Grants Awarded

Date of Award
December 2015

Amount of Award
$50,000

Layperson Summary
Histiocytic diseases are a group of blood disorders that affect both children and adults and can lead to severe disability and death. Until very recently, there were no effective treatments for the more severe forms of these diseases for adults. In 2011, it was discovered that about half of these patients have a mutation (a mistake in the DNA) in a gene called BRAF. Based on this pivotal discovery, we led an international study treating these patients with a medicine, vemurafenib, which blocks this BRAF mutation. The results of this study, which are recently accepted for publication in the New England Journal of Medicine, have been astounding. Not only did all patients feel better and have their disease shrink but, unlike other diseases where patients have received this drug, patients did not develop resistance to treatment over time. These data suggest that patients may be able to remain on vemurafenib indefinitely and carry on normal lives. Unfortunately, half of histiocytosis patients do not have the BRAF mutation and therefore cannot benefit from this breakthrough therapy. We and others have conducted intensive genetic analyses of these “non-BRAF” patients and found that nearly all have mutations in other genes that turn on a single tumor growth pathway. Fortunately, a class of medicines (called “MEK” inhibitors) blocks this pathway. We were able to get compassionate use of a MEK inhibitor in 2 adult patients dying from a histiocytic disorder and both had dramatic resolution of grave symptoms within days of starting treatment. Based on these data, Roche has agreed to provide us their MEK inhibitor, cobimetinib, for a clinical study in these non-BRAF patients. We believe this study will be as effective as the BRAF study and revolutionize care for the non-BRAF patients. This grant from the Histiocytosis Association would provide essential funds for our MEK inhibitor study and related experiments to rigorously prove that the medication works as expected.

Twelve Month Report
Histiocytic diseases are a group of blood disorders that affect both children and adults and can lead to severe disability and death. Until very recently, there were no effective treatments for the more severe forms of these diseases for adults. In 2011, it was discovered that about half of these patients have a mutation (a mistake in the DNA) in a gene called BRAF. Based on this pivotal discovery, we led an international study treating these patients with a medicine, vemurafenib, which blocks this BRAF mutation. The results of this study, which were recently published in the New England Journal of Medicine, have been astounding. Not only did all patients feel better and have their disease shrink but, unlike other diseases where patients have received this drug, patients did not develop resistance to treatment over time. These data suggest that patients may be able to remain on vemurafenib indefinitely and carry on normal lives.

Unfortunately, half of histiocytosis patients do not have the BRAF mutation and therefore cannot benefit from this breakthrough therapy. We and others have conducted intensive genetic analyses of these “non-BRAF” patients and found that nearly all have mutations in other genes that turn on a single tumor growth pathway. Fortunately, a class of medicines (called “MEK” inhibitors) blocks this pathway. Now with funding from the Histiocytosis Association we have launched a clinical trial of the MEK inhibitor cobimetinib for any adult with systemic histiocytosis over the age of 18 who lacks the BRAFV600E mutation and/or has the BRAFV600E mutation but cannot get access to or has failed a BRAF inhibitor. This study is based at Memorial Sloan Kettering Cancer Center and thus far 9 patients have enrolled in the study. You can find more details about this study at www.clinicaltrials.gov under the clinical trial identifier NCT02649972. The results thus far are promising with the treatment appearing to have efficacy as well as safety. In addition to treating patients as part of the clinical trial, we also performed detailed genetic analysis of every patient’s histiocytosis to identify the genetic alterations driving their disease. We hope to understand how each patient’s mutation affects his or her response to the drug.

We would like to thank the Histiocytosis Association as well as our patients and their families in the success of this research and the clinical trial.