Dabrafenib and trametinib in Langerhans cell histiocytosis and other histiocytic disorders
Eily Cournoyer,
Justin Ferrell,
Susan Sharp,
Anish Ray,
Michael Jordan,
Christopher Dandoy,
Michael Grimley,
Somak Roy,
Robert Lorsbach,
Arnold C. Merrow,
Adam Nelson,
Allison Bartlett,
Jennifer Picarsic,
Ashish Kumar
Affiliations
Eily Cournoyer
Cincinnati Children’s Hospital Medical Center Residency Training Program, Cincinnati
Justin Ferrell
Cincinnati Children’s Hospital Medical Center Residency Training Program, Cincinnati
Susan Sharp
University of Cincinnati College of Medicine, Division of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati
Anish Ray
Division of Hematology and Oncology, Cook Children’s Hospital, Fort Worth, Texas
Michael Jordan
University of Cincinnati College of Medicine, Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati
Christopher Dandoy
University of Cincinnati College of Medicine, Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati
Michael Grimley
University of Cincinnati College of Medicine, Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati
Somak Roy
University of Cincinnati College of Medicine, Division of Pathology, Cincinnati Children’s Hospital Medical Center, Cincinnati
Robert Lorsbach
University of Cincinnati College of Medicine, Division of Pathology, Cincinnati Children’s Hospital Medical Center, Cincinnati
Arnold C. Merrow
University of Cincinnati College of Medicine, Division of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati
Adam Nelson
University of Cincinnati College of Medicine, Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati
Allison Bartlett
University of Cincinnati College of Medicine, Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati
Jennifer Picarsic
University of Cincinnati College of Medicine, Division of Pathology, Cincinnati Children’s Hospital Medical Center, Cincinnati
Ashish Kumar
University of Cincinnati College of Medicine, Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati
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.
