Predictors of relapse in AML

In the Journal of Internal Medicine, Charles Craddock [co-chair of the AGP European Steering Committee] from Queen Elizabeth Hospital, Birmingham, UK, and colleagues, reported results from their retrospective study, which evaluated the kinetics of relapse in a cohort of adult de novo AML patients who either underwent Allogenic Stem Cell Transplant (allo-SCT) or treatment with Intensive Chemotherapy (IC) in First Complete Remission (CR1). The main objective of the study was to identify prognostic factors influencing relapse risk for patients alive at different time points after allo-SCT or IC.

Using the European Bone Marrow Transplantation registry, the authors identified 20,341 de novo AML patients who underwent transplantation in CR1 between 2000–2015. Of these, a total of 2,028 patients (median age = 51 years) with mutational analysis of the NPM1 gene and information regarding the presence and absence of FLT3-ITD were analyzed in this study. Of note, the median time of acquisition of CR1 to transplant was 98 days (range, 11–357) and patients were transplanted using either a sibling (n = 886) or an adult matched-unrelated (n = 1142) donor.

Additionally, 570 patients (median age = 47 years) who achieved CR1 after induction chemotherapy and whose subsequent treatment consisted of IC consolidation were also analyzed in this study. In this cohort of patients, the median time from diagnosis to the acquisition of CR1 was 35 days (range, 19 –140) and the median time from acquisition of CR1 to the commencement of IC was 59 days (range, 0–370)

 At 3, 6, and 12 months, landmark analyses were performed in order to detect prognostic factors of relapse.

Key findings:

Factors predicting for relapse in the allo-SCT cohort:

• Predictors for relapse in the first 3-months post-allo-SCT include: presence of FLT3-ITD at diagnosis (HR = 2.19, P < 0.001), age (HR = 1.19, P = 0.012), time of interval from CR1 to transplant (HR = 0.79, P < 0.001) and unrelated donor (HR = 0.69, P = 0.033)
• Predictors for relapse within 3–6 months post-allo-SCT include: presence of FLT3-ITD at diagnosis (HR = 1.85, P < 0.001), high WBC at diagnosis (HR = 1.02, P = 0.001), time of interval from diagnosis to CR1 (HR = 1.15, P = 0.013) and adverse cytogenetics (HR = 2.47, P < 0.001)
• Predictors of relapse for more 12-months post-allo-SCT include; time of interval from CR1 to transplant (HR = 0.88, P = 0.016), absence of NPM1 mutation (HR = 0.62, P = 0.018), adverse cytogenetics (HR = 1.94, P = 0.002), absence of chronic Graft versus Host Disease (HR = 0.66P = 0.037]) and use of in vivo T-cell depletion (P = 0.037)

Factors predicting for relapse in the IC cohort:

• Predictors of relapse in the first 3 months after IC include; adverse-risk cytogenetics (HR = 3.90, P < 0.001) and presence of FLT3-ITD at diagnosis (HR = 4.82, P = 0.001)
• Relapse between 6–12 months post- IC treatment was inversely associated with time interval from diagnosis to CR1 (HR = 0.38, P = 0.022) and from CR1 to consolidation (HR = 0.54, P = 0.012)

In summary, this is the first study to determine the kinetics of disease relapse in AML patients who underwent allo-SCT or IC treatment. Craddock et al. noted that their study demonstrates that “distinct leukemia and transplant specific factors contribute to the risk of early and late relapse”. Additionally, the “timing of relapse is driven by distinct transplant specific factors”.

The authors concluded that their data provides “novel insights into the mechanism of disease recurrence and identified complex interaction of factors determining the timing of disease relapse post-alloSCT and IC, and thus have the “potential to inform the design of novel maintenance strategies in both clinical settings.” They further noted that their study is limited by its retrospective nature and proposed that a prospective study should be used to validate their findings and also “limit the selection bias”.