Chemotherapy and dasatinib induce long-term hematologic and molecular remission in systemic mastocytosis with acute myeloid leukemia with KIT^D816V

Abstract 

Dasatinib has been reported to potently inhibit juxtamembrane domain mutant KIT^D816V autophosphorylation and KIT-dependent activation of down stream signaling important for cell growth and survival of neoplastic cells. Additionally, dasatinib induced apoptosis in mast cell and leukemia cell lines expressing KIT^D816V. Here, we present the first case report of long-term hematologic and molecular remission achieved with combined treatment with chemotherapy and dasatinib in a patient with systemic mastocytosis (SM) and acute myeloid leukemia (AML) with mutant KIT^D816V expression. A 50-year-old male presented with pancytopenia, organomegaly, lymphadenopathy, and lytic bone lesions in the pelvis. The patient was found to have systemic mastocytosis (SM) and acute myelogeneous leukemia (AML) positive for KIT^D816V and therefore diagnosed with SM with an associated clonal hematological non-mast cell lineage disease (SM-AHNMD). Both primary CD34+ cells containing myeloblasts and CD34− cells containing mastocytes obtained from the diagnostic BM lost viability markedly by in vitro dasatinib treatment. In addition, dasatinib diminished activity of STAT5, STAT3, AKT and ERK and attenuated the levels of c-KIT. The patient achieved a hematologic complete remission (HCR) by two induction chemotherapies with residual mastocytes. Dasatinib (70mg PO bid, days 1–4) was added to consolidation treatments composed of four cycles of high dose cytarabine and was then continued as maintenance therapy (50mg PO bid). Periodic bone marrow (BM) aspirate/biopsies (eight over 18 months) were performed. The patient remained in HCR, and the mastocyte burden decreased by 50%. The bone lytic lesions improved. The KIT^D816Vmutation progressively decreased and became undetectable in the last three BM analyses. This result was confirmed by an independent laboratory showing a lack of c-KIT mutation in both CD34+ cells and CD34− cells in the last BM. No significant adverse effects of dasatinib occurred. Dasatinib has in vitro and in vivo efficacy in SM-AML patients with KIT^D816V mutation. Along with chemotherapy, dasatinib should be considered in these patients particularly if they cannot undergo allogeneic stem cell transplantation for this poor prognostic AML.

Keywords: Systemic mastocytosis, Systemic mastocytosis with associated clonal hematological non-mast cell lineage disease, Acute myeloid leukemia, Asp816Val mutation, KIT^D816V, Tyrosine kinase inhibitor, Dasatinib