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Vemurafenib effective in relapsed, refractory hairy cell leukemia
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A short oral course of vemurafenib appeared effective for patients with relapsed or refractory hairy cell leukemia, according to the results of two phase 2 studies.
“Hairy cell leukemia is a chronic mature B-cell cancer with unique clinicopathologic and biologic features,” Brunangelo Falini, MD, professor at the Institute of Hematology at University of Perugia in Italy, and colleagues wrote. “Purine analogues induce durable complete responses in approximately 80% of patients with this cancer. However, in 30% to 50% of patients, the disease relapses and there is a progressively worse response to purine analogues, which can also cause cumulative myelotoxic effects and immune suppression. Thus, new therapeutic approaches are needed.”
Because the genetic lesion BRAF V600E underlies hairy cell leukemia, Falini and colleagues sought to determine the safety and efficacy of the oral BRAF inhibitor vemurafenib (Zelboraf, Hoffmann-La Roche/Genentech) for patients with hairy cell leukemia who relapsed after treatment with a purine analogue or who had disease refractory to purine analogues.
The researchers conducted two single-group phase 2 studies, one in Italy and one in the U.S. Both studies assigned 960 mg oral vemurafenib twice daily. The median duration of therapy was 16 weeks for the Italian study and 18 weeks for the U.S. study.
Complete response rate served as the primary endpoint for the Italian study, whereas overall response rate served as the primary endpoint for the U.S. study.
The Italian study reached its enrollment capacity of 28 patients (median age, 57 years; range, 27-84) in April 2013. At time of reporting, the U.S. study was still open and had enrolled 26 patients (median age, 62 years; range, 44-80) of a planned 36 patients.
Patients in both studies had received a median of three prior lines of treatment (range, 1-12 for the Italian study and 1-8 for the U.S. study).
Patients in the Italian study achieved an ORR of 96% (n = 25 of 26 evaluable patients) after a median of 8 weeks, whereas patients in the U.S. study achieved an ORR of 100% (n = 24) after a median of 12 weeks. Thirty-five percent of patients (n = 9) in the Italian study and 42% of patients (n = 10) in the U.S. study achieved a complete response.
The median follow-up for the Italian study was 23 months (range, 7-28). The median RFS was 19 months among patients who achieved a complete response and 6 months among patients who achieved a partial response (HR = 0.26; 95% CI, 0.1-0.68). Median length of treatment-free survival was 25 months among patients who achieved a complete response vs. 18 months for patients who achieved a partial response.
Median follow-up from the time of first vemurafenib enrollment in the U.S. trial was 11.7 months (range, 1.3-25.4). Seventy-three percent of patients achieved 1-year PFS and 91% achieved 1-year OS.
In both studies, the most common treatment-related adverse events included grade 2 arthralgia or arthritis (Italian, n = 10; U.S., n = 8) and rash or erythema (n = 11 for both). Fifty-eight percent of Italian patients and 50% of U.S. patients required dose reductions.
Further, seven patients (Italian, n = 3; U.S., n = 4) developed secondary cutaneous tumors, all treated with simple excision. One Italian patient and three U.S. patients who developed secondary cutaneous tumors had a history of basal cell carcinoma.
The researchers noted that the frequent persistence of phosphorylated ERK–positive leukemic cells in bone marrow following treatment suggested bypass reactivation of MEK or ERK as a resistance mechanism. In a post-hoc analysis, patients with residual phosphorylated ERK–positive leukemic cells had a median PFS of 8 months (range, 5-13), compared with 13 months (range, 8-24) for patients without these cells (P = .004).
“We used vemurafenib as single agent,” Falini and colleagues concluded. “However, BRAF inhibitors could be combined with anti-CD20 monoclonal antibodies (eg, rituximab [Rituxan; Genentech, Biogen Idec]) to potentially eradicate BRAF inhibitor-resistant hairy cell leukemia cells. … In conclusion, we find that vemurafenib is an active targeted drug for patients with relapsed or refractory hairy cell leukemia." – by Cameron Kelsall
Disclosure: Falini reports grants from the Italian Association for Cancer Research, the Hairy Cell Leukemia Foundation and the Italian Ministry for Education, University and Research, as well as grants and non-financial support from Roche during the conduct of this study. Further, he reports a patent related to hairy cell leukemia biomarkers licensed to Trovagene. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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Leslie Andritsos, MD
Since the discovery that the majority of patients with classic hairy cell leukemia (HCL) harbor the BRAF V600E mutation, investigators have hypothesized that BRAF V600E inhibition would have therapeutic benefit in HCL. The study by Tiacci and colleagues represents the combined efforts of Italian and U.S. investigators who independently performed phase 2, single-group multicenter trials of vemurafenib (Zelboraf; Genentech, Daiichi Sankyo) 960 mg by mouth daily for treatment of relapsed or refractory classic HCL. Both groups found high rates of early complete hematologic remissions in most cases. In the Italian group, the median RFS was 9 months, with a median treatment-free interval of 21.5 months. In the U.S. patients, the median duration of follow-up was 11.7 months, with a PFS of 73% at this time point.Of tremendous interest is the observation by both groups of early and robust improvement in peripheral blood cytopenias. This has important implications for the management of patients with HCL who require treatment but have concomitant infections. Rapid reversal of neutropenia using vemurafenib as a single agent could prove lifesaving in patients with sepsis or other life-threatening infections, a scenario in which conventional therapies are often contraindicated.
In contrast, despite the high rates of complete and overall responses, relatively short median PFS was observed. This likely indicates the need for a longer duration of treatment, or for combination therapy with either selected targeted therapies to inhibit resistance mechanisms or with conventional therapies to confer deeper and longer-lasting responses.
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