Presentation on theme: "Myelodysplastic Syndromes"— Presentation transcript:
1 Myelodysplastic Syndromes Nicole N. Balmer M.D.June 3rd, 2005
2 History of MDSFirst 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"
3 History of MDSIn 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.
5 The Myelodyplastic Syndromes Six types of myelodysplastic syndromes according to WHO.Refractory anemiaRefractory anemia with ringed sideroblastsRefractory cytopenia with multilineage dysplasiaRefractory anemia with excess blastsMyelodysplastic syndrome, unclassifiable5q- syndrome (myelodysplastic syndrome associated with isolated del (5q) chromosome abnormalityRelated syndromes:Myelodysplastic/Myeloproliferative diseases
6 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).
8 MDS Etiology Two etiologic categories of MDS: 1.) De Novo:Associated with:-benzene exposure (gasoline)-cigarettesmoking-viruses Fanconi’s anemia2.) Therapy related:-alkylating agent chemotherapy-radiation
9 Prognostic GroupsTwo groups based on survival and evolution to acute leukemia1.) “Good” groupRefractory anemia (RA)Refractory anemia with ringed sideroblasts (RARS)5q - syndrome2.) “Bad” groupRefractory anemia with excess blasts (RAEB)Refractory cytopenia with multilineage dysplasia (RCMD)MDS unclassified can be either
11 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:0.51.01.52.0% Blasts<55-10--11-2020-30KaryotypeNormal, -Y, del(5q), del(20q)Abnormal-itiesNOS≥ 3 abnormalities, chr 7 abnormalitiesCytopenia0-12-3
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.
13 IPSSOther 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).
14 Refractory Anemia RA Definition: Dyplasia of the erythroid series only.Clinically, anemia is refractory to hematinic therapyMyeloblasts < 1% blood and < 5% marrow<15% ringed sideroblasts in marrowNo Auer rodsOther etiologies of erythroid abnormalities must be excluded. These include:drug/toxin exposure vitamin deficiencyviral infection congenital disease
15 Refractory Anemia Epidemiology: 5-10% of MDS cases. Older patients Morphology:Anisopoikilocytosis on peripheral smearsDyserythropoiesis with nuclear abnormalities (megaloblastoid change)< 15% ringed sideroblasts
16 Refractory Anemia Genetics: 25% may have genetic abnormalities Prognosis:Median survival is 66 months6% rate of progression to acute leukemia
20 Refractory Anemia with Ringed Sideroblasts RARS definition:Dyplasia of the erythroid series only.Clinically, anemia is refractory to hematinic therapyMyeloblasts < 5% in marrow, absent in blood>15% ringed sideroblasts in marrowNo Auer rodsOther etiologies of ringed sideroblasts must be excluded. These include:Anti- tuberculosis drugsAlcoholism
21 Refractory Anemia with Ringed Sideroblasts Epidemiology:10-12% of MDS cases.Older patientsMales > femalesMorphology:Dimorphic pattern on peripheral smearsMajority RBC’s normochromic, 2nd population hypochromicDyserythropoiesis with nuclear abnormalities (megaloblastoid change)
22 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.
23 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
28 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
29 Refractory Cytopenia with Multilineage Dysplasia Epidemiology:24% of MDS cases.Older patientsMorphology:Neutrophil abnormalities may include:HypogranulationPseudo-Pelger-huet (hyposegmentation/barbells)Megkaryocyte abnormalities may includeHypolobation Micromegakaryocytes
30 Refractory Cytopenia with Multilineage Dysplasia Morphology (con’t.)Erythroid abnormalities may include nuclear abnormalities such as:megaloblastoid change -multilobationmultinucleationIn addition:Erythroid presursors may be PAS positiveIf >15% of erythroid precursors are ringed sideroblasts, call = RCMD-RS
31 Refractory Cytopenia with Multilineage Dysplasia Genetics:Clonal chromosomal abnormalities found in up to 50% of RCMD and RCMD-RS cases. The abnormalities include:Trisomy del(7q) del(5q)Monosomy Monosomy del(20q)Complex karyotypesPrognosis:Median survival 33 months11% rate of progression to acute leukemiaRCMD and RCMD-RS = similar survivalComplex karyotypes = worse survival (10-18 months)
37 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 marrowAuer rods present
38 Refractory Anemia with Excess Blasts Epidemiology: 40% of MDS cases.Older patients (over 50 years)Morphology:Dysplasia of all three cell lines often presentNeutrophil abnormalities may include:Hypogranulation hypersegmentationPseudo-Pelger-huet (hyposegmentation/barbells)Pseudo Chediak-Higashi granulesMegkaryocyte abnormalities may includeHypolobation Micromegakaryocytes
39 Refractory Anemia with Excess Blasts Morphology (con’t.)Erythroid precursor abnormalities may include:Abnormal lobulation -megaloblastoid changeMultinucleation0-19% myeloblasts in the blood5-19% in the marrowBone marrow:Usually hypercellular (10-15% hypocellular)Abnormal localization of immature precursors (ALIP) may be presentImmunophenotype:Blasts express CD 13, CD33 or CD117The only MDS with a relevant phenotype
40 Refractory Anemia with Excess Blasts Genetics:Clonal chromosomal abnormalities found in 30% - 50% of RAEB cases. The abnormalities include:– – del(5q)– – del(7q) – Complex karyotypesPrognosis:Median survival, RAEB-1 = 18 monthsMedian survival, RAEB-2 = 10 monthsRAEB-1 = 25% rate of progression to acute leukemiaRAEB-2 = 33% rate of progression to acute leukemia
44 Chediak-Higashi-like Granules Photograph courtesy of John Scariano, University of New Mexico, Dept. of Pathology
45 Myelodysplastic Syndrome, Unclassifiable MDS-U definition:Dysplasia of the neutrophil and/or megkaryocytic lines and no increased blastsNot otherwise classifiable as RA, RARS, RCMD and RAEB
46 Myelodysplastic Syndrome, Unclassifiable Epidemiology:Incidence unknownOlder or younger personsAssociated with a history of exposure to cytotoxic or radiation therapyMorphology:BmBx usually hypercellularDyplastic megakaryocytes may be prominent
47 Myelodysplastic Syndrome, Unclassifiable Genetics:May be normal, or clonal abnormalities the same as those found in other MDS syndromes.Prognosis:UnknownOccasionally defining characteristics develop. Then case should be reclassified.
48 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 marrowEpidemiology:Middle age to older womenClinical Presentation:Refractory anemia, often severeThrombocytosis may be present.
49 Myelodysplastic Syndrome Associated with Isolated del(5q) Chromosome Abnormality ( 5q- Syndrome) Morphology:Peripheral Smear:Marked macrocytic anemia.Slight leukopeniaNormal to elevated plateletsBmBx:Erythroid dysplasia, varying degreesSmall, hypolobated megakaryocytesScattered aggregates of small lymphocytes
50 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 survivalThose who develop more than 5% blasts may have shorter survival
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.
56 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
57 Stem Cell TransplantHEMATOPOIETIC 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 respectivelyTransplant-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 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.
59 RevlimidThalidomide 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.
60 DecitabineDecitabine — 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 rateMajor cytogenetic responses were noted in 31 percent of those with abnormal pretreatment cytogenetics and were associated with a reduced risk of deathHigh 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 responseSome of these patients have responded to immunosuppressive therapies such as antithymocyte globulin (ATG)
62 Future TherapiesValproic 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.
63 References1.)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.
64 References3.)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.
65 References7.)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; 121:7588.)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 mds10.)Coll DC, Landaw, SA Clnical manifestations and diagnosis of the myelodysplastic syndromes. Blood. 2004, 1;104(5):