Genomic Profiling, Targeted Therapy Effectively Treats Histiocytic Disorders

Genomic profiling should be applied to patients with histiocytic disorders at diagnosis in order to guide targeted therapy, according to research published in the Journal of Clinical Investigation Insight (February 2017;2[3]:e89473).

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Histiocytoses are a group of blood disorders involving abnormal accumulations of white blood cells forming tumors on vital organs within the body. Approximately half of patients with Langerhans cell histiocytoses or Erdheim-Chester disease can be treated with chemotherapy, but many have treatment-refractory disease or suffer recurrence. Recent findings of gene mutations within these disorders have generated options for targeted therapies.

Ashish R Kumar, MD, PhD, Cincinnati Children’s Hospital Medical Center (Ohio), and colleagues conducted a study that examined the genomic profiling of biopsies from 72 patients with a variety of treatment-refractory histiocytoses. Fifteen patients (21%) carried the BRAF V600E mutation, and 11 patients (15%) carried various mutations in MAP2K1, both of which are responsible for activating extracellular signal-regulated kinase (ERK).

Researchers determined that patients with such mutations would benefit from dabrafenib or trametinib—targeted molecular therapies designed to block the ERK pathway. As a result, three infant patients treated with one or the other of these oral medications are in remission.

Researchers also provided case studies involving four patients with histiocytic disorders resistant to chemotherapy. For one individual with BRAF-mutated hemophagocytic lymphohistiocytosis, targeted therapy stabilized organ function within 1 week.

As a result of their findings, researchers concluded that comprehensive genomic profiling should be regularly applied to patients with histiocytic disorders at diagnosis to test for BRAF- and MAP2K1-mutations. By doing so, clinicians would be able to select targeted therapies that may spare the toxicities of more aggressive chemotherapy regimens.

Dr Kumar and colleagues plan to test methodologies in clinical trials that could further the use of genomic profiling of patient biopsies as well as targeted molecular therapies in patients with recurrent, treatment-resistant disease. “Reports of disease breakthrough after prolonged treatment with BRAF inhibitors have emerged, emphasizing the need for structured clinical trials,” he said.