Contrasting Factors Determine the Kinetics of Disease Relapse after Allogeneic Stem Cell Transplantation (allo-SCT) for Acute Myeloid Leukaemia (AML): a Survey from the Acute Leukaemia Working Party of the EBMT
Authors: Craddock Charles , Labopin Myriam , Socie Gerard , Huyn Anne , Deconinck Eric , Volin Liisa , Milpied Noel , Bourhis Jean-Henri , Rambaldi Alessandro , Chevallier Patrice , Cornelissen Jan J. , Blaise Didier , Maertens Johann , Schmid Christoph , Nagler Arnon , Mohty Mohamad 
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 or adjunctive targeted therapies, represent novel strategies with the potential to reduce the risk of disease recurrence. Such approaches are however critically dependent on timely intervention prior to disease relapse. Whilst the factors predicting the overall risk of relapse have been well characterized determinants of the kinetics of disease relapse have not been extensively studied. We therefore performed a systematic analysis of factors determining the kinetics of disease relapse in patients allografted for AML.
1052 patients who received an allo-SCT for AML in first complete remission (CR1) between 2000 and 2012 were studied. Median age was 50 (18-72) years. 544 patients were transplanted using a sibling donor and 508 from an adult matched-unrelated donor. 538 patients received a myeloablative and 514 a reduced intensity conditioning regimen. 923 patients had good/intermediate risk and 129 had adverse risk cytogenetics at diagnosis. A series of landmark analyses were performed at 3, 6 and 12 months in order to identify prognostic factors of relapse for patients alive and well at the beginning of each time interval. 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 including time dependent variables. A backward stepwise procedure was used for variable selection.
With a median follow-up of 26 months, 244 patients relapsed. The 3 year cumulative incidence of relapse was 26% [95%CI: 23-28]. The cumulative incidence of relapse in the first three months post-transplant was 7.1% (95% CI: 5.6-8.8%), 8.3% (95% CI: 6.6-10.3) between 3-6 months, 8.3 (95% CI: 6.5-10.5) between 6 and 12 months and 3.8% (95% CI: 2.4-5.6) beyond 12 months post-transplant. Overall 84% of patients destined to relapse did so within the first year post-transplant. Factors predicting relapse for the whole population were: more than one course of chemotherapy to achieve CR1, FLT3 ITD positivity, adverse risk cytogenetics and a shorter interval from CR1 to transplant. The occurrence of acute GVHD grade II or greater (p=0.05) and chronic GVHD (p=0.03) were both associated with a lower risk of relapse.
Of interest, using landmark analyses, the factors determining relapse at different stages post transplant were observed to differ. In the first 3 months post-transplant the significant factors determining relapse risk were, flt3 ITD positivity (p=0.002), adverse risk cytogenetics (p=0.02) patient age (p=0.03), and prolonged interval from diagnosis to CR1 (p=0.05) aswell as the use of in vivo T cell depletion (p=0.003). The only factor observed to determine relapse risk between 3 and 6 months post-transplant was the presence at diagnosis of adverse risk cytogenetics (p=0.04). In patients who relapsed between 6 and 12 months post-transplant more than one course of chemotherapy to achieve CR1 (p=0.02), adverse risk cytogenetics (p=0.05) and FLT3 ITD positivity (p=0.00002) all predicted for relapse. Finally only CMV positivity predicted for relapse risk for more than 12 months post-transplant (p=0.05).
This study confirms the importance of factors previously demonstrated to increase the overall relapse risk in patients allografted for AML. Our data also demonstrate a complex interaction of disease specific and transplant factors contributing to the kinetics of disease recurrence at different times post-transplant. In addition to identifying the occurrence of a dynamic interplay between tumor biology and transplant factors in determining the pathobiology of disease relapse post-transplant the results of this analysis can be used to assist in the design of novel strategies with specific reference to the timing of post-transplant intervention.

Disclosures
No relevant conflicts of interest to declare.