Survival after Relapse in Higher Risk Acute Lymphoblastic Leukemia (ALL) in Children and Adolescents Is Independent of Prior Treatment Intensity: A Report from the Children’s Oncology Group (COG).
Authors: Freyer David Robert , Seibel Nita L. , La Mei K , Devidas Meenakshi , Carroll William L. , Hunger Stephen P. , Gaynon Paul S. 
Published: October 2019

Abstract
While intensification of therapy has improved event-free survival (EFS) and survival in newly diagnosed patients, outcomes after relapse have proved more difficult. In randomized clinical trials where statistically significant treatment-related differences appear, differences in EFS consistently exceed differences in survival. Intuitively, it might be expected that patients who relapse after inferior therapy would have a higher retrieval rate after relapse compared with those who relapse after more optimal treatment. However, such an effect has been difficult to document in studies examining factors that predict outcome after relapse (Nguyen K et al. Leukemia, in press). Children’s Cancer Group (CCG)-1961 compared stronger and standard post induction intensification (PII) for children and adolescents with NCI Higher Risk ALL and a rapid Day 7 marrow response. Stronger PII increased 5-year EFS from 72% to 81% (p< 0.001) and survival from 83% to 89% (p=0.003) (Seibel NL et al. Blood111:2548–55, 2008). With the results of CCG-1961, stronger PII has become the new “standard.” This study provides an opportunity to compare post-relapse survival for patients relapsing after stronger or after standard strength PII. After stronger and standard PII, respectively, early relapse (duration of 1st remission < 36 months) comprised 70% and 71% of relapses and CNS relapse comprised 28% and 22% of relapses (not significant). As expected, survival after relapse was worse with marrow vs. extramedullary site, early vs. late timing, precursor T vs. B cell disease and adolescent (16–20 years) vs. younger age. However, as indicated below, survival after relapse was largely independent of prior standard or stronger PII. The finding was consistent across various subgroups, namely, early and late relapses, patient age, and immunophenotype.
3-year Survival
All relapses Marrow Relapse CNS relapse Initial Therapy n Survival n Survival n Survival * Relative hazard ratio Standard 163 39±5% 112 32±5% 36 49±10% Stronger 107 35±6% 72 22±6% 30 56±11% Standard/stronger RHR*/p 0.92/0.63 RHR /p 0.82/0.29 RHR/p 1.3/0.51
In childhood acute lymphoblastic leukemia (ALL), relapse is a poorly understood biological process. Although relapse rate is dependent upon initial therapy, survival after relapse appears to be independent of initial treatment. Small numbers prevent detailed analysis of any possible interactions among initial treatment and site and timing of relapse. Collectively, our data suggest that intensification of treatment does not simply prevent “marginal relapses” that are salvageable with post-relapse therapy. Rather, our results are consistent with the Goldie-Coldman hypothesis (Semin Oncol12:222–30,1985; J Clin Oncol4:825, 1986) and suggest that a population of malignant cells escapes initial therapy, accumulates at relapse with further evolution and development of spontaneous mutations that are independent of prior treatment, and often gives rise to a refractory clone responsible for the patient’s demise.