Mohamad Jawhar

Mast cell leukemia (MCL) is a rare subtype of systemic mastocytosis 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 owing to low event rates), a diagnosis of MCL-AHN (hazard ratio [HR], 4.7; 95% confidence interval [CI], 1.7-13.0; P = .001) and abnormal karyotype (HR, 5.6; 95% CI, 1.4-13.3; P = .02) were associated with inferior OS; KIT D816V positivity (HR, 0.33; 95% CI, 0.11-0.98; P = .04) and midostaurin treatment (HR, 0.32; 95% CI, 0.08-0.72; P = .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.

In systemic mastocytosis (SM), qualitative and serial quantitative assessment of the KIT D816V mutation is of diagnostic and prognostic relevance. We investigated peripheral blood and bone marrow samples of 161 patients (indolent SM (ISM), n = 40; advanced SM, AdvSM, n = 121) at referral and during follow-up for the KIT D816V variant allele frequency (VAF) at the DNA-level and the KIT D816V expressed allele burden (EAB) at the RNA-level. A round robin test with four participating laboratories revealed an excellent correlation (r > 0.99, R² > 0.98) between three different DNA-assays. VAF and EAB strongly correlated in ISM (r = 0.91, coefficient of determination, R² = 0.84) but only to a lesser extent in AdvSM (r = 0.71; R² = 0.5). However, as compared to an EAB/VAF ratio ≤2 (cohort A, 77/121 patients, 64%) receiver operating characteristic (ROC) analysis identified an EAB/VAF ratio of >2 (cohort B, 44/121 patients, 36%) as predictive for an advanced phenotype and a significantly inferior median survival (3.3 vs. 11.7 years; p = 0.005). In terms of overall survival, Cox-regression analysis was only significant for the EAB/VAF ratio >2 (p = 0.006) but not for VAF or EAB individually. This study demonstrates for the first time that the transcriptional activity of KIT D816V may play an important role in the pathophysiology of SM.

Mastocytosis is a rare and complex disease characterized by expansion of clonal mast cells (MC) in skin and/or various internal organ systems. Involvement of internal organs leads to the diagnosis of systemic mastocytosis (SM). The WHO classification divides SM into indolent SM, smoldering SM and advanced SM variants, including SM with an associated hematologic neoplasm, aggressive SM, and MC leukemia. Historically, genetic analysis of individuals with pure cutaneous mastocytosis (CM) and SM have focused primarily on cohort studies of inherited single nucleotide variants and acquired pathogenic variants. The most prevalent pathogenic variant (mutation) in patients with SM is KIT p.D816V, which is detectable in most adult patients. Other somatic mutations have also been identified—especially in advanced SM—in TET2, SRSF2, ASXL1, RUNX1, CBL and JAK2, and shown to impact clinical and cellular phenotypes. Although only small patient cohorts have been analyzed, disease associations have also been identified in several germline variants within genes encoding certain cytokines or their receptors (IL13, IL6, IL6R, IL31, IL4R) and toll-like receptors. More recently, an increased prevalence of hereditary alpha-tryptasemia (HαT) caused by increased TPSAB1 copy number encoding alpha-tryptase has been described in patients with SM. Whereas HαT is found in 3–6% of general Western populations, it is identified in up to 17% of patients with SM. In the current manuscript we review the prevalence, functional role and clinical impact of various germline and somatic genetic variants in patients with mastocytosis.

Purpose: Systemic mastocytosis (SM) is characterized by the expansion of clonal mast cells that infiltrate various organ systems. The extent of organ infiltration and subsequent organ damage distinguishes between indolent SM (ISM) defined by a nearly normal life expectancy and advanced SM (AdvSM) defined by poor prognosis. In ISM, measurement of the bone mineral density (BMD) frequently reveals osteoporosis. In contrast, the clinical implication of an increased BMD and osteosclerosis remains unclear. Methods: BMD was evaluated in 61 patients with mastocytosis (ISM, n = 29, 48%; AdvSM, n = 32, 52%). We correlated the prevalence of osteoporosis, increased BMD and osteosclerosis with clinical parameters, disease variant and prognosis. Results: Osteoporosis was detected in 11/29 (38%) patients with ISM but only in 2/32 (6%) patients with AdvSM (p = 0.004). An increased BMD was detected in 1/29 (3%) patients with ISM and 24/32 (75%) patients with AdvSM (p < 0.001) while osteosclerosis was only detected in AdvSM patients (16/32, 50%). AdvSM patients with increased BMD had higher levels of bone marrow mast cell infiltration, higher serum tryptase and alkaline phosphatase levels compared to ISM as well as higher number of high-molecular risk mutations (p < 0.05). In addition, we found that the prognosis of AdvSM patients with increased BMD is inferior compared to those without increased BMD (median overall survival 3.6 years versus not reached, p = 0.031). Conclusions: Osteoporosis is a common feature in ISM but not in AdvSM. An increased BMD is frequently present in AdvSM but not in ISM and is associated with more advanced disease and inferior outcome.

Systemic mastocytosis (SM) is broadly subcategorized according to mast cell (MC) burden and organ involvement into indolent (ISM), smoldering (SSM), and advanced SM (AdvSM). However, the pattern and extent of bone involvement remains controversial. In this institutional review board (IRB)-approved study, 115 patients with different forms of SM (ISM (n = 37, 32%), SSM (n = 9, 8%), and AdvSM (n = 69, 60%)) underwent a whole-body magnetic resonance imaging including sagittal and coronal T1 and turbo inversion recovery magnitude (TIRM) sequences of the spine. The evaluation included the pattern and extent of pathologic bone marrow (BM) signals in the spine and extremities, osteolytic lesions, and vertebral fractures. A pathologic BM pattern was observed in 4/37 (11%), 8/9 (89%), and 66/69 (96%); affection of the appendicular skeleton in 3/37 (8%), 8/9 (89%), and 67/69 (97%); and vertebral fractures in 7/37 (19%), 0/9, and 13/69 (19%) patients with ISM, SSM, and AdvSM, respectively. In AdvSM, pathologic BM pattern included activated (62%), diffuse sclerotic (25%), and small-spotted BM (9%), respectively. Only activated/sclerotic BM was associated with significantly higher MC burden, organ damage, and inferior median survival (2.9 years, p = 0.04). Vertebral fractures resembled classical multi-segmental osteoporotic fractures in ISM but not in AdvSM in which they were only found in activated/sclerotic BM. Only one patient with AdvSM had a focal osteolytic lesion in the femur. Activated/sclerotic BM changes of the spine and affection of the appendicular skeleton are indicative for SSM or AdvSM. Osteolytic lesions, which are very rare, and osteoporotic fractures are ineligible for the diagnosis of AdvSM.

PURPOSE: To develop a risk score for patients with advanced systemic mastocytosis (AdvSM) that integrates clinical and mutation characteristics.PATIENTS AND METHODS: The study included 383 patients with AdvSM from the German Registry on Disorders of Eosinophils and Mast Cells (training set; n = 231) and several centers for mastocytosis in the United States and Europe, all within the European Competence Network on Mastocytosis (validation set; n = 152). A Cox multivariable model was used to select variables that were predictive of overall survival (OS).RESULTS: In multivariable analysis, the following risk factors were identified as being associated with OS: age greater than 60 years, anemia (hemoglobin < 10 g/dL), thrombocytopenia (platelets < 100 × 10⁹/L), presence of one high molecular risk gene mutation (ie, in SRSF2, ASXL1, and/or RUNX1), and presence of two or more high molecular risk gene mutations. By assigning hazard ratio–weighted points to these variables, the following three risk categories were defined: low risk (median OS, not reached), intermediate risk (median OS, 3.9 years; 95% CI, 2.1 to 5.7 years), and high risk (median OS, 1.9 years; 95% CI, 1.3 to 2.6 years; P < .001). The mutation-adjusted risk score (MARS) was independent of the WHO classification and was confirmed in the independent validation set. During a median follow-up time of 2.2 years (range, 0 to 23 years), 63 (16%) of 383 patients experienced a leukemic transformation to secondary mast cell leukemia (32%) or secondary acute myeloid leukemia (68%). The MARS was also predictive for leukemia-free survival ( P < .001).CONCLUSION: The MARS is a validated, five-parameter, WHO-independent prognostic score that defines three risk groups among patients with AdvSM and may improve up-front treatment stratification for these rare hematologic neoplasms.