Prediction of early (4-week) mortality in acute myeloid leukemia with intensive chemotherapy.

The progress with intensive chemotherapy and supportive care measures has improved survival in patients with newly diagnosed acute myeloid leukemia (AML). Given the recent development of effective low intensity therapies, an optimal decision on the therapy intensity may improve survival through the avoidance of early mortality. We reviewed the outcome of 3728 patients with newly diagnosed AML who received intensive chemotherapy between August 1980 and May 2020. Intensive chemotherapy was defined as a cumulative cytarabine dose ≥ 700 mg/m2 during induction therapy. We divided the whole cohort into a training and validation group at a 3:1 ratio. The population was divided into a training (2790 patients) and a validation cohort (938 patients). The median age was 55 years (range, 15-99). Among them, 442 patients (12%) had core-binding factor AML. Binary logistic regression identified older age, worse performance status, hyperbilirubinemia, elevated creatinine, hyperuricemia, cytogenetic abnormalities other than CBF and -Y, and pneumonia as adverse prognostic factors for an early 4-week mortality. This risk classification for early mortality was verified in the validation cohort of patients. In the validation cohort of more recently treated patients from 2000 to 2017, the 4-week mortality rates with intensive chemotherapy were 2%, 14%, and 50% in the low-, high-, and very high-risk group, respectively. The mortality rates with low intensity therapies were 3%, 9%, and 20%, respectively. The risk classification guides treatment intensity by the assessment of age, frailty, organ dysfunction, cytogenetic abnormality, and infection to avoid early mortality.

Venetoclax combined with FLAG-IDA induction and consolidation in newly diagnosed acute myeloid leukemia.

Multi-agent induction chemotherapy (IC) improves response rates in younger patients with acute myeloid leukemia (AML); however, relapse remains the principal cause of treatment failure. Improved induction regimens are needed. A prospective single-center phase Ib/II study evaluating fludarabine, cytarabine, G-CSF, and idarubicin combined with venetoclax (FLAG-IDA + VEN) in patients with newly diagnosed (ND) or relapsed/refractory AML. The primary efficacy endpoint was assessment of overall activity (overall response rate [ORR]: complete remission [CR] + CR with partial hematologic recovery [CRh] + CR with incomplete hematologic recovery [CRi] + morphologic leukemia free state + partial response). Secondary objectives included additional assessments of efficacy, overall survival (OS), and event-free survival (EFS). Results of the expanded ND cohort with additional follow-up are reported. Forty-five patients (median age: 44 years [range 20-65]) enrolled. ORR was 98% (N = 44/45; 95% credible interval 89.9%-99.7%). Eighty-nine percent (N = 40/45) of patients attained a composite CR (CRc + CRh + CRi) including 93% (N = 37/40) who were measurable residual disease (MRD) negative. Twenty-seven (60%) patients transitioned to allogeneic stem cell transplant (alloHSCT). Common non-hematologic adverse events included febrile neutropenia (44%; N = 20), pneumonia (22%, N = 10), bacteremia (18%, N = 8), and skin/soft tissue infections (44%, N = 20). After a median follow-up of 20 months, median EFS and OS were not reached. Estimated 24-month EFS and OS were 64% and 76%, respectively. FLAG-IDA + VEN is an active regimen in ND-AML capable of producing high MRD-negative remission rates and enabling transition to alloHSCT when appropriate in most patients. Toxicities were as expected with IC and were manageable. Estimated 24-month survival appears favorable compared to historical IC benchmarks.

New Approaches to Myelodysplastic Syndrome Treatment.

OPINION STATEMENT: The treatment of myelodysplastic syndromes (MDS) begins with risk stratification using a validated tool such as the International Prognostic Scoring System (IPSS) or its revised version (IPSS-R). This divides patients into lower- and higher- risk categories. Although treatment objectives in lower-risk MDS (LR-MDS) have traditionally been directed at improving cytopenias (usually anemia) as well as quality of life, recent data supports a potential role for early intervention in delaying transfusion dependency. In addition, careful individualized risk stratification incorporating clinical, cytogenetic, and mutational data might help identify patients at higher-than-expected risk for progression. Given the need for supportive care with red blood cell (RBC) transfusions leading to iron overload, iron chelation should be considered for patients with heavy transfusion requirements at risk for end-organ complications. For patients with LR-MDS and isolated anemia, no high-risk features, and endogenous erythropoietin (EPO) levels below 500 U/L, erythropoiesis-stimulating agents (ESAs) can be attempted to improve anemia. Some LR-MDS patient subgroups may also benefit from specific therapies including luspatercept (MDS with ring sideroblasts), lenalidomide (MDS with deletion 5q), or immunosuppressive therapy (hypocellular MDS). LR-MDS patients failing the above options, or those with multiple cytopenias and/or higher-risk features, can be considered for oral low-dose hypomethylating agent (HMA) therapy. Alternatively, these patients may be enrolled on a clinical trial with promising agents targeting the transforming-growth factor beta (TGF-ß) pathway, the hypoxia-inducible factor (HIF) pathway, telomerase activity, inflammatory signaling, or the splicing machinery. In higher-risk MDS (HR-MDS), therapy seeks to modify the natural history of the disease and prolong survival. Eligible patients should be considered for curative allogeneic hematopoietic stem cell transplantation (aHSCT). Despite promising novel combinations, the HMAs azacitidine (AZA) or decitabine (DAC) are still the standard of care for these patients, with intensive chemotherapy-based approaches being a potential option in a small subset of patients. Individuals who fail to respond or progress after HMA experience dismal outcomes and represent a major unmet clinical need. Such patients should be treated as part of a clinical trial if possible. Experimental agents to consider include venetoclax, myeloid cell leukemia 1 (MCL-1) inhibitors, eprenetapopt, CPX-351, immunotherapies (directed towards CD47, TIM3, or CD70), interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors, pevonedistat, seclidemstat, and eltanexor. In this review, we extensively discuss the current landscape of experimental therapies for both LR- and HR-MDS.

Integrating genetics and epigenetics in myelodysplastic syndromes: advances in pathogenesis and disease evolution.

The myelodysplastic syndromes (MDS) are a group of clonal diseases characterized by inefficient haematopoiesis, increased apoptosis and risk of evolution to acute myeloid leukaemia. Alterations in epigenetic processes, including DNA methylation, histone modifications, miRNA and splicing machinery, are well known pathogenical events in MDS. Although many advances have been made in determining the mutational frequency, distribution and association affecting these epigenomic regulators, functional integration to better understand pathogenesis of the disease is a challenging and expanding area. Recent studies are shedding light on the molecular basis of myelodysplasia and how mutations and epimutations can induce and promote this neoplastic process through aberrant transcription factor function (RUNX1, ETV6, TP53), kinase signalling (FLT3, NRAS, KIT, CBL) and epigenetic deregulation (TET2, IDH1/2, DNMT3A, EZH2, ASXL1, SF3B1, U2AF1, SRSF2, ZRSR2). In this review we will try to focus on the description of these mutations, their impact on prognosis, the functional connections between the different epigenetic pathways, and the existing and future therapies targeting these processes.

Geographic Disparity of Outcome in Patients With Cancer Over Decades: The Surveillance, Epidemiology, and End Results.

BACKGROUND: Improvements in prevention, early detection, and effective cancer therapy have decreased cancer-related mortality; however, significant health disparities exist. Therefore, we investigated the impact of these disparities on survival. METHODS: In the Surveillance, Epidemiology, and End Results, we identified 784,341 patients with cancer between 1990 and 2016 in Georgia, 68,493 between 1990 and 1999; 371,353 between 2000 and 2009; and 322,932 between 2010 and 2016. We assessed the overall survival (OS) of patients with all cancers, chronic myeloid leukemia (CML), and lung cancer, given the dramatic improvement in outcomes in patients with CML since 2000 compared to the generally considerably worse outcomes in lung cancer. In addition, we assessed the distance from each county to the Georgia Cancer Center (GCC) or the National Cancer Institute-designated Cancer Center (NCI-CC). RESULTS: The 5-year OS of patients with any cancer was 55%, and the 5-year OS of each county ranged from 33% to 82% (interquartile range, 51%-65%) (P < .001). In patients with lung cancer and CML, the 5-year OS rates were 15% and 52%, respectively. The geographic differences between counties were relatively small and constant over time for patients with lung cancer. However, geographic differences were more prominent in patients with CML and widened after the introduction of modern therapies. Multivariate Cox regression showed that age, median county income, race, and distance to GCC or NCI-CC were predictive factors. CONCLUSIONS: Significant disparities in cancer care exist among geographic locations. Geographic differences in survival appear more prominent when highly effective therapies are available.

Down-regulation of EZH2 expression in myelodysplastic syndromes.

EZH2 genetic mutations are common in myelodysplastic syndrome (MDS), which implies that this gene has a pathophysiological role in the disease. To further characterize molecular alterations of EZH2, and their potential prognostic impact in MDS, we assessed EZH2 RNA expression in primary bone marrow CD34+ cells from 78 patients. We found that 47% of patients have reduced EZH2 expression compared to normal controls. Further analyses revealed that EZH2 is significantly underexpressed in patients bearing chromosome 7 or 7q deletions (7-alt) when compared to controls, diploid patients, and patients with other cytogenetic alterations (p<0.05). In survival analysis, we found a non-significant trend toward overall survival (OS) being better among patients with EZH2 underexpression (median OS 55 vs. 36 months; p=0.71). Importantly, this trend became significant when the analysis was restricted to the subset of cases without alterations in chromosome 7 (62 vs. 36 months; p=0.033). Furthermore, our previous work has identified a spectrum of innate immune genes in MDS CD34+ cells that are deregulated via abnormal promoter histone methylation. Because EZH2 is a key regulator of histone methylation, we assessed the relationship between deregulation of these genes and EZH2 underexpression. We observed that the mRNA levels of 11 immune genes were higher in the EZH2 underexpression group and that immune gene expression was significantly higher in patients with concomitant EZH2 underexpression and KDM6B (also known as JMJD3, an H3K27 demethylase) overexpression. Taken together, these data indicate that EZH2 underexpression may have unique impact on the molecular pathogenesis and prognosis in MDS and be an important marker for patients without chromosome 7 alteration.

Lymphocyte recovery and infused CD34+ cells dose: Effect on the evolution after stem cell autotransplantation.

BACKGROUND AND OBJECTIVE: The number of infused CD34+cells (CD34+i) has been associated with absolute lymphocyte count (ALC) and the outcome undergoing autologous hematopoietic stem cell transplantation (HSCT) in patients with hematologic malignancies. The study's aim was to analyze the relationship between CD34+i, ALC and prognosis in this patients. PATIENTS AND METHOD: Medical records of 163 patients receiving HSCT between 2005 and 2012 were reviewed. RESULTS: We found significant and inversely proportional relationship between the CD34+i and the days required to reach ALC≥500/µl according to the regression line: days=-0.981×number of CD34+i+18.09. CONCLUSIONS: We have obtained a predictive model of lymphocyte recovery based recovery of CD34+i.