Dabrafenib and trametinib in Langerhans cell histiocytosis and other histiocytic disorders

Abstract

The standard treatment for Langerhans cell histiocytosis (LCH) is chemotherapy, although the failure rates are high. Since MAP-kinase activating mutations are found in most cases, BRAF- and MEK-inhibitors have been used successfully to treat patients with refractory or relapsed disease. However, data on long-term responses in children are limited and there are no data on the use of these inhibitors as first-line therapy. We treated 34 patients (26 with LCH, 2 with juvenile xanthogranuloma, 2 with Rosai-Dorfman disease, and 4 with presumed single site-central nervous system histiocytosis) with dabrafenib and/or trametinib, either as first line or after relapse or failure of chemotherapy. Sixteen patients, aged 1.3-21 years, had disease that was recurrent or refractory to chemotherapy, nine of whom had multisystem LCH with risk-organ involvement. With a median treatment duration of 4.3 years, 15 (94%) patients have sustained favorable responses. Eighteen patients, aged 0.2-45 years, received an inhibitor as first-line treatment. All of these have had sustained favorable responses, with a median treatment duration of 2.5 years. Three patients with presumed isolated central nervous system/pituitary stalk histiocytosis had stabilization or improvement of their disease. Overall, inhibitors were well tolerated. Five patients with single-system LCH discontinued therapy and remain off therapy without recurrence. In contrast, all four patients with multisystem disease who discontinued therapy had to restart treatment. Our data suggest that children suffering from histiocytoses can be treated safely and effectively with dabrafenib or trametinib. Additional studies are, however, needed to determine the long-term safety and optimal duration of therapy.

Figure 1.

Response to inhibitor therapy in patients with relapsed/refractory disease. (A) Graphical summary of all responses achieved in patients with refractory/recurrent disease. Response categories are represented by the segments of the doughnut plot. (B) Post-contrast brain magnetic resonance imaging (MRI) of a 7-year-old boy with a history of recurrent Langerhans cell histiocytosis when he developed sudden onset diabetes insipidus (upper panel). The arrow points to thickened infundibulum. He was treated with trametinib and repeat MRI 6 weeks later (lower panel) showed normal thickness of the enhanced infundibulum (red arrow). NAD: no active disease; DI: diabetes insipidus; ADS: active disease, stable; RDD: Rosai Dorfman disease; CNS: central nervous system; ADB: active disease, better.

Figure 2.

Isolated pituitary stalk disease diagnosed by HistioTrak. (A) Post-contrast brain magnetic resonance imaging (MRI) of a 4-year-old boy with sudden onset central diabetes insipidus, showing infundibular infiltration (arrow). Extensive evaluation was negative for histiocytosis or a germ cell tumor. A biopsy of the pituitary stalk was deemed unsafe. (B) Follow-up MRI a few months later showed worsening of pituitary stalk thickening (arrow). Treatment was initiated with trametinib. (C) Repeat MRI 3 months after initiation of trametinib showed resolution of the pituitary stalk infiltration (arrow). (D) HistioTrak on peripheral blood mononuclear DNA revealed the presence of the BRAF-V600E mutation (positive droplets circled).

Figure 3.

Response to inhibitor as first-line therapy. (A) Graphical summary of all responses achieved in patients treated with an inhibitor as first-line therapy. Response categories are represented by the segments of the doughnut plot. (B) Positron emission tomography (PET) of a 20-month-old female at diagnosis (left panel) with mixed histiocytosis with features of Langerhans cell histiocytosis and juvenile xanthogranuloma, demonstrating extensive disease including fluorodeoxyglucose (FDG)-avid lesions of the calvarium, chest wall, vertebrae, pelvis, and lower extremities, as well as splenomegaly and profound lymphadenopathy involving the neck, chest, abdomen and pelvis. Biopsy was positive for BRAF-V600E. Repeat imaging (right panel) following 8 weeks of therapy with trametinib, with marked interval decrease in size and FDG avidity of bony lesions, decrease in splenomegaly and marked improvement in lymphadenopathy throughout. (C) PET (upper and middle rows) and computed tomography (bottom row) of a 12-year-old male at diagnosis (left frames in each row) of multifocal bone LCH demonstrating a large bony lesion involving the L1 vertebral body, with a SUVmax value of 15. Repeat imaging (right frames) performed following 6 weeks of therapy with trametinib shows minimal FDG uptake and marked improvement of the vertebral lesion. NAD: no active disease; CNS: central nervous system; DI: diabetes insipidus.