A revised definition for cure of childhood acute lymphoblastic leukemia

Abstract

With improved contemporary therapy, we reassess long-term outcome in patients completing treatment for childhood acute lymphoblastic leukemia (ALL) to determine when cure can be declared with a high degree of confidence. In six successive clinical trials between 1984 and 2007, 1291 (84.5%) patients completed all therapies in continuous complete remission. The post-therapy cumulative risk of relapse or development of a second neoplasm and the event-free survival rate and overall survival were analyzed according to the presenting features and the three treatment periods defined by relative outcome. Over the three treatment periods, there has been progressive increase in the rate of event-free survival (65.2% vs 74.8% vs 85.1% (P<0.001)) and overall survival (76.5% vs 81.1% vs 91.7% (P<0.001)) at 10 years. The most important predictor of outcome after completion of therapy was the type of treatment. In the most recent treatment period, which omitted the use of prophylactic cranial irradiation, the post-treatment cumulative risk of relapse was 6.4%, death in remission 1.5% and development of a second neoplasm 2.3% at 10 years, with all relapses except one occurring within 4 years of therapy. None of the 106 patients with the t(9;22)/BCR-ABL1, t(1;19)/TCF3-PBX1 or t(4;11)/MLL-AFF1 had relapsed after 2 years from completion of therapy. These findings demonstrate that with contemporary effective therapy that excludes cranial irradiation, approximately 6% of children with ALL may relapse after completion of treatment, and those who remain in remission at 4 years post treatment may be considered cured (that is, less than 1% chance of relapse).

Figure 1

CONSORT diagram. Of the 562 patients treated in studies 11 and 12, 467 in study 13A, 13B and 14, and 498 in study 15, 438, 398, and 455 patients, respectively, remained in continuous complete remission upon the completion of treatment.

Figure 2

Cumulative risk of development of a second neoplasm (A) or relapse (B) after completion of therapy for patients in continuous remission according to Total Therapy study. The numbers of patients who remained event-free and were at risk of developing second neoplasm or relapse at any given year after completion of treatment for the three cohorts were provided in the bottom of the figure. Note the significant decrease in both adverse events for each successive treatment group.

Figure 3

Conditional probability of relapse for patients remaining in continuous complete remission for the given years after completion of treatment by Total Therapy study. Note the progressive decrease in the probability of off-therapy relapse for each successive treatment group, and the absence of relapse in patients remaining in remission at 4 years off therapy in study 15.