Concise Review for Primary-Care Physicians

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1 Concise Review for Primary-Care Physicians Myelodysplastic (Preleukemia) Syndromes: The Bone Marrow Factory Failure Problem H. CLARK HOAGLAND, M.D. The myelodysplastic syndromes are a group of hematologic disorders that adversely affect the levels of hemoglobin, platelets, erythrocytes, and leukocytes. Although the cause of this syndrome is unknown, new diagnostic techniques have facilitated identification and classification of these diseases into five categories: refractory anemia (refractory cytopenia), refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronicmyelomonocytic leukemia. Cytogenetic abnormalities may be present in more than 55% of the patients. Symptomatic pa- tients should be assessed relative to life-threatening versus non-life-threatening cytopenias and age. Management consists of primarily supportive measures, although certain approaches that are currently being used or under investigation, such as concomitant administration of erythropoietin and other growth factors, show promise for the future. (Mayo Clin Proc 1995; 70: ) AIDS = acquired immunodeficiency syndrome; FAB = French American-British; MDSs =myelodysplastic syndromes The myelodysplastic syndromes (MDSs) are a group of clonal hematologic diseases of unknown cause that result in the inability of the bone marrow to produce adequate numbers of erythrocytes, leukocytes, platelets, or some combination of these cells. The disorder is often termed "ineffective hematopoiesis." Patients with MDS have a decreased duration of survival and an increased probability for acute leukemia. MDS most often affects persons older than 60 years of age and is more prevalent among males than among females, similar to overt acute nonlymphocytic leukemia. 1 In the early 1980s, a group of French, American, and British hematologists (FAB) proposed a classification scheme for MDS2 and assessed more than 1,000 affected patients to gain a better understanding of the prevalence and leukemic conversion potential of these disorders and also to estimate the duration of survival of patients (Table 1). A substantial variability in survival and acute leukemic conversion was noted. The median age of patients at time of diagnosis of MDS is 64 years. Patients with these disorders die of complications of the disease or other unrelated medical problems commonly seen in the older population; therefore, these patients have a much shorter life span in compari- From the Division of Hematology and Internal Medicine, Mayo Clinic Rochester, Rochester, Minnesota. Address reprint requests to Dr. H. C. Hoagland, Division of Hematology, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN son with the normal aging population. 3 With the advent of new and improved technologies, including immunohistochemical stains, cytogenetics, fluorescent in situ hybridization, and in vitro bone marrow cell culture studies, the diagnosis is now easier to establish before the conversion to acute leukemia." DEFINITIONS OF SUBTYPES Refractory anemia, also called refractory cytopenia, usually manifests with fatigue and anemia that may be macrocytic, normocytic, or dimorphic with hypochromasia. A thorough history and physical examination and appropriate tests will exclude more common causes of anemia, such as vitamin B 12, folic acid, or iron deficiency, or anemia associated with primary diseases of the liver, thyroid gland, kidney, or bone marrow. Refractory anemia with ringed sideroblasts is similar to refractory anemia but with abnormal iron granules surrounding the nucleus in the mitochondria in more than 15% of the bone marrow normoblasts. Both refractory anemia and refractory anemia with ringed sideroblasts have less than 5% blasts in the bone marrow. Refractory anemia with excess blasts implies that not only does the patient have cytopenias but also the bone marrow contains more than 5% but less than 20% blasts, with accompanying dysplastic features of erythrocytes as well as megakaryocytes. Mayo Clin Proc 1995; 70: Mayo Foundation/or Medical Education and Research

2 674 MYELODYSPLASTICSYNDROMES Mayo Clin Proc, July 1995, Vol 70 Table l.-fab Classification of Myelodysplastic Syndromes* Leukemic Median Prevalence transformation survival Type of disorder (%) (%) (mo) Refractory anemia (refractory cytopenia) Refractory anemia with ringed sideroblasts Refractory anemia with excess blasts Refractory anemia with excess blasts in transformation Chronic myelomonocytic leukemia *FAB::: French-American-British. Refractory anemia with excess blasts in transformation is a progression of refractory anemia with excess blasts. In such cases, the bone marrow contains more than 20% but less than 30% blasts. (Greater than 30% blasts constitutes acute nonlymphocytic leukemia.) Chronic myelomonocytic leukemia is a disease often confused with chronic granulocytic leukemia or Ph chromosome-negative chronic granulocytic leukemia, as well as other atypical myeloproliferative syndromes. A peripheral monocytosis (more than 1,000 celis/ml) and a positive esterase stain of the bone marrow, which reveals increased numbers of monocytes and monocyte precursors, distinguish this condition from the aforementioned myeloproliferative syndromes. DIAGNOSIS The final diagnosis of MDS is based on not only the morphologic and cytogenetic abnormalities but also the clinical features of the patient. The possibility of the presence of other diseases that can mimic MDS in the peripheral blood and bone marrow but that are unassociated with abnormal cytogenetics and may disappear spontaneously must be excluded. Many factors suggest MDS as a possible diagnosis. Foremost among the clues are anemia, otherwise unexplained, in patients older than 60 years of age, especially if associated with unexplained neutropenia or thrombocytopenia (found in 50% of patients with MDSs) and particularly if macrocytosis and an increased mean corpuscularvolume are found on a routine complete blood cell count. On a wellstained peripheral blood smear, hypogranulation of the neutrophils, pseudo-pelger-huet-type cells, dimorphic erythrocytes, or oval macrocytosis should alert one to the possibility of MDS. Treatable diseases, such as iron deficiency anemia, vitamin B'2 deficiency, and folic acid deficiency, should always be excluded. The bone marrow demonstrates ineffective hematopoiesis of all cell lines. Cytogenetic abnormalities may be detected in more than 55% of the patients with MDS.! Recommended Diagnostic Studies.--Currently, the following tests are considered appropriate for making the diagnosis of MDS: (1) complete blood cell count or hematology group; (2) well-stained peripheral blood smear interpreted by a hematologist or hematopathologist with adequate knowledge of MDS; (3) reticulocyte count; (4) serum vitamin B!2 and folic acid levels; (5) serum iron, total ironbinding capacity, and percent saturation; (6) serum ferritin; (7) human immunodeficiency virus serology (acquired immunodeficiency syndrome [AIDS] can mimic MDS); (8) peripheral blood lymphocyte flow analysis (to search forrare lymphoproliferative processes, such as T-y, suppressor cell disease); (9) bone marrow aspirate, biopsy, iron stain, special stain for monocytes and their precursors as well as neutrophils, and cytogenetics; and (10) urine hemosiderin and, possibly, a sugar water test on the peripheral blood (to exclude another rare disease process known as paroxysmal nocturnal hemoglobinuria). Cytogenetic Analysis.-The most common clinical diagnostic study that solidifies the diagnosis of MDS is cytogenetics, which can disclose many types of nonspecific abnormalities that are not necessarily unique to MDSs.3 Certain research techniques can analyze the labeling index (degree of cellular proliferation) as well as the ability of the bone marrow to form colonies in vitro in a semisolid agar medium under appropriate stimulation by growth factors and cytokines. Furthermore, neutrophil function relative to migration, phagocytosis, and the ability to destroy microorganisms can also be evaluated. The cytogenetic abnormalities detected in more than 55% of the patients with MDS can be numerical, such as +8, +5, or +21; deletions (for example, 5q-, 7q-, 13q-, or 20q-) have also been seen. Translocations, isochromosomes, in-

3 Mayo Clio Proc, July 1995, Vol 70 versions, and duplications have been found but are less common. With new technology, cytogenetic abnormalities can be identified by fluorescent in situ hybridization with use of specific gene probes to detect simple and complex karyotypes in cells that are not undergoing mitosis. The 5q- syndrome is found more often in female than in male patients who have a high transfusion dependence at the time of diagnosis (greater than 80%). The median age is 68 years (range, 25 to 85). The female-to-male ratio is 2.3 to 1, which is the reverse of that seen in acute leukemia. The median duration of survival of these patients is 52 months, and 19% will have conversion to acute leukemia. At the time of initial assessment, these patients have macrocytic anemia and peripheral blood specimens that demonstrate striking oval macrocytes, suggestive of vitamin BIZ or folate deficiency. The bone marrow demonstrates multiple, atypical megakaryocytes that are small and hypolobulated. Part of chromosome 5 is missing, an area where numerous growth factor genes are found. Thus, it is not surprising that these patients have neutropenia as well as other abnormalities. The presence of other cytogenetic abnormalities in addition to the 5q- deletion increases the likelihood of conversion to acute leukemia and shortened survival. TREATMENT In the management of a patient with MDS, one must consider the following factors: (1) age of the patient at the time of diagnosis; (2) complications of the disease, such as infections, bleeding, transfusion-related problems, and iron overload; (3) failure of conservative or supportive measures; (4) specific FAB classification (refractory anemia with excess blasts and refractory anemia with excess blasts in transformation have a much higher potential for overt leukemic progression than do the other subtypes of MDS); and (5) abnormal laboratory findings associated with the morphologic diagnosis, such as abnormal chromosome karyotypes, abnormal results of cell culture, and number of blasts in the bone marrow (more than 5%). Once MDS has been diagnosed, several factors should be considered before a therapeutic program is initiated. Various scoring systems have been devised to predict survival, leukemic progression, and appropriate timing of aggressive management. The easiest and simplest scheme, the Boumemouth scoring system, uses the following criteria:' (1) the number of blasts in the bone marrow at initial diagnosis, (2) a platelet count of less than 100,000/mL, (3) absolute neutropenia of less than 2,000 leukocytes/ml, and (4) a hemoglobin concentration of less than 10 g/dl at the time of initial diagnosis. The greater the number of these prognostic factors present, the poorer the survival and the higher the incidence of leukemic transformation. This type of system may be helpful in the initial assessment of pa- MYELODYSPLASTIC SYNDROMES 675 tients with MDS and in planning for future therapeutic interventions. The uncommon patients who are asymptomatic should be observed to determine the natural progression of the disease. Patients who are symptomatic must be assessed relative to life-threatening versus non-life-threatening cytopenias, and this finding should be correlated with the age of the patient. Supportive measures" include the following: (1) transfusion of erythrocytes, depending on the activity status of the patient; (2) platelet transfusions to prevent active bleeding or excessive spontaneous bruising-the number of platelets per se should not be the determining factor; that finding should be assessed in combination with the clinical situation of the patient (excessive platelet transfusions can lead to formation of antibodies and platelet refractoriness because these patients are not immunosuppressed); (3) antibiotics and antifungal agents for culture-proven infections; (4) folic acid (l mg every day); (5) pyridoxine or vitamin B6 (200 mg every day); and (6) low-dose prednisone (5 to 7.5 mg/day), in patients who have low platelet counts and spontaneous or very easy bruising or excessive bleeding. Prednisone can act as a "vascular cement" in many of these patients. Iron chelation therapy is considered for young persons with excessive iron overload in whom complications related to secondary hemosiderosis and hemochromatosis are developing-those patients who have received an excess of 100 U and whose life expectancy with other comorbid medical conditions may be more than 3 years. Other considerations for patients with non-life-threatening cytopenias might include a synthetic androgen, such as danazol, especially when an immunologic basis may exist for the thrombocytopenia or neutropenia. Differentiating agents, such as retinoic acid compounds, have been tried but have been ineffective in improving the hemoglobin status and the functional capacity of the patient. Selected growth factors, such as granulocyte colony-stimulating factor for neutropenia with infection and erythropoietin, have also been used. Unfortunately, erythropoietin is not the answer in most patients with MDS. Only 25 to 30% of patients will respond, most of whom have lower than expected baseline erythropoietin levels relative to their degree of anemia. The erythropoietin level does not begin to increase until the hematocrit declines below 30% (Fig. 1). The level of serum erythropoietin will increase as the anemia becomes more severe. Even though the value may be above the normal range, it may be inappropriate for the degree of anemia. A brief (4- to 6-week) therapeutic trial of 50 to 150 U/kg of body weight administered subcutaneously three times a week may be advantageous. Currently, erythropoietin and other growth factors are being used jointly in investigational studies in attempts to improve the hematologic results.

4 676 MYELODYSPLASTIC SYNDROMES Mayo Clio Proc, July 1995,Vol ::J'... E :> o. 1.g :::L a w Hct (0/0) Fig. 1. Relationship between serum erythropoietin (EPO) level and degree of anemia (hematocrit [Het]). Patients younger than 50 years of age with life-threatening complications who have a human leukocyte antigenmatched sibling donor should be considered for allogeneic bone marrow transplantation. Although disease-free survival at 5 years can range from 35 to 45%, the relapse rate remains substantial. Furthermore, transplantation-related mortality is in excess of 30%.7 THE FUTURE The future for the management of the patient with MDS still remains optimistic as new growth factors and cytokines become available. With the isolation, purification, and production of thrombopoietin, that product may become available for clinical studies in the near future. Administration of interleukin 6 has yielded limited success in increasing the platelet count. Combined aggressive chemotherapy followed by the use of immunomodulators such as interleukin 2 to enhance the ability of the immune system to reduce the leukemic cell burden even further by increasing the proliferation of natural killer lymphocytes is also being investigated. Progress is slow, frustration levels are high, and research continues. Much more must be learned about the biologic aspects of this disease, and better therapeutic strategies must be developed. It is hoped that the 1990s will open doors to better management options for patients with MDS. REFERENCES 1. Todd WM, Pierre RV. Preleukaemia: a long-term prospective study of 326 patients. Scand J Haematol Suppl 1986; 45: Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, et a1. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982; 51: Noel P, Solberg LA Jr. Myelodysplastic syndromes: pathogenesis, diagnosis and treatment. Crit Rev Onco1 Hematol 1992; 12: Nowell PC, Besa EC, Stelmach T, Finan JB. Chromosome studies in preleukemic states. V. Prognostic significance of single versus multiple abnormalities. Cancer 1986; 58: Mufti GJ, Stevens JR, Oscier DG, Hamblin TJ, Machin D. Myelodysplastic syndromes: a scoring system with prognostic significance. Br J Haematol 1985; 59: Noel P. Management of patients with mye1odysp1astic syndromes. Mayo Clin Proc 1991; 66: Appelbaum FR, Barrall J, Storb R, Fisher LD, Schoch G, Ramberg RE, et al. Bone marrow transplantation for patients with myelodysplasia: pretreatment variables and outcome. Ann Intern Med 1990; 112:

5 Mayo Clio Proc, July 1995, Vol 70 MYELODYSPLASTIC SYNDROMES 677 Questions About Myelodysplastic Syndromes (See article, pages 673 to 676) 1. Which one of the following entities is unlikely to have features suggestive of myelodysplastic syndrome? a. Human immunodeficiency virus (HIV) infection b. Pernicious anemia c. Folic acid deficiency d. Rare lymphoproliferative diseases involving the T-cell subsets e. Multiple myeloma 2. Which one of the following is not a feature in patients with refractory anemia with ringed sideroblasts? a. Less than 5% blasts in the bone marrow b. Thrombocytopenia c. Anemia d. Ringed sideroblasts in the bone marrow e. More than 10% myeloblasts in the bone marrow 3. Which one of the following is the best therapeutic approach for management of thrombocytopenia in patients with myelodysplastic syndrome? a. Frequent platelet transfusions b. Administration of aspirin c. Treatment based on the number of platelets rather than the patient's clinical status d. Low-dose prednisone to act as a "vascular cement" e. Folic acid and pyridoxine 4. Which one of the following is not a palliative therapy in patients with myelodysplastic syndrome? a. Low-dose prednisone b. Cytosine arabinoside c. Packed erythrocyte transfusion d. Antibiotic or antifungal agents for culture-proven infections e. Folic acid 5. Which one of the following is not an appropriate therapy for patients with myelodysplastic syndrome who are elderly? a. Low-dose prednisone therapy b. Folic acid and pyridoxine c. Allogeneic bone marrow transplantation d. Aggressive chemotherapy if the blast count in the bone marrow exceeds 20% e. Observation only Correct answers: : J ''q'v ~ 'P'f 'ij'z 'ij'l