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

History of MDS First described in 1938 - 100 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"

History of MDS 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". These disorders, and other members of the MDS "family“ were subsequently defined by the WHO.

The Myelodyplastic Syndromes 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: Myelodysplastic/Myeloproliferative diseases

Myelodysplastic Syndromes 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. Epidemiology: Occur primarily in older patients (most common > 70 years).

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

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

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

Median Survival – Myelodysplastic Syndromes

Prognostic Scoring 0.5 1.0 1.5 2.0 <5 5-10 -- 11-20 20-30 0-1 2-3 The International Myelodysplastic Syndrome Working Group developed a scoring system based on 3 variables: 0.5 1.0 1.5 2.0 % Blasts <5 5-10 -- 11-20 20-30 Karyotype Normal, -Y, del(5q), del(20q) Abnormal-ities NOS ≥ 3 abnormalities, chr 7 abnormalities Cytopenia 0-1 2-3

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.

IPSS 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     -Mutations of the FLT3 gene  -Abnormal localization of immature precursors (ALIP).

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

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

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

Peripheral Smear - Anisopoikilocytosis

Dyserythropoeisis on Bone Marrow Aspirate

Megaloblastoid Change on Bone Marrow Aspirate

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

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

Refractory Anemia with Ringed Sideroblasts Morphology (con’t.) < 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.

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

Dimorphic Red Cell Population

Ringed Sideroblasts

Ringed Sideroblasts

Megaloblastoid Change

Refractory Cytopenia with Multilineage Dysplasia RCMD definition: Dyplasia in 10% or more of cells in 2 or more myeloid lines. Myeloblasts < 1% blasts in the blood and < 5% in marrow. No Auer rods < 1 x 109/L monocytes in blood

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

Refractory Cytopenia with Multilineage Dysplasia Morphology (con’t.) 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

Refractory Cytopenia with Multilineage Dysplasia Genetics: 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: Median survival 33 months 11% rate of progression to acute leukemia RCMD and RCMD-RS = similar survival Complex karyotypes = worse survival (10-18 months)

Pelgeroid (pseudo Pelger-Huet) Neutrophil

Pelgeroid (pseudo Pelger-Huet) Neutrophil

Dyserythropoiesis on Bone Marrow Aspirate

Hypersegmented Neutrophil

Micromegakaryocyte

Refractory Anemia with Excess Blasts RAEB definition: 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

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

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

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

Hypercellular Bone Marrow

Blasts and Hypogranulation

Myeloblast with Auer Rod

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

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

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

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

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

Myelodysplastic Syndrome Associated with Isolated del(5q) Chromosome Abnormality ( 5q- Syndrome) 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

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

Hypolobated megakaryocytes

Myelodysplastic/myeloproliferative diseases 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

CMML Diagnostic Criteria

MDS/MPD

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.

MDS Treatment     Patients < 60 years of age, who have good or excellent performance status and who are in the IPSS intermediate-2 or high risk categories (expected survival 0.3 to 1.8 years) = high intensity therapies.     Patients < 60 years of age, who have good or excellent performance status and who are in the low or intermediate-1 category (expected survival 5 to 12 years) = low intensity therapy or supportive care.     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     

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. 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.

Azacitidine 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.. 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.

Revlimid 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. 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. The results of multicenter phase II trials of this agent are awaited.

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]. 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 High toxicity = fever, infection, sepsis, neutropenia, anemia, and thrombocytopenia

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 Some of these patients have responded to immunosuppressive therapies such as antithymocyte globulin (ATG)

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. Recent studies have found that VPA is of therapeutic benefit for patients with MDS, and ATRA may be effective when added later.

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 2001. 2.)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.

References 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; 118:225. 5.)Ooi, J, Iseki, T, Takahashi, S, et al. Unrelated cord blood transplantation for adult patients with advanced myelodysplastic syndrome. Blood 2003; 101:4711. 6.) Albitar, M, Manshouri, T, Shen, Y, et al. Myelodysplastic syndrome is not merely "preleukemia". Blood 2002; 100:791.

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 8.)Cheson, BD, Zwiebel, JA, Dancey, J, Murgo, A. Novel therapeutic agents for the treatment of myelodysplastic syndromes. Semin Oncol 2000; 27:560. 9.)Estey E, Schrier S. Treatment and prognosis of mds www.uptodate.com, 2005. 10.)Coll DC, Landaw, SA Clnical manifestations and diagnosis of the myelodysplastic syndromes. Blood. 2004, 1;104(5):1266-9.

Acknowledgments Dr. John Ryder Dr. Bryan Abbott