Abstract
Introduction: Assessment of minimal residual disease (MRD) is a strong prognostic tool in determining the outcome of pts with ALL. In pediatric ALL, MRD has been validated to predict outcome and guide post-remission therapies. However, in adult ALL, MRD has limited role in directing treatment decisions due to lack of standardized MRD testing and definition. In this study, we stratify MRD status at different time points and investigate its impact on survival in adult patients with Philadelphia negative B-cell ALL.
Methods: We reviewed 419 newly diagnosed adult patients with Philadelphia negative B-cell ALL who received treatment at MD Anderson Cancer Center between 01/2000 and 01/2015. Complete response (CR) was defined as 5% or less blasts in marrow with a granulocyte count of 1 x 109/L or above and a platelet count of 100 x 109/L or higher. Patients who were alive and in CR with available bone marrow MRD assessment were eligible for inclusion (n=276). MRD testing was performed with multi-color flow cytometry (level of sensitivity 10-4) at two time points: 1- at CR (median 24 days, range 13-145), 2- at first post-CR assessment (median 2.8 months, range 1-5.5). Patients were stratified based on their MRD levels; MRD negative (level-0), 0.01-0.1% (level-1) and > 0.1% (level-2). We analyzed the following parameters at first post-CR evaluation: MRD level, relapse, allogeneic stem cell transplant, and death in CR. 36 pts (13%) were not evaluable for first post-CR assessment due to absence of one of these variables. We performed Kaplan-Meier analysis for overall survival (OS) and event-free survival (EFS).
Results: Clinical characteristics of pts at the time of diagnosis are summarized in Table 1. Overall, 186 pts (67%) achieved MRD negativity at CR, while 90 pts (33%) were MRD positive. Among MRD positive pts, 22 (8%) had level-1 MRD positivity and 68 (25%) had level-2 MRD positivity. At first post-CR assessment, 147 pts (92%) with negative MRD at CR maintained MRD negativity. Among the pts with level-1 and level-2 MRD at CR, 14 (78%) and 33 (53%) converted to MRD negative status at first post-CR assessment (Figure 1). Risk of relapse was higher in pts with level-2 and level-1 MRD compared with pts with negative MRD, 10%, 6% and 2%, respectively (p=0.07). The median overall survival (OS) was not reached in pts without MRD at CR, while pts with level-1 and level-2 MRD had median OS of 41 and 31 months respectively (p<0.001) (Figure 2). Accordingly, pts without MRD at CR had superior EFS of 65 months compared with 29 and 22 months in pts with level-1 and level-2 MRD, respectively (p<0.001).
Conclusion: The level of MRD at CR is an important prognostic tool in determining survival in Philadelphia negative B-cell ALL. Novel treatment agents, such as blinatumomab, inotuzumab ozogamicin, and CD19-directed chimeric antigen receptor T-cells, are known to be effective in achieving MRD negativity. Innovative clinical trial designs that incorporate these agents into the frontline ALL therapy are needed to improve the outcomes of pts with B-cell ALL.
Jabbour: Bristol-Myers Squibb: Consultancy. Khoury: Pfizer: Research Funding; Angle: Research Funding; Stemline Therapeutics: Research Funding; Kiromics: Research Funding. Cortes: Sun Pharma: Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Takahashi: Symbio Pharmaceuticals: Consultancy. Jain: Incyte: Research Funding; Abbvie: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding. Verstovsek: Roche: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Lilly Oncology: Research Funding; CTI BioPharma Corp: Research Funding; Seattle Genetics: Research Funding; Pfizer: Research Funding; Astrazeneca: Research Funding; Lilly Oncology: Research Funding; Incyte: Research Funding; Promedior: Research Funding; Bristol Myers Squibb: Research Funding; NS Pharma: Research Funding; Galena BioPharma: Research Funding; Gilead: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Blueprint Medicines Corp: Research Funding; Astrazeneca: Research Funding; Incyte: Research Funding; Promedior: Research Funding; Seattle Genetics: Research Funding; Roche: Research Funding; CTI BioPharma Corp: Research Funding; Galena BioPharma: Research Funding; Bristol Myers Squibb: Research Funding; Blueprint Medicines Corp: Research Funding; Genentech: Research Funding; Pfizer: Research Funding. Bose: Incyte Corporation: Honoraria. O'Brien: Aptose Biosciences, Inc.: Consultancy; Acerta: Other: Research Support: Honorarium, Research Funding; Pharmacyclics: Consultancy, Other: Research Support: Honorarium, Research Funding; ProNAI: Other: Research Support: Honorarium, Research Funding; Amgen: Consultancy; Regeneron: Other: Research Support: Honorarium, Research Funding; TG Therapeutics: Consultancy, Other: Research Support: Honorarium, Research Funding; Janssen: Consultancy; Vaniam Group LLC: Consultancy; Alexion: Consultancy; Celgene: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Gilead Sciences, Inc.: Consultancy, Other: Research Support: Honorarium, Research Funding; Pfizer: Consultancy, Research Funding; Sunesis: Consultancy; Astellas: Consultancy; GSK: Consultancy. Kantarjian: Delta-Fly Pharma: Research Funding; Novartis: Research Funding; ARIAD: Research Funding; Bristol-Meyers Squibb: Research Funding; Pfizer: Research Funding; Amgen: Research Funding.
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