Mastocytosis is a heterogeneous group of disorders characterized by the abnormal growth and accumulation of mast cells in one or more organs. Somatic mutations in the c-kit gene are associated with >80% of mastocytosis cases with the most common mutation identified as c-kit D816V. Imatinib mesylate is a potent inhibitor of c-kit tyrosine kinase activity, though the D816V mutation has been demonstrated to confer imatinib resistance both in vitro and in vivo. In this study we sought to determine the safety and efficacy of imatinib in patients with systemic mastocytosis who had no identified mutation that conferred imatinib resistance. We screened 24 patients and identified 5 patients who met study criteria, which included systemic mastocytosis by WHO consensus criteria (Valent et al, Leuk Res, 2003), impaired organ function to justify cytoreductive therapy, and wild-type c-kit exon 17 (including codon 816) DNA sequence analysis from peripheral blood, bone marrow, or lesional tissue specimens. In all cases patients were negative for the FIP1L1-PDGFRA fusion kinase. Four patients consented to the study and were treated with 400 mg of imatinib orally once daily in a dose-escalation protocol up to 800 mg daily for six months. Of the four patients entering the study, two had systemic mastocytosis with an associated hematologic non-mast cell disorder (in both cases CMML) and two had aggressive systemic mastocytosis. At the end of the six month treatment period all patients were assessed to have a partial response. Serum tryptase had fallen between 19–44% and skin lesions diminished in all patients with cutaneous involvement but did not resolve. All subjects reported subjective symptom improvement with regards to pruritis, flushing, GI symptoms, and other constitutional manifestations. However, bone marrow examination performed after the trial period when available demonstrated persistent mast cell infiltration. In two patients cutaneous mastocytosis lesions progressed within 6 months after discontinuation of imatinib. Imatinib was generally well-tolerated, though dose-dependent toxicity was noted in all patients and especially in patients > 65 years of age, and included edema, nausea, muscle cramps, conjunctivitis, cough, fatigue, and anemia.

Imatinib mesylate is safe and may have some efficacy in treating patients with systemic mastocytosis who lack imatinib-resistant mutations in c-kit.

Disclosures: This clinical trial was performed with IRB approval with an FDA IND.; Research funding provided by Novartis.; Dr. Katz – Speaker’s bureau for AstraZeneca, Pfizer.

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