Treatment with low-dose vemurafenib to activate the BRAF signaling pathway can lead to stable long-term remissions among patients with hairy cell leukemia, according to the results of a retrospective study.
However, continuous treatment with vemurafenib (Zelboraf, Genentech/Roche) may increase the risk for resistance formation and secondary malignancies.
The activating mutation BRAF V600 is the key driver in hairy cell leukemia, which suggests that targeted therapies may be successfully utilized in these patients.
Data from clinical trials in BRAF–mutated melanoma have prompted the evaluation of the BRAF inhibitor vemurafenib for patients with hairy cell leukemia, although appropriate dosing outside clinical trials has not been determined.
“We sought to assess the dosing of vemurafenib in patients with hairy cell leukemia,” Thorsten Zenz, MD, professor of medicine at University of Heidelberg and member of the department of translational oncology at National Center for Tumor Diseases and German Cancer Research Center, told HemOnc Today. “We also wanted to determine a dose–response relationship of BRAF inhibition, and to understand the effects of cell signaling.”
Zenz and colleagues observed 21 heavily pretreated patients (median age, 64 years; median prior treatment lines, 3) with hairy cell leukemia who took vemurafenib outside of clinical trials.
Seventeen patients began treatment at a dose of 240 mg twice per day, and 12 continued at this dose. Five patients received dose escalations to 480 mg (n = 1), 720 mg (n = 2) or 960 mg (n = 2).
The remaining patients received doses of 240 mg once daily (n = 1), 480 mg twice daily (n = 2) or 960 mg twice daily (n = 1), with no modifications.
Median observation time was 17 months.
Blood counts improved in all patients, including platelet recovery (median time, 28 days; range, 10-105), neutrophil recovery (median time, 43 days; range, 9-126) and hemoglobin recovery (median time, 55 days; range, 10-181). All but one patient achieved a hematologic response (95%).
Forty percent of evaluable patients (n = 6 of 15) achieved complete remission.
Median EFS was 17 months. Researchers observed that EFS was not impacted by cumulative administered dose (HR = 0.9; 95% CI, 0.8-1.1) or treatment duration (HR = 0.31; 95% CI, 0.6-2.1).
Eighty-eight percent of the cohort achieved 12-month OS. Three patients died, with deaths attributable to disease progression, pneumonia while in remission and acute myeloid leukemia.
Patients who achieved a complete remission after treatment had better EFS outcomes (HR = 0.2; 95% CI, 0.1-0.9).
Nine patients were retreated at relapse (range, 4-17 months). Six patients re-exposed to vemurafenib responded to treatment.
A pharmacodynamics analysis showed that vemurafenib at a dose of 480 mg per day completely removed ERK phosphorylation of hairy cells in vivo.
Patients on low-dose regimens experienced typical adverse events, including arthralgia (n = 4), mild elevation of liver enzymes (n = 4) and phototoxicity (n = 4).
Second malignancies observed included keratoacanthomas (n = 3), squamous cell papilloma (n = 1) and squamous cell carcinoma (n = 1).
One patient developed AML, which the researchers believed to be accelerated by vemurafenib treatment. A PI3K hotspot mutation (E545K) was identified in the AML clone, which provided a potential novel mechanism for BRAF activation.
“Our research argues for future studies into novel dosing approaches for both hairy cell leukemia and BRAF inhibition, as well as targeted agents in general,” Zenz said. “Doses used per label produce very similar results as the low-dose regimen, which has general implications for how targeted drugs are chosen.” – by Cameron Kelsall
Dietrich S, et al. Blood. 2016;doi:10.1182/blood-2015-11-680074.
For more information:
Thorsten Zenz, MD, can be reached at firstname.lastname@example.org.
Disclosure: The researchers report no relevant financial disclosures.