麻豆传媒

Patients with refractory or relapsed hairy-cell leukemia (HCL) can achieve a durable complete response with a short, chemotherapy-free, non-myelotoxic regimen of vemurafenib (Zelboraf) and rituximab, a small Italian study showed.

Compared with the historical data on vemurafenib alone, the percentage of patients in this study who achieved a complete response -- 87% -- more than doubled, while the median time to a complete response was halved, reported Enrico Tiacci, MD, of the University of Perugia in Italy, and colleagues.

Furthermore, all patients who had been refractory to chemotherapy or rituximab, and who had previously been treated with BRAF inhibitors, had a complete response, the authors noted in the .

HCL is a chronic and rare form of leukemia. According to the Leukemia and Lymphoma Society, about 2% of adult leukemia patients have HCL, which gets its name from the short, thin projections that look like hair on the cell.

As pointed out by Tiacci and colleagues, the BRAF V600E mutation is known to be the causal genetic event of HCL. Vemurafenib is a BRAF inhibitor, and while showed it had activity in patients with refractory or relapsed HCL, relapses were common, with one study showing a median relapse-free survival of 9 months after the end of treatment.

Rituximab is myelotoxic and may complement intracellular BRAF inhibition in killing leukemic cells by means of a different mechanism, the authors explained.

This phase II single-center trial included 30 patients with refractory or relapsed HCL. Patients had previously received a median of three therapies. The study treatment regimen consisted of 8 weeks of oral vemurafenib (960 mg twice daily) and eight intravenous rituximab infusions (375 mg/m² of body-surface area) administered over 18 weeks.

A complete response was achieved in 26 patients (87%) in the intent-to-treat population, occurring in all 10 patients who had disease that was refractory to purine analogs, in all seven who had previously been treated with a BRAF inhibitor, and in all five who had disease that was refractory to rituximab.

The progression-free survival rate was 78% at a median follow-up of 37 months, while the relapse-free survival rate for the 26 patients with a complete response was 85% at a follow-up of 34 months. Of these 26 patients, 17 (65%) were cleared of minimal residual disease (MRD).

In addition, the authors reported, a lack of previous exposure to a BRAF inhibitor and the occurrence of MRD negativity "considerably improved relapse-free survival."

For example, among patients with a complete response, the 19 who had not previously received a BRAF inhibitor achieved a relapse-free survival rate of 95% at a median of 34 months compared with 57% among the seven patients previously treated with a BRAF inhibitor. The relapse-free survival rate was 100% among the 17 patients with MRD negativity compared with 56% among the nine patients with MRD positivity.

As for toxic effects, Tiacci and colleagues reported that they were mostly grade 1 and 2 and had been previously seen in patients receiving vemurafenib and rituximab monotherapies.

"Owing to the absence of myelotoxic effects, this combination may also be helpful with regard to delivering a definitive treatment in contexts in which highly immunosuppressive chemotherapy is contraindicated, such as in patients who have active infections or are at risk for coronavirus disease 2019," the authors suggested. "A randomized comparison of vemurafenib plus rituximab is warranted against the chemotherapy-based standard of care in the context of first-line therapy to assess whether similar efficacy can be obtained with lower toxicity."

"This report of targeted therapy for hairy cell leukemia is very important, and the results are very encouraging considering the heavily pretreated nature of this patient population," Michael Grever, MD, of the Ohio State University in Columbus, and advisory board chair of the Hairy Cell Leukemia Foundation, told 麻豆传媒. "The detailed analysis of MRD with clinical outcome provides a useful guideline for future studies."

Grever, who was not involved with the study, said that he agreed with Tiacci's group in that additional prospective studies will be useful in defining the optimal dose and duration of vemurafenib. Furthermore, he added, "prospective studies of this regimen in comparison to purine analog-based therapies would be important in the effort to continuously improve the management of this leukemia."

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