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(D816V)mutation 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.