Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children's Oncology Group study

Abstract

Despite great progress in curing childhood acute lymphoblastic leukemia (ALL), survival after relapse remains poor. We analyzed survival after relapse among 9585 pediatric patients enrolled on Children's Oncology Group clinical trials between 1988 and 2002. A total of 1961 patients (20.5%) experienced relapse at any site. The primary end point was survival. Patients were subcategorized by the site of relapse and timing of relapse from initial diagnosis. Time to relapse remains the strongest predictor of survival. Patients experiencing early relapse less than 18 months from initial diagnosis had a particularly poor outcome with a 5-year survival estimate of 21.0+/-1.8%. Standard risk patients who relapsed had improved survival compared with their higher risk counterparts; differences in survival for the two risk groups was most pronounced for patients relapsing after 18 months. Adjusting for both time and relapse site, multivariate analysis showed that age (10+ years) and the presence of central nervous system disease at diagnosis, male gender, and T-cell disease were significant predictors of inferior post-relapse survival. It can be noted that there was no difference in survival rates for relapsed patients in earlier vs later era trials. New therapeutic strategies are urgently needed for children with relapsed ALL and efforts should focus on discovering the biological pathways that mediate drug resistance.

Figure 1

Figure 1A: Survival after relapse for patients experiencing isolated marrow relapse. Survival rates at 5 years after relapse for patients with isolated marrow relapse by timing of relapse (early: 11.5±1.9%, intermediate: 18.4±3.1%, late: 43.5±5.2%), p<0.0001. RHR: early vs late = 3.7, intermediate vs late = 2.3. Figure 1B: Survival after relapse for patients experiencing concurrent marrow relapse. Survival rates at 5 years after relapse for patients with concurrent marrow relapse by timing of relapse (early: 11.6±4.5%, intermediate: 39.8±9.3%, late: 60.3±8.3%), p<0.0001. RHR: early vs late = 4.9, intermediate vs late = 2.0. Figure 1C: Survival after relapse for patients experiencing isolated CNS relapse. Survival rates at 5 years after relapse for patients with isolated CNS relapse by timing of relapse (early: 43.5±4.5%, intermediate: 68.0±4.6%, late: 78.2±8.8%), p<0.0001. RHR: early vs late = 3.4, intermediate vs late = 1.5.

Figure 1

Figure 1A: Survival after relapse for patients experiencing isolated marrow relapse. Survival rates at 5 years after relapse for patients with isolated marrow relapse by timing of relapse (early: 11.5±1.9%, intermediate: 18.4±3.1%, late: 43.5±5.2%), p<0.0001. RHR: early vs late = 3.7, intermediate vs late = 2.3. Figure 1B: Survival after relapse for patients experiencing concurrent marrow relapse. Survival rates at 5 years after relapse for patients with concurrent marrow relapse by timing of relapse (early: 11.6±4.5%, intermediate: 39.8±9.3%, late: 60.3±8.3%), p<0.0001. RHR: early vs late = 4.9, intermediate vs late = 2.0. Figure 1C: Survival after relapse for patients experiencing isolated CNS relapse. Survival rates at 5 years after relapse for patients with isolated CNS relapse by timing of relapse (early: 43.5±4.5%, intermediate: 68.0±4.6%, late: 78.2±8.8%), p<0.0001. RHR: early vs late = 3.4, intermediate vs late = 1.5.

Figure 1

Figure 1A: Survival after relapse for patients experiencing isolated marrow relapse. Survival rates at 5 years after relapse for patients with isolated marrow relapse by timing of relapse (early: 11.5±1.9%, intermediate: 18.4±3.1%, late: 43.5±5.2%), p<0.0001. RHR: early vs late = 3.7, intermediate vs late = 2.3. Figure 1B: Survival after relapse for patients experiencing concurrent marrow relapse. Survival rates at 5 years after relapse for patients with concurrent marrow relapse by timing of relapse (early: 11.6±4.5%, intermediate: 39.8±9.3%, late: 60.3±8.3%), p<0.0001. RHR: early vs late = 4.9, intermediate vs late = 2.0. Figure 1C: Survival after relapse for patients experiencing isolated CNS relapse. Survival rates at 5 years after relapse for patients with isolated CNS relapse by timing of relapse (early: 43.5±4.5%, intermediate: 68.0±4.6%, late: 78.2±8.8%), p<0.0001. RHR: early vs late = 3.4, intermediate vs late = 1.5.

Figure 2. Kaplan-Meier estimates of survival after relapse for patients stratified by NCI risk group at diagnosis and timing of relapse

There were significant differences in outcome for those SR versus HR patients experiencing either an early (33.1±3.6% vs 14.9±2.1%, p<0.0001), intermediate (52.2±3.7% vs 22.0±3.9%, p<0.0001) or late relapse (59.6±4.6% vs 39.5±7.2%, p< 0.0001)).

Figure 3. Kaplan-Meier estimates of survival after relapse for patients stratified by treatment era and timing of relapse

There was no difference in survival between Early and Late trials among patients who experienced either an early relapse (19.3±2.1% vs 23.4±3.4%, p=0.10), or intermediate relapse (39.3±3.3% vs 36.0±4.8%, p=0.49), or late relapses (53.3±4.3% vs 54.4±9.2%, p=0.66).