Catherine C. Coombs

Therapy-Related Clonal Hematopoiesis in Patients with Non-hematologic Cancers Is Common and Associated with Adverse Clinical Outcomes

Clonal hematopoiesis (CH), as evidenced by recurrent somatic mutations in leukemia-associated genes, commonly occurs among aging human hematopoietic stem cells. We analyzed deep-coverage, targeted, next-generation sequencing (NGS) data of paired tumor and blood samples from 8,810 individuals to assess the frequency and clinical relevance of CH in patients with non-hematologic malignancies. We identified CH in 25% of cancer patients, with 4.5% harboring presumptive leukemia driver mutations (CH-PD). CH was associated with increased age, prior radiation therapy, and tobacco use. PPM1D and TP53 mutations were associated with prior exposure to chemotherapy. CH and CH-PD led to an increased incidence of subsequent hematologic cancers, and CH-PD was associated with shorter patient survival. These data suggest that CH occurs in an age-dependent manner and that specific perturbations can enhance fitness of clonal hematopoietic stem cells, which can impact outcome through progression to hematologic malignancies and through cell-non-autonomous effects on solid tumor biology.

Molecular therapy for acute myeloid leukaemia

Acute myeloid leukaemia (AML) is a heterogeneous disease that is, in general, associated with a very poor prognosis. Multiple cytogenetic and molecular abnormalities that characterize different forms of AML have been used to better prognosticate patients and inform treatment decisions. Indeed, risk status in patients with this disease has classically been based on cytogenetic findings; however, additional molecular characteristics have been shown to inform risk assessment, including FLT3, NPM1, KIT, and CEBPA mutation status. Advances in sequencing technology have led to the discovery of novel somatic mutations in tissue samples from patients with AML, providing deeper insight into the mutational landscape of the disease. The majority of patients with AML (>97%) are found to have a clonal somatic abnormality on mutational profiling. Nevertheless, our understanding of the utility of mutation profiling in clinical practice remains incomplete and is continually evolving, and evidence-based approaches to application of these data are needed. In this Review, we discuss the evidence-base for integrating mutational data into treatment decisions for patients with AML, and propose novel therapeutic algorithms in the era of molecular medicine.

Mutational correlates of response to hypomethylating agent therapy in acute myeloid leukemia

Acute myeloid leukemia (AML) is an aggressive malignancy with median age at diagnosis of 67 years, stressing the importance of developing treatments that are both effective and tolerable in elderly patients. Hypomethylating agents (HMAs) have been extensively studied in AML, typically in older adults who are deemed to be unfit for standard induction chemotherapy, demonstrating improved complete response (CR) rate and trends toward improvement in overall survival (OS) compared with conventional care regimens in the phase III setting with less favorable responses in the relapsed/refractory setting. Genome-wide studies of AML patients have revealed that 44% of patients with de novo AML harbor mutations in genes affecting DNAmethylation, including DNMT3A (26%), IDH1/2 (20%), TET2 (8%), and WT1 (6%). The presence of these mutations has been suggested to have therapeutic implications in small, retrospective series. Using data from two large referral centers together with previously reported data, we sought to investigate the relationship between somatic gene mutations affecting DNA methylation and HMA response in an expanded AML patient cohort. We did not observe a relationship between response to HMAs and IDH1/2 and TET2 mutations. We identified DNMT3A mutations to predict response to HMAs in patients treated in the frontline setting [odds ratio (OR), 3.12; P=0.001], but not in the total cohort when including relapsed/refractory patients (OR 1.72; P=0.23). This is a dual institution, retrospective study. Permission to review medical records was obtained by the Institutional Review Board of each participating institution. From March 2010 to December 2014, 242 patients were identified at Memorial Sloan Kettering Cancer Center (MSKCC) who had a diagnosis of AML by World Health Organization (WHO) criteria and next-gen-

Prognostic Role of Gene Mutations in Chronic Myelomonocytic Leukemia Patients Treated With Hypomethylating Agents

Somatic mutations contribute to the heterogeneous prognosis of chronic myelomonocytic leukemia (CMML). Hypomethylating agents (HMAs) are active in CMML, but analyses of small series failed to identify mutations predicting response or survival. We analyzed a retrospective multi-center cohort of 174 CMML patients treated with a median of 7 cycles of azacitidine (n = 68) or decitabine (n = 106). Sequencing data before treatment initiation were available for all patients, from Sanger (n = 68) or next generation (n = 106) sequencing. Overall response rate (ORR) was 52%, including complete response (CR) in 28 patients (17%). In multivariate analysis, ASXL1 mutations predicted a lower ORR (Odds Ratio [OR] = 0.85, p = 0.037), whereas TET2mut/ASXL1wt genotype predicted a higher CR rate (OR = 1.18, p = 0.011) independently of clinical parameters. With a median follow-up of 36.7 months, overall survival (OS) was 23.0 months. In multivariate analysis, RUNX1mut (Hazard Ratio [HR] = 2.00, p = .011), CBLmut (HR = 1.90, p = 0.03) genotypes and higher WBC (log10(WBC) HR = 2.30, p = .005) independently predicted worse OS while the TET2mut/ASXL1wt predicted better OS (HR = 0.60, p = 0.05). CMML-specific scores CPSS and GFM had limited predictive power. Our results stress the need for robust biomarkers of HMA activity in CMML and for novel treatment strategies in patients with myeloproliferative features and RUNX1 mutations.