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ACUTE MYELOID LEUKEMIA

Utility of the Treatment-Related Mortality (TRM) score to predict outcomes of adults with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation

Leukemia volume 36, pages 1563–1574 (2022)Cite this article

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Abstract

There is long-standing interest in estimating non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT) for AML, but existing tools have limited discriminative capacity. Using single-institution data from 861 adults with AML, we retrospectively examined the Treatment-Related Mortality (TRM) score, originally developed to predict early mortality following induction chemotherapy, as a predictor of post-HCT outcome. NRM risks increased stepwise across the four TRM score quartiles (at 3 years: 9% [95% confidence interval: 5–13%] in Q1 vs. 28% [22–34%] in Q4). The 3-year risk of relapse was lower in patients with lower TRM score (26% [20–32%] in Q1 vs. 37% [30–43%] in Q4). Consequently, relapse-free survival (RFS) and overall survival (OS) estimates progressively decreased (RFS at 3 years: 66% [59–72%] in Q1 vs. 36% [29–42%] in Q4; OS at 3 years: 72% [66–78%] in Q1 vs. 39% [33–46%] in Q4). With a C-statistic of 0.661 (continuous variable) or 0.642 (categorized by quartile), the TRM score predicted NRM better than the Pretransplantation Assessment of Mortality (PAM) score (0.603) or the HCT-CI/age composite score (0.576). While post-HCT outcome prediction remains challenging, these findings suggest that the TRM score may be useful for risk stratification for adults with AML undergoing allogeneic HCT.

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Fig. 1: Post-HCT outcomes for 861 adults with AML undergoing allogeneic HCT while in first or second morphologic remission, stratified by quartile of TRM score.
Fig. 2: Prediction of post-HCT outcomes with TRM score.

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References

  1. Cornelissen JJ, Gratwohl A, Schlenk RF, Sierra J, Bornhäuser M, Juliusson G, et al. The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: an integrated-risk adapted approach. Nat Rev Clin Oncol. 2012;9:579–90.

    Article  CAS  PubMed  Google Scholar 

  2. Cornelissen JJ, Blaise D. Hematopoietic stem cell transplantation for patients with AML in first complete remission. Blood. 2016;127:62–70.

    Article  CAS  PubMed  Google Scholar 

  3. Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106:2912–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sorror ML, Giralt S, Sandmaier BM, De Lima M, Shahjahan M, Maloney DG, et al. Hematopoietic cell transplantation specific comorbidity index as an outcome predictor for patients with acute myeloid leukemia in first remission: combined FHCRC and MDACC experiences. Blood. 2007;110:4606–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Raimondi R, Tosetto A, Oneto R, Cavazzina R, Rodeghiero F, Bacigalupo A, et al. Validation of the Hematopoietic Cell Transplantation-Specific Comorbidity Index: a prospective, multicenter GITMO study. Blood. 2012;120:1327–33.

    Article  CAS  PubMed  Google Scholar 

  7. Sorror ML, Logan BR, Zhu X, Rizzo JD, Cooke KR, McCarthy PL, et al. Prospective validation of the predictive power of the Hematopoietic Cell Transplantation Comorbidity Index: a Center for International Blood and Marrow Transplant Research study. Biol Blood Marrow Transplant. 2015;21:1479–87.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Parimon T, Au DH, Martin PJ, Chien JW. A risk score for mortality after allogeneic hematopoietic cell transplantation. Ann Intern Med. 2006;144:407–14.

    Article  PubMed  Google Scholar 

  9. Au BKC, Gooley TA, Armand P, Fang M, Madtes DK, Sorror ML, et al. Reevaluation of the pretransplant assessment of mortality score after allogeneic hematopoietic transplantation. Biol Blood Marrow Transplant. 2015;21:848–54.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Gratwohl A. The EBMT risk score. Bone Marrow Transplant. 2012;47:749–56.

    Article  CAS  PubMed  Google Scholar 

  11. Hemmati PG, Terwey TH, le Coutre P, Vuong LG, Massenkeil G, Dörken B, et al. A modified EBMT risk score predicts the outcome of patients with acute myeloid leukemia receiving allogeneic stem cell transplants. Eur J Haematol. 2011;86:305–16.

    Article  PubMed  Google Scholar 

  12. Barba P, Martino R, Pérez-Simón JA, Fernández-Avilés F, Castillo N, Piñana JL, et al. Combination of the Hematopoietic Cell Transplantation Comorbidity Index and the European Group for Blood and Marrow Transplantation score allows a better stratification of high-risk patients undergoing reduced-toxicity allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2014;20:66–72.

    Article  PubMed  Google Scholar 

  13. Armand P, Kim HT, Logan BR, Wang Z, Alyea EP, Kalaycio ME, et al. Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. Blood. 2014;123:3664–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yanada M, Konuma T, Mizuno S, Saburi M, Shinohara A, Tanaka M, et al. Predicting non-relapse mortality following allogeneic hematopoietic cell transplantation during first remission of acute myeloid leukemia. Bone Marrow Transplant. 2021;56:387–94.

    Article  PubMed  Google Scholar 

  15. Shouval R, Fein JA, Cho C, Avecilla ST, Ruiz J, Tomas AA, et al. The Simplified Comorbidity Index: a new tool for prediction of nonrelapse mortality in allo-HCT. Blood Adv. 2022;6:1525–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Shouval R, Fein JA, Shouval A, Danylesko I, Shem-Tov N, Zlotnik M, et al. External validation and comparison of multiple prognostic scores in allogeneic hematopoietic stem cell transplantation. Blood Adv. 2019;3:1881–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Al-Shaibani E, Cyriac S, Chen S, Lipton JH, Kim DD, Viswabandya A, et al. Comparison of the prognostic ability of the HCT-CI, the modified EBMT, and the EBMT-ADT pre-transplant risk scores for acute leukemia. Clin Lymphoma Myeloma Leuk. 2021;21:e559–e568.

    Article  PubMed  Google Scholar 

  18. Walter RB, Othus M, Borthakur G, Ravandi F, Cortes JE, Pierce SA, et al. Prediction of early death after induction therapy for newly diagnosed acute myeloid leukemia with pretreatment risk scores: a novel paradigm for treatment assignment. J Clin Oncol. 2011;29:4417–23.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.

    Article  CAS  PubMed  Google Scholar 

  20. Walter RB, Gooley TA, Wood BL, Milano F, Fang M, Sorror ML, et al. Impact of pretransplantation minimal residual disease, as detected by multiparametric flow cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute myeloid leukemia. J Clin Oncol. 2011;29:1190–7.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Walter RB, Buckley SA, Pagel JM, Wood BL, Storer BE, Sandmaier BM, et al. Significance of minimal residual disease before myeloablative allogeneic hematopoietic cell transplantation for AML in first and second complete remission. Blood. 2013;122:1813–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Walter RB, Gyurkocza B, Storer BE, Godwin CD, Pagel JM, Buckley SA, et al. Comparison of minimal residual disease as outcome predictor for AML patients in first complete remission undergoing myeloablative or nonmyeloablative allogeneic hematopoietic cell transplantation. Leukemia. 2015;29:137–44.

    Article  CAS  PubMed  Google Scholar 

  23. Walter RB, Sandmaier BM, Storer BE, Godwin CD, Buckley SA, Pagel JM, et al. Number of courses of induction therapy independently predicts outcome after allogeneic transplantation for acute myeloid leukemia in first morphological remission. Biol Blood Marrow Transplant. 2015;21:373–8.

    Article  PubMed  Google Scholar 

  24. Araki D, Wood BL, Othus M, Radich JP, Halpern AB, Zhou Y, et al. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia: is it time to move toward a minimal residual disease-based definition of complete remission. J Clin Oncol. 2016;34:329–36.

    Article  PubMed  Google Scholar 

  25. Zhou Y, Othus M, Araki D, Wood BL, Radich JP, Halpern AB, et al. Pre- and post-transplant quantification of measurable (‘minimal’) residual disease via multiparameter flow cytometry in adult acute myeloid leukemia. Leukemia. 2016;30:1456–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hoffmann AP, Besch AL, Othus M, Morsink LM, Wood BL, Mielcarek M, et al. Early achievement of measurable residual disease (MRD)-negative complete remission as predictor of outcome after myeloablative allogeneic hematopoietic cell transplantation in acute myeloid leukemia. Bone Marrow Transplant. 2020;55:669–72.

    Article  PubMed  Google Scholar 

  27. Morsink LM, Bezerra ED, Othus M, Wood BL, Fang M, Sandmaier BM, et al. Comparative analysis of total body irradiation (TBI)-based and non-TBI-based myeloablative conditioning for acute myeloid leukemia in remission with or without measurable residual disease. Leukemia. 2020;34:1701–5.

    Article  PubMed  Google Scholar 

  28. Morsink LM, Othus M, Bezerra ED, Wood BL, Fang M, Sandmaier BM, et al. Impact of pre-transplant measurable residual disease on outcome of allogeneic hematopoietic cell transplantation in adult monosomal karyotype AML. Leukemia. 2020;34:1577–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Morsink LM, Sandmaier BM, Othus M, Palmieri R, Granot N, Bezerra ED, et al. Conditioning intensity, pre-transplant flow cytometric measurable residual disease, and outcome in adults with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation. Cancers. 2020;12:2339.

  30. Paras G, Morsink LM, Othus M, Milano F, Sandmaier BM, Zarling LC, et al. Conditioning intensity and peritransplant flow cytometric MRD dynamics in adult AML. Blood. 2022;139:1694–706.

    Article  CAS  PubMed  Google Scholar 

  31. Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood. 2010;116:354–65.

    Article  CAS  PubMed  Google Scholar 

  32. Breems DA, Van Putten WLJ, De Greef GE, Van Zelderen-Bhola SL, Gerssen-Schoorl KBJ, Mellink CHM, et al. Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype. J Clin Oncol. 2008;26:4791–7.

    Article  PubMed  Google Scholar 

  33. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649–55.

    Article  CAS  PubMed  Google Scholar 

  34. Sorror ML, Storb RF, Sandmaier BM, Maziarz RT, Pulsipher MA, Maris MB, et al. Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation. J Clin Oncol. 2014;32:3249–56.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Michelis FV, Messner HA, Uhm J, Alam N, Lambie A, McGillis L, et al. Modified EBMT pretransplant risk score can identify favorable-risk patients undergoing allogeneic hematopoietic cell transplantation for AML, not identified by the HCT-CI score. Clin Lymphoma Myeloma Leuk. 2015;15:e73–81.

    Article  PubMed  Google Scholar 

  36. Giralt S, Ballen K, Rizzo D, Bacigalupo A, Horowitz M, Pasquini M, et al. Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant. 2009;15:367–9.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant. 2009;15:1628–33.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Wood BL. Acute myeloid leukemia minimal residual disease detection: the difference from normal approach. Curr Protoc Cytom. 2020;93:e73.

    CAS  PubMed  Google Scholar 

  39. Gönen M, Heller G. Concordance probability and discriminatory power in proportional hazards regression. Biometrika. 2005;92:965–70.

    Article  Google Scholar 

  40. Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M, et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med. 2010;363:2091–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. McDonald GB, Sandmaier BM, Mielcarek M, Sorror M, Pergam SA, Cheng GS, et al. Survival, nonrelapse mortality, and relapse-related mortality After allogeneic hematopoietic cell transplantation: comparing 2003-2007 versus 2013-2017 cohorts. Ann Intern Med. 2020;172:229–39.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Cooper JP, Storer BE, Granot N, Gyurkocza B, Sorror ML, Chauncey TR, et al. Allogeneic hematopoietic cell transplantation with non-myeloablative conditioning for patients with hematologic malignancies: improved outcomes over two decades. Haematologica. 2021;106:1599–607.

    Article  CAS  PubMed  Google Scholar 

  43. Halpern AB, Othus M, Huebner EM, Buckley SA, Pogosova-Agadjanyan EL, Orlowski KF, et al. Mitoxantrone, etoposide and cytarabine following epigenetic priming with decitabine in adults with relapsed/refractory acute myeloid leukemia or other high-grade myeloid neoplasms: a phase 1/2 study. Leukemia. 2017;31:2560–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Walter RB, Othus M, Orlowski KF, McDaniel EN, Scott BL, Becker PS, et al. Unsatisfactory efficacy in randomized study of reduced-dose CPX-351 for medically less fit adults with newly diagnosed acute myeloid leukemia or other high-grade myeloid neoplasm. Haematologica. 2018;103:e106–e109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Halpern AB, Othus M, Huebner EM, Scott BL, Becker PS, Percival MEM, et al. Phase 1/2 trial of GCLAM with dose-escalated mitoxantrone for newly diagnosed AML or other high-grade myeloid neoplasms. Leukemia. 2018;32:2352–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Halpern AB, Othus M, Huebner EM, Scott BL, Hendrie PC, Percival MEM, et al. Phase I/II trial of cladribine, high-dose cytarabine, mitoxantrone, and G-CSF with dose-escalated mitoxantrone for relapsed/refractory acute myeloid leukemia and other high-grade myeloid neoplasms. Haematologica. 2019;104:e143–e146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Mabrey FL, Gardner KM, Shannon Dorcy K, Perdue A, Smith HA, Davis AM, et al. Outpatient intensive induction chemotherapy for acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood Adv. 2020;4:611–6.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Research reported in this publication was supported by grants P01-CA078902, P01-CA018029, and P30-CA015704 from the National Cancer Institute/National Institutes of Health (NCI/NIH), Bethesda, MD, USA. The authors acknowledge the excellent care provided by the physicians and nurses of the HCT teams, the staff in the Long-Term Follow-up office at the Fred Hutchinson Cancer Research Center, the Hematopathology Laboratory at the University of Washington, and the patients for participating in our research protocols.

Funding

This work was supported by grants P01-CA078902, P01-CA018029, and P30-CA015704 from the National Cancer Institute/National Institutes of Health (NCI/NIH).

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Authors and Affiliations

  1. Department of Medicine, Residency Program, University of Washington, Seattle, WA, USA

    Lucas C. Zarling

  2. Public Health Science Division, Fred Hutchinson Cancer Center, Seattle, WA, USA

    Megan Othus

  3. Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA

    Brenda M. Sandmaier, Filippo Milano, Gary Schoch, Chris Davis, Marie Bleakley, H. Joachim Deeg, Frederick R. Appelbaum, Rainer Storb & Roland B. Walter

  4. Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, USA

    Brenda M. Sandmaier, Filippo Milano, H. Joachim Deeg, Frederick R. Appelbaum & Rainer Storb

  5. Department of Pediatrics, University of Washington, Seattle, WA, USA

    Marie Bleakley

  6. Department of Medicine, Division of Hematology, University of Washington, Seattle, WA, USA

    Roland B. Walter

  7. Department of Laboratory Medicine & Pathology, University of Washington, Seattle, WA, USA

    Roland B. Walter

  8. Department of Epidemiology, University of Washington, Seattle, WA, USA

    Roland B. Walter

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Contributions

LCZ contributed to the collection and assembly of data and drafting of the manuscript. MO conducted all statistical analyses and participated in data interpretation and drafting of the manuscript. BMS, FM, MB, HJD, FRA, and RS contributed to the provision of study material, patient recruitment, and acquisition of data. GS and CD contributed to the collection and assembly of data. RBW conceptualized and designed this study and participated in data analysis and interpretation and drafting of the manuscript. All authors revised the manuscript critically and gave final approval to submit for publication.

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Correspondence to Roland B. Walter.

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Zarling, L.C., Othus, M., Sandmaier, B.M. et al. Utility of the Treatment-Related Mortality (TRM) score to predict outcomes of adults with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation. Leukemia 36, 1563–1574 (2022). https://doi.org/10.1038/s41375-022-01574-5

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