Relapse of AML after hematopoietic stem cell transplantation: methods of monitoring and preventive strategies. A review from the ALWP of the EBMT

Bone Marrow Transplantation (2016) 51, 1431–1438 © 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 0268-3369/16 www.nature.com/bmt SPECIAL REPORT Relapse of AML after hematopoietic stem cell transplantation: methods of monitoring and preventive strategies. A review from the ALWP of the EBMT P Tsirigotis1,11, M Byrne2,11, C Schmid3, F Baron4, F Ciceri5, J Esteve6, NC Gorin7, S Giebel8, M Mohty9, BN Savani2,12 and A Nagler10,12 Allogeneic hematopoietic stem cell transplantation (allo-SCT) remains the therapeutic method with the most potent anti-leukemic activity mediated by the graft versus leukemia effect. However, a significant proportion of patients with AML will relapse after allo-SCT. The prognosis for these patients is dismal, with a probability of long-term survival of o 20%. Data from previous studies have shown that disease-specific prognostic factors, are in general, the same as those in patients treated with conventional chemotherapy. Minimal residual disease (MRD) and chimerism status monitoring after allo-SCT may be used as predictors of impending relapse and should be part of routine follow-up for AML patients. A significant number of studies have shown that pre-emptive administration of donor lymphocyte infusion (DLI) based on MRD and chimerism monitoring, as well as prophylactic DLI in AML patients at high risk of relapse is effective in preventing relapse. In this review, we discuss strategies for the identification of high-risk patients, review current therapeutic options and provide our recommendations for the management of post-SCT AML. Bone Marrow Transplantation (2016) 51, 1431–1438; doi:10.1038/bmt.2016.167; published online 13 June 2016 INTRODUCTION Allogeneic hematopoietic stem cell transplantation (allo-SCT) results in the most durable remissions for patients with high-risk AML. Transplant-related mortality (TRM) and disease relapse, however, remain two of the most significant barriers to longterm survival for these patients. Approximately 40% of post-SCT AML patients will relapse and face a dismal prognosis with a 2-year survival of o20%. Salvage treatment options include intensive chemotherapy followed by donor lymphocyte infusion (DLI), second allo-SCT, clinical trial enrollment or best supportive care.1,2 The efficacy of hypomethylating agents and targeted therapies in this setting has been reported in several small case series.3 Additional poor-risk factors include relapse within 6 months of allo-SCT, active GvHD at relapse and age 440 years.1 Due to the near-uniformly poor prognosis, and challenges in providing optimal therapies to these patients, strategies directed at the prevention of relapse are highly desirable. An approach that couples the pre-emptive identification of high-risk patients with diligent post-transplant monitoring and strategies for early intervention is necessary to improve the disease outcomes for these patients. AML is a biologically aggressive disease. Even among patients with favorable risk, core-binding factor (CBF) AML, 58% will die by 10 years.4 In the setting of poor-risk AML, allogeneic SCT favorably alters the disease course for some; however, a significant number of these adverse-risk patients will relapse and face a shortened overall survival (OS). To some extent, many of these relapses are predictable. Pre-transplant markers that are used to identify patients with biologically aggressive disease, and to guide consolidation therapy recommendations, may predict for relapse after SCT. Other factors, including reduced intensity conditioning (RIC), utilization of bone marrow (BM) allografts and other technical components of allo-SCT are associated with relapse in the post-SCT period. Post-SCT changes, including the development of low-volume disease or a mixed chimera, may also precede occult relapse. Several groups have reported that the early identification of these high-risk patients, coupled with the prescription of aggressive immunotherapy and/or chemotherapy, may improve disease outcomes.5–9 In this manuscript, we outline our recommendations for an individualized, risk-adapted strategy for the early identification and prevention of relapsed AML in the postSCT period. It should be emphasized that several of these strategies fall outside of the current standard of care. IDENTIFICATION OF PATIENTS AT HIGH RISK FOR RELAPSE AFTER ALLO-SCT Disease-related parameters Many of the disease-specific risk factors used to identify high-risk disease in the pre-SCT setting are validated predictors of post-SCT relapse (Table 1).10–15 Therefore, the basic prognostic scheme 1 Second Department of Internal Medicine, Division of Hematology, ATTIKON University Hospital, National and Kapodistrian University of Athens, Athens, Greece; 2Department of Medicine, Hematology and Stem Cell Transplant Section, Vanderbilt University Medical Center, Nashville, TN, USA; 3Klinikum Augsburg, Department of Hematology and Oncology, University of Munich, Augsburg, Germany; 4Department of Medicine, Division of Hematology, University of Liège, Liège, Belgium; 5Hematology, IRCCS San Raffaele Scientific Institute, University Vita-Salute San Raffaele, Milano, Italy; 6Department of Hematology, Hospital Clinic, Barcelona, Spain; 7Department of Hematology, Saint Antoine Hospital, APHP and University UPMC, Paris, France; 8Maria Sklodowska-Curie Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland; 9Department of Haematology, Saint Antoine Hospital, Paris, France and 10Hematology Division, Chaim Sheba Medical Center, Tel Hashomer, Israel. Correspondence: Professor BN Savani, Hematology and Stem Cell Transplant Section, Vanderbilt University Medical Center, 1301 Medical Center Dr, 2665 TVC, Nashville, TN 37212, USA. E-mail: 11 These authors contributed equally to this work. 12 Co-senior authors. Received 17 January 2016; revised 3 May 2016; accepted 5 May 2016; published online 13 June 2016 AML relapse after transplantation P Tsirigotis et al 1432 Table 1. Risk factors for relapse after allogeneic hematopoietic stem cell transplantation in patients with AML Parameter Relapse incidence Disease-related risk factors Cytogenetic risk group Favorable risk Intermediate risk Poor risk Other cytogenetic abnormalities Monosomal karyotype Molecular markers NPM1mut, FLT3-WT Bialleleic CEBPA-mut FLT3-ITD NPM1-WT, FLT3-WT, CEBPA-WT Additional myeloid mutations CR status CR1 Beyond CR1 MRD status MRD positivity at the time of allo-SCT Transplant-related risk factors Conditioning regimen GvHD prophylaxis regimen GvHD RIC regimens Intensive regimens containing anti-T-cell antibodies or ATG, T-cell-depleted grafts Absence of chronic GvHD Ref Low Intermediate High High Low Low High Intermediate Indeterminate Low High High 21–25 High Controversial 31–33 41,43–45 High 10,11 17 12,13 14–16 28–30 18–20 42 Abbreviations: ATG = anti-thymocyte globulin; RIC = reduced intensity conditioning; SCT = stem cell transp (...truncated)