Myelodysplastic Syndrome

Educational Objectives

The goal of this lecture is to improve the management of myelodysplastic syndrome (MDS). After hearing and assimilating this lecture, the clinician will be better able to:

1. Identify the appropriate patients for MDS workup.

2. Choose the appropriate treatment for low- and high-risk MDS.

Summary

Introduction: myelodysplastic syndrome (MDS) clonal bone marrow disorder (ie, cancer); results in ineffective hematopoiesis that leads to cytopenia; bone marrow hypercellular, with decreased number of cells in circulation; recognized in its own right as myeloid malignancy; ≈33% of cases progress to acute myeloid leukemia (AML)

Adverse effects on quality of life: study found that most patients experienced excessive fatigue; other complications included bleeding or easy bruising, night sweats, recurrent fevers, weight loss, bone pain, and infection

Biopsy of bone marrow: findings include pseudo-Pelger-Huët anomaly (neutrophils have abnormal number of nuclear lobes), abnormal erythroid precursors (marked in some cases by sideroblasts around nuclei), and disorders of megakaryocytes (which are decreased in size and hyponucleated); examination of biopsy by hematopathologist recommended if MDS suspected

Epidemiology: incidence rising; median age of onset 71 yr; 80% of all patients ≥70 yr of age; predominant in men and patients of white ethnicity; may be associated with smoking and exposure to hair dyes and pesticides; not believed to be associated with alcohol use; ≈10% of cases secondary (ie, patients previously exposed to chemotherapy or radiation); may be associated with some congenital disorders (eg, Down syndrome, Fanconi syndrome, Bloom syndrome); often associated with juvenile myelomonocytic leukemia and congenital minus 7 syndrome in children and young adults; incidence increases with age

Diagnosis: criteria — morphologic evidence of dysplasia in any of 3 myeloid lineages involving ≥10% of cells examined; abnormal cytogenetics (evidence of clonal hematopoiesis; type of cytogenetic abnormality dictates prognosis and therapeutic approach); evidence of abnormal immunophenotypes or abnormal localization of immature precursors

Classification: pre-2008 classification — subtypes included refractory anemia (RA), RA with ringed sideroblasts (RARS), and RA with excess blasts (RAEB); 2008 expanded classification — RA changed to refractory cytopenia (RC); new classification included RC with unilineage dysplasia, RC with multilineage dysplasia, RA with increased blasts in bone marrow (RAEB-1, RAEB-2), and MDS unclassified; RAEB in transformation (RAEB-T) changed to AML; separate form of MDS associated with loss of part of chromosome 5 (5q minus syndrome) has favorable prognosis and tends to respond to lenalidomide; outcome better in patients with RARS than in patients with RAEB-1 and RAEB-2 (less aggressive MDS, longer time to conversion to AML, and longer overall survival)

Identification: patients present with persistent cytopenia for which no obvious explanation exists; anemia with aging abnormal; all forms of anemia or cytopenia warrant appropriate evaluation, regardless of age of patient; megaloblastic anemia classic presentation (patient anemic but mean corpuscular volume [MCV] larger than normal); anemia observed in 80% of MDS cases (most common cytopenia), whereas neutropenia and TCP observed in 40% of MDS cases; be especially suspicious if patients have history of chemotherapy or radiation exposure

Prognosis: some patients have aggressive disease and rapid progression to AML, whereas others have indolent disease; prognostic factors — number and degree of cytopenias, recurrent chromosomal abnormalities seen on bone marrow biopsy at time of diagnosis, and percentage of myeloblasts in bone marrow

Appropriate workup: includes CBC (to establish cytopenia), reticulocyte count (to establish underproduction anemia; MDS bone marrow failure state), comprehensive metabolic panel (to rule out liver or renal dysfunction or hemolytic process; evidence of hemolysis argues against diagnosis of MDS), iron, vitamin B12, and folate levels (to rule out deficiencies), thyroid-stimulating hormone (to rule out hypothyroidism), and copper level (deficiency can mimic MDS); review medications (methotrexate and divalproex can mimic MDS); alcohol abuse can lead to cytopenia with large MCV (mimics MDS); perform serum protein electrophoresis to rule out multiple myeloma

Therapies: low-risk MDS — observe if patient asymptomatic; if transfusion required, growth factors can be used (particularly darbepoetin alfa [Aranesp] or erythropoietin); lenalidomide — for 5q minus syndrome with transfusion requirement; hypomethylating agents — for low- or high-risk MDS not responsive to other agents; these agents include azacytidine and decitabine; induction chemotherapy and hematopoietic stem cell transplantation — only curative therapy, but outcomes of allogeneic bone marrow transplantation usually poor in elderly patients

Lenalidomide: derivative of thalidomide; antiangiogenic and immunomodulatory; mechanism of action undetermined; study found complete cytogenetic response in 75% of patients with 5q minus syndrome, and anemia improved in most cases; treatment of choice for 5q minus syndrome in patients with low-risk disease

Hypomethylating agents: treatment of choice for high-risk MDS; inhibit DNA methyltransferases, which reverses hypermethylation and results in reexpression of tumor suppressor genes; azacytidine and decitabine thought to have similar mechanisms of action, but azacytidine has proven survival benefit; in patients with high-risk disease, the earlier treatment started with azacytidine, the better the response

Readings

Balleari E et al: Age and comorbidities deeply impact on clinical outcome of patients with myelodysplastic syndromes. Leuk Res, 2015 Aug;39(8):846-52; Della Porta MG et al: Validation of WHO classification-based Prognostic Scoring System (WPSS) for myelodysplastic syndromes and comparison with the revised International Prognostic Scoring System (IPSS-R). A study of the International Working Group for Prognosis in Myelodysplasia (IWG-PM). Leukemia, 2015 Jul;29(7):1502-13; Klepin HD et al: Acute myeloid leukemia and myelodysplastic syndromes in older adults. J Clin Oncol, 2014 Aug 20;32(24):2541-52; Lauseker M et al: In patients with myelodysplastic syndromes with del(5q), factors other than age and sex contribute to the prognostic advantage, which diminishes over time. Br J Haematol, 2015 Sep;170(5):687-93; Liu P et al: Tea consumption reduces the risk of de novo myelodysplastic syndromes. Leuk Res, 2015 Feb;39(2):164-9; Shucheng G et al: Decitabine treatment could ameliorate primary iron-overload in myelodysplastic syndrome patients. Cancer Invest, 2015 Apr;33(4):98-106; Sun LM et al: Radiotherapy- and chemotherapy-induced myelodysplasia syndrome: a nationwide population-based nested case-control study. Medicine (Baltimore), 2015 May;94(17):e737; Tamari R, Castro-Malaspina H: Transplant for MDS: challenges and emerging strategies. Best Pract Res Clin Haematol, 2015 Mar;28(1):43-54; Vozella F et al: Lenalidomide for myelodysplastic syndromes with del(5q): how long should it last? Hematol Oncol, 2015 Mar;33(1):48-51.

Disclosures

For this lecture, the following has been disclosed: Dr. Pardee is on the Speakers’ Bureau for Celgene and Novartis AG. The planning committee reported nothing to disclose.

Acknowledgements

Dr. Pardee was recorded at the 44th Annual Emery C. Miller Medical Symposium, held August 3-7, 2015, in Myrtle Beach, SC, and sponsored by the Wake Forest University School of Medicine. For information about upcoming CME activities from the Wake Forest University School of Medicine, please visit www.northwestahec.org. The Audio Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this lecture.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

IM630302

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.