Stably acquired mutations in hematopoietic cells represent substrates of selection that may lead to clonal hematopoiesis (CH), a common state in cancer patients that is associated with a heightened ...risk of leukemia development. Owing to technical and sample size limitations, most CH studies have characterized gene mutations or mosaic chromosomal alterations (mCAs) individually. Here we leverage peripheral blood sequencing data from 32,442 cancer patients to jointly characterize gene mutations (n = 14,789) and mCAs (n = 383) in CH. Recurrent composite genotypes resembling known genetic interactions in leukemia genomes underlie 23% of all detected autosomal alterations, indicating that these selection mechanisms are operative early in clonal evolution. CH with composite genotypes defines a patient group at high risk of leukemia progression (3-year cumulative incidence 14.6%, CI: 7-22%). Multivariable analysis identifies mCA as an independent risk factor for leukemia development (HR = 14, 95% CI: 6-33, P < 0.001). Our results suggest that mCA should be considered in conjunction with gene mutations in the surveillance of patients at risk of hematologic neoplasms.
Article Note: Funding information NIH Clinical Center, Grant/Award Numbers: P01 CA23766, P30 CA008748 CAPTION(S): Appendix S1. Supporting Information Byline: Brian J. Ball, Meier Hsu, Sean M. Devlin, ...Maria Arcila, Mikhail Roshal, Yanming Zhang, Chris A. Famulare, Aaron D. Goldberg, Sheng F. Cai, Andrew Dunbar, Zachary Epstein-Peterson, Kamal N. Menghrajani, Jacob L. Glass, Justin Taylor, Aaron D. Viny, Sergio S. Giralt, Boglarka Gyurkocza, Brian C. Shaffer, Roni Tamari, Ross L. Levine, Martin S. Tallman, Eytan M. Stein
•High-risk CH mutations in JAK2, RUNX1, and XPO1 anticipate hematologic malignancy in patients with cancer.•Functionally neutral silent CH variants are significant predictors of hematologic ...malignancy risk.
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Clonal hematopoiesis (CH) identified by somatic gene variants with variant allele fraction (VAF) ≥ 2% is associated with an increased risk of hematologic malignancy. However, CH defined by a broader set of genotypes and lower VAFs is ubiquitous in older individuals. To improve our understanding of the relationship between CH genotype and risk of hematologic malignancy, we analyzed data from 42 714 patients who underwent blood sequencing as a normal comparator for nonhematologic tumor testing using a large cancer-related gene panel. We cataloged hematologic malignancies in this cohort using natural language processing and manual curation of medical records. We found that some CH genotypes including JAK2, RUNX1, and XPO1 variants were associated with high hematologic malignancy risk. Chronic disease was predicted better than acute disease suggesting the influence of length bias. To better understand the implications of hematopoietic clonality independent of mutational function, we evaluated a set of silent synonymous and noncoding mutations. We found that silent CH, particularly when multiple variants were present or VAF was high, was associated with increased risk of hematologic malignancy. We tracked expansion of CH mutations in 26 hematologic malignancies sequenced with the same platform. JAK2 and TP53 VAF consistently expanded at disease onset, whereas DNMT3A and silent CH VAFs mostly decreased. These data inform the clinical and biological interpretation of CH in the context of nonhematologic cancer.
Acute myeloid leukemia is the most common form of leukemia and can present with a wide variety of signs and symptoms. This article presents a case of a middle-aged male who presented with ongoing ...upper respiratory cold-like symptoms and was then found to be severely pancytopenic. A diagnosis of acute myeloid leukemia was made after a bone marrow biopsy, and the patient underwent induction chemotherapy. This article brings to light the uncommon diagnosis of acute myeloid leukemia, from a common presentation, a common cold. Additionally, it discusses the initial workup and diagnostic process of acute myeloid leukemia, risk stratification, and a basic treatment algorithm.
Treatments for acute myeloid leukemia (AML) had remained essentially unchanged for several years; however, the advent of molecular testing has generated insight into the biology of this disease which ...is now being translated into clinical practice. New treatment strategies which improve drug delivery and exploit cellular targets are changing the landscape of how we treat this disease.
Induction therapy is in the process of changing for several patient populations. The introduction of CPX-351 offers a novel strategy for treating patients with therapy-related AML or AML with myelodysplasia-related changes; gemtuzumab ozogamicin may become incorporated into standard induction therapy, especially for patients with core-binding factor leukemias; and for older adults, combination therapy with venetoclax may offer a more efficacious strategy than the single-agent regimens previously used. Additionally, targeted therapies are now becoming available for patients with mutations in FMS-like tyrosine kinase 3 (FLT3) or isocitrate dehydrogenase 2 (IDH2), ushering in an era of personalized medicine in the treatment of AML.
The US Food and Drug Administration approval of several agents in 2017 will change the way AML treatment is approached and will offer both clinicians and patients a new armamentarium with which to treat this disease.
Oncogenic mutations in isocitrate dehydrogenases 1 and 2 (IDH1/2) produce 2-hydroxyglutarate (2HG), which inhibits dioxygenases that modulate chromatin dynamics. The effects of 2HG have been reported ...to sensitize IDH tumors to poly-(ADP-ribose) polymerase (PARP) inhibitors. However, unlike PARP-inhibitor-sensitive BRCA1/2 tumors, which exhibit impaired homologous recombination, IDH-mutant tumors have a silent mutational profile and lack signatures associated with impaired homologous recombination. Instead, 2HG-producing IDH mutations lead to a heterochromatin-dependent slowing of DNA replication accompanied by increased replication stress and DNA double-strand breaks. This replicative stress manifests as replication fork slowing, but the breaks are repaired without a significant increase in mutation burden. Faithful resolution of replicative stress in IDH-mutant cells is dependent on poly-(ADP-ribosylation). Treatment with PARP inhibitors increases DNA replication but results in incomplete DNA repair. These findings demonstrate a role for PARP in the replication of heterochromatin and further validate PARP as a therapeutic target in IDH-mutant tumors.
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•Tumors with IDH mutations lack signatures of impaired homologous recombination•IDH mutations lead to impaired DNA replication and replication stress•Replication stress in IDH-mutant cells is dependent on increased heterochromatin•PARP is required for the resolution of replication stress in IDH-mutant cells
Schvartzman et al. reveal that IDH-mutant tumors, although sensitive to PARP inhibitors, have fewer mutations than BRCA1/2-mutant tumors. Rather than exploiting synthetic lethality with the loss of DNA-break repair pathways, PARP inhibitors’ effects in IDH-mutant cells correlated with heterochromatic DNA replication stress, potentially broadening the clinical applications of these drugs.
Azacitidine + venetoclax, decitabine + venetoclax, and low-dose cytarabine + venetoclax are now standard treatments for newly diagnosed older or unfit patients with acute myeloid leukemia (AML). ...Although these combinations are also commonly used in relapsed or refractory AML (RR-AML), clinical and molecular predictors of response and survival in RR-AML are incompletely understood. We retrospectively analyzed clinical and molecular characteristics and outcomes for 86 patients with RR-AML who were treated with venetoclax combinations. The complete remission (CR) or CR with incomplete hematologic recovery (CRi) rate was 24%, and the overall response rate was 31% with the inclusion of a morphologic leukemia-free state. Azacitidine + venetoclax resulted in higher response rates compared with low-dose cytarabine + venetoclax (49% vs 15%; P = .008). Median overall survival (OS) was 6.1 months, but it was significantly longer with azacitidine + venetoclax compared with low-dose cytarabine + venetoclax (25 vs 3.9 months; P = .003). This survival advantage of azacitidine + venetoclax over low-dose cytarabine + venetoclax persisted when patients were censored for subsequent allogeneic stem cell transplantation (8.1 vs 3.9 months; P = .035). Mutations in NPM1 were associated with higher response rates, whereas adverse cytogenetics and mutations in TP53, KRAS/NRAS, and SF3B1 were associated with worse OS. Relapse was driven by diverse mechanisms, including acquisition of novel mutations and an increase in cytogenetic complexity. Venetoclax combination therapy is effective in many patients with RR-AML, and pretreatment molecular characteristics may predict outcomes. Trials that evaluate novel agents in combination with venetoclax therapy in patients with RR-AML that have adverse risk genomic features are warranted.
•In patients with RR-AML, venetoclax combination therapy resulted in responses in 31% of patients and a median OS of 6.1 months.•NPM1 mutations predicted higher response rates; adverse cytogenetics and mutations in TP53, KRAS/NRAS, and SF3B1 predicted worse OS.
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