Background Gliomas are the most common primary brain tumor in adults. Current treatments involve surgery, radiation, and temozolomide (TMZ) chemotherapy, however prognosis remains poor and new approaches are required. Circadian medicine aims to maximize treatment efficacy and/or minimize toxicity by timed delivery of medications in accordance with the daily rhythms of the patient. We published a retrospective study showing greater anti-tumor efficacy for morning, relative to evening, administration of TMZ in patients with glioblastoma. We conducted this prospective randomized trial to determine the feasibility, and potential clinical impact, of TMZ chronotherapy in patients with gliomas (NCT02781792). Methods Adult patients with gliomas (WHO Grade II-IV) were enrolled prior to initiation of monthly TMZ therapy and were randomized to receive TMZ either in the morning (AM) before 10 am or in the evening (PM) after 8 pm. Pill diaries were recorded to measure compliance and FACT-Br Quality of Life (QoL) surveys were completed throughout treatment. Study compliance, adverse events (AE), and overall survival were compared between the two arms. Results A total of 35 evaluable patients, including 21 with GBM, were analyzed (18 AM patients and 17 PM patients). Compliance data demonstrated feasibility of timed TMZ dosing. There were no significant differences in AEs, QoL, or survival between the arms. Conclusions Chronotherapy with TMZ is feasible. A larger study is needed to validate the effect of chronotherapy on clinical efficacy.

The B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (VEN) in combination with lower-intensity therapy is an efficacious treatment for acute myeloid leukemia (AML). VEN in combination with the hypomethylating agent azacitidine improved rates of response and measurable residual disease (MRD)-negative remissions in addition to overall survival in the pivotal phase 3 VIALE-A trial compared with azacitidine monotherapy and has since emerged as the current standard of care in older or unfit patients with AML. In younger, fit patients with AML, intensive induction and consolidation chemotherapy (IC) is commonly employed as frontline therapy; however, relapse remains the principal cause of treatment failure in approximately 30–40% of patients. Improved IC regimens that increase MRD-negative response rates, result in durable remissions, and enable transition to curative allogeneic hematopoietic stem cell transplantation in appropriate patients remain an area of active inquiry. Preliminary results from trials investigating the combination of VEN with IC have reported promising findings to date, with composite complete remission and MRD-negative remission rates of approximately 89–94% and 82–93%, respectively, correlating with improved 12-month event-free and overall survival compared to historical outcomes with IC. Herein, we discuss ongoing trials investigating VEN in combination with IC in addition to outcomes within specific molecularly defined subgroups; review the molecular mechanisms of sensitivity and resistance to VEN, and highlight future combinations of VEN with novel targeted therapies for the treatment of AML.

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