Study Examines Low-Dose Vemurafenib in Patients with Hairy Cell Leukemia

A long-term, retrospective follow-up of 21 patients with refractory classic hairy cell leukemia (HCL) indicated that low doses of the BRAF inhibitor vemurafenib are active in HCL, suggesting that systemic dose reconsiderations are warranted in HCL and potentially other cancers with BRAF mutations.

“A low dose of a BRAF inhibitor is effective in HCL treatment, suggesting a need for careful dose-finding and maybe re-evaluation of dosing,” Thorsten Zenz, MD, from the National Center for Tumor Diseases and the German Cancer Research Center and a corresponding author of the study, told ASH Clinical News. “These data are an exciting example of precision medicine, and we hope that our careful examination of dosing has implications for other BRAF-driven cancers.”

Mutations of the BRAF serine/threonine protein kinase (V600E) occur in most patients (95 to 100%) with classic HCL, which suggests opportunities for targeted treatment, Dr. Zenz and co-authors, led by Sascha Dietrich, MD, from the University of Heidelberg in Germany, explained. In previous studies, vemurafenib has improved HCL patients’ blood count, but the rates of complete remission (CR) and minimal residual disease (MRD) after treatment have been disappointing. Vemurafenib was first studied in patients with BRAF-mutant melanoma; dose-limiting toxicities were observed and the maximum tolerated dose was established, but responses were observed at the lowest dose levels evaluated.

Dr. Dietrich and colleagues used clinical data and follow-up information from patient charts collected at 11 European centers between 2011 and 2014 to assess the efficacy of vemurafenib in HCL.

Patients were considered in CR if they achieved:

  • Platelet count >100,000/μL
  • Hemoglobin level >12 g/dL
  • Neutrophil count >1,000/μL
  • Normalized spleen size
  • Bone marrow biopsy negative for hairy cells

The BRAF V600E mutation occurred in all 21 patients, identified via immunohistochemical staining (n=6) or sequencing (n=15). At the initiation of vemurafenib, the median patient age was 64 years (range = 45-89 years), the median time from diagnosis to treatment was eight years (range = 0-31 years), and most patients had received a median of three prior therapies (n=19; range = 0-12 therapies).

All patients were treated outside of a clinical trial. Seventeen patients followed a vemurafenib 240 mg twice-daily dosing schedule; 12 patients continued at this dose for the entire study, while the remaining five patients received escalating doses of vemurafenib:

  • 480 mg twice daily (n=1)
  • 720 mg twice daily (n=2)
  • 960 mg twice daily (n=2)

Dr. Dietrich and co-authors did not have information as to why dose escalations were performed.

The median duration of treatment was 90 days (range = 56-266 days), with a median cumulative treatment dose of 51,000 mg (range = 27,000-311,000 mg).

Almost all patients (95%; n=20/21) achieved a hematologic response. The remaining patient developed erythroleukemia after treatment with vemurafenib.

Blood counts improved in all patients, with a median time to target platelet count (>100,000/uL) of 28 days (range = 10-105 days), and a median time to neutrophil and hemoglobin recovery of 43 days (range = 9-126 days) and 55 days (range = 10-181), respectively. Treatment duration did not affect the reconstitution of blood counts (platelets: p=0.15; hemoglobin: p=0.13; neutrophils: p=0.284).

Despite the rapid improvement in blood counts, CR was achieved in just 40 percent of evaluable patients (n=6/15).

In a logistic regression analysis, achieving CR was not significantly associated with cumulative vemurafenib dose (p=0.73) or treatment (p=0.76).

After a median observation of 17 months, median event-free survival (EFS) was 17 months, and EFS was not affected by cumulative administered dose of vemurafenib (hazard ratio [HR] = 0.90; 95% CI 0.8-1.1; p=0.23) or treatment duration (HR=1.3; 95% CI 0.6-2.1; p=0.31). Achievement of a CR after vemurafenib treatment was associated with better EFS (HR=0.2; 95% CI 0.1-0.9; p=0.04).

The median time to relapse (defined as deterioration of blood counts below remission thresholds) was 14 months, and overall survival at 12 months was 88 percent.

In addition, nine patients (42%), including the two who were treated upfront, were retreated at relapse. Six were re-exposed to vemurafenib and responded, the authors noted.

Three of the 21 patients died, due to disease progression (n=1), pneumonia in remission (n=1), and AML (n=1).

Adverse events associated with vemurafenib included arthralgia (n=4) and mild reversible elevation of liver enzymes (n=4).

Though long-term stable remissions on low-dose vemurafenib were recorded, “continuous treatment involves the risk of resistance formation and secondary malignancies,” Dr. Dietrich and colleagues wrote. “This risk might be reduced with altered on-off dosing schedules.”

“Our findings indicate that a short course of BRAF inhibition with [a] low dose of vemurafenib can effectively inhibit MEK/ERK signaling in vivo, reduce HCL load, and induce CR in HCL,” the authors wrote. “The data also suggest that optimal dosing schedules for vemurafenib may need to be re-assessed in clinical trials, which could have major pharmaco-economic implications,” Dr. Dietrich and co-authors noted.

Limitations of this study include the small sample size, the retrospective design, and that patients were not treated, nor was response formally assessed, as part of a clinical trial. The researchers clarified, though, that their “analysis provides starting points for re-evaluation of traditional approaches to dose-finding for targeted cancer drugs.”


Dietrich S, Pircher A, Endris V, et al. BRAF inhibition in hairy cell leukemia with low dose vemurafenib. Blood. 2016 March 3. [Epub ahead of print]