Long-term outcomes for children with acute lymphoblastic leukemia (ALL) treated on The Cancer Institute of New Jersey ALL trial (CINJALL)

Although five-year survival rates for childhood acute lymphoblastic leukemia (ALL) are now over 80% in most industrialized countries, not all children have benefited equally from this progress. Ethnic differences in survival after childhood ALL have been reported in many clinical studies, with poorer survival observed among African Americans or those with Hispanic ethnicity when compared with European Americans or Asians. The causes of ethnic differences remain uncertain, although both genetic and non-genetic factors are likely important. Interrogating genome-wide germline SNP genotypes in an unselected large cohort of children with ALL, we observed that the component of genomic variation that co-segregated with Native American ancestry was associated with risk of relapse (P = 0.0029) even after adjusting for known prognostic factors (P = 0.017). Ancestry-related differences in relapse risk were abrogated by the addition of a single extra phase of chemotherapy, indicating that modifications to therapy can mitigate the ancestry-related risk of relapse.

Systemic exposure to mercaptopurine (MP) is critical for durable remissions in children with acute lymphoblastic leukemia (ALL). Nonadherence to oral MP could increase relapse risk and also contribute to inferior outcome in Hispanics. This study identified determinants of adherence and described impact of adherence on relapse, both overall and by ethnicity. A total of 327 children with ALL (169 Hispanic; 158 non-Hispanic white) participated. Medication event-monitoring system caps recorded date and time of MP bottle openings. Adherence rate, calculated monthly, was defined as ratio of days of MP bottle opening to days when MP was prescribed. After 53,394 person-days of monitoring, adherence declined from 94.7% (month 1) to 90.2% (month 6; P < .001). Mean adherence over 6 months was significantly lower among Hispanics (88.4% v 94.8%; P < .001), patients age ≥ 12 years (85.8% v 93.1%; P < .001), and patients from single-mother households (80.6% v 93.1%; P = .001). A progressive increase in relapse was observed with decreasing adherence (reference: adherence ≥ 95%; 94.9% to 90%: hazard ratio [HR], 4.1; 95% CI,1.2 to 13.5; P = .02; 89.9% to 85%: HR, 4.0; 95% CI, 1.0 to 15.5; P = .04; < 85%: HR. 5.7; 95% CI, 1.9 to 16.8; P = .002). Cumulative incidence of relapse (± standard deviation) was higher among Hispanics (16.5% ± 4.0% v 6.3% ± 2.2%; P = .02). Association between Hispanic ethnicity and relapse (HR, 2.6; 95% CI, 1.1 to 6.1; P = .02) became nonsignificant (HR, 1.8; 95% CI, 0.6 to 5.2; P = .26) after adjusting for adherence and socioeconomic status. At adherence rates ≥ 90%, Hispanics continued to demonstrate higher relapse, whereas at rates < 90%, relapse risk was comparable to that of non-Hispanic whites. Lower adherence to oral MP increases relapse risk. Ethnic difference in relapse risk differs by level of adherence-an observation currently under investigation.

The Dana-Farber Cancer Institute (DFCI) ALL Consortium has been conducting multi-institutional clinical trials in childhood ALL since 1981. The treatment backbone has included 20–30 consecutive weeks of asparaginase during intensification and frequent vincristine/corticosteroid pulses during the continuation phase. Between 1985–2000, 1457 children aged 0–18 years were treated on four consecutive protocols: 85-01 (1985–7), 87-01 (1987–91), 91-01 (1991–5) and 95-01 (1996–2000). The 10-year event-free survival (EFS) ± standard error by protocol was 77.9 ± 2.8% (85-01), 74.2± 2.3 (87-01), 80.8 ± 2.1% (91-01) and 80.5 ± 1.8% (95-01). Approximately 82% of patients treated in the 1980s and 88% treated in the 1990s were long-term survivors. Both EFS and overall survival (OS) rates were significantly higher for patients treated in the 1990s compared with the 1980s (p=0.05 and 0.01, respectively). On the two protocols conducted in the 1990s, EFS was 79–85% for T-ALL patients and 75–78% for adolescents (age 10–18 years). Results of randomized studies revealed that dexrazoxane prevented acute cardiac injury without adversely impacting EFS or OS in high-risk patients and frequently-dosed intrathecal chemotherapy was an effective substitute for cranial radiation in standard-risk patients. Current studies continue to focus on improving efficacy while minimizing acute and late toxicities.