patients had their doses increased again days later.
“The relatively high rate of infusion reactions was striking but not uncommon for obinutuzumab. This was because the obinutuzumab was given all at once on day 1, while in other protocols for other lymphomas, the first dose is split over two days, which may reduce the reaction intensity and allow for easy adoption of the protocol,” said Dr. Banerji, who was not involved with the trial.
“This newer regimen is also a time-limited regimen, like our SOC, but has the potential to remove chemotherapy and become a new SOC in HCL,” Dr. Banjeri said.
“We now need longer-term follow-up to understand if the combination is as durably effective as cladribine plus rituximab,” noted Dr. Stone, who was involved in the front-line vemurafenib trial.
“We’re excited to see continued durable remissions at six years in our front-line vemurafenib study. For any other cancers, this can be considered a cure, but for HCL, we need to wait longer because patients can relapse even 10 years out,” Dr. Park noted.
According to Dr. Kreitman, that 26 out of 27 patients were MRD free in just under three years on the trial “is very good.”
The trial measured MRD using bone marrow samples for the first year and from blood samples thereafter. “The peripheral blood MRD status looks good so far, but there can be a long lead time of peripheral blood MRD negativity but bone marrow positivity in my experience,” Dr. Kreitman cautioned. “We still need longer-term results from this trial.”
Currently, Dr. Kreitman advises his patients that the vemurafenib plus obinutuzumab combination regimen is a reasonable alternative to chemotherapy for patients who prefer to undergo a chemotherapy-free treatment but doesn’t have as long a follow-up as cladribine plus rituximab. “The two regimens may be equally effective in the long term, but we just don’t know yet,” Dr. Kreitman said.
While the phase II data mature, Dr. Park and colleagues are also working to initiate a randomized trial to directly compare vemurafenib plus obinutuzumab to cladribine plus rituximab in the front-line setting (ID NCT06561360). “We hope that the results of this new trial as well as the longer-term results of our single-arm trial will convince payers to cover this newer regimen in HCL,” Dr. Park said.
“Even if younger patients can tolerate the chemotherapy, we believe that they will benefit more from vemurafenib plus obinutuzumab in the long term. The impact on quality of life and being able to function at work and with their family and avoid hospitalization — that makes a huge difference for patients,” he said. “We want to make their lives easier.”
References
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- Golomb HM, Catovsky D, Golde DW. Hairy cell leukemia: a five-year update on seventy-one patients. Ann Intern Med. 1983;99(4):485-486.
- Else M, Dearden CE, Catovsky D. Long-term follow-up after purine analogue therapy in hairy cell leukaemia. Best Pract Res Clin Haematol. 2015;28(4):217-229.
- Tiacci E., Trifonov V., Schiavoni G, et al. BRAF mutations in hairy-cell leukemia. N Engl J Med. 2011;364(24):2305-2315.
- Bruno W, Martinuzzi, C, Andreotti V, et al. Heterogeneity and frequency of BRAF mutations in primary melanoma: comparison between molecular methods and immunohistochemistry. Oncotarget. 2017;8(5):8069-8082.
- Tiacci E, Park JH, De Carolis L, et al. Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia. N Engl J Med. 2015;373(18):1733-1747.
- Park JH, Devlin S, Durham BH, et al. Vemurafenib and obinutuzumab as frontline therapy for hairy cell leukemia. NEJM Evidence. 2023;2(10);EVIDoa2300074.
- Teras LR, DeSantis CE, Cerhan JR, et al. 2016 US lymphoid malignancy statistics by World Health Organization subtypes. CA Cancer J Clin. 2016;66(6):443-459.
- Troussard X, Maître E, Cornet E. Hairy cell leukemia 2022: update on diagnosis, risk-stratification, and treatment. Am J Hematol; 2022;97(2):226-236.
- Chihara D, Arons E, Stetler-Stevenson M, et al. Randomized phase II study of first-line cladribine with concurrent or delayed rituximab in patients with hairy cell leukemia. J Clin Oncol. 2020;38(14):1527-1538.
