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Rhode Island Medical Journal (2013) Apr 2020Acute myeloid leukemia (AML) is a malignancy of the stem cell precursors of the myeloid lineage (red blood cells, platelets, and white blood cells other than B and T... (Review)
Review
Acute myeloid leukemia (AML) is a malignancy of the stem cell precursors of the myeloid lineage (red blood cells, platelets, and white blood cells other than B and T cells). Like other malignancies, it is due to genetic variations that lead to neoplastic changes and clonal proliferation. AML remains a rare malignancy, accounting for only 1.2% of all new cancer diagnoses in the United States per year, but it accounts for close to one third of all leukemias diagnosed.* For much of the 20th and early 21st century treatment paradigms were unchanged with survival curves remaining stagnant for many decades. Recent changes in our understanding of the genetic variations in the disease have led to some promising new therapies with hopes for improved outcomes in the future. Below we review the definitions, diagnosis and classification of AML and how this affects the evolving treatment paradigm of AML.
Topics: Antineoplastic Agents; Forecasting; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Recurrence; Treatment Outcome
PubMed: 32236160
DOI: No ID Found -
American Journal of Hematology Mar 2023Acute myeloid leukemia (AML) is a frequently fatal bone marrow stem cell cancer characterized by unbridled proliferation of malignant marrow stem cells with associated... (Review)
Review
DISEASE OVERVIEW
Acute myeloid leukemia (AML) is a frequently fatal bone marrow stem cell cancer characterized by unbridled proliferation of malignant marrow stem cells with associated infection, anemia, and bleeding. An improved understanding of pathophysiology, improvements in measurement technology and at least 10 recently approved therapies have led to revamping the diagnostic, prognostic, and therapeutic landscape of AML.
DIAGNOSIS
One updated and one new classification system were published in 2022, both emphasizing the integration of molecular analysis into daily practice. Differences between the International Consensus Classification and major revisions from the previous 2016 WHO system provide both challenges and opportunities for care and clinical research.
RISK ASSESSMENT AND MONITORING
The European Leukemia Net 2022 risk classification integrates knowledge from novel molecular findings and recent trial results, as well as emphasizing dynamic risk based on serial measurable residual disease assessment. However, how to leverage our burgeoning ability to measure a small number of potentially malignant myeloid cells into therapeutic decision making is controversial.
RISK ADAPTED THERAPY
The diagnostic and therapeutic complexity plus the availability of newly approved agents requires a nuanced therapeutic algorithm which should integrate patient goals of care, comorbidities, and disease characteristics including the specific mutational profile of the patient's AML. The framework we suggest only represents the beginning of the discussion.
Topics: Humans; Bone Marrow; Leukemia, Myeloid, Acute; Mutation; Prognosis; Risk Assessment
PubMed: 36594187
DOI: 10.1002/ajh.26822 -
Haematologica Feb 2023Research into the underlying pathogenic mechanisms of acute myeloid leukemia (AML) has led to remarkable advances in our understanding of the disease. Mutations now... (Review)
Review
Research into the underlying pathogenic mechanisms of acute myeloid leukemia (AML) has led to remarkable advances in our understanding of the disease. Mutations now allow us to explore the enormous diversity among cytogenetically defined subsets of AML, particularly the large subset of cytogenetically normal AML. Despite the progress in unraveling the tumor genome, only a small number of recurrent mutations have been incorporated into risk-stratification schemes and have been proven to be clinically relevant, targetable lesions. The current World Health Organization Classification of myeloid neoplasms and leukemia includes eight AML categories defined by recurrent genetic abnormalities as well as three categories defined by gene mutations. We here discuss the utility of molecular markers in AML in prognostication and treatment decision-making. New therapies based on targetable markers include IDH inhibitors (ivosidenib, enasidenib), venetoclax-based therapy, FLT3 inhibitors (midostaurin, gilteritinib, and quizartinib), gemtuzumab ozogamicin, magrolimab and menin inhibitors.
Topics: Humans; Leukemia, Myeloid, Acute; Gemtuzumab
PubMed: 36722402
DOI: 10.3324/haematol.2022.280801 -
The Journal of Clinical Investigation Apr 2020In spite of the recent approval of new promising targeted therapies, the clinical outcome of patients with acute myeloid leukemia (AML) remains suboptimal, prompting the... (Review)
Review
In spite of the recent approval of new promising targeted therapies, the clinical outcome of patients with acute myeloid leukemia (AML) remains suboptimal, prompting the search for additional and synergistic therapeutic rationales. It is increasingly evident that the bone marrow immune environment of AML patients is profoundly altered, contributing to the severity of the disease but also providing several windows of opportunity to prompt or rewire a proficient antitumor immune surveillance. In this Review, we present current evidence on immune defects in AML, discuss the challenges with selective targeting of AML cells, and summarize the clinical results and immunologic insights from studies that are testing the latest immunotherapy approaches to specifically target AML cells (antibodies, cellular therapies) or more broadly reactivate antileukemia immunity (vaccines, checkpoint blockade). Given the complex interactions between AML cells and the many components of their environment, it is reasonable to surmise that the future of immunotherapy in AML lies in the rational combination of complementary immunotherapeutic strategies with chemotherapeutics or other oncogenic pathway inhibitors. Identifying reliable biomarkers of response to improve patient selection and avoid toxicities will be critical in this process.
Topics: Animals; Humans; Immunologic Surveillance; Immunotherapy; Leukemia, Myeloid, Acute
PubMed: 32235097
DOI: 10.1172/JCI129204 -
Current Oncology (Toronto, Ont.) Aug 2022Acute myeloid leukemia (AML) is a hematologic malignancy that most frequently develops in older adults. Overall, AML is associated with a high mortality although... (Review)
Review
Acute myeloid leukemia (AML) is a hematologic malignancy that most frequently develops in older adults. Overall, AML is associated with a high mortality although advancements in genetic risk stratification and new treatments are leading to improvements in outcomes for some subgroups. In this review, we discuss an individualized approach to intensive therapy with a focus on the role of recently approved novel therapies as well as the selection of post-remission therapies for patients in first remission. We discuss the management of patients with relapsed and refractory AML, including the role of targeted treatment and allogeneic stem cell transplant. Next, we review non-intensive treatment for older and unfit AML patients including the use of azacitidine and venetoclax. Finally, we discuss the integration of palliative care in the management of patients with AML.
Topics: Aged; Azacitidine; General Practitioners; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute
PubMed: 36135060
DOI: 10.3390/curroncol29090491 -
Current Treatment Options in Oncology Jun 2020Relapse is still a common scenario in acute myeloid leukemia (AML) treatment and occurs in 40-50% of younger and the great majority of elderly patients. The prognosis in... (Review)
Review
Relapse is still a common scenario in acute myeloid leukemia (AML) treatment and occurs in 40-50% of younger and the great majority of elderly patients. The prognosis in relapsed AML patients is generally poor but depends largely on the timing of relapse (early versus late) and the possibility of allogeneic hematopoietic stem cell transplantation (HSCT). At the time of relapse, we again perform a mutational screening and cytogenetic analysis in all AML patients as clonal evolution of disease is frequent. Clinical trials should be first priority in all relapsed patients. In fit patients without prior transplant, we aim to perform HSCT after salvage therapy. In AML patients relapsing after HSCT and good performance status, intensive therapy can be considered with subsequent cellular therapy such as donor lymphocyte infusion (DLI) or a second HSCT. However, less than 20% of these patients are alive after 5 years. For those patients that are unfit, the therapeutic aim is to prolong life with acceptable quality of life. Here, hypomethylating agents (HMA), low-dose AraC (LDAC), and solely cytoreductive therapy with hydroxurea are options depending on first-line therapy. For those patients that have not been treated with venetoclax in first line, the combination therapy of venetoclax with demethylating agents achieves encouraging response rates. Venetoclax is currently also studied in combination with intensive salvage therapy. Importantly, for patients with isocitrate dehydrogenase (IDH) 1/2-mutated AML, ivosidenib, an IDH1 inhibitor, and enasidenib, an IDH2 inhibitor, present well-tolerated options in the setting of refractory or relapsed (r/r) disease even in elderly and heavily pre-treated patients with response rates of 30-40%. Both substances have been approved by the U.S. Food and Drug Administration (FDA) for r/r AML patients with IDH1/2 mutations (but not yet by the European Medicines Agency (EMA)). For patients with FMS-like tyrosine kinase 3 (FLT3) mutations, treatment with the selective FLT3 inhibitor gilteritinib is well tolerated and leads to improved outcome compared with standard salvage therapy. The approval has been granted by the FDA and the EMA. Generally, we would recommend targeted therapy for IDH1/2- and FLT3-mutated AML if available. In order to improve outcome in relapsed AML, it will be important to intelligently combine novel substances with each other as well as chemotherapy in prospective clinical trials. The development of therapies with bispecific antibodies or chimeric antigen receptor T cells (CAR-T) are still in early development.
Topics: Biomarkers, Tumor; Clinical Decision-Making; Combined Modality Therapy; Disease Management; Disease Susceptibility; Humans; Leukemia, Myeloid, Acute; Recurrence; Retreatment; Standard of Care; Treatment Outcome
PubMed: 32601974
DOI: 10.1007/s11864-020-00765-5 -
Blood Mar 2023Metabolic rewiring and cellular reprogramming are trademarks of neoplastic initiation and progression in acute myeloid leukemia (AML). Metabolic alteration in leukemic... (Review)
Review
Metabolic rewiring and cellular reprogramming are trademarks of neoplastic initiation and progression in acute myeloid leukemia (AML). Metabolic alteration in leukemic cells is often genotype specific, with associated changes in epigenetic and functional factors resulting in the downstream upregulation or facilitation of oncogenic pathways. Targeting abnormal or disease-sustaining metabolic activities in AML provides a wide range of therapeutic opportunities, ideally with enhanced therapeutic windows and robust clinical efficacy. This review highlights the dysregulation of amino acid, nucleotide, lipid, and carbohydrate metabolism in AML; explores the role of key vitamins and enzymes that regulate these processes; and provides an overview of metabolism-directed therapies currently in use or development.
Topics: Humans; Leukemia, Myeloid, Acute; Cellular Reprogramming; Cell Transformation, Neoplastic
PubMed: 36548959
DOI: 10.1182/blood.2022018092 -
Acta Haematologica 2021Myeloproliferative neoplasms (MPNs) can transform into blast phase MPN (leukemic transformation; MPN-BP), typically via accelerated phase MPN (MPN-AP), in ∼20-25% of... (Review)
Review
BACKGROUND
Myeloproliferative neoplasms (MPNs) can transform into blast phase MPN (leukemic transformation; MPN-BP), typically via accelerated phase MPN (MPN-AP), in ∼20-25% of the cases. MPN-AP and MPN-BP are characterized by 10-19% and ≥20% blasts, respectively. MPN-AP/BP portend a dismal prognosis with no established conventional treatment. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the sole modality associated with long-term survival.
SUMMARY
MPN-AP/BP has a markedly different mutational profile from de novo acute myeloid leukemia (AML). In MPN-AP/BP, TP53 and IDH1/2 are more frequent, whereas FLT3 and DNMT3A are rare. Higher incidence of leukemic transformation has been associated with the most aggressive MPN subtype, myelofibrosis (MF); other risk factors for leukemic transformation include rising blast counts above 3-5%, advanced age, severe anemia, thrombocytopenia, leukocytosis, increasing bone marrow fibrosis, type 1 CALR-unmutated status, lack of driver mutations (negative for JAK2, CALR, or MPL genes), adverse cytogenetics, and acquisition of ≥2 high-molecular risk mutations (ASXL1, EZH2, IDH1/2, SRSF2, and U2AF1Q157). The aforementioned factors have been incorporated in several novel prognostic scoring systems for MF. Currently, elderly/unfit patients with MPN-AP/BP are treated with hypomethylating agents with/without ruxolitinib; these regimens appear to confer comparable benefit to intensive chemotherapy but with lower toxicity. Retrospective studies in patients who acquired actionable mutations during MPN-AP/BP showed positive outcomes with targeted AML treatments, such as IDH1/2 inhibitors, and require further evaluation in clinical trials. Key Messages: Therapy for MPN-AP patients represents an unmet medical need. MF patients, in particular, should be appropriately stratified regarding their prognosis and the risk for transformation. Higher-risk patients should be monitored regularly and treated prior to progression to MPN-BP. MPN-AP patients may be treated with hypomethylating agents alone or in combination with ruxolitinib; also, patients can be provided with the option to enroll in rationally designed clinical trials exploring combination regimens, including novel targeted drugs, with an ultimate goal to transition to transplant.
Topics: Allografts; Blast Crisis; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Mutation; Myeloproliferative Disorders; Neoplasm Proteins
PubMed: 33882481
DOI: 10.1159/000512929 -
Blood Jun 2023The European LeukemiaNet recently revised both the clinical (2022) and measurable residual disease testing (2021) guidelines for acute myeloid leukemia (AML). The...
The European LeukemiaNet recently revised both the clinical (2022) and measurable residual disease testing (2021) guidelines for acute myeloid leukemia (AML). The updated World Health Organization and International Consensus Classification for myeloid neoplasms were also published in 2022. Together, these documents update the classification, risk stratification, prognostication, monitoring recommendations, and response assessment of patients with AML. Increased appreciation of the genetic drivers of AML over the past decade and our increasingly sophisticated understanding of AML biology have been translated into novel therapies and more complex clinical treatment guidelines. Somatic genetic abnormalities and germ line predispositions now define and guide treatment and counseling for the subtypes of this hematologic malignancy. In this How I Treat article, we discuss how we approach AML in daily clinical practice, considering the recent updates in the context of new treatments and discoveries over the past decade.
Topics: Humans; Leukemia, Myeloid, Acute; Neoplasm, Residual; Consensus; Genotype; Hematologic Neoplasms
PubMed: 36758209
DOI: 10.1182/blood.2022017808 -
Current Treatment Options in Oncology May 2023Although safe and effective immune therapies have been developed in several cancers, this has not been so in acute myeloid leukaemia (AML). Studies of antibodies to... (Review)
Review
Although safe and effective immune therapies have been developed in several cancers, this has not been so in acute myeloid leukaemia (AML). Studies of antibodies to CD33, CD123 and CLL-1 report with unconvincing efficacy and substantial adverse events. Lacking AML-specific target antigens, these approaches using non-specific antigen targets often cause unacceptable bone marrow toxicity and off-target adverse events. Studies of AML incidence in persons with immune deficiency indicate little if any immune surveillance against AML. In contrast, data studies of recipients of haematopoietic cell transplants support an effective allogeneic anti-AML effect associated with graft-versus-host disease (GvHD) and possibly a specific graft-versus-leukaemia (GvL) effect. A special problem in the immune therapy of AML is few neo-antigens compared with solid cancers because of a relatively low mutation frequency. Studies of CAR-T-, CAR-NK-adaptor CAR-T- and allogeneic NK-cells are progressing as are approaches using synthetic biology. Presently, there are no convincing data of efficacy of immune therapy in AML.
Topics: Humans; Receptors, Chimeric Antigen; Leukemia, Myeloid, Acute; Immunotherapy; Immunotherapy, Adoptive
PubMed: 36949279
DOI: 10.1007/s11864-023-01066-3