Systemic Mastocytosis with Associated Acute Myeloid Leukemia (SM-AML): a Poor-Risk Multi-Mutated Disease That Follows a Distinct Diagnostic Algorithm and Requires High-Dose Stem Cell-Targeting Therapy

In systemic mastocytosis (SM), clinical phenotype, response to treatment and prognosis are influenced by the KIT D816V mutation (80-90% of patients positive), additional mutations in SRSF2, ASXL1 or RUNX1 (S/A/R^pos) and chromosomal aberrations. In core-binding factor acute myeloid leukemias (CBF-AML), KIT mutations are identified in about 30% of cases, conferring an adverse prognostic impact on survival. However, patients with AML are not routinely checked for the contemporaneous presence or absence of SM. We sought to evaluate a) clinical and molecular characteristics, b) responses to treatment and survival, and c) prognostic factors in 44 patients with SM and associated AML (SM-AML). The median age was 64 years (range 28-83), 64% were male. In the majority of patients (30/44, 68%), AML evolved a median of 24 months (range 2-153) after diagnosis of SM without (6/30, 20%) or with (24/30, 80%) an associated hematologic neoplasm (AHN) such as myelodysplastic syndrome (SM-MDS), myeloproliferative neoplasm (SM-MPN) or MDS/MPN (SM-MDS/MPN). Based on histopathology, SM was contemporaneously diagnosed with AML in 14/44 (32%) patients. At diagnosis of SM-AML, the median bone marrow infiltration by mast cells and myeloid blasts was 15% (range 5-65; ≥20% in 45% of patients) and 39% (range 20-95), respectively, and the median serum tryptase level was 92 μg/l (range 2-885; ≥150 in 39% of patients). In the majority of patients, material was available for molecular analyses and revealed the following markers at diagnosis of SM-AML: a) KIT D816V in 36/41 (88%) patients, b) additional mutations by targeted next-generation sequencing (NGS, 28 myeloid gene panel) in 32/33 (97%) patients, the most frequent mutations were: RUNX1 (n=12, 36%), TET2 (n=11, 33%), SRSF2 (n=11, 33%), ASXL1 (n=9, 27%), IDH1 / 2 (n=6, 18%), NPM1 (n=6, 18%), BCOR (n=5, 15%), DNMT3A (n=4, 12%), and, c) an aberrant karyotype in 25/35 (71%) patients (in analogy to related myeloid neoplasms, e.g. MDS or AML, patients were classified according to their karyotype into three groups: favorable-, intermediate- and poor-risk; only 1 patient with a CBF translocation). Patients with a known history of SM were frequently S/A/R^pos (19/22, 86%) and acquisition of additional mutations (NPM1, n=2; IDH1, n=2; BCOR / JAK2 / TP53 / PHF6 / RUNX1, n=1) or karyotype evolution at time of SM-AML was observed in 8/15 (53%) or 9/13 (69%) patients, respectively. NGS on DNA derived from CD34+ myeloid blasts of 6 KIT D816V positive patients revealed the presence of KIT D816V positive blasts in only 1/6 (17%) patients while additional mutations were found in blast cells of all 6 patients. Eight patients received supportive care due to age and/or comorbidity. In 36 patients, disparate combinations of AML-type chemotherapy ± hypomethylating agents (HMA) ± cladribine (n=16) were administered. Cytarabine-based consolidation treatment was administered in 4/36 (11%) patients in complete remission (CR). Allogeneic stem cell transplantation (SCT) was performed in 15/36 (42%) patients, only 6/15 (40%) patients were in CR prior to allogeneic SCT. Overall, 5/10 (50%) patients in CR of AML showed persistence of SM. From diagnosis of SM-AML, the median observation was 10 months (range 0-200); 32/44 (73%) patients died during observation. The median overall survival (OS) was 11 months (95% confidence interval [CI], 4-17) with median OS of 2 (range 0-5), 4 (range 0-12) and 74 (range 0-149) months for patient cohorts who were treated with supportive care, intensive chemotherapy/HMA and intensive chemotherapy followed by allogeneic SCT, respectively (P=0.0002). On multivariate analysis, the only independent prognostic marker for OS was favorable-risk karyotype (n=14) vs. intermediate-/poor-risk karyotype (n=21; median OS 21 vs. 7 months; HR 3.2 [1.3-7.8], P=0.007). We conclude that a) SM-AML seems to be more frequent than commonly believed, b) SM-AML should be regarded as secondary AML evolving from multimutated SM-AHN, c) KIT mutations are not restricted to CBF-AML, d) progression to SM-AML is often triggered by acquisition of new mutations and/or karyotype evolution, e) SM-AML has an aggressive phenotype and a poor prognosis, f) treatment of SM-AML should include a combination of intensive chemotherapy and allogeneic SCT for eligible patients and g) the disease frequency and poor prognosis warrant routine screening of all AML cases for serum tryptase and KIT D816V.