Classification, risk stratification and response assessment in myelodysplastic syndromes/neoplasms (MDS): A state-of-the-art report on behalf of the International Consortium for MDS (icMDS).

The guidelines for classification, prognostication, and response assessment of myelodysplastic syndromes/neoplasms (MDS) have all recently been updated. In this report on behalf of the International Consortium for MDS (icMDS) we summarize these developments. We first critically examine the updated World Health Organization (WHO) classification and the International Consensus Classification (ICC) of MDS. We then compare traditional and molecularly based risk MDS risk assessment tools. Lastly, we discuss limitations of criteria in measuring therapeutic benefit and highlight how the International Working Group (IWG) 2018 and 2023 response criteria addressed these deficiencies and are endorsed by the icMDS. We also address the importance of patient centered care by discussing the value of quality-of-life assessment. We hope that the reader of this review will have a better understanding of how to classify MDS, predict clinical outcomes and evaluate therapeutic outcomes.

Geriatric assessment for older adults receiving less-intensive therapy for acute myeloid leukemia: report of CALGB 361101.

Geriatric assessment (GA) predicts survival among older adults with acute myeloid leukemia (AML) treated intensively. We evaluated the predictive utility of GA among older adults treated with low-intensity therapy on a multisite trial. We conducted a companion study (CALGB 361101) to a randomized phase 2 trial (CALGB 11002) of adults ≥60 years and considered "unfit" for intensive therapy, testing the efficacy of adding bortezomib to decitabine therapy. On 361101, GA and quality of life (QOL) assessment was administered prior to treatment and every other subsequent cycle. Relationships between baseline GA and QOL measures with survival were evaluated using Kaplan-Meier estimation and Cox proportional hazards models. One-hundred sixty-five patients enrolled in CALGB 11002, and 96 (52%) of them also enrolled in 361101 (median age, 73.9 years). Among participants, 85.4% completed ≥1 baseline assessment. In multivariate analyses, greater comorbidity (hematopoietic cell transplantation-specific comorbidity index >3), worse cognition (Blessed Orientation-Memory-Concentration score >4), and lower European Organization for Research and Treatment of Cancer global QOL scores at baseline were significantly associated with shorter overall survival (P < .05 each) after adjustment for Karnofsky Performance Status, age, and treatment arm. Dependence in instrumental activities of daily living and cognitive impairment were associated with 6-month mortality (hazard ratio [HR], 3.5; confidence interval [CI], 1.2-10.4; and HR, 3.1; CI, 1.1-8.6, respectively). GA measures evaluating comorbidity, cognition, and self-reported function were associated with survival and represent candidate measures for screening older adults planned to receive lower-intensity AML therapies. This trial was registered at www.clinicaltrials.gov as #NCT01420926 (CALGB 11002).

Comparison of Multiple Clinical Testing Modalities for Assessment of NPM1-Mutant AML.

BACKGROUND: NPM1 mutation status can influence prognosis and management in AML. Accordingly, clinical testing (i.e., RT-PCR, NGS and IHC) for mutant NPM1 is increasing in order to detect residual disease in AML, alongside flow cytometry (FC). However, the relationship of the results from RT-PCR to traditional NGS, IHC and FC is not widely known among many practitioners. Herein, we aim to: i) describe the performance of RT-PCR compared to traditional NGS and IHC for the detection of mutant NPM1 in clinical practice, and also compare it to FC, and ii) provide our observations regarding the advantages and disadvantages of each approach in order to inform future clinical testing algorithms. METHODS: Peripheral blood and bone marrow samples collected for clinical testing at variable time points during patient management were tested by quantitative, real-time, RT-PCR and results were compared to findings from a Myeloid NGS panel, mutant NPM1 IHC and FC. RESULTS: RT-PCR showed superior sensitivity compared to NGS, IHC and FC with the main challenge of NGS, IHC and FC being the ability to identify a low disease burden (<0.5% NCN by RT-PCR). Nevertheless, the positive predictive value of NGS, IHC and FC were each ≥ 80% indicating that positive results by those assays are typically associated with RT-PCR positivity. IHC, unlike bulk methods (RT-PCR, NGS and FC), is able provide information regarding cellular/architectural context of disease in biopsies. FC did not identify any NPM1-mutated residual disease not already detected by RT-PCR, NGS or IHC. CONCLUSION: Overall, our findings demonstrate that RT-PCR shows superior sensitivity compared to a traditional Myeloid NGS, suggesting the need for "deep-sequencing" NGS panels for NGS-based monitoring of residual disease in NPM1-mutant AML. IHC provides complementary cytomorphologic information to RT-PCR. Lastly, FC may not be necessary in the setting of post-therapy follow up for NPM1-mutated AML. Together, these findings can help inform future clinical testing algorithms.

Real-world diagnostic testing patterns for assessment of ring sideroblasts and SF3B1 mutations in patients with newly diagnosed lower-risk myelodysplastic syndromes.

INTRODUCTION: The presence of ring sideroblasts (RS) and mutation of the SF3B1 gene are diagnostic of lower-risk (LR) myelodysplastic syndromes (MDS) and are correlated with favorable outcomes. However, information on testing and reporting in community-based clinical settings is scarce. This study from the Connect® MDS/AML Disease Registry aimed to compare the frequency of RS and SF3B1 reporting for patients with LR-MDS, before and after publication of the 2016 World Health Organization (WHO) MDS classification criteria. METHODS: Ring sideroblasts assessment and molecular testing data were collected from patients with LR-MDS at enrollment in the Registry. Patients enrolled between December 2013 and the data cutoff of March 2020 were included in this analysis. RESULTS: Among 489 patients with LR-MDS, 434 (88.8%) underwent RS assessment; 190 were assessed prior to the 2016 WHO guidelines (Cohort A), and 244 after (Cohort B). In Cohort A, 87 (45.8%) patients had RS identified; 29 (33.3%) patients had RS < 15%, none of whom underwent molecular testing for SF3B1. In Cohort B, 96 (39.3%) patients had RS identified; 31 (32.3%) patients had < 15% RS, with 13 undergoing molecular testing of which 10 were assessed for SF3B1. CONCLUSIONS: In the Connect® MDS/AML Registry, only 32% of patients with <15% RS underwent SF3B1 testing after the publication of the WHO 2016 classification criteria. There was no change in RS assessment frequency before and after publication, despite the potential impact on diagnostic subtyping and therapy selection, suggesting an unmet need for education to increase testing rates for SF3B1 mutations.

Special considerations in the management of adult patients with acute leukaemias and myeloid neoplasms in the COVID-19 era: recommendations from a panel of international experts.

The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 is a global public health crisis. Multiple observations indicate poorer post-infection outcomes for patients with cancer than for the general population. Herein, we highlight the challenges in caring for patients with acute leukaemias and myeloid neoplasms amid the COVID-19 pandemic. We summarise key changes related to service allocation, clinical and supportive care, clinical trial participation, and ethical considerations regarding the use of lifesaving measures for these patients. We recognise that these recommendations might be more applicable to high-income countries and might not be generalisable because of regional differences in health-care infrastructure, individual circumstances, and a complex and highly fluid health-care environment. Despite these limitations, we aim to provide a general framework for the care of patients with acute leukaemias and myeloid neoplasms during the COVID-19 pandemic on the basis of recommendations from international experts.

Applicability and reproducibility of acute myeloid leukaemia stem cell assessment in a multi-centre setting.

Leukaemic stem cells (LSC) have been experimentally defined as the leukaemia-propagating population and are thought to be the cellular reservoir of relapse in acute myeloid leukaemia (AML). Therefore, LSC measurements are warranted to facilitate accurate risk stratification. Previously, we published the composition of a one-tube flow cytometric assay, characterised by the presence of 13 important membrane markers for LSC detection. Here we present the validation experiments of the assay in several large AML research centres, both in Europe and the United States. Variability within instruments and sample processing showed high correlations between different instruments (Rpearson  > 0·91, P < 0·001). Multi-centre testing introduced variation in reported LSC percentages but was found to be below the clinical relevant threshold. Clear gating protocols resulted in all laboratories being able to perform LSC assessment of the validation set. Participating centres were nearly unanimously able to distinguish LSChigh (>0·03% LSC) from LSClow (<0·03% LSC) despite inter-laboratory variation in reported LSC percentages. This study proves that the LSC assay is highly reproducible. These results together with the high prognostic impact of LSC load at diagnosis in AML patients render the one-tube LSC assessment a good marker for future risk classification.

Prevalence, management, and clinical consequences of QT interval prolongation during treatment with arsenic trioxide.

PURPOSE: Arsenic trioxide (ATO) is a highly effective agent for the treatment of acute promyelocytic leukemia (APL). QT interval prolongation is common with ATO and can pose a barrier to effective administration. The objective of this study was to characterize the prevalence, management, and clinical consequences of QT prolongation in a large cohort of patients treated with ATO. PATIENTS AND METHODS: We analyzed 3,011 electrocardiograms from 113 patients with non-APL acute myeloid leukemia and myelodysplastic syndrome who were treated on a previously reported clinical trial. QT intervals were assessed using four different correction formulas, and data were correlated with clinical parameters and treatment with ATO. RESULTS: There were no clinically significant cardiac events in the study population. Of those receiving ATO therapy, 29 patients (26%) had rate-uncorrected QT values above 470 ms and 13 (12%) had values exceeding 500 ms. With the commonly used Bazett rate correction formula, 102 patients (90%) had QTc greater than 470 ms, including 74 (65%) above 500 ms. By using alternative rate correction formulas, only 24% to 32% of patients had rate-corrected QT intervals above 500 ms. CONCLUSION: QT interval prolongation is common with ATO treatment, but clinically significant arrhythmias are rare and can be avoided with appropriate precautions. Use of the Bazett correction may result in unnecessary interruptions in ATO therapy, and alternative rate correction formulas should be considered for routine electrocardiographic monitoring.