Outcomes of patients aged ≥26 years with relapsed or refractory B-cell acute lymphoblastic leukemia in ZUMA-3 and historical trials.

Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 CAR T-cell therapy approved in the USA and European Union (EU) for adults with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL; aged ≥26 years in EU). Here, outcomes for patients with R/R B-ALL aged ≥26 years in ZUMA-3 treated with brexu-cel were compared with historical standard-of-care (SOC) therapy. After median follow-up of 26.8 months, the overall complete remission (CR) rate among patients treated with brexu-cel in Phase 2 (N = 43) was 72% and median overall survival (OS) was 25.4 months (95% CI, 15.9-NE). Median OS was improved in Phase 2 patients versus matched historical SOC-treated patients. Compared with aggregate historical trial data, Phase 1 and 2 patients had improved OS versus blinatumomab, inotuzumab, and chemotherapy in a matching-adjusted indirect comparison (MAIC) study. These data demonstrate clinical benefit of brexu-cel relative to SOC in patients ≥26 years with R/R B-ALL.

Interactions of pyrrolobenzodiazepine dimers and duplex DNA from methicillin-resistant Staphylococcus aureus.

Binding of two bactericidal pyrrolobenzodiazepine (PBD) dimers, SJG-136 and ELB-21, to genomic DNA from Staphylococcus aureus EMRSA-16 was investigated. Both agents cross-linked purified EMRSA-16 DNA. The more potent agent, ELB-21, had a greater capacity to cross-link DNA after incubation with intact cells than SJG-136. Extensive interstrand cross-linking at multiple sites on the EMRSA-16 genome was demonstrated by probing EcoRI-restricted DNA with mecA and 16S rDNA. Cross-linking was again greater in DNA extracted from ELB-21-treated cells and was compatible with frequency analysis of preferred binding sequences in EMRSA-16 DNA. These studies support the premise that the potency of ELB-21 is due to efficient cell penetration and provide evidence that the antibacterial activity of PBD dimers results from cross-linking at specific genomic sites.

Pyrrolobenzodiazepine dimers: novel sequence-selective, DNA-interactive, cross-linking agents with activity against Gram-positive bacteria.

OBJECTIVES: Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimers are synthetic sequence-selective interstrand DNA minor-groove cross-linking agents developed from anthramycins. We investigated the antibacterial activity of three dimers, SJG-136, DRG-16 and ELB-21, which differ in the structure of the PBD monomeric unit and the length of the linker region between the two identical PBD monomers. METHODS: MICs were determined against 38 methicillin-resistant Staphylococcus aureus (MRSA), 20 vancomycin-resistant enterococci (VRE), 12 isolates of Streptococcus pyogenes, 12 of Streptococcus agalactiae, 12 of Listeria monocytogenes and 24 Gram-negative clinical isolates. Binding to double-stranded DNA was assessed by determination of the DNA melting temperature (T(m)). RESULTS: MIC(90) values for SJG-136 were 0.5 mg/L against MRSA, VRE and L. monocytogenes, 0.06 mg/L against S. pyogenes and 0.03 mg/L against S. agalactiae; these were below the maximum tolerated dose of the drug. MIC(90)s for DRG-16 were 0.125, >0.5, 0.125, 0.015 and <0.008 mg/L, respectively. The most potent compound was ELB-21, with corresponding MIC(90) values of 0.03, 0.06, 0.06, 0.015 and 0.015 mg/L. There was little or no variation in sensitivity amongst isolates from any one species. All Gram-negative species (Acinetobacter, Pseudomonas, Klebsiella, Proteus spp.) were not susceptible due to the barrier function of the outer membrane. PBD dimers showed bactericidal activity against MRSA and VRE and there was a significant post-antibiotic effect (1.5--3.5 h). Incubation of EMRSA-16 genomic DNA (50 microM) with 20 microM ELB-21 resulted in a large increase in T(m) suggesting that PBD dimers exert their antibacterial effect by cross-linking of the two DNA strands. CONCLUSIONS: These data indicate that this novel class of antibacterial agents warrants further investigation as potential antibiotics for the treatment of severe infections caused by Gram-positive pathogens.