Abstract
Objectives: Systemic mastocytosis (SM) is mainly a clonal disease with a variable clinical outcome. Prognosis is very much related to additional symptoms. If so called c-findings are present, survival is often limited to months. Until recently only Interferon and Cladribine could show some effect on the disease progression. With the introduction of Imatinib some hope grew to treat the disease by acting on c-KIT (CD 117; stem cell factor receptor). However, the substitution of valine for aspartic acid at position 816 in c-KIT (D816V) leads to prolonged mast cell survival and increased proliferation because of constitutive activation of the tyrosine kinase of c-KIT. Between 31% and 100% of patients with SM harbour the c-KIT D816V mutation which is invariably related to Imatinib resistance. Fortunately, the new tyrosinkinase inhibitor Dasatinib (BMS-354825) could show a much higher inhibition of the c-KIT D816V mutated receptor in vitro. Therefore we treated a patient with systemic mastocytosis with associated hematologic clonal non mast cell lineage disease (SM-AHNMD) and c-findings with Dasatinib.
Case description: A 69 year old patient was diagnosed 5 years ago with cutaneous mastocytosis. Because of a markedly increased tryptase levels of 130μg/l he was referred to our clinic for further investigation. In a bone marrow biopsy, the classical signs of SM could be found together with a chronic myelomonocytic leukemia (CMML) without any cytogenetic alterations. During 2 years the patient remained clinically stable without any treatment. Subsequently the patient droped weight and got strong lumbar pain. A MRI scan revealed fractures of L2 and L4 without signs for osteoporosis. Additionally, splenomegaly and hepatomegaly have been noticed with enlarged lymph nodes in the retroperitoneal space together with profound thrombocytopenia. Even SM-AHNMD is by definition of the ‘year 2000 Working Conference on Mastocytosis’ a distinct entity, the occurring c-findings together with a rapid increase in tryptase levels have been associated with an aggressive disease course. A c-KIT mutation analysis showed a D816V mutation. We decided after approval from the medical council to start the patient on Dasatinib. We started with 50mg daily for 3 days. Because no signs of acute mastcell degranulation we increased the dose to 50mg BID and continued the treatment for 13 weeks. Due to non-hematologic toxicity (fatigue) Dasatinib had to be stopped. Hepatosplenomegaly remained stable, lumbar pain disappeared even after cessation of analgetic therapy and weight increased gradually. However, laboratory follow up (tryptase, soluble interleukin 2 receptor) showed inconsistent results.
Conclusion: Our patient with SM-CMML had many signs of systemic aggressive mastocytosis which is a mostly fatal variant of SM. With the introduction of Imatinib, a potent c-kit inhibitor, a novel approach to inhibit mastcell-proliferation was described. However, the most common mutation in CD117 of mastcells (D816V mutation) turned out to be resistant to Imatinib. However, Dasatinib a recently introduced tyrosinkinase inhibitor showed significant efficacy in vitro. A phase II study of Dasatinib in patients with Philadelphia-negative myeloproliferative disorders, including SM has recently been presented by Verstovsek and colleagues showing an overall response rate of 42% in SM. However, these patients were c-KIT mutation negative. This case report shows first evidence of clinical activity of Dasatinib in a patient with systemic aggressive mastocytosis harbouring the c-KIT mutation D816V. Further clinical studies in this patient population are warranted.
Gastrointestinale Stromatumoren (GIST)