Characterization of Factors Determining the Kinetics of Disease Relapse after Allogeneic Stem Cell Transplantation (allo-SCT) or Chemotherapeutic Consolidation for Acute Myeloid Leukaemia (AML) in First CR: A Survey from HOVON-SAKK and the Acute Leukaemia Working Party of the EBMT
Authors: Craddock Charles , Versluis Jurjen , Labopin Myriam , Socie Gerard , Huyn Anne , Deconinck Eric , Volin Liisa , Milpied Noel , Bourhis Jean Henri , Rambaldi Alessandro , Chevallier Patrice , Blaise Didier , Markus Manz , Vellenga Edo , Vekemans Marie Christiane , Maertens Johan , Passweg Jakob R. , Schmid Christoph , Ossenkoppele G J. , Vyas Paresh , Löwenberg Bob , Mohty Mohamad , Cornelissen Jan J. , Nagler Arnon 
Published: October 2019

Abstract
Disease relapse remains the major cause of treatment failure in patients allografted for AML. Post-transplant interventions such as donor lymphocyte infusion (DLI) or administration of targeted pharmacological agents, represent important novel strategies to reduce relapse but their effectiveness is critically dependent on timely administration. Whilst the predictors of overall relapse risk after allo-SCT have been well characterized little is understood of the determinants of the timing of early or late relapse and this hampers the design of novel post-transplant strategies. We have therefore examined the factors determining relapse kinetics in patients with AML in first complete remission (CR1) undergoing allo-SCT and compared these with patients receiving intensive chemotherapy alone as CR1 consolidation.
1057 patients, reported to the EBMT Acute Leukemia Working Party, who received an allo-SCT for AML in CR1 between 2000 and 2012 were studied. The median age was 51 years and 86% had good/intermediate risk cytogenetics. A control population of 570 patients who received mitoxantrone and etoposide alone as consolidation therapy was derived from prospective trials of the HOVON-SAKK. The median age of the comparator group was 47 years and 60% of patients had intermediate risk cytogenetics. A series of landmark analyses were performed at 3, 6 and 12 months in order to identify prognostic factors of relapse for patients alive at the beginning of each time interval in both populations. The probabilities of relapse were calculated by using the cumulative incidence estimator to accommodate for death as a competing risk. Factors predicting relapse were studied using Cox regression model. A backward stepwise procedure was used for variable selection.
With a median follow-up of 48 months, 284 (27%) of the allo-SCT recipients relapsed. The 3 year cumulative incidence of relapse was 26% [95%CI: 23-29]. 75% of patients destined to relapse did so within the first year post-transplant. In the first three months after allo-SCT the significant factors determining relapse risk were patient age (p=.009), a prolonged interval from diagnosis to CR1 (p=.013), the presence of a FLT3-ITD mutation (p<.001), adverse risk cytogenetics (p=.02) and donor type (p=.05). Relapse between six and twelve months post-transplant was associated with a higher white blood cell count at diagnosis (p=.013) and absence of chronic graft versus host disease (GVHD) (p<.001). The predictors of late relapse (>12 months) were a longer time from diagnosis to achievement of CR1 (p=.003) and a wild-type NPM1 genotype (p=.008). Within the chemotherapy cohort, a total of 302 (53%) patients relapsed with a median follow-up of 86 months. The cumulative incidence of relapse at 3 years was 54% [95%CI: 50-58). 212 (70%) of the patients destined to relapse did so within the first year after the conclusion of chemotherapy. Factors significantly associated with relapse in the first three months were the presence of a FLT3-ITD mutation (p=0.001) and adverse risk cytogenetics (p<0.001). The same factors also predicted for relapse within three and six months (both p<0.001). The time interval from diagnosis to CR1 and from CR1 to consolidation (p=0.012) were inversely associated with relapse between six and twelve months post chemotherapy.
We conclude that the kinetics of disease relapse after allo-SCT are determined by both disease and transplant specific factors. These data provide novel insights into the biology of disease recurrence after allo-SCT and are consistent with heterogeneous mechanisms of relapse. Distinct disease specific factors also determine the kinetics of early and late relapse after chemotherapeutic consolidation. Of interest the leukemia specific characteristics predicting early and late relapse after allo-SCT and chemotherapy are broadly similar. These data have the potential to inform the design of novel post-transplant intervention strategies. Specifically they highlight the importance of early administration of adjunctive therapies in patients with a FLT3-ITD mutation or adverse risk cytogenetics. Whilst severe acute GVHD is to be avoided, induction of limited chronic GVHD by adoptive immunotherapy, such as low dose DLI, may be considered in allo-SCT recipients at a higher risk of relapse beyond 6 months post-transplant.

Disclosures
Maertens: Astellas: Consultancy, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy.