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Protocol Title:
Protocol number:
Name of the study group (if appropriate):
Study coordinator(s): State departement, phone, fax, e-mail
Statistician: State departement, phone, fax, e-mail
Datamanagers: State departement, phone, fax, e-mail
Registration: State departement, phone, fax, e-mail
Version:
Date of activation:
Approved by:
Table of contents
TOC \o "1-3" \h \z HYPERLINK \l "_Toc106781334" List of abbreviations PAGEREF _Toc106781334 \h 4
HYPERLINK \l "_Toc106781335" 1. Background and Introduction PAGEREF _Toc106781335 \h 5
HYPERLINK \l "_Toc106781336" 2. Objectives of the study PAGEREF _Toc106781336 \h 6
HYPERLINK \l "_Toc106781337" 2.1. Primary objective(s) PAGEREF _Toc106781337 \h 6
HYPERLINK \l "_Toc106781338" 2.2. Secondary objective(s) PAGEREF _Toc106781338 \h 6
HYPERLINK \l "_Toc106781339" 3. Patient selection criteria PAGEREF _Toc106781339 \h 6
HYPERLINK \l "_Toc106781340" 3.1. Inclusion criteria PAGEREF _Toc106781340 \h 6
HYPERLINK \l "_Toc106781341" 3.2. Exclusion criteria PAGEREF _Toc106781341 \h 6
HYPERLINK \l "_Toc106781342" 4. Study design PAGEREF _Toc106781342 \h 7
HYPERLINK \l "_Toc106781343" 4.1. Treatment schedule PAGEREF _Toc106781343 \h 7
HYPERLINK \l "_Toc106781344" 4.2. Rationale for study design PAGEREF _Toc106781344 \h 7
HYPERLINK \l "_Toc106781345" 4.3. Dose modifications PAGEREF _Toc106781345 \h 7
HYPERLINK \l "_Toc106781346" 5. Drug availability and toxicity PAGEREF _Toc106781346 \h 7
HYPERLINK \l "_Toc106781347" 6. Concomitant therapy PAGEREF _Toc106781347 \h 7
HYPERLINK \l "_Toc106781348" 6.1. Recommended concomitant therapy PAGEREF _Toc106781348 \h 7
HYPERLINK \l "_Toc106781349" 6.2. Prohibited concomitant therapy PAGEREF _Toc106781349 \h 8
HYPERLINK \l "_Toc106781350" 7. Supportive care PAGEREF _Toc106781350 \h 8
HYPERLINK \l "_Toc106781351" 8. Required clinical evaluations, laboratory tests and follow-up PAGEREF _Toc106781351 \h 8
HYPERLINK \l "_Toc106781352" 8.1. Before start of treatment PAGEREF _Toc106781352 \h 8
HYPERLINK \l "_Toc106781353" 8.2. During treatment PAGEREF _Toc106781353 \h 8
HYPERLINK \l "_Toc106781354" 8.3. Follow-up PAGEREF _Toc106781354 \h 8
HYPERLINK \l "_Toc106781355" 9. Reasons for going off study PAGEREF _Toc106781355 \h 8
HYPERLINK \l "_Toc106781356" 10. Criteria of evaluation PAGEREF _Toc106781356 \h 9
HYPERLINK \l "_Toc106781357" 10.1. Example of response items for non-intensive therapy PAGEREF _Toc106781357 \h 9
HYPERLINK \l "_Toc106781358" 10.2. Example of response items for intensive therapy PAGEREF _Toc106781358 \h 9
HYPERLINK \l "_Toc106781359" 11. Statistical considerations PAGEREF _Toc106781359 \h 10
HYPERLINK \l "_Toc106781360" 11.1. Datasets to be analyzed PAGEREF _Toc106781360 \h 10
HYPERLINK \l "_Toc106781361" 11.2. Statistical methodology PAGEREF _Toc106781361 \h 10
HYPERLINK \l "_Toc106781362" 11.3. Sample size PAGEREF _Toc106781362 \h 10
HYPERLINK \l "_Toc106781363" 11.4. Randomization and stratifications PAGEREF _Toc106781363 \h 10
HYPERLINK \l "_Toc106781364" 12. Stop criterion /Data safety monitoring PAGEREF _Toc106781364 \h 10
HYPERLINK \l "_Toc106781365" 13. Registration and randomization PAGEREF _Toc106781365 \h 10
HYPERLINK \l "_Toc106781366" 14 Forms and procedures for collecting data PAGEREF _Toc106781366 \h 11
HYPERLINK \l "_Toc106781367" 14.1 Case report forms and schedule for completion PAGEREF _Toc106781367 \h 11
HYPERLINK \l "_Toc106781368" 14.2 Data flow PAGEREF _Toc106781368 \h 11
HYPERLINK \l "_Toc106781369" 15 Reporting adverse events PAGEREF _Toc106781369 \h 11
HYPERLINK \l "_Toc106781370" 15.1 Definitions PAGEREF _Toc106781370 \h 11
HYPERLINK \l "_Toc106781371" 15.2 Reporting procedure PAGEREF _Toc106781371 \h 11
HYPERLINK \l "_Toc106781372" 15.2.1 Non- serious adverse events and/or non-serious adverse drug reactions PAGEREF _Toc106781372 \h 12
HYPERLINK \l "_Toc106781373" 15.2.2 Serious adverse events or serious adverse drug reactions PAGEREF _Toc106781373 \h 12
HYPERLINK \l "_Toc106781374" 16. Ethical considerations PAGEREF _Toc106781374 \h 13
HYPERLINK \l "_Toc106781375" 16.1. Patient protection PAGEREF _Toc106781375 \h 13
HYPERLINK \l "_Toc106781376" 16.2. Subject identification PAGEREF _Toc106781376 \h 13
HYPERLINK \l "_Toc106781377" 16.3. Informed consent PAGEREF _Toc106781377 \h 13
HYPERLINK \l "_Toc106781378" 17. Administrative responsibilities and publication policy PAGEREF _Toc106781378 \h 13
HYPERLINK \l "_Toc106781379" 18. Trial sponsorship PAGEREF _Toc106781379 \h 14
HYPERLINK \l "_Toc106781380" 19. Trial insurance PAGEREF _Toc106781380 \h 14
HYPERLINK \l "_Toc106781381" 20. Participating centres PAGEREF _Toc106781381 \h 14
HYPERLINK \l "_Toc106781382" Appendix 1 References PAGEREF _Toc106781382 \h 15
HYPERLINK \l "_Toc106781383" Appendix 2 Clinical evaluation, laboratory tests and follow-up PAGEREF _Toc106781383 \h 17
HYPERLINK \l "_Toc106781384" Appendix 3 WHO classification of myelodysplastic syndromes (21) PAGEREF _Toc106781384 \h 18
HYPERLINK \l "_Toc106781385" Appendix 4 FAB classification of Myelodysplastic Syndromes (6) PAGEREF _Toc106781385 \h 19
HYPERLINK \l "_Toc106781386" Appendix 5 IPSS for MDS: Survival and AML Evolution (16,17) PAGEREF _Toc106781386 \h 20
HYPERLINK \l "_Toc106781387" Appendix 6 WHO performance status scale PAGEREF _Toc106781387 \h 21
HYPERLINK \l "_Toc106781388" Appendix 7 Common Terminology Criteria for Adverse Events PAGEREF _Toc106781388 \h 22
HYPERLINK \l "_Toc106781389" Appendix 8 Measurement of response/treatment effect in MDS (25) PAGEREF _Toc106781389 \h 23
HYPERLINK \l "_Toc106781390" Appendix 9 Definitions of endpoints for clinical trials in MDS (25) PAGEREF _Toc106781390 \h 25
HYPERLINK \l "_Toc106781391" Appendix 10 Standard format for an informed consent document PAGEREF _Toc106781391 \h 26
List of abbreviations
ADRAdverse Drug ReactionAEAdverse eventALT (SGPT)Alanine transaminase (serum glutamate pyruvic transaminase)ANCAll nucleated cellsAST (SGOT)Aspartate transaminase (serum glutamic oxaloacetic transaminase)BUNBlood urea nitrogenCRComplete remissionCTCCommon toxicity criteriaDFSDisease free survivalDMCData Monitoring CommitteeECGElectrocardiogramECOGEastern Cooperative Oncology GroupERBEthical Review BoardGCPGood clinical practiceHIHematological improvementHIVHuman immunodeficiency virusICHInternational Conference on HarmonizationIPSSInternational prognostic scoring systemLDHLactate dehydrogenaseLVEFLeft Ventricular Ejection FractionMCHCMean corpuscular hemoglobin concentrationMCVMean corpuscular volumeMGGMay-Grnwald-Giemsa stainingNCINational Cancer InstitutePDProgressive diseasePRPartial responseRBCRed blood cell (count)RDCRemote Data CaptureRDWRed cell Distribution WidthSADRSerious Adverse Drug ReactionSAESerious adverse eventSDStable diseaseTSHThyroid stimulating hormoneWBCWhite blood cell (count)WCBPWomen of child bearing potentialWHOWorld Health Organization
1. Background and Introduction
The myelodysplastic syndromes (MDS) form a heterogeneous group of clonal stem cell disorders characterized by a hypercellular bone marrow, peripheral cytopenias and dysplastic features in blood and bone marrow. The spectrum of the disease may vary from an indolent course over several years to more rapid progression to acute myeloid leukemia (AML) ADDIN REFMGR.CITE Mufti19851Myelodysplastic syndromes: a scoring system with prognostic significanceJournal1Myelodysplastic syndromes: a scoring system with prognostic significanceMufti,G.J.Stevens,J.R.Oscier,D.G.Hamblin,T.J.Machin,D.1985/3AgedanalysisbloodBone MarrowBone Marrow DiseasesdiagnosisFemaleFollow-Up StudiesHemoglobinsHumanLeukocyte CountMaleMiddle AgedmortalityNeutrophilspathologyPlatelet CountPreleukemiaPrognosisSupport,Non-U.S.Gov'tSyndromeIn File425433Br.J.Haematol.593PM:3970861Br.J.Haematol.1(1). MDS is predominantly diagnosed in elderly patients. In a population-based study in Germany the annual incidence of MDS in patients over 50 years was 4.9 per 100 000 persons compared to an incidence of 1.8 per 100 000 for acute myeloid leukemia in the same age-group ADDIN REFMGR.CITE Aul19922Age-related incidence and other epidemiological aspects of myelodysplastic syndromesJournal2Age-related incidence and other epidemiological aspects of myelodysplastic syndromesAul,C.Gattermann,N.Schneider,W.1992/10Acute DiseaseAdolescentAdultadverse effectsAge FactorsAgedAged,80 and overanalysisBone MarrowChildChild,PreschoolclassificationepidemiologyetiologyFemaleGermanyHumanIncidenceInfantLeukemia,MyeloidLeukemia,Radiation-InducedMaleMiddle AgedMyelodysplastic SyndromesRadiotherapySyndromeIn File358367Br.J.Haematol.822Department of Internal Medicine, Heinrich Heine University, Dusseldorf, GermanyPM:1419819Br.J.Haematol.1(2). In the last decades the incidence of MDS seems to increase. In part this may be due to a greater readiness to perform bone marrow examinations in elderly patients, but there is also some evidence for a real increase due to occupational and environmental exposure to chemicals like benzene and other organic solvents ADDIN REFMGR.CITE Aksoy19853Malignancies due to occupational exposure to benzeneJournal3Malignancies due to occupational exposure to benzeneAksoy,M.1985Adultadverse effectsBenzenechemically inducedCholera VaccinesetiologyHumanIncidenceLeukemiaLung NeoplasmsLymphomaMiddle AgedMultiple MyelomaOccupational DiseasesPancytopeniaPreleukemiaTurkeyIn File395402Am.J.Ind.Med.75-6PM:4003402Am.J.Ind.Med.1Reizenstein19914Increasing prevalence of the myelodysplastic syndrome. An international Delphi studyJournal4Increasing prevalence of the myelodysplastic syndrome. An international Delphi studyReizenstein,P.Dabrowski,L.1991/5Delphi TechniqueepidemiologyHumanIncidenceMyelodysplastic SyndromesPrevalenceSupport,Non-U.S.Gov'tSwedenSyndromeIn File10691070Anticancer Res.113Division of Hematology, Karolinska Institute and Hospital, Stockholm, SwedenPM:1888140Anticancer Res.1Aul19955Epidemiological and etiological aspects of myelodysplastic syndromesJournal5Epidemiological and etiological aspects of myelodysplastic syndromesAul,C.Gattermann,N.Schneider,W.1995/1Bone MarrowclassificationdiagnosisepidemiologyetiologyFemaleGermanyHumanIncidenceLeukemiaMaleMyelodysplastic SyndromesPreleukemiaSupport,Non-U.S.Gov'tSyndromeIn File247262Leuk.Lymphoma163-4Department of Internal Medicine, Heinrich-Heine-University, Dusseldorf, GermanyPM:7719233Leuk.Lymphoma1(3-5). Furthermore, treatment with radiotherapy and/or certain chemotherapeutic agents promotes the development of therapy-related MDS and AML (tMDS/tAML).
Since 1982 the myelodysplastic syndromes have been classified according to FAB (French-American-British) criteria (Appendix 4) ADDIN REFMGR.CITE Bennett198210Proposals for the classification of the myelodysplastic syndromesJournal10Proposals for the classification of the myelodysplastic syndromesBennett,J.M.Catovsky,D.Daniel,M.T.Flandrin,G.Galton,D.A.Gralnick,H.R.Sultan,C.1982/6Anemia,AplasticAnemia,SideroblasticbloodBone MarrowCell CountclassificationdiagnosisErythroblastsGranulocytesHumanLeukemia,MyeloidMegakaryocytesMiddle AgedMyelodysplastic SyndromespathologyPrognosisSyndromeIn File189199Br.J.Haematol.512PM:6952920Br.J.Haematol.1(6). Five subcategories have been described based on the percentage of blast cells in blood and bone marrow, the percentage of ringed sideroblasts and monocytes: refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess of blasts (RAEB), refractory anemia with excess of blasts in transformation (RAEBt) and chronic myelomonocytic leukemia (CMML). The natural course of MDS is variable. RA, RARS and RAEB with less than 10% blast cells in the bone marrow can be considered as less advanced MDS. These patients have a lower risk of developing secondary AML and most patients die of bone marrow failure or due to iron overload as a result of repeated blood transfusions (7). Advanced MDS is defined as RAEB with more than 10% blast cells, RAEBt and CMML. Median survival of these patients is generally shorter than 12 months (8).
The FAB-classification has several limitations. There are significant differences in outcome of patients within each subcategory. The FAB classification is entirely based on morphological criteria and the number of blasts in blood and bone marrow, whereas other clinical and biological variables have not been incorporated in this classification. Therefore, numerous other classification systems have been proposed to predict the prognosis of individual patients ADDIN REFMGR.CITE Mufti19851Myelodysplastic syndromes: a scoring system with prognostic significanceJournal1Myelodysplastic syndromes: a scoring system with prognostic significanceMufti,G.J.Stevens,J.R.Oscier,D.G.Hamblin,T.J.Machin,D.1985/3AgedanalysisbloodBone MarrowBone Marrow DiseasesdiagnosisFemaleFollow-Up StudiesHemoglobinsHumanLeukocyte CountMaleMiddle AgedmortalityNeutrophilspathologyPlatelet CountPreleukemiaPrognosisSupport,Non-U.S.Gov'tSyndromeIn File425433Br.J.Haematol.593PM:3970861Br.J.Haematol.1Sanz198911Two regression models and a scoring system for predicting survival and planning treatment in myelodysplastic syndromes: a multivariate analysis of prognostic factors in 370 patientsJournal11Two regression models and a scoring system for predicting survival and planning treatment in myelodysplastic syndromes: a multivariate analysis of prognostic factors in 370 patientsSanz,G.F.Sanz,M.A.Vallespi,T.Canizo,M.C.Torrabadella,M.Garcia,S.Irriguible,D.San Miguel,J.F.1989/7analysisBone MarrowdiagnosisetiologyFemaleHumanLeukemiaMaleMyelodysplastic SyndromesPlatelet CountPrognosisRegression AnalysisRisk FactorsSyndrometherapyIn File395408Blood741Hematology Service Hospital La Fe, Valencia, SpainPM:2752119Blood1Aul199212Primary myelodysplastic syndromes: analysis of prognostic factors in 235 patients and proposals for an improved scoring systemJournal12Primary myelodysplastic syndromes: analysis of prognostic factors in 235 patients and proposals for an improved scoring systemAul,C.Gattermann,N.Heyll,A.Germing,U.Derigs,G.Schneider,W.1992/1AdolescentAdultAgedAged,80 and overanalysisbloodBone MarrowclassificationdiagnosisenzymologyFemaleFollow-Up StudiesGermanyHumanL-Lactate DehydrogenaseLeukemiaMaleMiddle AgedmortalityMultivariate AnalysisMyelodysplastic SyndromesPlatelet CountPrognosisRegression AnalysisRetrospective StudiesRiskSurvival RateSyndromeIn File5259Leukemia61Department of Internal Medicine, Heinrich Heine University, Dusseldorf, GermanyPM:1736014Leukemia1Morel199313Cytogenetic analysis has strong independent prognostic value in de novo myelodysplastic syndromes and can be incorporated in a new scoring system: a report on 408 casesJournal13Cytogenetic analysis has strong independent prognostic value in de novo myelodysplastic syndromes and can be incorporated in a new scoring system: a report on 408 casesMorel,P.Hebbar,M.Lai,J.L.Duhamel,A.Preudhomme,C.Wattel,E.Bauters,F.Fenaux,P.1993/9AdolescentAdultAgedAged,80 and overanalysisbloodBone MarrowChromosome AberrationsclassificationdiagnosisFemalegeneticsHumanKaryotypingLeukemiaLeukemia,Myelocytic,AcuteMaleMiddle AgedmortalityMultivariate AnalysisMyelodysplastic SyndromesPlatelet CountPredictive Value of TestsPrognosisProportional Hazards ModelsRegression AnalysisRiskSurvival RateSyndromeIn File13151323Leukemia79Service des Maladies du Sang, C.H.U., Lille, FrancePM:8371581Leukemia1Worsley198814Prognostic features of chronic myelomonocytic leukaemia: a modified Bournemouth score gives the best prediction of survivalJournal14Prognostic features of chronic myelomonocytic leukaemia: a modified Bournemouth score gives the best prediction of survivalWorsley,A.Oscier,D.G.Stevens,J.Darlow,S.Figes,A.Mufti,G.J.Hamblin,T.J.1988/1AgedAged,80 and overBone MarrowFemaleFollow-Up StudiesHumanLeukemia,MyeloidLeukocyte CountMaleMiddle AgedMonocytesmortalityNeutrophilspathologyPrognosisSupport,Non-U.S.Gov'tIn File1721Br.J.Haematol.681Department of Haematology, Royal Victoria Hospital, BournemouthPM:3422815Br.J.Haematol.1(1;9-12). In 1997 an international workshop combined the data of seven previous reported studies ADDIN REFMGR.CITE Mufti19851Myelodysplastic syndromes: a scoring system with prognostic significanceJournal1Myelodysplastic syndromes: a scoring system with prognostic significanceMufti,G.J.Stevens,J.R.Oscier,D.G.Hamblin,T.J.Machin,D.1985/3AgedanalysisbloodBone MarrowBone Marrow DiseasesdiagnosisFemaleFollow-Up StudiesHemoglobinsHumanLeukocyte CountMaleMiddle AgedmortalityNeutrophilspathologyPlatelet CountPreleukemiaPrognosisSupport,Non-U.S.Gov'tSyndromeIn File425433Br.J.Haematol.593PM:3970861Br.J.Haematol.1Sanz198911Two regression models and a scoring system for predicting survival and planning treatment in myelodysplastic syndromes: a multivariate analysis of prognostic factors in 370 patientsJournal11Two regression models and a scoring system for predicting survival and planning treatment in myelodysplastic syndromes: a multivariate analysis of prognostic factors in 370 patientsSanz,G.F.Sanz,M.A.Vallespi,T.Canizo,M.C.Torrabadella,M.Garcia,S.Irriguible,D.San Miguel,J.F.1989/7analysisBone MarrowdiagnosisetiologyFemaleHumanLeukemiaMaleMyelodysplastic SyndromesPlatelet CountPrognosisRegression AnalysisRisk FactorsSyndrometherapyIn File395408Blood741Hematology Service Hospital La Fe, Valencia, SpainPM:2752119Blood1Aul199212Primary myelodysplastic syndromes: analysis of prognostic factors in 235 patients and proposals for an improved scoring systemJournal12Primary myelodysplastic syndromes: analysis of prognostic factors in 235 patients and proposals for an improved scoring systemAul,C.Gattermann,N.Heyll,A.Germing,U.Derigs,G.Schneider,W.1992/1AdolescentAdultAgedAged,80 and overanalysisbloodBone MarrowclassificationdiagnosisenzymologyFemaleFollow-Up StudiesGermanyHumanL-Lactate DehydrogenaseLeukemiaMaleMiddle AgedmortalityMultivariate AnalysisMyelodysplastic SyndromesPlatelet CountPrognosisRegression AnalysisRetrospective StudiesRiskSurvival RateSyndromeIn File5259Leukemia61Department of Internal Medicine, Heinrich Heine University, Dusseldorf, GermanyPM:1736014Leukemia1Morel199313Cytogenetic analysis has strong independent prognostic value in de novo myelodysplastic syndromes and can be incorporated in a new scoring system: a report on 408 casesJournal13Cytogenetic analysis has strong independent prognostic value in de novo myelodysplastic syndromes and can be incorporated in a new scoring system: a report on 408 casesMorel,P.Hebbar,M.Lai,J.L.Duhamel,A.Preudhomme,C.Wattel,E.Bauters,F.Fenaux,P.1993/9AdolescentAdultAgedAged,80 and overanalysisbloodBone MarrowChromosome AberrationsclassificationdiagnosisFemalegeneticsHumanKaryotypingLeukemiaLeukemia,Myelocytic,AcuteMaleMiddle AgedmortalityMultivariate AnalysisMyelodysplastic SyndromesPlatelet CountPredictive Value of TestsPrognosisProportional Hazards ModelsRegression AnalysisRiskSurvival RateSyndromeIn File13151323Leukemia79Service des Maladies du Sang, C.H.U., Lille, FrancePM:8371581Leukemia1Toyama199315Clinical implications of chromosomal abnormalities in 401 patients with myelodysplastic syndromes: a multicentric study in JapanJournal15Clinical implications of chromosomal abnormalities in 401 patients with myelodysplastic syndromes: a multicentric study in JapanToyama,K.Ohyashiki,K.Yoshida,Y.Abe,T.Asano,S.Hirai,H.Hirashima,K.Hotta,T.Kuramoto,A.Kuriya,S..1993/4AdolescentAdultAge FactorsAgedanalysisbloodCell Transformation,NeoplasticChromosome AberrationsdiagnosisgeneticsHemoglobinometryHumanJapanLeukemiaLeukocyte CountMiddle AgedmortalityMyelodysplastic SyndromesPrognosisRetrospective StudiesRiskRisk FactorsSupport,Non-U.S.Gov'tSyndromeTime FactorsIn File499508Leukemia74Department of Internal Medicine, Tokyo Medical College, JapanPM:8464227Leukemia1Oscier198716Myelodysplastic syndromesJournal16Myelodysplastic syndromesOscier,D.G.1987/6AgedblooddiagnosisetiologygeneticsHumanMyelodysplastic SyndromesphysiopathologyPrognosisSyndrometherapyIn File389426Baillieres Clin.Haematol.12PM:3322443Baillieres Clin.Haematol.1Greenberg P199317Phase III randomized multicenter trial of G-CSF vs. observation for myelodysplastic syndromesJournal17Phase III randomized multicenter trial of G-CSF vs. observation for myelodysplastic syndromesGreenberg PTaylor KLarson R1993Myelodysplastic SyndromesSyndromeNot in File196aBlood82Blood1(1;9-11;13-15) to generate an International Prognostic Scoring System (IPSS) (Appendix 5) ADDIN REFMGR.CITE Greenberg199718International scoring system for evaluating prognosis in myelodysplastic syndromesJournal18International scoring system for evaluating prognosis in myelodysplastic syndromesGreenberg,P.Cox,C.LeBeau,M.M.Fenaux,P.Morel,P.Sanz,G.Sanz,M.Vallespi,T.Hamblin,T.Oscier,D.Ohyashiki,K.Toyama,K.Aul,C.Mufti,G.Bennett,J.1997/3/15Acute DiseaseAdolescentAdultAge FactorsAgedanalysisBone MarrowclassificationFemaleFollow-Up StudiesgeneticsHumanLeukemiaLeukemia,MyeloidMaleMiddle AgedmortalityMultivariate AnalysisMyelodysplastic SyndromespathologyPrognosisRiskRisk AssessmentSex FactorsSupport,Non-U.S.Gov'tSurvival AnalysisSyndromeIn File20792088Blood896Hematology Division, Stanford University Medical Center, CA 94305, USAPM:9058730Blood1199890ERRATUMJournal90ERRATUM1998/2/1Not in File1100Blood913http://www.bloodjournal.orgBlood1(16;17). Greenberg et al. distinguished four risk groups for survival and AML evolution (low, intermediate-1, intermediate-2 and high risk) based on cytogenetic subgroup, percentage of bone marrow blasts and number of cytopenias. Age was an additional prognostic factor for survival, but not for AML evolution. The IPSS seems to be an improved classification system for evaluating prognosis in MDS ADDIN REFMGR.CITE Maes199919Application of the International Prognostic Scoring System for myelodysplastic syndromesJournal19Application of the International Prognostic Scoring System for myelodysplastic syndromesMaes,B.Meeus,P.Michaux,L.Bijnens,L.Boogaerts,M.Hagemeijer,A.Wolf-Peeters,C.Verhoef,G.1999/7Age FactorsclassificationComparative StudydiagnosisFemaleFollow-Up StudiesgeneticsGliomaHumanMaleMiddle AgedMyelodysplastic SyndromesPrognosisSupport,Non-U.S.Gov'tSyndrometherapyTime FactorsTreatment OutcomeIn File825829Ann.Oncol.107Center for Human Genetics, K.U. Leuven, BelgiumPM:10470430Ann.Oncol.1(18). However, Estey et al. applied the IPSS to 219 untreated patients referred to M.D. Anderson and reported a lower survival expectation in the low, intermediate-1 and intermediate-2 categories compared to the corresponding IPSS patients ADDIN REFMGR.CITE Estey199720Application of the International Scoring System for myelodysplasia to M.D. Anderson patientsJournal20Application of the International Scoring System for myelodysplasia to M.D. Anderson patientsEstey,E.Keating,M.Pierce,S.Beran,M.1997/10/1AgedclassificationComparative StudyepidemiologyFemaleHumanMaleMiddle AgedmortalityMyelodysplastic SyndromesPrognosisSeverity of Illness IndexTexasIn File28432846Blood907PM:9326255Blood1(19). Furthermore, the IPSS has been derived from patients treated with transfusions, biologic response modifiers and low-dose oral chemotherapy. Patients treated with intensive chemotherapy including stem cell transplantation have been excluded from this analysis. It is still unknown whether the IPSS is also applicable to patients treated with intensive treatment strategies ADDIN REFMGR.CITE Appelbaum199821Allogeneic bone marrow transplantation for myelodysplastic syndrome: outcomes analysis according to IPSS scoreJournal21Allogeneic bone marrow transplantation for myelodysplastic syndrome: outcomes analysis according to IPSS scoreAppelbaum,F.R.Anderson,J.1998/9AdolescentAdultAgedanalysisBone MarrowBone Marrow TransplantationChildChild,PreschooldiagnosisDisease-Free SurvivalepidemiologyFemaleHumanInfantKaryotypingMaleMiddle AgedmortalityMultivariate AnalysisMyelodysplastic SyndromesPrognosisRecurrenceRetrospective StudiesRiskRisk FactorsSurvival RateSyndrometherapyTreatment OutcomeIn FileS25S29Leukemia12 Suppl 1Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USAPM:9777891Leukemia1(20).
In 1997 a new classification system for MDS has been proposed by the World Health Organization (WHO) (Appendix 3) ADDIN REFMGR.CITE Jaffe ES200166World Health Organization classification of tumours: pathology and genetics of tumours of haematopoietic and lymphoid tissuesBook Chapter66World Health Organization classification of tumours: pathology and genetics of tumours of haematopoietic and lymphoid tissuesJaffe ESHarris NLStein HVardiman JW2001classificationgeneticspathologyNot in FileLyon, FranceIARC Press3(21). This classification recognizes several limitations of the FAB classification. The importance of cytogenetic abnormalities in MDS reflects the definition of the 5q- syndrome as cases with de novo isolated del(5q), less than 5% marrow myeloblasts and the characteristic morphologic finding of hypolobulated megakaryocytes as a distinct entity ADDIN REFMGR.CITE Giagounidis200473Clinical, morphological, cytogenetic, and prognostic features of patients with myelodysplastic syndromes and del(5q) including band q31Journal73Clinical, morphological, cytogenetic, and prognostic features of patients with myelodysplastic syndromes and del(5q) including band q31Giagounidis,A.A.Germing,U.Haase,S.Hildebrandt,B.Schlegelberger,B.Schoch,C.Wilkens,L.Heinsch,M.Willems,H.Aivado,M.Aul,C.2004/1AdultAgedAged,80 and overBone MarrowChromosome DeletionChromosomes,Human,Pair 5Erythroid Progenitor CellsFemalegeneticsGermanyHumanKaryotypingLeukemiaLeukocytesMaleMegakaryocytesMiddle AgedMyelodysplastic SyndromespathologyPrognosisSupport,Non-U.S.Gov'tSurvival RateSyndromeWorld Health OrganizationIn File113119Leukemia181St. Johannes Hospital, Medizinische Klinik II, Duisburg, Germany. gia@krebs-duisburg.dePM:14586479Leukemia1(22). One of the major changes in the WHO classification compared to the FAB classification is lowering the blast percentage for the diagnosis of acute myeloid leukemia from 30% to 20%. Several studies have suggested that there is little difference between RAEBt and AML in terms of prognosis and response to chemotherapy ADDIN REFMGR.CITE Greenberg200067Problematic WHO reclassification of myelodysplastic syndromes. Members of the International MDS Study GroupJournal67Problematic WHO reclassification of myelodysplastic syndromes. Members of the International MDS Study GroupGreenberg,P.Anderson,J.De Witte,T.Estey,E.Fenaux,P.Gupta,P.Hamblin,T.Hellstrom-Lindberg,E.List,A.Mufti,G.Neuwirtova,R.Ohyashiki,K.Oscier,D.Sanz,G.Sanz,M.Willman,C.2000/10/1Acute DiseaseclassificationHumanLeukemia,MyeloidMyelodysplastic SyndromesSyndromeWorld Health OrganizationIn File34473452J.Clin.Oncol.1819PM:11013289J.Clin.Oncol.1Estey199755Effect of diagnosis (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or acute myeloid leukemia [AML]) on outcome of AML-type chemotherapyJournal55Effect of diagnosis (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or acute myeloid leukemia [AML]) on outcome of AML-type chemotherapyEstey,E.Thall,P.Beran,M.Kantarjian,H.Pierce,S.Keating,M.1997/10/15Acute DiseaseAdolescentAdultAgedAged,80 and overanalysisAnemiaAnemia,Refractory,with Excess of BlastsAntineoplastic AgentsCytogeneticsdiagnosisDisease-Free Survivaldrug therapyFemaleHemoglobinsHumanKaryotypingLeukemiaLeukemia,MyeloidLeukocyte CountMaleMiddle AgedMultivariate AnalysisNeutrophilsOutcome Assessment (Health Care)Platelet CountPrognosisRiskTexastherapeutic useIn File29692977Blood908Department of Hematology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USAPM:9376577Blood1(23;24). As a consequence RAEBt (refractory anemia with excess of blasts in transformation) has been eliminated from the MDS classification. The new WHO classification distinguishes MDS with morphologic dysplasia restricted to the erythroid lineage (RA: refractory anemia) from MDS with multilineage dysplasia (RCMD: refractory cytopenia with multilineage dysplasia).
The new classification system has been criticized for several reasons: 1) lowering the blast percentage for a diagnosis of AML to 20 % in stead of 30% is arbitrary as well and introduces difficulties in comparing future AML/MDS studies with historical controls. 2) the definition of MDS as a clonal stem cell disorder based solely on dysplasia in the erythroid lineage is precarious. 3) the prognostic value of cytogenetic abnormalities is inconsistently incorporated in the classification. Clearly the optimal classification system for MDS and AML cannot be based on clinical features only, but also on data on gene expression patterns and other biologic parameters. Insight gained from the molecular analysis of MDS provides the basis for a more refined classification and future revisions of the WHO proposal will be necessary.
Addition: Briefly discuss current therapies for disease to be treated focussed on type of MDS (low risk, high risk etc.), rationale for this study, clinical experience with the drug or therapy up to now and biological activity of the drug (if applicable).
2. Objectives of the study
2.1. Primary objective(s)
State primary objectives here such as:
To evaluate the effect of treatment with state study drug on hematopoietic response and anemia (maintain what is appropriate) in MDS patients.
To acquire safety data on treatment with state study drug in MDS patients.
2.2. Secondary objective(s)
State secondary objectives here such as:
To evaluate the feasibility of treatment with state study drug in MDS patients.
To assess the quality of life.
3. Patient selection criteria
Approximately X number subjects with state disease/stage to be studied will be screened for enrollment and must meet the eligibility criteria below. Target number of patients is *
3.1. Inclusion criteria
Maintain all those that are appropriate and include those that are necessary and not listed.
-Subject is able and willing to sign the Informed Consent Form according to ICH/EU GCP and national/local regulations.
-Expected co-operation of patient with regard to treatment and follow-up.
-Age (18 years at the time of signing the informed consent form.
-State disease and stage here.
-The blood and bone marrow picture should be one of the following categories: *
-All previous or concurrent use of other cancer therapy, including radiation, hormonal therapy and surgery, must have been discontinued at least * weeks prior to treatment in this study (if appropriate).
-WHO performance status of ( 2 at study entry (see Appendix 6).
-Laboratory test results within these ranges:
-Women of childbearing potential (WCBP) must have a negative serum or urine pregnancy test within 7 days of starting study drug. In addition, sexually active WCBP must agree to use adequate contraceptive methods while on study drug. Men must agree not to father a child and agrees to use a condom if his partner is of child bearing potential.
3.2. Exclusion criteria
Maintain all those that are appropriate and include those that are necessary and not listed.
-Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.
-Pregnant or lactating females.
-Use of any other experimental drug or therapy within 28 days of baseline.
-Known hypersensitivity to state study drug.
-Previous state study drug therapy within * weeks before start of treatment.
-Prior malignant disease.
-Known positive for HIV or infectious hepatitis, type B or C.
-Active infections.
4. Study design
State the following:
Prospective/retrospective
Phase of study
Single institution or multi-center
Randomized or single arm
State number patients will be treated with state study drug for state how long.
Visits at week * (schedule see Appendix 2)
4.1. Treatment schedule
Patients will receive state treatment to be administered here.
State how the study treatment will be selected for an individual patient if this is a randomized study or a dose finding study, as appropriate.
After going off study patients will receive supportive care including state study drug if appropriate (according to the opinion of the treating physician).
Figure 1 Treatment Scheme
If appropriate outline treatment scheme here.
4.2. Rationale for study design
4.3. Dose modifications
In case of insufficient response *
Stopping rule: *
Subjects experiencing adverse events may need study treatment modifications.
Table 2: Dose Modification for state study drugNCI CTC Toxicity GradeDay * of Cycle*
5. Drug availability and toxicity
State study drug will be supplied by state pharmaceutical company and is available as state packing. State whether or not the study drug is registered.
The most common side effects are *.
Toxicity will be scored using CTCAE version 3.0 for toxicity and adverse event reporting (Appendix 7).
6. Concomitant therapy
(If appropriate)
6.1. Recommended concomitant therapy
6.2. Prohibited concomitant therapy
7. Supportive care
(If appropriate)
8. Required clinical evaluations, laboratory tests and follow-up
8.1. Before start of treatment
Screening assessments occur ( 28 days from Baseline (Baseline: first day of study drug administration).
List any additional assessments that are required or delete those that are not necessary.
Medical history including prior (prior to MDS) chemotherapy and irradiation, concomitant medication, tendency for bleeding/bruising, TB infection, opportunistic infections, chronic and recurrent infections, HIV status, hepatitis B and C history, presence of allergies, transplants.
MDS history: prior treatments.
Physical examination including height (at screening only), and weight, liver and spleen size, lymph node enlargement, gingival hypertrophy, dermal infiltration, fever, haemorrhages.
WHO Assessment. Determine the subjects WHO performance status (Appendix 6).
Vital signs. Resting blood pressure, pulse and temperature (cardio-pulmonary status).
Chest X-ray, ECG and/or LVEF measurement by echocardiography.
Serum chemistry including sodium, potassium, chloride, calcium, magnesium, phosphorus, BUN, creatinine, glucose, albumin, total protein, alkaline phosphatase, total bilirubin, AST, ALT, LDH, uric acid.
Optional: coagulation factors (fibrinogen and others), CO diffusion of the lungs (on indication).
RBC-folate/S-folic acid, cobalamine, iron, TIBC, ferritin, haptoglobin, DAT (Coombs test), S-erythropoietin, S- protein electrophoresis (S-immunoglobulins).
Serum pregnancy test for women of childbearing potential within 1 week prior to randomization.
Hematology: WBC, differential, hemoglobin, platelet count, red blood cell indices (MCV, MCHC, RDW) and reticulocyte count.
Bone marrow analysis (complete myelogram) and peripheral blood smear.
A good quality diagnostic bone marrow analysis includes marrow aspirate (MGG / equivalent and iron staining) and a bone marrow biopsy either decalcified / paraffin embedded or plastic embedded. Staining should include Htx-Eosin / equivalent and iron staining.
Cytogenetic examination of bone marrow blasts.
Immunophenotyping of leukemic blasts according to the recommendations of the Cytology
Committee, by flow cytometry with an extended panel of anti-myeloid (CD13, CD14, CD33,
CD34) and anti-lymphoid (B-lineage and T-lineage markers) monoclonal antibodies.
8.2. During treatment
List those assessments that are required during treatment.
Subjects will be evaluated for AEs at each visit. Toxicity will be scored using CTCAE version 3.0 for toxicity and adverse event reporting (Appendix 7).
8.3. Follow-up
Subjects will be followed state frequency if patients are to be followed after discontinuation of therapy for information on state what will be followed.
9. Reasons for going off study
-Treatment with study drug is discontinued when any of the following occurs:
-No compliance of the patient
-Adverse event(s) that, in the judgment of the Investigator, may cause severe or permanent harm or which rule out continuation of study drug.
-Death.
-Disease progression/ Lack of therapeutic effect.
-Major protocol violation (other treatments than those described in 4).
-Lost to follow-up.
-Major violation of the study protocol.
-Withdrawal of consent.
-Suspected pregnancy.
At treatment discontinuation, subjects will undergo safety assessments as per the Schedule Appendix 2. All subjects who discontinue treatment will continue to be followed for state if there will be any follow-up, for how long and what will be followed.
10. Criteria of evaluation
For details see Appendix 8 and 9 (25)
10.1. Example of response items for non-intensive therapy
State what is appropriate.
Complete remission (CR)
Cytogenetic response
Complete cytogenetic response
Minor cytogenetic response
Partial response (PR)
Hematological improvement (HI)
Erythroid improvement (HI-E)
Major improvement (HI-E)
Minor improvement (HI-E)
Platelet improvement (HI-P)
Major improvement (HI-P)
Minor improvement (HI-P)
Neutrophil improvement (HI-N)
Major improvement (HI-N)
Minor improvement (HI-N)
Stable disease (SD)
Progressive disease (PD)
10.2. Example of response items for intensive therapy
State what is appropriate.
Criteria of response
Complete remission (CR)
Partial remission (PR)
Failure
Toxic death
Criteria of relapse
Time to event analyses
Disease free survival (DFS)
Incidence of relapse
Incidence of death in CR/CRp
Duration of survival from CR/CRp
Duration of survival from date of registration
Criteria of toxicity
Criteria of severe acute toxicity
11. Statistical considerations
11.1. Datasets to be analyzed
State which data will be included in the analysis
11.2. Statistical methodology
Describe statistical analysis methods to be used
State how the primary endpoint will be calculated
State how the secondary endpoint will be calculated
11.3. Sample size
State sample size and power considerations.
11.4. Randomization and stratifications
12. Stop criterion /Data safety monitoring
When more then 30% of the patient develop Leukaemia (> 20% blasts) within the first 365 days the study will be closed.
Describe any data safety monitoring that will take place at the institution such as the following example
The Data Monitoring Committee (DMC) will be composed of medical and statistical independent reviewers and will meet to review the efficacy and safety data and determine a risk/benefit analysis in this subject population. The purpose of the DMC is to advise on serious safety considerations, lack of efficacy and any other considerations within the charge to the Committee. The DMC may request additional meetings or safety reports as deemed necessary upon discussion with Celgene and its representatives. The DMC may stop the study following review of results from each interim analysis. The first interim analysis will examine only safety information; the second interim, conducted when the database is more mature, will examine both safety and efficacy. Appropriate efficacy and safety data summaries will be provided to the DMC after each interim analysis.
13. Registration and randomization
State procedures to register or randomize patients in the trial.
14 Forms and procedures for collecting data
14.1 Case report forms and schedule for completion
All information is gathered by data managers of the *and registered in case report forms.
All forms must be dated and signed by the responsible investigator or one of his/her authorized staff members, either by handwritten signature or electronic signature for RDC forms.
14.2 Data flow
15 Reporting adverse events
15.1 Definitions
An Adverse Event (AE) is defined as any untoward medical occurrence or experience in a patient or clinical investigation subject which occurs following the administration of the trial medication regardless of the dose or causal relationship. This can include any unfavorable and unintended signs (such as rash or enlarged liver), or symptoms (such as nausea or chest pain), an abnormal laboratory finding (including blood tests, x-rays or scans) or a disease temporarily associated with the use of the protocol treatment. (ICH-GCP)
An Adverse Drug Reaction (ADR) (marketed products) are responses to a drug which are noxious and unintended and which occur at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of physiological function. (ICH-GCP)
An Adverse Drug Reaction (ADR) (non-marketed products) is defined as any response to a medical product, that is noxious and/or unexpected, related to any dose. (ICH-GCP)
Response to a medicinal product (used in the above definition) means that a causal relationship between the medicinal product and the adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out.
An Unexpected Adverse Drug Reaction is any adverse reaction for which the nature or severity is not consistent with the applicable product information (e.g., Investigators Brochure). (ICH-GCP)
A Serious Adverse Event (SAE) is defined as any undesirable experience occurring to a patient, whether or not considered related to the protocol treatment. A Serious Adverse Event (SAE) which is considered related to the protocol treatment is defined as a Serious Adverse Drug Reaction (SADR).
Adverse events and adverse drug reactions which are considered as serious are those which result in:
. death
. a life threatening event (i.e. the patient was at immediate risk of death at the time the reaction was observed)
. hospitalization or prolongation of hospitalization
. persistent or significant disability/incapacity
. a congenital anomaly/birth defect
. any other medically important condition (i.e. important adverse reactions that are not immediately life threatening or do not result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the other outcomes listed above). (ICH-GCP)
REMARK: In this study death due to progression of disease will not be considered as an SAE and
must therefore not be reported as an SAE.
15.2 Reporting procedure
15.2.1 Non- serious adverse events and/or non-serious adverse drug reactions
Adverse Events (AE) and /or Adverse Drug Reactions (ADR) must be recorded as indicated in the protocol.
15.2.2 Serious adverse events or serious adverse drug reactions
All Serious Adverse Events (SAE), related or not to the protocol treatment, occurring during the treatment period and within 30 days after the last protocol treatment administration, must be reported to the *.
(see Appendix 7).
Any late Serious Adverse Drug Reaction (SADR), occurring after this 30-day period also must be reported to the *.
This must be done by fax within 24 hours of the initial observation of the event. The principal investigator will decide if these events are related to the protocol treatment (i.e. unrelated, likely related, and not assessable) and the decision will be recorded on the Serious Adverse Event form, if necessary with the reasoning of the principal investigator.
The assessment of causality is made by the investigator using the following definitions:
Relationship to
the protocol
treatmentDescription
UNRELATEDThere is no evidence of any causal relationship to the protocol
treatmentLIKELY RELATEDThere is (some) evidence to suggest a causal relationship to the
protocol treatment and influence of other factors is unlikely or
absent.NOT ASSESSABLEThere is insufficient or incomplete evidence to make a clinical
judgement of the causal relationship to the protocol treatment.
Details should be documented on the specified Serious Adverse Event Form.
PLEASE FAX THE REPORT TO: *
The * will forward all Serious Adverse Event reports within 24 hours of receipt to all appropriate persons.
All unexpected SADR reports and all reports involving expected SADR that are life threatening or caused death, will additionally be forwarded to all participating investigators.
Upon receipt of a safety report, from the *, it is the responsibility of the investigators to promptly report this to the Ethical Review Board (ERB) according to the local regulation.
To enable the * to comply with regulatory reporting requirements,
completed documentation of any reported serious adverse events or serious adverse drug reactions must be returned within 10 calendar days of the initial report. If the completed form is not received within this deadline, the Safety Desk will make a written request to the investigator.
PLEASE SEND THE ORIGINAL REPORT TO:
Safety Desk: *
It should be recognized that Serious Adverse Drug Reactions (SADR) which have not been previously documented in the Investigators Brochure, or which occur in a more severe form than anticipated (i.e. they are unexpected by nature or severity), are subject to rapid reporting to the Regulatory Authorities by the sponsor/promoter.
ANY QUESTION CONCERNING SAE OR SADR REPORTING CAN BE DIRECTED TO:
Safety Desk
Phone:
Fax:
e-mail:
ALL FORMS MUST BE DATED AND SIGNED BY THE RESPONSIBLE
INVESTIGATOR OR ONE OF HIS/HER AUTHORIZED STAFF MEMBERS.
16. Ethical considerations
16.1. Patient protection
The responsible investigator will ensure that this study is conducted in agreement with either the Declaration of Helsinki (Tokyo, Venice and Hong Kong amendments), or the laws and regulations of the country whichever provides the greatest protection of the patient.
The protocol has been written, and the study will be conducted according to the guidelines for Good Clinical Practice issued by the European Union. The protocol will be approved by the local, Regional or National Review Boards.
16.2. Subject identification
The name of the patient will not be asked for nor recorded at *. A sequential identification number will be automatically attributed to each patient registered in the trial. This number will identify the patient and must be included on all case report forms. In order to avoid identification errors, patient standard initials and gender or date of birth will also be reported on the case report forms.
16.3. Informed consent
All patients will be informed of the aims of the study, the possible adverse events, the procedures and possible hazards to which he/she will be exposed, and the mechanism of treatment allocation. They will be informed as to the strict confidentiality of their patient data, but that authorized individuals other than the treating physicians may review their medical records for trial purposes. An example of a patient informed consent statement is given as Appendix (10) to this protocol.
It will be emphasized that the participation is voluntary and that the patient is allowed to refuse further participation in the protocol whenever he/she wants. This will not prejudice the patient's subsequent care. Documented informed consent must be obtained for all patients included in the study before they are registered or randomized at the *. This must be done in accordance with the national and local regulatory requirements.
17. Administrative responsibilities and publication policy
All questions concerning the data processing aspects of this study should be addressed to the *
All other questions should be addressed to the study coordinator: * HYPERLINK "mailto:M.Oosterveld@hemat.umcn.nl"
No partial or complete written publication of the results will be made by the study coordinators without a previous information and agreement of the participating members selected as co-authors on the basis of accrual of patients evaluable and eligible (selection made by the trial committee).
Participating centres are allowed to make complementary studies in parallel to this trial. They should require the authorization of the study coordinator.
18. Trial sponsorship
State financing and educational grant if applicable.
19. Trial insurance
State what is applicable.
The insurance programme of the participating centre is expected to cover the patients since the study regimen consists of a registered drug.
A clinical trial insurance has been taken according to the laws of the countries where the study will be conducted. An insurance certificate will be made available to the participating sites at the time of study initiation.
20. Participating centres
Appendix 1 References
Mufti GJ, Stevens JR, Oscier DG, Hamblin TJ, Machin D. Myelodysplastic syndromes: a scoring system with prognostic significance. Br J Haematol 1985; 59(3):425-433.
Aul C, Gattermann N, Schneider W. Age-related incidence and other epidemiological aspects of myelodysplastic syndromes. Br J Haematol 1992; 82(2):358-367.
Aksoy M. Malignancies due to occupational exposure to benzene. Am J Ind Med 1985; 7(5-6):395-402.
Reizenstein P, Dabrowski L. Increasing prevalence of the myelodysplastic syndrome. An international Delphi study. Anticancer Res 1991; 11(3):1069-1070.
Aul C, Gattermann N, Schneider W. Epidemiological and etiological aspects of myelodysplastic syndromes. Leuk Lymphoma 1995; 16(3-4):247-262
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982; 51(2):189-199.
Mufti GJ, Stevens JR, Oscier DG, Hamblin TJ, Machin D. Myelodysplastic syndromes: a scoring system with prognostic significance. British Journal of Haematology 1984; 59: 425-433
Kantarjian HM, Keating MJ, Walters RS, Smith TL, Cork A, McCredie KB, Freireich EJ. Therapy-related leukemia and myelodysplastic syndrome: clinical, cytogenetic, and prognostic features. Journal of Clinical Oncology 1986; 4: 1748-1757
Sanz GF, Sanz MA, Vallespi T, Canizo MC, Torrabadella M, Garcia S, Irriguible D, San Miguel JF. Two regression models and a scoring system for predicting survival and planning treatment in myelodysplastic syndromes: a multivariate analysis of prognostic factors in 370 patients. Blood 1989; 74(1):395-408.
Aul C, Gattermann N, Heyll A, Germing U, Derigs G, Schneider W. Primary myelodysplastic syndromes: analysis of prognostic factors in 235 patients and proposals for an improved scoring system. Leukemia 1992; 6(1):52-59.
Morel P, Hebbar M, Lai JL, Duhamel A, Preudhomme C, Wattel E, Bauters F, Fenaux P. Cytogenetic analysis has strong independent prognostic value in de novo myelodysplastic syndromes and can be incorporated in a new scoring system: a report on 408 cases. Leukemia 1993; 7(9):1315-1323.
Worsley A, Oscier DG, Stevens J, Darlow S, Figes A, Mufti GJ, Hamblin TJ. Prognostic features of chronic myelomonocytic leukaemia: a modified Bournemouth score gives the best prediction of survival. Br J Haematol 1988; 68(1):17-21.
Toyama K, Ohyashiki K, Yoshida Y, Abe T, Asano S, Hirai H, Hirashima K, Hotta T, Kuramoto A, Kuriya S, . Clinical implications of chromosomal abnormalities in 401 patients with myelodysplastic syndromes: a multicentric study in Japan. Leukemia 1993; 7(4):499-508.
Oscier DG. Myelodysplastic syndromes. Baillieres Clin Haematol 1987; 1(2):389-426.
Greenberg P, Taylor K, Larson R. Phase III randomized multicenter trial of G-CSF vs. observation for myelodysplastic syndromes. Blood 1993; 82:196a.
Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89(6):2079-2088.
ERRATUM. Blood 1998; 91(3):1100.
Maes B, Meeus P, Michaux L, Bijnens L, Boogaerts M, Hagemeijer A, Wolf-Peeters C, Verhoef G. Application of the International Prognostic Scoring System for myelodysplastic syndromes. Ann Oncol 1999; 10(7):825-829.
Estey E, Keating M, Pierce S, Beran M. Application of the International Scoring System for myelodysplasia to M.D. Anderson patients. Blood 1997; 90(7):2843-2846.
Appelbaum FR, Anderson J. Allogeneic bone marrow transplantation for myelodysplastic syndrome: outcomes analysis according to IPSS score. Leukemia 1998; 12 Suppl 1:S25-S29.
Jaffe ES, Harris NL, Stein H, Vardiman JW. World Health Organization classification of tumours: pathology and genetics of tumours of haematopoietic and lymphoid tissues. Lyon, France: IARC Press, 2001.
Giagounidis AA, Germing U, Haase S, Hildebrandt B, Schlegelberger B, Schoch C, Wilkens L, Heinsch M, Willems H, Aivado M, Aul C. Clinical, morphological, cytogenetic, and prognostic features of patients with myelodysplastic syndromes and del(5q) including band q31. Leukemia 2004; 18(1):113-119.
Greenberg P, Anderson J, De Witte T, Estey E, Fenaux P, Gupta P, Hamblin T, Hellstrom-Lindberg E, List A, Mufti G, Neuwirtova R, Ohyashiki K, Oscier D, Sanz G, Sanz M, Willman C. Problematic WHO reclassification of myelodysplastic syndromes. Members of the International MDS Study Group. J Clin Oncol 2000; 18(19):3447-3452.
Estey E, Thall P, Beran M, Kantarjian H, Pierce S, Keating M. Effect of diagnosis (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or acute myeloid leukemia [AML]) on outcome of AML-type chemotherapy. Blood 1997; 90(8):2969-2977.
Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD, Lowenberg B, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Wijermans PW, Gore S, Greenberg PL; World Health Organization(WHO) international working group. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood. 2000 Dec 1;96(12):3671-4.
Appendix 2 Clinical evaluation, laboratory tests and follow-up
Day-28 to 0Follow
UpInformed consentxScreening eligibility criteriaxMedical historyxPhysical examinationxWHO AssessmentxVital signsxChest X-ray, ECG and/or LVEFxSerum chemistryxPregnancy testxWhenever pregnancy suspectedHematologyxBM analysisxCytogeneticsxImmunophenotypingxAdverse eventsResponse assessmentStudy medication
Appendix 3 WHO classification of myelodysplastic syndromes (21)
Peripheral blood and bone marrow findings.
DiseaseBlood findingsBone marrow findingsRefractory anaemia (RA)Anaemia
No or rare blasts
Erythroid dysplasia only
<5% blasts
<15% ringed sideroblasts
Refractory anaemia with ringed sideroblasts (RARS)Anaemia
No blasts
e"1 5 % r i n g e d s i d e r o b l a s t s
E r y t h r o i d d y s p l a s i a o n l y
<