Surrogates of endothelial injury predict survival after post-transplant cyclophosphamide.

BACKGROUND: Post-transplant cyclophosphamide (PT-Cy) is becoming the standard of care for preventing graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplant (alloHCT). Cyclophosphamide is associated with endothelial injury. We hypothesized that the endothelial activation and stress index (EASIX) score, being a marker of endothelial dysfunction, will predict non-relapse mortality (NRM) in alloHCT patients receiving PT-Cy for GVHD prophylaxis. OBJECTIVE: We evaluate the prognostic ability of the HCT-CI and EASIX scores, and report other factors influencing survival, in patients with hematologic malignancies undergoing alloHCT and receiving PT-Cy based GVHD prophylaxis. STUDY DESIGN: Adult patients with hematologic malignancies who underwent alloHCT and received PT-Cy for GVHD prophylaxis at the three Mayo Clinic locations were included in this study. We retrospectively reviewed the Mayo Clinic database and the available electronic medical records to determine the patient, disease and transplant characteristics. An HCT-CI score of ≥3 was considered high. The EASIX score was calculated from labs available between day -28 (of alloHCT) to the day of starting conditioning and analyzed on log2 transformed values. A log2-EASIX score ≥ 2.32 was considered high. The cumulative incidence of NRM was determined using competing risk analysis, with relapse considered as competing risk. Overall survival (OS) from transplant was determined using Kaplan-Meier and log-rank methods. Cox-proportional hazard method was used to evaluate factors impacting survival. RESULTS: A total of 199 patients were evaluated. Patients with a high log2-EASIX score had a significantly higher cumulative incidence of NRM at 1 years after alloHCT (34.5% vs. 12.3%, P = 0.003). Competing risk analysis showed that a high log2-EASIX score (HR 2.92, 95% CI 1.38 - 6.17, P = 0.005) and pre-alloHCT hypertension (HR 2.15, 95% CI 1.06 - 4.36, P = 0.034) were independently predictive of 1 year-NRM. Accordingly, we combined the two factors to develop a composite risk model stratifying patients in low, intermediate, and high-risk groups: 111 (55.8%) patients were considered low-risk, 76 (38.2%) were intermediate and 12 (6%) were high-risk. Compared to patients in the low-risk group, the intermediate (HR 2.38, 95% CI 1.31 - 4.33, P = 0.005) and high risk (HR 5.77, 95% CI 2.31 - 14.39, P < 0.001) groups were associated with a significantly inferior 1-year OS. Multiorgan failure (MOF) was among the common causes of NRM (14/32, 43.8%) particularly among patients with prior pulmonary comorbidities [7 (50%) patients]. CONCLUSION: Our study shows that EASIX score is predictive of survival after PT-Cy. The novel EASIX-HTN composite risk model may stratify patients prior to transplant. MOF is a common cause of NRM in patients receiving PT-Cy, particularly among patients with pulmonary comorbidities.

Senescence in the bone marrow microenvironment: A driver in development of therapy-related myeloid neoplasms.

Therapy-related myeloid neoplasms (t-MN) are a growing concern due to the continued use of cytotoxic therapies to treat malignancies. Cytotoxic therapies have been shown to drive therapy-induced senescence in normal tissues, including in the bone marrow microenvironment (BMME), which plays a crucial role in supporting normal hematopoiesis. This review examines recent work that focuses on the contribution of BMME senescence to t-MN pathogenesis, as well as offers a perspective on potential opportunities for therapeutic intervention.

FLT3 inhibitors potentially improve response rates in acute myeloid leukemia harboring t(6;9)(DEK::NUP214): The Mayo Clinic experience.

Not available.

The impact of cytotoxic therapy on the risk of progression and death in clonal cytopenia(s) of undetermined significance.

ABSTRACT: Clonal cytopenia of undetermined significance (CCUS) is defined by a myeloid driver mutation in the context of otherwise unexplained cytopenia. CCUS has an inherent risk of progressing to myeloid neoplasm. However, it is unknown how exposure to previous cytotoxic therapy may impact the risk of progression and survival. We stratified patients with CCUS by prior exposure to DNA-damaging therapy. Of 151 patients, 46 (30%) had received cytotoxic therapy and were classified as therapy-related CCUS (t-CCUS), whereas 105 (70%) had de novo CCUS. A lower proportion of t-CCUS had hypercellular marrows (17.8% vs 44.8%, P = .002) but had higher median bone marrow blast percentages. After a median follow-up of 2.2 years, t-CCUS had significantly shorter progression-free survival (PFS, 1.8 vs 6.3 years; hazard ratio [HR], 2.1; P = .007) and median overall survival (OS; 3.6 years vs not reached; HR, 2.3; P = .007) compared with CCUS. Univariable and multivariable time-to-event analyses showed that exposure to cytotoxic therapy independently accounted for inferior PFS and OS. Despite the similarities in clinical presentation between CCUS and t-CCUS, we show that exposure to prior cytotoxic therapies was an independent risk factor for inferior outcomes. This suggests that t-CCUS represents a unique clinical entity that needs more stringent monitoring or earlier intervention strategies.

IDH-mutant myeloid neoplasms are associated with seronegative rheumatoid arthritis and innate immune activation.

ABSTRACT: High prevalence of IDH mutations in seronegative rheumatoid arthritis (RA) with myeloid neoplasm, elevated 2-hydroxyglutarate, dysregulated innate immunity, and proinflammatory microenvironment suggests causative association between IDH mutations and seronegative RA. Our findings merit investigation of IDH inhibitors as therapeutics for seronegative IDH-mutated RA.

Cardiac events in newly diagnosed acute myeloid leukaemia during treatment with venetoclax + hypomethylating agents.

Among 301 newly diagnosed patients with acute myeloid leukaemia receiving venetoclax and a hypomethylating agent, 23 (7.6%) experienced major cardiac complications: 15 cardiomyopathy, 5 non-ST elevation myocardial infarction and/or 7 pericarditis/effusions. Four patients had more than one cardiac complication. Baseline characteristics included median age ± interquartile range; 73 ± 5 years; 87% males; 96% with cardiovascular risk factors; and 90% with preserved baseline ejection fraction. In multivariate analysis, males were more likely (p = 0.02) and DNMT3A-mutated cases less likely (p < 0.01) to be affected. Treatment-emergent cardiac events were associated with a trend towards lower composite remission rates (43% vs. 62%; p = 0.09) and shorter survival (median 7.7 vs. 13.2 months; p < 0.01). These observations were retrospectively retrieved and warrant further prospective examination.

Features and Factors Associated With Myeloid Neoplasms After Chimeric Antigen Receptor T-Cell Therapy.

This case-control study examines the incidence and risks of myeloid neoplasms in adults treated for B-cell lymphoproliferative disorders or multiple myeloma.

Genetic landscape and clinical outcomes of patients with BCOR mutated myeloid neoplasms.

The BCL6-corepressor (BCOR) is a tumor-suppressor gene located on the short arm of chromosome X. Data are limited regarding factors predicting survival in BCOR-mutated (mBCOR) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We evaluated 138 patients with mBCOR myeloid disorders, of which 36 (26.1%) had AML and 63 (45.6%) had MDS. Sixty-six (47.8%) patients had a normal karyotype while 18 (13%) patients had complex karyotype. BCOR-mutated MDS/AML were highly associated with RUNX1 and U2AF1 co-mutations. In contrast, TP53 mutation was infrequently seen with mBCOR MDS. Patients with an isolated BCOR mutation had similar survival compared to those with high-risk co-mutations by European LeukemiaNet (ELN) 2022 criteria (median OS 1.16 vs. 1.27 years, P=0.46). Complex karyotype adversely impacted survival among mBCOR AML/MDS (HR 4.12, P<0.001), while allogeneic stem cell transplant (alloSCT) improved survival (HR 0.38, P=0.04). However, RUNX1 co-mutation was associated with an increased risk of post-alloSCT relapse (HR 88.0, P=0.02), whereas melphalan-based conditioning was associated with a decreased relapse risk (HR 0.02, P=0.01). We conclude that mBCOR is a high-risk feature across MDS/AML, and that alloSCT improves survival in this population.

Clinical characteristics, molecular aberrations, treatments, and outcomes of malignant histiocytosis.

Malignant histiocytosis (MH) is an extremely rare neoplasm of the macrophage-dendritic cell lineage. We report the clinical characteristics, molecular aberrations, treatments, and outcomes of patients with MH seen at two referral centers from January 2000 to May 2023. We identified 43 patients with MH, of which 26 had histiocytic sarcoma (MH-H), 9 interdigitating dendritic cell sarcoma (MH-IDC), and 8 Langerhans cell sarcoma (MH-LC). The median age at diagnosis was 61 years (range, 3-83). Thirty-three patients (77%) had multifocal disease, while 10 had unifocal involvement. Tumor specimens from 22 patients (51%) underwent targeted next generation sequencing, and 19 of 22 (86%) had at least one pathogenic mutation, including mutations in MAPK pathway genes (73%). The median overall survival (OS) among the entire cohort was 16 months (95% CI: 8-50). The outcomes of those with multifocal disease were significantly shorter than their unifocal counterpart: median OS of 10 months versus 50 months (p = .07). Patients with risk organ involvement (bone marrow, spleen, or liver) had significantly inferior outcomes. Chemotherapy and surgery were the most common first-line treatments for multifocal and unifocal disease, respectively. While the outcome for patients with multifocal disease was poor, there was a subset of patients who had durable responses to treatment. Our study highlights that MH has heterogeneous clinical presentation, frequent oncogenic mutations, and prognosis, which is strongly tied to disease extent and type of organ involvement.

Temporal trends in critical care utilization and outcomes in allogeneic hematopoietic stem cell transplant recipients.

Historically, the prognosis of allogeneic hematopoietic stem cell transplant (allo-HCT) recipients who require intensive care unit (ICU) admission has been poor. We aimed to describe the epidemiological trends of ICU utilization and outcomes in allo-HCT patients. We conducted a retrospective cohort study including adults (≥ 18) undergoing allo-HCT between 01/01/2005 and 31/12/2020 at Mayo Clinic, Rochester. Temporal trends in outcomes were assessed by robust linear regression modelling. Risk factors for hospital mortality were chosen a priori and assessed with multivariable logistic regression modelling. Of 1,249 subjects, there were 486 ICU admissions among 287 individuals. Although older patients underwent allo-HCT (1.64 [95% CI: 1.11 to 2.45] years per year; P = 0.025), there was no change in ICU utilization over time (P = 0.91). The ICU and hospital mortality rates were 19.2% (55/287) and 28.2% (81/287), respectively. There was a decline in ICU mortality (-0.38% [95% CI: -0.70 to -0.06%] per year; P = 0.035). The 1-year post-HCT mortality for those requiring ICU admission was 56.1% (161/287), with no significant difference over time, versus 15.8% (141/891, 71 missing) among those who did not. The frequency and duration of invasive mechanical ventilation (IMV) declined. In multivariable analyses, higher serum lactate, higher sequential organ failure assessment (SOFA) scores, acute respiratory distress (ARDS), and need for IMV were associated with greater odds of hospital mortality. Over time, rates of ICU utilization have remained stable, despite increasing patient age. Several trends suggest improvement in outcomes, notably lower ICU mortality and frequency of IMV. However, long-term survival remains unchanged. Further work is needed to improve long-term outcomes in this population.

Venetoclax duration (14 vs. 21 vs. 28 days) in combination with hypomethylating agent in newly diagnosed acute myeloid leukemia: Comparative analysis of response, toxicity, and survival.

Overall survival and response rates of 270 patients with newly diagnosed acute myeloid leukemia receiving venetoclax (Ven) plus hypomethylating agent, stratified by Ven dosing schedule (Cycle 1 Ven 14 vs. 21 vs. 28 days).