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Professor of Medicine and Pathology
Division of Hematology, Oncology, and Stem Cell Transplant
Director, MDS/MPN/Aplastic Anemia Program
Rush University Medical Center
Jamile Shammo, MD, FASCP, FACP, has disclosed that she has received research grants paid to her institution from AbbVie, Alexion, AstraZeneca, Bristol-Myers Squibb, CTI, Incyte, Kartos, Novartis, and Stemline; has received consulting fees from Alexion, Apellis, Bristol-Myers Squibb, Incyte, Novartis, Sanofi, and Takeda; has served on speaker bureaus for Alexion, Bristol-Myers Squibb, Incyte, and Sanofi; and has ownership interest in AbbVie, Baxter, and Takeda.
Myelodysplastic syndromes (MDS) are a group of hematopoietic stem cell neoplasms characterized by peripheral blood cytopenias accompanied by distinctive morphologic features in the bone marrow and increased risk of transformation to acute myeloid leukemia. MDS occurs most commonly in older individuals and individuals with previous exposure to cytotoxic therapy. In general, the prognosis of patients with MDS can be determined by using risk-stratification tools such as the Revised International Prognostic Scoring System (IPSS‐R), which assigns various scores to clinical variables including blood counts, percentage of blasts in the bone marrow, and cytogenetic categories. More recently, the incorporation of somatic mutations has been advocated for optimal risk assessment, but a formal tool has not yet been developed as such.
As the life span for patients who have higher-risk MDS is rather limited, most physicians who treat this population recommend allogeneic stem cell transplantation, as it continues to be the sole potentially curative modality. This option, however, is reserved for fit patients for whom the goal of therapy is to cure their disease. For less-fit patients, or those with comorbidities, goals of therapy are less concrete and vary from improving quality of life to prolonging survival and delaying leukemic transformation.
The Challenge of Older Patients With MDS and Comorbidities
However, achieving these goals requires active therapy, which may not be feasible in some older patients with MDS; these individuals may receive supportive care instead of life-prolonging treatments due to comorbid conditions. This is not surprising given that the majority of patients with newly diagnosed MDS have 1 or more comorbidities, with cardiac disease and diabetes being the most frequently observed.
To optimize the care of an older patient with MDS, it is important not only to understand the disease characteristics, but also to assess the patient and perform a thorough evaluation of organ function at baseline. Decline in organ function has the potential to increase toxicities of certain chemotherapies used to treat MDS.
Tools such as the Charlson Comorbidity Index (CCI) and the Hematopoietic Stem Cell Transplantation-specific Comorbidity Index have demonstrated the significant prognostic influence of comorbidities on the survival outcome of patients with MDS.
Improved risk stratification has also been demonstrated through the integration of the Myelodysplastic Syndromes Comorbidity Index with the IPSS-R. However, despite these findings, an optimal comorbidity index for clinical use has not yet been established.
A recent population-based study confirmed that a majority of patients with MDS have comorbidities and that a combination of comorbidities, reflected by an increasing CCI score, is associated with significantly worse overall survival. As most of those patients would have been excluded from clinical trials, future clinical trials should include more patients with MDS with at least 1 comorbidity, so new therapeutic agents and treatment options are tested in the population in which they will eventually be used. This issue is exemplified by “real-life” data demonstrating that the clinical outcomes of novel therapies in MDS usually fall short of those from clinical trials—the median survival times in patients with high-risk MDS treated with azacitidine range from 12.0 to 16.4 months, instead of the expected 24 months seen in the practice-changing AZA-001 clinical trial.
For example, azacitidine and its metabolites are primarily excreted by the kidney. Patients with renal impairment are at increased risk for renal toxicity and should be monitored closely. Of interest, but not surprising, patients with MDS and renal impairment were excluded from the clinical studies evaluating azacitidine. For these patients, monitor serum creatinine and electrolytes before the initiation of therapy and with each cycle, and reduce or hold the dose if there is a rise in creatinine. Otherwise, exaggerated cytopenias can be the result.
Similarly, of the 148 patients with MDS and del(5q) enrolled on the CC-5013-MDS-003 trial of lenalidomide, more patients older than 65 years of age discontinued because of adverse reactions than younger patients (27% vs 16%, respectively). Of interest, no differences in efficacy were observed whether patients were older or younger than 65 years of age. No patient was enrolled with a creatinine level >1.5 mg/dL, but it became clear that dose adjustment of lenalidomide is useful in patients with renal impairment (ie, low creatinine clearance). Adjusting the lenalidomide dose as needed is important to decrease the risk of prolonged cytopenias that could lead to treatment discontinuation.
Optimizing care of patients with MDS requires a comprehensive understanding of the disease in the context of an older population, so therapeutic interventions can be tailored to both the disease risk and a patient’s suitability for therapy.
Available therapies for MDS range from supportive care for symptomatic cytopenia in low-risk patients, to immunomodulatory agents, chemotherapies, and allogeneic stem cell transplantation (ASCT). Novel therapeutics approved in 2020 include luspatercept and an oral formulation of decitabine. At this time, the sole potential cure for MDS is ASCT. Transplantation is typically considered for patients with higher-risk MDS, but the procedure is associated with substantial risk. As a result, most transplant centers have an age limit of 65-70 years, with few centers allowing transplants up to the age of 75 years. Of note, with the median age of diagnosis for patients with MDS older than 70 years, this excludes most patients from a potential cure. Therefore, prolonging survival and optimizing quality of life by improving cytopenias, including anemia, and reducing the need for transfusions remain the alternative goals of treatment for older patients with MDS.
Choice of initial and subsequent treatment for MDS should be based on a thorough evaluation of patients, their disease characteristics (including mutational analyses and next-generation sequencing), and response assessment. Such an approach is integral for the optimal management of patients with MDS.
This commentary is part of a series of educational activities with the goal to guide healthcare professionals to apply the principles of MDS assessment, integrate the latest clinical data into practice to manage MDS especially in the older patient population, and become familiar with available clinical trials and novel agents for this disease. Additional activities include training workshops discussing various clinical scenarios that will be applicable to patients in general hematology practice, a toolkit containing a treatment algorithm for MDS directed to healthcare professionals, and a guide for patients. A series of 15-minute CME/CE/CPE-certified videos available on both the Clinical Care Options and MDS Foundation websites will address various aspects of MDS in older patients, including challenges in making the diagnosis, the utility of molecular testing, and therapeutic planning.
To get individualized recommendations on managing patients with MDS from multidisciplinary experts, please visit CCO’s Interactive Decision Support Tool: Expert Treatment Guidance for Myelodysplastic Syndromes.
How is your practice changing with an aging MDS population and new agents? Share your experience in the comment box below!