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All TopicsAll Topics▸Section 1: Clinical hematology: Non-malignant hematology▸1A Red cell and iron disorders-1Aa Anemias due to deficiency (iron, B12, folate)-1Ab Anemia of chronic disease-1Ac Anemia due to toxic exposure-1Ad Pure red cell aplasia-1Ae Thalassemia including HbE disorders-1Af Sickle cell disease-1Ah Red blood cell membrane and enzyme disorders (e.g. Spherocytosis and G6PD deficiency)-1Ag Other hemoglobinopathies-1Ai Acquired immune hemolytic anemias-1Aj Acquired non-immune hemolytic anemias-1Ak Other congenital anemias (CDA, sideroblastic anemia)-1Al Erythrocytosis (other than PV)-1Am Primary hemochromatosis-1An Secondary hemochromatosis-1Ao Porphyria and other rare metabolic disorders (e.g. Gaucher, methemoglobinemia)▸1B Bone marrow failure-1Ba Acquired aplastic anemia-1Bb Paroxysmal nocturnal hemoglobinuri-1Bc Fanconi’s anemia-1Bd Other inherited bone marrow failure syndromes (e.g. Blackfan-Diamond, Dyskeratosis congenital, Telomere diseases)-1Be Idiopathic cytopenia of undetermined significance (ICUS)▸1C Non-malignant white blood cell disorders-1Ca Granulocyte dysfunction disorders-1Cb Congenital granulocytopenia-1Cc Acquired granulocytopenia-1Cd Lymphopenia and Immune deficiency syndromes-1Ce Hemophagocytic lymphohistiocytosis-1Cf Secondary leukocytosis-1Cg Eosinophilia▸1D Platelet disorders and angiopathies-1Dc Heparin-induced thrombocytopenia-1Dd Thrombocytopenia in pregnancy-1Da Immune thrombocytopenia-1Db Thrombotic microangiopathies (e.g. TTP)-1De Disorders with telangiectasias (e.g. Rendu-Osler-Weber disease) (For other platelet disorders see section Coagulation)▸1E Consultative hematology-1Ef Hyposplenism and hypersplenism-1Ec Hematological variations and abnormalities in pregnancy-1Eb Hematological manifestations of congenital metabolism disorders-1Ea Hematological manifestations of non-hematological disorders-1Ed Neonatal hematological variations and abnormalities-1Ee Hematological manifestations in HIV and other infectious diseases▸Section 2: Clinical hematology: Myeloid malignancies▸2A Myeloproliferative and myelodysplastic neoplasm-2Aa Chronic myeloid leukemia, BCR-ABL1-positive-2Ab Polycythemia vera-2Ac Myelofibrosis-2Ad Essential thrombocythemia-2Ag Myelodysplastic syndromes-2Ae Mastocytosis-2Ah Other Myeloproliferative and Myelodysplastic disorders in adults-2Af Myelodysplastic/myeloproliferative neoplasms▸2C Pediatric myeloid disorders-2Cb JMML-2Ca Myeloid proliferations related to Down syndrome-2Cc Myelodysplastic syndromes-2Cd AML▸2B Acute myeloid leukemia (AML) and leukemias of ambiguous lineage-2Ba AML with recurrent genetic abnormalities-2Bb AML with MDS related changes-2Bc Therapy related AML and MDS-2Bd Other AML (including genetic predisposition syndromes)-2Be Acute leukemia of ambiguous lineage▸Section 3: Clinical hematology Lymphoid malignancies and plasma cell disorders▸3A B-cell neoplasms and B-cell disorders-3Aa B lymphoblastic leukemia/lymphoma-3Ab Diffuse large B-cell lymphoma-3Ac Burkitt's lymphoma-3Ad Rare aggressive B-cell lymphomas (e.g. double-hit, intravascular, plasmablastic, ALK+ and ALK- large B-cell lymphoma-3Ae Mantle cell lymphoma-3Af Follicular lymphoma-3Ag Other indolent B-cell lymphomas (e.g. lymphoplasmacytic lymphoma, hairy cell leukemia)-3Ah Marginal zone lymphomas-3Aj Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)-3Ai Monoclonal B-cell lymphocytosis (MBL)▸3B T-cell lymphomas and NK-cell neoplasms-3Ba T lymphoblastic leukemia/lymphoma-3Bb Common T-cell lymphomas-3Bc Rare T- and NK-cell lymphomas▸3C Hodgkin lymphoma-3Cb Nodular lymphocyte predominant HL-3Ca Classical HL▸3D Other special entities-3De Castlemann disease-3Da Lymphomas in immunodeficient patients (including PTLD, HIV-associated lymphoma)-3Db Cutaneous lymphomas-3Dc Primary CNS lymphoma-3Dd Histiocytic and dendritic cell neoplasms▸3E Plasma cell neoplasms-3Ea Monoclonal gammopathy of undetermined significance (MGUS)-3Eb Solitary plasmacytoma-3Ec Plasma cell myeloma (Multiple myeloma)-3Ed Monoclonal immunoglobulin deposition diseases (e.g. amyloidosis)▸3F Pediatric lymphoid malignancies-3Fa Acute lymphoblastic leukemia (B or T)-3Fb Pediatric lymphoma▸Section 4: Treatment of hematological disorders▸4B Stem cell transplantation and other cellular therapies-4Ba Indication for autologous stem cell transplantation-4Bd Criteria for selection of intensity for the preparative regimens-4Be Identification and selection of stem cell donor-4Bf Acute and chronic graft versus host disease-4Bg Pulmonary complications, veno-occlusive disease of the liver, hemorrhagic cystitis and other complications-4Bc Mobilization, collection and manipulation of hematopoeitic stem cells-4Bj Indication for specific and gene-modified cell therapy-4Bb Indication for allogeneic stem cell transplantation-4Bh Post-transplant monitoring-4Bi Late complication (including long term follow-up)▸4A Principals of treatment-4Aa Drug therapy including targeted drugs: mechanisms of action, pharmacology and drug resistance-4Ab Short and long term complications of chemotherapy and radiotherapy-4Ac Hematological malignancies in pregnancy▸4C Infectious complications-4Ca Neutropenic fever (including growth factors)-4Cb Bacterial infection-4Cc Fungal disease-4Cd Cytomegalovirus (CMV) /EBV , herpes, hepatitis and other viral infections▸4D Supportive and emergency care-4Da Hyperleukocytosis, hyperviscosity, and tumor lysis syndrome-4Db Rare complications (Spinal cord compression and other neurological and psychiatric disturbances, superior vena cava syndrome)-4Dc Nausea and pain management-4Dd Nutrition▸4E Pharmacology and pharmacovigilance-4Ec Drug interactions-4Ed Critically appraisal of biosimilars-4Ea Pharmacovigilance-4Eb Adverse event management▸Section 5: Laboratory diagnosis▸5A Good laboratory practice-5Ae Integrating diagnosis from laboratory investigations and relating them to the clinical picture-5Aa Principles of laboratory management and organization-5Ab Laboratory quality management and accreditation/certification (including internal and external quality control)-5Ac Hazards and safety-5Ad Reference ranges of laboratory values, with relevance to gender, age and ethnicity▸5B Blood count and morphology-5Bf Pseudo thrombocytopenia-5Ba Automated complete blood count with white blood cell differential-5Bb Performing aspiration and biopsy of bone marrow, lumbar puncture and lymph node fine needle aspiration and preparation of slides, touch preparations and trephine rolls-5Bc Preparation, fixation, staining, reading and reporting of peripheral blood smears and bone marrow aspirates and trephine rolls-5Bd Cytochemical, special stains and immunostaining of blood and bone marrow smears in hematological conditions-5Be Review and interpretation of trephine, lymph node and other relevant tissue biopsies together with a pathologist▸5C Other laboratory techniques-5Ce Progenitor quantification in semi-solid culture conditions-5Ca Hemoglobin analyses (e.g. hemoglobin electrophoresis)-5Cb Other red blood cell laboratory techniques (e.g. sickling process, oxygen affinity, red blood cell enzyme assays - pyruvate kinase, glucose-6-phosphate dehydrogenase)-5Cc Laboratory work-up on iron metabolism and vitamin deficiencies-5Cd Detection of immunoglobulin abnormalities▸5D Immunophenotyping by flow cytometry-5Da Clinical applications of flow cytometry for diagnosis, classification, prognosis, evaluation of minimal residual disease and stem cell quantification-5Db Pre-analytical and analytical phase of flow cytometry of blood, bone marrow, and body fluids (e.g. specimen processing, surface vs. intracytoplasmic staining, acquiring data, gating strategies)-5Dc Essential cellular markers, disease-oriented antibody panels applied in hematological conditions-5Dd Data analysis and interpretation (e.g. determination of the lineage of cells of interest, clonality, stem cell quantification, telomere length and specific subtypes of hematological condition)▸5E Genetics and molecular biology-5Ee Other techniques for detection and quantification of recurrent mutations-5Ef Other techniques for gene discovery and expression-5Eb Conventional cytogenetics, chromosome breakage and fluorescence in situ hybridization-5Ec Polymerase chain reactions for the detection of gene mutations, fusion genes, clonality assessment, and gene expression-5Ed Other techniques for detection of copy number variations and gene polymorphisms-5Ea Clinical applications of these techniques for diagnosis, classification, prognosis, minimal residual disease of hematological disorders▸5F Coagulation-5Fa Techniques for assessing coagulation and platelets-5Fb Assays for inhibitors-5Fc Assays for monitoring anticoagulants▸5G Immunohematology-5Ga Red cell typing and allocation-5Gb Minor RBC, platelet and neutrophil antigens-5Gc Laboratory diagnosis of alloimmune and autoimmune cytopenia▸Section 6: Thrombosis and hemostasis▸6A Acquired bleeding disorders-6Aa Massive bleeding in obstetrics, trauma and surgery-6Ab Disseminated intravascular coagulation (DIC)-6Ac Bleeding associated with renal and liver disease-6Ad Bleeding related to anticoagulants and antithrombotic therapy-6Ae Acquired bleeding disorders in adults (inhibitors to F VIII and vWF)-6Af Acquired bleeding disorders in children-6Ag Adverse effects of treatment used in acute bleeding (blood products, pro-hemostatic drugs)▸6B Congenital bleeding disorders-6Ba Hemophilia A & B-6Bb Von Willebrand disease-6Bc Other clotting factor disorders-6Bd Considerations in carriers of hemophilia in relation to pregnancy and management of neonates with hemophilia-6Bf Safety of treatment with blood products and factor concentrates-6Be Congenital platelet disorders▸6C Thrombotic disorders-6Ca Diagnosis and treatment of venous thromboembolism-6Cb Anticoagulant and thrombolytic therapy in other medical conditions-6Cc Thrombophilia (congenital and acquired)-6Cd Treatment and prophylaxis of venous thromboembolism in pregnancy-6Ce Specific therapy in thrombotic disorders (e.g. caval filters)-6Cf Thrombosis in children (including purpura fulminans)▸Section 7: Transfusion medicine▸7B Clinical use of blood components-7Bb Use of blood products and alternatives in medical patients (e.g. liver, renal, cardiac disease, hematological)-7Be Blood alternatives. Management of patients who refuse blood transfusion-7Ba Indication, choice and application of blood components-7Bc Use of blood products and alternatives in surgical and obstetric patients (e.g. trauma, cardiac surgery)-7Bd Use of blood products and alternatives in fetal, neonatal and pediatric patients-7Bf Transfusion reactions and complications (including hemovigilance)▸7C Specific techniques-7Ca Indications and complications of apheresis-7Cb Indications and complications of therapeutic phlebotomy▸7A Blood donation-7Aa Selection of blood donors-7Ab Epidemiology and screening of blood borne infections-7Ac Blood collection procedures▸Section 8: General skills▸8A Basic biological concepts-8Aa Hematopoiesis and stem cell biology-8Ab Chromosome and gene structure-8Ac The role of deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and proteins in normal cellular processes-8Ad Basic concepts of transcription and translation, epigenetic regulation, RNA splicing, signal transduction, cell cycle regulation and apoptosis and methods of investigation-8Ae Mechanisms in hemostasis▸8B Evidence based medicine-8Ba Fundamental principles of evidence based medicine-8Bb Critical appraisal of scientific literature including statistical methods-8Bc Strategic and economic implications of combining drugs and clinical biomarkers▸8C Good clinical practice and clinical trials-8Cb Clinical trial-related international and local guidelines and legislation (GCP)-8Cc Obtaining informed consent in clinical trials and in routine daily medical practice-8Ca Multidisciplinary discussion-making-8Cd Methods for assessing patient reported outcomes including quality of life-8Ce The impact of age on patient management (geriatric/co-morbidity assessment) rephrased▸8D Ethics and law-8Dg Definition and disclosure of conflict of interest as well as current conflict-of-interest policies, (e.g., standards of conduct in collaboration between physicians and industry)-8Da Basic principles of medical ethics (including HELSINKI DECLARATION)-8Db Functions of the Ethics Committee-8Dc National regulations on how to manage a patient with reduced autonomy-8Dd Regulations concerning the use of human cells and tissues (bio-banking)-8De Basic principles of health economics and cost-effectiveness-8Df European and national directives on patient rights▸8E Communication skills and psychosocial issues-8Ee Collecting a history and physical examination directed at hematological diseases, e.g. bleeding disorders, inherited malignancies, etc.-8Ea Communication with patients-8Eb Communication with patients'' relatives and cohabitants-8Ec Communication within a multi-disciplinary team-8Ed Psychosocial assessment▸8F Palliative care and End-of-life-8Fa Palliative care decisions-8Fb Management and decision-making related to end-of-life situations-Section 9: European Hematology Curriculum
Abstract: LB2600
Type: Presidential Symposium
Presentation during EHA24: On Friday, June 14, 2019 from 17:00 - 17:15
Location: Hall 5
Background
Patients with acute myeloid leukemia (AML) are at risk of relapse after allogeneic hematopoietic cell transplantation (alloHCT). AML measurable residual disease (MRD) status prior to alloHCT has been shown to be prognostic. It is currently unknown if modulating the intensity of the alloHCT conditioning regimen in AML patients testing positive for MRD can prevent relapse and improve survival rates.
BMT CTN 0901 [NCT NCT01339910] was a phase III randomized clinical trial comparing outcomes by conditioning intensity in adult patients with myeloid malignancy undergoing an alloHCT in morphological complete remission (ie: <5% marrow myeloblasts at the time of pre-transplant assessment, CR).
Aims
To determine the impact of alloHCT conditioning intensity on post-transplant outcomes in AML patients in CR but with pre-transplant genomic evidence of residual disease.
Methods
A custom 51kb anchored multiplex PCR panel (ArcherDx, CO) with coverage of 13 commonly mutated genes in AML (ASXL1, DNMT3A, FLT3, IDH1, IDH2, JAK2, KIT, NPM1, NRAS, RUNX1, SF3B1, TET2 and TP53) was deployed, using an automated liquid handler, on 400ng of gDNA isolated from a frozen blood sample. Libraries, each with a unique dual index, were sequenced using an average of 41 million paired-end reads of a HiSeq 2500 rapid run. Error-corrected consensus clustering analysis required ≥5 independent UMI read families per variant (each with ≥3 supporting reads) and ≥5 unique start sites. Filtering for sample strand and sequencing direction bias, homopolymer runs, heterozygosity, variant effect and gnomAD population frequency was performed. A parametric model of sequencing error was estimated by grouping samples with similar error profiles with outliers to the model identified as variants. Based on depth of unique molecule sequencing (average 5,000 UMI read families) a limit of detection was set at an allele frequency of 0.001
Cox proportional hazards regression models were fit to TRM, Relapse, DFS, and OS.
Results
Of 218 AML patients randomized, 190 research blood samples collected immediately pre-conditioning were available. Analyzed samples (n=188) came equally from those receiving either myeloablative (MAC) or reduced intensity conditioning (RIC) and were well matched for other baseline characteristics including age, gender, comorbidity, disease risk, disease duration, cytogenetics, donor type and match, graft type and ATG use.
No genomic variants were detected in pre-conditioning blood of 31% of MAC and 33% of RIC patients, these groups had similar survival (3yr OS: 58% vs. 65%, p: 0.98). In those with detectable variants however, survival was significantly different between the arms (3yr OS: 61% vs. 44%, p: 0.02, see figure). In those relapsing in the first year after transplant, 76% had at least one detectable variant pre-conditioning. In multivariate analysis for those with detectable variants, adjusting for disease risk and donor group, reduced conditioning intensity was significantly associated with increased relapse (HR: 5.98 [3.19-11.26], p: <0.001), decreased DFS (HR: 2.80 [1.76-4.44], p<0.001) and decreased overall survival (HR: 2.16 [1.30-3.60], p: 0.003] compared to MAC.
Conclusion
Detection of an AML-associated variant using ultra-deep next-generation DNA sequencing in the blood of AML patients in CR prior to alloHCT was associated with increased relapse rate and inferior overall survival in those randomized to RIC. This study provides evidence that intervention for AML patients with MRD can result in improved survival.
Session topic: 22. Stem cell transplantation - Clinical
Keyword(s): Acute myeloid leukemia, Allogeneic hematopoietic stem cell transplant, MRD, Randomized
Abstract: LB2600
Type: Presidential Symposium
Presentation during EHA24: On Friday, June 14, 2019 from 17:00 - 17:15
Location: Hall 5
Background
Patients with acute myeloid leukemia (AML) are at risk of relapse after allogeneic hematopoietic cell transplantation (alloHCT). AML measurable residual disease (MRD) status prior to alloHCT has been shown to be prognostic. It is currently unknown if modulating the intensity of the alloHCT conditioning regimen in AML patients testing positive for MRD can prevent relapse and improve survival rates.
BMT CTN 0901 [NCT NCT01339910] was a phase III randomized clinical trial comparing outcomes by conditioning intensity in adult patients with myeloid malignancy undergoing an alloHCT in morphological complete remission (ie: <5% marrow myeloblasts at the time of pre-transplant assessment, CR).
Aims
To determine the impact of alloHCT conditioning intensity on post-transplant outcomes in AML patients in CR but with pre-transplant genomic evidence of residual disease.
Methods
A custom 51kb anchored multiplex PCR panel (ArcherDx, CO) with coverage of 13 commonly mutated genes in AML (ASXL1, DNMT3A, FLT3, IDH1, IDH2, JAK2, KIT, NPM1, NRAS, RUNX1, SF3B1, TET2 and TP53) was deployed, using an automated liquid handler, on 400ng of gDNA isolated from a frozen blood sample. Libraries, each with a unique dual index, were sequenced using an average of 41 million paired-end reads of a HiSeq 2500 rapid run. Error-corrected consensus clustering analysis required ≥5 independent UMI read families per variant (each with ≥3 supporting reads) and ≥5 unique start sites. Filtering for sample strand and sequencing direction bias, homopolymer runs, heterozygosity, variant effect and gnomAD population frequency was performed. A parametric model of sequencing error was estimated by grouping samples with similar error profiles with outliers to the model identified as variants. Based on depth of unique molecule sequencing (average 5,000 UMI read families) a limit of detection was set at an allele frequency of 0.001
Cox proportional hazards regression models were fit to TRM, Relapse, DFS, and OS.
Results
Of 218 AML patients randomized, 190 research blood samples collected immediately pre-conditioning were available. Analyzed samples (n=188) came equally from those receiving either myeloablative (MAC) or reduced intensity conditioning (RIC) and were well matched for other baseline characteristics including age, gender, comorbidity, disease risk, disease duration, cytogenetics, donor type and match, graft type and ATG use.
No genomic variants were detected in pre-conditioning blood of 31% of MAC and 33% of RIC patients, these groups had similar survival (3yr OS: 58% vs. 65%, p: 0.98). In those with detectable variants however, survival was significantly different between the arms (3yr OS: 61% vs. 44%, p: 0.02, see figure). In those relapsing in the first year after transplant, 76% had at least one detectable variant pre-conditioning. In multivariate analysis for those with detectable variants, adjusting for disease risk and donor group, reduced conditioning intensity was significantly associated with increased relapse (HR: 5.98 [3.19-11.26], p: <0.001), decreased DFS (HR: 2.80 [1.76-4.44], p<0.001) and decreased overall survival (HR: 2.16 [1.30-3.60], p: 0.003] compared to MAC.
Conclusion
Detection of an AML-associated variant using ultra-deep next-generation DNA sequencing in the blood of AML patients in CR prior to alloHCT was associated with increased relapse rate and inferior overall survival in those randomized to RIC. This study provides evidence that intervention for AML patients with MRD can result in improved survival.
Session topic: 22. Stem cell transplantation - Clinical
Keyword(s): Acute myeloid leukemia, Allogeneic hematopoietic stem cell transplant, MRD, Randomized
Abstract: LB2600
Type: Presidential Symposium
Presentation during EHA24: On Friday, June 14, 2019 from 17:00 - 17:15
Location: Hall 5
Background
Patients with acute myeloid leukemia (AML) are at risk of relapse after allogeneic hematopoietic cell transplantation (alloHCT). AML measurable residual disease (MRD) status prior to alloHCT has been shown to be prognostic. It is currently unknown if modulating the intensity of the alloHCT conditioning regimen in AML patients testing positive for MRD can prevent relapse and improve survival rates.
BMT CTN 0901 [NCT NCT01339910] was a phase III randomized clinical trial comparing outcomes by conditioning intensity in adult patients with myeloid malignancy undergoing an alloHCT in morphological complete remission (ie: <5% marrow myeloblasts at the time of pre-transplant assessment, CR).
Aims
To determine the impact of alloHCT conditioning intensity on post-transplant outcomes in AML patients in CR but with pre-transplant genomic evidence of residual disease.
Methods
A custom 51kb anchored multiplex PCR panel (ArcherDx, CO) with coverage of 13 commonly mutated genes in AML (ASXL1, DNMT3A, FLT3, IDH1, IDH2, JAK2, KIT, NPM1, NRAS, RUNX1, SF3B1, TET2 and TP53) was deployed, using an automated liquid handler, on 400ng of gDNA isolated from a frozen blood sample. Libraries, each with a unique dual index, were sequenced using an average of 41 million paired-end reads of a HiSeq 2500 rapid run. Error-corrected consensus clustering analysis required ≥5 independent UMI read families per variant (each with ≥3 supporting reads) and ≥5 unique start sites. Filtering for sample strand and sequencing direction bias, homopolymer runs, heterozygosity, variant effect and gnomAD population frequency was performed. A parametric model of sequencing error was estimated by grouping samples with similar error profiles with outliers to the model identified as variants. Based on depth of unique molecule sequencing (average 5,000 UMI read families) a limit of detection was set at an allele frequency of 0.001
Cox proportional hazards regression models were fit to TRM, Relapse, DFS, and OS.
Results
Of 218 AML patients randomized, 190 research blood samples collected immediately pre-conditioning were available. Analyzed samples (n=188) came equally from those receiving either myeloablative (MAC) or reduced intensity conditioning (RIC) and were well matched for other baseline characteristics including age, gender, comorbidity, disease risk, disease duration, cytogenetics, donor type and match, graft type and ATG use.
No genomic variants were detected in pre-conditioning blood of 31% of MAC and 33% of RIC patients, these groups had similar survival (3yr OS: 58% vs. 65%, p: 0.98). In those with detectable variants however, survival was significantly different between the arms (3yr OS: 61% vs. 44%, p: 0.02, see figure). In those relapsing in the first year after transplant, 76% had at least one detectable variant pre-conditioning. In multivariate analysis for those with detectable variants, adjusting for disease risk and donor group, reduced conditioning intensity was significantly associated with increased relapse (HR: 5.98 [3.19-11.26], p: <0.001), decreased DFS (HR: 2.80 [1.76-4.44], p<0.001) and decreased overall survival (HR: 2.16 [1.30-3.60], p: 0.003] compared to MAC.
Conclusion
Detection of an AML-associated variant using ultra-deep next-generation DNA sequencing in the blood of AML patients in CR prior to alloHCT was associated with increased relapse rate and inferior overall survival in those randomized to RIC. This study provides evidence that intervention for AML patients with MRD can result in improved survival.
Session topic: 22. Stem cell transplantation - Clinical
Keyword(s): Acute myeloid leukemia, Allogeneic hematopoietic stem cell transplant, MRD, Randomized
Abstract: LB2600
Type: Presidential Symposium
Presentation during EHA24: On Friday, June 14, 2019 from 17:00 - 17:15
Location: Hall 5
Background
Patients with acute myeloid leukemia (AML) are at risk of relapse after allogeneic hematopoietic cell transplantation (alloHCT). AML measurable residual disease (MRD) status prior to alloHCT has been shown to be prognostic. It is currently unknown if modulating the intensity of the alloHCT conditioning regimen in AML patients testing positive for MRD can prevent relapse and improve survival rates.
BMT CTN 0901 [NCT NCT01339910] was a phase III randomized clinical trial comparing outcomes by conditioning intensity in adult patients with myeloid malignancy undergoing an alloHCT in morphological complete remission (ie: <5% marrow myeloblasts at the time of pre-transplant assessment, CR).
Aims
To determine the impact of alloHCT conditioning intensity on post-transplant outcomes in AML patients in CR but with pre-transplant genomic evidence of residual disease.
Methods
A custom 51kb anchored multiplex PCR panel (ArcherDx, CO) with coverage of 13 commonly mutated genes in AML (ASXL1, DNMT3A, FLT3, IDH1, IDH2, JAK2, KIT, NPM1, NRAS, RUNX1, SF3B1, TET2 and TP53) was deployed, using an automated liquid handler, on 400ng of gDNA isolated from a frozen blood sample. Libraries, each with a unique dual index, were sequenced using an average of 41 million paired-end reads of a HiSeq 2500 rapid run. Error-corrected consensus clustering analysis required ≥5 independent UMI read families per variant (each with ≥3 supporting reads) and ≥5 unique start sites. Filtering for sample strand and sequencing direction bias, homopolymer runs, heterozygosity, variant effect and gnomAD population frequency was performed. A parametric model of sequencing error was estimated by grouping samples with similar error profiles with outliers to the model identified as variants. Based on depth of unique molecule sequencing (average 5,000 UMI read families) a limit of detection was set at an allele frequency of 0.001
Cox proportional hazards regression models were fit to TRM, Relapse, DFS, and OS.
Results
Of 218 AML patients randomized, 190 research blood samples collected immediately pre-conditioning were available. Analyzed samples (n=188) came equally from those receiving either myeloablative (MAC) or reduced intensity conditioning (RIC) and were well matched for other baseline characteristics including age, gender, comorbidity, disease risk, disease duration, cytogenetics, donor type and match, graft type and ATG use.
No genomic variants were detected in pre-conditioning blood of 31% of MAC and 33% of RIC patients, these groups had similar survival (3yr OS: 58% vs. 65%, p: 0.98). In those with detectable variants however, survival was significantly different between the arms (3yr OS: 61% vs. 44%, p: 0.02, see figure). In those relapsing in the first year after transplant, 76% had at least one detectable variant pre-conditioning. In multivariate analysis for those with detectable variants, adjusting for disease risk and donor group, reduced conditioning intensity was significantly associated with increased relapse (HR: 5.98 [3.19-11.26], p: <0.001), decreased DFS (HR: 2.80 [1.76-4.44], p<0.001) and decreased overall survival (HR: 2.16 [1.30-3.60], p: 0.003] compared to MAC.
Conclusion
Detection of an AML-associated variant using ultra-deep next-generation DNA sequencing in the blood of AML patients in CR prior to alloHCT was associated with increased relapse rate and inferior overall survival in those randomized to RIC. This study provides evidence that intervention for AML patients with MRD can result in improved survival.
Session topic: 22. Stem cell transplantation - Clinical
Keyword(s): Acute myeloid leukemia, Allogeneic hematopoietic stem cell transplant, MRD, Randomized