Tsiporah Shore

Background: Relapse remains the leading cause of treatment failure following allogeneic hematopoietic stem cell transplantation (alloHCT) for high-risk myeloid malignancies. Epigenetic dysregulation contributes to leukemogenesis and therapeutic resistance. We hypothesized that pre-transplant epigenetic priming with azacitidine could enhance chemosensitivity and improve post-transplant outcomes.Methods: We conducted an open-label, prospective phase II study evaluating azacitidine incorporated into reduced-intensity conditioning in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing alloHCT. Azacitidine was administered prior to conditioning chemotherapy followed by alloHCT from matched related or matched unrelated donors. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included relapse incidence, non-relapse mortality (NRM), and pharmacodynamic evaluation of DNA methylation changes in bone marrow CD34+ cells.Findings: Thirty-nine patients were enrolled (median age, 60 years). Most patients had AML (85%), 62% with adverse-risk AML or high/very high-risk MDS, and 23% had TP53 mutations. Neutrophil and platelet engraftment occurred in 97% of patients at median times of 13 and 16 days, respectively. One-year OS and PFS were 64% and 54%, respectively, with NRM of 15% and relapse incidence of 31%. Pharmacodynamic analyses demonstrated azacitidine-induced DNA hypomethylation in bone marrow CD34+ cells, which correlated with improved survival outcomes. Higher baseline methylation levels were also associated with superior survival.Interpretation: Azacitidine priming prior to alloHCT is feasible and demonstrates encouraging survival outcomes in older patients with high-risk myeloid malignancies. Epigenetic priming induces measurable biologic reduction of DNA methylation that is plausibly linked to improved relapse-free survival. These findings support further evaluation in randomized studies and suggest DNA methylation may serve as a predictive biomarker of response.

CD3xCD20 bispecific antibody (BsAb) therapy and CD19-directed chimeric antigen receptor T-cell therapy (CAR T) are novel immunotherapies that have shown impressive efficacy in B-cell lymphomas, but also come with significant morbidity and mortality, including infections. This meta-analysis compares rates of infections between commercially approved CAR T and BsAb therapy in patients with B-cell non-Hodgkin lymphoma (B-NHL). We conducted a systematic review for prospective trials assessing commercially approved CAR T and BsAbs in patients with B-NHL. Twenty-five studies comprising 3202 patients were included in the analysis. We used random effects models to evaluate all-grade infections, grade 3+ infections, and infection-related mortality, calculating both pooled rates per patient and per patient-month. While CAR T and BsAbs had similar rates of all-grade infections per patient (0.44 vs 0.54; P = .18), BsAbs had a higher rate of infection per patient-month (0.0397 vs 0.0167; P = .0012). Similarly, CAR T and BsAbs had similar rates of grade 3+ infections per patient (0.16 vs 0.22; P = .08), while BsAbs had a higher rate of grade 3+ infections per patient-month (0.0165 vs 0.0069; P = .0003). CAR T and BsAb products had similar rates of infection-related mortality per patient (0.04 vs 0.03; P = .26) and per patient-month (0.0023 vs 0.0022; P = .96). Our findings point to the potential increased burden of infections over time in patients receiving BsAb therapy, particularly for patients on indefinite therapy.

Older patients with lymphoma are typically underrepresented in clinical trials with chimeric antigen receptor T cell (CAR T) therapy. In this multicenter, observational study we aimed to assess the safety and efficacy of standard CD19 CAR T in patients 80 years of age or older. At total of 88 patients, median age 82 (range, 80-89) years, were included. Diffuse large B cell lymphoma (DLBCL) (N = 60, 68.2%) represented the most common histology. Patients were treated mostly with axicabtagene ciloleucel (N = 41, 46.6%) followed by lisocabtagene maraleucel (N = 25, 28.4%). Cytokine release syndrome (CRS) (any grade) was seen in 68 (77.3%) and 51 (58%) developed immune effector cell-associated neurotoxicity syndrome (ICANS). Incidence of grade 3-4 CRS and ICANS were 7.4% and 31.4%, respectively. For patients with DLBCL/tFL, the 1-year NRM, relapse, PFS, and OS were 11.6%, 40.8%, 47.6%, and 61.2%, respectively. We conclude that CAR T is feasible and effective in patients 80 years or older with B cell lymphomas. These patients must be provided the opportunity to be evaluated for this curative approach.

Supplementary Figures and Tables

Supplementary Table 1 from XPO1 Enables Adaptive Regulation of mRNA Export Required for Genotoxic Stress Tolerance in Cancer Cells

Supplementary Figures and Tables