Thukral, Jatin

Abstract Background Thrombotic Thrombocytopenic Purpura (TTP) is a rare, typically acquired disorder due to an immune-mediated deficiency of ADAMTS13, a metalloprotease responsible for cleaving large multimers of von Willebrand Factor (vWF). In the absence of ADAMTS13 activity, ultra-large vWF multimers accumulate, promoting widespread platelet aggregation and microvascular thrombosis. This consumptive cascade leads to thrombocytopenia, microangiopathic hemolytic anemia, fever, neurological symptoms, and rarely renal dysfunction. Although therapeutic plasma exchange (TPE) has long been the cornerstone of TTP treatment, the FDA approved Caplacizumab as a first-line treatment for TTP in 2019. This drug is a bivalent single-domain antibody that binds to the A1 domain of vWF and prevents its interaction with platelets, thus effectively interrupting the pathogenic cascade, which is associated with a risk of bleeding. Methods We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, comprising data from 152 healthcare organizations. Adults (≥18 years) with a diagnosis of TTP who received Caplacizumab plus TPE were compared to patients with TTP who received TPE alone. 1:1 propensity score matching (PSM) was performed to balance characteristics between cohorts. The primary outcomes assessed were all-cause mortality and major bleeding events over a period of 1 month. Results A total of 4084 patients with TTP were identified, of whom 356 received caplacizumab with TPE and 3728 received TPE. After PSM, 2 balanced cohorts were created: C+P (Caplacizumab + TPE), P only (TPE), each comprising 356 patients. The average age in C+P and P only, after PSM, was 50.4 +/- 16.2 and 50.8 +/- 16.2 years, respectively. Females formed 65.7% of both C+P and P only, and males accounted for 28.4% and 28.7% of C+P and P only, respectively. 2.8% patients in C+P and 7.06% patients in P only had all-cause mortality at the end of 1 month. One-month all-cause mortality was significantly lower in C+P (2.8%) compared to P only (7.06%), with an odds ratio (OR) of 0.385 (95% CI 0.182 to 0.814, p=0.010). Upon assessment of bleeding outcomes, no statistically significant risk difference was noted between the 2 groups, with the odds ratio being 0.974 (95% CI 0.399 to 2.379, p=0.954). Conclusion Our large database study suggests that the addition of caplacizumab to standard TPE therapy is associated with a reduction in one-month all-cause mortality in patients with TTP, without a corresponding increase in major bleeding. However, given the lack of granular clinical data, such as contraindications to caplacizumab use, it is possible that patients who received TPE alone were inherently at a higher risk. As such, while these findings support the potential benefit of early caplacizumab use, they should be interpreted with caution and warrant prospective validation to confirm causality and assess long-term outcomes.

Abstract Background: RUNX1 mutations are established high-risk features in acute myeloid leukemia (AML), associated with poor response to induction therapy and reduced overall survival (OS). Current prognostic models, including the ELN 2022 classification, incorporate RUNX1 mutation status but are based largely on cohorts of European ancestry. This raises concerns about their generalizability to underrepresented populations, particularly African American patients, who continue to experience worse outcomes in AML across treatment settings. Methods: We analyzed publicly available datasets, including TCGA-LAML, Beat AML, and a recent multi-omic study of 100 African American AML patients (Stiff et al., Nat Genet 2024). We evaluated RUNX1 mutation frequency, OS outcomes, and co-mutation patterns, stratified by race. To contextualize survival differences by ancestry, we performed a survival analysis of adult AML patients using the SEER 17 registries (2010–2020), accessed through SEER*Stat. Kaplan-Meier estimates and median OS were compared by race using disease-specific survival. Results: RUNX1 mutations were present in approximately 10–15% of AML cases and consistently associated with inferior OS (median 16–24 months) in both de novo and AML-MRC subsets. Co-mutations in DNMT3A and TET2 further worsened the prognosis. In the African American cohort described by Stiff et al., the frequency of RUNX1 mutations was similar to that in White patients; however, African American patients showed enrichment for IDH2, RAS, and WT1 mutations and lower incidence of NPM1 mutations. Despite comparable mutation rates, African American patients demonstrated significantly worse OS, even under standardized treatment. SEER 17 survival analysis of 5,932 AML cases (683 African American) confirmed shorter median OS in African American patients compared to non-African American patients (10.4 vs. 15.7 months, p<0.01).Conclusions: RUNX1 mutations confer adverse prognosis in AML, but current risk models may not adequately reflect risk in African American patients due to differing co-mutation patterns and underrepresentation in genomic datasets. These findings highlight the need for ancestry-aware risk stratification and inclusive genomic profiling to reduce disparities in AML outcomes. References: Lew-Derivry et al. Leukemia. 2023 Jalili et al. PMCID: PMC5980915 Stiff et al. Nat Genet. 2024 Bhatnagar et al. PMCID: PMC7933110 Tang et al. Blood. 2009 Mendler et al. JCO. 2012 He et al. Scand J Clin Lab Invest. 2020 Döhner et al. Blood. 2022. PMID: 35926292