Kumar, Mahesh

Abstract Background: The International Consensus Classification (ICC) for systemic mastocytosis (SM) recognizes mast cell leukemia (MCL) and SM with associated myeloid neoplasm (SM-AMN) as distinct categories of advanced SM (SM-Adv; Arber et al. Blood 2022;140:1200). Contemporary risk models in SM, including the Mayo Alliance Prognostic System (MAPS), do not account for the prognostic heterogeneity among ICC-defined SM-Adv subcategories. Methods: Mayo Clinic databases were utilized to access patient information. Diagnoses of SM and its morphological subcategories were confirmed through clinical evaluations and review of BM pathology. Diagnostic criteria were retrospectively fitted to be consistent with those of the ICC (Arber et al. Blood 2022;140:1200); diagnosis of MCL required the presence of immature cytomorphology of mast cells and only myeloid neoplasms were listed under the category of SM-AMN.Next-generation sequencing and cytogenetic studies was performed in a subset of the study patients according to previously described methodologies. Statistical analyses were conducted on clinical and laboratory data collected at the time of initial diagnosis while survival analysis was censored at the time of allogeneic stem cell transplant (ASCT). Results: A total of 910 Mayo Clinic patients with SM (median age 56 years, range 12-89; males 50%) were accessed in order to conduct a series of multivariable analyses (MVA) in search of independent risk factors for transplant-censored overall survival (OS). All patients were evaluable for assignment to specific ICC categories of SM: indolent (ISM; N=553), aggressive (ASM; N=114), SM-AMN (N=235), and MCL (N=8); the AMN components in SM-AMN included acute myeloid leukemia (N=18), chronic myelomonocytic leukemia (N=70), myelodysplastic syndromes (N=32), MDS/myeloproliferative overlap (N=81), myelofibrosis (N=7), polycythemia vera or essential thrombocythemia (PV/ET; N=19), and others (N=8). In addition, subsets of patients were evaluable for hemoglobin level (N= 865), white blood cell count (WBC; N=858), platelet count (N= 859), serum alkaline phosphatase (ALP; N=761), serum tryptase level (N=706), karyotype (N=574), and mutations (N=240). Median follow-up for living patients was 70 months (range, 0-520); during this time 346 (38%) deaths, 16 leukemic transformations, and 20 ASCTs were documented. ROC analysis-determined optimal cutoff levels for predicting OS included age at ≥60 years, platelet count <150 x 109/L, tryptase level ≥100 ng/mL, WBC ≥10 x 109/L, hemoglobin below sex-adjusted lower limit of normal (anemia), and ALP >210 U/L in women or >170 U/L in men (increased). All except WBC ≥10 x 109/L retained significance during MVA that included ICC-specified SM categories: MCL (HR 74.8, 26.0-215.3; p<0.01); SM-AMN (HR 3.9, 2.5-6.0; p<0.01); ASM (HR 2.2, 1.4-3.5; p<0.01); age ≥60 years (HR 3.3, 2.2-4.7; p<0.01); platelets <150 x 109/L (HR 2.8, 2.0-3.9; p<0.01); tryptase ≥100 ng/mL (HR 2.1, 1.5-2.9; p<0.01); anemia (HR 1.7, 1.1-2.4; p<0.01); and increased ALP (HR1.5, 1.1-2.0; p=0.01). A subsequent HR-weighted risk model effectively delineated 5 risk levels ranging in median survivals from 11 months to 372 months (Figure 1). Figure 2 outlines complementary subtype-specific risk models; to that end, risk factors for ISM included age ≥60 years (HR 4.5, 2.5-7.9), tryptase ≥100 ng/mL (HR 3.5, 2.1-6.0); platelets <150 x 109/L (HR 3.4, 1.5-7.9), and anemia (HR 2.4, 1.2-4.8); for ASM age ≥60 years (HR 2.3, 1.3-4.3), platelets <150 x 109/L (HR 2.4, 1.4-4.0), and anemia (HR 2.0, 1.2-3.4); and for SM-AMN age ≥60 years (HR 2.9, 1.6-5.2), platelets <150 x 109/L (HR 2.5, 1.6-3.9), and tryptase ≥100 ng/mL (HR 2.5, 1.6-3.9) [Figure 2]. In SM-AMN, additional prognostic relevance from subcategorization into PV/ET vs. all other types of AMN was appreciated (Figure 3; HR 4.0, 1.6-3.9) and incorporated into the risk model for SM-AMN (Figure 2). Abnormal karyotype (AK) and high risk mutations(HRM; ASXL1, SRSF2, RUNX1, NRAS)clustered withSM-AMN with AK and ASXL1MUT displaying independent prognostic relevance that was most apparent in SM-AMN. Conclusions : MAPS-R relies on the prognostic eminence of ICC-defined morphologic subcategories and allows for additional SM subtype-specific risk stratification. SM associated with ET or PV is a prognostically unique subcategory of SM-AMN and should be recognized as such in future classification schemes. SM-AMN must be thoroughly ruled out in the presence of AK or HRM.

Abstract Introduction: DDX41 (DEAD-box helicase 41) mutations (mt) represent the most prevalent germline predisposition syndrome (GPS) in adult patients (pts) with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). This molecular subtype is typically associated with late-onset disease, runs an indolent clinical course, with a relative absence of high-risk co-mutations. While several retrospective studies have reported favorable responses to venetoclax (VEN)-based therapies, anecdotal observations suggest variable outcomes. We aimed to evaluate the clinical characteristics and treatment outcomes of patients with DDX41-mt MDS/AML treated at the Mayo Clinic. Methods: We conducted a retrospective study of pts diagnosed with DDX41-mt germline predisposition syndrome with concurrent myeloid neoplasms at our institution. Germline testing was conducted under an IRB approved protocol (Mayo Clinic IRB# 16-004173; clinical-trials gov. Identifier: NCT02958462). Of 198 pts with DDX41-mt myeloid neoplasms, 77 had high-risk disease—43 with MDS with increased blasts (MDS-IB1, n = 11; IB2, n = 32) and 34 with AML (WHO 2022). We assessed how clinical, and disease features influenced outcomes in this subgroup. Among these pts, 69 (90%) pts had likely pathogenic/pathogenic variant (DDX41path) variants and 8 (10%) pts had variant of undetermined significance (DDX41VUS) according to variant classification criteria from the American College of Medical Genetics/ the Association of Medical Genetics/ the Association for Molecular Pathology (ACMG/AMP) guidelines. Results: The median age was 68 years (yrs) (range [R],34-92), 70% were male and the median bone marrow blast % was 15 (R,5-60). The most common DDX41 germlinevariants (> 5% cases) included p.D140fs (26%), p.M1I (22%), and p.P258L (6.5%). 74% had DDX41 truncating variants. Thirty-one (40%) acquired a somatic DDX41-mt (R525H [81%]) and 43 (56%) had other somatic mutations. Among these, the most frequent were ASXL1 (n= 9, 21%), TP53 (n= 8, 10%), splicing factor (n= 7, 9%), and DNMT3A (n= 5, 6%). Twenty-six, (34%), 26 (34%), 15 (19%) and 9 (12%) pts were treated with hypomethylating agents (HMA), HMA+VEN, intensive chemotherapy (IC) and active surveillance/supportive care, respectively. Overall, the composite complete remission rate (cCR) in high-risk MDS and AML was 56%. The cCR rates (41%, 59% and 68.7%, p= 0.10) and median duration of response (DOR; 43.7, 44.9 and 28.9 months [mo], p= 0.46) were not significantly different with HMA, HMA+VEN, and IC induction. Thirty-one (40%) pts received allogeneic stem cell transplantation (allo-HCT); 4 (36%), 15 (47%) and 12 (35%) in MDS-IB1, MDS-IB2 and AML groups, respectively (p= 0.56). With a median follow up of 34.7 mo (R, 0.7-136.7), the median overall survival (OS) from the time of diagnosis was 56.9 mo (95% CI, 50.7-63.0) and was not significantly (NS) different between MDS-IB1 (not reached, 70% at 3 yrs), MDS-IB2 (56.9 mo, 86% at 3 yrs) and AML (55.7 mo, 60% at 3 yrs) groups, p= 0.16). The median OS was NS different between DDX41path and DDX41VUS (58.6 vs 55.7 mo, p= 0.50), respectively. We conducted a multivariable analysis for OS using variables that showed significance or trend towards significance in univariable analysis. Concurrent splicing factor mutations (HR; 5.29, 95% CI: 1.29-21.6, p= 0.02) remained negatively prognostic, while there was a trend towards better survival outcomes with allo-HCT (HR; 0.48, 95% CI: 0.21-1.07, p= 0.07). Bone marrow blast ≥ 20% (HR; 1.87, p= 0.12) and TP53-mt (HR; 2.14, p= 0.12) did not retain significance. Conclusion: In our cohort of patients with germline DDX41-mt high-risk MDS and AML, VEN-based regimens were not superior to HMA alone or IC, in terms of response rates and outcomes. On multivariable analysis, the presence of concurrent splicing factor mutations independently and negatively impacted survival with a trend towards better outcomes with allo-HCT. These findings highlight the heterogeneity within DDX41-mt myeloid neoplasms and underscore the need for future studies in larger cohorts to better define predictors of response and survival.

Hyperkalemia is a common and potentially life-threatening electrolyte abnormality in patients with heart failure, particularly among those with diabetes or chronic kidney disease. It often results from the use of renin–angiotensin–aldosterone system inhibitors, which, while improving survival, increase serum potassium levels. Elevated potassium produces cardiotoxic effects, often recognized by characteristic electrocardiographic changes. Acute management focuses on stabilizing cardiac membranes with intravenous calcium and shifting potassium intracellularly through insulin-dextrose, β₂-agonists, or sodium bicarbonate, with caution to avoid fluid overload. Potassium elimination may be achieved using diuretics or hemodialysis when refractory. For chronic management, newer potassium-binding agents such as patiromer and sodium zirconium cyclosilicate offer improved safety and efficacy compared with traditional resins, enabling the continuation and up-titration of renin–angiotensin–aldosterone system inhibitors. These therapies support optimal neurohormonal blockade, improve adherence, and reduce morbidity and mortality in heart failure.

ABSTRACTThe current study includes 910 patients with systemic mastocytosis (SM) seen at the Mayo Clinic from 1968 to 2024. The primary objective was to examine the prognostic contribution of the International Consensus Classification (ICC), in the context of the Mayo Alliance Prognostic System (MAPS) for SM. World Health Organization classification (WHO‐HAEM5) subcategories included (i) indolent/smoldering SM (ISM/SSM; N = 518), (ii) SM associated with another hematological neoplasm (SM‐AHN; N = 273), with the latter including both myeloid and lymphoid neoplasms, (iii) aggressive SM (ASM; N = 106), and (iv) WHO‐defined mast cell leukemia (MCL; N = 13), which included mast cells with both “mature” and “immature” morphology. The ICC‐defined subcategories were mostly similar with the exception that SM‐AHN was replaced by SM associated with another myeloid neoplasm (SM‐AMN; N = 235) and WHO‐defined MCL was replaced by ICC‐defined MCL (N = 8), which included only those with immature MC morphology. Overall survival (OS) was similar between WHO‐defined MCL (median 1.8 years) vs. SM‐AHN (median 2.3 years; p = 0.3) but significantly different between ICC‐defined MCL (median 0.08 years) vs. SM‐AMN (median 2.0 years; p < 0.01). Significant difference in OS was also apparent between ICC‐defined SM‐AMN and SM associated with lymphoid neoplasm (SM‐ALN; median 8.1 years; HR 3.4; p < 0.01). Multivariable analysis confirmed the inter‐independent prognostic contributions of both ICC‐defined morphologic subcategories and MAPS risk variables, including age > 60 years, anemia, alkaline phosphatase > ULN, and platelet count < 150 × 109/L (p < 0.03 in all instances); the same was not true for WHO‐HAEM5‐defined SM subcategories. The addition of mutational information into the multivariable model resulted in ousting anemia and inclusion of ASXL1 (p < 0.01), SRSF2 (p = 0.01), and NRAS (p = 0.01) mutations as additional risk factors. Classification of SM by ICC is prognostically more accurate, compared to WHO‐HAEM5, and strengthens the prognostic contribution of morphology to current clinical and molecular risk models.