Serum chemistry profiling and prognostication in systemic mastocytosis: a registry-based study of the ECNM and GREM.

ABSTRACT: Certain laboratory abnormalities correlate with subvariants of systemic mastocytosis (SM) and are often prognostically relevant. To assess the diagnostic and prognostic value of individual serum chemistry parameters in SM, 2607 patients enrolled within the European Competence Network on Mastocytosis and 575 patients enrolled within the German Registry on Eosinophils and Mast Cells were analyzed. For screening and diagnosis of SM, tryptase was identified as the most specific serum parameter. For differentiation between indolent and advanced SM (AdvSM), the following serum parameters were most relevant: tryptase, alkaline phosphatase, ß2-microglobulin, lactate dehydrogenase (LDH), albumin, vitamin B12, and C-reactive protein (P < .001). With regard to subvariants of AdvSM, an elevated LDH of ≥260 U/L was associated with multilineage expansion (leukocytosis, r = 0.37, P < .001; monocytosis, r = 0.26, P < .001) and the presence of an associated myeloid neoplasm (P < .001), whereas tryptase levels were highest in mast cell leukemia (MCL) vs non-MCL (308µg/L vs 146µg/L, P = .003). Based on multivariable analysis, the hazard-risk weighted assignment of 1 point to LDH (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.1-4.0; P = .018) and 1.5 points each to ß2-microglobulin (HR, 2.7; 95% CI, 1.4-5.4; P = .004) and albumin (HR, 3.3; 95% CI, 1.7-6.5; P = .001) delineated a highly predictive 3-tier risk classification system (0 points, 8.1 years vs 1 point, 2.5 years; ≥1.5 points, 1.7 years; P < .001). Moreover, serum chemistry parameters enabled further stratification of patients classified as having an International Prognostic Scoring System for Mastocytosis-AdvSM1/2 risk score (P = .027). In conclusion, serum chemistry profiling is a crucial tool in the clinical practice supporting diagnosis and prognostication of SM and its subvariants.

Prevalence of hypersensitivity reactions in various forms of mastocytosis: A pilot study of 2485 adult patients with mastocytosis collected in the ECNM registry.

BACKGROUND: Hypersensitivity reactions (HR) are common in mastocytosis. However, little is known about triggers and risk factors. The registry of the European Competence Network on Mastocytosis (ECNM) enables reliable studies in a larger cohort of mastocytosis patients. We assessed prevalence, triggers and risk factors of HR in adults with mastocytosis in the ECNM registry. METHODS: Data were collected in 27 ECNM centers. We analyzed potential triggers (Hymenoptera venoms, food, drug, inhalant and others) and risk factors at diagnosis and during follow-up. The study group consisted of 2485 adults with mastocytosis, 1379 women (55.5%) and 1106 men (44.5%). Median age was 48.2 years (range 18-91 years). RESULTS: Nine hundred and forty eight patients (38.1%) reported one or more HR`. Most common triggers were Hymenoptera venoms in cutaneous mastocytosis (CM) and indolent systemic mastocytosis (ISM), whereas in advanced SM (advSM), most common elicitors were drugs, including nonsteroidal anti-inflammatory agents and penicillin. In multivariate analyses, tryptase level < 90 ng/mL, <15% infiltration by mast cells in bone marrow biopsy-sections, and diagnosis of ISM were identified as independent risk factors for HR. For drug-induced HR, prominent risk factors were advSM and high tryptase levels. New reactions were observed in 4.8% of all patients during 4 years follow-up. CONCLUSIONS: HR are mainly triggered by Hymenoptera venoms in patients with CM and ISM and by drugs in patients with advSM. Tryptase levels <90 ng/mL, mast cell bone marrow infiltration <15%, and WHO category ISM are predictors of HR. New HR occur in 4.8% of all patients within 4 years.

Allogeneic Hematopoietic Cell Transplantation in Advanced Systemic Mastocytosis: A retrospective analysis of the DRST and GREM registries.

We identified 71 patients with AdvSM (aggressive SM [ASM], SM with an associated hematologic neoplasm [SM-AHN, e.g., acute myeloid leukemia, SM-AML], mast cell leukemia [MCL]) in two national registries (DRST/GREM) who received an allogeneic hematopoietic cell transplantation (alloHCT) performed in Germany from 1999-2021. Median overall survival (OS) of ASM/SM-AHN (n = 30, 45%), SM-AML (n = 28, 39%) and MCL ± AHN (n = 13, 19%) was 9.0, 3.3 and 0.9 years (P = 0.007). Improved median OS was associated with response of SM (17/41, 41%; HR 0.4 [0.2-0.9], P = 0.035) and/or of AHN (26/43, 60%, HR 0.3 [0.1-0.7], P = 0.004) prior to alloHCT. Adverse predictors for OS included absence of KIT D816V (10/61, 16%, HR 2.9 [1.2-6.5], P < 0.001) and a complex karyotype (9/60, 15%, HR 4.2 [1.8-10.0], P = 0.016). HLA-match, conditioning type or transplantation at centers reporting above-average alloHCTs (≥7) had no impact on OS. Taking into account competing events at years 1, 3 and 5, relapse-related mortality and non-relapse mortality rate were 15%/23%, 20%/30% and 23%/35%, respectively. Irrespective of subtype, subsequent treatment response was achieved in 13/30 (43%) patients and was highest on midostaurin/avapritinib (7/9, 78%). We conclude that outcome of alloHCT in AdvSM is more affected by disease phenotype and treatment response prior to transplant than by transplant characteristics.

Poor Applicability of Currently Available Prognostic Scoring Systems for Prediction of Outcome in KIT D816V-Negative Advanced Systemic Mastocytosis.

Within our nationwide registry, we identified a KIT D816V mutation (KIT D816Vpos.) in 280/299 (94%) patients with advanced systemic mastocytosis (AdvSM). Age, cytopenias and the presence of additional somatic mutations confer inferior overall survival (OS). However, little is known about the characteristics of KIT D816V-negative (D816Vneg.) AdvSM. In 19 D816Vneg. patients, a combination of clinical, morphological and genetic features revealed three subgroups: (a) KIT D816H- or Y-positive SM (KIT D816H/Ypos., n = 7), predominantly presenting as mast cell leukemia (MCL; 6/7 patients), (b) MCL with negative KIT sequencing (KITneg. MCL, n = 7) and (c) KITneg. SM with associated hematologic neoplasm (KITneg. SM-AHN, n = 5). Although >70% of patients in the two MCL cohorts (KIT D816H/Ypos. and KITneg.) were classified as low/intermediate risk according to prognostic scoring systems (PSS), treatment response was poor and median OS was shorter than in a KIT D816Vpos. MCL control cohort (n = 29; 1.7 vs. 0.9 vs. 2.6 years; p < 0.04). The KITneg. SM-AHN phenotype was dominated by the heterogeneous AHN (low mast cell burden, presence of additional mutations) with a better median OS of 4.5 years. We conclude that (i) in MCL, negativity for D816V is a relevant prognostic factor and (ii) PSS fail to correctly classify D816Vneg. patients.

Prognostic Impact of Organomegaly in Mastocytosis: An Analysis of the European Competence Network on Mastocytosis.

BACKGROUND: Organomegaly, including splenomegaly, hepatomegaly, and/or lymphadenopathy, are important diagnostic and prognostic features in patients with cutaneous mastocytosis (CM) or systemic mastocytosis (SM). OBJECTIVES: To investigate the prevalence and prognostic impact of 1 or more organomegalies on clinical course and survival in patients with CM/SM. METHODS: Therefore, 3155 patients with CM (n = 1002 [32%]) or SM (n = 2153 [68%]) enrolled within the registry of the European Competence Network on Mastocytosis were analyzed. RESULTS: Overall survival (OS) was adversely affected by the number of organomegalies (OS: #0 vs #1 hazard ratio [HR], 4.9; 95% CI, 3.4-7.1, P < .001; #1 vs #2 HR, 2.1, 95% CI, 1.4-3.1, P < .001; #2 vs #3 HR, 1.7, 95% CI, 1.2-2.5, P = .004). Lymphadenopathy was frequently detected in patients with smoldering SM (SSM, 18 of 60 [30%]) or advanced SM (AdvSM, 137 of 344 [40%]). Its presence confered an inferior outcome in patients with AdvSM compared with patients with AdvSM without lymphadenopathy (median OS, 3.8 vs 2.6 years; HR, 1.6; 95% CI, 1.2-2.2; P = .003). OS was not different between patients having organomegaly with either ISM or SSM (median, 25.5 years vs not reached; P = .435). At time of disease progression, a new occurrence of any organomegaly was observed in 17 of 40 (43%) patients with ISM, 4 of 10 (40%) patients with SSM, and 33 of 86 (38%) patients with AdvSM, respectively. CONCLUSIONS: Organomegalies including lymphadenopathy are often found in SSM and AdvSM. ISM with organomegaly has a similar course and prognosis compared with SSM. The number of organomegalies is adversely associated with OS. A new occurrence of organomegaly in all variants of SM may indicate disease progression.

Capitalizing on paradoxical activation of the mitogen-activated protein kinase pathway for treatment of Imatinib-resistant mast cell leukemia.

Prevention of fatal side effects during cancer therapy of cancer patients with high-dosed pharmacological inhibitors is to date a major challenge. Moreover, the development of drug resistance poses severe problems for the treatment of patients with leukemia or solid tumors. Particularly drug-mediated dimerization of RAF kinases can be the cause of acquired resistance, also called "paradoxical activation." In the present work we re-analyzed the effects of different tyrosine kinase inhibitors (TKIs) on the proliferation, metabolic activity, and survival of the Imatinib-resistant, KIT V560G, D816V-expressing human mast cell (MC) leukemia (MCL) cell line HMC-1.2. We observed that low concentrations of the TKIs Nilotinib and Ponatinib resulted in enhanced proliferation, suggesting paradoxical activation of the MAPK pathway. Indeed, these TKIs caused BRAF-CRAF dimerization, resulting in ERK1/2 activation. The combination of Ponatinib with the MEK inhibitor Trametinib, at nanomolar concentrations, effectively suppressed HMC-1.2 proliferation, metabolic activity, and induced apoptotic cell death. Effectiveness of this drug combination was recapitulated in the human KIT D816V MC line ROSAKIT D816V and in KIT D816V hematopoietic progenitors obtained from patient-derived induced pluripotent stem cells (iPS cells) and systemic mastocytosis patient samples. In conclusion, mutated KIT-driven Imatinib resistance and possible TKI-induced paradoxical activation can be efficiently overcome by a low concentration Ponatinib and Trametinib co-treatment, potentially reducing the negative side effects associated with MCL therapy.

Mast cell leukemia: clinical and molecular features and survival outcomes of patients in the ECNM Registry.

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.

Immunoglobulins to mitigate paraneoplastic Lambert Eaton Myasthenic Syndrome under checkpoint inhibition in Merkel cell carcinoma.

Lambert-Eaton myasthenic syndrome (LEMS) is a rare, autoimmune or paraneoplastic condition characterized by muscle weakness and fatigability. In cancer therapy, immune checkpoint inhibitors (ICI) sensitize the immune system for tumor antigens. We report a 62-year-old, female patient with paraneoplastic LEMS as first manifestation of Merkel cell carcinoma. Under avelumab, the LEMS exacerbated with worsening of limb weakness and a severely reduced vital capacity (< 1 l). To treat this immunological side effect, we added a regimen with intravenous immunoglobulins. Hereby, the LEMS improved significantly. As we were able to continue the cancer treatment, the Merkel cell carcinoma has been in remission so far. This is the first description of paraneoplastic LEMS, avelumab, and Merkel cell carcinoma. We conclude that immunoglobulins are an option to control an ICI-associated deterioration of paraneoplastic symptoms.

Outcome of non-mold effective anti-fungal prophylaxis in patients at high-risk for invasive fungal infections after allogenic stem cell transplantation.

Patients who develop severe graft-versus-host disease (GvHD) after allogeneic stem cell transplantation (alloSCT) have a higher risk for invasive fungal infection (IFI). At our center, fluconazole prophylaxis is standard and upfront mold-effective prophylaxis performed only in patients with specific risk constellations. A total of 290 patients undergoing alloSCT between May 2002 and August 2011 were analyzed. Patients were regarded as high-risk if they suffered from acute GvHD II-IV° or extensive chronic GvHD. The 2-year incidence of an IFI after alloSCT was 8.97% (26/290) in the entire cohort and 7.78% (7/90) in the high-risk group. Mortality due to IFI was 3.85% (1/26) without including a high-risk patient. In the multivariate analysis a pre-transplant fungal infection was the only significant risk factor for developing an IFI after alloSCT (HR = 5.298; p = .001). A fluconazole prophylaxis in patients with GvHD after alloSCT is feasible in facilities with HEPA filtration and high awareness of clinical signs for IFI.

[Leukopenia - A Diagnostic Guideline for the Clinical Routine]. / Leukopenie ­ ein diagnostischer Leitfaden für die Praxis.

Reasons for leukopenia can be numerous. To get close to the diagnosis it's always useful to check previous blood counts of the patient to get a feeling for the dynamic development of the leukopenia. Furthermore, it's important to check the red blood cell count and platelet count as well; a bi- or a pancytopenia usually implies an insufficient production in the bone marrow. Nevertheless, a manual counted peripheral blood smear is an essential step towards the right diagnosis in leukopenia: Beside cell counts of the single subgroups of leucocytes it also provides information on potential causes such as dysplasia.Leukopenia can be life-threatening for the patient especially if the patient presents with an agranulocytosis and fever: In this case admission is mandatory and the patient has to be treated immediately with broad-spectrum antibiotics to reduce mortality.