Myelodysplastic Syndrome

Definition and Classification
    The myelodysplastic syndromes (MDS) are a group of disorders which are characterized by abnormal stem cell differentiation resulting primarily in peripheral cytopenias.  They are fatal disorders which lead to death either through bone marrow failure or by transformation to leukemia.  Life expectancy and likelihood of leukemic transformation varies with subtype of disease.  MDS was initially referred to as refractory anemia because it was refractory to vitamin supplimentation.  It has also been called preleukemia because of the presence of blasts in the marrows of some of these patients and smoldering leukemia because despite the presence of blasts the disease course is more protracted than AML.  The most recent FAB classification goes a long way towards helping to organize MDS as each of the 5 subtypes has a somewhat different histology and prognosis.  They are as follows:

• Refractory anemia without ringed sideroblasts (RA) usually presents clinically with anemia, thrombocytopenia, and neutropenia.  There are no blasts on the peripheral smear and the bone marrow shows less 15% ringed sideroblasts and less than 5% blasts.
•  Refractory anemia with ringed sideroblasts (RARS) is similar to RA but the abnormalities both in the periphery and in the marrow are more confined to the erythroid line.  >15% of the erythrocytes are ringed sideroblasts.  The ring is formed by iron deposits resulting from derangements in erythropoiesis
•  Refractory anemia with excess blasts (RAEB) demonstrates severe dyspoiesis in all three cell lines.  In addition there in less than 5% blasts in the periphery and 5-20% blasts in the marrow.
•  RAEB in transformation (RAEB-T) is a preleukemic state.  It resembles RAEB but has 5-10% peripheral blasts and <30% blasts on marrow biopsy.  One differentiating feature from AML is that there is usually no thrombocytopenia.
•  Chronic Myelomonocytic Leukemia (CMML) is probably the most controversial member of the class.  It resembles the other members of MDS in that it consists of anemia, neutropenia, and thrombocytopenia, but it also resembles members of the myeloproliferative disorders with monocytosis, circulating blasts, and splenomegaly.  The differentiation from CML by the monocytosis and lack of the Philadelphia chromosome.

Clinical
 MDS is usually seen in people greater than 60 and is slightly more common in men.  Presentation is either due to effects of pancytopenia (bleeding, infection, or fatigue) or on work-up of an anemia.  MDS usually occurs de novo but it also may be seen in patients who have had alkylating chemotherapy in the past.  The classic smear would show an anemia with slight macrocytosis and bilobed (Pelger-Huet) neutrophils, possibly with decreased or dysmorphic granules.  Marrow will show a hypercellular marrow with tri-lineage dyspoiesis.  Erythroid precursors may have multiple nuclei, Howell Jolly bodies and cytoplasmic asynchrony.  PMNs range from Pelger Huet cells to blasts.  there may be micromegakaryocytes.

Pathogenesis
 The pathogenesis is not clear but some things are well known.  There is a defect in progenitor cells leading to abnormalities in maturation.  This somehow provides a growth advantage which leads cells from the abnormal precursors dominating the marrow.  As time goes on other mutations might occur leading to leukemic transformation.  It is known that MDS can be caused by genetic damage since secondary MDS occurs in those patients who received radiation and cytotoxic drugs.  These are the patients in which MDS may be hardest to diagnose since they have other reasons for pancytopenia.  50% of patients with MDS has clonal karyotypic abnormalities.  Some of those that have been well characterized are a 5q- syndrome where the long arm of chromosome 5, containing 5 growth factors is lost; activation of the n-Ras oncogene (present in 30-40% of MDS patients); and monosomy 7, which is also a poor prognostic factor since the long arm of chromosome 7 codes a potential drug resistance gene.

Prognosis
 Untreated the prognosis for these diseases are poor. RA and RARS carry a 30-40 month prognosis, RAEB and CMML portend a 10-15 month survival and pts with RAEB-t live on average only 6 months.  The tables on the next page show some data on mortality and on transformation to AML.

Treatment
 “All modes of therapy for MDS other than supportive care are considered empiric or investigational, and physicians are encouraged to enter their patients or refer them for clinical trials.” (1)  Supportive care is the mainstay of treatment with transfusions, antibiotics and growth factors.  Androgens, vitamins and steroids have not showed promise.  Cytotoxic chemotherapy is indicated for those transforming to AML but these patients tend to do worse than those with de novo AML.  In fact many patients with de novo AML who respond poorly to routine chemo may have actually transformed from RAEB-t.  Allo BMT can be successful in a subset of patients.  Recent work has been with differentiating agents such as 13-cis retinoic acid with or without vitamin E.  This has had some promising results and is theoretically attractive since we believe that MDS is a disorder of stem cell differentiation.

 Adam Cifu

References
 Besa, E., Myelodysplatic Syndromes, A Perspective of the Biologic, Clinical and Therapeutic Issues in The Medical Clinics of North America, Vol. 76 (3) May 1992 pp.599-613.
 Cheson,B. The Myelodysplastic Syndrome: Current Approaches to Therapy, Annals of Internal Medicine, Vol 112 (12), June 1990, pp.932-941.