Acute myeloid leukemia (AML) is a malignant disorder of the bone marrow which is characterized by the clonal expansion and differentiation arrest of myeloid progenitor cells. The age-adjusted ...incidence of AML is 4.3 per 100,000 annually in the United States (US). Incidence increases with age with a median age at diagnosis of 68 years in the US. The etiology of AML is heterogeneous. In some patients, prior exposure to therapeutic, occupational or environmental DNA-damaging agents is implicated, but most cases of AML remain without a clear etiology. AML is the most common form of acute leukemia in adults and has the shortest survival (5-year survival = 24%). Curative therapies, including intensive chemotherapy and allogeneic stem cell transplantation, are generally applicable to a minority of patients who are younger and fit, while most older individuals exhibit poor prognosis and survival. Differences in patient outcomes are influenced by disease characteristics, access to care including active therapies and supportive care, and other factors. After many years without therapeutic advances, several new therapies have been approved and are expected to impact patient outcomes, especially for older patients and those with refractory disease.
Myelodysplastic syndromes (MDS) consist of a heterogeneous group of myeloid neoplasms characterized by inefficient hematopoiesis, variable cytopenias and a considerable risk of progression to acute ...myeloid leukemia. Epidemiological assessment of MDS has been hampered by evolving diagnostic criteria and delayed classification of MDS as cancers until 2001. The poorly-understood nature of these neoplasms combined with the lack of effective therapies for decades contributed to suboptimal case ascertainment and underreporting. The annual age-adjusted incidence in the United States is approximately 4.0/100,000 persons, and the incidence substantially rises with age. Beyond age, other risk factors include male gender, obesity, smoking, and prior receipt of radiotherapy or chemotherapy, but most cases remain idiopathic in nature. The overall 5-year survival probability remains relatively poor at approximately 31% without a clear temporal improvement in outcomes despite the approval of three MDS-specific therapies since 2004 and increasing use of allogeneic hematopoietic stem cell transplantation. Better understanding of epidemiological trends of MDS will likely require incorporation of the key genetic determinants of the disease into consistent diagnostic paradigms that go beyond traditional morphologic assessments. The heterogeneity of the disease and lack of uniformly-defined genetic markers makes such a task difficult. Thorough case ascertainment and reporting efforts can provide vital insights that could inform treatment decisions and eventually improve the outcomes of patients with MDS.
Myelodysplastic syndromes (MDS) comprise a diverse group of clonal and malignant myeloid disorders characterized by ineffective hematopoiesis, resultant peripheral cytopenias, and a meaningful ...increased risk of progression to acute myeloid leukemia. A wide array of recurring genetic mutations involved in RNA splicing, histone manipulation, DNA methylation, transcription factors, kinase signaling, DNA repair, cohesin proteins, and other signal transduction elements has been identified as important substrates for the development of MDS. Cytogenetic abnormalities, namely those characterized by loss of genetic material (including 5q‐ and 7q‐), have also been strongly implicated and may influence the clonal architecture which predicts such mutations and may provoke an inflammatory bone marrow microenvironment as the substrate for clonal expansion. Other aspects of the molecular pathogenesis of MDS continue to be further elucidated, predicated upon advances in gene expression profiling and the development of new, and improved high‐throughput techniques. More accurate understanding of the genetic and molecular basis for the development of MDS directly provides additional opportunity for treatment, which to date remains limited. In this comprehensive review, we examine the current understanding of the molecular pathogenesis and pathophysiology of MDS, as well as review future prospects which may enhance this understanding, treatment strategies, and hopefully outcomes.
The classical myeloproliferative neoplasms (MPNs), specifically chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), represent ...clonal myeloid disorders whose pathogenesis is driven by well-defined molecular abnormalities. In this comprehensive review, we summarize the epidemiological literature and present our own analysis of the most recent the Surveillance, Epidemiology, and End Results (SEER) program data through 2016. Older age and male gender are known risk factors for MPNs, but the potential etiological role of other variables is less established. The incidences of CML, PV, and ET are relatively similar at 1.0–2.0 per 100,000 person-years in the United States, while PMF is rarer with an incidence of 0.3 per 100,000 person-years. The availability of tyrosine kinase inhibitor therapy has dramatically improved CML patient outcomes and yield a life expectancy similar to the general population. Patients with PV or ET have better survival than PMF patients.
Aplastic anemia (AA) is rare disorder of bone marrow failure which if severe and not appropriately treated is highly fatal. AA is characterized by morphologic marrow features, namely hypocellularity, ...and resultant peripheral cytopenias. The molecular pathogenesis of AA is not fully understood, and a uniform process may not be the culprit across all cases. An antigen‐driven and likely autoimmune dysregulated T‐cell homeostasis is implicated in the hematopoietic stem cell injury which ultimately founds the pathologic features of the disease. Defective telomerase function and repair may also play a role in some cases as evidenced by recurring mutations in related telomerase complex genes such as TERT and TERC. In addition, recurring mutations in BCOR/BCORL, PIGA, DNMT3A, and ASXL1 as well as cytogenetic abnormalities, namely monosomy 7, trisomy 8, and uniparental disomy of the 6p arm seem to be intimately related to AA pathogenesis. The increased incidence of late clonal disease has also provided clues to accurately describe plausible predispositions to the development of AA. The emergence of newer genomic sequencing and other techniques is incrementally improving the understanding of the pathogenic mechanisms of AA, the detection of the disease, and ultimately offers the potential to improve patient outcomes. In this comprehensive review, we discuss the current understanding of the immunobiology, molecular pathogenesis, and future directions of such for AA.
The World Health Organization classification and definition of “myeloid sarcoma” is imprecise and misleading. A more accurate term is “extramedullary acute myeloid leukemia tumor (eAML).” The ...pathogenesis of eAML has been associated with aberrancy of cellular adhesion molecules, chemokine receptors/ligands and RAS-MAPK/ERK signaling. eAML can present with or without synchronous or metachronous intramedullary acute myeloid leukemia (AML) so a bone marrow evaluation is always recommended. Accurate diagnosis of eAML requires tissue biopsy. eAML confined to one or a few sites is frequently treated with local therapy such as radiotherapy. About 75–90% of patients with isolated eAML will develop metachronous intramedullary AML with a median latency period ranging from 4 to 12 months; thus, patients with isolated eAML may also be treated with systemic anti-leukemia therapy. eAML does not appear to have an independent prognostic impact; selection of post-remission therapy including allogeneic hematopoietic cell transplant (alloHCT) is typically guided by intramedullary disease risk. Management of isolated eAML should be individualized based on patient characteristics as well as eAML location and cytogenetic/molecular features. The role of PET/CT in eAML is also currently being elucidated. Improving outcomes of patients with eAML requires further knowledge of its etiology and mechanism(s) as well as therapeutic approaches beyond conventional chemotherapy, ideally in the context of controlled trials.
Immune checkpoint inhibitors (ICI) have yielded mixed but largely underwhelming results in clinical trials in patients with acute myeloid leukemia and myelodysplastic syndromes to date. However, ...increasing understanding of the immunologic landscape, potential biomarkers for benefits, and mechanisms of resistance, as well as the use of rational combinations, and identification of novel targets leaves plenty of room for optimism. Herein, we review recent advances in the preclinical and clinical development of ICI therapy in patients with myeloid malignancies and explore some of the important challenges facing the field such as the absence of validated biomarkers, the development of synergistic and safe combination therapies, and efforts to determine the best setting of ICI along the disease course. We finally foresee the future of the field and propose solutions to some of the major beforementioned obstacles.
Hyperleukocytosis in acute myeloid leukemia (AML) is associated with inferior outcomes. There is limited high quality evidence to support the benefits of leukapheresis. We retrospectively collected ...data from patients with newly-diagnosed AML who presented with a white cell count (WBC) >50 × 10
/L to 12 centers in the United States and Europe from 2006 to 2017 and received intensive chemotherapy. Logistic regression models estimated odds ratios for 30-day mortality and achievement of composite complete remission (CRc). Cox proportional hazard models estimated hazard ratios for overall survival (OS). Among 779 patients, clinical leukostasis was reported in 27%, and leukapheresis was used in 113 patients (15%). Thirty-day mortality was 16.7% (95% CI: 13.9-19.3%). Median OS was 12.6 months (95% CI: 11.5-14.9) among all patients, and 4.5 months (95% CI: 2.7-7.1) among those ≥65 years. Use of leukapheresis did not significantly impact 30-day mortality, achievement of CRc, or OS in multivariate analysis based on available data or in analysis based on multiple imputation. Among patients with investigator-adjudicated clinical leukostasis, there were statistically significant improvements in 30-day mortality and OS with leukapheresis in unadjusted analysis, but not in multivariate analysis. Given the significant resource use, cost, and potential complications of leukapheresis, randomized studies are needed to evaluate its value.
No two diagnoses of myelodysplastic syndrome are genuinely alike, owing to differing and dynamic mutational topography and epigenetic aberrancy. Consequently, no two patients with myelodysplastic ...syndrome are identical and disease-specific and patient-specific factors are considered in formulating the optimal treatment, which includes few that are disease modifying. Age itself should not be an absolute contraindication to therapy, including intensive therapy such as allogeneic hematopoietic stem cell transplantation, which is the only curative therapy. However, age associates with an increased prevalence of frailty and comorbidities that must be considered and may preclude a path to cure. Palliative therapies are the mainstay for many patients with myelodysplastic syndrome, which is a disease of older adults with the majority of patients diagnosed at age ≥ 75 years. The older patient requires heightened attention to end organ function/reserve and drug-drug interactions as well as insurance, income, cost, and socioeconomic and psychosocial issues that influence management. Many prior studies have included relatively younger populations or have not specifically performed high-quality subgroup analyses of older patients. In this review, we discuss the available standard-of-care therapies for myelodysplastic syndrome as they specifically relate to the older population and assess the emerging therapeutics that may further the pursuit for personalized treatment and improve both the outcomes and quality of life of the older patient with myelodysplastic syndrome.
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