Pediatric and adult high-grade gliomas (HGGs) frequently harbor PDGFRA alterations. We hypothesized that cotreatment with everolimus may improve the efficacy of dasatinib in PDGFRα-driven glioma through combinatorial synergism and increased tumor accumulation of dasatinib. We performed dose-response, synergism, P-glycoprotein inhibition, and pharmacokinetic studies in in vitro and in vivo human and mouse models of HGG. Six patients with recurrent PDGFRα-driven glioma were treated with dasatinib and everolimus. We found that dasatinib effectively inhibited the proliferation of mouse and human primary HGG cells with a variety of PDGFRA alterations. Dasatinib exhibited synergy with everolimus in the treatment of HGG cells at low nanomolar concentrations of both agents, with a reduction in mTOR signaling that persisted after dasatinib treatment alone. Prolonged exposure to everolimus significantly improved the CNS retention of dasatinib and extended the survival of PPK tumor–bearing mice (mutant TP53, mutant PDGFRA, H3K27M). Six pediatric patients with glioma tolerated this combination without significant adverse events, and 4 patients with recurrent disease (n = 4) had a median overall survival of 8.5 months. Our results show that the efficacy of dasatinib treatment of PDGFRα-driven HGG was enhanced with everolimus and suggest a promising route for improving targeted therapy for this patient population.

Background: Older adults with acute myeloid leukemia (AML) represent a cancer population in which disease-based risk factors, comorbidities, patient goals, and treatment risks and benefits influence treatment recommendations. Objective: These evidence-based guidelines from the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health professionals in their decisions about management of AML in older adults. Methods: ASH formed a multidisciplinary guideline panel, including patient representatives, that minimized bias from conflicts of interest. Clarity Research Group at McMaster University supported the guideline development process, including updating or performing systematic evidence reviews. The panel prioritized questions and outcomes according to their importance for clinicians and patients. The panel used the grading of recommendations assessment, development and evaluation approach, including evidence-to-decision frameworks, to assess evidence and make recommendations. Results: The panel agreed on 9 critical clinical recommendations for managing AML in older adults, mirroring real-time practitioner-patient conversations: the decision to pursue antileukemic treatment vs best supportive management; traditional induction and postremission therapy vs hypomethylating agent or low-dose cytarabine, or combinations with venetoclax; the role and duration of postremission therapy; combinations with venetoclax vs monotherapy; the use of targeted therapy, including isocitrate dehydrogenase and FMS-like tyrosine kinase 3 (FLT3) inhibitors, in appropriate patients; the role of hematopoietic stem cell transplantation in nonfavorable prognosis AML; and the role of transfusion support for patients no longer receiving antileukemic therapy. Conclusions: Key recommendations of these guidelines include treatment over best supportive care; venetoclax-based regimens over monotherapies; and incorporation of FLT3 inhibitors into traditional induction and postremission therapy.