Entospletinib with decitabine in acute myeloid leukemia with mutant TP53 or complex karyotype: A phase 2 substudy of the Beat AML Master Trial.

BACKGROUND: Patients with acute myeloid leukemia (AML) who have tumor protein p53 (TP53) mutations or a complex karyotype have a poor prognosis, and hypomethylating agents are often used. The authors evaluated the efficacy of entospletinib, an oral inhibitor of spleen tyrosine kinase, combined with decitabine in this patient population. METHODS: This was a multicenter, open-label, phase 2 substudy of the Beat AML Master Trial (ClinicalTrials.gov identifier NCT03013998) using a Simon two-stage design. Eligible patients aged 60 years or older who had newly diagnosed AML with mutations in TP53 with or without a complex karyotype (cohort A; n = 45) or had a complex karyotype without TP53 mutation (cohort B; n = 13) received entospletinib 400 mg twice daily with decitabine 20 mg/m2 on days 1-10 every 28 days for up to three induction cycles, followed by up to 11 consolidation cycles, in which decitabine was reduced to days 1-5. Entospletinib maintenance was given for up to 2 years. The primary end point was complete remission (CR) and CR with hematologic improvement by up to six cycles of therapy. RESULTS: The composite CR rates for cohorts A and B were 13.3% (95% confidence interval, 5.1%-26.8%) and 30.8% (95% confidence interval, 9.1%-61.4%), respectively. The median duration of response was 7.6 and 8.2 months, respectively, and the median overall survival was 6.5 and 11.5 months, respectively. The study was stopped because the futility boundary was crossed in both cohorts. CONCLUSIONS: The combination of entospletinib and decitabine demonstrated activity and was acceptably tolerated in this patient population; however, the CR rates were low, and overall survival was short. Novel treatment strategies for older patients with TP53 mutations and complex karyotype remain an urgent need.

Rates and Predictors of Nonadherence to the Post-Allogeneic Hematopoietic Cell Transplantation Medical Regimen in Patients and Caregivers.

Allogeneic hematopoietic cell transplantation (HCT) requires a complex, multicomponent medical regimen after hospital discharge. Patients must manage multiple medications; care for their catheter; minimize exposure to sources of potential infection; follow diet, exercise, and self-care guidelines; and attend frequent follow-up medical appointments. Their caregivers are tasked with helping them manage the regimen. Despite the importance of this management in preventing adverse clinical outcomes, there has been little study of regimen nonadherence and its predictors. We sought to prospectively determine rates and predictors of nonadherence to components of the post-HCT medical regimen during the first 8 weeks after hospital discharge. Patients (n = 92) and their caregivers (n = 91) (total n = 183) completed interview assessments pre-HCT, and at 4 weeks and 8 weeks after hospital discharge post-HCT. Sociodemographic factors (eg, age, sex), patient clinical status (eg, disease type, donor type), patient and caregiver self-reported health-related factors (eg, medical comorbidities), and patient and caregiver psychosocial factors (eg, anxiety, depression, HCT task-specific and general self-efficacy, relationship quality) were assessed pre-HCT. Nonadherence to each of 17 regimen tasks was assessed at 4 and 8 weeks after hospital discharge via self and caregiver collateral reports. Nonadherence rates varied among tasks, with 11.2% to 15.7% of the sample reporting nonadherence to immunosuppressant medication, 34.8% to 38.6% to other types of medications, 14.6% to 67.4% to required infection precautions, and 27.0% to 68.5% to lifestyle-related behaviors (eg, diet/exercise). Nonadherence rates were generally stable but worsened over time for lifestyle-related behaviors. The most consistent nonadherence predictors were patient and caregiver pre-HCT perceptions of lower HCT task efficacy. Higher caregiver depression, caregiver perceptions of poorer relationship with the patient, having a nonspousal caregiver, and having diseases other than acute myelogenous leukemia also predicted greater nonadherence in 1 or more areas. Rates of nonadherence varied across tasks, and both patient and caregiver factors, particularly self-efficacy, predicted nonadherence. The findings highlight the importance of considering not only patient factors, but also caregiver factors, in post-HCT regimen nonadherence.

The Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of acute leukemia.

Acute leukemia is a constellation of rapidly progressing diseases that affect a wide range of patients regardless of age or gender. Traditional treatment options for patients with acute leukemia include chemotherapy and hematopoietic cell transplantation. The advent of cancer immunotherapy has had a significant impact on acute leukemia treatment. Novel immunotherapeutic agents including antibody-drug conjugates, bispecific T cell engagers, and chimeric antigen receptor T cell therapies have efficacy and have recently been approved by the US Food and Drug Administration (FDA) for the treatment of patients with acute leukemia. The Society for Immunotherapy of Cancer (SITC) convened a panel of experts to develop a clinical practice guideline composed of consensus recommendations on immunotherapy for the treatment of acute lymphoblastic leukemia and acute myeloid leukemia.

Significance and implications of FDA approval of pembrolizumab for biomarker-defined disease.

The U.S. Food and Drug Administration (FDA) recently approved pembrolizumab, an anti- programmed cell death protein 1 cancer immunotherapeutic, for use in advanced solid tumors in patients with the microsatellite-high/DNA mismatch repair-deficient biomarker. This is the first example of a tissue-agnostic FDA approval of a treatment based on a patient's tumor biomarker status, rather than on tumor histology. Here we discuss key issues and implications arising from the biomarker-based disease classification implied by this historic approval.

Chimeric antigen receptor (CAR) T therapies for the treatment of hematologic malignancies: clinical perspective and significance.

Chimeric Antigen Receptor (CAR) T cell therapies - adoptive T cell therapies that have been genetically engineered for a new antigen-specificity - have displayed significant success in treating patients with hematologic malignancies, leading to three recent US Food and Drug Administration approvals. Based on the promise generated from these successes, the field is rapidly evolving to include new disease indications and CAR designs, while simultaneously reviewing and optimizing toxicity and management protocols. As such, this review provides expert perspective on the significance and clinical considerations of CAR T cell therapies in order to provide timely information to clinicians about this revolutionary new therapeutic class.