An 80-year-old white man with a history of HCL presented with complaints of fatigue, dizziness, shortness of breath, blurring of vision, and headache. He also had a history of diabetes, hypertension, and sleep apnea. HCL was initially diagnosed 9 years prior and treated with cladribine with partial response. He relapsed 3 years later after first-line therapy and was treated with pentostatin and rituximab. Follow-up evaluation with PET/CT and bone marrow biopsy showed no signs of residual disease. Following disease relapse 5 years later when he presented with lymphocytosis and splenomegaly, molecular testing was positive for BRAF V600E mutation. He was treated with cladribine and rituximab but was incompletely treated due to complications of neutropenic fever and an admission for intracranial hemorrhage.
Physical examination revealed multiple petechiae and bruising in the upper and lower extremities. He had marked abdominal distension with a spleen tip palpable beyond the umbilicus. Neurologic examination showed no focal deficits. Axillary and inguinal lymph nodes were palpable. Labs showed a marked leukocytosis of 371,700 x 109/L (normal: 3,500-13,000 x 109/L) with 82% atypical lymphocytes, 4% segmented neutrophils, 3% lymphocytes, and 3% monocytes; hemoglobin of 6.4 g/dl (normal: 11-17 g/dl); and platelet count of 99,000 x 109/L (normal: 135,000-450,000 x 109/L). The patient was hospitalized with these acute findings. A peripheral blood smear showed significant lymphocytosis with oval to slightly irregular nuclei, homogenous ground-glass chromatin, and abundant pale blue cytoplasmic hairy projections, normocytic anemia with anisopoikilocytosis, and marked thrombocytopenia ( Figure 1 ). A computerized tomography (CT) scan of the chest, abdomen, and pelvis showed splenomegaly of 22 cm, ground-glass opacities in bilateral upper lung fields, and small pleural effusions bilaterally. With worsening shortness of breath, increasing oxygen requirement, and the CT findings concerning leukostasis ( Figure 2 ), he was started on hydroxyurea 2 g daily and underwent three sessions of leukapheresis over a period of a week with significant cytoreduction. He reported improvement in respiratory symptoms with an objective reduction in white blood count (WBC) to 89,000 x 109/L. Flow cytometry on peripheral blood returned a kappa light chain monoclonal B-cell population expressing CD11c, partially dim CD10, CD103, and aberrant CD5, but without CD25 expression, consistent with relapsed HCL.
To identify the etiology of headache and dizziness, a CT scan of the head was done, which revealed foci of minimal hypoattenuation in both cerebellar hemispheres and periventricular white matter. This was followed by a magnetic resonance imaging (MRI) of the head with and without contrast, which showed multiple soft tissue masses in the supratentorial and infratentorial regions involving the cerebellar lobes, the left frontal and bilateral temporal lobes, with the largest lesion seen in the left cerebellum (14 x 12mm) ( Figure 3A ). A biopsy was not pursued due to the risk of the procedure and medical frailty. Extensive infectious disease evaluation was pursued with negative serology for HIV, hepatitis B and C, syphilis, toxoplasma, and fungal organisms including Aspergillus, Blastomyces, coccidiosis, histoplasma, and quantiferon TB. We initiated therapy with ibrutinib at 420 mg daily, but this was discontinued due to thrombocytopenia, epistaxis, and retinal hemorrhage after 7 days of treatment. Therapy was changed to BRAF inhibitor vemurafenib at 240 mg twice daily. Because he tolerated the treatment well and his symptoms improved, the dose was increased to 480 mg twice daily and he was discharged home.
He reported that his neurologic symptoms had resolved completely 1 month later. Labs showed a WBC of 28,400 x 109/L, hemoglobin of 13.7 g/dl, and platelet count of 44,000 x 109/L. An MRI of the brain, 3 months after initiation of vemurafenib, showed complete resolution of the intracranial lesions ( Figure 3B ), and abdominal imaging revealed a marked decrease in spleen size. Follow-up ophthalmologic evaluation showed resolution of leukemic retinopathy. He is planning to continue vemurafenib, with a goal to discontinue treatment once a bone marrow biopsy confirms morphologic remission