2024
Future directions in myelodysplastic syndromes/neoplasms and acute myeloid leukaemia classification: from blast counts to biology
Della Porta M, Bewersdorf J, Wang Y, Hasserjian R. Future directions in myelodysplastic syndromes/neoplasms and acute myeloid leukaemia classification: from blast counts to biology. Histopathology 2024 PMID: 39450427, DOI: 10.1111/his.15353.Peer-Reviewed Original ResearchAcute myeloid leukemiaIntegration of genomic dataGenomic informationGenomic dataPresence of SF3B1 mutationsDisease entityMethylation profilesAML classificationRecurrent genetic abnormalitiesHaematopoietic cell proliferationPercentage of myeloblastsGene expressionGenetic featuresMultiple diagnostic modalitiesPatient risk stratificationSF3B1 mutationsBlast countDisease pathogenesisGenetic abnormalitiesCell proliferationTP53 abnormalitiesDiagnostic modalitiesMyeloid leukemiaBone marrowPatient cohortData-driven, harmonised classification system for myelodysplastic syndromes: a consensus paper from the International Consortium for Myelodysplastic Syndromes
Komrokji R, Lanino L, Ball S, Bewersdorf J, Marchetti M, Maggioni G, Travaglino E, Al Ali N, Fenaux P, Platzbecker U, Santini V, Diez-Campelo M, Singh A, Jain A, Aguirre L, Tinsley-Vance S, Schwabkey Z, Chan O, Xie Z, Brunner A, Kuykendall A, Bennett J, Buckstein R, Bejar R, Carraway H, DeZern A, Griffiths E, Halene S, Hasserjian R, Lancet J, List A, Loghavi S, Odenike O, Padron E, Patnaik M, Roboz G, Stahl M, Sekeres M, Steensma D, Savona M, Taylor J, Xu M, Sweet K, Sallman D, Nimer S, Hourigan C, Wei A, Sauta E, D’Amico S, Asti G, Castellani G, Delleani M, Campagna A, Borate U, Sanz G, Efficace F, Gore S, Kim T, Daver N, Garcia-Manero G, Rozman M, Orfao A, Wang A, Foucar M, Germing U, Haferlach T, Scheinberg P, Miyazaki Y, Iastrebner M, Kulasekararaj A, Cluzeau T, Kordasti S, van de Loosdrecht A, Ades L, Zeidan A, Della Porta M, Syndromes I. Data-driven, harmonised classification system for myelodysplastic syndromes: a consensus paper from the International Consortium for Myelodysplastic Syndromes. The Lancet Haematology 2024, 11: e862-e872. PMID: 39393368, DOI: 10.1016/s2352-3026(24)00251-5.Peer-Reviewed Original ResearchGenomic featuresData-driven approachTP53 inactivationGenomic heterogeneityEntity labelsGenetic featuresDel(7q)/-7Myelodysplastic syndromeGenomic profilingData scientistsMutated SF3B1Cluster assignmentComplex karyotypeRUNX1 mutationsModified Delphi consensus processDel(5qIsolated del(5qAcute myeloid leukemiaData-drivenDelphi consensus processMarrow blastsIntensive induction chemotherapy vs hypomethylating agents in combination with venetoclax in NPM1-mutant AML
Bewersdorf J, Shimony S, Shallis R, Liu Y, Berton G, Schaefer E, Zeidan A, Goldberg A, Stein E, Marcucci G, Bystrom R, Lindsley R, Chen E, Perez J, Stein A, Pullarkat V, Aldoss I, DeAngelo D, Neuberg D, Stone R, Garciaz S, Ball B, Stahl M. Intensive induction chemotherapy vs hypomethylating agents in combination with venetoclax in NPM1-mutant AML. Blood Advances 2024, 8: 4845-4855. PMID: 38941537, PMCID: PMC11416634, DOI: 10.1182/bloodadvances.2024012858.Peer-Reviewed Original ResearchIntensive induction chemotherapyAcute myeloid leukemiaNPM1-Mutant Acute Myeloid LeukemiaInduction chemotherapyHypomethylating agentsMulticenter retrospective cohort study of patientsPatients treated with ICAllogeneic stem cell transplantationRetrospective cohort study of patientsMulticenter retrospective cohort studyCohort study of patientsComposite complete remissionStem cell transplantationYears-oldFLT3-ITD mutationStudy of patientsStandard of careNormal cytogeneticsComplete remissionCell transplantationNPM1 mutationsMyeloid leukemiaFLT3-ITDYounger patientsOlder patientsBeyond HMAs: Novel targets and therapeutic approaches
Getz T, Bewersdorf J, Kewan T, Stempel J, Bidikian A, Shallis R, Stahl M, Zeidan A. Beyond HMAs: Novel targets and therapeutic approaches. Seminars In Hematology 2024 PMID: 39389839, DOI: 10.1053/j.seminhematol.2024.08.001.Peer-Reviewed Original ResearchAcute myeloid leukemiaDelays progression to acute myeloid leukemiaHeterogeneous group of clonal hematopoietic disordersGroup of clonal hematopoietic disordersMolecular International Prognostic Scoring SystemRandomized phase 3 clinical trialProgression to acute myeloid leukemiaInternational Prognostic Scoring SystemLower-risk MDS patientsRisk stratification of patientsPhase 3 clinical trialsCombination of azacitidineHypomethylating agent combinationsCurrent treatment landscapeFirst line therapyPrognostic Scoring SystemBiomarker-directed therapiesClonal hematopoietic disordersLack of therapeutic agentsStratification of patientsEarly phase trialsErythropoiesis stimulating agentsTreated with therapiesVariable clinical featuresStandard of careAcute myeloid leukemia (AML) with chromosome 3 inversion: biology, management, and clinical outcome
Alhajahjeh A, Bewersdorf J, Bystrom R, Zeidan A, Shimony S, Stahl M. Acute myeloid leukemia (AML) with chromosome 3 inversion: biology, management, and clinical outcome. Leukemia & Lymphoma 2024, 65: 1541-1551. PMID: 38962996, DOI: 10.1080/10428194.2024.2367040.Peer-Reviewed Original ResearchAcute myeloid leukemiaIntensive chemotherapyHypomethylating agentsMyeloid leukemiaAllogeneic stem cell transplantationAcute myeloid leukemia casesAcute myeloid leukemia subtypesStem cell transplantationComplex hematological malignancyCurrent treatment modalitiesRare genetic anomalyCell transplantationHematologic malignanciesTreatment modalitiesClinical outcomesTreatment responseInv(3Genetic alterationsLeukemia developmentTreatment strategiesCellular processesGenetic anomaliesLeukemiaFusion geneClinical implicationsPrognostic impact of ‘multi-hit’ versus ‘single-hit’ TP53 alteration in patients with acute myeloid leukemia: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases
Badar T, Nanaa A, Atallah E, Shallis R, Craver E, Li Z, Goldberg A, Saliba A, Patel A, Bewersdorf J, Duvall A, Burkart M, Bradshaw D, Abaza Y, Stahl M, Palmisiano N, Murthy S, Zeidan A, Kota V, Patnaik M, Litzow M. Prognostic impact of ‘multi-hit’ versus ‘single-hit’ TP53 alteration in patients with acute myeloid leukemia: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases. Haematologica 2024, 109: 3533-3542. PMID: 38813716, PMCID: PMC11532685, DOI: 10.3324/haematol.2024.285000.Peer-Reviewed Original ResearchAcute myeloid leukemiaMyelodysplastic syndromeComplex cytogeneticsMyeloid leukemiaAllogeneic hematopoietic stem cell transplantationLower-risk myelodysplastic syndromesHematopoietic stem cell transplantationHigher-risk myelodysplastic syndromesOutcomes of SHStem cell transplantationAllo-HCTTP53 alterationsPrognostic impactMyeloid malignanciesTP53 mutationsCell transplantationFLT3-ITDIDH1 mutationMultivariate analysisSupportive careUS academic institutionsNeoplastic diseasePatientsSuperior EFSPredicting outcomeCost-effectiveness of adding quizartinib to induction chemotherapy for patients with FLT3-mutant acute myeloid leukemia
Bewersdorf J, Patel K, Shallis R, Podoltsev N, Kewan T, Stempel J, Mendez L, Stahl M, Stein E, Huntington S, Goshua G, Zeidan A. Cost-effectiveness of adding quizartinib to induction chemotherapy for patients with FLT3-mutant acute myeloid leukemia. Leukemia & Lymphoma 2024, 65: 1136-1144. PMID: 38648559, PMCID: PMC11265977, DOI: 10.1080/10428194.2024.2344052.Peer-Reviewed Original ResearchQuality-adjusted life yearsCompletion of consolidation therapyFLT3-mutant acute myeloid leukemiaAllogeneic hematopoietic cell transplantationIncremental cost-effectiveness ratioProbabilistic sensitivity analysesImproved overall survivalHematopoietic cell transplantationPartitioned survival analysis modelAcute myeloid leukemiaCost-effectiveness ratioFLT3 inhibitor quizartinibHealth economic implicationsConsolidation therapyInduction chemotherapyAverage wholesale priceOverall survivalCell transplantationContinuous therapyMyeloid leukemiaITD mutationQuizartinibIncremental costCost-effective optionLife yearsComparing venetoclax in combination with hypomethylating agents to hypomethylating agent-based therapies for treatment naive TP53-mutated acute myeloid leukemia: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND)
Badar T, Nanaa A, Atallah E, Shallis R, Guilherme S, Goldberg A, Saliba A, Patel A, Bewersdorf J, DuVall A, Bradshaw D, Abaza Y, Murthy G, Palmisiano N, Zeidan A, Kota V, Litzow M. Comparing venetoclax in combination with hypomethylating agents to hypomethylating agent-based therapies for treatment naive TP53-mutated acute myeloid leukemia: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND). Blood Cancer Journal 2024, 14: 32. PMID: 38378617, PMCID: PMC10879201, DOI: 10.1038/s41408-024-01000-2.Peer-Reviewed Original ResearchHypomethylating agents plus venetoclax compared with intensive induction chemotherapy regimens in molecularly defined secondary AML
Shimony S, Bewersdorf J, Shallis R, Liu Y, Schaefer E, Zeidan A, Goldberg A, Stein E, Marcucci G, Lindsley R, Chen E, Ramos Perez J, Stein A, DeAngelo D, Neuberg D, Stone R, Ball B, Stahl M. Hypomethylating agents plus venetoclax compared with intensive induction chemotherapy regimens in molecularly defined secondary AML. Leukemia 2024, 38: 762-768. PMID: 38378841, DOI: 10.1038/s41375-024-02175-0.Peer-Reviewed Original ResearchAssociated with improved OSHypomethylating agentsCPX-351Overall survivalSplicing factor mutationsCo-mutationsAllogeneic hematopoietic stem cell transplantationAssociated with better OSAssociated with worse OSSecondary acute myeloid leukemiaHematopoietic stem cell transplantationMedian overall survivalStem cell transplantationPatients aged >Acute myeloid leukemiaTreated with daunorubicinLiposomal daunorubicinMonosomal karyotypeNRAS/KRAS mutationsImproved OSSecondary AMLMyeloid diseasesMyeloid neoplasmsAML patientsAML treatmentIntegrated genetic, epigenetic, and immune landscape of TP53 mutant AML and higher risk MDS treated with azacitidine
Zeidan A, Bewersdorf J, Hasle V, Shallis R, Thompson E, de Menezes D, Rose S, Boss I, Halene S, Haferlach T, Fox B. Integrated genetic, epigenetic, and immune landscape of TP53 mutant AML and higher risk MDS treated with azacitidine. Therapeutic Advances In Hematology 2024, 15: 20406207241257904. PMID: 38883163, PMCID: PMC11180421, DOI: 10.1177/20406207241257904.Peer-Reviewed Original ResearchHigher-risk myelodysplastic syndromesAcute myeloid leukemiaBone marrowMutation statusImmune landscapeImmunological landscapeAnti-PD-L1 antibody durvalumabHR-MDS patientsWild-type acute myeloid leukemiaTP53-mutant acute myeloid leukemiaMutant acute myeloid leukemiaAzacitidine-based therapyWild-type patientsImmune checkpoint proteinsImmune checkpoint expressionT cell populationsWild-typeStatistically significant decreaseAZA therapyImmunosuppressive microenvironmentPD-L1Mutant patientsDNA methylation arraysCheckpoint expressionMyelodysplastic syndrome
2023
A multicenter phase Ib trial of the histone deacetylase inhibitor entinostat in combination with pembrolizumab in patients with myelodysplastic syndromes/neoplasms or acute myeloid leukemia refractory to hypomethylating agents
Bewersdorf J, Shallis R, Sharon E, Park S, Ramaswamy R, Roe C, Irish J, Caldwell A, Wei W, Yacoub A, Madanat Y, Zeidner J, Altman J, Odenike O, Yerrabothala S, Kovacsovics T, Podoltsev N, Halene S, Little R, Piekarz R, Gore S, Kim T, Zeidan A. A multicenter phase Ib trial of the histone deacetylase inhibitor entinostat in combination with pembrolizumab in patients with myelodysplastic syndromes/neoplasms or acute myeloid leukemia refractory to hypomethylating agents. Annals Of Hematology 2023, 103: 105-116. PMID: 38036712, DOI: 10.1007/s00277-023-05552-4.Peer-Reviewed Original ResearchConceptsDose-limiting toxicityAcute myeloid leukemiaMarrow complete remissionPhase Ib trialAdverse eventsIb trialDose escalationNCI Cancer Therapy Evaluation ProgramAcute myeloid leukemia refractoryHematologic adverse eventsProtocol-defined responseDose level 1Anti-PD1 therapyAnti-PD1 antibodyDose-escalation designLimited clinical efficacySystems immunology approachHistone deacetylase inhibitor entinostatLeukemia refractoryMCR patientsComplete remissionRespiratory failureSuppressor cellsEscalation designClinical efficacyMoving toward disease modification in polycythemia vera
Bewersdorf J, How J, Masarova L, Bose P, Pemmaraju N, Mascarenhas J, Rampal R. Moving toward disease modification in polycythemia vera. Blood 2023, 142: 1859-1870. PMID: 37729609, DOI: 10.1182/blood.2023021503.Peer-Reviewed Original ResearchConceptsAcute myeloid leukemiaProgression to myelofibrosisPolycythemia veraCytoreductive therapyBCR-ABL1-negative myeloproliferative neoplasmsLow-risk PVLow-risk diseaseHistory of thrombosisHigh-risk diseaseDisease-modifying treatment modalitiesAssociated with higher ratesEvolving treatment landscapeClinically meaningful outcome measuresDisease-related symptomsInterferon alfaMyeloproliferative neoplasmsThromboembolic eventsPatient ageMyeloid leukemiaTreatment modalitiesIFN-a2bTherapeutic phlebotomyActivating mutationsVasomotor symptomsDisease courseTP53 Y220C Mutations in Patients with Myeloid Malignancies
Gener-Ricos G, Bewersdorf J, Loghavi S, Goldberg A, Famulare C, Issa G, Borthakur G, Kadia T, Carter B, Patel K, Andreeff M, Stein E, DiNardo C. TP53 Y220C Mutations in Patients with Myeloid Malignancies. Blood 2023, 142: 1477. DOI: 10.1182/blood-2023-189343.Peer-Reviewed Original ResearchLeukemia-free survivalAcute myeloid leukemiaMedian leukemia-free survivalVariant allele frequencyMedian follow-upStem cell transplantationMyeloid neoplasmsHot spot mutationsTP53 mutationsCo-mutationsFollow-upMyelodysplastic syndromeMyeloid malignanciesOverall survivalHematologic malignanciesMyeloid leukemiaSolid tumorsTransformation to acute myeloid leukemiaMedian variant allele frequencyTherapy-related myeloid neoplasmsAcute myeloid leukemia transformationMemorial Sloan-Kettering Cancer CenterY220C mutationTP53 co-mutationsNext generation sequencing assayE7820, an Anti-Cancer Sulfonamide, in Combination with Venetoclax in Patients with Splicing Factor Mutant Myeloid Malignancies: A Phase II Clinical Trial
Bewersdorf J, Chandhok N, Watts J, Derkach A, Abdel-Wahab O, Stein E, Taylor J. E7820, an Anti-Cancer Sulfonamide, in Combination with Venetoclax in Patients with Splicing Factor Mutant Myeloid Malignancies: A Phase II Clinical Trial. Blood 2023, 142: 1547. DOI: 10.1182/blood-2023-182369.Peer-Reviewed Original ResearchAcute myeloid leukemiaEastern Cooperative Oncology GroupPhase II clinical trialChronic myelomonocytic leukemiaMyelodysplastic syndromePatient-derived xenograftsII clinical trialsPreclinical dataSplicing factor genesMyeloid malignanciesClinical trialsAdequate end-organ functionContext of combination therapyDay 1Safety run-in phaseRefractory acute myeloid leukemiaSimon 2-stage designResponse rateDynamic BH3 profilingCycles of therapyNegative prognostic impactEvent-free survivalMyelodysplastic syndrome patientsHuman acute myeloid leukemiaPhase II trialIntensive Induction Chemotherapy (IC) Vs Hypomethylating Agents + Venetoclax (HMA/VEN) in IDH1- or IDH2-Mutant Newly Diagnosed Acute Myeloid Leukemia (AML) - a Multicenter Cohort Study
Bewersdorf J, Shimony S, Shallis R, Liu Y, Schaefer E, Zeidan A, Goldberg A, Stein E, Marcucci G, Lindsley R, Chen E, Ramos J, Stein A, DeAngelo D, Neuberg D, Stone R, Ball B, Stahl M. Intensive Induction Chemotherapy (IC) Vs Hypomethylating Agents + Venetoclax (HMA/VEN) in IDH1- or IDH2-Mutant Newly Diagnosed Acute Myeloid Leukemia (AML) - a Multicenter Cohort Study. Blood 2023, 142: 1589. DOI: 10.1182/blood-2023-174283.Peer-Reviewed Original ResearchIntensive induction chemotherapyAcute myeloid leukemiaComposite complete responseMedian overall survivalOverall survivalComplete responseIDH2 mutationsAllo-SCTLarge multicenter retrospective cohort studyMulticenter retrospective cohort studyAllogeneic stem cell transplantationSecondary acute myeloid leukemiaComparable overall survivalIDH1 inhibitor ivosidenibHigh rateRetrospective cohort studyStem cell transplantationLog-rank testStandard of careLarge academic centerYears of ageEffect of treatmentIDH-mutant AMLMultivariable stepwiseFit patientsWhat Is the Optimal Treatment Modality in Molecularly Defined Secondary AML? a Multicenter Cohort Study
Shimony S, Bewersdorf J, Shallis R, Liu Y, Schaefer E, Zeidan A, Goldberg A, Stein E, Marcucci G, Chen E, Ramos J, Lindsley R, Stein A, DeAngelo D, Neuberg D, Stone R, Ball B, Stahl M. What Is the Optimal Treatment Modality in Molecularly Defined Secondary AML? a Multicenter Cohort Study. Blood 2023, 142: 1478. DOI: 10.1182/blood-2023-172763.Peer-Reviewed Original ResearchAcute myeloid leukemiaComposite complete responseStem cell transplantationOverall survivalCPX-351Complete responseTreatment modalitiesMonosomal karyotypeCohort studyOdds ratioTreatment groupsLarge multicenter retrospective cohort studyMulticenter retrospective cohort studyAllogeneic stem cell transplantationSecondary acute myeloid leukemiaIncomplete count recoveryImproved overall survivalMedian overall survivalMulticenter cohort studyRetrospective cohort studyWorse overall survivalOptimal treatment modalityOptimal treatment selectionLog-rank testEffect of treatmentIntensive Induction Chemotherapy Vs Hypomethylating Agents + Venetoclax (HMA/VEN) in NPM1-Mutant Newly Diagnosed Acute Myeloid Leukemia (AML) - a Multicenter Cohort Study
Bewersdorf J, Shimony S, Shallis R, Liu Y, Schaefer E, Zeidan A, Goldberg A, Stein E, Marcucci G, Lindsley R, Chen E, Ramos J, Stein A, DeAngelo D, Neuberg D, Stone R, Ball B, Stahl M. Intensive Induction Chemotherapy Vs Hypomethylating Agents + Venetoclax (HMA/VEN) in NPM1-Mutant Newly Diagnosed Acute Myeloid Leukemia (AML) - a Multicenter Cohort Study. Blood 2023, 142: 2964. DOI: 10.1182/blood-2023-174285.Peer-Reviewed Original ResearchNPM1 mutant acute myeloid leukemiaIntensive induction chemotherapyAcute myeloid leukemiaComposite complete responseMedian overall survivalOverall survivalComplete responseAllo-SCTPt ageAbnormal cytogeneticsCohort studyMyelodysplastic syndromePolymerase chain reactionClinical trialsMyeloid leukemiaNPM1 mutationsLarge multicenter retrospective cohort studyTime-varying covariatesMulticenter retrospective cohort studyAllogeneic stem cell transplantationPrior myelodysplastic syndromeMulticenter cohort studyRetrospective cohort studyStem cell transplantationPrior chemotherapy exposureComparable Survival of Treatment Naïve TP53 Mutated Acute Myeloid Leukemia Treated with Hypomethylating Agent Compared to Hypomethylating Agent Plus Venetoclax Based Therapy
Badar T, Atallah E, Shallis R, Patel A, De Camargo Correia G, Goldberg A, Saliba A, Bewersdorf J, Duvall A, Bradshaw D, Abaza Y, Murthy S, Palmisiano N, Kota V, Litzow M. Comparable Survival of Treatment Naïve TP53 Mutated Acute Myeloid Leukemia Treated with Hypomethylating Agent Compared to Hypomethylating Agent Plus Venetoclax Based Therapy. Blood 2023, 142: 592. DOI: 10.1182/blood-2023-184626.Peer-Reviewed Original ResearchAcute myeloid leukemiaComplete remission rateOverall survivalDuration of responseMultivariable analysisComplex cytogeneticsAllo-HCTRemission rateMyeloid leukemiaAllogeneic stem cell transplantSecondary acute myeloid leukemiaAdverse-risk diseaseCR/CRiMedian overall survivalOutcome of ptsResults Baseline characteristicsKaplan-Meier methodMore effective treatment strategiesSignificant univariate predictorsStem cell transplantEffective treatment strategiesReal-world studyLogistic regression modelsMedian followVEN groupWhen to use which molecular prognostic scoring system in the management of patients with MDS?
Kewan T, Bewersdorf J, Gurnari C, Xie Z, Stahl M, Zeidan A. When to use which molecular prognostic scoring system in the management of patients with MDS? Best Practice & Research Clinical Haematology 2023, 36: 101517. PMID: 38092484, DOI: 10.1016/j.beha.2023.101517.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsInternational Prognostic Scoring SystemPrognostic scoring systemAcute myeloid leukemiaScoring systemRisk stratificationRecurrent molecular alterationsHigh-risk patientsAppropriate risk stratificationManagement of patientsRecurrent genetic mutationsIntensive therapyMyeloid leukemiaTreatment strategiesPrognostic toolDisease pathogenesisMolecular alterationsHematopoietic cancersClinical decisionHeterogeneous groupGenetic mutationsNext-generation sequencingPrognostic systemPatientsVariable propensitySubsequent revisionManagement of Acute Myeloid Leukemia with Myelodysplasia-Related Changes and Therapy-Related Acute Myeloid Leukemia
Bewersdorf J, Zeidan A. Management of Acute Myeloid Leukemia with Myelodysplasia-Related Changes and Therapy-Related Acute Myeloid Leukemia. 2023, 119-128. DOI: 10.1007/978-981-99-3810-0_8.ChaptersTherapy-related AMLAcute myeloid leukemiaSecondary AMLAML-MRCMyeloid leukemiaRandomized phase III clinical trialsPhase III clinical trialsAdverse cytogenetic featuresOverall survival benefitDe novo AMLT-AML patientsYears of ageHigh-risk mutationsInduction chemotherapyMonosomal karyotypeCPX-351Intensive chemotherapyNovo AMLSurvival benefitTreatment landscapeAdverse prognosisFrontline treatmentSubgroup analysisClinical trialsConventional chemotherapy