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.

Patterns of Diagnostic Evaluation and Determinants of Treatment in Older Patients With Non-transfusion Dependent Myelodysplastic Syndromes.

BACKGROUND: Older patients with myelodysplastic syndromes (MDS), particularly those with no or one cytopenia and no transfusion dependence, typically have an indolent course. Approximately, half of these receive the recommended diagnostic evaluation (DE) for MDS. We explored factors determining DE in these patients and its impact on subsequent treatment and outcomes. PATIENTS AND METHODS: We used 2011-2014 Medicare data to identify patients ≥66 years of age diagnosed with MDS. We used Classification and Regression Tree (CART) analysis to identify combinations of factors associated with DE and its impact on subsequent treatment. Variables examined included demographics, comorbidities, nursing home status, and investigative procedures performed. We conducted a logistic regression analysis to identify correlates associated with receipt of DE and treatment. RESULTS: Of 16 851 patients with MDS, 51% underwent DE. patients with MDS with no cytopenia (n = 3908) had the lowest uptake of DE (34.7%). Compared to patients with no cytopenia, those with any cytopenia had nearly 3 times higher odds of receiving DE [adjusted odds ratio (AOR), 2.81: 95% CI, 2.60-3.04] and the odds were higher for men than for women [AOR, 1.39: 95%CI, 1.30-1.48] and for Non-Hispanic Whites [vs. everyone else (AOR, 1.17: 95% CI, 1.06-1.29)]. The CART showed DE as the principal discriminating node, followed by the presence of any cytopenia for receiving MDS treatment. The lowest percentage of treatment was observed in patients without DE, at 14.6%. CONCLUSION: In this select older patients with MDS, we identified disparities in accurate diagnosis by demographic and clinical factors. Receipt of DE influenced subsequent treatment but not survival.

A geno-clinical decision model for the diagnosis of myelodysplastic syndromes.

The differential diagnosis of myeloid malignancies is challenging and subject to interobserver variability. We used clinical and next-generation sequencing (NGS) data to develop a machine learning model for the diagnosis of myeloid malignancies independent of bone marrow biopsy data based on a 3-institution, international cohort of patients. The model achieves high performance, with model interpretations indicating that it relies on factors similar to those used by clinicians. In addition, we describe associations between NGS findings and clinically important phenotypes and introduce the use of machine learning algorithms to elucidate clinicogenomic relationships.

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.

The National MDS Natural History Study: design of an integrated data and sample biorepository to promote research studies in myelodysplastic syndromes.

Myelodysplastic syndromes (MDS), a spectrum of heterogeneous hematopoietic stem cell diseases, vary in clinical severity, response to therapy, and propensity toward progression to acute myeloid leukemia. These are acquired clonal disorders resulting from somatic mutations within the hematopoietic stem or progenitor cell population. Understanding the natural history and the risk of developing leukemia and other adverse outcomes is dependent on access to well-annotated biospecimens linked to robust clinical and molecular data. To facilitate the acquisition and distribution of MDS biospecimens to the wider scientific community and support scientific discovery in this disease, the National MDS Natural History study was initiated by the National Heart, Lung, and Blood Institute (NHLBI) and is being conducted in collaboration with community hospitals and academic medical centers supported by the National Cancer Institute (NCI). The study will recruit up to 2000 MDS patients or overlapping myeloproliferative neoplasms (MDS/MPN) and up to 500 cases of idiopathic cytopenia of undetermined significance (ICUS). The National MDS Natural History Study (NCT02775383) will offer the world's largest disease-focused tissue biobank linked to longitudinal clinical and molecular data in MDS. Here, we report on the study design features and describe the vanguard phase of 200 cases. The study assembles a comprehensive clinical database, quality of life results, laboratory data, histopathology slides and images, genetic information, hematopoietic and germline tissues representing high-quality biospecimens and data from diverse centers across the United States. These resources will be available to the scientific community for investigator-initiated research.

Strategies for success in creating an effective multihospital health-system pharmacy and therapeutics committee.

PURPOSE: Lessons learned from the creation of a multihospital health-system formulary management and pharmacy and therapeutics (P&T) committee are described. SUMMARY: A health system can create and implement a multihospital system formulary and P&T committee to provide evidence-based medications for ideal healthcare. The formulary and P&T process should be multidisciplinary and include adequate representation from system hospitals. The aim of a system formulary and P&T committee is standardization; however, the system should allow flexibility for differences. Key points for a successful multihospital system formulary and P&T committee are patience, collaboration, resilience, and communication. When establishing a multihospital health-system formulary and P&T committee, the needs of individual hospitals are crucial. A designated member of the pharmacy department needs to centrally coordinate and manage formulary requests, medication reviews and monographs, meeting agendas and minutes, and a summary of decisions for implementation. It is imperative to create a timeline for formulary reviews to set expectations, as well as a process for formulary appeals. Collaboration across the various hospitals is critical for successful formulary standardization. When implementing a health-system P&T committee or standardizing a formulary system, it is important to be patient and give local sites time to make practice changes. Evidence-based data and rationale must be provided to all sites to support formulary changes. Finally, there must be multidisciplinary collaboration. CONCLUSION: There are several options for formulary structures and P&T committees in a health system. Potential strengths and barriers should be evaluated before selecting a formulary management process.

Treatment of MDS: something old, something new, something borrowed...

As opposed to the treatment landscape for myelodysplastic syndromes (MDS) two decades ago, potential therapies now abound for the treatment of lower-risk and higher-risk populations. In lower-risk patients, decision tools can be used to determine the likelihood of response to erythropoiesis stimulating agents (ESAs), which have demonstrated survival advantages in retrospective studies in patients with MDS, and whether these patients should be treated initially with ESAs or non-growth factor ("active") therapies. Lenalidomide has shown good activity in transfusion-dependent patients with the del(5q) cytogenetic abnormality and modest activity in other lower-risk patients. In higher-risk patients, the DNA methyltransferase inhibitors produce complete and partial responses in 20% to 30% of patients, and for the first time, the MDS drug azacitidine has demonstrated a survival advantage when compared with conventional therapies. Newer therapies stimulate platelet production and target novel pathways, while a panoply of combination studies are underway or recently completed and that likely represent the next frontier in MDS therapy.

Characteristics of US patients with myelodysplastic syndromes: results of six cross-sectional physician surveys.

BACKGROUND: Myelodysplastic syndromes (MDS) comprise a group of pathologically and cytogenetically distinct bone marrow disorders. Little is known about the characteristics of MDS patients, including their pathological and prognostic classifications, cytopenias, transfusion and supportive care needs, and treatment regimens. We describe these characteristics in a large group of recently diagnosed and existing (ie, established) MDS patients. METHODS: We conducted six consecutive cross-sectional surveys among US hematology and medical oncology specialists (identified from an American Medical Association [AMA] database of physicians who administer chemotherapy) between June 2005 and January 2007. A questionnaire collected data on the characteristics and treatment patterns of the 4-10 most recently seen MDS patients for each physician, including demographic data, transfusion needs, treatment approaches, and consideration for clinical trials or bone marrow transplantation. RESULTS: A panel of 101 physicians who were geographically representative of physicians registered with the AMA characterized 614-827 patients per survey, for a total of 4514 responses. Among recently diagnosed patients, 55% were male (95% confidence interval [CI] = 52% to 59%), the median age at diagnosis was 71 years (range = 65-80 years), and 10% (95% CI = 8% to 12%) had MDS secondary to chemotherapy, radiation therapy, or environmental exposure. The median duration of MDS in established patients ranged from 13 to 16 months over the six surveys. Among recently diagnosed MDS patients, fewer patients with lower-risk disease than with higher-risk disease were dependent on either red blood cell transfusions (22% vs 68%) or platelet transfusions (6% vs 33%). More than 50% of all newly diagnosed and established patients used erythropoiesis-stimulating agents. A small percentage of all patients either had had or were being considered for bone marrow transplantation (recently diagnosed: 4%; established: 4% or less) or were being treated on clinical trials (recently diagnosed: 1%; established: 4% or less). CONCLUSIONS: MDS patients in the United States have substantial transfusion needs, and use of erythropoiesis-stimulating agents and are seldom considered for bone marrow transplantation or clinical trials. These data may be useful in characterizing the health care resource use and pharmacoeconomic impact of MDS in the United States.

A Decision analysis to determine the appropriate treatment for low-risk myelodysplastic syndromes.

BACKGROUND: The myelodysplastic syndromes (MDS) are divided into low-risk and high-risk diseases. Predictive models for response to growth factors (GF) have been developed based on red blood cell transfusion needs and erythropoietin levels. For low-risk MDS the optimal initial therapy (GF vs nongrowth factor [NGF] therapies, including differentiation and immunomodulatory agents) based on response rates to NGF and GF and survival, has not been defined. METHODS: A Markov decision analysis was performed on 799 low-risk MDS patients treated with either GF or NGF to determine the appropriate initial therapy. The treatment strategies analyzed included initial GF or NGF therapies, assuming 3 different states: Patients were either in the good GF predictive group (low transfusion needs and low erythropoietin levels), intermediate, or the poor GF predictive group (high transfusion needs and high erythropoietin levels). RESULTS: In the good GF predictive group, initial therapy with GF improved survival compared with NGF therapies at 3.38 years vs 2.57 years for a typical MDS patient. The advantage of GF to NGF was lost when NGF therapies produced a response in >or=46% of patients. In the intermediate or poor GF predictive groups, NGF maximized survival, provided response rates for NGF were >14% and 4%, respectively, for each predictive group. Quality of life adjustment did not alter the preferred strategy. CONCLUSIONS: Modeling estimates suggest that patients who fall into a good GF predictive group should almost always receive GF initially, whereas those in intermediate and poor predictive groups should almost always be treated with NGF.

The impact of a physician awareness group and the first year of training on hematology-oncology fellows.

PURPOSE: To assess the impact of a Balint-like physician awareness group on hematology-oncology fellows' attitudes and measure changes in attitudes during the first fellowship year. PATIENTS AND METHODS: We used a modified crossover design in which one half of a fellowship class at a time was exposed to the group intervention over a 2-year period (2000 to 2002). Two 14-fellow classes were followed for 1 year each and were given three "attitudes" questionnaires, at the beginning, middle, and end of the academic year. RESULTS: Forty Balint group sessions were held during the 2-year study period; 82 questionnaires of the 84 administered (98%) were recovered. Instrument content and criterion validity were demonstrated, as was topic domain reliability. Overall, mean attitude scores increased following the group intervention, from 3.6 (95% CI, 3.5 to 3.7) to 3.7 (95% CI, 3.6 to 3.8; P =.09). Within domains, scores increased in a "fellow's views of him/herself as a physician," from 3.8 (95% CI, 3.6 to 3.9) to 4.1 (95% CI, 3.9 to 4.2; P =.008) and "comfort dealing with emotional patient/clinical situations," from 3.5 (95% CI, 3.3 to 3.7) to 3.7 (95% CI, 3.6 to 3.9; P =.11). Changes in responses to individual questions included: an increase in fellows' comfort with the technical aspects of being an oncologist (P <.03); an increase in fellows' comfort with discussing the stress of home at work (P <.023); and an increase among fellows in feeling pressed for time to discuss psychosocial issues with patients (P =.035). CONCLUSION: A physician awareness group was feasible and enhanced fellows' development as physicians. Further research is needed to determine how to incorporate such groups into oncology fellowships.

On the Edge of Life, I: Assessment of, Reaction to, and Management of the Terminally Ill Recorded in an Intensive Care Unit Journal.

BACKGROUND: In a general hospital, few clinical settings match the intensity of the intensive care unit (ICU) experience. Clinical rotations in ICUs elicit and emphasize the struggles house officers face on a daily basis throughout their training. METHOD: These struggles were recorded by hundreds of residents in a journal maintained in the Massachusetts General Hospital's Medical ICU for the past 20 years. We systematically reviewed these unsolicited entries to define and to illustrate how house officers respond to caring for terminally ill patients. The 3 overarching topics that surfaced repeatedly were assessment of terminally ill patients, reaction to their prognosis, and management of their disease or their eventual demise. RESULTS: House officers record affective reactions and cognitive assessments to cope with the stress and dysfunction associated with the care of the critically ill and to facilitate their management of these patients. Journal entries by residents reveal a deep concern for the welfare of their patients, conflict about the technological advances and limitations of the system, and reflection on how involved physicians should become with their patients. CONCLUSION: House officer journal entries reflect a combination of newly gained medical knowledge and coping strategies in managing terminally ill patients. House officers also demonstrate a deep concern for the welfare of their patients. Insight from years of reflection from past house officers can help prepare trainees and residency programs for the breadth and intensity of the ICU experience and for work in clinical practice settings that follow completion of training.