A phase 1/2 study of mini-hyper-CVD plus venetoclax in patients with relapsed/refractory acute lymphoblastic leukemia.

ABSTRACT: Preclinical studies suggest that Bcl-2 inhibition with venetoclax has antileukemic activity in acute lymphoblastic leukemia (ALL) and may synergize with conventional chemotherapy. We designed a phase 1/2 clinical trial to evaluate the safety and efficacy of low-intensity chemotherapy in combination with venetoclax in adults with relapsed or refractory ALL. Patients received the mini-hyper-CVD regimen (dose-attenuated hyperfractionated cyclophosphamide, vincristine, and dexamethasone alternating with methotrexate and cytarabine) in combination with venetoclax (200 mg or 400 mg daily) on days 1 to 14 in cycle 1 and on days 1 to 7 in consolidation cycles. Twenty-two patients were treated. The median number of prior therapies was 2 (range, 1-6). Thirteen patients (59%) had undergone prior allogeneic stem cell transplant (allo-SCT), and 7 of 18 patients (39%) with B-cell ALL had previously received both inotuzumab ozogamicin and blinatumomab. The recommended phase 2 dose of venetoclax in the combination regimen was 400 mg daily. The composite complete remission (CR) and CR with incomplete hematologic recovery (CRi) rate was 57% (CR, 43%; CRi, 14%), and 45% of responders achieved measurable residual disease negativity by multiparameter flow cytometry. Four patients proceeded to allo-SCT. The median duration of response was 6.3 months. The median overall survival was 7.1 months, and the 1-year overall survival rate was 29%. The most common grade ≥3 nonhematologic adverse events were infection in 17 patients (77%) and febrile neutropenia in 4 patients (18%). Overall, the combination of mini-hyper-CVD plus venetoclax was active in heavily pretreated relapsed/refractory ALL. Further development of venetoclax-based combinations in ALL is warranted. This trial is registered at www.clinicaltrials.gov as #NCT03808610.

Synthesis and characterizations of new glycidyl-based cationic poly(aminoester) and study on gene delivery.

New glycidyl-based (epoxide-based) poly(aminoester) (EPAE) containing hydroxyl and amino groups in the backbone and side chain was synthesized. EPAE self-assembled readily with the plasmid DNA(pCMV-betagal) in HEPES buffer and was characterized by dynamic light scattering, Zeta-potential, fluorescence images, and XTT cell viability assays. To evaluate the effect of molecular weight of EPAE system on transfection, EPAE polymers with three different molecular weights (EPAE22k, EPAE18k, and EPAE8k) were also prepared. This study found that all EPAE polymers were able to bind plasmid DNA and yielded positively charged complexes with a nano-sized particles (200 nm). The EPAE22k/DNA and EPAE18k/DNA complexes were able to transfect COS-7 cell in vitro with higher transfection efficiency than other EPAE8k/DNA. These results demonstrated that molecular weight of EPAE system had a significant effect on transferring ability. Examination of the cytotoxicity of PEI25k and EPAEs system revealed that EPAEs system had lower cytotoxicity. In this article, EPAEs seemed to be a novel cationic poly(aminoester) for gene delivery and an interesting candidate for further study.