Rational drug combinations with CDK4/6 inhibitors in acute lymphoblastic leukemia.

Despite improvements in outcomes for children with B- and T-cell acute
lymphoblastic leukemia (B-ALL and T-ALL), patients with resistant or
relapsed disease fare poorly. Previous studies have demonstrated the
essential role of cyclin D3 in T-ALL disease initiation and progression and
that targeting of the CDK4/6-cyclin D complex can suppress T-ALL
proliferation, leading to efficient cell death in animal models. Studies in
leukemia and other malignancies, suggest that schedule is important when
combining CDK4/6 inhibitors (CDKi) with cytotoxic agents. Based on these
observations, we broadened evaluation of two CDKi, palbociclib (PD-0332991,
Pfizer) and ribociclib (LEE011, Novartis) in B- and T-ALL as single agent
and in combination with conventional cytotoxic chemotherapy, using
different schedules in preclinical models. As monotherapy, CDKi caused cell
cycle arrest with a significant decrease in S phase entry and were active
in vivo across a broad number of patient-derived xenograft samples.
Prolonged monotherapy induces resistance, for which we identified a
potential novel mechanism using transcriptome profiling. Importantly,
simultaneous but not sequential treatment of CDKi with conventional
chemotherapy (dexamethasone, L-asparaginase and vincristine) led to
improved efficacy compared to monotherapy in vivo. We provide novel
evidence that combining CDKi and conventional chemotherapy can be safe and
effective. These results led to the rational design of a clinical trial.