Prognostic value of prior consolidation in acute myeloid leukemia patients undergoing hematopoietic cell transplantation in minimal residual disease‐negative first complete remission
Authors: Joan How, Kiran R. Vij, Maryam Ebadi, Todd E. DeFor, Rizwan Romee, Michelle M. Dolan, Celalettin Ustun, Daniel J. Weisdorf, Michael A. Linden, Armin Rashidi
Journal: American Journal of Hematology (2018)

To the Editor: Prognostic factors among acute myeloid leukemia (AML) patients undergoing allogeneic hematopoietic cell transplantation (HCT) in minimal residual disease (MRD)-negative first complete remission (CR1) are unknown. Previous studies of MRD in the transplant setting either did not consider prior consolidation in analysis1-3 or had too few patients without consolidation.4 In a single-center retrospective analysis at the University of Minnesota,5 we addressed the question: In AML patients undergoing HCT in MRD-negative CR1, does a history of prior consolidation provide additional prognostic information for relapse? Our hypothesis was that among MRD-negative patients, where MRD status is no longer a variable, specifics of previous treatments may reflect varying depths of remission and hence may be prognostic. We evaluated 126 patients with the following inclusion criteria: (i) Age > 18 years, (ii) AML in CR1 after 1-2 cycles of intensive induction chemotherapy, with or without consolidation (defined as ≥1 g/m2/day cytarabine after achieving CR1), (iii) First allogeneic HCT between 2003 and 2016, (iv) Available standard-sensitivity 4-color flow cytometry results from a bone marrow aspiration at diagnosis and after completion of all previous chemotherapy (induction[s] with any consolidation) within 1 month prior to HCT, and (v) Flow cytometry-based MRD-negative status at the time of HCT. We found that prior consolidation was associated with lower risk of relapse (hazard ratio [HR] 0.50, 95% confidence interval [CI] 0.27-0.92, P = 0.025). Understanding the limitations of single-center studies, we recognized that the results warranted testing in a multi-center study. In addition, as there is no single standard MRD detection method, different centers and laboratories use different methods with different sensitivities.6 Therefore, the second goal of the present study was to explore the effects of this heterogeneity in the real-world setting. A total of 111 new patients (2007-2017) with similar inclusion criteria were retrospectively identified in a collaborative study between the University of Minnesota and Washington University in St. Louis. All pathology data (including a subset of primary histograms) were reviewed by at least one pathologist (MAL and/or KV). For the University of Minnesota cases, an in-house standard-sensitivity flow cytometry (4 color/4 tube prior to 2016; 10 color/2 tube beginning in 2016) with a lower limit of detection of 0.5% was performed.6 At Washington University, an in-house 5 color/1 tube method was used to enumerate blasts prior to 2016. After reviewing paired diagnostic and post-treatment flow cytometry cases, samples with greater than 4% blasts with an immunophenotype similar to diagnosis were considered "positive" and excluded. Beginning in 2016, the in-house method at Washington University changed to an 8 color/1 tube method with an estimated lower limit of detection of 0.5-1%. A subset of the samples was sent to a reference laboratory for high-sensitivity MRD analysis. This laboratory used a 4 color/8 tube method with a lower limit of detection of 0.1%. For the purposes of this study, the in-house methods in both universities were grouped as "low sensitivity" and the reference lab method as "high sensitivity." Of the 111 patients, 96 were transplanted at Washington University and 15 at the University of Minnesota. Patients included in our previous single-center study were not included here. Table 1 compares baseline patient-, disease-, and treatment-related characteristics between the groups with (n = 80, 72%) vs without (n = 31, 28%) consolidation. Patients with prior consolidation more frequently required only one induction cycle to achieve CR1 (P < 0.01), less frequently had a history of myelodysplastic syndrome (MDS; P < 0.01), and had a shorter diagnosis-to-CR interval (P < 0.01), higher HCT-specific comorbidity index (HCT-CI; P < 0.01), and, as expected, longer CR-to-HCT interval (P < 0.01). Backward regression analysis was performed in a Fine and Gray proportional hazards model with prior consolidation (>0 vs 0 cycle) and MRD detection sensitivity (high vs low) forced in. Predetermined covariates included conditioning intensity (reduced-intensity vs myeloablative), number of induction cycles (2 vs 1), prior MDS (yes vs no), and the 2017 European LeukemiaNet cytogenetic/genetic risk group (adverse vs favorable/intermediate). In this analysis, prior consolidation (hazard ratio [HR]: 3.2, 95% confidence interval [95%CI]: 0.9-10.8, P = 0.07) and MRD detection sensitivity (3.3 [0.7-15.7], P = 0.12) did not significantly change the risk of relapse. Reduced-intensity conditioning and prior MDS were significant predictors of relapse (4.3 [1.8-10.1] and 6.3 [2.4-16.5], respectively; P < 0.01 for both). Since the primary endpoint of interest was relapse, we evaluated whether nonrelapse mortality (NRM) as a competing risk influenced the number of patients alive and at risk for relapse between the groups with vs without consolidation. This analysis did not show any significant association (HR [95%CI] for NRM, with vs without consolidation: 0.7 [0.3-1.8], P = 0.45). In conclusion, this multi-center study did not reproduce the results of our previous single-center report. Potential reasons include population heterogeneity and differences in MRD detection methodology and sensitivity. As new MRD detection techniques are developed, many institutions change their preferred diagnostic approach. These real-world changes occurred over time in the two centers that collaborated in the present study. Although we did not find a significant association between MRD detection sensitivity and relapse in multivariable analysis, our sample size did not permit inclusion of an interaction term (consolidation × MRD detection sensitivity). Nonetheless, the path to MRD negativity may still be of importance and consolidation may be of particular benefit in those with higher risk features, including MRD positivity after induction, preceding MDS, secondary AML or if reduced-intensity conditioning is planned. Prospective and more comprehensive analyses of all factors influencing post-HCT risk of relapse are required to guide decision-making about the indications for consolidation prior to HCT. Research reported in this publication was supported by National Institutes of Health grant P30 CA77598 utilizing the Biostatistics and Bioinformatics Core shared resource of the Masonic Cancer Center, University of Minnesota and by the National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1TR000114. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors have no conflicts of interest. Designed the study: AR, CU, MAL; Collected the data: AR, JH, ME; Defined MRD: KRV, MAL; Performed statistical analysis: TED; Evaluated the results and wrote the manuscript: AR, JH, KRV, ME, TED, RR, MMD, CU, DJW, MAL.