HS 4160 Critical Scientific Analysis Week 3: Efficacy of erythropoietin in the myelodysplastic syndromes: a meta-analysis of 205 patients from 17 studies HS 4160 Critical Scientific Analysis

Objectives Learn how to quickly locate background information for a given topic. Outline structure of a systematic review and meta-analysis paper. Determine elements of an Introduction section. Define elements of a Discussion section Critically extract information from tables. Discuss strength and weakness of a meta-analysis paper.

Hematopoiesis Pools Stem cell and bone marrow pool overlap. Not all cells in the peripheral blood are actively functioning. So you have granulocytes and thrombocytes can be resting or in storage.

Cytokines and Interleukins GM-CSF Stimulates proliferation of granulocyte and macrophages/monocytes G-CSF Stimulates proliferation of neutrophil and enhances function M-CSF Stimulates proliferation of monocytes/ macrophages Interleukin Stimulates proliferation and differentiation of specific cell lines and work together with CSFs Erythropoietin Erythropoietic stimulating factor produced in the kidney Thrombopoietin Hormonal factor that controls production and release of platelets

MDS Myelodysplastic Syndromes Myeloid Disease MDS Myelodysplastic Syndromes

MDS Failure of differentiation Hypercellular marrows. Peripheral cytopenias. Displastic blood cells. Preleukemia – 1/3 to AML.

MDS is caused by Poor hematopoietic maturation Poor hematopoietic differentiation Over production of G-CSF None of the above

Clinical Overlap/Associations

MDS is a form of blood cancer True False

FAB vs. WHO FAB Classification WHO 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

WHO Classification MDS RA Refr. cytopenia w. multlineage dysplasia with ringed sideroblasts without ringed sideroblasts Refr. cytopenia w. multlineage dysplasia Refr. Anemia with excess blasts 5q- syndrome MDS, unclassifiable

Lab Tests

Which of the following is a main clinical feature of MDS? >30% blast cells in BM Respond well to epo Refractory anemia Reduced risk to AML

Ringed Sideroblast

Vitamin A Magnesium Iron Folic acid Blue granules seen in ringed sideroblast indicate the cell could not use___ Vitamin A Magnesium Iron Folic acid

Chromosome Changes in MDS

Chromosome Changes in MDS

Chromosome abnormality most frequently seen in MDS del(3) del(5) add(10) None of the above

5q Deletion Syndrome Deletion span 5q13-5q33. Most frequent in 5q31. Genes related to hematopoiesis.

Cytogenetic Predictors In one study, patients with 5q- had the best cumulative median survival (115 months). Patients with 20q- and –Y had a favorable course. Abnormalities of chromosome 7, 8 and complex aberrations had a poor outcome (less than 10 months). AML evolution was most frequent in patients with complex abnormalities (50%)and with trisomy 8 (33%).

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)

Molecular Abnormalities in MDS Gene Type of anomaly Incidence (%) RAS (N or K) Point mutation (codon 12, 13 or 61) 10-30% P53 Point mutation or deletion of other allele 5 FMS (encodes M-CSF receptor) (codon 969 or rarely 301) 5-10

Chromosome abnormality seen in MDS with most favorable outcome? inv(3) del(5q) +8 t(1;3)

IPSS Definition International Prognostic Scoring System

IPSS Scoring System & Risk:

Overall IPSS score and survival Overall score: Median survival: Low 0 5.7 years Intermediate 1 (0.5 or 1) 3.5 years 2 (1.5 or 2) 1.2 years High > 2.5 0.4 years

Lower IPSS score means Good survival Medium survival Poor survival None of the above