Mast cell leukemia (MCL) is a rare subtype of systemic mastocytosis (SM) defined by >20% mast cells (MC) on a bone marrow aspirate. We evaluated 92 patients with MCL from the European Competence Network on Mastocytosis registry. Thirty-one (34%) patients had a diagnosis of MCL with an associated hematologic neoplasm (MCL-AHN). Chronic MCL (lack of C-findings) comprised 14% of patients, and only 4.5% had 'leukemic MCL' (≥ 10% circulating MCs). KIT D816V was found in 62/85 (73%) evaluable patients; 9 (11%) individuals exhibited alternative KIT mutations, and no KIT variants were detected in 14 (17%) subjects. Ten evaluable patients (17%) had an abnormal karyotype and the poor-risk SRSF2, ASXL1, and RUNX1 (S/A/R) mutations were identified in 16/36 (44%) patients who underwent next-generation sequencing. Midostaurin was the most common therapy, administered to 65% of patients, and 45% as first-line therapy. The median overall survival (OS) was 1.6 years. In multivariate analysis (S/A/R mutations excluded due to low event rates), a diagnosis of MCL-AHN (HR 4.7, 95% CI 1.7 - 13.0, p = 0.001) and abnormal karyotype (HR 5.6, 95% CI 1.4 - 13.3, p = 0.02) were associated with inferior OS; KIT D816V positivity (HR 0.33, 95% CI 0.11 - 0.98, p = 0.04) and midostaurin treatment (HR 0.32, 95% CI 0.08 - 0.72, p = 0.008) were associated with superior OS. These data provide the most comprehensive snapshot of the clinicopathologic, molecular, and treatment landscape of MCL to date, and should help further inform subtyping and prognostication of MCL.

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Advanced systemic mastocytosis (AdvSM) is a rare myeloid neoplasm, driven by KIT D816V mutation in >90% of patients. Avapritinib, a potent, highly selective inhibitor of D816V-mutant KIT, is approved for treatment of adults with AdvSM by the US Food and Drug Administration, regardless of prior therapy, and the European Medicines Agency, for patients with prior systemic therapy, based on EXPLORER (NCT02561988) and PATHFINDER (NCT03580655) clinical studies. We present latest pooled efficacy and safety analyses from patients who received ≥1 systemic therapy prior to avapritinib in EXPLORER/PATHFINDER. Overall response rate in response-evaluable patients (n=31) was 71% (95% confidence interval: 52-86%; 22/31), including 19% (6/31) with complete remission (CR)/CR with partial recovery of peripheral blood counts (CRh). Median time to response was 2.3 months; median time to CR/CRh was 7.4 months; median duration of response was not reached. Reductions ≥50% in bone marrow mast cell infiltration (89%), KIT D816V variant allele fraction (66%), serum tryptase (89%), and reductions ≥35% in spleen size (70%) occurred in most patients. With median follow up of 17.7 months, median OS was not reached. Avapritinib was effective in all AdvSM subtypes, regardless of number/type of prior therapies or somatic mutations associated with poor prognosis. Treatment-related adverse events (TRAEs) were observed in 94% of patients, most commonly grade 1 or 2; 57% had TRAEs ≥grade 3; 81% remained on treatment at 6 months. Avapritinib in adults with AdvSM who received prior systemic therapy was generally well tolerated with high response rates regardless of prior systemic therapy.