Superior Survival with Post-Remission Pediatric-Inspired Chemotherapy Compared to Myeloablative Allogeneic Hematopoietic Cell Transplantation in Adolescents and Young Adults with Ph-Negative Acute Lymphoblastic Leukemia in First Complete Remission: Comparison of CALGB 10403 to Patients Reported to the CIBMTR
Authors: Wieduwilt Matthew J. , Stock Wendy , Advani Anjali S. , Luger Selina M. , Larson Richard A. , Tallman Martin S. , Appelbaum Frederick R. , Zhang Mei-Jie , Bo-Subait Khalid , Sandmaier Brenda M. , de Lima Marcos , Kebriaei Partow , Litzow Mark , Saber Wael , Weisdorf Daniel J. 
Published: February 2020

Optimal post-remission therapy for adolescents and young adults (AYAs, 16-39 years) with Ph-negative (Ph-) acute lymphoblastic leukemia (ALL) in first complete remission (CR1) is not well established. We hypothesized that post-remission therapy with a pediatric-inspired regimen would yield superior outcomes to myeloablative allogeneic HCT for AYA patients with Ph- ALL in CR1. We compared overall survival (OS), disease-free survival (DFS), relapse, and non-relapse mortality (NRM) for patients receiving post-remission therapy on CALGB 10403 to a contemporary matched AYA cohort undergoing myeloablative allogeneic HCT in CR1 reported to the CIBMTR (Table). The allogeneic HCT cohort consisted of patients 16-39 years of age with Ph- ALL in CR1 undergoing myeloablative transplant from a matched sibling/relative or unrelated donor using peripheral blood or bone marrow stem cells between 11/2002 and 8/2012 in the United States. Patients receiving post-remission therapy with pediatric-inspired chemotherapy had superior OS (P&lt;0.0001), DFS (P=0.0011), and NRM (P&lt;0.001) compared to allogeneic HCT. Patterns of relapse were time-dependent and examined in the Cox model. In multivariate analysis of Cox model, receiving allogeneic HCT was associated with inferior OS (HR 1.99, 95% CI 1.5-2.65, P &lt;0.001), inferior DFS (HR 1.51, 95% CI 1.17-1.94, P 0.002), and increased NRM (HR 3.93, 95% CI 2.53-6.10, P &lt;0.001; Figure). In the early post-remission period (≤15 months after CR1), relapse was more likely with allogeneic HCT (HR 1.63, 95% CI 1.03-2.59, p=0.04) whereas beyond 15 months after CR1 relapse was more likely in the chemotherapy arm (HR 0.35, 95% CI 0.19-0.62, P &lt;0.001; Figure). Obesity (BMI ≥30) was independently associated with inferior OS (HR 2.22, 95% CI 1.69-2.91, P&lt;0.001), inferior DFS (HR 1.96, 95% CI 1.52-2.53, P &lt;0.001), increased relapse (1.90, 95% CI 1.37-2.64, P &lt;0.001), and increased NRM (HR 1.99, 95% CI 1.33-2.97, P &lt;0.001). Extramedullary disease at diagnosis was independently associated with inferior OS (HR 1.34, 95% CI 1.00-1.79, P=0.05). We conclude from this large retrospective study that post-remission therapy with pediatric-inspired chemotherapy as given on CALGB 10403 was superior to allogeneic HCT in CR1 for OS, DFS, and NRM in AYAs with newly-diagnosed Ph-negative B- and T-cell ALL. Late relapse was more likely with chemotherapy whereas early relapse was more likely with allogeneic HCT. Future study should aim to elucidate the impact of measurable residual disease at CR1 and high-risk genetics, including Ph-like ALL, on the superiority of post-remission pediatric-inspired chemotherapy over allogeneic HCT.
Figure. Allogeneic HCT (HCT) vs. CALGB 10403 pediatric-inspired chemotherapy (chemo) after CR1: Adjusted (left-truncated) overall survival, disease-free survival, cumulative incidence of relapse, and cumulative incidence of non-relapse mortality.

Disclosures
Wieduwilt: Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen, Leadiant, Merck, Servier: Research Funding; Reata Pharmaceuticals: Equity Ownership. Stock:Astellas: Membership on an entity's Board of Directors or advisory committees; Research to Practice: Honoraria; Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria. Advani:Macrogenics: Research Funding; Abbvie: Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Kite Pharmaceuticals: Consultancy; Glycomimetics: Consultancy, Research Funding. Luger:Ariad: Research Funding; Biosight: Research Funding; Celgene: Research Funding; Cyslacel: Research Funding; Daichi Sankyo: Honoraria; Genetech: Research Funding; Jazz: Honoraria; Kura: Research Funding; Onconova: Research Funding; Pfizer: Honoraria; Seattle Genetics: Research Funding; Agios: Honoraria. Larson:Novartis: Honoraria, Other: Contracts for clinical trials; Agios: Consultancy; Celgene: Consultancy. Tallman:Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biosight: Research Funding; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kebriaei:Kite: Honoraria; Jazz: Consultancy; Amgen: Research Funding; Pfizer: Honoraria. Weisdorf:Pharmacyclics: Consultancy; Incyte: Research Funding; Fate Therapeutics: Consultancy.