Response of relapsed central nervous system hairy cell leukemia to vemurafenib

Hairy cell leukemia (HCL) is a rare chronic B-cell lymphoproliferative malignancy that accounts for 2% of all adult leukemias. [1] There have been previous reports of CNS involvement by HCL, but these cases are extremely rare and usually present with highly fatal leptomeningeal disease or direct leukemic brain infiltration. [2–5] In this report, we describe the durable treatment response of a relapsed BRAF V600E-mutated HCL with extensive CNS involvement to vemurafenib. In August 2013, a 59-year-old Caucasian man presented to an outside institution with multifocal cranial neuropathies. The patient had primary complaints of headaches, dizziness, episodic confusion, slurred speech, frequent falls, and a left facial droop. He had suffered many years of general malaise, and had a past medical history significant for hypertension, COPD, tobacco and alcohol abuse, and a cholecystectomy in 2008. His family history was significant for a sister who died of a brain tumor, but there was no history of hematological malignancies in family members. A lower extremity MRI obtained in April 2010 showed extensive lytic bone lesions, but was attributed to an infection. Initial evaluations revealed marked splenomegaly, celiac axis lymphadenopathy, a CBC showing pancytopenia, and a bone marrow biopsy displaying low-grade B-cell lymphoma favoring a preliminary diagnosis of mantle cell lymphoma with CNS involvement. He was referred to the Hillman Cancer Center, University of Pittsburgh Medical Center, for further evaluation. A repeat CBC confirmed pancytopenia (leukocytes 2.6 10/l, Hgb 9.4 g/dl, platelets 53 10/l). Lumbar puncture cytology was positive for low levels of malignant CD19 lymphocytes with elevated CSF protein. An axial brain MRI demonstrated multiple enhancing supraand infratentorial leptomeningeal-based foci with slightly nodular appearances. Examination of the peripheral blood smear revealed atypical lymphocytes with fimbriated surfaces. Histology of the bone marrow biopsy showed fibrosis with extensive infiltration of CD20 B-cells along with positive annexin A1 and BRAF V600E mutation staining). The BRAF V600E mutation was subsequently confirmed by Sanger sequencing analysis. Flow cytometric evaluation confirmed the presence of a monoclonal B-cell population co-expressing C20, C25, CD11c, and CD103. The overall findings were diagnostic of HCL with leptomeningeal involvement. The patient was then admitted, where he initiated high-dose cytarabine along with systemic rituximab and intrathecal methotrexate. A follow-up MRI in September 2013 showed partial response with resolution of numerous enhancing foci and overall reduction in size of the existing lesions. Two weeks later, the patient was admitted with seizures. An MRI at that time showed extensive leptomeningeal disease with left occipital parenchymal edema. He was treated with intrathecal methotrexate and rituximab. While this initially stabilized his symptoms, a restaging MRI obtained in September 2014 demonstrated persistent diffuse disease. The patient initiated vemurafenib 960 mg b.i. d. in December 2014. A restaging MRI scan obtained in January 2015 demonstrated resolution of areas of intracranial enhancement with no new areas of enhancement consistent with a complete response. The patient initially tolerated vemurafenib quite well, but developed a generalized acneiform rash and was subsequently placed on a drug holiday. In May 2015, he was found to have several enhancing lesions on MRI, including one in the lesser cerebellum and cortical lesions, which had progressed. He was restarted on a reduced dose of vemurafenib 720 mg b.i. d, which he has tolerated well. Three months after re-initiation of vemurafenib, MRI demonstrated resolution of all lesions, which has persisted on repeat imaging in February 2016 [Figure 1].