Two-inhibitor salvage therapy for hairy cell leukemia

In this issue of Blood, Kreitman and colleagues¹ report the results of treatment with dabrafenib plus trametinib in a cohort of patients with relapsed/refractory BRAF V600E mutation–positive hairy cell leukemia. This cohort was from a multicenter, open-label, nonrandomized phase 2 basket study of dabrafenib plus trametinib in patients with BRAF V600E mutation–positive rare cancers. The patients registered to this trial had been extensively pretreated with standard agents used for hairy cell leukemia. All patients had been treated with purine analogs (either pentostatin or cladribine) and had relapsed or progressed. Most patients underwent at least 2 prior regimens. Prior treatment regimens included multiple agents. For example, 63% of patients had received rituximab, and 20% had received moxetumomab. In this extensively pretreated patient group, the overall response to dabrafenib plus trametinib was 89.1% with 65.5% achieving complete remission. Patients were continued on therapy until unacceptable toxicity, disease progression, or death occurred.

Of the 55 patients in the treatment group, 49 patients had a confirmed response with progression-free survival and overall survival estimated to be 94.4% and 94.5%, respectively, at 24 months. All patients experienced adverse events with 63.6% experiencing grade 3 or greater events. However, adverse events were manageable through treatment interruption, dose modification, and concomitant medications. With the planned long-term treatment, there were patients who discontinued treatment (22%). In addition, there were patients who developed secondary malignancies. Whether these secondary malignancies were related to the increased risk for malignancy in these patients with hairy cell leukemia or to prolonged treatment with dabrafenib and trametinib requires further consideration. In addition to the aforementioned factors, they had been treated with numerous agents before receiving therapy on this trial.

Tremendous progress in the treatment of hairy cell leukemia over the past 3 decades has resulted in many patients living a nearly normal life span. However, many of these patients relapse and require several additional therapeutic attempts to recapture a remission. Both pentostatin and cladribine have changed the natural history of this disease, but relapse after treatment has prompted continued research to improve the quality of the remissions. The addition of rituximab (Rituxan) to either cladribine or pentostatin at relapse has increased the response rate and duration in these patients after relapse. In fact, investigators have incorporated rituximab into the initial therapeutic regimen in an effort to achieve a longer initial remission.² Many investigators incorporate rituximab with a purine analog for patients requiring retreatment after relapse.³ 

Since the discovery of the importance of the gene BRAF V600E in the pathogenesis of hairy cell leukemia, inhibition of this target has resulted in induction of remission in many patients with classic hairy cell leukemia.^4,5 Inhibitors of BRAF V600E have provided impressive responses in patients with hairy cell leukemia. Addition of rituximab to the BRAF inhibitor, vemurafenib, has resulted in durable responses in hairy cell leukemia.⁶ Likewise, dabrafenib in combination with the MEK (MAPK/ERK kinase) inhibitor (trametinib) is now used to treat patients with the BRAF V600E mutation. This report by Kreitman and colleagues adds the combination of dabrafenib and trametinib to the list of effective inhibitors in patients with relapsed and refractory hairy cell leukemia.

Although cladribine remains the most frequently used agent to induce remission in hairy cell leukemia, it may increase the risk of complications in patients with uncontrolled infection. The treatment of patients with hairy cell leukemia with uncontrolled infection and pancytopenia is particularly challenging. Several reported approaches have included initial treatment with vemurafenib.⁷ Recently, patients with classic hairy cell leukemia and the BRAF V600E mutation, complicated by active infection, have been successfully treated with a BRAF V600E inhibitor with or without rituximab. However, the onslaught of the COVID-19 pandemic has further complicated the use of standard induction therapy with cladribine and rituximab. There is concern that the immunosuppression resulting from the combination of a purine analog and the anti-CD20 monoclonal antibody (rituximab) will markedly suppress the immune system for months, thus increasing the danger to those who become infected with the COVID-19 virus and significantly dampen their response to vaccination.⁸ 

Consequently, the combination of a BRAF V600E inhibitor (dabrafenib) with an inhibitor of downstream MEK (trametinib) to induce remission in patients with classic hairy cell leukemia is of interest. Vemurafenib alone is effective in inducing remission in relapsed hairy cell leukemia, but the duration of response to this agent alone is often time limited. Although the addition of rituximab to vemurafenib increases the response in relapsed/refractory hairy cell leukemia, this combination has the potential to increase the risks of immunosuppression and susceptibility to COVID-19. Therefore, strategies incorporating dabrafenib with trametinib are especially appealing as a potential salvage regimen in this disease. The article by Kreitman and colleagues provides a promising therapeutic regimen for patients with classic hairy cell leukemia who have relapsed and require therapy.

Conflict-of-interest disclosure: The author has served as a consultant to AstraZeneca, Ascerta, Pharmacyclics, Innate Pharma, Serono, and Axio, Inc; serves on the advisory board for the Hairy Cell Leukemia Foundation; and receives financial support for the Hairy Cell Leukemia Foundation Patient Data Registry.