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Myelodysplastic Syndromes Between FAB and WHO

Myelodysplastic Syndromes Between FAB and WHO. Mona F. Melhem, MD Professor, Department of Pathology University of Pittsburgh School of Medicine Chief Hematology VA Medical Center of Pittsburgh Pittsburgh, Pennsylvania. Myelodysplastic Syndromes (MDS).

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Myelodysplastic Syndromes Between FAB and WHO

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  1. Myelodysplastic SyndromesBetween FAB and WHO • Mona F. Melhem, MD Professor, Department of Pathology University of Pittsburgh School of Medicine Chief Hematology VA Medical Center of Pittsburgh Pittsburgh, Pennsylvania

  2. Myelodysplastic Syndromes (MDS) • Clonal hematopoietic Stem Cell Disease • Dysplasia • Ineffective Hematopoiesis (1 or more lines) • Myeloblasts < 20% of all marrow cells • Synonyms: • Dysmyelopoietic syndromes • Preleukemic syndromes • Oligoblastic leukemia

  3. MDS: Epidemiology • Older adults (median age: 70 years) • Primary vs. Secondary MDS (S/P chemotherapy) • Incidence: 3/100,000 non-age corrected 20/100,000 over age 70

  4. MDS: Clinical • Symptoms of Cytopenia • Anemia > Neutropenia +/- Thrombocytopenia • Organomegaly (infrequent)

  5. MDS: Etiology • Primary • No known history of toxic exposure • Possible etiologies: Virus, Benzene, cigarette (2 fold risk), Fanconi anemia. • Therapy-related • Chemotherapy (alkylating agents) • Radiation Therapy

  6. MDS: Morphology • % blasts in marrow and blood • Type and degree of dysplasia • +/- ringed sideroblasts • Cytogenetic abnormalities del (5q) • 500 cell diff in marrow • 200 cell diff in PB

  7. MDS: Differential Diagnosis • B12/folate deficiency • Heavy metals (Arsenic) • Congenital dyserythropoietic anemia • Parvovirus B19 • GCSF therapy (increased blasts)

  8. FAB Classification RA RARS RAEB RAEB-T CMML WHO classification Myelodysplastic Syndromes RA RARS RCMD & RCMD-RS RAEB-1 & RAEB-2 MDS Unclassified MDS del(5q) Myelodysplastic/Myeloproliferative Diseases CMML Atypical CML Juvenile CMML MDS/MPD, unclassified Myelodysplastic Syndromes

  9. MDS: Genetics • 5q- syndrome (women, megakaryocyte anomalies • Del 17p (pseudo Pelger-Huet anomaly, therapy related) • Complex cytogenetic (chromosomes 5 & 7) unfavorable prognosis • Del(20q) (erythroid and megakaryocytes) • Abnormal Ch 3 (abnormal megas)

  10. MDS: Prognosis • Low Risk group: • RA and RARS • Normal cytogenetics, del(5q), del(20q) and -Y • High Risk • RAEB and RCMD • Complex abnormalities • Abnormal Ch 7

  11. MDS: Score predicts survival • Low = 0 • INT-1 = 0.5-1.0 • INT-2 = 1.5-2.0 • High >= 2.5

  12. WHO classification Myelodysplastic Syndromes RA RARS RCMD & RCMD-RS RAEB-1 & RAEB-2 MDS Unclassified MDS del(5q) Myelodysplastic/Myeloproliferative Diseases CMML Atypical CML Juvenile CMML MDS/MPD, unclassified Myelodysplastic Syndromes

  13. Myelodysplastic Syndromes • Refractory Anemia • Blood: Anemia, no or rare blasts • BM: Erythroid Dysplasia only < 5% blasts < 15% ringed sideroblasts

  14. Refractory Anemia (RA) • Unilineage Dysplasia (Erythroid) • Anemia refractory to therapy • Unequivocal dyserythropoiesis • Exclude all other possibilities i.e: • Drugs, toxins, virus, immunologic, congenital and vitamin deficiencies

  15. Refractory Anemia (RA) • Observe for 6 months and re-evaluate • Myeloblasts: <1% PB and <5% BM • DD: Other MDS with multilineage dysplasia or Ringed Sideroblasts

  16. Refractory Anemia (RA) • PB: Normochromic, Normocytic RBCs • Anisocytosis • Poikilocytosis • Blasts <1% • Normal neutrophils and platelets

  17. Refractory Anemia (RA) • BM: Hypercellular, normocellular or hypocellular • Dyserythropoiesis • Nuclear budding, internuclear bridging, karyorrhexis, multinuclearity, megaloblastoid features • Cytoplasmic vacuolization, PAS positivity • Ringed Sideroblasts <15% erythroid precursors • Myeloblasts < 5% all marrow cells • Aur rods absent

  18. Refractory Anemia (RA) • Genetics (useful, not specific) • 25% of cases • Del (20q), +8, abnormal 5 and/or 7

  19. Refractory Anemia (RA) • Prognosis: • 66 months survival • 6% progress to leukemia

  20. Refractory Anemia with Ringed Sideroblasts (RARS) • 15% erythroid precursors are ringed sideroblasts • 1/3 or more of the nucleus encircled by sideroblastic granules (Fe stain) • Myeloblasts <5% • R/O other causes of sideroblasts (anti-TB drugs, alcohol…)

  21. Refractory Anemia with Ringed Sideroblasts (RARS) • 10-12% of MDS cases • Older patients • Males > females • Moderate anemia (Normo or Macro) • Dysplasia restricted to erythroid lineage • Genetic abnormalities in <10% of cases • 1-2% evolve to AML • Median survival: 6 years

  22. Refractory Cytopenia with Multilineage Dysplasia (RCMD) • Bi-cytopenia or pancytopenia • Dysplasia 10% of cells, 2 or more lineages • <1% blasts (PB) • <5% blasts (BM) • Absent Aur Rods • Monocytes < 1x109/L

  23. Refractory Cytopenia with Multilineage Dysplasia (RCMD) • RCMD 24% cases of MDS • RCMD-RS 15% cases of MDS • Older patients • BM failure, cytopenia 2 or more myeloid lineage • Dysplasia >10% of marrow cells • Trisomy 8, monosomy 7, del(7q), monosomy 5, del (5q), del (20q) • 11% progress to AML, Mean survival 33 mo

  24. Refractory Anemia with Excess blasts (RAEB) • 5-19% myeloblasts in BM • RAEB-1 5-9% blasts (BM) <5% blasts (PB) • RAEB-2 10-19% blasts (BM) or 5-19% blasts (PB) & <10% blasts (BM) or Presence of Aur Rods

  25. Refractory Anemia with Excess Blasts (RAEB) • 40% of all patients with MDS • 50 yrs and older • Anemia, thrombocytopenia or neutropenia • Abnormalities in all three lines (PB) • Anisopoikilocytosis • Atypical plts • Pseudo Pelger Huet anomaly • Blasts (0-19%)

  26. Refractory Anemia with Excess Blasts (RAEB) • BM: Mostly Hypercellular + ALIPs • Neutrophil Hyperplasia with dysplasia • Small, nuclear hypolobation, hypersegmentation, hypogranularity • Erythroid dyserythropoiesis • Megakaryocytes hypolobated, micromegas, widely separated nucleii

  27. Refractory Anemia with Excess Blasts (RAEB) • 30%-50% clonal cytogenetic abnormalities • +8, -5, del(5q), -7, del(7q) and del(20q) • Immunophemotype: • Blasts express CD13, CD33, CD117 • 25% RAEB-1 and 33% RAEB-2 progress to AML • Median survival: 18 mo (RAEB-1), 10 mo (RAEB-2)

  28. MDS, unclassified • No specific morphologic findings • Neutropenia and thrombocytopenia • Dysplasia restricted to myeloid or megas • Hyper/normo or hypocellular marrow • No specific cytogenetic findings • Older or younger patients, even children • No increase in blasts

  29. 5q- syndrome • Myelodysplastic syndrome associated with isolated del (5q) chromosome • < 5% Blasts in marrow and blood • Predominantly middle-aged to older women • Severe Refractory Anemia (Macrocytic) • Hypercellular marrow with abnormal megas

  30. FAB Classification RA RARS RAEB RAEB-T CMML WHO classification Myelodysplastic Syndromes RA RARS RCMD & RCMD-RS RAEB-1 & RAEB-2 MDS Unclassified MDS del(5q) Myelodysplastic/Myeloproliferative Diseases CMML Atypical CML Juvenile CMML MDS/MPD, unclassified Myelodysplastic Syndromes

  31. Myelodysplastic/Myeloproliferative Diseases (MDS/MPD) • Chronic Myelomonocytic Leukemia (CMML) • Atypical Chronic Myeloid Leukemia (CML) • Juvenile CMML • MDS/MPD, unclassified

  32. Myelodysplastic/Myeloproliferative Diseases (MDS/MPD) • Clonal hematopoietic neoplasms • Clinical/lab/morph supporting MDS • + finding c/w Chronic myeloproliferative diseases, No Ph’chromosome • Hypercellular marrow, spleno & hepatomegaly • Dysplasia • Blasts <20%

  33. Myelodysplastic/Myeloproliferative Diseases (MDS/MPD) • t(5;12) (q31:p12) and t(5;10)(q33;q22), enhances the tyrosine kinase of PDGF-R, leading to abnormal RAS activation. • JMML associated with neurofibromatosis type-1 (NF-1) • Survival ranges from months to years • Complications of cytopenias, leukemia

  34. Chronic Myelomonocytic Leukemia (CMML) • Clonal disorder of marrow stem cell • Persistent Monocytosis >1x109/L (PB), 3mo • (-) Philadelphia and BCR/ABL fusion gene • <20% blasts (PB & BM), including myeloblasts, monoblasts and promonocytes • +/- Dysplasia in 1 or more BM lineages.

  35. Chronic Myelomonocytic Leukemia (CMML) • Differntial diagnosis • Tumors (leukemoid reaction) • Infection • Inflammation • CML • Other myeloproliferative disorders

  36. Chronic Myelomonocytic Leukemia (CMML) • 31% of cases of MDS • Median age at Dx: 65-75 yrs • Male predominance 1.5-3.1:1 • Blood & BM involvement +/- spleen, liver, skin, LN extramedullary leukemic infiltrate

  37. Chronic Myelomonocytic Leukemia (CMML) • WBC normal (50% of cases), or increased • Monocytosis with neutropenia • Fatigue, wt loss, fever, night sweat, infection, bleeding • Hepatomegaly & splenomegaly if WBC hi • Unknown etiology (carcinogens, radiation, cytotoxic agents….)

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