Superior survival with pediatric-style chemotherapy compared to myeloablative allogeneic hematopoietic cell transplantation in older adolescents and young adults with Ph-negative acute lymphoblastic leukemia in first complete remission: analysis from CALGB 10403 and the CIBMTR

Matthew J Wieduwilt,David Ritchie,Michael A Pulsipher ,Wendy Stock,Mehdi Hamadani,Anjali S Advani ,Pere Barba,Omer Jamy,Frederick R Appelbaum ,Marcos De Lima,Akshay Sharma,Khalid Bo-Subait,Partow Kebriaei,Martin S Tallman ,Selina M Luger ,Mark R Litzow ,Richard A Larson,Wael Saber,Hai Lin Wang ,Tim Prestidge,Mary Eapen,Vijaya Raj Bhatt,Mei Jie Zhang ,David A Rizzieri ,Brenda M Sandmaier,Bhagirathbhai Dholaria,Daniel J Weisdorf

doi:10.1038/s41375-021-01213-5

Abstract

Optimal post-remission therapy for adolescents and young adults (AYAs) with Ph-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1) is not established. 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 cohort undergoing myeloablative (MA) allogeneic hematopoietic cell transplantation (HCT) in CR1. In univariate analysis, OS was superior with chemotherapy compared to MA allogeneic HCT (3-year OS 77% vs. 53%, P < 0.001). In multivariate analysis, allogeneic HCT showed inferior OS (HR 2.00, 95% CI 1.5–2.66, P < 0.001), inferior DFS (HR 1.62, 95% CI 1.25–2.12, P < 0.001), and increased NRM (HR 5.41, 95% CI 3.23–9.06, P < 0.001) compared to chemotherapy. A higher 5-year relapse incidence was seen with chemotherapy compared to allogeneic HCT (34% vs. 23%, P = 0.011). Obesity was independently associated with inferior OS (HR 2.17, 95% CI 1.63–2.89, P < 0.001), inferior DFS (HR 1.97, 95% CI 1.51–2.57, P < 0.001), increased relapse (1.84, 95% CI 1.31–2.59, P < 0.001), and increased NRM (HR 2.10, 95% CI 1.37–3.23, P < 0.001). For AYA ALL patients in CR1, post-remission therapy with pediatric-style chemotherapy is superior to MA allogeneic HCT for OS, DFS, and NRM.

Highlights

The optimal post-remission therapy for AYAs with Phnegative acute lymphoblastic leukemia (ALL) in CR1 is not known in the era of pediatricinspired chemotherapy regimens with more intensive postremission therapy than traditional adult regimens
Allogeneic hematopoietic cell transplantation (HCT) is indicated for Ph-negative ALL in CR1 based on trials using donor vs. no donor comparisons
UKALLXII/ECOG2993 showed improved survival with allogeneic HCT for adults aged 15–54 years with Phnegative ALL when compared to chemotherapy or autologous HCT (5-year overall survival (OS) 54% vs. 44%, P = 0.007) [1]

Summary

Objectives

The start time for outcomes was the date of CR1. The primary objective was to compare OS between patients receiving postremission therapy with MA allogeneic HCT vs chemotherapy. Secondary objectives included DFS, relapse rate, and NRM rate between the allogeneic HCT and chemotherapy cohorts. Additional secondary objectives included determination of patient and disease factors influencing outcomes of post-remission therapy using either approach. The primary endpoint of OS was defined as the time from CR1 to the last contact date or death from any cause. Surviving patients were censored at last time reported alive and in continued remission. Allogeneic HCT cohort endpoints included acute grade II–IV graft-versus-host disease (GVHD) fulfilling the Consensus criteria and chronic GVHD defined as the occurrence of symptoms in any organ diagnostic of chronic GVHD

Methods

Results

Conclusion