REGULAR ARTICLE Risk classification at diagnosis predicts post-HCT outcomes in intermediate-, adverse-risk, and KMT2A-rearranged AML Kamal Menghrajani,1 Alexandra Gomez-Arteaga,2 Rafael Madero-Marroquin,3 Mei-Jie Zhang,4,5 Khalid Bo-Subait,4 Jonathan Sanchez,4 Hai-Lin Wang,4 Mahmoud Aljurf,6 Amer Assal,7 Vera Ulrike Bacher,8 Sherif M. Badawy,9,10 Nelli Bejanyan,11 Vijaya Raj Bhatt,12 Christopher Bredeson,13,14 Michael Byrne,15 Paul Castillo,16 Jan Cerny,17 Saurabh Chhabra,4,18 Stefan Octavian Ciurea,19 Zachariah DeFilipp,20 Nosha Farhadfar,21 Shahinaz Gadalla,22 Robert Peter Gale,23 Siddhartha Ganguly,24 Lohith Gowda,25 Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/3/828/1873691/advancesadv2021004881.pdf by guest on 09 November 2023 Michael R. Grunwald,26 Shahrukh Hashmi,27,28 Gerhard Hildebrandt,29 Christopher G. Kanakry,30 Ankit Kansagra,31 Farhad Khimani,32 Maxwell Krem,33 Hillard Lazarus,34 Hongtao Liu,35 Rodrigo Martino,36 Fotios V. Michelis,37 Sunita Nathan,38 Taiga Nishihori,12 Richard Olsson,39,40 Ran Reshef,41,42 David Rizzieri,43 Jacob M. Rowe,44 Bipin N. Savani,45 Sachiko Seo,46 Akshay Sharma,47 Melhem Solh,48 Celalettin Ustun,49 Leo F. Verdonck,50 Christopher Hourigan,51 Brenda Sandmaier,52,53 Mark Litzow,54 Partow Kebriaei,55 Daniel Weisdorf,56 Yanming Zhang,57 Martin S. Tallman,1,57 and Wael Saber4 1 Leukemia Service and 2Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; 3Department of Medicine, Icahn School of Medicine, Mount Sinai St Luke’s and Mount Sinai West, New York, NY; 4Center for International Blood and Marrow Transplant Research (CIBMTR), Department of Medicine and 5Division of Biostatistics, Institute for Health and Equity, Medical College of Wisconsin, Milwaukee, WI; 6Department of Oncology, King Faisal Specialist Hospital Center and Research, Riyadh, Saudi Arabia; 7Department of Medicine, Bone Marrow Transplant and Cell Therapy Program, Columbia University Irving Medical Center, New York, NY; 8Department of Hematology, Inselspital, Bern University Hospital, University of Bern, Switzerland; 9Division of Hematology, Oncology and Stem Cell Transplant, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL; 10Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL; 11 Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL; 12The Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE; 13The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa ON, Canada; 14Ottawa Hospital Research Institute, Ottawa, ON, Canada; 15Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN; 16Division of Hematology & Oncology, Department of Pediatrics in the College of Medicine, UF Health Shands Children's Hospital, Gainesville, FL; 17Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical Center, Worcester, MA; 18Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI; 19Division of Cancer Medicine, Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX; 20Blood and Marrow Transplant Program, Massachusetts General Hospital, Boston, MA; 21Division of Hematology/Oncology, University of Florida College of Medicine, Gainesville, FL; 22Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI) Clinical Genetics Branch, National Institutes of Health (NIH), Rockville, MD; 23Haematology Research Centre, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom; 24Division of Hematological Malignancy and Cellular Therapeutics, University of Kansas Health System, Kansas City, KS; 25Section of Hematology, Department of Medicine, Yale University School of Medicine, Yale Comprehensive Cancer Center, Yale New Haven Hospital, New Haven, CT; 26Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Atrium Health, Charlotte, NC; 27Department of Internal Medicine, Mayo Clinic, Rochester, MN; 28Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; 29Markey Cancer Center, University of Kentucky, Lexington, KY; 30 Experimental Transplantation and Immunology Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD; 31UT Southwestern Medical Center, Blood and Marrow Transplant Program, Dallas, TX; 32H Lee Moffitt Cancer Center and Research Institute, Tampa, FL; 33Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY; 34Department of Medicine, University Hospitals Case Medical Center and Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH; 35Section of Hematology/Oncology, University of Chicago Medicine, Chicago, IL; 36Division of Clinical Hematology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 37Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer Centre, Toronto, ON, Canada; 38Section of Bone Marrow Transplant and Cell Therapy, Rush University Medical Center, Chicago, IL; 39Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; 40Centre for Clinical Research Sormland, Uppsala University, Uppsala, Sweden; 41Blood and Marrow Transplantation Program and 42Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY; 43Division of Hematologic Malignancies and Cellular Therapy, Duke University, Durham, NC; 44Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel; 45Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN; 46Department of Hematology and Oncology, Dokkyo Medical University, Tochigi, Japan; 47Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children’s Research Hospital, Memphis, TN; 48The Blood and Marrow Transplant Group of Georgia, Northside Hospital, Atlanta, GA; 49Hematology, Oncology, and Cell Therapy, Rush University Medical Center, Chicago, IL; 50Department of Hematology and Oncology, Isala Clinic, Zwolle, The Netherlands; 51National Heart Lung, and Blood Institute, NIH, Bethesda, MD; 52 Division of Medical Oncology, University of Washington, Seattle, WA; 53Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; 54Division of Hematology and Transplant Center, Mayo Clinic Rochester, Rochester, MN; 55Department of Stem Cell Transplantation, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX; 56Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN; and 57 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY Submitted 31 March 2021; accepted 11 July 2021; prepublished online on Blood Advan- and confidentiality. Please send requests to the corresponding author: menghrak@ ces First Edition 22 September 2021; final version published online 1 February 2022. DOI mskcc.org. 10.1182/bloodadvances.2021004881. The full-text version of this article contains a data supplement. CIBMTR supports accessibility of research in accordance with the National Institutes ß 2022 by The American Society of Hematology. Licensed under Creative Commons of Health (NIH) Data Sharing Policy and the National Cancer Institute (NCI) Cancer Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), per- Moonshot Public Access and Data Sharing Policy. The CIBMTR releases only dei- mitting only noncommercial, nonderivative use with attribution. All other rights dentified datasets that comply with all relevant global regulations regarding privacy reserved. 828 8 FEBRUARY 2022 • VOLUME 6, NUMBER 3 Little is known about whether risk classification at diagnosis predicts post-hematopoietic Key Points cell transplantation (HCT) outcomes in patients with acute myeloid leukemia (AML). We  Patients with KMT2A- evaluated 8709 patients with AML from the CIBMTR database, and after selection and rearranged AML have manual curation of the cytogenetics data, 3779 patients in first complete remission were post-HCT leukemia- included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 free and overall with KMT2A-rearranged disease. An adjusted multivariable analysis detected an survival rates similar increased risk of relapse for patients with KMT2A-rearranged or adverse-risk AML as to those with adverse compared to those with intermediate-risk disease (hazards ratio [HR], 1.27; P 5 .01; HR, risk AML. 1.71; P , .001, respectively). Leukemia-free survival was similar for patients with KMT2A  Adverse-risk AML rearrangement or adverse risk (HR, 1.26; P 5 .002, and HR, 1.47; P , .001), as was overall Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/3/828/1873691/advancesadv2021004881.pdf by guest on 09 November 2023 confers a 71% higher survival (HR, 1.32; P , .001, and HR, 1.45; P , .001). No differences in outcome were risk of relapse and a detected when patients were stratified by KMT2A fusion partner. This study is the largest 45% higher risk of conducted to date on post-HCT outcomes in AML, with manually curated cytogenetics death after HCT than used for risk stratification. Our work demonstrates that risk classification at diagnosis intermediate-risk AML. remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A-rearranged and adverse-risk disease. Introduction with intermediate- and adverse-risk disease, but that outcomes for patients with KMT2A rearrangement would depend on the translo- cation partner present. In this report, we present an analysis from Cytogenetic abnormalities are the most useful prognostic indicators the Center for International Blood and Marrow Transplant Research for patients with acute myeloid leukemia (AML) and can provide (CIBMTR) database comparing adult patients who underwent HCT insight into overall patient outcomes.1-7 There are few studies, and in the first complete remission (CR1) with those with intermediate- no large, AML-specific studies, that analyzed how well cytogenetics or adverse-risk or KMT2A-rearranged AML, with a focus on the dif- at the time of diagnosis predicts outcomes after allogeneic hemato- ferences in relapse, leukemia-free survival (LFS), nonrelapse mortality poietic cell transplant (HCT).8,9 (NRM), and overall survival (OS). To date, this is the largest anno- The 2010 AML-Medical Research Council classification system cat- tated cohort of post-HCT outcomes of patients with AML and is egorized patients with AML based purely on cytogenetic character- reflective of real-world outcomes based on contemporary practice. istics as either intermediate or adverse risk.2 One subset, patients with 11q23 translocations (site of the lysine (K)-specific methyltrans- Methods ferase 2A [KMT2A] gene), could be classified in either category, based on the translocation partner. Data sources This was a retrospective registry study approved and conducted Translocations of 11q23 involve KMT2A, which encodes a histone through the CIBMTR. The CIBMTR is a collaborative research effort 3, a lysine 4 methyltransferase that is involved in epigenetic regula- between the National Marrow Donor Program/Be the Match Regis- tion of transcriptional activation.10-12 These translocations are fre- try and the Medical College of Wisconsin. More than 450 centers quently referred to as rearrangements of MLL, the mixed-lineage around the world contribute detailed clinical, pathological, and out- leukemia gene, as this was the name before changes in the Human comes data to the CIBMTR on their patients who undergo stem cell Genome Organization gene nomenclature. KMT2A translocations transplant. are seen in patients with de novo AML, secondary AML after myelo- dysplastic syndrome (MDS), or therapy-related AML (tAML) after All patients included in this study signed a written, informed consent treatment with a topoisomerase II inhibitor.13-15 for data capture in the CIBMTR database. The National Marrow Donor Program Institutional Review Board approved the study. As KMT2A rearrangements can occur with many translocation partners; with all CIBMTR studies, this work was performed in compliance at least 135 have been described.16 Among the most common in with all applicable federal regulations pertaining to the protection of adult AML are KMT2A-AF9 t(9;11)(p22;q23), KMT2A-ENL human research subjects. t(11;19)(q23; p13.3), KMT2A-AF6 t(6;11) (q27;q23), and KMT2A- AF10 t(10;11) (p12;q23). Recent prognostic classification systems Study population for AML have made distinctions between translocation partners. Some have noted that outcomes for t(9;11), and possibly for Adult patients with AML aged 18 to 70 years who were in CR1 and t(11;19), are similar to intermediate-risk AML, whereas all other had undergone the first HCT from 2007 through 2016 were consid- translocation partners are classified as poor or adverse risk.1,2 ered for additional review (n 5 8709). Patients with acute promyelo- cytic leukemia, favorable risk or unknown cytogenetics, syngeneic We hypothesized that risk classification at diagnosis of patients with transplants, mismatched unrelated donors (,7 of 8), multiple AML would be predictive of post-HCT outcomes among patients donors, ex vivo T-cell depletion, or previous allogeneic transplants 8 FEBRUARY 2022 • VOLUME 6, NUMBER 3 REAL-WORLD HCT OUTCOMES BY AML RISK AT DIAGNOSIS 829 were excluded. Data were not used for patients from whom consent considered the covariates of age at time of HCT, sex, Karnofsky per- for research was not obtained, whose data were associated with an formance status score at time of HCT, HCT comorbidity index embargoed center, or who did not have the appropriate data forms (HCT-CI) score, time from diagnosis to achieving CR1, time from available (supplemental Table 1). CR1 to HCT, white blood cell (WBC) count at the time of diagno- Manual curation (KM, YZ, AGA, and RMM) to define KMT2A rear- sis, de novo vs therapy-related vs secondary AML, MRD status at rangements and the presence of additional cytogenetic abnormali- time of HCT, KMT2A subtype, year of transplant, donor type, recipi- ties was performed on the data of 3999 patients, according to the ent cytomegalovirus (CMV) serostatus, conditioning intensity (mye- AML-Medical Research Council 2010 classification system.2 Chro- loablative [MA] with total body irradiation (TBI) vs MA with mosomal data from forms submitted on each patient were used to chemotherapy only vs reduced-intensity/non-MA [RIC/NMA] condi- determine their cytogenetic classification. Images of the karyotypes tioning), use of in vivo T-cell depletion, and choice of GVHD prophy- and fluorescence in situ hybridization data were not available for laxis. Interactions between main effect and all covariates were confirmation. Patients were classified as carrying KMT2A-rear- tested at a stringent significance level of P , .01, given the number Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/3/828/1873691/advancesadv2021004881.pdf by guest on 09 November 2023 ranged, intermediate-risk or adverse-risk AML. An additional 86 of comparisons. Adjusted probabilities of outcomes were calculated patients with favorable cytogenetics and 9 patients with an ambigu- with the final Cox models, stratified by main effect and weighted by ous classification were excluded. the pooled sample proportion value for each prognostic factor. Imputation was not performed for missing data; only available data A total of 426 patients were identified as having an 11q23 translo- were analyzed. Analyses were performed in SAS, version 9.4.18,19 cation, based on available cytogenetics data from the CIBMTR forms. Translocations involving 11q23 were categorized as t(6;11), t(9;11), t(10,11), or t(11;19); the remaining rearrangements for Results which a partner was known were categorized as “other.” Patients Patient characteristics with an 11q23 rearrangement and no information regarding translo- cation partner were categorized as “undefined.” Manual curation for Of the 8709 adult patients with AML considered for inclusion in the complex karyotypes (CKs) was limited by the available data, as was study, 3779 were selected as outlined in supplemental Table 1, identification of deletion or loss of chromosomes 5, 7, and 17p. with completeness of follow-up shown in supplemental Table 2. Patient characteristics are shown in Table 1. A total of 426 patients Measurable residual disease with KMT2A rearrangement were studied, compared with 2384 The CIBMTR operational definition of measurable residual disease patients without KMT2A rearrangement who had intermediate-risk (MRD) at the time of HCT for AML was used to define the presence disease and 969 patients without KMT2A rearrangement who had or absence of MRD. During the study period, participating centers adverse-risk disease. may have defined MRD by flow cytometry, cytogenetics, or molecu- lar sequencing. Additional information on the criteria used can be Patients with KMT2A rearrangement were younger, with a median found in the supplemental Information. age of 46, and more than half the patients presented before age 60. tAML was most frequently seen in the KMT2A-rearrangment End points and definitions group, 21% compared with 4% in the intermediate-risk group and The primary outcome was OS, defined as time from HCT to death 6% in the adverse-risk group. More patients with KMT2A rearrange- from any cause. Secondary outcomes included LFS, defined as ment had been treated for breast cancer (11%, as opposed to 2% time to disease relapse or death from any cause; relapse, defined and 3% in patients with intermediate or adverse risk, respectively), as the reappearance of at least 5% blasts on morphological, cyto- and more women were diagnosed with KMT2A-rearranged AML genetic, flow, or molecular evaluation in bone marrow, blood, or an whereas the other 2 groups had a slight male predominance. extramedullary site, per the treating center; NRM, defined as time to Antecedent MDS was less common in patients with rearrangement death without evidence of disease relapse; and a composite out- in KMT2A, found in 6%, but was noted in 19% of the intermediate- come of graft-versus-host disease (GVHD)–free, relapse-free sur- risk group and 23% of the adverse-risk group. vival (GRFS), defined as time to development of grades 3 to 4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or Although all 3 groups achieved CR1 at similar rates, patients with death within the first 12 months after HCT.17 adverse-risk disease more commonly required 2 inductions and were less likely to achieve CR1 within 4 weeks. Statistical considerations Patient- and transplant-related variables were compared using the Patient characteristics by KMT2A x2 test for categorical variables and the Kruskal-Wallis test for con- translocation partner tinuous variables. Kaplan-Meier curves were used to estimate the Of the 426 patients found to have a KMT2A rearrangement (Table probability of OS and LFS. Cumulative incidence was used to esti- 2), 112 patients (26%) had t(9;11) and comprised the largest sub- mate the probability of relapse and NRM, with each treated as a type group. Translocation t(11;19) was the next most common (62 competing risk for the other. For all 4 outcomes, patients were cen- patients, 15%), followed by t(6;11) with 41 patients (10%) and sored at the time of last follow-up. In addition, 95% confidence t(10;11) with 28 patients (7%). Translocation partners other than intervals (CI) were reported for all probability estimates. chromosomes 6, 9, 10, and 11 were detected in 47 patients A Cox proportional hazards model was built for the outcomes of (11%), designated “KMT2A other.” An additional 136 patients had relapse, NRM, LFS, and OS with the main effect of KMT2A- 11q23 rearrangements with an unspecified translocation partner rearranged vs intermediate-risk vs adverse-risk disease. The model and were categorized as “KMT2A undefined.” 830 MENGHRAJANI et al 8 FEBRUARY 2022 • VOLUME 6, NUMBER 3 Table 1. Characteristics of study population Characteristic KMT2A Intermediate Adverse P* Patients, n 426 2384 969 Centers, n 112 165 141 Patient characteristics Patient age at HCT, n (%) ,.001 Median (min-max) 46.4 (18.2-70) 54.5 (18-70) 55.3 (18.5-70) 18-29 72 (17) 237 (10) 90 (9) 30-39 70 (16) 249 (10) 97 (10) 40-49 108 (25) 418 (18) 155 (16) Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/3/828/1873691/advancesadv2021004881.pdf by guest on 09 November 2023 50-59 118 (28) 730 (31) 328 (34) 60-69 58 (14) 750 (31) 299 (31) Sex, n (%) ,.001 Male 179 (42) 1222 (51) 532 (55) Female 247 (58) 1162 (49) 437 (45) Karnofsky score, n (%) .004 ,90 136 (32) 773 (32) 375 (39) $90 280 (66) 1576 (66) 577 (60) Missing 10 (2) 35 (1) 17 (2) HCT-CI, n (%) ,.001 0 89 (21) 659 (28) 227 (23) 1-2 116 (27) 679 (28) 225 (23) 31 182 (43) 832 (35) 418 (43) Missing 39 (9) 214 (9) 99 (10) Recipient CMV serostatus, n (%) .73 Negative 147 (35) 840 (35) 340 (35) Positive 277 (65) 1516 (64) 620 (64) Missing 2 (0) 28 (1) 9 (1) Disease characteristics Type of AML, n (%) ,.001 tAML 88 (21) 106 (4) 87 (9) Antecedent MDS 27 (6) 449 (19) 221 (23) De novo disease 311 (73) 1829 (77) 661 (68) KMT2A subtype, n (%) KMT2A t(9;11) 112 (26) KMT2A t(10;11) 28 (7) KMT2A t(6;11) 41 (10) KMT2A t(11;19) 62 (15) KMT2A other 47 (11) KMT2A undefined 136 (32) Prior disease, n (%) ,.001 AML, not therapy related 338 (79) 2278 (96) 882 (91) HD 5 (1) 8 (0) 5 (1) NHL 14 (3) 11 (0) 12 (1) Breast cancer 48 (11) 36 (2) 27 (3) Solid tumor 9 (2) 20 (1) 18 (2) Other 11 (3) 31 (1) 25 (3) Missing 1 (0) 0 (0) 0 (0) ATG, antithymocyte globulin; CSA, cyclosporine; HD, Hodgkin disease; KMT2A, mixed lineage leukemia; NA, not available; NHL, non-Hodgkin lymphoma; Tac, tacrolimus; Post tx-cy, Post-transplant cyclophosphamide. *Hypothesis testing: Pearson x2 test. 8 FEBRUARY 2022 • VOLUME 6, NUMBER 3 REAL-WORLD HCT OUTCOMES BY AML RISK AT DIAGNOSIS 831 Table 1. (continued) Characteristic KMT2A Intermediate Adverse P* Therapy for previous disease, n (%) ,.001 AML, not therapy related 338 (79) 2278 (96) 882 (91) Chemotherapy 43 (10) 45 (2) 39 (4) Chemotherapy1radiation 40 (9) 39 (2) 32 (3) Radiation alone 2 (0) 4 (0) 7 (1) Auto HCT 0 (0) 5 (0) 2 (0) Other 3 (1) 13 (1) 7 (1) Extramedullary disease at diagnosis, n (%) .35 Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/3/828/1873691/advancesadv2021004881.pdf by guest on 09 November 2023 No 394 (92) 2195 (92) 909 (94) Yes 23 (5) 148 (6) 43 (4) Missing 9 (2) 41 (2) 17 (2) White blood count at diagnosis, AML (3109/L), n (%) ,.001 Median (min-max) 1.2 (0.1-432) 8.9 (0-427.5) 3.6 (0-450) #10 191 (45) 1117 (47) 646 (67) 10-100 153 (36) 831 (35) 212 (22) .100 41 (10) 213 (9) 31 (3) Missing 41 (10) 223 (9) 80 (8) Time to achieve CR1 (wk), n (%) ,.001 Median (min-max) 5.6 (0.4-45.6) 6 (0.1-51.4) 7 (0.1-50.7) #4 103 (24) 493 (21) 157 (16) 4-8 199 (47) 1067 (45) 415 (43) .8 121 (28) 769 (32) 381 (39) Missing 3 (1) 55 (2) 16 (2) Time from CR1 to HCT (mo), n (%) .04 Median (min-max) 2.8 (0.3-16.8) 2.8 (0-86.3) 2.6 (0.2-20.4) ,3 239 (56) 1290 (54) 576 (59) 3-6 146 (34) 823 (35) 305 (31) .6 38 (9) 216 (9) 72 (7) Missing 3 (1) 55 (2) 16 (2) Number of courses of induction for CR1 cases, n (%) ,.001 1 312 (73) 1636 (69) 593 (61) 2 64 (15) 451 (19) 245 (25) 3 13 (3) 66 (3) 28 (3) 4 0 14 (1) 6 (1) 5 0 2 (0) 0 Missing 37 (9) 215 (9) 97 (10) MRD at time of HCT, n (%) ,.001 Negative 296 (69) 1289 (54) 594 (61) Positive 69 (16) 632 (27) 210 (22) Missing 61 (14) 463 (19) 165 (17) Transplant characteristics Donor type, n (%) ,.001 HLA-identical sibling 107 (25) 736 (31) 245 (25) Haploidentical 23 (5) 136 (6) 68 (7) Other related 9 (2) 90 (4) 22 (2) Well-matched unrelated (8/8) 173 (41) 912 (38) 377 (39) ATG, antithymocyte globulin; CSA, cyclosporine; HD, Hodgkin disease; KMT2A, mixed lineage leukemia; NA, not available; NHL, non-Hodgkin lymphoma; Tac, tacrolimus; Post tx-cy, Post-transplant cyclophosphamide. *Hypothesis testing: Pearson x2 test. 832 MENGHRAJANI et al 8 FEBRUARY 2022 • VOLUME 6, NUMBER 3 Table 1. (continued) Characteristic KMT2A Intermediate Adverse P* Partially matched unrelated (7/8) 39 (9) 192 (8) 99 (10) Cord blood 75 (18) 318 (13) 158 (16) Conditioning intensity, n (%) ,.001 MA-TBI 105 (25) 450 (19) 175 (18) MA-chemotherapy 183 (43) 922 (39) 370 (38) RIC/NMA 129 (30) 986 (41) 416 (43) Under review 9 (2) 26 (1) 8 (1) GVHD prophylaxis, n (%) .33 Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/3/828/1873691/advancesadv2021004881.pdf by guest on 09 November 2023 Post tx-cy 35 (8) 144 (6) 66 (7) Tac based 295 (69) 1682 (71) 662 (68) CSA based 89 (21) 491 (21) 219 (23) Other 2 (0) 32 (1) 7 (1) Missing 5 (1) 35 (1) 15 (2) ATG/alemtuzumab, n (%) .62 ATG alone 90 (21) 557 (23) 227 (23) Alemtuzumab alone 9 (2) 46 (2) 20 (2) No ATG or alemtuzumab 326 (77) 1773 (74) 722 (75) Missing 1 (0) 8 (0) 0 Graft type, n (%) ,.001 Bone marrow 80 (19) 318 (13) 120 (12) Peripheral blood 271 (64) 1748 (73) 691 (71) Cord blood 75 (18) 318 (13) 158 (16) Year of transplant, n (%) .02 2007 39 (9) 214 (9) 99 (10) 2008 57 (13) 266 (11) 123 (13) 2009 56 (13) 262 (11) 121 (12) 2010 60 (14) 226 (9) 107 (11) 2011 16 (4) 132 (6) 50 (5) 2012 22 (5) 115 (5) 38 (4) 2013 42 (10) 269 (11) 86 (9) 2014 56 (13) 316 (13) 143 (15) 2015 38 (9) 321 (13) 119 (12) 2016 40 (9) 263 (11) 83 (9) Follow-up - median (min-max) 49.24 (3.32-126.41) 37.96 (1.84-122.63) 48.09 (2.89-120.23) ATG, antithymocyte globulin; CSA, cyclosporine; HD, Hodgkin disease; KMT2A, mixed lineage leukemia; NA, not available; NHL, non-Hodgkin lymphoma; Tac, tacrolimus; Post tx-cy, Post-transplant cyclophosphamide. *Hypothesis testing: Pearson x2 test. Patients with t(10;11) had the youngest median age, at 34; the The majority of patients in all subcategories required only 1 course patients classified as KMT2A other had the highest median age, at of induction to achieve CR1. Most patients with KMT2A rearrange- 54. For t(9;11), t(11;19), t(6;11), and t(10;11), there were nearly ment achieved MRD2 status before transplant, regardless of trans- twice as many female as male patients per category. location partner. tAML was found most frequently in those with t(9;11), with 38 Donor type and graft type were similar in all subgroups, as were (34%) patients having received prior therapy. Breast cancer was rejection and GVHD prophylaxis regimens and year of transplant. the most common prior malignancy. Other prior diagnoses included The percentage of patients who underwent MA conditioning was lymphoma (both Hodgkin and non-Hodgkin) and solid tumors. similar for all translocation partners, but the use of chemotherapy vs Extramedullary disease was present at diagnosis at a single-digit fre- TBI varied somewhat. CMV1status was more common than CMV2 quency in all groups. status in all groups. 8 FEBRUARY 2022 • VOLUME 6, NUMBER 3 REAL-WORLD HCT OUTCOMES BY AML RISK AT DIAGNOSIS 833 Table 2. Patient characteristics by translocation partner KMT2A KMT2A KMT2A KMT2A KMT2A KMT2A Characteristic t(9;11) t(10;11) t(6;11) t(11;19) Other undefined Patients, n 112 28 41 62 47 136 Centers, n 63 24 31 39 37 64 Patient characteristics Patient age at HCT, n (%) Median (min-max) 45.8 (20.1-69.9) 34.3 (18.4-67.4) 45.5 (18.3-62.7) 45.2 (18.4-69.8) 53.7 (18.3-69.3) 49.6 (18.2-70) 18-29 18 (16) 9 (32) 7 (17) 9 (15) 5 (11) 24 (18) 30-39 19 (17) 9 (32) 7 (17) 12 (19) 6 (13) 17 (13) 40-49 36 (32) 5 (18) 13 (32) 17 (27) 7 (15) 30 (22) Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/3/828/1873691/advancesadv2021004881.pdf by guest on 09 November 2023 50-59 26 (23) 3 (11) 13 (32) 18 (29) 19 (40) 39 (29) 60-69 13 (12) 2 (7) 1 (2) 6 (10) 10 (21) 26 (19) Sex, n (%) Male 43 (38) 8 (29) 11 (27) 23 (37) 25 (53) 69 (51) Female 69 (62) 20 (71) 30 (73) 39 (63) 22 (47) 67 (49) Karnofsky score, n (%) ,90 36 (32) 12 (43) 13 (32) 23 (37) 17 (36) 35 (26) $90 73 (65) 16 (57) 27 (66) 37 (60) 29 (62) 98 (72) Missing 3 (3) 0 1 (2) 2 (3) 1 (2) 3 (2) HCT-CI, n (%) 0 15 (13) 9 (32) 9 (22) 11 (18) 8 (17) 37 (27) 1-2 29 (26) 6 (21) 14 (34) 21 (34) 13 (28) 33 (24) 31 59 (53) 8 (29) 14 (34) 24 (39) 20 (43) 57 (42) Missing 9 (8) 5 (18) 4 (10) 6 (10) 6 (13) 9 (7) Recipient CMV serostatus, n (%) Negative 41 (37) 8 (29) 10 (24) 27 (44) 17 (36) 44 (32) Positive 71 (63) 20 (71) 31 (76) 35 (56) 29 (62) 91 (67) Missing 0 0 0 0 1 (2) 1 (1) Disease characteristics Type of AML, n (%) tAML 38 (34) 3 (11) 4 (10) 9 (15) 10 (21) 24 (18) Antecedent MDS 1 (1) 3 (11) 1 (2) 6 (10) 6 (13) 10 (7) De novo disease 73 (65) 22 (79) 36 (88) 47 (76) 31 (66) 102 (75) Prior disease, n (%) AML, not therapy related 74 (66) 25 (89) 37 (90) 53 (85) 37 (79) 112 (82) HD 2 (2) 0 0 0 (0) 0 (0) 3 (2) NHL 5 (4) 0 1 (2) 2 (3) 3 (6) 3 (2) Breast cancer 24 (21) 1 (4) 3 (7) 3 (5) 6 (13) 11 (8) Solid tumor 2 (2) 0 0 3 (5) 0 (0) 4 (3) Other 4 (4) 2 (7) 0 1 (2) 1 (2) 3 (2) Missing 1 (1) 0 0 0 (0) 0 (0) 0 (0) Therapy for previous disease, n (%) AML, not therapy related 74 (66) 25 (89) 37 (90) 53 (85) 37 (79) 112 (82) Chemotherapy 19 (17) 2 (7) 2 (5) 2 (3) 5 (11) 13 (10) Chemotherapy 1 radiation 16 (14) 1 (4) 2 (5) 6 (10) 4 (9) 11 (8) Radiation alone 2 (2) 0 0 0 (0) 0 (0) 0 (0) Other 1 (1) 0 0 1 (2) 1 (2) 0 (0) Extramedullary disease at diagnosis, n (%) No 101 (90) 25 (89) 36 (88) 59 (95) 44 (94) 129 (95) ATG, anti-thymocyte globulin; CSA, cyclosporine; NA, not available; HD, Hodgkin disease; NHL, non-Hodgkin lymphoma; Post tx-cy, Post-transplant cyclophosphamide. 834 MENGHRAJANI et al 8 FEBRUARY 2022 • VOLUME 6, NUMBER 3 Table 2. (continued) KMT2A KMT2A KMT2A KMT2A KMT2A KMT2A Characteristic t(9;11) t(10;11) t(6;11) t(11;19) Other undefined Yes 8 (7) 2 (7) 3 (7) 3 (5) 3 (6) 4 (3) Missing 3 (3) 1 (4) 2 (5) 0 0 3 (2) WBC count at diagnosis, AML (x 109/L), n (%) Median (min-max) 7.4 (0.6-432) 7.1 (0.8-128) 37.3 (1-284) 17.8 (0.7-270) 12.3 (0.4-228) 7.2 (0.1-318.2) # 10 57 (51) 13 (46) 13 (32) 24 (39) 19 (40) 65 (48) 10-100 38 (34) 10 (36) 16 (39) 27 (44) 23 (49) 39 (29) . 100 7 (6) 2 (7) 8 (20) 5 (8) 3 (6) 16 (12) Missing 10 (9) 3 (11) 4 (10) 6 (10) 2 (4) 16 (12) Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/3/828/1873691/advancesadv2021004881.pdf by guest on 09 November 2023 Time to achieve CR1 (weeks), n (%) Median (min-max) 5 (1.6-20.4) 6.8 (1.9-36.4) 7.1 (2-18.6) 5 (2-30) 6.7 (2-45.6) 5.6 (0.4-29.9) #4 wk 31 (28) 6 (21) 5 (12) 18 (29) 8 (17) 35 (26) 4-8 wk 54 (48) 11 (39) 20 (49) 31 (50) 18 (38) 65 (48) .8 wk 26 (23) 11 (39) 15 (37) 13 (21) 21 (45) 35 (26) Missing 1 (1) 0 1 (2) 0 0 1 (1) Time from CR1 to HCT (months), n (%) Median (min-max) 3 (0.3-16.8) 2.9 (0.7-8.7) 2.4 (0.5-7.3) 2.6 (0.5-7.6) 2.5 (0.5-11.1) 2.8 (0.4-12.8) ,3 mo 56 (50) 16 (57) 26 (63) 35 (56) 30 (64) 76 (56) 3-6 mo 41 (37) 9 (32) 9 (22) 25 (40) 13 (28) 49 (36) .6 mo 14 (13) 3 (11) 5 (12) 2 (3) 4 (9) 10 (7) Missing 1 (1) 0 1 (2) 0 0 1 (1) Number of courses of induction for CR1 cases, n (%) 1 85 (76) 21 (75) 27 (66) 47 (76) 33 (70) 99 (73) 2 12 (11) 2 (7) 10 (24) 6 (10) 8 (17) 26 (19) 3 5 (4) 0 1 (2) 3 (5) 1 (2) 3 (2) Missing 10 (9) 5 (18) 3 (7) 6 (10) 5 (11) 8 (6) MRD at time of HCT, n (%) Negative 82 (73) 18 (64) 28 (68) 38 (61) 33 (70) 97 (71) Positive 13 (12) 4 (14) 6 (15) 12 (19) 8 (17) 26 (19) Missing 17 (15) 6 (21) 7 (17) 12 (19) 6 (13) 13 (10) Transplant characteristics Donor type, n (%) HLA-identical sibling 23 (21) 9 (32) 13 (32) 18 (29) 9 (19) 35 (26) Haplo-identical 9 (8) 0 0 6 (10) 2 (4) 6 (4) Other related 4 (4) 0 0 1 (2) 0 4 (3) Well-matched unrelated (8/8) 43 (38) 10 (36) 16 (39) 26 (42) 23 (49) 55 (40) Partially matched unrelated (7/8) 10 (9) 2 (7) 6 (15) 3 (5) 5 (11) 13 (10) Cord blood 23 (21) 7 (25) 6 (15) 8 (13) 8 (17) 23 (17) Conditioning intensity, n (%) MA-TBI 23 (21) 12 (43) 12 (29) 19 (31) 11 (23) 28 (21) MA-Chemo 54 (48) 11 (39) 15 (37) 25 (40) 16 (34) 62 (46) RIC/NMA 32 (29) 5 (18) 13 (32) 16 (26) 20 (43) 43 (32) Under review 3 (3) 0 1 (2) 2 (3) 0 3 (2) GVHD prophylaxis, n (%) Post tx-cy 17 (15) 0 3 (7) 6 (10) 2 (4) 7 (5) Tac based 71 (63) 16 (57) 31 (76) 43 (69) 36 (77) 98 (72) CSA based 21 (19) 11 (39) 6 (15) 13 (21) 9 (19) 29 (21) Other 1 (1) 0 0 0 0 1 (1) ATG, anti-thymocyte globulin; CSA, cyclosporine; NA, not available; HD, Hodgkin disease; NHL, non-Hodgkin lymphoma; Post tx-cy, Post-transplant cyclophosphamide. 8 FEBRUARY 2022 • VOLUME 6, NUMBER 3 REAL-WORLD HCT OUTCOMES BY AML RISK AT DIAGNOSIS 835 Table 2. (continued) KMT2A KMT2A KMT2A KMT2A KMT2A KMT2A Characteristic t(9;11) t(10;11) t(6;11) t(11;19) Other undefined Missing 2 (2) 1 (4) 1 (2) 0 0 1 (1) ATG/Campath, n (%) ATG alone 18 (16) 8 (29) 8 (20) 9 (15) 11 (23) 36 (26) Alemtuzumab alone 3 (3) 0 0 1 (2) 0 5 (4) No ATG or alemtuzumab 91 (81) 19 (68) 33 (80) 52 (84) 36 (77) 95 (70) Missing 0 1 (4) 0 0 0 0 Graft type, n (%) Bone marrow 26 (23) 3 (11) 6 (15) 11 (18) 7 (15) 27 (20) Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/3/828/1873691/advancesadv2021004881.pdf by guest on 09 November 2023 Peripheral blood 63 (56) 18 (64) 29 (71) 43 (69) 32 (68) 86 (63) Cord blood 23 (21) 7 (25) 6 (15) 8 (13) 8 (17) 23 (17) Year of transplant, n (%) 2007 9 (8) 5 (18) 4 (10) 6 (10) 6 (13) 9 (7) 2008 14 (13) 3 (11) 9 (22) 7 (11) 6 (13) 18 (13) 2009 13 (12) 7 (25) 5 (12) 6 (10) 7 (15) 18 (13) 2010 13 (12) 2 (7) 4 (10) 10 (16) 6 (13) 25 (18) 2011 6 (5) 1 (4) 2 (5) 1 (2) 1 (2) 5 (4) 2012 5 (4) 1 (4) 3 (7) 4 (6) 2 (4) 7 (5) 2013 9 (8) 3 (11) 1 (2) 7 (11) 4 (9) 18 (13) 2014 23 (21) 1 (4) 4 (10) 9 (15) 8 (17) 11 (8) 2015 11 (10) 2 (7) 2 (5) 7 (11) 5 (11) 11 (8) 2016 9 (8) 3 (11) 7 (17) 5 (8) 2 (4) 14 (10) Follow-up, median (min-max) 49.24 (6.12-126.41) 52.57 (3.36-100.07) 55.89 (3.42-90) 47.4 (3.32-99.28) 71.45 (3.49-97.86) 48.19 (5.92-116.18) ATG, anti-thymocyte globulin; CSA, cyclosporine; NA, not available; HD, Hodgkin disease; NHL, non-Hodgkin lymphoma; Post tx-cy, Post-transplant cyclophosphamide. Table 3. Univariable analysis KMT2A (n 5 426) Intermediate (n 5 2384) Adverse (n 5 969) Outcomes, y n Prob, % (95% CI) n Prob, % (95% CI) n Prob, % (95% CI) P Relapse 426 2383 968 ,.001 1 225 25 (21-30) 1292 24 (22-26) 433 34 (31-37) ,.001 3 115 34 (30-39) 660 31 (29-33) 198 44 (40-47) ,.001 5 74 37 (32-42) 393 33 (31-35) 128 46 (42-49) ,.001 NRM 426 2383 968 .411 1 225 16 (13-20) 1292 14 (13-16) 433 17 (14-19) .295 3 115 23 (19-28) 660 20 (18-22) 198 23 (21-26) .070 5 74 25 (21-29) 393 24 (22-26) 128 25 (22-28) .801 LFS 426 2383 968 ,.001 1 223 59 (54-63) 1284 62 (60-64) 431 49 (46-53) ,.001 3 114 43 (38-48) 659 49 (47-52) 197 33 (30-36) ,.001 5 73 38 (33-44) 393 43 (41-46) 127 30 (27-33) ,.001 OS 426 2384 969 ,.001 1 259 68 (63-72) 1472 70 (68-72) 521 60 (57-63) ,.001 3 119 45 (40-51) 748 55 (53-57) 225 38 (35-41) ,.001 5 79 42 (37-48) 443 48 (46-50) 141 34 (30-37) ,.001 NE, nonevaluable; Prob, probability. 836 MENGHRAJANI et al 8 FEBRUARY 2022 • VOLUME 6, NUMBER 3 A Relapse Co-variates Event / N (%) HR (95% CI) P Value Main effect <.001 Intermediate 697/2383 (29.2) Baseline KMT2A 142/426 (33.3) 1.27 (1.06 - 1.53) Adverse 409/968 (42.3) 1.71 (1.51 - 1.94) WBC at diagnosis (x109/L) <.001 ≤ 10 599/1952 (30.7) Baseline 10 - 100 421/1196 (35.2) 1.40 (1.23 - 1.59) > 100 120/285 (42.1) 1.92 (1.57 - 2.36) Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/3/828/1873691/advancesadv2021004881.pdf by guest on 09 November 2023 Type of AML <.001 De-Novo disease 880/2801 (31.4) Baseline Antecedent MDS 280/695 (40.3) 1.42 (1.23 - 1.63) t-AML 88/281 (31.3) 0.95 (0.76 - 1.19) Time to achieve CR1 (weeks) 0.010 ≤4 weeks 217/753 (28.8) Baseline >4 weeks 1005/2950 (34.1) 1.26 (1.08 - 1.46) Time from CR1 to HCT (months) <.001 <6 months 1146/3377 (33.9) Baseline >6 months 76/326 (23.3) 0.61 (0.48 - 0.77) MRD at time of HCT 0.012 Negative 710/2177 (32.6) Baseline Positive 296/911 (32.5) 1.23 (1.06 - 1.42) Conditioning intensity <.001 MA-TBI 202/730 (27.7) Baseline MA-Chemo 440/1475 (29.8) 1.22 (1.02 - 1.45) RIC/NMA 593/1529 (38.8) 1.92 (1.62 -2.26) Donor type <.001 HLA-identical sibling 410/1088 (37.7) Baseline Haplo-identical and other relatives 111/348 (31.9) 0.89 (0.72 - 1.11) Well-matched unrelated (8/8) 467/1461 (32.0) 0.79 (0.69 - 0.90) Partially-matched unrelated (7/8) 84/330 (25.5) 0.63 (0.50 - 0.80) Cord blood 176/550 (32.0) 0.94 (0.78 - 1.13) Year of HCT <.001 2007-2011 681/1826 (37.3) Baseline 2012-2016 567/1951 (29.1) 0.80 (0.71 - 0.91) 0.25 0.5 1 2 4 Figure 1. Multivariable analyses. (A) The outcome of relapse, with the main effect of cytogenetic category and including the listed covariates. The HR for relapse among those with KMT2A rearrangement was 1.27, and among those with adverse risk was 1.71. (B) The outcome of NRM, with the main effect of cytogenetic category and including the listed covariates. The HR for NRM was not significantly different among the groups. (C) The outcome of LFS, with the main effect of cytogenetic category and including the listed covariates. The HR among those with KMT2A rearrangement was 1.26, and among patients with adverse risk was 1.47. (D) The outcome of OS, with the main effect of cytogenetic category and including the listed covariates. The HR for death among those with KMT2A rearrangement was 1.32 and among patients with adverse risk was 1.45. Relapse of AML 1.51-1.94; P , .001), respectively, when compared with the intermediate-risk group (Figure 1A). Other predictors of relapse A univariable analysis of the risk of relapse at 1, 3, and 5 years after transplantation found that it was comparable in patients with included higher WBC count at diagnosis, a longer time to KMT2A translocation and intermediate risk but higher at all time achieve CR1, pre-HCT MRD positivity, conditioning other than points in patients with adverse-risk disease (Table 3). The probability TBI-based MA conditioning, and donors other than HLA- of relapse at 1 year was similar across KMT2A subtypes. identical siblings. Relapse risk was also more apt to occur in those with a history of prior MDS, but not in those with therapy- In the multivariable analysis, the KMT2A-rearranged and adverse- related disease. Data on therapies used in the post-HCT risk groups had an increased hazard ratio (HR) for relapse relapse setting outside of the second transplant were not avail- of 1.27 (95% CI, 1.06-1.53; P 5 .01) and 1.71 (95% CI, able for analysis. 8 FEBRUARY 2022 • VOLUME 6, NUMBER 3 REAL-WORLD HCT OUTCOMES BY AML RISK AT DIAGNOSIS 837 B Non-relapse mortality Co-variates Event / N (%) HR (95% CI) P Value Main effect 0.099 Intermediate 487/2383 (20.4) Baseline KMT2A 98/426 (23.0) 1.16 (0.93 - 1.45) Adverse 223/968 (23.0) 1.17 (1.00 - 1.38) Patient age at HCT <.001 18-29 79/399 (19.8) Baseline 30-39 67/416 (16.1) 0.75 (0.54 - 1.04) 40-49 124/681 (18.2) 0.92 (0.69 - 1.22) Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/3/828/1873691/advancesadv2021004881.pdf by guest on 09 November 2023 50-59 257/1176 (21.9) 1.32 (1.02 - 1.71) 60-69 281/1105 (25.4) 1.84 (1.39 -244) Karnofsky score 0.016 <90 294/1282 (22.9) Baseline ≥90 496/2433 (20.4) 0.82 (0.70 -0.95) HCT-CI <.001 0 169/975 (17.3) Baseline 1-2 191/1019 (18.7) 1.15 (0.94 - 1.42) 3+ 337/1432 (23.5) 1.46 (1.20 - 1.76) Conditioning intensity 0.005 MA-TBI 188/730 (25.8) Baseline MA-Chemo 286/1475 (19.4) 0.75 (0.61 - 0.91) RIC/NMA 327/1529 (21.4) 0.71 (0.57 - 0.88) Donor type <.001 HLA-identical sibling 166/1088 (15.3) Baseline Haplo-identical and other relatives 56/348 (16.1) 1.44 (1.05 - 1.97) Well-matched unrelated (8/8) 317/1461 (21.7) 1.41 (1.17 - 1.70) Partially-matched unrelated (7/8) 112/330 (33.9) 2.27 (1.78 - 2.89) Cord blood 157/550 (28.5) 2.26 (1.80 - 2.83) Recipient CMV serostatus <.001 Negative 249/1326 (18.8) Baseline Positive 548/2412 (22.7) 1.32 (1.13 - 1.53) Year of HCT 0.003 2007-2011 479/1826 (26.2) Baseline 2012-2016 329/1951 (16.9) 0.78 (0.67 - 0.92) 0.25 0.5 1 2 4 Figure 1 (continued) The adjusted cumulative incidence function (CIF) for relapse is LFS shown in Figure 2A. LFS at 1, 3, and 5 years after transplantation was worse for patients NRM with adverse-risk disease (Figure 2C). The 1-year probability of LFS overlapped for the KMT2A-rearranged and intermediate-risk groups NRM rates were similar for patients with KMT2A-rearrangement, but was worse for those in the adverse-risk group. Similar trends intermediate-risk, or adverse-risk disease at 1, 3, and 5 years after were seen at 3 and 5 years in the univariable analysis (Table 3). No transplant by univariable analysis (Table 3). NRM risk was similar for differences in LFS according to translocation partner were noted all translocation partners in patients with KMT2A rearrangement (Table 4). (Table 4). The CIF curve is shown in Figure 2B. As shown in Figure 1C, the multivariable analysis detected worse Figure 1B demonstrates that the results of multivariable analysis for LFS for the KMT2A-rearranged and adverse-risk groups, compared NRM was not significantly different among cytogenetic groups, with with the intermediate-risk group (HR, 1.26; 95% CI, 1.09-1.46; P 5 HR, 1.16 (95% CI, 0.93-1.45) for KMT2A-rearranged disease and .002, and HR, 1.47; 95% CI, 1.33-1.62; P , .001, respectively). HR, 1.17 (95% CI, 1.00-1.38) for adverse-risk disease (P 5 .099). Increasing WBC count was a predictor of LFS, as was longer time Predictors of NRM included older age, poor performance status, to CR1. MRD1patients, those who underwent RIC/NMA, and those higher HCT-CI score, conditioning regimen, donor type, CMV posi- with a cord blood donor also had worse LFS. In addition, patients tivity, and year of transplant. with prior MDS had worse LFS. 838 MENGHRAJANI et al 8 FEBRUARY 2022 • VOLUME 6, NUMBER 3 C Leukemia-free survival Co-variates Event / N (%) HR (95% CI) P Value Main effect <.001 Intermediate 1184/2383 (49.7) Baseline KMT2A 240/426 (56.3) 1.26 (1.09 - 1.46) Adverse 632/968 (65.3) 1.47 (1.33 - 1.62) Patient age at HCT <.001 18-29 196/399 (49.1) Baseline 30-39 188/416 (45.2) 0.87 (0.71 - 1.06) 40-49 334/681 (49.0) 0.96 (0.81 - 1.15) Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/3/828/1873691/advancesadv2021004881.pdf by guest on 09 November 2023 50-59 667/1176 (56.7) 1.18 (1.00 - 1.40) 60-69 671/1105 (60.7) 1.31 (1.10 -1.57) Karnofsky score 0.007 <90 744/1282 (58.0) Baseline ≥90 1277/2433 (52.5) 0.86 (0.79 -0.94) WBC at diagnosis (x109/L) <.001 ≤ 10 1046/1952 (53.6) Baseline 10 - 100 649/1196 (54.3) 1.21 (1.09 - 1.34) > 100 165/285 (57.9) 1.47 (1.24 - 1.74) Type of AML <.001 De-Novo disease 1442/2801 (51.5) Baseline Antecedent MDS 456/695 (65.6) 1.31 (1.18 - 1.47) t-AML 158/281 (56.2) 1.02 (0.86 - 1.21) Time to achieve CR1 (weeks) 0.012 ≤4 weeks 371/753 (49.3) Baseline >4 weeks 1644/2950 (55.7) 1.19 (1.06 - 1.33) Time from CR1 to HCT (months) <.001 <6 months 1856/3377 (55.0) Baseline >6 months 159/326 (48.8) 0.74 (0.62 - 0.87) MRD at time of HCT 0.026 Negative 1200/2177 (55.1) Baseline Positive 446/911 (49.0) 1.13 (1.01 - 1.27) Conditioning intensity <.001 MA-TBI 390/730 (53.4) Baseline MA-Chemo 726/1475 (49.2) 0.99 (0.87 - 1.13) RIC/NMA 920/1529 (60.2) 1.26 (1.09 - 1.45) Donor type <.001 HLA-identical sibling 576/1088 (52.9) Baseline Haplo-identical and other relatives 167/348 (48.0) 1.06 (0.89 - 1.27) Well-matched unrelated (8/8) 784/1461 (53.7) 0.97 (0.87 - 1.08) Partially-matched unrelated (7/8) 196/330 (59.4) 1.09 (0.92 - 1.29) Cord blood 333/550 (60.5) 1.34 (1.16 - 1.54) Year of HCT <.001 2007-2011 1160/1826 (63.5) Baseline 2012-2016 896/1951 (45.9) 0.81 (0.73 - 0.89) 0.25 0.5 1 2 4 Figure 1 (continued) GRFS analysis, and was significantly worse among patients with adverse GRFS at 1, 3, and 5 years was similarly poor for patients with risk (9% vs 15%). KMT2A-rearranged or adverse-risk disease and was somewhat bet- A multivariable analysis for GRFS detected that it was not signifi- ter for those with intermediate-risk disease (Table 5). Five-year cantly worse in patients with KMT2A rearrangement but it was GRFS could be compared only between the intermediate- and worse for patients in the adverse-risk group, compared with those in adverse-risk groups, given the number of patients available for the intermediate-risk group (HR, 1.14; 95% CI, 1.01-1.28; P 5 .03, 8 FEBRUARY 2022 • VOLUME 6, NUMBER 3 REAL-WORLD HCT OUTCOMES BY AML RISK AT DIAGNOSIS 839 D Overall survival Co-variates Event / N (%) HR (95% CI) P Value Main effect <.001 Intermediate 1051/2384 (44.1) Baseline KMT2A 219/426 (51.4) 1.32 (1.13 - 1.53) Adverse 579/969 (59.8) 1.45 (1.31 - 1.61) Patient age at HCT <.001 18-29 175/399 (43.9) Baseline 30-39 149/416 (35.8) 0.77 (0.62 - 0.96) 302/681 (44.3) 0.98 (0.81 -1.18) Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/3/828/1873691/advancesadv2021004881.pdf by guest on 09 November 2023 40-49 50-59 614/1176 (52.2) 1.27 (1.07 - 1.50) 60-69 609/1107 (55.0) 1 .53 (1.29 - 1.82) Karnofsky score <.001 <90 689/1284 (53.7) Baseline ≥90 1126/2433 (46.3) 0.82 (0.75 - 0.91) HCT-CI <.001 0 430/975 (44.1) Baseline 1-2 466/1020 (45.7) 1.10 (0.96 - 1.26) 3+ 734/1432 (51.3) 1.28 (1.13 - 1.45) WBC at diagnosis (x109/L) <.001 ≤10 947/1954 (48.5) Baseline 10 - 100 578/1196 (48.3) 1.16 (1.05 - 1.30) >100 146/285 (51.2) 1.41 (1.18 - 1.69) Type of AML Baseline <.001 De-Novo disease 1276/2801 (45.6) 1.34 (1.19 - 1.50) Antecedent MDS 427/697 (61.3) 0.95 (0.79 - 1.1 5) t-AML 146/281 (52 .0) Time to achieve CR1 (weeks) 0.011 ≤4 weeks 326/753 (43.3) Baseline >4 weeks 1485/2952 (50.3) 1 .20 (1.07 - 1.36) Time from CR1 to HCT (months) <.001 <6 months 1667/3379 (49.3) Baseline >6 months 144/326 (44.2) 0.75 (0.63 - 0.89) Donor type <.001 HLA-identical sibling 510/1088 (46.9) Baseline Haplo-identical and other relatives 145/348 (41.7) 1.21 (1.00 - 1.46) Well-matched unrelated (8/8) 700/1462 (47.9) 1.00 (0.89 - 1.1 2) Partially-matched unrelated (7/8) 188/330 (57.0) 1 .26 (1 .06 - 1.49) Cord blood 306/551 (55.5) 1.54 (1 .34 - 1.79) Recipient CMV serostatus <.026 Negative 633/1327 (47.7) Baseline Positive 1200/2413 (49.7) 1.14 (1.04 - 1.26) Year of HCT <.001 2007-2011 1090/1828 (59.6) Baseline 2012-2016 759/1951 (38.9) 0.81 (0.73 - 0.90) 0.25 0.5 1 2 4 Figure 1 (continued) and HR, 1.23; 95% CI, 1.14-1.34; P , .001, respectively) (Table 6). OS Age was included in the model but was not statistically signifi- A univariable analysis showed a 42% 5-year OS for the KMT2A- cant. Later transplant was associated with improved GRFS, rearranged group, compared with 48% for the intermediate-risk and a history of antecedent MDS was associated with a sig- group and 34% for the adverse-risk group (Table 3). No difference nificantly worse outcome (HR, 1.19; 95% CI, 1.08-1.30; in OS was detected according to KMT2A translocation partner P , .001). (Table 4). 840 MENGHRAJANI et al 8 FEBRUARY 2022 • VOLUME 6, NUMBER 3 Table 4. Univariable analysis by translocation partner t(9;11) (n 5 112) t(10;11) (n 5 28) t(6;11) (n 5 41) t(11;19) (n 5 62) Other (n 5 47) Undefined (n 5 136) Prob, % Prob, % Prob, % Prob, % Prob, % Prob, % Outcomes, y n (95% CI) n (95% CI) n (95% CI) n (95% CI) n (95% CI) n (95% CI) P Relapse 112 28 41 62 47 136 .265 1 71 22 (14-30) 16 22 (9-40) 19 29 (15-44) 34 30 (19-42) 27 13 (5-25) 62 30 (22-38) .148 2 48 27 (19-36) 9 NE 12 NE 22 38 (26-51) 19 26 (14-40) 48 32 (24-40) .295 NRM 112 28 41 62 47 136 .606 1 71 14 (8-22) 16 15 (4-31) 19 16 (6-29) 34 13 (6-23) 27 24 (13-37) 62 17 (11-24) .818 2 48 21 (13-29) 9 NE 12 NE 22 17 (8-28) 19 26 (15-40) 48 22 (15-30) .838 LFS 112 28 41 62 47 136 .432 Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/3/828/1873691/advancesadv2021004881.pdf by guest on 09 November 2023 1 70 64 (55-73) 15 63 (44-80) 18 55 (39-71) 33 57 (44-69) 26 63 (49-76) 61 54 (45-62) .62 2 47 53 (43-62) 8 NE 11 NE 21 45 (32-58) 18 48 (33-63) 47 46 (37-55) .72 OS 112 28 41 62 47 136 .295 1 79 72 (63-80) 17 70 (52-86) 21 63 (47-78) 39 70 (57-81) 28 67 (53-80) 75 65 (56-73) .85 2 51 58 (48-67) 10 NE 14 NE 25 59 (45-71) 20 57 (42-71) 50 48 (39-57) .649 NE, nonevaluable; Prob, probability. Table 5. Univariable analysis of GRFS KMT2A (n 5 426) Intermediate (n 5 2384) Adverse (n 5 969) Outcomes n Prob (95% CI) n Prob (95% CI) n Prob (95% CI) P value GVHD-free, relapse-free survival 410 — 2326 — 948 — ,.001 1 72 21 (17-25) 527 27 (25-29) 150 19 (16-21) ,.001 3 26 12 (9-16) 187 17 (15-19) 54 10 (8-12) ,.001 5 13 NE 103 15 (13-16) 39 9 (7-11) ,.001 Univariable analysis of GRFS by translocation partner is not provided, as not enough cases remained at risk at 1 y (most events occurred earlier). Table 6. Multivariable analysis for GRFS respectively). Poorer OS was also noted in those .50 years of age, Covariates n HR, (95% CI) P with poor performance status, higher HCT-CI, score, higher WBC Main effect ,.001 at diagnosis, and longer time to achieve CR1. Patients who under- went HCT ,6 months after CR1 had worse OS, as did those with Intermediate 2326 Reference donors who were not well-matched or identical. Secondary AML KMT2A 410 1.14 (1.01-1.28) .03 was again a poor predictor, whereas tAML was not. Adverse 948 1.23 (1.14-1.34) ,.001 The Kaplan-Meier curve for OS is shown in Figure 2D. Patient age at HCT, y .04 18-29 387 Reference MRD 30-39 411 0.93 (0.80-1.09) .40 The proportion of patients with MRD positivity was similar between 40-49 657 0.97 (0.84-1.12) .70 the groups: 21% of patients with a KMT2A rearrangement, 30% of 50-59 1156 1.06 (0.93-1.21) .36 patients with intermediate-risk disease, and 30% of patients with 60-69 1073 1.11 (0.97-1.27) .12 adverse-risk disease. Pre-HCT MRD positivity was associated with Year of HCT ,.001 relapse but did not meet statistical significance for LFS (HR, 1.23; 95% CI, 1.06-1.42; P 5 .006, and HR, 1.13; 95% CI, 1.01-1.27; 2007-2011 1790 Reference P 5 .04, respectively). MRD was not associated with NRM or OS. 2012-2016 1894 0.83 (0.77-0.89) ,.001 Type of AML .002 Outcomes among KMT2A translocation partners De novo disease 2741 Reference A secondary analysis was performed to determine the influence of Antecedent MDS 683 1.19 (1.08-1.30) ,.001 translocation partner on outcomes for patients with KMT2A rear- tAML 260 1.03 (0.90-1.19) .64 rangement. We excluded the patients whose translocation partner had not been defined from the secondary analysis. We then com- pared the 112 patients with t(9;11) against the remaining patients OS in a multivariable model (Figure 1D) was again worse for the with KMT2A rearrangement and the 62 patients with t(11;19) with KMT2A-rearranged and adverse-risk groups (HR, 1.32; 95% CI, the remaining patients with KMT2A rearrangement and then com- 1.13-1.53; P , .001, and HR, 1.45; 95% CI, 1.31-1.61; P , .001, bined both the t(9;11) and t(11;19) groups and compared them 8 FEBRUARY 2022 • VOLUME 6, NUMBER 3 REAL-WORLD HCT OUTCOMES BY AML RISK AT DIAGNOSIS 841 Adjusted NRM A Adjusted relapse B 1.0 1.0 KMT2A vs. Intermediate: HR = 1.16 (0.93-1.45), p = 0.19 KMT2A vs. Intermediate: HR = 1.27 (1.06-1.53), p = 0.01 Adverse vs. KMT2A: HR = 1.01 (0.80-1.29), p = 0.92 Adverse vs. KMT2A: HR = 1.34 (1.10-1.63), p = 0.003 0.8 0.8 0.6 Probability 0.6 Probability 0.4 0.4 0.2 0.2 Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/3/828/1873691/advancesadv2021004881.pdf by guest on 09 November 2023 0.0 0.0 0 12 24 36 48 60 0 12 24 36 48 60 Months from HCT Months from HCT Intermediate KMT2A Adverse Intermediate KMT2A Adverse C Adjusted LFS D Adjusted OS 1.0 1.0 KMT2A vs. Intermediate: HR = 1.26 (1.09-1.46), p = 0.002 KMT2A vs. Intermediate: HR = 1.32 (1.13-1.53), p < 0.001 Adverse vs. KMT2A: HR = 1.17 (1.00-1.36), p = 0.05 Adverse vs. KMT2A: HR = 1.10 (0.94-1.29), p = 0.25 0.8 0.8 0.6 Probability 0.6 Probability 0.4 0.4 0.2 0.2 0.0 0.0 0 12 24 36 48 60 0 12 24 36 48 60 Months from HCT Months from HCT Intermediate KMT2A Adverse Intermediate KMT2A Adverse Figure 2. Adjusted multivariable analysis by cytogenetic group. (A) Curves of the CIF for the outcome of relapse, showing the highest risk of relapse was among patients with adverse risk. KMT2A-rearranged patients also had an increased risk of relapse after 12 months. (B) Curves of the CIF for the outcome of NRM, showing no significant difference among the intermediate-risk, adverse-risk, or KMT2A-rearranged groups. (C) Kaplan-Meier curves for the outcome of LFS, demonstrating that patients with KMT2A rearrangements did worse than those with intermediate risk but similarly to patients with adverse risk. (D) Kaplan-Meier curves for the outcome of OS, where the KMT2A-rearranged group’s survival closely approximated that of the adverse-risk group. with the remaining 116 patients for whom a translocation partner abnormality in 39 patients and with other abnormalities in 23 had been defined. We looked at the risk of relapse, NRM, LFS, and others. Monosomy 7 was detected in 10 patients, del(7q) in 3; OS and found no difference between the groups for any outcome monosomy 5 was found in 3 patients and del(5q) in 10. In sup- (Table 4; Figure 3; multivariable analysis results in supplemental plemental Table 4, we present exploratory multivariable analyses Table 3). for patients in the intermediate- and adverse-risk groups in com- We also performed a multivariable analysis for our main 4 outcomes parison with all the patients in the KMT2A-rearranged group, that included only patients in the KMT2A-rearranged group who those in the KMT2A-rearranged group without additional abnor- had t(9;11) as compared to those with intermediate-risk disease malities, and those in the group with additional abnormalities. (Table 7). In this analysis, NRM, relapse, LFS, and OS were not sig- KMT2A with additional abnormalities had outcomes similar to nificantly different between patients with t(9;11) and those with those of patients with intermediate risk for all 4 outcomes at our intermediate risk. level of significance (P , .01). LFS and OS were significantly shorter for the patients in the KMT2A-rearranged group who did Additional chromosomal abnormalities and not have additional abnormalities. CK analysis We performed a manual review to determine cytogenetic com- Of the 426 patients with KMT2A rearrangement in our study, plexity in the KMT2A-rearranged group and found 29 instances 145 had additional karyotypic abnormalities, and 281 had an of CK among them: 7 with t(9;11), 1 with t(11;19), 3 each with 11q23 translocation alone. The most common additional chromo- t(6;11) and t(10;11), 2 with a different translocation partner, and somal abnormality was trisomy 8, which occurred as an isolated 13 in whom the translocation partner was not defined. We 842 MENGHRAJANI et al 8 FEBRUARY 2022 • VOLUME 6, NUMBER 3 Table 7. Multivariable analysis of t(9;11) vs intermediate risk vs posttransplant setting. The KMT2A-rearranged group had a higher adverse risk risk of relapse than the intermediate-risk group, but a lower relapse Covariates n HR, (95% CI) P risk than the adverse-risk group. No differences in NRM were seen NRM based on cytogenetic grouping. Patients with KMT2A rearrange- ment with t(9;11) were analyzed as a separate group in a multivari- Main effect — — .15 able model, and their outcomes were indistinguishable from those in Intermediate 2384 Reference the intermediate-risk group, suggesting that their risk classification t(9;11) 112 1.04 (0.70-1.55) .85 at diagnosis remains predictive of their post-HCT outcomes. When Adverse 968 1.18 (1.00-1.38) .05 all patients with KMT2A rearrangement were stratified by transloca- Relapse tion partner, our study did not detect differences between the groups in any outcome. Main effect — — ,.001 Intermediate 2384 Reference We also provide quantitative, real-world data on the long-term out- Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/3/828/1873691/advancesadv2021004881.pdf by guest on 09 November 2023 t(9;11) 112 0.98 (0.67-1.42) .91 comes of patients with AML who undergo HCT. For those with intermediate or adverse risk, our univariable analysis showed that Adverse 968 1.67 (1.48-1.89) ,.001 5-year post-HCT OS was 48% and 34%, respectively. Patients LFS with KMT2A rearrangement had a 5-year OS of 42%. Although we Main effect — — ,.001 could not perform a direct comparison with non-transplant treatment Intermediate 2384 Reference approaches with our available dataset, we noted that large studies t(9;11) 112 1.05 (0.79-1.38) .74 of patients with AML have shown a 5-year OS for patients with Adverse 968 1.45 (1.31-1.60) ,.001 KMT2A rearrangement of 20% to 25%.7 OS In addition, our real-world data show that KMT2A-rearranged dis- Main effect — — ,.001 ease was more common among women and that antecedent breast Intermediate 2384 Reference cancer had been detected in 4 to 6 times as many patients in the KMT2A-rearranged group as in the intermediate- or adverse-risk t(9;11) 112 1.12 (0.84-1.49) .45 groups. These data reinforce the association between KMT2A Adverse 969 1.45 (1.30-1.61) ,.001 translocations and antecedent chemotherapy and highlight the The same adjusting factors as those in the main model were selected, but only the necessity of counseling women who have been treated with main effect is presented in the table. anthracycline-based regimens about the risks of developing tAML.23-27 Prior studies looking at whether translocation partner is predictive of performed a univariable analysis to evaluate our main outcomes in outcomes in the posttransplant setting are mixed. A 2015 study of 159 patients with KMT2A-rearranged AML drew from the European those in the KMT2A-rearranged group with CK, compared with Group for Blood and Marrow Transplantation database.28 They those without CK; no significant differences were detected (sup- found that patients with t(11;19) had the highest 2-year OS plemental Table 5). at 73% 6 10%, followed by t(9;11) at 64% 6 6%, t(10;11) at 40% 6 13%, and t(6;11) at 24% 6 11%. The results suggested Discussion that the stratification was driven by a high relapse risk in the latter 2 For most patients with AML with intermediate- or adverse-risk groups of 50% at 2 years. Our study found lower rates of relapse prognostic features, allogeneic HCT remains the only curative ther- that were similar for different translocation partners: 20% to 30% apy.20-22 Until now, there have been limited quantitative data to at 1 year. A multivariable analysis of 49 patients in the KMT2A-rear- compare post-HCT outcomes between these groups. This study is ranged group who underwent allo-HCT by the German Acute Mye- the largest presentation to date of real-world evidence on post-HCT loid Leukemia Intergroup did not find a significant difference in post- HCT OS based on KMT2A subtype.29 Our analysis also did not AML outcomes using curated cytogenetics data. We used a refined detect a significant difference in post-HCT outcomes based on the stratification by diagnostic risk after expert manual curation and KMT2A partner, despite having more patients per translocation sub- robust clinical and outcomes data collected from 165 centers by group than any other cohort in the published literature. the CIBMTR to provide quantitative comparisons. Our results show that patients with adverse risk have a 71% increased risk of relapse, The relatively poor OS of patients with KMT2A rearrangement sug- 47% increased risk of death from recurrent leukemia, and 45% gests that novel therapies are needed to treat this high-risk popula- increased risk of death overall, compared with those with tion. KMT2A rearrangements lead to the recruitment of the H3K79 intermediate-risk disease. Although HCT remains an essential com- histone methyltransferase DOT1L, which alters histone methylation ponent of curative therapy for patients with AML, it may not fully and results in the overexpression of HoxA9 and Meis1 and a subse- overcome the differences in disease biology detected at diagnosis. quent block in cellular differentiation.30 A phase 1 study of the DOT1L inhibitor pinometostat found that it is well tolerated, with Patients with a KMT2A rearrangement may fall into either the inter- modest clinical activity as a single agent.31 A combination study of mediate- or adverse-risk category at the time of diagnosis, based on pinometostat and azacitidine in patients with relapsed/refractory dis- translocation partner, and thus provide a compelling subgroup for ease is ongoing, as is a trial of pinometostat with induction therapy further analysis. We found that LFS and OS for patients with in patients who were previously untreated.32,33 Preclinical studies KMT2A rearrangement are similar to those with adverse risk in the have shown that targeting menin, a protein that binds to the 8 FEBRUARY 2022 • VOLUME 6, NUMBER 3 REAL-WORLD HCT OUTCOMES BY AML RISK AT DIAGNOSIS 843 A Relapse B Non-relapse VE mortality 1.0 p = 0.27 1.0 p = 0.61 Translocation Translocation partner partner 0.8 Other 0.8 Other t(10;11) t(10;11) t(11;19) t(11;19) 0.6 0.6 Probability Probability t(6;11) t(6;11) t(9;11) t(9;11) 0.4 undefined 0.4 undefined 0.2 0.2 Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/3/828/1873691/advancesadv2021004881.pdf by guest on 09 November 2023 0.0 0.0 0 3 6 12 0 3 6 12 Months from HCT Months from HCT C Leukemia free survival D Overall survival 1.0 1.0 p = 0.43 p = 0.30 0.8 0.8 0.6 Translocation 0.6 Translocation Probability Probability partner partner Other Other 0.4 t(10;11) 0.4 t(10;11) t(11;19) t(11;19) t(6;11) t(6;11) 0.2 0.2 t(9;11) t(9;11) undefined undefined 0.0 0.0 0 3 6 12 0 3 6 12 Months from HCT Months from HCT Figure 3. Univariable analysis by translocation partner. (A) CIF curves for the outcome of relapse, where patients with KMT2A rearrangement were stratified by translocation partner. No significant differences were noted between the groups. Log-rank, P 5 .27. (B) CIF curves for the outcome of NRM, where patients with KMT2A rearrangement were stratified by translocation partner. No significant differences were noted between the groups. Log-rank, P 5 .61. (C) Kaplan-Meier curves for the outcome of LFS, where patients with KMT2A rearrangement were stratified by translocation partner. No significant differences were noted between the groups. Log-rank, P 5 .43. (D) Kaplan-Meier curves for the outcome of OS, where patients with KMT2A rearrangement were stratified by translocation partner. No significant differences were noted between the groups. Log-rank, P 5 .27. N-terminus of KMT2A fusion proteins, may also provide an avenue balance, conditioning intensity did not play a role in OS in our analy- for directed therapy in these patients.34 Clinical trials are also ongo- sis. MA conditioning may be most useful for patients selected based ing with menin inhibitors, and preclinical data suggest that combin- on age, HCT-CI, and other patient- and disease-related factors, ing DOT1L and menin inhibition may ultimately result in better such as MRD positivity. Patients who go into transplant with MRD outcomes for these patients than the use of either class of agent have been described to be more likely to relapse and have a alone.35-37 The spleen tyrosine kinase inhibitor entospletinib is also decreased OS.39 In a recent study, Hourigan et al found that these in early-phase trials in this population.38 Although these studies are risks may be mitigated by the use of MA conditioning in patients taking place in patients before HCT, including their use as a bridge with molecular MRD.40 Prospective studies are needed to evaluate to transplant, studies of their use in the post-HCT setting as mainte- whether MA regimens should be preferred among patients with nance therapies are clearly needed. KMT2A rearrangement, and the role of MRD in this setting should be examined. In addition, as patients with KMT2A rearrangement do As trials of targeted therapies are ongoing, our study provides worse than those with intermediate-risk disease, use of donor lym- insights into transplant strategies that may be effective in this popu- phocyte infusions or posttransplant maintenance may also be con- lation. A subgroup analysis showed that those who underwent MA sidered as early interventions in this population. conditioning, especially with TBI, had improved LFS and lower relapse risk, compared with those who received RIC/NMA trans- In conclusion, our analysis is the largest to date of the posttrans- plants. The benefits of MA conditioning, however, must be consid- plant outcomes of patients with AML. Diagnostic risk classifica- ered against the risk of NRM, which was higher in this group; on tion remains predictive of transplant outcomes, but 5-year OS 844 MENGHRAJANI et al 8 FEBRUARY 2022 • VOLUME 6, NUMBER 3 after HCT is robust and provides evidence of the curative poten- manually curated the data; M.-J.Z. performed the statistical analyses tial of this strategy. Post-HCT outcomes for t(9;11) patients hew and interpreted the data; H.-L.W. managed the project, performed closely to those of patients with intermediate-risk disease. In statistical analyses, curated and interpreted the data, and created aggregate, however, patients with KMT2A rearrangement have the tables and figures; K.B.-S. managed the project, curated the LFS and OS similar to patients with adverse-risk disease. Stratifi- data, performed the statistical analysis, and created the tables; J.S. cation of all patients with KMT2A rearrangement by translocation managed the project, performed statistical analyses, and curated partner did not show significant differences. This may be the data; C.H., B.S., M.L., P.K., and D.W. provided project oversight, because, despite having the largest analysis published to date, interpreted the data, and reviewed the manuscript; Y.Z. initiated and we remain underpowered to detect such a difference. We recog- designed the project, manually curated and interpreted the data, nize that our analysis of registry data may be limited by the het- and reviewed the manuscript; M.S.T. provided project oversight, erogeneity of the contributing centers, changes in MRD reviewed the statistical analyses, interpreted the data, and reviewed assessment over the study period, and missing data, as well as the manuscript; and all remaining authors interpreted the data and Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/3/828/1873691/advancesadv2021004881.pdf by guest on 09 November 2023 the lack of genomic information. However, our study highlights reviewed the manuscript. the need to consider whether prognostic scoring systems for Conflict-of-interest disclosure: J.C. reports conflicts with Incyte patients with AML who undergo HCT should include all cytoge- Inc, Jazz Pharmaceuticals, Daiichi-Sankyo, and Pfizer Inc, and owns netic data from the time of diagnosis. Further studies are needed stock in Bluebird Bio Inc. V.R.B. reports receiving personal fees to evaluate the role of genomic data and clonal evolution in refin- from Agios, Takeda, Partner Therapeutics, Incyte, Omeros, AbbVie, ing risk prediction for this population. In the case of KMT2A, we Partnership for Health and Analytic Research LLC, Pfizer, CSL Beh- posit that targeted approaches to treatment and transplantation ring, and Rigel Pharmaceuticals; grants from Jazz, National Marrow in this unfavorable patient subset represent a critical unmet need. Donor Program, and Tolero Pharmaceuticals; and other support from Oncoceutics, outside the submitted work. M.R.G. reports Acknowledgments receiving grants, personal fees, and nonfinancial support from Incyte; grants from Janssen, Genentech, and Forma Therapeutics; This work was funded in part by the Weinberg Family and Mortimer grants and nonfinancial support from Amgen; personal fees from J. Lacher fellowships, an American Society of Clinical Oncology AbbVie, Agios, Astellas, Daiichi Sankyo, Cardinal Health, Premier, Young Investigator Award (ASCO YIA), a National Institutes of Trovagene, Pfizer, Merck, and BMS/Celgene; and other support Health K12 Paul Calabresi Career Development Award for Clinical from Medtronic, outside the submitted work. G.H. reports other Oncology (K12-CA184746), and under the auspices of the Memo- support from Pfizer, Kite Pharma, Incyte, Jazz Pharmaceuticals, rial Sloan Kettering Cancer Center (MSKCC) Clinical Research Pharmacyclics, Takeda, the Falk Foundation, Astellas Pharma, out- Methodology Curriculum (CRMC)/Weill Cornell Clinical and Transla- side the submitted work. C.H. reports other support from Merck tional Science Center (CTSC) (K.M.). The CIBMTR is supported pri- and Sellas, outside the submitted work. A.A. reports grants and marily by National Institutes of Health grant U24CA076518 from the personal fees from Incyte Corporation, Boston Biomedical, and National Cancer Institute (NCI), the National Heart, Lung, and Blood Null, outside the submitted work. A.K. reports conflicts with BMS, Institute (NHLBI), and the National Institute of Allergy and Infectious Takeda, Pfizer, Janssen, Sanofi, Karyopharm, and GSK. H.L. Diseases (NIAID); by grant HHSH250201700006C from the Health reports grants from BMS and Karyopharm and personal fees from Resources and Services Administration (HRSA); and by grants Agios, outside the submitted work. T.N. reports other support from N00014-20-1-2705 and N00014-20-1-2832 from the Office of Karyopharm and Novartis, outside the submitted work. R.R. reports Naval Research. Support was also provided by Be the Match Foun- personal fees from Kite/Gilead, Bristol Myers, Monsanto, Incyte, dation, the Medical College of Wisconsin, the National Marrow Magenta, Pharmacyclics, and Atara, outside the submitted work. Donor Program, and from the following commercial entities: AbbVie, D.R. reports personal fees from Amgen, Kite, AROG, Pharmacy- Actinium Pharmaceuticals Inc, Adaptive Biotechnologies Corporation, clics, Seattle Genetics, Pfizer, Novartis, Sanofi-Aventis, Incyte, Gil- Adienne SA, Allovir Inc, Amgen Inc, Angiocrine Bioscience, Astellas ead, Jazz, Celegene, and AbbVie; other support from Celltron/ Pharma US, Bluebird Bio Inc, Bristol Myers Squibb Co, CSL Beh- Teva, Mustang, Bayer, Stemline, outside the submitted work. A.S. ring, CytoSen Therapeutics Inc, Daiichi Sankyo Co Ltd, Eurofins Vir- reports research collaboration with CRISPR Therapeutics/Vertex acor, ExcellThera, Fate Therapeutics, Gamida-Cell Ltd, Genentech Pharmaceuticals, and Novartis Pharmaceuticals; he is the principal Inc, GlaxoSmithKline, Incyte Corporation, Janssen/Johnson and John- investigator of a clinical trial for gene therapy of sickle cell disease son, Jasper Therapeutics, Jazz Pharmaceuticals Inc, Karyopharm sponsored by Vertex Pharmaceuticals/CRISPR Therapeutics, and Therapeutics, Kiadis Pharma, Kite (a Gilead company), Kyowa Kirin, the sponsor provides funding for the clinical trial, which includes Legend Biotech, Magenta Therapeutics, Medac GmbH, Merck and salary support paid to his institution; the support is not related in Co, Millennium, the Takeda Oncology Co, Miltenyi Biotec Inc, Mor- any way to this work product. He also has research collaboration phoSys, Novartis Pharmaceuticals Corporation, Omeros Corporation, with Novartis on their sickle cell gene therapy clinical trial for Oncoimmune Inc, Orca Biosystems Inc, Pfizer Inc, Pharmacyclics which he is not financially compensated in any way. C.U. reports LLC, Sanofi Genzyme, Seagen Inc, Stemcyte, Takeda Pharmaceuti- other support from Jazz Pharmaceutical, outside the submitted cals, Tscan, Vertex, Vor Biopharma, Xenikos BV. work. D.W. reports grants from Incyte and personal fees from Fate, outside the submitted work. The remaining authors declare Authorship no competing financial interests. Contribution: K.M., initiated the project, manually curated and ana- ORCID profiles: A.G.-A., 0000-0003-0897-3790; A.A., lyzed the data, and drafted the manuscript; A.G.-A. manually curated 0000-0003-4707-9265; V.U.B., 0000-0001-8771-947X; N.B., and interpreted the data and edited the manuscript; R.M.-M. 0000-0003-0194-7338; V.R.B., 0000-0003-2513-0533; J.C., 8 FEBRUARY 2022 • VOLUME 6, NUMBER 3 REAL-WORLD HCT OUTCOMES BY AML RISK AT DIAGNOSIS 845 0000-0002-6602-5505; S.C., 0000-0001-9117-8696; Z.D.F., 0000-0002-4308-2152; A.S., 0000-0003-3281-2081; C.U., 0000-0002-7994-8974; S.G., 0000-0002-3255-8143; R.P.G., 0000-0001-6896-6213; C.H., 0000-0002-6189-8067; B.S., 0000-0002-9156-1676; S.H., 0000-0002-8914-7927; G.H., 0000-0002-9767-9739; M.L., 0000-0002-9816-6302; D.W., 0000-0003-0478-3340; A.K., 0000-0001-6901-0782; M.K., 0000-0001-8078-8579. 0000-0003-3980-480X; H.L., 0000-0002-1159-5607; H.L., 0000-0002-3190-7807; R.M., 0000-0001-5143-4042; F.V.M., Correspondence: Kamal Menghrajani, Leukemia Service, 0000-0003-2956-0848; T.N., 0000-0002-2621-7924; R.O., Department of Medicine, Memorial Sloan Kettering Cancer 0000-0001-5970-2128; R.R., 0000-0003-2185-9546; D.R., Center, 1275 York Ave, New York, NY 10065; e-mail: 0000-0001-9886-5771; B.N.S., 0000-0002-3304-9965; S.S., menghrak@mskcc.org. 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