2024
Oral decitabine–cedazuridine versus intravenous decitabine for myelodysplastic syndromes and chronic myelomonocytic leukaemia (ASCERTAIN): a registrational, randomised, crossover, pharmacokinetics, phase 3 study
Garcia-Manero G, McCloskey J, Griffiths E, Yee K, Zeidan A, Al-Kali A, Deeg H, Patel P, Sabloff M, Keating M, Zhu N, Gabrail N, Fazal S, Maly J, Odenike O, Kantarjian H, DeZern A, O'Connell C, Roboz G, Busque L, Buckstein R, Amin H, Randhawa J, Leber B, Shastri A, Dao K, Oganesian A, Hao Y, Keer H, Azab M, Savona M. Oral decitabine–cedazuridine versus intravenous decitabine for myelodysplastic syndromes and chronic myelomonocytic leukaemia (ASCERTAIN): a registrational, randomised, crossover, pharmacokinetics, phase 3 study. The Lancet Haematology 2024, 11: e15-e26. PMID: 38135371, DOI: 10.1016/s2352-3026(23)00338-1.Peer-Reviewed Original ResearchConceptsChronic myelomonocytic leukemiaIntravenous decitabineMyelodysplastic syndromeMyelomonocytic leukemiaOral therapyPrimary endpointAdverse eventsEastern Cooperative Oncology Group performance status 0Treatment cyclesCycle 1Full treatment dosePerformance status 0Treatment-related deathsFrequent adverse eventsSerious adverse eventsPhase 3 studyPhase 3 trialPotential treatment benefitsCommunity-based clinicsAcute myeloid leukemiaNext treatment cycleTreatment of individualsOral decitabineStatus 0Treatment discontinuation
2023
The ELEMENT-MDS Trial: A Phase 3 Randomized Study Evaluating Luspatercept Versus Epoetin Alfa in Erythropoiesis-Stimulating Agent-Naive, Non-Transfusion-Dependent, Lower-Risk Myelodysplastic Syndromes
Zeidan A, Komrokji R, Buckstein R, Santini V, Rose S, Malini P, Lew G, Aggarwal D, Keeperman K, Jiang H, Giuseppi A, Zhang J, Cluzeau T, Shortt J, Platzbecker U. The ELEMENT-MDS Trial: A Phase 3 Randomized Study Evaluating Luspatercept Versus Epoetin Alfa in Erythropoiesis-Stimulating Agent-Naive, Non-Transfusion-Dependent, Lower-Risk Myelodysplastic Syndromes. Blood 2023, 142: 6503. DOI: 10.1182/blood-2023-178635.Peer-Reviewed Original ResearchRBC transfusion dependenceErythropoiesis-stimulating agentsLR-MDSEpoetin alfaMyelodysplastic syndromeTransfusion dependenceSecondary endpointsStarting doseOverall survivalTransfusion independenceWeek 1Baseline serum erythropoietin levelsIntermediate-risk myelodysplastic syndromesIPSS-R risk categoryLower-risk myelodysplastic syndromesRed blood cell transfusionHigh-risk myelodysplastic syndromeInternational Prognostic Scoring SystemAdditional secondary endpointsRBC transfusion independenceTransfusion-free survivalKey secondary endpointBlood cell transfusionPatient Global ImpressionPhase 3 studyEfficacy of Imetelstat in Achieving Red Blood Cell Transfusion Independence (RBC-TI) across Different Risk Subgroups in Patients with Lower-Risk Myelodysplastic Syndromes (LR-MDS) Relapsed/Refractory (R/R) to Erythropoiesis-Stimulating Agents (ESAs) in IMerge Phase 3 Study
Komrokji R, Santini V, Fenaux P, Savona M, Madanat Y, Berry T, Sherman L, Navada S, Feller F, Sun L, Xia Q, Wan Y, Huang F, Zeidan A, Platzbecker U. Efficacy of Imetelstat in Achieving Red Blood Cell Transfusion Independence (RBC-TI) across Different Risk Subgroups in Patients with Lower-Risk Myelodysplastic Syndromes (LR-MDS) Relapsed/Refractory (R/R) to Erythropoiesis-Stimulating Agents (ESAs) in IMerge Phase 3 Study. Blood 2023, 142: 194. DOI: 10.1182/blood-2023-181237.Peer-Reviewed Original ResearchInternational Prognostic Scoring SystemLower-risk myelodysplastic syndromesDifferent risk subgroupsErythropoiesis stimulating agentsLow-risk subgroupsRisk groupsRisk subgroupsResponse rateTI ratesRBC-TIClinical efficacyRisk categoriesHigh riskLower riskRed blood cell transfusion independenceIPSS risk groupPhase 3 portionIntermediate-risk groupCytogenetic risk groupHigh-risk patientsPhase 3 studyPrognostic scoring systemIntermediate-risk subgroupsHigh-risk subgroupsHigh-risk groupImpact of Mutational Status on Clinical Response to Imetelstat in Patients with Lower-Risk Myelodysplastic Syndromes in the IMerge Phase 3 Study
Santini V, Zeidan A, Fenaux P, Madanat Y, Berry T, Feller F, Sun L, Xia Q, Wan Y, Huang F, Savona M, Platzbecker U. Impact of Mutational Status on Clinical Response to Imetelstat in Patients with Lower-Risk Myelodysplastic Syndromes in the IMerge Phase 3 Study. Blood 2023, 142: 4603. DOI: 10.1182/blood-2023-179378.Peer-Reviewed Original ResearchLower-risk myelodysplastic syndromesPlacebo groupTransfusion independenceTI ratesHot spot mutationsPoor prognosisMyelodysplastic syndromeRed blood cell transfusion independenceASXL1 mutationsErythropoiesis-stimulating agentsPhase 3 studyStudy of patientsTI responsesPresence of mutationsSpecific mutationsClinical responseStudy entryClinical efficacyClinical benefitPeripheral bloodMutation subgroupsDNMT3A mutationsEpigenetic modifiersPatientsRUNX1 mutations
2021
Phase 3 VERONA study of venetoclax with azacitidine to assess change in complete remission and overall survival in treatment-naïve higher-risk myelodysplastic syndromes.
Zeidan A, Garcia J, Fenaux P, Platzbecker U, Miyazaki Y, Xiao Z, Zhou Y, Naqvi K, Kye S, Garcia-Manero G. Phase 3 VERONA study of venetoclax with azacitidine to assess change in complete remission and overall survival in treatment-naïve higher-risk myelodysplastic syndromes. Journal Of Clinical Oncology 2021, 39: tps7054-tps7054. DOI: 10.1200/jco.2021.39.15_suppl.tps7054.Peer-Reviewed Original ResearchHematopoietic stem cell transplantOverall survivalAcute myeloid leukemiaCR rateComplete remissionTransfusion independenceCell transplantationDisease progressionMyeloid leukemiaDay 1B-cell lymphoma-2 inhibitorRed blood cell transfusion independenceHigh-risk myelodysplastic syndromeAllogenic stem cell transplantationCo-morbid patientsIWG 2006 criteriaPhase 1b studyPlatelet transfusion independenceMedian overall survivalFirst-line treatmentPhase 3 studyBone marrow blastsDe novo patientsHematopoietic cell transplantationStudy days 1IMerge: A phase 3 study to evaluate imetelstat in transfusion-dependent subjects with IPSS low or intermediate-1 risk myelodysplastic syndromes that are relapsed/refractory to erythropoiesis-stimulating agent treatment.
Platzbecker U, Komrokji R, Fenaux P, Zeidan A, Sekeres M, Savona M, Madanat Y, Sherman L, Dougherty S, Sun L, Huang F, Wan Y, Rizo A, Berry T, Feller F, Santini V. IMerge: A phase 3 study to evaluate imetelstat in transfusion-dependent subjects with IPSS low or intermediate-1 risk myelodysplastic syndromes that are relapsed/refractory to erythropoiesis-stimulating agent treatment. Journal Of Clinical Oncology 2021, 39: tps7056-tps7056. DOI: 10.1200/jco.2021.39.15_suppl.tps7056.Peer-Reviewed Original ResearchInternational Prognostic Scoring SystemErythropoiesis-stimulating agentsPhase 3 partRisk myelodysplastic syndromesMyelodysplastic syndromeRBC-TIRed blood cell (RBC) transfusion-dependent patientsErythropoiesis-stimulating agent treatmentLower-risk myelodysplastic syndromesPhase 2 partProgression of MDSRBC transfusion independenceTransfusion dependent subjectsPlacebo-controlled trialPhase 2/3 studyPhase 3 studyPrognostic scoring systemCurrent treatment optionsTransfusion-dependent patientsQuality of lifeMedian TI durationRate of CRVariant allele frequencyMechanism of actionAdult pts
2020
Clinical benefit of luspatercept in patients (pts) with lower-risk MDS (LR-MDS) and high transfusion burden in the phase III MEDALIST study.
Zeidan A, Garcia-Manero G, Dezern A, Fenaux P, Greenberg P, Savona M, Jurcic J, Verma A, Mufti G, Buckstein R, Santini V, Laadem A, Zhang J, Rampersad A, Sinsimer D, Louis C, Linde P, List A, Sekeres M. Clinical benefit of luspatercept in patients (pts) with lower-risk MDS (LR-MDS) and high transfusion burden in the phase III MEDALIST study. Journal Of Clinical Oncology 2020, 38: 7554-7554. DOI: 10.1200/jco.2020.38.15_suppl.7554.Peer-Reviewed Original ResearchTreatment-emergent adverse eventsLow-risk MDSRBC transfusion burdenTransfusion burdenRing sideroblastsRBC-TITransfusion eventsClinical benefitWeek 1Significant clinical unmet needPT populationHigh transfusion burdenRBC transfusion independenceRegular RBC transfusionsAcceptable safety profilePhase 3 studyClinical unmet needErythropoiesis-stimulating agentsSerious AEsMedian durationAdverse eventsMedian timeRBC transfusionSafety profileTreatment options
2019
Pharmacokinetic Exposure Equivalence and Preliminary Efficacy and Safety from a Randomized Cross over Phase 3 Study (ASCERTAIN study) of an Oral Hypomethylating Agent ASTX727 (cedazuridine/decitabine) Compared to IV Decitabine
Garcia-Manero G, McCloskey J, Griffiths E, Yee K, Zeidan A, Al-Kali A, Dao K, Deeg H, Patel P, Sabloff M, Keating M, Zhu N, Gabrail N, Fazal S, Maly J, Odenike O, Shastri A, DeZern A, O'Connell C, Roboz G, Oganesian A, Hao Y, Keer H, Azab M, Savona M. Pharmacokinetic Exposure Equivalence and Preliminary Efficacy and Safety from a Randomized Cross over Phase 3 Study (ASCERTAIN study) of an Oral Hypomethylating Agent ASTX727 (cedazuridine/decitabine) Compared to IV Decitabine. Blood 2019, 134: 846. DOI: 10.1182/blood-2019-122980.Peer-Reviewed Original ResearchPhase 3 studyFixed-dose combinationClinical trialsHematologic improvementAdverse eventsAstex PharmaceuticalsSpeakers bureauIncyte CorporationSafety findingsComplete responseRandomized crossOtsuka PharmaceuticalClinical activityHypomethylating agentOral fixed-dose combinationCelgene CorporationRandomized phase 3 studyBoehringer IngelheimAdvisory CommitteeSeattle GeneticsDaiichi SankyoClinic visit frequencyComparable clinical activityDifferent myeloid malignanciesPlatelet transfusion dependence
2018
Preliminary Safety, Pharmacokinetics (PK) and Pharmacodynamic (PD) Analysis of the Polo-like Kinase-1 (PLK1) Inhibitor PCM-075, in Combination with Low-Dose Cytarabine (LDAC) or Decitabine (D) in Patients with Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML)
Zeidan A, Schiller G, Spira A, Patel P, Tsai M, Ridinger M, Silberman S, Erlander M, Cortes J. Preliminary Safety, Pharmacokinetics (PK) and Pharmacodynamic (PD) Analysis of the Polo-like Kinase-1 (PLK1) Inhibitor PCM-075, in Combination with Low-Dose Cytarabine (LDAC) or Decitabine (D) in Patients with Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML). Blood 2018, 132: 4043. DOI: 10.1182/blood-2018-99-112590.Peer-Reviewed Original ResearchAcute myeloid leukemiaR AMLPhase 1 trialAdverse eventsPLK1 inhibitionBlast cellsPK profilesNon-hematologic adverse eventsPrevious phase 1 trialRandomized phase 2 studyStandard dose-escalation designRefractory acute myeloid leukemiaBM blast cellsGrade 1 fatigueGrade 1 nauseaPreclinical AML modelsTreatment-related deathsLow-dose cytarabinePhase 2 studySerious adverse eventsSpeakers bureauDose-escalation trialFurther dose escalationPhase 3 studyDose-escalation design