Myelodysplastic Syndromes (MDS)

Transcription

1 Myelodysplastic Syndromes (MDS) Treatment Policy Prepared by Dr. Rena Buckstein Updated July 2003 Introduction The myelodysplastic syndromes are a heterogeneous group of acquired stem cell disorders with varying degrees of cytopenias, functional abnormalities of hematopoietic stem cells and an increased risk of transformation to acute leukemia. MDS usually develops in older adults with a median age of 6075 years in most series [1]. MDS is relatively common with a reported incidence of per 100,000. The incidence increases to 1550/100,000 beyond age 70, making it as common as CLL or myeloma in this age group [2]. Autoimmune complications may be associated with MDS in 1013% of patients and may respond to immunosuppressive therapies [3, 4]. They can be classified into acute systemic vasculitis or autoimmune disorders, chronic or isolated autoimmune phenomena, classical connective tissue disorders (Sjögren s, PMR, SLE, RA, relapsing polychondritis), immune mediated hematological abnormalities (ITP, AIHA) and asymptomatic serological immunological abnormalities. Diagnosis The diagnosis of MDS is dependent on demonstration of dysplastic features in the peripheral blood and marrow. Myelofibrotic [5] and hypoplastic variants [6] are also reported. Classically, MDS has trilineage dysplasia, but occasionally dysplasia may be confined to 1 or 2 lines. The differential diagnosis includes [7]: Vitamin B 12 or folate deficiency Proven exposure to heavy metals Recent cytotoxic therapy HIV Autoimmune diseases Chronic liver diseases and/or chronic alcohol use MDS has until recently been classified from the FrenchAmericanBritish (FAB) system [8]. Recently the World Health Organization (WHO) system has become the international standard [9]. The criteria for these two systems are summarized in the table on page 2. Major distinguishing features include recognizing differences between morphologic dysplasia restricted to one cell lineage or all cell lineages, deeming the 5q syndrome to be an entity of its own, creating the entity MDS unclassifiable and lowering the diagnostic BM blast percent for AML from 30% to 20% (see Table 1 on page 2). Prognosis and Staging (for CMML see page 6) MDS is a heterogeneous group of diseases with variable outcome [7, 10, 11]. Factors that predict inferior outcome include: WHO subtype Complex karyotype [10] Chromosome 5 or 7 abnormalities [10] Increased CD34 expression [12, 13] Abnormal localization or immature precursors (ALIP) [13] Therapy related MDS Fibrosis [14] Mutational status [15] Increased VEGF and microvessel density Beta2 microglobulin [16] TSRCC Hematology Site Group Treatment Policies 1/10

2 Two commonly used tools that predict outcome are the International Prognostic Scoring System (IPSS) [10] and the Sanz Score [11]. The IPSS is most commonly used, but can only be applied if cytogenetics analysis has been performed. Table 1 Myelodysplastic Syndromes (MDS) FAB subtype [9a] WHO subtype [33] Bone marrow blasts (%) Blasts in peripheral blood (%) Monocytes >1000/µl in peripheral blood Ringed sideroblasts >15% RA RA without ringed sideroblasts a <1 RARS RAEB CMML RA with ringed sideroblasts a Refractory cytopenia with multilineage dysplasia b 5q syndrome RAEB RAEB1 RAEB2 MDS unclassifiable Myelodysplastic/myeloproliferative syndromes CMML[9] <13,000 leukocytes/µl Atypical CML Juvenile myelomonocytic leukemia % 1120% <120 <1 <1 <1 <120 < / RAEBT AML / +/ AML, acute myeloid leukemia; CMML, chronic myelomonocytic leukemia; RA, refractory anemia; RAEB, refractory anemia with excess of blasts; RAEBT, refractory anemia with excess of blasts in transformation; RARS, refractory anemia with ringed sideroblasts. a Only erythroid lineage b At least two lineages involved + +/ +/ +/ +/ +/ +/ Table 2 The International Prognostic Scoring System (IPSS) BM Blast % Score Karyotype Normal, Y,5q,20q Other abnormalities Complex, or chromosome 7 abnormalities Score Cytopenias (# of lineages involved) 0/1 2/3 Score Total Score >2 Risk Group Low Intermediate 1 Intermediate 2 High Median Survival (Years) /10 Myelodysplastic Syndromes (MDS)

3 Baseline Investigations The following should be performed in most patients with MDS at time of initial assessment: CBC, differential Blood film Retic count Direct antiglobulin test (DAT) Bone marrow aspirate and biopsy with cytogenetics Vitamin B 12, red cell folate, ferritin, iron saturation TSH Serum EPO level Liver and renal profile In Toronto and the metro area, send cytogenetics to: Cancer Cytogenetics The Banting Institute (Room 77) 100 College Street Toronto, Ontario, M5G 1L5 Telephone #: If patient has secondary MDS, specific chromosomal abnormalities (eg. chromosome 7, 5 or 11) may be requested by FISH. Treatment The following therapeutic options are available for patients with MDS: 1. Allogeneic hematopoietic stem cell transplant 2. AMLtype chemotherapy [17] 3. Biologic, presumably targeted therapies For CMML see Page 6 For patients that are symptomatic, the following treatment options exist: a. Stem Cell Transplantation Allogeneic transplant is the only known curative therapy for MDS. In a registry study of 885 patients with MDS or secondary AML who received MSD HLA matched transplants, 3year relapsefree survival was 53% for RA, 46% for RAEB, and 38% for RAEBT/sAML [18]. Nonrelapse mortality can be as high as 39% for older patients (5566) [19]. Predictive factors of good outcome include younger age, shorter disease duration, HLA compatibility, primary MDS, < 10% blasts, good risk cytogenetics and low IPSS score. In more advanced FAB subtypes nonmyeloablative (mini) transplants are being investigated, but have unproven efficacy at this time [2022]. Because some patients with MDS can have cytogenetically normal polyclonal hematopoiesis after treatment with chemotherapy, autologous transplantation is an experimental option [23] and shows some promise [24]. Nevertheless, ABMT should only be performed within the context of a clinical trial. b. AMLtype Chemotherapy AMLtype chemotherapy is capable of inducing complete responses in 4050%, but they are rarely durable. The response to antiaml therapy is similar in high risk MDS and AML [25]. Historically, CR rates appear lower than for denovo AML, but may be similar for highly selected patients with favorable characteristics (Age <45 with normal karyotype) [26]. Early mortality ranges from 824% with median survivals of 924 mo [27]. RAEBT in the FAB classification is now considered AML and should be treated as AML. TSRCC Hematology Site Group Treatment Policies 3/10

4 c. Growth Factors Erythropoietin and GCSF have been extensively studied in MDS and are the subject of a CCO evidencebased guideline. In a randomized trial erythropoietin resulted in an improvement in transfusion requirement compared to placebo [28]. Used alone, erythropoietin may improve the anemia in 1520% of patients. The addition of GCSF to erythropoietin appears to increase erythroid response, particularly in RARS patients [29, 30]. Responses to erythropoietin appear to be greater in patients with a serum erythropoietin level 00 and/or a requirement of 2 units of red blood cells per month (see table below for predictive scoring model) This has been validated by the same authors in a prospective test sample of 53 patients [31], using doses of erythropoietin of 10,000 units SQ for 5/7 days and neupogen 75, 150 or 300 µg tiw dose adjusted to keep ANC of 610). Median durations of CR and PR responses were 29 months and 5.5 months. Recommended starting doses of erythropoietin are 50,000units/week, but up to 70,000 units/week may be needed. There is no role for prophylactic GCSF or GMCSF for severe neutropenia, although its use may be considered during an episode of sepsis. Probability of Response to Erythropoietin in MDS Erythropoietin < >500 Score points RBC Transfusion needed <2 units/month > 2 units/month Score 2 2 Total Score >+1 ±1 <1 Response 74% 23% 7% Other growth factors such as IL11 for thrombocytopenia have mild efficacy in MDS, but have troublesome side effects and no data is yet available on the therapeutic use of thrombopoietin (TPO) in MDS [32]. d. Immunosuppressive Therapy Immune mechanisms have been implicated in the pathogenesis of marrow failure in MDS [33]. Immunosuppressive therapy has activity in MDS [3436]. Options studied included antithymocyte globulin (ATG) and cyclosporin A. In the largest published study to date [37, 38], 61 patients with transfusion dependent MDS were treated with ATG (40 mg/kg/day for 4 days). 33% of patients became red cell transfusion independent within 8 months (median 75d); 56% severely thrombocytopenic patients had sustained platelet increases and 44% of severely neutropenic patients had sustained neutrophil counts >1000/µl. Of 41 patients with Int1 risk score, responders had 100% survival at 3 years and no disease progression compared with 45% survival and 51% progression in non responders. The median response duration was 10 months [34], but 76% of responders maintained transfusion independence for 32 months. Cyclosporin A (35 mg/kg) has been studied alone and in combination with ATG for hypoplastic or normocellular MDS [35, 36, 39]. Pooled results from 3 case series with a total of 36 patients (95% RA and 50% hypoplastic) demonstrated a RR of 55%87%. Predictors for response to immunosuppression include HLADRB115 haplotype, younger age, normal cytogenetics, bi or trilineage dysplasia, refractory anemia and shorter period of transfusion dependence. Randomized trials of immunosuppression compared with supportive care are underway in the US and Europe. e. Cytokine Inhibition Marrow and serum levels of TNFα, interferonα, IL1β, TGFβ, and interferonγ are increased in MDS. Amifostine, pentoxifylline, dexamethasone and ciprofloxacin appear to inhibit the production of these cytokines and have been studied in small series. Amifostine as monotherapy in 75 evaluable patients has demonstrated single or multilineage responses in 36% of patients although no red cell transfusion independence was achieved. The three times weekly IV schedule of amifostine is inconvenient to administer [4042]. A combination of amifostine with pentoxifylline, ciprofloxacin and dexamethasone was associated with modest transient improvement in a small series [43]. Soluble TNFα receptor has also been tried with modest results [44]. Remicade (chimeric humanmurine monoclonal antibody capable of neutralizing TNFα in humans) is currently being tested in clinical trials with some success [45] and may work well in combination therapy with drugs that target the neoplastic clone. 4/10 Myelodysplastic Syndromes (MDS)

5 f. Low Dose Chemotherapy Low dose cytosine arabinoside (AraC) is the most extensively studied agent. Low dose arac achieves complete or partial remissions in approximately 30% of patients with RAEB, RAEBT and MDS. The only prospective randomized phase III comparing low dose arac with supportive care failed to show a difference in survival between the two alternatives [46, 47]. Responses may be as high as 55% in patients with platelet counts >150, or without ringed sideroblasts, cellularity >70%, or complex karyotype [48]. Low dose melphalan (2 mg/day) has been studied in two small series with response rates of 38% and 40% [49, 50], but responses may not be durable and may be associated with the development of 17p deletion [51]. g. Differentiating Agents Polyclonal CD34(+) stem cells have been identified in PBPC harvests [23]. Retinoids including 13 cisretinoic acid, vitamin D 3, interferons, hematopoietic growth factors, and ATRA have been studied and demonstrate either minimal activity or, absence of overall survival (OS) or leukemia free survival (LFS) benefits [5259]. h. Hypomethylating Agents Hypermethylation of specific DNA sequences, thus suppressing gene transcription has been implicated in the pathogenesis of MDS. The DNA hypomethylating pyrimidine analogs 5AZAcytidine and 5AZAdecitabine (DAC) are being investigated in high risk MDS and showing great promise. In a large CALGB randomized Phase III study [60], 5AZA given subcutaneously 7 out of 28 days was studied against observation in a crossover model. The overall response rate was 60% (7% CR, 16% PR, 37% Improved) compared with 5% in control arm. Median time to leukemic transformation was 21 months in the 5AZA arm versus 13 months in supportive care arm (P=0.003) suggesting that the drug decreased the rate of transformation to AML. There was no significant difference in survival. MDS risk group did not predict for response. Quality of life was enhanced in responding patients (toxic side effects were few and treatmentrelated mortality was low) who experienced decreased fatigue and dyspnea, and improved psychological well being [61]. Decitabine given IV has been evaluated in a large multicentre phase II study of 66 patients with MDS [62]. The overall response rate was 49% and 64% in patients with IPSS high risk. A significant rise in platelet count occurred in 54% of patients after only 1 cycle of decitabine. Cytogenetic normalization was seen (31%) even in some highrisk karyotypes. Myelosuppression was common and 7% therapyrelated deaths were reported related to this and infection. Decitabine appears to have increased hematological toxicity compared with 5AZA. To reduce toxicity, decitabine is currently being tested in a MD Anderson dose deescalation trial using lower doses, but longer schedules. i. Topotecan The topoisomerase1 inhibitor, topotecan has been studied in MDS [6365] alone or with AraC [66]. Topotecan 1.25 mg/m 2 by continuous IV infusion for 5 days every 48 weeks + arac 1 g/m2 IV for 5 days for 2 courses was associated with a 4866% CR rate, but a high rate of toxicity and 10% induction death rate in high risk MDS. This regimen was particularly effective in patients with secondary MDS or poor prognosis karyotypes (CR rates of 69 and 63%). The CR rate and survival appeared higher in MDS compared with CMML, but survival was short for both (60 weeks MDS and 41 weeks CMML) and infectious morbidity was high. Topotecan/AraC is equivalent to idarubicin/arac for survival and complete responses in MDS. j. Novel Agents There are a number of new drugs in development and early phase 2 trials with multifaceted modes of action. These include arsenic (trisenox) which may work to increase tumor cell differentiation, apoptosis and inhibit angiogenesis. Patients with high pretherapy Evi1 expression may be uniquely sensitive to arsenic +/ thalidomide and may eventually be a useful preselection criterion for therapy with this agent. [67]. k. Angiogenesis Inhibitors Angiogenesis is increased in MDS [6871] and AML studies suggest a correlation between increased VEGF and progression to leukemia possibly via autocrine and paracrine stimulation [7275]. Antiangiogenic agents being studied in MDS include thalidomide, thalidomide analogues (CC5013) as well as VEGF receptor antagonists and matrix metalloproteinase inhibitors to name a few [76, 77]. In a recently published series of 83 patients with MDS treated with thalidomide ( mg/day) the response rate was 19% in part due to a high rate of intolerance to therapy (32/83 patients). Responses were greater in patients with good risk disease, lower blast counts and higher platelet counts. Few patients with RAEB responded. Responses may take 35 months to be seen. Combination approaches of TSRCC Hematology Site Group Treatment Policies 5/10

6 thalidomide with other agents are being explored. SU5416, a VEGF receptor antagonist has also shown some success in MDS [78] and its successor S6668 and others are currently in clinical trials. Supportive Care l. Transfusion In MDS patients, there is a positive correlation between Hb level and health related quality of life [79]. Red cell transfusion can effectively palliate fatigue in patients with MDS. No single threshold should be used for all patients, but a symptomatic threshold should be identified for each patient. Because of platelet alloimmunization, platelet transfusion should be reserved for patients with excessive bleeding or bruising. Tranexamic acid may be used to minimize mucosal bleeding (1 g PO BIDTID). m. Iron Chelation Patients with good risk myelodysplastic syndrome projected to live 3.5 years or more who are transfusion dependent are at risk of transfusional iron overload. Each unit of blood (400 cc) contains 200 mg of iron. Secondary hemochromatosis can develop when total body iron reaches 715 g. Desferrioxamine administered by subcutaneous pump 3040 mg/kg daily for 5 days via CAD pump or 1 g bolus twice daily subcutaneously is the only licensed iron chelator in Canada. Preliminary evidence suggests desferrioxamine may improve transfusion requirements and cytopenias in patients with MDS [80]. Oral chelators are currently being tested and show efficacy [81]. TSRCC Policy 1. What is patient s IPSS score? 2. Is patient eligible for clinical trials? Approach for enrollment 3. Is patient appropriate for allogeneic transplant? 4. Is patient appropriate for AMLtype chemotherapy? Age <65 with related donor and high intermediate or high risk, age <45 with unrelated donor and high risk Age >65 with related donor, high intermediate or high risk score and nonmyeloablative transplant available Refer for transplant assessment RAEBII, age <65, high intermediate or high risk, planned stem cell transplant Consider 7+3 induction chemotherapy, or hypomethylating agents 5. Is patient appropriate for trial of EPO? 6. Is patient neutropenic (<1.0) or thrombocytopenic (<30)? 7. Is patient projected to live >2 years and has received grater than 25 blood transfusions? Prognostic score 1 or higher, low to low intermediate risk score EPO 40,000 U SC weekly x 6 Add GCSF 100 µg SC 3 x weekly x 8 weeks if no response to EPO alone If patient has RARS and symptomatic anemia, commence combination treatment from outset. In asymptomatic patients with hgb > 100g/l, ANC > 1.0 and plt > 75,000, observation alone is appropriate. Low risk: Cyclosporin A +/ ATG (second line thalidomide) Int.High: 5AZA or decitabine if available. Low dose melphalan, low dose AraC may be considered in selected cases Desferrioxamine 3040mg/kilo daily for 5 days by CAD pump subcutaneously or subcutaneously bolus injections 1g twice daily Audiometry and ophthalmology review are essential prior to commencement of desferrioxamine and should be performed annually thereafter. The target ferritin should be <1000 µg/l. If the ferritin concentration falls below 2000 µg/l, the dose of desferrioxamine should not exceed 25 mg/kg. Vitamin C mg daily should be commenced after one month of desferrioxamine therapy. CMML CMML shares features both of MDS and a chronic myeloproliferative disorder. Patients can be divided into dysplastic (MDS CMML) and proliferative (MPD CMML). Patients with MPD CMML typically have hepatosplenomegaly, high leukocyte counts (>12 x 10 9 /L) and an elevated LDH [82]. There is no significant difference in survival between the two groups. Patients with MDS CMML should be treated similarly to other patients with MDS. It is important to note that the IPSS score excluded CMML patients with white counts more than 12,000 and may not apply to the myeloproliferative form of CMML. Response to hydroxyurea is 60% and is superior to VP16 [28]. Responses can be durable (median 24 mo). 6/10 Myelodysplastic Syndromes (MDS)

7 Responses and survival are inferior for patients with unfavorable karyotype or severe anemia. Patients with MPD CMML who are symptomatic should be treated with hydroxyurea (14 g/day). Dose should be titrated to maintain WBC (1015 x 10 9 /L) and platelet count >30 x 10 9 /L. 5AZA and DAC may also be alternative treatments, but are not currently available off study. Patients who fail hydroxyurea can be offered low dose arac or melphalan. References 1. Aul, C., N. Gattermann, and W. Schneider, Epidemiological and etiological aspects of myelodysplastic syndromes. Leuk Lymphoma, (34): p Aul, C., et al., Increasing incidence of myelodysplastic syndromes: real or fictitious? Leuk Res, (1): p Enright, H., et al., Paraneoplastic autoimmune phenomena in patients with myelodysplastic syndromes: response to immunosuppressive therapy. Br J Haematol, (2): p Saif, M.W., J.L. Hopkins, and S.D. Gore, Autoimmune phenomena in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia. Leuk Lymphoma, (11): p Steensma, D.P., et al., Myelodysplasia with fibrosis: a distinct entity? Leuk Res, (10): p Nand, S. and J.E. Godwin, Hypoplastic myelodysplastic syndrome. Cancer, (5): p Verhoef, G.E., et al., FAB classification of myelodysplastic syndromes: merits and controversies. Ann Hematol, (1): p Bennett, J.M., et al., Proposals for the classification of the myelodysplastic syndromes. Br J Haematol, (2): p Bennett, J.M., World Health Organization classification of the acute leukemias and myelodysplastic syndrome. Int J Hematol, (2): p Greenberg, P., et al., International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood, (6): p Sanz, G.F., et al., Two regression models and a scoring system for predicting survival and planning treatment in myelodysplastic syndromes: a multivariate analysis of prognostic factors in 370 patients. Blood, (1): p Lambertenghi Deliliers, G., et al., The diagnostic and prognostic value of bone marrow immunostaining in myelodysplastic syndromes. Leuk Lymphoma, (34): p Verburgh, E., et al., Additional prognostic value of bone marrow histology in patients subclassified according to the International Prognostic Scoring System for myelodysplastic syndromes. J Clin Oncol, (2): p Verhoef, G.E., et al., Myelodysplastic syndromes with bone marrow fibrosis: a myelodysplastic disorder with proliferative features. Ann Hematol, (5): p Gallagher, A., R.L. Darley, and R. Padua, The molecular basis of myelodysplastic syndromes. Haematologica, (2): p Gatto, S., et al., Contribution of B2 microglobulin levels to the prognostic stratification of survival in patients with myelodysplastic syndromes (MDS). Blood, : p Estey, E.H., Current challenges in therapy of myelodysplastic syndromes. Curr Opin Hematol, (1): p De Witte, T., Stem cell transplantation for patients with myelodysplastic syndrome and secondary leukemias. Int J Hematol, (2): p Deeg, H.J., et al., Allogeneic and syngeneic marrow transplantation for myelodysplastic syndrome in patients 55 to 66 years of age. Blood, (4): p Nevill, T.J., et al., Cytogenetic abnormalities in primary myelodysplastic syndrome are highly predictive of outcome after allogeneic bone marrow transplantation. Blood, (6): p Slavin, S., et al., Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood, (3): p McSweeney, P.A., et al., Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing highdose cytotoxic therapy with graftversus tumor effects. Blood, (11): p Delforge, M., et al., Polyclonal primitive hematopoietic progenitors can be detected in mobilized peripheral blood from patients with highrisk myelodysplastic syndromes. Blood, (10): p TSRCC Hematology Site Group Treatment Policies 7/10

8 24. De Witte, T., et al., Autologous bone marrow transplantation for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia following MDS. Chronic and Acute Leukemia Working Parties of the European Group for Blood and Marrow Transplantation. Blood, (10): p Estey, E., et al., Effect of diagnosis (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or acute myeloid leukemia [AML]) on outcome of AMLtype chemotherapy. Blood, (8): p Fenaux, P., et al., Prognostic factors in adult de novo myelodysplastic syndromes treated by intensive chemotherapy. Br J Haematol, (4): p Beran, M., Intensive chemotherapy for patients with highrisk myelodysplastic syndrome. Int J Hematol, (2): p A randomized doubleblind placebocontrolled study with subcutaneous recombinant human erythropoietin in patients with lowrisk myelodysplastic syndromes. Italian Cooperative Study Group for rhuepo in Myelodysplastic Syndromes. Br J Haematol, (4): p HellstromLindberg, E., et al., Treatment of anemia in myelodysplastic syndromes with granulocyte colonystimulating factor plus erythropoietin: results from a randomized phase II study and longterm followup of 71 patients. Blood, (1): p Negrin, R.S., et al., Maintenance treatment of the anemia of myelodysplastic syndromes with recombinant human granulocyte colonystimulating factor and erythropoietin: evidence for in vivo synergy. Blood, (10): p HellstromLindberg, E., et al., A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colonystimulating factor: significant effects on quality of life. Br J Haematol, (6): p Kurzrock, R., et al., Pilot study of lowdose interleukin11 in patients with bone marrow failure. J Clin Oncol, (21): p Hamblin, T.J., Immunological abnormalities in myelodysplastic syndromes. Semin Hematol, (2): p Molldrem, J.J., et al., Antithymocyte globulin for patients with myelodysplastic syndrome. Br J Haematol, (3): p Catalano, L., et al., Prolonged response to cyclosporina in hypoplastic refractory anemia and correlation with in vitro studies. Haematologica, (2): p Jonasova, A., et al., Cyclosporin A therapy in hypoplastic MDS patients and certain refractory anaemias without hypoplastic bone marrow. Br J Haematol, (2): p HellstromLindberg, E., et al., Achievements in Understanding and Treatment of Myelodysplastic Syndromes. Hematology (Am Soc Hematol Educ Program), 2000: p Barrett, A., Immune mechanisms and modulations in MDS. American Society of Hematology Education Program Book, 2000: p Biesma, D.H., J.G. van den Tweel, and L.F. Verdonck, Immunosuppressive therapy for hypoplastic myelodysplastic syndrome. Cancer, (8): p Blood, (10): p. 305a. 41. Hofmann, W.K., et al., Effect of treatment with amifostine used as a single agent in patients with refractory anemia on clinical outcome and serum tumor necrosis factor alpha levels. Ann Hematol, (5): p List, A.F., et al., Stimulation of hematopoiesis by amifostine in patients with myelodysplastic syndrome. Blood, (9): p Raza, A., et al., Patients with myelodysplastic syndromes benefit from palliative therapy with amifostine, pentoxifylline, and ciprofloxacin with or without dexamethasone. Blood, (5): p Deeg, H., et al., Soluble TNF receptor fusion protein (TNF;Fc;Enbrel) in the treatment of patients with myelodysplastic syndromes (MDS). Blood, : p. 146a. 45. Lisak, L., et al., Hematologic response to antitumor necrosis factor therapy with remicade in patients with myelodysplastic syndrome (MDS). Leukemia Research, (Supplement 1): p. S Cheson, B.D. and R. Simon, Lowdose arac in acute nonlymphocytic leukemia and myelodysplastic syndromes: a review of 20 years' experience. Semin Oncol, (2 Suppl 1): p Miller, K.B., et al., The evaluation of lowdose cytarabine in the treatment of myelodysplastic syndromes: a phaseiii intergroup study. Ann Hematol, (4): p HellstromLindberg, E., et al., A predictive model for the clinical response to low dose arac: a study of 102 patients with myelodysplastic syndromes or acute leukaemia. Br J Haematol, /10 81(4):p Myelodysplastic Syndromes (MDS)

9 49. Omoto, E., et al., Lowdose melphalan for treatment of highrisk myelodysplastic syndromes. Leukemia, (4): p Denzlinger, C., et al., Lowdose melphalan induces favourable responses in elderly patients with highrisk myelodysplastic syndromes or secondary acute myeloid leukaemia. Br J Haematol, (1): p Bowen, D.T. and E. HellstromLindberg, Best supportive care for the anaemia of myelodysplasia: inclusion of recombinant erythropoietin therapy? Leuk Res, (1): p Clark, R.E., et al., A randomized trial of 13cis retinoic acid with or without cytosine arabinoside in patients with the myelodysplastic syndrome. Br J Haematol, (1): p Koeffler, H.P., et al., Randomized study of 13cis retinoic acid v placebo in the myelodysplastic disorders. Blood, (3): p Motomura, S., et al., The effect of 1hydroxyvitamin D3 for prolongation of leukemic transformationfree survival in myelodysplastic syndromes. Am J Hematol, (1): p Hellstrom, E., et al., Treatment of myelodysplastic syndromes with retinoic acid and 1 alphahydroxyvitamin D3 in combination with lowdose arac is not superior to arac alone. Results from a randomized study. The Scandinavian Myelodysplasia Group (SMG). Eur J Haematol, (5): p Mellibovsky, L., et al., Vitamin D treatment in myelodysplastic syndromes. Br J Haematol, (3): p Gisslinger, H., et al., Longterm alphainterferon therapy in myelodysplastic syndromes. Leukemia, (2): p Catalano, L., et al., A further case of intracerebral tumor in AML. Haematologica, (2): p Cazzola, M., et al., A patientoriented approach to treatment of myelodysplastic syndromes. Haematologica, (10): p Silverman, L.R., et al., Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol, (10): p Kornblith, A.B., et al., Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a Cancer and Leukemia Group B study. J Clin Oncol, (10): p Wijermans, P., et al., Lowdose 5aza2'deoxycytidine, a DNA hypomethylating agent, for the treatment of highrisk myelodysplastic syndrome: a multicenter phase II study in elderly patients. J Clin Oncol, (5): p Estey, E.H., Incorporating new modalities into guidelines. Topotecan for myelodysplastic syndromes. Oncology (Huntingt), (11A): p Beran, M., et al., Topotecan, a topoisomerase I inhibitor, is active in the treatment of myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood, (7): p Beran, M. and H. Kantarjian, Topotecan in the treatment of hematologic malignancies. Semin Hematol, (3 Suppl 4): p Beran, M., et al., Topotecan and cytarabine is an active combination regimen in myelodysplastic syndromes and chronic myelomonocytic leukemia. J Clin Oncol, (9): p Raza, A., et al., Myelodysplastic syndromes (MDS) patients with high level EVI1 expression respond well to a combination of arsenic trioxide (Trisenox) and thalidomide. Leukemia Research, (Supplement No. 1): p. S Aguayo, A., F. Giles, and M. Albitar, Vascularity, angiogenesis and angiogenic factors in leukemias and myelodysplastic syndromes. Leuk Lymphoma, (2): p Aguayo, A., et al., Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. Blood, (6): p Pruneri, G., et al., Angiogenesis in myelodysplastic syndromes. Br J Cancer, (8): p Padro, T., et al., Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia. Blood, (8): p Dias, S., et al., Autocrine stimulation of VEGFR2 activates human leukemic cell growth and migration. J Clin Invest, (4): p Bellamy, W.T., et al., Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes. Blood, (5): p TSRCC Hematology Site Group Treatment Policies 9/10

10 74. Hattori, K., et al., Vascular endothelial growth factor and angiopoietin1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells. J Exp Med, (9):p Bautz, F., et al., Expression and secretion of vascular endothelial growth factora by cytokinestimulated hematopoietic progenitor cells. Possible role in the hematopoietic microenvironment. Exp Hematol, (6): p Raza, A., et al., Thalidomide produces transfusion independence in longstanding refractory anemias of patients with myelodysplastic syndromes. Blood, (4): p Smolich, B.D., et al., The antiangiogenic protein kinase inhibitors SU5416 and SU6668 inhibit the SCF receptor (ckit) in a human myeloid leukemia cell line and in acute myeloid leukemia blasts. Blood, (5): p Giles, F.J., et al., SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes. Blood, : p Jansen, A.J., et al., Quality of life measurement in patients with transfusiondependent myelodysplastic syndromes. Br J Haematol, (2): p Jensen, P.D., et al., The effect of iron chelation on haemopoiesis in MDS patients with transfusional iron overload. Br J Haematol, (2): p Kersten, M.J., et al., Longterm treatment of transfusional iron overload with the oral iron chelator deferiprone (L1): a Dutch multicenter trial. Ann Hematol, (5): p Germing, U., et al., Problems in the classification of CMMLdysplastic versus proliferative type. Leuk Res, (10): p /10 Myelodysplastic Syndromes (MDS)