Treatment with vemurafenib, a RAF inhibitor, triggered proliferation of leukemia cells in a patient receiving therapy for metastatic melanoma, according to a case report published Nov. 7 in the New England Journal of Medicine.
Increased use of RAF inhibitors such as vemurafenib (Zelboraf) and the still-experimental dabrafenib are likely to stimulate additional cases of leukemia and other cancers in patients with coincidental RAS mutations, warn Dr. Paul D. Chapman of Memorial Sloan-Kettering Cancer Center in New York, and his coauthors.
Dr. Paul D. Chapman
Patients being treated with RAF inhibitors should be closely monitored, the authors advise, and any rapid rise in white-cell count "should be investigated promptly and the drug withheld until the cause of the rise in white cells is clarified." For now, they recommend that adjuvant treatment with RAF inhibitors should only be offered in the context of a clinical trial (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1208958]).
The patient in the case report, a 76-year-old man with stage IV melanoma, experienced improved breathing but also developed "new, profound fatigue" after starting vemurafenib, according to the report. Clinicians determined that he had marked elevations in his white blood count, along with increases in monocytes and neutrophils.
Vemurafenib was stopped, after which white cell and monocyte counts decreased. As the patient responded to treatment, he is again taking vemurafenib, but with clinicians adjusting the dose based on changes in white-cell counts.
Investigation of the case led the authors to hypothesize that vemurafenib was hyperactivating the ERK pathway and stimulating growth of chronic myelomonocytic leukemia cells carrying a preexisting NRAS mutation. They were able to verify this in vitro, and also came up with another hypothesis – that MEK inhibitors might weaken ERK signaling and suppress the proliferation of leukemic cells indirectly caused by vemurafenib.
As of publication, however, the authors were unable obtain a MEK inhibitor to test this hypothesis in a patient, as none are approved by the Food and Drug Administration. MEK inhibitors are being studied in combination with RAF inhibitors and have been shown to improve progression-free survival (N. Engl. J. Med. 2012;367:1694-703 [doi: 10.1056/NEJMoa1210093]).
About half of metastatic melanomas carry BRAF mutations, and about half of patients with BRAF mutations have been found to respond to vemurafenib. This led the FDA to approve vemurafenib in 2011 for treatment of inoperable or metastatic melanoma carrying the BRAFV600E mutation. One side effect of vemurafenib treatment has been an increase in cutaneous skin conditions in about a quarter of patients.
"This case report shows that paradoxical ERK activation by RAF inhibitors is not restricted to proliferations such as squamous cell carcinomas and keratoacanthomas. It is clear that paradoxical activation can be seen in other premalignant lesions in which there are RAS mutations or other genetic changes that result in upstream activation of this pathway," Dr. Chapman and his coauthors wrote.
Dr. Chapman disclosed financial relationships with Roche/Genentech and GlaxoSmithKline and a pending institutional patent title Methods of Using BRAF Inhibitors for Cancer Screening and Imaging.