A 76-year-old man with stage IV (T3aNxM1b) BRAF V600K–mutant melanoma presented for evaluation. Six years earlier he had received a diagnosis of stage IIA melanoma on his neck that had been widely excised. One month before presentation, a subcarinal mass developed that compressed his left main-stem bronchus and caused dyspnea. Bronchoscopic débridement and biopsy of the mass confirmed the diagnosis of metastatic melanoma, and he was subsequently referred to our institution. At that time, his white-cell count was elevated, at 18,100 cells per cubic millimeter (reference range, 4000 to 11,000), with an increase in the absolute monocyte count to 3000 cells per cubic millimeter (reference range, 0 to 1300) (). He was initially treated with intravenous ipilimumab (3 mg per kilogram of body weight every 3 weeks, for a total of 4 doses). Progression of the tumor was documented at 12 weeks and 18 weeks from the date of initial treatment.
The Clinical Course of a Patient with BRAF V600K–Mutant Melanoma and NRAS G12R–Mutant Chronic Myelomonocytic Leukemia on Treatment with Vemurafenib
An analysis of genomic DNA from the biopsy specimen of the tumor revealed a BRAF V600K mutation. No RAS mutation was detected. The patient began taking 960 mg of vemurafenib twice a day. At the time vemurafenib was initiated, his white-cell count was 25,600 per cubic millimeter; the leukocytosis was attributed to a resolving postobstructive pneumonia. After 11 days, the patient noted a dramatic improvement in his breathing, although he also reported new, profound fatigue. On evaluation, it was noted that his white-cell count had become markedly elevated (80,900 per cubic millimeter), and there were also increases in the absolute number of monocytes (27,600 per cubic millimeter) and neutrophils (35,900 per cubic millimeter) (). Vemurafenib was stopped, although on physical examination it was determined that a previously palpable subcutaneous tumor had nearly resolved.
A review of the peripheral-blood smear confirmed the monocytosis. A bone marrow–biopsy specimen and aspirate were obtained. On examination, the samples revealed increased numbers of monocytes and neutrophils, a left shift with dysplastic myeloid precursors, and 6% blasts (). Immunophenotyping of bone marrow aspirate and peripheral blood with the use of flow cytometry identified a monocyte population characterized by expression of CD14, CD13, CD33, and HLA-DR, with aberrant expression of CD56 and CD2 (Fig. 1 in the Supplementary Appendix
, available with the full text of this article at NEJM.org). Together, the clinical and hematopathological findings were diagnostic of chronic myelomonocytic leukemia. Karyotypic analysis and fluorescence in situ hybridization revealed no cytogenetic abnormalities.
Two weeks after the vemurafenib was discontinued, the patient’s white-cell and monocyte counts had decreased, to 26,900 per cubic millimeter and 6400 per cubic millimeter, respectively. In an attempt to attenuate the rise in the white-cell count with vemurafenib, treatment was resumed at a lower dose (720 mg twice daily). However, within days, the patient’s white-cell count again began to rise (). Hydroxyurea (500 mg daily) was added to the vemurafenib treatment, but there was no significant reduction in the white-cell count. Vemurafenib was withheld once the white-cell count reached 69,000 per cubic millimeter. After 2 weeks, the white-cell count had fallen to 28,600 per cubic millimeter.
Computed tomographic scans obtained 8 weeks and 16 weeks after the patient started taking vemurafenib showed that there had been a partial response to treatment, with a 43% decrease in disease burden at 16 weeks, including a reduction in the mediastinal lymphadenopathy and resolution of a hepatic metastasis (). Also noted at this interval was the development of splenomegaly, which was consistent with progressive chronic myelomonocytic leukemia. At present, the patient is being treated with intermittent dosing of vemurafenib, guided by changes in white-cell counts.