Abstract
The activating BRAF mutation V600E has been identified in many human cancers, including colon and lung adenocarcinoma, papillary thyroid cancer, malignant melanoma, and hairy cell leukemia. Here we report for the first time treatment of hairy cell leukemia and malignant melanoma both harboring the BRAF V600E mutation with the BRAF inhibitor dabrafenib.
The patient is a 67-year-old man with a history of classic hairy cell leukemia (immunophenotype CD11c, CD19, CD20 (bright), CD25, and CD103). At the time of diagnosis he had pancytopenia and received therapy with cladribine 0.12 mg/kg/day as a 2 hour infusion daily for 5 days, achieving a complete hematologic remission (CHR). His disease recurred 2 years later and he was again treated with cladribine 0.9 mg/kg/day as a 7 day continuous infusion, achieving a CHR. He remained in remission for 5 years, and this time received salvage therapy with pentostatin 4 mg/m2 every 2 weeks for a total of 12 doses. He achieved a CHR with minimal residual disease on bone marrow biopsy (0.3% of lymphocytes). He also had dyserythropoiesis concerning for myelodysplastic syndrome in addition to neurologic toxicity with gait imbalance. He was managed expectantly for the next 2 years, during which time he developed an 8 mm red nodule on the extensor surface of his right forearm, and a shave biopsy showed nodular melanoma, Clark’s level IV. He underwent a wide local excision with a negative axillary sentinel lymph node biopsy followed by adjuvant sargramostim (GM-CSF) for 12 months. His melanoma then recurred at the site of the prior excision. A PET scan showed an additional lesion in the midportion of the right arm. The excised solitary recurrence was sent for BRAF V600E mutation testing, which was positive. He received a course of radiotherapy (30 Gy over 14 days) to the affected limb, after which he had no evidence of disease. During this time, he was found to have worsening thrombocytopenia and splenomegaly, as well as a rising IL2 receptor level (peak 3952 U/mL; normal < 970), while bone marrow biopsy showed a 20% cellular marrow with 40% involvement by classic HCL. BRAF testing of the bone marrow by Sanger sequencing was positive for the V600E mutation. Because both his HCL and melanoma harbored the BRAF V600E mutation, the patient was eligible for and enrolled on a phase I clinical trial of dabrafenib for BRAF V600E mutant malignancies. Dabrafenib was initiated orally at a dose of 150 mg twice daily. Each cycle was 28 days. After 3 cycles, the bone marrow cellularity had improved to 30% with a decrease in the leukemic content to 10-15% of marrow cellularity. After 6 cycles, the bone marrow cellularity was normal for age with no residual HCL detectable by immunohistochemical stains or flow cytometric immunophenotyping. PET/CT scan at this time demonstrated no FDG avid lesions and no splenomegaly. Toxicites have consisted of characteristic RAF-associated skin changes and one instance of squamous cell carcinoma, which was excised. He has otherwise had no side effects from therapy.
The patient has now completed 12 cycles of therapy with dabrafenib without evidence of either HCL or melanoma. He will remain on therapy as long as he is deriving clinical benefit per protocol. Given the increased risk of second primary malignancies in HCL, BRAF mutation testing should be considered for patients developing solid tumors in which this has been described, as co-treatment may be possible.
Disclosures:
Off Label Use: Dabrafenib for treatment of hairy cell leukemia. Kendra:Glaxo Smith-Kline: Research Funding.
Immunohistochemical Analysis of BRAF (V600E) Mutation and P16 Expression in Malignant Melanoma in Lagos, Nigeria: A 10-Year Retrospective Study