Frontline Combo Yields High Remission Rate in Hairy Cell Leukemia

Derick Alison
Derick Alison
6 Min Read

Use of the BRAF inhibitor vemurafenib (Zelboraf) combined with the anti-CD20 monoclonal antibody obinutuzumab (Gazyva) led to high rates of complete remission as frontline therapy for patients with hairy cell leukemia in a small phase II study.

Of the 30 patients enrolled in the study, 27 achieved a complete remission, while the remaining three patients discontinued treatment early due to adverse events and were not evaluable for response, reported Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues.

In addition, 26 of the responders achieved minimal residual disease (MRD) negativity, they noted in NEJM Evidence.

At a median follow-up of 34.9 months from the first vemurafenib dose, the estimated overall survival rate was 97% at both 24 and 36 months after treatment initiation. The estimated progression-free survival rate was also 97% at these time points.

Among the 27 patients who completed the treatment, no patients experienced disease relapse, and all patients were alive at the time the study was published.

“These data strongly support further investigation of the vemurafenib plus obinutuzumab regimen versus cladribine plus rituximab in a randomized trial,” Park and team wrote.

They noted that while the purine analogues cladribine and pentostatin have been the first-line therapy for hairy cell leukemia for over two decades (achieving complete remission rates in approximately 80% of cases), the disease remains incurable and many patients will relapse.

Furthermore, they pointed out that rates of detectable MRD range from 13% to 61% with frontline purine analogue therapy, with the magnitude of MRD corresponding to an increased risk of relapse.

While the addition of rituximab to cladribine has improved MRD-undetectable remission rates and relapse rates, Park and colleagues said that purine analogue-based therapy has been associated with risks of prolonged myelosuppression, severe infections, and secondary malignancies.

The authors had previously reported overall response rates of more than 90% using vemurafenib in patients with relapsed or refractory hairy cell leukemia. Complete remissions were low (33%), however, and all patients with a complete remission had detectable MRD, with two-thirds of the patients experiencing relapse at a median follow-up of 40 months.

A recent study also showed that the addition of rituximab to vemurafenib resulted in high rates of complete remission and MRD negativity in relapsed or refractory hairy cell leukemia, although that combination was not studied in the frontline setting.

In this study, Park and colleagues chose obinutuzumab because it has previously shown single-agent activity in other indolent non-Hodgkin lymphomas and chronic lymphocytic leukemia.

The study was conducted at three sites in the U.S. from March 2018 to February 2021, and included adults (median age 54, 90% men) with previously untreated classical hairy cell leukemia. They received oral vemurafenib 960 mg twice daily for four cycles of 28 days each. Treatment was not stopped between cycles, and patients did not receive obinutuzumab during the first cycle. Intravenous obinutuzumab 1,000 mg was given on days 1, 8, and 15 of cycle 2 and on day 1 of cycles 3 and 4.

The most common vemurafenib-related adverse events (AEs) were rash, arthralgia, and pruritus. Febrile neutropenia occurred in two patients, and blood or platelet transfusions were required in two patients.

Vemurafenib dose reductions were allowed for drug-related AEs, and the dose was reduced in 26 of the 27 patients who completed four cycles of vemurafenib. Dose reductions were most likely due to arthralgia and rash during the first month of treatment, which Park and team said were transient and reversible. The most common final dose was 480 mg twice daily.

The authors acknowledged a number of limitations to the study, including the fact it was a small, single-arm study of a small number of patients with no comparator group.

They also noted that the trial design “precludes a formal statistical analysis of the clinical efficacy of the vemurafenib and obinutuzumab combination against other established regimens such as cladribine plus rituximab or vemurafenib plus rituximab.”

In addition, while none of the patients in this study relapsed, Park and colleagues noted that follow-up was relatively short.

“A longer follow-up is needed to verify the durability of remissions achieved with the study’s combinational treatment approach,” they wrote.

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    Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.

Disclosures

This study was supported by the Leukemia and Lymphoma Society, the Hairy Cell Leukemia Foundation, the National Cancer Institute, and Genentech.

Park reported relationships with Affyimmune, Allogene, Amgen, Artiva Biotherapeutics, Autolus, BioGene, Bright Pharmaceutical Services, Bristol Myers Squibb, Curocell, Intellia Therapeutics, Kite Pharma, Kura Oncology, Minerva Biotechnologies, Pfizer, Precision Bio, Servier Pharmaceuticals, Sobi, Takeda Oncology, and Umoja.

Co-authors also reported multiple relationships with industry.

Primary Source

NEJM Evidence

Source Reference: Park JH, et al “Vemurafenib and obinutuzumab as frontline therapy for hairy cell leukemia” NEJM Evid 2023; DOI: 10.1056/EVID0a2300074.

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