Functional Precision Medicine Provides Clinical Benefit in Advanced Aggressive Hematologic Cancers and Identifies Exceptional Responders.

Personalized medicine aims to match the right drug with the right patient by using specific features of the individual patient's tumor. However, current strategies of personalized therapy matching provide treatment opportunities for less than 10% of patients with cancer. A promising method may be drug profiling of patient biopsy specimens with single-cell resolution to directly quantify drug effects. We prospectively tested an image-based single-cell functional precision medicine (scFPM) approach to guide treatments in 143 patients with advanced aggressive hematologic cancers. Fifty-six patients (39%) were treated according to scFPM results. At a median follow-up of 23.9 months, 30 patients (54%) demonstrated a clinical benefit of more than 1.3-fold enhanced progression-free survival compared with their previous therapy. Twelve patients (40% of responders) experienced exceptional responses lasting three times longer than expected for their respective disease. We conclude that therapy matching by scFPM is clinically feasible and effective in advanced aggressive hematologic cancers. SIGNIFICANCE: This is the first precision medicine trial using a functional assay to instruct n-of-one therapies in oncology. It illustrates that for patients lacking standard therapies, high-content assay-based scFPM can have a significant value in clinical therapy guidance based on functional dependencies of each patient's cancer.See related commentary by Letai, p. 290.This article is highlighted in the In This Issue feature, p. 275.

High-dose Bendamustine-EAM followed by autologous stem cell rescue results in long-term remission rates in lymphoma patients, without renal toxicity.

BACKGROUND: Autologous stem cell transplantation (ASCT) following BEAM (BCNU, etoposide, cytarabine, melphalan) conditioning is standard of care in relapsed low- and high-grade B-cell lymphoma (DLBCL) and other lymphoproliferative disorders, but BCNU is associated with interstitial pneumonia and an increased mortality. A less toxic regimen might improve the outcome of patients with lymphoma after transplantation. OBJECTIVES: We investigated the role of bendamustine replacing BCNU in the BEAM regimen in patients with lymphoma undergoing ASCT. PATIENTS/METHODS: The conditioning regimen BendaEAM consisted of bendamustine, cytarabine, etoposide, and melphalan and was used in patients with Hodgkin's disease (HD) and Non-Hodgkin lymphoma (NHL). RESULTS: Forty-one patients with HD (n = 9) or NHL (n = 32) were consecutively treated with Benda-BEAM replacing BCNU. No pulmonary or renal toxicities occurred, and no patient died related to transplant. After a median follow-up of 55 months, CR rate was 56%, 18 patients (44%) showed progression after a median time of 7 months after transplantation (range: 2-29 months), and 11 patients (24%) have died, all due to lymphoma progression. The 1-, 2-, and 4-year PFS are 73.2%, 58.6%, and 55.6% and the 1-, 2-, and 4-year OS 85.4%, 78.0%, and 72.6%, respectively. CONCLUSION: BendaEAM seems to be feasible with a promising response rate and acceptable toxicity.

A phase I study of lenalidomide in patients with chronic myelomonocytic leukemia (CMML) - AGMT_CMML-1.

According to former classification systems chronic myelomonocytic leukemia (CMML) is listed within myelodysplastic syndromes (MDS). Therefore data regarding treatment of CMML is largely derived from MDS trials. Two published studies suggest efficacy of lenalidomide in a proportion of patients with CMML, but the number of patients included was very low. We initiated this phase I trial with lenalidomide in patients with CMML. Primary objective of the current study was to determine the maximum tolerated dose (MTD). Secondary objectives were safety, tolerability and response. Twenty patients were enrolled and received lenalidomide using a classical 3 + 3 design. Lenalidomide 5 mg daily was confirmed as MTD. Best response achieved was partial remission in one patient and stable disease in nine patients. Lack of response with primary progressive disease was seen in three patients. Lenalidomide had a good toxicity profile in this study with thrombocytopenia being the main toxicity observed. Efficacy needs to be confirmed in further trials.

Evaluation of the prognostic significance of eosinophilia and basophilia in a larger cohort of patients with myelodysplastic syndromes.

BACKGROUND: Lineage involvement and maturation arrest are considered to have prognostic significance in patients with myelodysplastic syndromes (MDS). However, although the prognostic value of neutropenia, thrombocytopenia, and monocytosis have been documented, little is known about the impact of eosinophils and basophils. METHODS: The authors examined the prognostic significance of eosinophils and basophils in 1008 patients with de novo MDS. Patients were enrolled from 3 centers of the Austrian-German MDS Working Group and were analyzed retrospectively. Blood eosinophils and basophils were quantified by light microscopy, and their impact on survival and leukemia-free survival was calculated by using Cox regression. RESULTS: Eosinophilia (eosinophils >350/microL) and basophilia (basophils >250/microL) predicted a significantly reduced survival (P < .05) without having a significant impact on leukemia-free survival. In multivariate analysis, eosinophilia and basophilia were identified as lactate dehydrogenase (LDH)-independent prognostic variables with International Prognostic Scoring System (IPSS)-specific impact. Although elevated LDH was identified as a major prognostic determinant in IPSS low-risk, intermediate-1 risk, and high-risk subgroups, the condition "eosinophilia and/or basophilia" was identified as a superior prognostic indicator in the IPSS intermediate-2 risk subgroup. CONCLUSIONS: The evaluation of eosinophils and basophils in patients with MDS was helpful and may complement the spectrum of variables to optimize prognostication in MDS.