[en] Late relapse (LR) after allogeneic hematopoietic stem cell transplantation (AHSCT) for acute leukemia is a rare event (nearly 4.5%) and raises the questions of prognosis and outcome after salvage therapy. We performed a retrospective multicentric study between January 1, 2010, and December 31, 2016, using data from the French national retrospective register ProMISe provided by the SFGM-TC (French Society for Bone Marrow Transplantation and Cellular Therapy). We included patients presenting with LR, defined as a relapse occurring at least 2 years after AHSCT. We used the Cox model to identify prognosis factors associated with LR. During the study period, a total of 7582 AHSCTs were performed in 29 centers, and 33.8% of patients relapsed. Among them, 319 (12.4%) were considered to have LR, representing an incidence of 4.2% for the entire cohort. The full dataset was available for 290 patients, including 250 (86.2%) with acute myeloid leukemia and 40 (13.8%) with acute lymphoid leukemia. The median interval from AHSCT to LR was 38.2 months (interquartile range [IQR], 29.2 to 49.7 months), and 27.2% of the patients had extramedullary involvement at LR (17.2% exclusively and 10% associated with medullary involvement). One-third of the patients had persistent full donor chimerism at LR. Median overall survival (OS) after LR was 19.9 months (IQR, 5.6 to 46.4 months). The most common salvage therapy was induction regimen (55.5%), with complete remission (CR) obtained in 50.7% of cases. Ninety-four patients (38.5%) underwent a second AHSCT, with a median OS of 20.4 months (IQR, 7.1 to 49.1 months). Nonrelapse mortality after second AHSCT was 18.2%. The Cox model identified the following factors as associated with delay of LR: disease status not in first CR at first HSCT (odds ratio [OR], 1.31; 95% confidence interval [CI], 1.04 to 1.64; P = .02) and the use of post-transplantation cyclophosphamide (OR, 2.23; 95% CI, 1.21 to 4.14; P = .01). Chronic GVHD appeared to be a protective factor (OR, .64; 95% CI, .42 to .96; P = .04). The prognosis of LR is better than in early relapse, with a median OS after LR of 19.9 months. Salvage therapy associated with a second AHSCT improves outcome and is feasible, without creating excess toxicity.
Disciplines :
Hematology
Author, co-author :
Kaphan, Eléonore ; Department of Hematology-Transplantation, CHU Grenoble, Grenoble, France. Electronic address: eleonore.kaphan@aphp.fr
Bettega, François; Department of Clinical Research, Inserm, University Grenoble Alpes, CHU Grenoble Alpes, Grenoble, France
Forcade, Edouard; Department of Hematology-Transplantation, Hôpital de Bordeaux, Bordeaux, France
Labussière-Wallet, Hélène; Department of Hematology-Transplantation, CHU Lyon Sud, Pierre-Bénite, France
Fegueux, Nathalie; Department of Hematology, CHU Montpellier, Montpellier, France
Robin, Marie; Department of Hematology-Transplantation, Hôpital Saint-Louis, APHP, Université de Paris, Paris, France
Peffault De Latour, Régis; Department of Hematology-Transplantation, Hôpital Saint-Louis, APHP, Université de Paris, Paris, France
Huynh, Anne; Department of Hematology, Transplantation, and Cellular Therapy, IUCT Oncopole, Toulouse, France
Lapierre, Léopoldine; Department of Hematology, Transplantation, and Cellular Therapy, IUCT Oncopole, Toulouse, France
Berceanu, Ana; Department of Intensive Care and Transplantation, CHU Jean Minjoz, Besançon, France
Marcais, Ambroise; Department of Hematology, Hôpital Necker, Paris, France
Debureaux, Pierre-Edouard ; Department of Hematology-Transplantation, Hôpital Saint-Louis, APHP, Université de Paris, Paris, France
Vanlangendonck, Nicolas; Department of Hematology, Université Catholique de Louvain, Louvain-la-Neuve, Belgium
Bulabois, Claude-Eric ; Department of Hematology-Transplantation, CHU Grenoble, Grenoble, France
Magro, Leonardo; Department of Hematology-Transplantation, CHRU Lille, Lille, France
Daniel, Adrien; Department of Hematology, Université Catholique de Louvain, Louvain-la-Neuve, Belgium
Galtier, Jean; Department of Hematology-Transplantation, Hôpital de Bordeaux, Bordeaux, France
Lioure, Bruno; Department of Hematology, CHRU Strasbourg, Strasbourg, France
Chevallier, Patrice; Department of Hematology, CHU Nantes, Nantes, France
Antier, Chloé; Department of Hematology, CHU Nantes, Nantes, France
Loschi, Michael ; Department of Hematology-Transplantation, CHU Nice, Nice, France
Guillerm, Gaelle; Department of Hematology, CHRU Brest, Brest, France
Mear, Jean-Baptiste; Department of Hematology-Transplantation, Hôpital de Rennes, Rennes, France
Chantepie, Sylvain ; Basse-Normandie Hematology Institute, CHU Caen, Caen, France
Cornillon, Jérome; Department of Clincial Hematology and Cellular Therapy, CHU Saint-Étienne, Saint-Priest-en-Jarez, France
Rey, Gaelle; Department of Clincial Hematology and Cellular Therapy, CHU Saint-Étienne, Saint-Priest-en-Jarez, France
Poire, Xavier; Department of Hematology, CHU Saint-Luc, Brussels, Belgium
Bazarbachi, Ali; Bone Marrow Transplantation Program, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
Rubio, Marie-Thérèse; Department of Hematology, CHU Nancy, Nancy, France
Contentin, Nathalie; Department of Hematology, Centre Henri Becquerel, Rouen, France
Orvain, Corentin; Department of Hematology-Transplantation, CHU Angers, Angers, France
Dulery, Rémy ; Department of Clinical Hematology, CHU St Antoine, APHP, Paris, France
Bay, Jacques Olivier; Department of Clinical Hematology and Cellular Therapy, CHU Estaing, Clermont-Ferrand, France
Croizier, Carolyne ; Department of Clinical Hematology and Cellular Therapy, CHU Estaing, Clermont-Ferrand, France
Beguin, Yves ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'hématologie clinique
Charbonnier, Aude; Department of Hematology-Transplantation, CHU Amiens, Amiens, France
Skrzypczak, Caroline; Department of Hematology-Transplantation, CHU Amiens, Amiens, France
Desmier, Déborah; Department of Hematology, CHU Poitiers, Poitiers, France
Villate, Alban; Department of Hematology, CHRU Tours, Tours, France
Carré, Martin; Department of Hematology-Transplantation, CHU Grenoble, Grenoble, France
Thiebaut-Bertrand, Anne; Department of Hematology-Transplantation, CHU Grenoble, Grenoble, France
The authors thank all the patients and their families for their participation in this study, all the nurses, the doctors who referred the patients for transplantation, and all the SFGM-TC members. They also thank Nicolas Raus for data management and David Williams for proofreading. Financial disclosure: There are no financial disclosure to report, Conflict of interest statement: There are no conflicts of interest to report. Financial disclosure: See Acknowledgments on page 362.e10.
Bejanyan, N, Weisdorf, DJ, Logan, BR, et al. Survival of patients with acute myeloid leukemia relapsing after allogeneic hematopoietic cell transplantation: a Center for International Blood and Marrow Transplant Research study. Biol Blood Marrow Transplant, 21, 2015, 454‑459.
Kuhlen, M, Willasch, AM, Dalle, JH, et al. Outcome of relapse after allogeneic HSCT in children with ALL enrolled in the ALL-SCT 2003/2007 trial. Br J Haematol, 180, 2018, 82‑89.
Schmid, C, Labopin, M, Nagler, A, et al. Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation. Blood, 119, 2012, 1599‑1606.
Giles, F, O'Brien, S, Cortes, J, et al. Outcome of patients with acute myelogenous leukemia after second salvage therapy. Cancer, 104, 2005, 547‑554.
Kantarjian, HM, Keating, MJ, Walters, RS, McCredie, KB, Freireich, EJ., The characteristics and outcome of patients with late relapse acute myelogenous leukemia. J Clin Oncol, 6, 1988, 232‑238.
Spyridonidis, A, Labopin, M, Schmid, C, et al. Outcomes and prognostic factors of adults with acute lymphoblastic leukemia who relapse after allogeneic hematopoietic cell transplantation. An analysis on behalf of the Acute Leukemia Working Party of EBMT. Leukemia., 26, 2012, 1211‑1217.
Wingard, JR, Majhail, NS, Brazauskas, R, et al. Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. J Clin Oncol, 29, 2011, 2230‑2239.
Socié, G, Stone, JV, Wingard, JR, et al. Long-term survival and late deaths after allogeneic bone marrow transplantation. Late Effects Working Committee of the International Bone Marrow Transplant Registry. N Engl J Med, 341, 1999, 14‑21.
Döhner, H, Estey, E, Grimwade, D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood, 129, 2017, 424‑447.
Heuser, M, Freeman, SD, Ossenkoppele, GJ, et al. 2021 update on MRD in acute myeloid leukemia: a consensus document from the European LeukemiaNet MRD Working Party. Blood, 138, 2021, 2753‑2767.
van Dongen, JJM, van der Velden, VHJ, Brüggemann, M, Orfao, A., Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies. Blood, 125, 2015, 3996‑4009.
Przepiorka, D, Weisdorf, D, Martin, P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant, 15, 1995, 825‑828.
Jagasia, MH, Greinix, HT, Arora, M, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant, 21, 2015 389-401.e1.
Thanarajasingam, G, Kim, HT, Cutler, C, et al. Outcome and prognostic factors for patients who relapse after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant, 19, 2013, 1713‑1718.
Molina, B, Gonzalez Vicent, M, Herrero, B, et al. Kinetics and risk factors of relapse after allogeneic stem cell transplantation in children with leukemia: a long-term follow-up single-center study. Biol Blood Marrow Transplant, 25, 2019, 100‑106.
Green, ML, Leisenring, WM, Xie, H, et al. CMV reactivation after allogeneic HCT and relapse risk: evidence for early protection in acute myeloid leukemia. Blood, 122, 2013, 1316‑1324.
Nagler, A, Labopin, M, Dholaria, B, et al. Graft-versus-host disease prophylaxis with post-transplantation cyclophosphamide versus cyclosporine A and methotrexate in matched sibling donor transplantation. Transplant Cell Ther, 28, 2022 86.e1-86.e8.
Lim, ABM, Curley, C, Fong, CY, et al. Acute myeloid leukaemia relapsing after allogeneic haemopoietic stem cell transplantation: prognostic factors and impact of initial therapy of relapse. Intern Med J., 48, 2018, 276‑285.
Yanada, M, Fukuda, T, Tanaka, M, et al. Long-term results of reduced-intensity conditioning allogeneic hematopoietic cell transplantation for older patients with acute myeloid leukemia: a retrospective analysis of 10-year follow-up data. Bone Marrow Transplant, 55, 2020, 2008‑2016.
Oriol, A, Vives, S, Hernández-Rivas, JM, et al. Outcome after relapse of acute lymphoblastic leukemia in adult patients included in four consecutive risk-adapted trials by the PETHEMA study group. Haematologica, 95, 2010, 589‑596.
Aldoss, I, Pillai, R, Yang, D, et al. Late and very late relapsed acute lymphoblastic leukemia: clinical and molecular features, and treatment outcomes. Blood Cancer J, 11, 2021, 125.
Yilmaz, M, Wang, F, Loghavi, S, et al. Late relapse in acute myeloid leukemia (AML): clonal evolution or therapy-related leukemia?. Blood Cancer J, 9, 2019, 7.
Verma, D, Kantarjian, H, Faderl, S, et al. Late relapses in acute myeloid leukemia: analysis of characteristics and outcome. Leuk Lymphoma, 51, 2010, 778‑782.
Medeiros, BC, Minden, MD, Schuh, AC, et al. Characteristics and outcomes of acute myelogenous leukemia patients with very late relapse (>5 years). Leuk Lymphoma, 48, 2007, 65‑71.
Patel, A, Agha, M, Raptis, A, et al. Outcomes of patients with acute myeloid leukemia who relapse after 5 years of complete remission. Oncol Res, 28, 2021, 811‑814.
Rizzari, C, Valsecchi, MG, Aricò, M, et al. Outcome of very late relapse in children with acute lymphoblastic leukemia. Haematologica, 89, 2004, 427‑434.
Ganzel, C, Wang, XV, Rowe, JM, et al. At three years, patients with acute lymphoblastic leukaemia are still at risk for relapse. Results of the international MRC UKALLXII/ECOG E2993 trial. Br J Haematol, 191, 2020, 37‑43.
Harris, AC, Kitko, CL, Couriel, DR, et al. Extramedullary relapse of acute myeloid leukemia following allogeneic hematopoietic stem cell transplantation: incidence, risk factors and outcomes. Haematologica, 98, 2013, 179‑184.
Lee, KH, Lee, JH, Choi, SJ, et al. Bone marrow vs extramedullary relapse of acute leukemia after allogeneic hematopoietic cell transplantation: risk factors and clinical course. Bone Marrow Transplant, 32, 2003, 835‑842.
Clark, WB, Strickland, SA, Barrett, AJ, Savani, BN., Extramedullary relapses after allogeneic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndrome. Haematologica, 95, 2010, 860‑863.
Shem-Tov, N, Saraceni, F, Danylesko, I, et al. Isolated extramedullary relapse of acute leukemia after allogeneic stem cell transplantation: different kinetics and better prognosis than systemic relapse. Biol Blood Marrow Transplant, 23, 2017, 1087‑1094.
Ge, L, Ye, F, Mao, X, et al. Extramedullary relapse of acute leukemia after allogeneic hematopoietic stem cell transplantation: different characteristics between acute myelogenous leukemia and acute lymphoblastic leukemia. Biol Blood Marrow Transplant, 20, 2014, 1040‑1047.
Michonneau, D, Sagoo, P, Breart, B, Garcia, Z, Celli, S, Bousso, P., The PD-1 axis enforces an anatomical segregation of CTL activity that creates tumor niches after allogeneic hematopoietic stem cell transplantation. Immunity, 44, 2016, 143‑154.
Spinella, JF, Richer, C, Cassart, P, Ouimet, M, Healy, J, Sinnett, D., Mutational dynamics of early and late relapsed childhood ALL: rapid clonal expansion and long-term dormancy. Blood Adv, 2, 2018, 177‑188.
Quek, L, Ferguson, P, Metzner, M, et al. Mutational analysis of disease relapse in patients allografted for acute myeloid leukemia. Blood Adv, 1, 2016, 193‑204.
Schmalbrock, LK, Dolnik, A, Cocciardi, S, et al. Clonal evolution of acute myeloid leukemia with FLT3-ITD mutation under treatment with midostaurin. Blood, 137, 2021, 3093‑3104.
Bullinger, L, Döhner, K, Döhner, H., Genomics of acute myeloid leukemia diagnosis and pathways. J Clin Oncol, 35, 2017, 934‑946.
Welch, JS, Ley, TJ, Link, DC, et al. The origin and evolution of mutations in acute myeloid leukemia. Cell, 150, 2012, 264‑278.
Russo, A, Oliveira, G, Berglund, S, et al. NK cell recovery after haploidentical HSCT with posttransplant cyclophosphamide: dynamics and clinical implications. Blood, 131, 2018, 247‑262.
Rambaldi, B, Kim, HT, Reynolds, C, et al. Impaired T- and NK-cell reconstitution after haploidentical HCT with posttransplant cyclophosphamide. Blood Adv, 5, 2021, 352‑364.
Schroeder, T, Czibere, A, Platzbecker, U, et al. Azacitidine and donor lymphocyte infusions as first salvage therapy for relapse of AML or MDS after allogeneic stem cell transplantation. Leukemia, 27, 2013, 1229‑1235.
Schmid, C, Labopin, M, Nagler, A, et al. Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem-cell transplantation in adults with acute myeloid leukemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. J Clin Oncol, 25, 2007, 4938‑4945.
Andreola, G, Labopin, M, Beelen, D, et al. Long-term outcome and prognostic factors of second allogeneic hematopoietic stem cell transplant for acute leukemia in patients with a median follow-up of ≥10 years. Bone Marrow Transplant, 50, 2015, 1508‑1512.
Shimoni, A, Labopin, M, Finke, J, et al. Donor selection for a second allogeneic stem cell transplantation in AML patients relapsing after a first transplant: a study of the Acute Leukemia Working Party of EBMT. Blood Cancer J, 9, 2019, 88.
Savani, BN, Mielke, S, Reddy, N, Goodman, S, Jagasia, M, Rezvani, K., Management of relapse after allo-SCT for AML and the role of second transplantation. Bone Marrow Transplant, 44, 2009, 769‑777.
Vrhovac, R, Labopin, M, Ciceri, F, et al. Second reduced intensity conditioning allogeneic transplant as a rescue strategy for acute leukaemia patients who relapse after an initial RIC allogeneic transplantation: analysis of risk factors and treatment outcomes. Bone Marrow Transplant, 51, 2016, 186‑193.
Bosi, A, Laszlo, D, Labopin, M, et al. Second allogeneic bone marrow transplantation in acute leukemia: results of a survey by the European Cooperative Group for Blood and Marrow Transplantation. J Clin Oncol, 19, 2001, 3675‑3684.
Christopeit, M, Kuss, O, Finke, J, et al. Second allograft for hematologic relapse of acute leukemia after first allogeneic stem-cell transplantation from related and unrelated donors: the role of donor change. J Clin Oncol, 31, 2013, 3259‑3271.
Hosing, C, Saliba, RM, Shahjahan, M, et al. Disease burden may identify patients more likely to benefit from second allogeneic hematopoietic stem cell transplantation to treat relapsed acute myelogenous leukemia. Bone Marrow Transplant, 36, 2005, 157‑162.
Rezvani, K, Kanfer, EJ, Marin, D, et al. EBMT risk score predicts outcome of allogeneic hematopoietic stem cell transplantation in patients who have failed a previous transplantation procedure. Biol Blood Marrow Transplant, 18, 2012, 235‑240.
Ortí, G, Sanz, J, García-Cadenas, I, et al. Analysis of relapse after transplantation in acute leukemia: a comparative on second allogeneic hematopoietic cell transplantation and donor lymphocyte infusions. Exp Hematol 62 (2018), 24–32.
Xuan, L, Wang, Y, Huang, F, et al. Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial. Lancet Oncol, 21, 2020, 1201‑1212.
Romero, D., Sorafenib prevents AML relapse after allo-HSCT. Nat Rev Clin Oncol, 17, 2020, 591.
Nagler, A, Labopin, M, Dholaria, B, et al. Second allogeneic stem cell transplantation in patients with acute lymphoblastic leukaemia: a study on behalf of the Acute Leukaemia Working Party of the European Society for Blood and Marrow Transplantation. Br J Haematol, 186, 2019, 767‑776.
Duployez, N, Largeaud, L, Duchmann, M, et al. Prognostic impact of DDX41 germline mutations in intensively treated acute myeloid leukemia patients: an ALFA-FILO study. Blood 140 (2022), 756–768.
