Dasatinib therapy for systemic mastocytosis: four cases

To the Editor: Systemic mastocytosis (SM) is an uncommon disorder characterised by clonal proliferation and tissue infiltration by mast cells. Effective treatment options for patients with this disease are currently limited. Malignant mast cells are derived from stem cells with activating mutations of the KIT receptor tyrosine kinase (1, 2). The KIT mutation has been implicated in a significant proportion of SM cases (3). Dasatinib (BMS-354825; Bristol-Myers Squibb, New York, NY, USA) is a novel tyrosine kinase inhibitor which has been proven effective in inhibiting D816V positive mast cells in vitro (4, 5). There are currently no published clinical studies evaluating dasatinib in patients with SM. We report four cases of SM treated with dasatinib. The clinical, histological and genetic features of each case are summarised in Table 1. D816V mutation was detected in unfractionated bone marrow cells using a PCR assay (6), while fluorescence in situ hybridisation (FISH) studies were performed for FIP1L1-PDGFRa (7). Mast cell tryptase was measured using the UniCAP 100 (Pharmacia & Upjohn Diagnostics, Uppsala, Sweden) immunoabsorbant assay. Bone marrow trephine biopsies were examined and graded for the extent of involvement by mast cells as outlined in Table 1. Dasatinib was obtained from Bristol-Myers Squibb on compassionate grounds. Case 1 is a 20-year-old female who presented with pruritic skin rash, anorexia, diarrhoea and weight loss of 15 kg (18% of total body weight). Treatment with dasatinib 50 mg daily commenced with concomitant hydrocortisone (100 mg intravenously) and anti-histamine for the first three doses. A moderate exacerbation of skin rash, pruritus and nausea occurred 1 h after the first dose and resolved at 4 d. Dasatinib dose was increased to 50 mg twice daily at 1 month. A moderate reduction in pruritus, improved appetite and weight gain of 10 kg occurred after 6 months, though there was not significant change on repeat bone marrow biopsy. Case 2 is a 52-year-old male who presented with symptomatic pericardial effusion, hepatomegaly and splenomegaly (6 cm). Bone marrow biopsy showed myelodysplasia and diffuse infiltrates of mast cells. Initial treatment with imatinib was not effective and the patient developed moderate diarrhoea and generalised pruritic skin rash. Treatment with dasatinib commenced at 70 mg twice daily with concomitant antihistamines. The patient suffered significantly worse diarrhoea, pruritus and headaches from day 2 to day 5. Complete remission of diarrhoea and skin rash occurred after day 5. Bone marrow examination at 7 months revealed histological response (see Table 1). After 11 months, the patient developed acute myeloid leukaemia and dasatinib therapy ceased. Case 3 is a 60-year-old female who presented with an 18-month history of pruritic skin rash, headaches and lethargy. Early treatment including prednisolone, cladribine, nilotinib, interferon-alpha and splenic radiotherapy was ineffective and the patient developed grade 4 pancytopenia. Dasatinib therapy commenced 5 yr after initial diagnosis. Dose was escalated from 20 mg twice daily to 70 mg twice daily over 3 d, with administration of corticosteroid (hydrocortisone 100 mg intravenously, one dose only) and anti-histamines prior to each dose. Prednisolone 37.5 mg daily was weaned over the following 6 wk. No adverse effects occurred during early treatment. There was no evidence of significant clinical or histological response despite dose increase to 90 mg twice daily and then 110 mg twice daily. Dasatinib therapy ceased after 2 months. Two months later the patient died of complications related to sepsis. Case 4 is a 49-year-old man who was diagnosed with indolent systemic mastocytosis with prominent mast cell degranulation symptoms (ISMSY) after presenting with anaphylactic shock on a background of four previous episodes of anaphylaxis. Interferon-alpha, cladribine, prednisolone and intravenous human immunoglobulin were ineffective and episodes of anaphylaxis occurred with increasing frequency. Dasatinib commenced at 4 yr after diagnosis. Concomitant therapy included ranitidine (ceased with first dasatinib dose), dexchlorpheniramine, sodium cromoglycate, ketolifen and montelukast. No adverse effects were observed. Episodes of anaphylaxis occurred with the same frequency. Dasatinib therapy ceased after 6 months. Dasatinib was generally well tolerated. Cases 1 and 2 suffered early adverse effects that are likely to have been mediated by mast cell mediator release. A similar phenomenon is observed with other cytoreductive agents in SM (8). Cases 3 and 4 showed no response to dasatinib therapy. Both had been heavily pretreated prior to commencing treatment. This small series suggests that dasatinib has some in vivo activity in SM, treating symptoms and reversing disease progression in some patients. The doi:10.1111/j.1600-0609.2008. 01048.x European Journal of Haematology ISSN 0902-4441