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The authors identify 11 discrete genetic subsets of acute myeloid leukemia on the basis of the expression and coexpression of particular mutations. Prospective studies may elucidate distinct approaches to their management. Acute myeloid leukemia (AML) is characterized by clonal expansion of undifferentiated myeloid precursors, resulting in impaired hematopoiesis and bone marrow failure. Although many patients with AML have a response to induction chemotherapy, refractory disease is common, and relapse represents the major cause of treatment failure. 1 Cancer develops from somatically acquired driver mutations, which account for the myriad biologic and clinical complexities of the disease. A classification of cancers that is based on causality is likely to be durable, reproducible, and clinically relevant. This is already evident in the case of AML, for which there has been a progressive shift from . . .

The immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide are highly effective treatments for multiple myeloma. However, virtually all patients eventually relapse due to acquired drug resistance with resistance-causing genetic alterations being found only in a small subset of cases. To identify non-genetic mechanisms of drug resistance, we here perform integrated global quantitative tandem mass tag (TMT)-based proteomic and phosphoproteomic analyses and RNA sequencing in five paired pre-treatment and relapse samples from multiple myeloma patients. These analyses reveal a CDK6-governed protein resistance signature that includes myeloma high-risk factors such as TRIP13 and RRM1. Overexpression of CDK6 in multiple myeloma cell lines reduces sensitivity to IMiDs while CDK6 inhibition by palbociclib or CDK6 degradation by proteolysis targeting chimeras (PROTACs) is highly synergistic with IMiDs in vitro and in vivo. This work identifies CDK6 upregulation as a druggable target in IMiD-resistant multiple myeloma and highlights the use of proteomic studies to uncover non-genetic resistance mechanisms in cancer. Acquired resistance to immunomodulatory drugs is common in multiple myeloma patients, but rarely attributed to genetic alterations. Here, proteomic, phosphoproteomic and RNA sequencing analysis in five paired pre-treatment and relapse samples reveals a CDK6-regulated protein resistance signature.

Mutations in the nucleophosmin 1 ( NPM1 ) gene are considered founder mutations in the pathogenesis of acute myeloid leukemia (AML). To characterize the genetic composition of NPM1 mutated ( NPM1 mut ) AML, we assess mutation status of five recurrently mutated oncogenes in 129 paired NPM1 mut samples obtained at diagnosis and relapse. We find a substantial shift in the genetic pattern from diagnosis to relapse including NPM1 mut loss ( n  = 11). To better understand these NPM1 mut loss cases, we perform whole exome sequencing (WES) and RNA-Seq. At the time of relapse, NPM1 mut loss patients (pts) feature distinct mutational patterns that share almost no somatic mutation with the corresponding diagnosis sample and impact different signaling pathways. In contrast, profiles of pts with persistent NPM1 mut are reflected by a high overlap of mutations between diagnosis and relapse. Our findings confirm that relapse often originates from persistent leukemic clones, though NPM1 mut loss cases suggest a second “de novo” or treatment-associated AML (tAML) as alternative cause of relapse. NPM1 gene mutation is a founding event in acute myeloid leukaemia. Here, the authors find that at relapse, some patients lose the NPM1 mutation and show distinct mutational and gene expression patterns, highlighting a potential route for relapse.

The 9th web-based European Conference on Infections in Leukemia (ECIL-9), held September 16-17, 2021, reviewed the risk of infections and febrile neutropenia associated with more recently approved immunotherapeutic agents and molecular targeted drugs for the treatment of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Novel antibody based treatment approaches (inotuzumab ozogamicin, gemtuzumab ozogamicin, flotetuzumab), isocitrate dehydrogenases inhibitors (ivosidenib, enasidenib, olutasidenib), FLT3 kinase inhibitors (gilteritinib, midostaurin, quizartinib), a hedgehog inhibitor (glasdegib) as well as a BCL2 inhibitor (venetoclax) were reviewed with respect to their mode of action, their immunosuppressive potential, their current approval and the infectious complications and febrile neutropenia reported from clinical studies. Evidence-based recommendations for prevention and management of infectious complications and specific alerts regarding the potential for drug-drug interactions were developed and discussed in a plenary session with the panel of experts until consensus was reached. The set of recommendations was posted on the ECIL website for a month for comments from members of EBMT, EORTC, ICHS and ELN before final approval by the panelists. While a majority of these agents are not associated with a significantly increased risk when used as monotherapy, caution is required with combination therapy such as venetoclax plus hypomethylating agents, gemtuzumab ozogamicin plus cytotoxic drugs or midostaurin added to conventional AML chemotherapy.

The therapeutic approach for acute myeloid leukemia (AML) remains challenging, since over the last four decades a stagnation in standard cytotoxic treatment has been observed. But within recent years, remarkable advances in the understanding of the molecular heterogeneity and complexity of this disease have led to the identification of novel therapeutic targets. In the last two years, seven new targeted agents (midostaurin, gilteritinib, enasidenib, ivosidenib, glasdegib, venetoclax and gemtuzumab ozogamicin) have received US Food and Drug Administration (FDA) approval for the treatment of AML. These drugs did not just prove to have a clinical benefit as single agents but have especially improved AML patient outcomes if they are combined with conventional therapy. In this review, we will focus on currently approved and promising upcoming agents and we will discuss controversial aspects and limitations of targeted treatment strategies.

Clinical recommendations for Acute Myeloid Leukemia (AML) classification and risk-stratification remain heavily reliant on cytogenetic findings at diagnosis, which are present in <50% of patients. Using comprehensive molecular profiling data from 3,653 patients we characterize and validate 16 molecular classes describing 100% of AML patients. Each class represents diverse biological AML subgroups, and is associated with distinct clinical presentation, likelihood of response to induction chemotherapy, risk of relapse and death over time. Secondary AML-2, emerges as the second largest class (24%), associates with high-risk disease, poor prognosis irrespective of flow Minimal Residual Disease (MRD) negativity, and derives significant benefit from transplantation. Guided by class membership we derive a 3-tier risk-stratification score that re-stratifies 26% of patients as compared to standard of care. This results in a unified framework for disease classification and risk-stratification in AML that relies on information from cytogenetics and 32 genes. Last, we develop an open-access patient-tailored clinical decision support tool. Classification and risk-stratification for Acute Myeloid Leukemia (AML) at diagnosis are primarily based on cytogenetics and only a few gene mutations. Here, the authors study the genomic landscape of 3653 AML patients and characterize 16 non-overlapping molecular subgroups of clinical relevance for disease classification and risk prognostication.

Cancer development is an evolutionary genomic process with parallels to Darwinian selection. It requires acquisition of multiple somatic mutations that collectively cause a malignant phenotype and continuous clonal evolution is often linked to tumor progression. Here, we show the clonal evolution structure in 15 myelofibrosis (MF) patients while receiving treatment with JAK inhibitors (mean follow-up 3.9 years). Whole-exome sequencing at multiple time points reveal acquisition of somatic mutations and copy number aberrations over time. While JAK inhibition therapy does not seem to create a clear evolutionary bottleneck, we observe a more complex clonal architecture over time, and appearance of unrelated clones. Disease progression associates with increased genetic heterogeneity and gain of RAS/RTK pathway mutations. Clonal diversity results in clone-specific expansion within different myeloid cell lineages. Single-cell genotyping of circulating CD34 + progenitor cells allows the reconstruction of MF phylogeny demonstrating loss of heterozygosity and parallel evolution as recurrent events. Myelofibrosis is a myeloproliferative neoplasm. Here, the authors show the clonal evolution of myelofibrosis during JAK inhibitor therapy, revealing how the treatment results in an increase in clonal complexity and a gain of RAS pathway mutations.

Peter Campbell, Hartmut Döhner and colleagues present an analysis of genetic mutations and clinical information from 1,540 patients with acute myeloid leukemia, demonstrating the utility of clinical knowledge banks for personalized medicine. They show that use of their approach could reduce the number of hematopoietic cell transplants in patients with AML by up to 25% while maintaining survival rates. Underpinning the vision of precision medicine is the concept that causative mutations in a patient's cancer drive its biology and, by extension, its clinical features and treatment response. However, considerable between-patient heterogeneity in driver mutations complicates evidence-based personalization of cancer care. Here, by reanalyzing data from 1,540 patients with acute myeloid leukemia (AML), we explore how large knowledge banks of matched genomic–clinical data can support clinical decision-making. Inclusive, multistage statistical models accurately predicted likelihoods of remission, relapse and mortality, which were validated using data from independent patients in The Cancer Genome Atlas. Comparison of long-term survival probabilities under different treatments enables therapeutic decision support, which is available in exploratory form online. Personally tailored management decisions could reduce the number of hematopoietic cell transplants in patients with AML by 20–25% while maintaining overall survival rates. Power calculations show that databases require information from thousands of patients for accurate decision support. Knowledge banks facilitate personally tailored therapeutic decisions but require sustainable updating, inclusive cohorts and large sample sizes.

Clonal hematopoiesis of indeterminate potential (CHIP) occurs in an age-related manner and associates with an increased risk of hematologic cancer, atherosclerotic disease, and shorter overall survival. Little is known about the cell of origin, repartition patterns of clonal mutations within the hematopoietic differentiation tree, and its dynamics under evolutionary pressure. Using targeted sequencing, CHIP was identified in 121 out of 437 elderly individuals (27.7%). Variant allele frequencies (VAFs) of 91 mutations were studied in six peripheral blood cell fractions. VAFs were significantly higher in monocytes, granulocytes, and NK-cells compared to B- or T cells. In all cases with available bone marrow material, mutations could be identified in Lin−CD34+CD38− HSCs with subsequent expansion to myeloid primed progenitors. In 22 patients with solid cancer receiving (radio-)chemotherapy, longitudinal study of 32 mutations at 121 time points identified relative VAF changes of at least 50% in 13/32 mutations. VAFs of DNMT3A, were stable in 12/13 cases (P < .001). Cancer patients with a clonal mutation other than DNMT3A required more often red blood cell transfusions and dose reductions. Our results provide novel insights into cellular distribution of clonal mutations, their dynamics under chemotherapy, and advocate for systematic analyses for CHIP in cancer patients.