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Myelodysplastic Syndromes Nicole N. Balmer M.D. June 3 rd, 2005.

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1 Myelodysplastic Syndromes Nicole N. Balmer M.D. June 3 rd, 2005

2 History of MDS First described in patients with refractory anemia were described; Subsequently, the terms "preleukemic anemia“ and “preleukemia” were used. First described in patients with refractory anemia were described; Subsequently, the terms "preleukemic anemia“ and “preleukemia” were used. In 1963, a variant of acute leukemia was described, characterized by a prolonged and often benign clinical course, with a comparatively lower but variable percentage of bone marrow blasts; the authors termed this condition "smoldering acute leukemia" In 1963, a variant of acute leukemia was described, characterized by a prolonged and often benign clinical course, with a comparatively lower but variable percentage of bone marrow blasts; the authors termed this condition "smoldering acute leukemia"

3 History of MDS In the 1970s, chronic myelomonocytic leukemia (CMML) was recognized as a unique preleukemic syndrome. In the 1970s, chronic myelomonocytic leukemia (CMML) was recognized as a unique preleukemic syndrome. In 1976, the French-American-British (FAB) Cooperative Group initially defined refractory anemia with excess blasts (RAEB) and CMML as preleukemic states. Six years later, the FAB group added three more categories to this classification scheme and adopted the present term "myelodysplastic syndromes". In 1976, the French-American-British (FAB) Cooperative Group initially defined refractory anemia with excess blasts (RAEB) and CMML as preleukemic states. Six years later, the FAB group added three more categories to this classification scheme and adopted the present term "myelodysplastic syndromes". These disorders, and other members of the MDS "family“ were subsequently defined by the WHO. These disorders, and other members of the MDS "family“ were subsequently defined by the WHO.

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5 The Myelodyplastic Syndromes Six types of myelodysplastic syndromes according to WHO. Six types of myelodysplastic syndromes according to WHO. –Refractory anemia –Refractory anemia with ringed sideroblasts –Refractory cytopenia with multilineage dysplasia –Refractory anemia with excess blasts –Myelodysplastic syndrome, unclassifiable –5q- syndrome (myelodysplastic syndrome associated with isolated del (5q) chromosome abnormality Related syndromes: Related syndromes: –Myelodysplastic/Myeloproliferative diseases

6 Myelodysplastic Syndromes MDS Definition: MDS Definition: A group of disorders presenting with some evidence of bone marrow failure and dysplasia of one or more of the myeloid lineages, with <20% blasts in the blood or marrow. A group of disorders presenting with some evidence of bone marrow failure and dysplasia of one or more of the myeloid lineages, with <20% blasts in the blood or marrow. Epidemiology: Epidemiology: Occur primarily in older patients (most common > 70 years). Occur primarily in older patients (most common > 70 years).

7 MDS – Clinical Symptoms Ecchymoses Ecchymoses Fatigue Fatigue Pallor Pallor Ecchymoses/petechiae Ecchymoses/petechiae Abnormal bleeding Abnormal bleeding Infection Infection

8 MDS Etiology Two etiologic categories of MDS: Two etiologic categories of MDS: 1.) De Novo: Associated with: -benzene exposure (gasoline) -benzene exposure (gasoline) -cigarettesmoking -cigarettesmoking -viruses -Fanconi’s anemia -viruses -Fanconi’s anemia 2.) Therapy related: Associated with: -alkylating agent chemotherapy -alkylating agent chemotherapy -radiation -radiation

9 Prognostic Groups Two groups based on survival and evolution to acute leukemia Two groups based on survival and evolution to acute leukemia 1.) “Good” group 1.) “Good” group –Refractory anemia (RA) –Refractory anemia with ringed sideroblasts (RARS) –5q - syndrome 2.) “Bad” group 2.) “Bad” group –Refractory anemia with excess blasts (RAEB) –Refractory cytopenia with multilineage dysplasia (RCMD) MDS unclassified can be either MDS unclassified can be either

10 Median Survival – Myelodysplastic Syndromes

11 Prognostic Scoring The International Myelodysplastic Syndrome Working Group developed a scoring system based on 3 variables: The International Myelodysplastic Syndrome Working Group developed a scoring system based on 3 variables: % Blasts < Karyotype Normal, -Y, del(5q), del(20q) Abnormal- ities NOS ≥ 3 abnormalities, chr 7 abnormalities Cytopenia0-12-3

12 International Prognostic Scoring System Data (IPSS) Overall median survival was 5.7, 3.5, 1.2, and 0.4 years for patients with IPSS scores of zero (low risk), 0.5 to 1.0 (intermediate-1 risk), 1.5 to 2.0 (intermediate-2 risk), and 2.5 to 3.5 (high risk), respectively. The time for 25 percent of the patients in each of the four risk groups to evolve into acute leukemia was 9.4, 3.3, 1.1, and 0.2 years, respectively. Overall median survival was 5.7, 3.5, 1.2, and 0.4 years for patients with IPSS scores of zero (low risk), 0.5 to 1.0 (intermediate-1 risk), 1.5 to 2.0 (intermediate-2 risk), and 2.5 to 3.5 (high risk), respectively. The time for 25 percent of the patients in each of the four risk groups to evolve into acute leukemia was 9.4, 3.3, 1.1, and 0.2 years, respectively.

13 IPSS Other adverse prognostic factors which may improve the prognostic value of the IPSS include: Other adverse prognostic factors which may improve the prognostic value of the IPSS include: -CD34 positivity of bone marrow nucleated cells -Increased expression of the Wilms' tumor gene (WT1) -Increased serum beta-2 microglobulin concentration -CD34 positivity of bone marrow nucleated cells -Increased expression of the Wilms' tumor gene (WT1) -Increased serum beta-2 microglobulin concentration -Mutations of the FLT3 gene -Mutations of the FLT3 gene -Abnormal localization of immature precursors (ALIP). -Abnormal localization of immature precursors (ALIP).

14 Refractory Anemia RA Definition: RA Definition: Dyplasia of the erythroid series only. Dyplasia of the erythroid series only. Clinically, anemia is refractory to hematinic therapy Clinically, anemia is refractory to hematinic therapy Myeloblasts < 1% blood and < 5% marrow Myeloblasts < 1% blood and < 5% marrow <15% ringed sideroblasts in marrow <15% ringed sideroblasts in marrow No Auer rods No Auer rods Other etiologies of erythroid abnormalities must be excluded. These include: Other etiologies of erythroid abnormalities must be excluded. These include: –drug/toxin exposure -vitamin deficiency –viral infection -congenital disease

15 Refractory Anemia Epidemiology: Epidemiology: 5-10% of MDS cases. 5-10% of MDS cases. Older patients Older patients Morphology: Morphology: Anisopoikilocytosis on peripheral smears Anisopoikilocytosis on peripheral smears Dyserythropoiesis with nuclear abnormalities (megaloblastoid change) Dyserythropoiesis with nuclear abnormalities (megaloblastoid change) < 15% ringed sideroblasts < 15% ringed sideroblasts

16 Refractory Anemia Genetics: Genetics: 25% may have genetic abnormalities 25% may have genetic abnormalities Prognosis: Prognosis: Median survival is 66 months Median survival is 66 months 6% rate of progression to acute leukemia 6% rate of progression to acute leukemia

17 Peripheral Smear - Anisopoikilocytosis

18 Dyserythropoeisis on Bone Marrow Aspirate

19 Megaloblastoid Change on Bone Marrow Aspirate

20 Refractory Anemia with Ringed Sideroblasts RARS definition: RARS definition: Dyplasia of the erythroid series only. Dyplasia of the erythroid series only. Clinically, anemia is refractory to hematinic therapy Clinically, anemia is refractory to hematinic therapy Myeloblasts < 5% in marrow, absent in blood Myeloblasts < 5% in marrow, absent in blood >15% ringed sideroblasts in marrow >15% ringed sideroblasts in marrow No Auer rods No Auer rods Other etiologies of ringed sideroblasts must be excluded. These include: Other etiologies of ringed sideroblasts must be excluded. These include: –Anti- tuberculosis drugs –Alcoholism

21 Refractory Anemia with Ringed Sideroblasts Epidemiology: Epidemiology: 10-12% of MDS cases % of MDS cases. Older patients Older patients Males > females Males > females Morphology: Morphology: Dimorphic pattern on peripheral smears Dimorphic pattern on peripheral smears –Majority RBC’s normochromic, 2 nd population hypochromic Dyserythropoiesis with nuclear abnormalities (megaloblastoid change) Dyserythropoiesis with nuclear abnormalities (megaloblastoid change)

22 Refractory Anemia with Ringed Sideroblasts Morphology (con’t.) Morphology (con’t.) < 15% ringed sideroblasts (RS) < 15% ringed sideroblasts (RS) –RS = Erythroid precursor with ≥ 10 siderotic granules encircling 1/3 or more of the nucleus. –If excess blasts present, this dictates diagnosis, despite percentage of RS’s.

23 Refractory Anemia with Ringed Sideroblasts Genetics: Genetics: Clonal chromosomal abnormalities in Clonal chromosomal abnormalities in <10%; in fact, development of such an abnormality should prompt reassessment of diagnosis. <10%; in fact, development of such an abnormality should prompt reassessment of diagnosis. Prognosis: Prognosis: Median survival 6 years (72 months) Median survival 6 years (72 months) 1-2% rate of progression to acute leukemia 1-2% rate of progression to acute leukemia

24 Dimorphic Red Cell Population

25 Ringed Sideroblasts

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27 Megaloblastoid Change

28 Refractory Cytopenia with Multilineage Dysplasia RCMD definition: RCMD definition: Dyplasia in 10% or more of cells in 2 or more myeloid lines. Dyplasia in 10% or more of cells in 2 or more myeloid lines. Myeloblasts < 1% blasts in the blood and < 5% in marrow. Myeloblasts < 1% blasts in the blood and < 5% in marrow. No Auer rods No Auer rods < 1 x 10 9 /L monocytes in blood < 1 x 10 9 /L monocytes in blood

29 Refractory Cytopenia with Multilineage Dysplasia Epidemiology: Epidemiology: 24% of MDS cases. 24% of MDS cases. Older patients Older patients Morphology: Morphology: Neutrophil abnormalities may include: Neutrophil abnormalities may include: –Hypogranulation –Pseudo-Pelger-huet (hyposegmentation/barbells) Megkaryocyte abnormalities may include Megkaryocyte abnormalities may include –Hypolobation -Micromegakaryocytes

30 Refractory Cytopenia with Multilineage Dysplasia Morphology (con’t.) Morphology (con’t.) Erythroid abnormalities may include nuclear abnormalities such as: Erythroid abnormalities may include nuclear abnormalities such as: –megaloblastoid change -multilobation –multinucleation –In addition:  Erythroid presursors may be PAS positive  If >15% of erythroid precursors are ringed sideroblasts, call = RCMD-RS

31 Refractory Cytopenia with Multilineage Dysplasia Genetics: Genetics: Clonal chromosomal abnormalities found in up to 50% of RCMD and RCMD-RS cases. The abnormalities include: Clonal chromosomal abnormalities found in up to 50% of RCMD and RCMD-RS cases. The abnormalities include: –Trisomy 8 -del(7q) -del(5q) –Monosomy 7 -Monosomy 5 -del(20q) –Complex karyotypes Prognosis: Prognosis: Median survival 33 months Median survival 33 months 11% rate of progression to acute leukemia 11% rate of progression to acute leukemia RCMD and RCMD-RS = similar survival RCMD and RCMD-RS = similar survival Complex karyotypes = worse survival (10-18 months) Complex karyotypes = worse survival (10-18 months)

32 Pelgeroid (pseudo Pelger-Huet) Neutrophil

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34 Dyserythropoiesis on Bone Marrow Aspirate

35 Hypersegmented Neutrophil

36 Micromegakaryocyte

37 Refractory Anemia with Excess Blasts RAEB definition: RAEB definition: Refractory anemia with 5-19% myeloblasts in the bone marrow. Refractory anemia with 5-19% myeloblasts in the bone marrow. –RAEB-1:  5-9% blasts in bone marrow and <5% blasts in blood. –RAEB-2:  10-19% blasts in the bone marrow  Auer rods present

38 Refractory Anemia with Excess Blasts Epidemiology: 40% of MDS cases. Epidemiology: 40% of MDS cases. Older patients (over 50 years) Older patients (over 50 years) Morphology: Morphology: Dysplasia of all three cell lines often present Dysplasia of all three cell lines often present Neutrophil abnormalities may include: Neutrophil abnormalities may include: –Hypogranulation -hypersegmentation –Pseudo-Pelger-huet (hyposegmentation/barbells) –Pseudo Chediak-Higashi granules Megkaryocyte abnormalities may include Megkaryocyte abnormalities may include –Hypolobation -Micromegakaryocytes

39 Refractory Anemia with Excess Blasts Morphology (con’t.) Morphology (con’t.) Erythroid precursor abnormalities may include: Erythroid precursor abnormalities may include: –Abnormal lobulation -megaloblastoid change –Multinucleation 0-19% myeloblasts in the blood 0-19% myeloblasts in the blood 5-19% in the marrow 5-19% in the marrow Bone marrow: Bone marrow: –Usually hypercellular (10-15% hypocellular) –Abnormal localization of immature precursors (ALIP) may be present Immunophenotype: Immunophenotype: –Blasts express CD 13, CD33 or CD117 –The only MDS with a relevant phenotype

40 Refractory Anemia with Excess Blasts Genetics: Genetics: Clonal chromosomal abnormalities found in 30% - 50% of RAEB cases. The abnormalities include: Clonal chromosomal abnormalities found in 30% - 50% of RAEB cases. The abnormalities include: –+8 – -5 – del(5q) – -7 – del(7q) – Complex karyotypes Prognosis: Prognosis: Median survival, RAEB-1 = 18 months Median survival, RAEB-1 = 18 months Median survival, RAEB-2 = 10 months Median survival, RAEB-2 = 10 months RAEB-1 = 25% rate of progression to acute leukemia RAEB-1 = 25% rate of progression to acute leukemia RAEB-2 = 33% rate of progression to acute leukemia RAEB-2 = 33% rate of progression to acute leukemia

41 Hypercellular Bone Marrow

42 Blasts and Hypogranulation

43 Myeloblast with Auer Rod

44 Chediak-Higashi-like Granules Photograph courtesy of John Scariano, University of New Mexico, Dept. of Pathology Photograph courtesy of John Scariano, University of New Mexico, Dept. of Pathology

45 Myelodysplastic Syndrome, Unclassifiable MDS-U definition: MDS-U definition: Dysplasia of the neutrophil and/or megkaryocytic lines and no increased blasts Dysplasia of the neutrophil and/or megkaryocytic lines and no increased blasts Not otherwise classifiable as RA, RARS, RCMD and RAEB Not otherwise classifiable as RA, RARS, RCMD and RAEB

46 Myelodysplastic Syndrome, Unclassifiable Epidemiology: Epidemiology: Incidence unknown Incidence unknown Older or younger persons Older or younger persons Associated with a history of exposure to cytotoxic or radiation therapy Associated with a history of exposure to cytotoxic or radiation therapy Morphology: Morphology: BmBx usually hypercellular BmBx usually hypercellular Dyplastic megakaryocytes may be prominent Dyplastic megakaryocytes may be prominent

47 Myelodysplastic Syndrome, Unclassifiable Genetics: Genetics: May be normal, or clonal abnormalities the same as those found in other MDS syndromes. May be normal, or clonal abnormalities the same as those found in other MDS syndromes. Prognosis: Prognosis: Unknown Unknown Occasionally defining characteristics develop. Then case should be reclassified. Occasionally defining characteristics develop. Then case should be reclassified.

48 Myelodysplastic Syndrome Associated With Isolated del(5q) Chromosome Abnormality ( 5q- Syndrome) 5q- syndrome definition: 5q- syndrome definition: MDS with an isolated del(5q) MDS with an isolated del(5q) <5% blasts in blood and bone marrow <5% blasts in blood and bone marrow Epidemiology: Epidemiology: Middle age to older women Middle age to older women Clinical Presentation: Clinical Presentation: Refractory anemia, often severe Refractory anemia, often severe Thrombocytosis may be present. Thrombocytosis may be present.

49 Myelodysplastic Syndrome Associated with Isolated del(5q) Chromosome Abnormality ( 5q- Syndrome) Morphology: Morphology: –Peripheral Smear:  Marked macrocytic anemia.  Slight leukopenia  Normal to elevated platelets –BmBx:  Erythroid dysplasia, varying degrees  Small, hypolobated megakaryocytes  Scattered aggregates of small lymphocytes

50 Myelodysplastic Syndrome Associated with Isolated del(5q) Chromosome Abnormality ( 5q- Syndrome) Genetics: Genetics: Deletion between bands q31 and q 33 on chromosome 5. Deletion between bands q31 and q 33 on chromosome 5. Size of deletion and breakpoints are variable. Size of deletion and breakpoints are variable. Any additional cytogenetic abnormality excludes placement in this category. Any additional cytogenetic abnormality excludes placement in this category. Prognosis: Prognosis: Good = long survival Good = long survival Those who develop more than 5% blasts may have shorter survival Those who develop more than 5% blasts may have shorter survival

51 Hypolobated megakaryocytes

52 Myelodysplastic/myeloproliferative diseases WHO category consists of 4 entities WHO category consists of 4 entities –Chronic myelomonocytic leukemia (CMML)  Formerly an MDS –Atypical chronic myeloid leukemia (aCML)  CML without BCR/ABL fusion gene –Juvenile myelomonocytic leukemia (JMML) –MDS/MPD-unclassified

53 CMML Diagnostic Criteria

54 MDS/MPD

55 High vs. low intensity treatment High intensity = treatment requiring hospitalization, and included intensive combination chemotherapy and hematopoietic cell transplantation. Low intensity = outpatient-type treatments, such as use of hematopoietic growth factors, differentiation-inducing agents, biologic response modifiers, and low intensity chemotherapy. High intensity = treatment requiring hospitalization, and included intensive combination chemotherapy and hematopoietic cell transplantation. Low intensity = outpatient-type treatments, such as use of hematopoietic growth factors, differentiation-inducing agents, biologic response modifiers, and low intensity chemotherapy.

56 MDS Treatment Patients 60 years of age with good performance status and who are in the IPSS intermediate-2 or high risk categories (expected survival 0.5 to 1.1 years) = low intensity therapy, although selected patients could be candidates for high intensity therapies. Patients >60 years of age with good performance status and who are in the low or intermediate-1 category (expected survival 3 to 5 years) = supportive care or low intensity therapy Patients 60 years of age with good performance status and who are in the IPSS intermediate-2 or high risk categories (expected survival 0.5 to 1.1 years) = low intensity therapy, although selected patients could be candidates for high intensity therapies. Patients >60 years of age with good performance status and who are in the low or intermediate-1 category (expected survival 3 to 5 years) = supportive care or low intensity therapy

57 Stem Cell Transplant HEMATOPOIETIC CELL TRANSPLANTATION Allogeneic HCT should be considered for patients with MDS who are under the age of 60 and who have an HLA-matched sibling donor. HEMATOPOIETIC CELL TRANSPLANTATION Allogeneic HCT should be considered for patients with MDS who are under the age of 60 and who have an HLA-matched sibling donor. 60 and 40% chance of cure after allo-HCT in low and intermediate risk patients respectively 60 and 40% chance of cure after allo-HCT in low and intermediate risk patients respectively Transplant-related mortality and the relapse rate at five years are as high as 40 percent. Transplant-related mortality and the relapse rate at five years are as high as 40 percent.

58 Azacitidine Azacitadine (Vidaza) the first approved treatment of MDS Azacitadine (Vidaza) the first approved treatment of MDS Azacitidine is a member of a class of drugs in development known as "hypomethylating" or "demethylating" agents.. Azacitidine is a member of a class of drugs in development known as "hypomethylating" or "demethylating" agents.. About 15% of patients in the three trials had complete or partial responses to Vidaza. (complete or partial normalization of blood in the bone marrow and normal levels of blood cells and need for blood transfusions was eliminated) About 15% of patients in the three trials had complete or partial responses to Vidaza. (complete or partial normalization of blood in the bone marrow and normal levels of blood cells and need for blood transfusions was eliminated) Side effects = nausea, anemia, low platelets in blood, diarrhea, fatigue, irritation at the injection site, and constipation. Side effects = nausea, anemia, low platelets in blood, diarrhea, fatigue, irritation at the injection site, and constipation.

59 Revlimid Thalidomide derivative (revlimid) — Revlimid is a thalidomide derivative without the neurologic toxicity of the parent compound. Used in MM and promising in MDS. Thalidomide derivative (revlimid) — Revlimid is a thalidomide derivative without the neurologic toxicity of the parent compound. Used in MM and promising in MDS. Restoration of a normal karyotype was noted in 11 of 17 informative patients. Restoration of a normal karyotype was noted in 11 of 17 informative patients. Erythroid response was highest in patients with Low/Int- 1 IPSS scores (71 percent) and in those with the 5q- syndrome (91 percent). Erythroid response was highest in patients with Low/Int- 1 IPSS scores (71 percent) and in those with the 5q- syndrome (91 percent). Dose-dependent myelosuppression was the most common adverse event. Dose-dependent myelosuppression was the most common adverse event. The results of multicenter phase II trials of this agent are awaited. The results of multicenter phase II trials of this agent are awaited.

60 Decitabine Decitabine — Another pyrimidine nucleoside similar to 5-aza is 5-aza-2'-deoxycytidine (DAC, decitabine). Both agents strongly inhibit DNA methylation and are capable of inducing cell differentiation [86-88]. Decitabine — Another pyrimidine nucleoside similar to 5-aza is 5-aza-2'-deoxycytidine (DAC, decitabine). Both agents strongly inhibit DNA methylation and are capable of inducing cell differentiation [86-88] % resopnse rate 25-61% resopnse rate Major cytogenetic responses were noted in 31 percent of those with abnormal pretreatment cytogenetics and were associated with a reduced risk of death Major cytogenetic responses were noted in 31 percent of those with abnormal pretreatment cytogenetics and were associated with a reduced risk of death High toxicity = fever, infection, sepsis, neutropenia, anemia, and thrombocytopenia High toxicity = fever, infection, sepsis, neutropenia, anemia, and thrombocytopenia

61 Hypocellular MDS Treatment Immunosuppressive drugs — Patients with hypocellular MDS are believed to have immune-mediated hematopoietic suppression, perhaps due to the presence of an abnormal T cell response Immunosuppressive drugs — Patients with hypocellular MDS are believed to have immune-mediated hematopoietic suppression, perhaps due to the presence of an abnormal T cell response Some of these patients have responded to immunosuppressive therapies such as antithymocyte globulin (ATG) Some of these patients have responded to immunosuppressive therapies such as antithymocyte globulin (ATG)

62 Future Therapies Valproic acid (VPA) has been shown to inhibit histone deacetylase activity and to synergize with all-trans retinoic acid (ATRA) in the differentiation induction of acute myelogenous leukemia (AML) blasts in vitro. Valproic acid (VPA) has been shown to inhibit histone deacetylase activity and to synergize with all-trans retinoic acid (ATRA) in the differentiation induction of acute myelogenous leukemia (AML) blasts in vitro. Recent studies have found that VPA is of therapeutic benefit for patients with MDS, and ATRA may be effective when added later. Recent studies have found that VPA is of therapeutic benefit for patients with MDS, and ATRA may be effective when added later.

63 References 1.)Brunning, RD, Bennett, JM, Flandrin, G, et al. Myelodysplastic syndromes: Introduction. In Jaffe, ES, Harris, NL, Stein, H, Vardiman, JW, editors. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon )Brunning, RD, Bennett, JM, Flandrin, G, et al. Myelodysplastic syndromes: Introduction. In Jaffe, ES, Harris, NL, Stein, H, Vardiman, JW, editors. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon )Wells, DA, Benesch, M, Loken, MR, et al. Myeloid and monocytic dyspoiesis as determined by flow cytometric scoring in myelodysplastic syndrome correlates with the IPSS and with outcome after hematopoietic stem cell transplantation. Blood 2003; 102: )Wells, DA, Benesch, M, Loken, MR, et al. Myeloid and monocytic dyspoiesis as determined by flow cytometric scoring in myelodysplastic syndrome correlates with the IPSS and with outcome after hematopoietic stem cell transplantation. Blood 2003; 102:394.

64 References 3.)Seo, IS, Li, CY, Yam, LT. Myelodysplastic syndrome: Diagnostic implications of cytochemical and immunocytochemical studies. Mayo Clin Proc 1993; 68:47. 3.)Seo, IS, Li, CY, Yam, LT. Myelodysplastic syndrome: Diagnostic implications of cytochemical and immunocytochemical studies. Mayo Clin Proc 1993; 68:47. 4.)So, CC, Wong, KF. Valproate-associated dysmyelopoiesis in elderly patients. Am J Clin Pathol 2002; 118: )So, CC, Wong, KF. Valproate-associated dysmyelopoiesis in elderly patients. Am J Clin Pathol 2002; 118: )Ooi, J, Iseki, T, Takahashi, S, et al. Unrelated cord blood transplantation for adult patients with advanced myelodysplastic syndrome. Blood 2003; 101: )Ooi, J, Iseki, T, Takahashi, S, et al. Unrelated cord blood transplantation for adult patients with advanced myelodysplastic syndrome. Blood 2003; 101: ) Albitar, M, Manshouri, T, Shen, Y, et al. Myelodysplastic syndrome is not merely "preleukemia". Blood 2002; 100: ) Albitar, M, Manshouri, T, Shen, Y, et al. Myelodysplastic syndrome is not merely "preleukemia". Blood 2002; 100:791.

65 References 7.)Passmore, SJ, Chessells, JM, Kempski, H, et al. Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia in the UK: a population- based study of incidence and survival. Br J Haematol 2003; 121:758 7.)Passmore, SJ, Chessells, JM, Kempski, H, et al. Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia in the UK: a population- based study of incidence and survival. Br J Haematol 2003; 121:758 8.)Cheson, BD, Zwiebel, JA, Dancey, J, Murgo, A. Novel therapeutic agents for the treatment of myelodysplastic syndromes. Semin Oncol 2000; 27: )Cheson, BD, Zwiebel, JA, Dancey, J, Murgo, A. Novel therapeutic agents for the treatment of myelodysplastic syndromes. Semin Oncol 2000; 27: )Estey E, Schrier S. Treatment and prognosis of mds )Estey E, Schrier S. Treatment and prognosis of mds )Coll DC, Landaw, SA Clnical manifestations and diagnosis of the myelodysplastic syndromes. Blood. 2004, 1;104(5): )Coll DC, Landaw, SA Clnical manifestations and diagnosis of the myelodysplastic syndromes. Blood. 2004, 1;104(5):

66 Acknowledgments Dr. John Ryder Dr. John Ryder Dr. Bryan Abbott Dr. Bryan Abbott


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