Objectives: A simplified comorbidity index (SCI) was recently introduced and demonstrated effective risk stratification for non-relapse mortality (NRM) in cohorts from MSKCC and Sheba Medical Center. Methods: We retrospectively analysed registry data from 1,677 patients with haematologic malignancies or bone marrow failure syndromes who underwent allogeneic HCT with unmanipulated grafts between 2008 and 2019 at Asan Medical Center, Seoul, Korea. Results: In univariate analyses, the 5-year NRM rates by HCT-CI scores (0, 1, 2, 3, ≥4) were 8.3%, 22.9%, 15.1%, 17.2%, and 23.4%, respectively (P<0.001); by SCI scores (0, 1, 2, 3, ≥4), they were 17.9%, 15.5%, 16.0%, 24.2%, and 28.5%, respectively (P<0.001). Notably, SCI scores of 0–2 did not effectively stratify NRM risk. In multivariate analysis, an SCI score of ≥3 was independently associated with increased NRM (hazard ratio [HR], 1.68; P<0.001) and decreased overall survival (OS) (HR, 1.39; P<0.001). An exploratory Revised SCI incorporating clinically anchored threshold adjustments showed enhanced beta coefficients across comorbidity components. Conclusions: SCI score of ≥3 predicted increased NRM and decreased OS following HCT. The Revised SCI provided a hypothesis-generating basis for future prospective validation in independent cohorts.
Introduction: The clinical and prognostic significance of splicing factor (SF) mutations in newly diagnosed adult de novo acute myeloid leukemia (AML) remains incompletely defined. This study aimed to characterize the clinical features, co-mutation profiles, treatment responses, and prognostic impact of SF mutations in this population. Methods: We retrospectively analyzed 323 newly diagnosed adult patients with de novo non-acute promyelocytic leukemia AML treated between 2015 and 2023. Targeted next-generation sequencing assessed at least 32 recurrently mutated genes. SF-mutated (SFmut) status was defined by the presence of mutations in SF3B1, SRSF2, U2AF1, or ZRSR2. Clinical characteristics, co-mutation profiles, treatment regimens, treatment responses, and survival outcomes were compared between the SFmut and SF-wild-type (SFwt) groups. Survival was analyzed using Kaplan-Meier methods and Cox proportional hazards models. Results: SF mutations were identified in 58 of 323 patients (17.96%) and were largely mutually exclusive. Compared with SFwt patients, SFmut patients were more often male and older, had a higher CD4/CD8 ratio, and more frequently received low-intensity therapy. SFmut cases were enriched for co-mutations in ASXL1, RUNX1, CBL, IDH1, PHF6, SETBP1, BCORL1, and STAG2. The SFmut group had a lower composite complete remission rate than the SFwt group (50.9% vs. 71.3%, p=0.003) and significantly shorter overall survival (median, 6.73 vs. 19.07 months; p<0.001). In the overall multivariable model, SFmut status, age ≥65 years, and WBC ≥100 × 109/L were independently associated with inferior overall survival, whereas intensive therapy was independently protective. Intermediate and adverse cytogenetic risk were also associated with progressively worse overall survival. SFmut status showed nonsignificant trends toward shorter overall survival in both treatment strata and was independently associated with poorer overall survival in the non-intensive, but not the intensive, subgroup; however, the interaction between SF status and treatment intensity was not significant. Exploratory unadjusted co-mutation analyses showed the most consistent adverse signals for SF/ASXL1 and SF/RUNX1, whereas other findings were heterogeneous or based on small subgroups. Conclusion: SF mutations define a clinically distinct subgroup of newly diagnosed adult de novo AML characterized by adverse co-mutation profiles, lower remission rates, and inferior survival. Their adverse prognostic effect was most evident among patients receiving non-intensive therapy, although no significant interaction with treatment intensity was observed. The prognostic implications of individual SF co-mutation patterns require validation in larger independent cohorts.
Background: Lactoferrin is an iron-binding glycoprotein found in secretions and neutrophil granules that regulates iron availability in conjunction with host defense. Furthermore, it modulates innate and adaptive immune responses and affects iron handling during inflammation. Consequently, there is renewed interest in lactoferrin because of its potential therapeutic applications in iron deficiency, inflammatory disorders, and infectious diseases. Summary: This review summarizes the current knowledge regarding lactoferrin as a modulator of immunity and iron homeostasis, with an emphasis on recent experimental and clinical findings. Key results indicate that lactoferrin regulates NF-κB-mediated inflammation and the IL-6-hepcidin-ferroportin pathway, both of which are central to iron-restricted erythropoiesis. This review details how lactoferrin influences cytokine signaling, leukocyte function, and mucosal-microbiota interactions, which are relevant to iron sequestration and intestinal iron handling. Clinically, studies support the efficacy and tolerability of lactoferrin in iron deficiency anemia and anemia of inflammation, with outcomes varying according to the formulation, dosing, and duration. This review identifies the need for standardized biomarkers and harmonized endpoints for future research. Key Messages: (i) Lactoferrin may influence immunity and iron availability in inflammatory anemia. (ii) Key pathways are NF-κB signaling and IL-6-hepcidin-ferroportin axis. (iii) Clinical results show that lactoferrin can improve hematological indices and shows good overall tolerability. (iv) Evidence derives from high-risk-of-bias or very small studies. (v) Therefore, there is a need for improved clinical trials with standardized endpoints and biomarkers.
Background: Hypomethylating agents (HMAs) are a cornerstone of therapy for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Oral formulations offer an alternative to intravenous (IV) administration, but comparative real-world toxicity data remain limited. We evaluated hematologic toxicity and adverse events associated with oral versus IV HMAs. Methods: We conducted a multicenter retrospective cohort study of 33 patients with MDS or AML treated with oral decitabine/cedazuridine or oral azacitidine between January 1, 2016 and June 1, 2023 across three academic cancer centers. Twenty patients who also received IV HMAs were included in an intrapatient paired analysis. Cytopenias were assessed by absolute values and percent change from baseline to nadir. Wilcoxon signed-rank tests were used for intrapatient comparisons, and clinically significant adverse events were recorded descriptively. Results: Among the 20 patients included in the intrapatient analysis, median decreases in hemoglobin were 20.8% during oral HMA therapy and 20.5% during IV HMA therapy. Median decreases in absolute neutrophil count were 95.9% and 97.3%, respectively, while median decreases in platelet count were 81.9% and 88.6%, respectively. No statistically significant differences were observed between oral and IV HMA therapy for hemoglobin (p = 0.60), absolute neutrophil count (p = 0.63), or platelet count (p = 0.06). Hospitalization occurred in 60.6% of patients during oral HMA therapy and 70.0% during IV HMA therapy, while neutropenic fever occurred in 51.5% and 60.0%, respectively. Conclusions: Oral HMAs demonstrated cytopenia severity and adverse event rates comparable to IV HMAs, supporting oral formulations as a practical alternative in patients with MDS and AML. Although encouraging, these findings should be interpreted in the context of the retrospective design and modest sample size.
BACKGROUND:The prognostic impact of therapy-related chronic myelomonocytic leukemia (t-CMML) compared with de novo CMML (dnCMML) remains uncertain, in part due to the absence of therapy-related designations in cancer registries. METHODS:Using the Surveillance, Epidemiology, and End Results (SEER) database, we compared outcomes between de novo CMML (dnCMML) and therapy-related CMML (t-CMML), operationally defined by antecedent chemotherapy and/or radiotherapy and diagnosis as a subsequent primary malignancy. Survival was evaluated by antecedent treatment exposure and within major antecedent malignancy groups. Additional operational definitions of t-CMML were evaluated to assess the robustness of findings. RESULTS:Among 8,432 patients diagnosed with CMML between 2000 and 2022 after exclusion of antecedent myeloid malignancies, 594 (7.0%) met criteria for the primary definition of t-CMML. Median overall survival (OS) for the entire CMML cohort was 18 months, with shorter median OS observed for t-CMML compared with de novo CMML (14 vs 19 months). On multivariable Cox regression adjusted for age, sex, race, and era of diagnosis, t-CMML was associated with an increased risk of death (hazard ratio 1.20, 95% CI 1.09-1.32). Compared with dnCMML, inferior OS was observed among patients with recorded chemotherapy exposure but not among those treated with radiotherapy alone. Direct comparisons between chemotherapy-exposed and radiotherapy-only patients showed no significant difference in OS in the pooled adjusted analysis or within individual antecedent malignancy groups. Increasing definitional stringency was associated with stepwise worsening OS. CONCLUSION:Registry-defined t-CMML was associated with inferior survival compared with de novo disease. Although chemotherapy-exposed t-CMML was associated with poorer outcomes relative to dnCMML, OS did not differ significantly between chemotherapy-exposed and radiotherapy-only patients in direct pooled or malignancy-specific comparisons. Studies integrating detailed treatment histories with molecular and cytogenetic data are needed to clarify the biology and prognostic significance of t-CMML.
