Venetoclax and dinaciclib elicit synergistic preclinical efficacy against hypodiploid acute lymphoblastic leukemia.

Hypodiploid acute lymphoblastic leukemia (ALL) is an aggressive blood cancer with a poor prognosis despite intensive chemotherapy or stem cell transplant. Children and adolescents with positive end-of-induction minimal residual disease have an overall survival lower than 30%. However, data regarding therapeutic alternatives for this disease is nearly nonexistent, emphasizing the critical need for new or adjunctive therapies that can improve outcomes. We previously reported on the therapeutic efficacy of venetoclax (ABT-199) in hypodiploid B-lineage ALL but with limitations as monotherapy. In this study, we set out to identify drugs enhancing the anti-leukemic effect of venetoclax in hypodiploid ALL. Using a highthroughput drug screen, we identified dinaciclib, a cyclin-dependent kinase inhibitor that worked synergistically with venetoclax to induce cell death in hypodiploid cell lines. This combination eradicated leukemic blasts within hypodiploid ALL patient-derived xenografts mice with low off-target toxicity. Our findings suggest that dual inhibition of BCL-2 (venetoclax) and CDK9/MCL-1 (dinaciclib) is a promising therapeutic approach in hypodiploid ALL, warranting further investigation to inform clinical trials in this high-risk patient population.

Bcl-2 Is a Therapeutic Target for Hypodiploid B-Lineage Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. The highest rates of treatment failure occur in specific genetic subsets of ALL, including hypodiploid B-cell ALL (B-ALL), for which effective alternative therapies to current intensive chemotherapy treatments have yet to be developed. Here, we integrated biochemical and genomic profiling with functional drug assays to select effective agents with therapeutic potential against hypodiploid B-ALL. ABT-199, a selective Bcl-2 inhibitor, was effective in reducing leukemic burden in vitro and in vivo in patient-derived xenograft models of hypodiploid B-ALL. Daily oral treatment with ABT-199 significantly increased survival in xenografted mice. The unexpected efficacy of ABT-199 observed in hypodiploid leukemias lacking BIM expression (the major reported mediator of ABT-199-induced apoptosis) led us to investigate the mechanism of action of ABT-199 in the absence of BIM. Treatment with ABT-199 elicited responses in a dose-dependent manner, from cell-cycle arrest at low nanomolar concentrations to cell death at concentrations above 100 nmol/L. Collectively, these results demonstrate the efficacy of Bcl-2 inhibition and potential therapeutic strategy in hypodiploid B-ALL. SIGNIFICANCE: These results demonstrate the efficacy of ABT-199 in vivo and provide encouraging preclinical data of Bcl-2 as a potential target for the treatment of hypodiploid B-ALL.

Determination of Key Drivers of Patient Experience in a Midsize Pediatric Hematology-Oncology Ambulatory Clinic.

BACKGROUND: Patient perception of care is positively associated with better medical outcomes, clinician job satisfaction, and fewer malpractice claims and also has significant downstream economic impact for healthcare organizations. A sparse amount of data exists regarding provider and practice characteristics driving high levels of patient experience in the pediatric hematology-oncology (PHO) ambulatory setting. The aims of this study were to determine key drivers of high care provider ratings and of the likelihood of recommending our ambulatory PHO practice. METHODS: Patient experience was measured using the Consumer Assessment of Healthcare Providers and Systems Clinician & Group Survey (CG-CAHPS). The study outcomes were to determine the survey items most associated with top-box scores for "Rate This Provider" and for "Likelihood of Your Recommending Our Practice to Others." RESULTS: The survey items Explanations the care provider gave you about your problem or condition and Concern the care provider showed for your questions or worries were most strongly correlated with high provider ratings. How well the staff worked together to care for you and Friendliness/courtesy of nurse/assistant were most strongly correlated with the likelihood of recommending the practice. CONCLUSION: High provider ratings were most associated with the physician's ability to explain problems and conditions to families. Staff teamwork and nursing attitude were most associated with patient recommendations of the PHO practice. By identifying key drivers of high provider and practice ratings by patients in the PHO ambulatory setting, a targeted approach with a focus on physician-specific communication attributes, teamwork, and nursing attitude can be deployed to improve the patient experience.