SUMMARY There is a lack of effective predictive biomarkers to precisely assign optimal therapy to cancer patients. While most efforts are directed at inferring drug response phenotype based on genotype, there is very focused and useful phenotypic information to be gained from directly perturbing the patient’s living cancer cell with the drug(s) in question. To satisfy this unmet need we developed the Dynamic BH3 Profiling technique to measure early changes in net pro-apoptotic signaling at the mitochondrion (‘priming’) induced by chemotherapeutic agents in cancer cells, not requiring prolonged ex vivo culture. We find in cell line and clinical experiments that early drug-induced death signaling measured by Dynamic BH3 Profiling predicts chemotherapy response across many cancer types and many agents, including combinations of chemotherapies. We propose that Dynamic BH3 Profiling can be used as a broadly applicable predictive biomarker to predict cytotoxic response of cancers to chemotherapeutics in vivo.
On the basis of the data suggesting that adolescents and young adult patients with acute lymphoblastic leukemia (ALL) have improved outcomes when treated on pediatric protocols, we assessed the feasibility of treating adult patients aged 18–50 years with ALL with the DFCI Pediatric ALL Consortium regimen utilizing a 30-week course of pharmacokinetically dose-adjusted E. coli L-asparaginase during consolidation. Between 2002 and 2008, 92 eligible patients aged 18–50 years were enrolled at 13 participating centers. Seventy-eight patients (85%) achieved a complete remission (CR) after 1 month of intensive induction therapy. With a median follow-up of 4.5 years, the 4-year disease-free survival (DFS) for the patients achieving a CR was 69% (95% confidence interval (CI) 56–78%) and the 4-year overall survival (OS) for all eligible patients was 67% (95% CI 56–76%). The 4-year DFS for the 64 patients who achieved a CR and were Philadelphia chromosome negative (Ph−) was 71% (95% CI 58–81%), and for all 74 Ph− patients the 4-year OS was 70% (95% CI 58–79%). We conclude that a pediatric-like treatment strategy for young adults with de novo ALL is feasible, associated with tolerable toxicity, and results in improved outcomes compared with historical regimens in young adult patients with ALL.
Background Health care utilization in older adults (≥60) with acute myeloid leukemia (AML) has not been well-studied. Methods We conducted a retrospective analysis of 330 consecutive older patients diagnosed with AML between 5/1/2005 and 12/23/2011 at two hospitals in Boston to examine their health care utilization and end of life (EOL) care. Using multivariable logistic and linear regression models adjusting for covariates, we also compared health care utilization for patients undergoing intensive induction (n=197; cytarabine/ anthracyline combination) versus non-intensive chemotherapy (n=133; single-agent therapy). Results The median number of hospitalizations for the entire cohort was 4.2 (range 1–18). Patients who died spent a mean of 28.3% of their life from diagnosis in the hospital and 13.8% of their life attending outpatient clinic appointments. Although the majority (87.9%) of patients died during the 2-year follow-up period, a minority (16.2% and 23.1%) utilized palliative care or hospice services, respectively. Within 30 days of death, 84.5% of patients were hospitalized, with 61.0% dying in the hospital. Among patients who died, those treated with intensive induction (versus non-intensive therapy) spent 30% more of their life in the hospital (p < 0.0001), and were less likely to utilize hospice services (OR 0.45, P = 0.05). Conclusions These findings highlight the intensity of health care utilization of older patients with AML, regardless of treatment modality. Despite the poor prognosis, palliative care and hospice services are rarely used. Future work should study novel health-care delivery models to optimize care throughout the course of illness and at the EOL.
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