Heather A. Leitch, MD, PhD, FRCPC (biography and disclosures)
Disclosures: The MDS Clear Path was supported by an unrestricted educational grant from Celgene Corporation. All content was developed independently by the panel of hematologists involved. Heather A. Leitch has received honoraria, research funding and served on advisory boards of Alexion, Celgene and Novartis Corporations. She is a member of the Exjade Speaker’s Bureau. Mitigating Potential Bias: Recommendations are consistent with current practice patterns. The MDS Clear Path is a comprehensive clinical practice guideline for the diagnosis, workup and management of MDS. It incorporates information from clinical trials, multiple guidelines, and usual clinical practice. Treatments or recommendations in this article are unrelated to products/services/treatments involved in disclosure statements.
What care gaps or frequently asked questions I have noticed
Case A
A 68 year old man presents with a 12 month history of fatigue. A complete blood count (CBC) shows a white blood cell (WBC) count of 6 x 109/L, hemoglobin (Hb) of 95 g/dL, and platelet count of 450 x 109/L. What information would be helpful next? The mean cellular volume (MCV) is 78 (normal range 80-100) fL, and a peripheral blood smear (pathologist’s review) shows microcytosis, hypochromia, and pencil cells. The serum ferritin level is 15 ng/mL, indicating iron deficiency.
Iron deficiency is a matter of intake (diet, supplements), absorption (in the proximal duodenum) and loss (subclinical blood loss from the lower gastrointestinal [GI] tract in this age group, menorrhagia, in women of childbearing age, other sources of blood loss). Iron deficiency is very rarely a hematologic disorder, and warrants evaluation of the patient’s diet, the GI tract, the genitourinary tract, or other sources of blood loss as per the patient’s history.
Case B
A 68 year old man presents with a 12 month history of fatigue. A complete blood count (CBC) shows a white blood cell (WBC) count of 6 x 109/L, hemoglobin (Hb) of 95 g/dL, and platelet count of 450 x 109/L. The MCV is 102 fL and the ferritin level is 150 ng/mL. Serum B12 and TSH levels are normal. Electrolytes, blood urea nitrogen, creatinine, calcium, and a complete liver profile including lactate dehydrogenase levels are all normal. Serum protein electrophoresis and urine protein electrophoresis (urine for Bence-Jones proteins) are normal. The peripheral blood smear shows macrocytosis, hypogranular neutrophils and pelgeroid changes. What investigation is warranted next? A bone marrow aspirate and biopsy shows trilineage dysplasia, 2% blasts and 7% ring sideroblasts. The patient is diagnosed with refractory cytopenia with multilineage dysplasia (RCMD) under the World Health Organization (WHO) classification (1). The cytogenetic analysis shows deletion of the long arm of chromosome 20 [del(20)q]. What comes next for this patient?
Data that answers these questions or gaps
The myelodysplastic syndromes (MDS) are a heterogeneous group of bone marrow disorders characterized by cytopenias and an increased risk of developing acute myelogenous leukemia (AML). In the past, MDS was referred to as a pre-leukemia, but now it is considered to be a form of cancer. The incidence of MDS, like many bone marrow cancers, is increasing, a phenomenon which is partially related to the aging Canadian population, particularly in British Columbia. The median age of onset of MDS is in the mid-60’s to mid-70’s and peaks in the 80’s (after which aggressive investigations for MDS are likely not pursued in many patients). The incidence of hematologic malignancies including MDS essentially triples with each decade up to the 80’s, and the prevalence is increasing as patients are living longer. Predisposing factors for MDS are unknown in over 80% of patients, but secondary causes include prior cytotoxic chemotherapy, radiation, exposure to chemicals, and immunosuppressive medications.
MDS significantly reduces life expectancy; even lower risk patients have much shorter estimated survival rates than the age-matched population and survival without treatment is only a few months in higher risk patients (2, 3). About 40% of lower risk and nearly 80% of higher risk MDS patients are red blood cell transfusion dependent, which impacts not only on quality of life, but is an adverse prognostic factor for survival (4). There are several prognostic scores for predicting survival and AML risk. Much has been learned about MDS biology and genetics in recent years, but most importantly, new treatment options are available for MDS patients that were not available a decade ago, and that decrease transfusion dependence, improve quality of life, and improve survival.
What I recommend (practice tip)
The MDS Clear Path algorithm is an internet-based interactive tool that was developed to support health care providers in the workup, diagnosis and management of MDS. The Clear Path was developed by a group of 60 Canadian hematologists with an interest in MDS, through a series of national and regional meetings, with further refinements by conference call. The process began in 2011, and the algorithm went live in September 2014. Objectives were to develop a unified approach to MDS care, with an evidence-based approach to decision points and identification of areas where data are lacking; in such areas guidance is given by expert opinion, as well as information on when to refer MDS patients.
The algorithm provides a step by step approach to managing patients. An approach to MDS diagnosis is provided as is a prognostic calculator for all scoring systems. All references and supporting data are found within the algorithm. There is a link from references to the pubmed abstract for each article. For primary care physicians and Internists, the sections on workup and diagnosis of MDS should prove most helpful, however, information is also provided on all specific and supportive medications and procedures (such as hematopoietic stem cell transplantation) available in Canada to support MDS patients, including dosing and dose adjustment, efficacy, toxicity, and provincial reimbursement. There is a ‘self-directed’ mode, the overall algorithm, but also a ‘treatment wizard’ which takes the user through decision points step by step until a treatment recommendation is reached. The MDS Clear Path can be accessed at www.MDSClearPath.org and is available to download as an iPad app from the Apple store, free of charge.
In all but the most remote areas or special circumstances, patients with a suspected or confirmed diagnosis of MDS should be referred to a hematologist. However, feedback from health care providers regionally, nationally and internationally indicate that this algorithm is found useful during day to day care, not only by hematologists and other physicians, but also by allied providers, and is helpful as well as for training purposes.
Practice tips:
- Iron deficiency is rarely a hematologic disorder. It requires age-appropriate screening and intervention, which would occur in a more timely manner by bypassing hematology.
- New treatment options are available to MDS patients which require accurate diagnosis and hematology referral.
- A screen for MDS should be prompted by persistent or progressive cytopenias, and any cytopenia with dysplastic changes on peripheral blood smear.
- An evidence-based approach to the workup, diagnosis and management of MDS was developed by Canadian hematologists, and is available at MDSClearPath.org
References
- Vardiman J, Hyjek E. World health organization classification, evaluation, and genetics of the myeloproliferative neoplasm variants. Hematology / the Education Program of the American Society of Hematology American Society of Hematology Education Program. 2011;2011:250-6. Free full text
- Canada S. Life expectancy, at birth and at age 65, by sex and by province and territory 2012 [cited 2015 June 27]; Available from: http://www.statcan.gc.ca/tables-tableaux/sum-som/l01/cst01/health72a-eng.htm
- Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997 Mar 15;89(6):2079-88.
Free full text Erratum - Malcovati L, Porta MG, Pascutto C, Invernizzi R, Boni M, Travaglino E, et al. Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making. J Clin Oncol. 2005 Oct 20;23(30):7594-603.
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Good reminder of some of the red flags for hematologic causes of anemia.
However, this article feels a bit like a plug for CelGene’s products (e.g. the MDS Clear Path names medications that are manufactured by CelGene).
I find the serum ferritin a misleading test unless the person is youngish and healthyish as it rises with any background inflammatory response be it oncogenic,infectious, or arthritic so I wonder if it should be married to the CRP or ESR for fuller interpretation ( 2 other tests which I find fraught with spinoffs) or can one stick to serum iron in the elderly and avoid a highly forked algorithm.
PS I like the new info on MDS as I always felt it was unnameable to effective interventions. For rural folks though is it feasible to get involved in stem cell business as i find my urban patients are constantly having tweaks to their steroid and interferon doses on a weekly basis for months.