Recent Advances in Myelodysplastic

Haematologica 1998; 83:910-935 decision making and problem solving Recent Advances in Myelodysplastic Syndromes Guest Editors: Miguel Angel Sanz, Guillermo Sanz & Teresa Vallespí A patient-oriented approach to treatment of myelodysplastic syndromes MARIO CAZZOLA,* JEANNE E. ANDERSON,° ARNOLD GANSER,# EVA HELLSTRÖM-LINDBERG@ *Department of Internal Medicine and Medical Therapy, Section of Internal Medicine and Medical Oncology, University of Pavia School of Medicine, IRCCS Policlinico S. Matteo, Pavia, Italy; °Department of Medicine, Division of Hematology, University of Texas Health Science Center at San Antonio, USA; #Department of Hematology/Oncology, Hannover Univer- sity Medical School, Hannover, Germany; @Department of Hematology, Huddinge University Hospital, Huddinge, Sweden Abstract Background and Objective. There are several thera- experience an improvement in quality of life but very peutic options for patients with myelodysplastic syn- few studies have addressed this question so far. The drome (MDS) but most of them are poorly effective majority of MDS patients still rely upon supportive and the potentially curative ones are available only for therapy. A clinical decision path based on findings of a minority of individuals. The aim of this article is to clinical trials and the patient’s expectations can help define a rational basis for a patient-oriented approach physicians in decision making. Because of the inade- to treatment of MDS. quacies of all current treatment modalities, participi- ation in clinical trials should always be encouraged. Evidence and Information Sources. All four authors ©1998, Ferrata Storti Foundation have done clinical studies of treatment of MDS, including stem cell transplantation, intensive and low- dose chemotherapy, and use of hematopoietic growth Key words: myelodysplastic syndromes, therapy factors. They also participated in the Fourth Interna- tional Symposium on MDS (Barcelona, 24-27 April ecent papers in this journal have analyzed the 1997). In addition, the present review critically exam- pathogenesis and clinical features of myelo- ines relevant articles and abstracts published in jour- dysplastic syndromes (MDS).1-5 For the pur- nals covered by the Science Citation Index® and Med- R line®. pose of this article on the therapy of MDS, the fol- lowing two points need to be recollected: State of the Art and Perspectives. At present, the only a) MDS are clonal disorders of hematopoiesis in two treatments that can prolong survival are allo- which peripheral blood cell production is inefficiently geneic stem cell transplantation (SCT) and intensive chemotherapy, but only a minority of MDS patients sustained by hematopoietic progenitors belonging 1 can really benefit from them. The heterogeneity of to the abnormal clone(s). A few observations indi- MDS patients, the wide variety of patient inclusion cri- cate that the normal hematopoietic stem cell reser- teria and transplant procedures used, and relatively voir may be preserved early after diagnosis,6 but small numbers of patients in the individual reports of undergoes decline with time, so that most patients allogeneic SCT make it difficult to draw many defini- with long-lasting, advanced disease would have very tive conclusions. However, approximately 40% of few normal residual stem cells left; patients with MDS who are eligible for allogeneic SCT are likely to be cured by this treatment. Intensive b) Although the disease progression is highly vari- chemotherapy with a combination of cytosine arabi- able from patient to patient, the International Prog- noside and an anthracycline should be offered to all nostic Scoring System (IPSS)7 provides an improved patients with an increase in bone marrow blasts who method for evaluating prognosis in individual MDS are not eligible for allogeneic SCT, especially those patients, as long as they remain untreated. patients up to 65 years of age. Complete remission The list of therapeutic options available for MDS rates are similar to those obtained in patients with patients is as long as the list of names previously used acute myelogenous leukemia, but probability of long- for defining these conditions.8 Unfortunately most of term survival is low. The remaining treatments vali- dated in clinical trials (erythropoietin and/or granulo- these therapeutic tools are poorly effective, especially cyte colony-stimulating factor, low-dose cytosine ara- when given to unselected patient populations, while binoside) can improve the efficiency of hematopoiesis the potentially curative ones (see later) are available in subsets of patients. Responsive individuals might only for a minority of individuals. Facing an individual patient with MDS and bearing the above con- siderations in mind, as clinicians we first have to Correspondence: Prof. Mario Cazzola; Internal Medicine and Medical define treatment objectives. We basically have three Oncology, IRCCS Policlinico S. Matteo, 27100 Pavia, Italy. Phone: international +39-0382-526263 • Fax: international +39-0382- choices: 525222 • E-mail: [email protected] 1) to avoid any manipulation of hematopoiesis Therapy of myelodysplastic syndromes 911 and just rely upon supportive therapy; Table 1. Criteria for supportive therapy in MDS patients. 2) to stimulate normal residual hematopoietic progenitors and/or improve the efficiency of the Anemia myelodysplastic hematopoiesis; Red cell transfusions should be given when anemia is sympto- 3) to eradicate the myelodysplastic clone and matic. restore a normal (autologous or allogeneic) poly- Any low or intermediate-1 risk patient (with an average life clonal hematopoiesis. expectancy > 4 years according to the IPSS7) who has received at ≥ We will first consider the single therapeutic options least 30 blood transfusions or whose serum ferritin is 1,000 µg/L should be regularly treated with subcutaneous desferrioxam- within each of the above categories and then shall pro- ine, 30-40 mg/kg daily for 5 days a week. pose a patient-oriented approach to MDS therapy. Granulocytopenia Therapeutic options for MDS patients Since there is no clear evidence that regular administration Before making therapeutic decisions we recom- of G-CSF can prevent infective episodes and/or prolong survival mend that the diagnostic process be carefully in neutropenic MDS patients, this use is not recommended. reviewed in order to be sure that the individual However, individual patients may benefit from short-term treatment with G-CSF during an infective episode. patient has MDS. This diagnosis is often difficult and diagnostic errors are possible, some being quite Thrombocytopenia common while others more rare. Among the former Platelet transfusions should be given when the platelet count must be included megaloblastic anemia and anemia drops below 103109/L, or with higher platelet counts during hem- associated with other disorders. With respect to more orrhagic episodes. subtle misdiagnoses, Cotter et al.9 reported a previously unaffected 77-year-old male who developed severe anemia: the initial diagnosis was sideroblastic anemia with ring sideroblasts. This patient respond- ed dramatically to pyridoxine with normalization of gens and/or corticosteroids in MDS patients. If the hemoglobin values. Since anemia was microcytic, he clinical condition is stable and a curative treatment is was studied for point mutations in the erythroid-spe- not feasible, close follow-up with no treatment may cific delta-aminolevulinate synthase gene (ALAS2) be the best choice. and found to have an A to C transversion in exon 7. This patient therefore had a late-onset form of X- Supportive treatment 10 linked sideroblastic anemia, which can be distin- Once a cytopenia becomes symptomatic, sup- guished from refractory anemia with ringed siderob- portive therapy with blood products and conservative lasts (RARS) by microcytosis, pyridoxine-responsive- measures are still the mainstay of therapy (Table 1). ness, and ALAS2 mutations. Symptomatic anemia requires regular transfusions Watchful-waiting strategy of red cells, and transfusional iron overload is inevitable. One unit of blood (400 mL) contains The approach to a patient with MDS should begin about 200 mg of iron, so that the annual burden may with a period of observation, with sequential periph- be 2-4 g on average. Although transfusional iron is eral blood counts – and sometimes bone marrow primarily taken up by the reticuloendothelial cells, it examinations – to assess the rate of progression, if any. Not all patients need be treated. A considerable is later redistributed to parenchymal cells, with the portion of MDS patients have Hb levels > 9-10 g/dL, redistribution rate being proportional to erythroid neutrophil count > 0.53109/L and platelet count proliferation and plasma iron turnover. When the >503109/L. In elderly patients such Hb levels may be body iron load exceeds 100-200 mg/kg, secondary compatible with a reasonably good quality of life, hemochromatosis develops and liver disease, dia- and the above degrees of granulocytopenia and betes mellitus, hypogonadotropic hypogonadism, 16 thrombocytopenia are generally not troublesome and and eventually heart failure may occur. can just be followed regularly. In addition, occasion- We believe that any low or intermediate-1 risk al patients may have spontaneous improvement in patient (with an average life expectancy > 4 years blood counts. according to the IPSS7) who has received at least 30 Responses of anemia to androgens,11,12 of granulo- blood transfusions or whose

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