Reduced Morbidity and Mortality in Survivors of Childhood Acute Lymphoblastic Leukemia: A Report From the Childhood Cancer Survivor Study

Abstract

Purpose: Risk-stratified therapy, which modifies treatment on the basis of clinical and biologic features, has improved 5-year overall survival of childhood acute lymphoblastic leukemia (ALL) to 90%, but its impact on long-term toxicity remains unknown.

Methods: We assessed all-cause and health-related late mortality (including late effects of cancer therapy), subsequent malignant neoplasms (SMNs), chronic health conditions, and neurocognitive outcomes among 6,148 survivors of childhood ALL (median age, 27.9 years; range, 5.9-61.9 years) diagnosed between 1970 and 1999. Therapy combinations and treatment intensity defined 6 groups: 1970s-like (70s), standard- or high-risk 1980s-like (80sSR, 80sHR) and 1990s-like (90sSR, 90sHR), and relapse/transplantation (R/BMT). Cumulative incidence, standardized mortality ratios, and standardized incidence ratios were compared between treatment groups and with the US population.

Results: Overall, 20-year all-cause late mortality was 6.6% (95% CI, 6.0 to 7.1). Compared with 70s, 90sSR and 90sHR experienced lower health-related late mortality (rate ratio [95% CI]: 90sSR, 0.2 [0.1 to 0.4]; 90sHR, 0.3 [0.1 to 0.7]), comparable to the US population (standardized mortality ratio [95% CI]: 90sSR, 1.3 [0.8 to 2.0]; 90sHR, 1.7 [0.7 to 3.5]). Compared with 70s, 90sSR had a lower rate of SMN (rate ratio [95% CI], 0.3 [0.1 to 0.6]) that was not different from that of the US population (standardized incidence ratio [95% CI], 1.0 [0.6 to 1.6]). The 90sSR group had fewer severe chronic health conditions than the 70s (20-year cumulative incidence [95% CI], 11.0% [9.7% to 12.3%] v 22.5% [19.4% to 25.5%]) and a lower prevalence of impaired memory (prevalence ratio [95% CI], 0.7 [0.6 to 0.9]) and task efficiency (0.5 [0.4 to 0.7]).

Conclusion: Risk-stratified therapy has reduced late morbidity and mortality among contemporary survivors of standard-risk ALL, represented by 90sSR. Health-related late mortality and SMN risks among 5-year survivors of contemporary, standard-risk childhood ALL are comparable to the general population.

FIG 1.

Cumulative incidence of late mortality as (A) all-cause, (B) recurrence, and (C) health-related late mortality among 5-year survivors of childhood acute lymphoblastic leukemia by treatment group. 70s, 1970s therapy; 80sHR, 1980s high-risk therapy; 80sSR, 1980s standard-risk therapy; 90sHR, 1990s high-risk therapy; 90sSR, 1990s standard-risk therapy; R/BMT, relapse or with hematopoietic cell transplantation.

FIG 2.

Standardized mortality ratios (SMRs) for health-related late mortality stratified by time since diagnosis and treatment group compared with the age-, sex-, race-, and year-matched US population. Treatment groups are representative of 1970s therapy (70s), 1980s and 1990s standard- and high-risk therapy (80sSR, 80sHR, 90sSR, 90sHR), and therapy for relapse or with hematopoietic cell transplantation (R/BMT). The dashed line at an SMR of 1.0 represents an observed rate of death that is no different from the expected rate in the general US population. Vertical bars represent 95% CIs.

FIG 3.

Rate ratios of any and specific grade 3-5 chronic health conditions by treatment group compared with 70s, adjusted for sex, race, age at diagnosis, and attained age. No grade 3-5 heart failure events were observed in the 90sSR group; RR = 0.0. 70s, 1970s therapy; 80sHR, 1980s high-risk therapy; 80sSR, 1980s standard-risk therapy; 90sHR, 1990s high-risk therapy; 90sSR, 1990s standard-risk therapy; R/BMT, relapse or with hematopoietic cell transplantation. The dashed line at a RR of 1.0 represents no difference from 70s. Vertical bars represent 95% CIs.

FIG A1.

Diagram of study population. ALL, acute lymphoblastic leukemia; CCSS, Childhood Cancer Survivor Study; HR, high risk; SR, standard risk.

FIG A2.

Cumulative incidence of subsequent neoplasms as (A) subsequent malignant neoplasm (SMN), (B) benign meningioma, and (C) nonmelanoma skin cancer (NMSC) among 5-year survivors of childhood acute lymphoblastic leukemia by treatment group. 70s, 1970s therapy; 80sHR, 1980s high-risk therapy; 80sSR, 1980s standard-risk therapy; 90sHR, 1990s high-risk therapy; 90sSR, 1990s standard-risk therapy; R/BMT, relapse or with hematopoietic cell transplantation.

FIG A3.

Standardized incidence ratios comparing rate of subsequent malignant neoplasm by time since diagnosis and treatment group to the age-, sex-, race-, and year-matched US population. 70s, 1970s therapy; 80sHR, 1980s high-risk therapy; 80sSR, 1980s standard-risk therapy; 90sHR, 1990s high-risk therapy; 90sSR, 1990s standard-risk therapy; R/BMT, relapse or with hematopoietic cell transplantation.

FIG A4.

Cumulative incidence of severe or disabling, life-threatening, or fatal (Common Terminology Criteria for Adverse Events grade 3-5) chronic health conditions (A) overall, and of selected conditions including (B) congestive heart failure, (C) coronary artery disease, (D) stroke, (E) diabetes, and (F) major joint replacement among 5-year survivors of childhood acute lymphoblastic leukemia by treatment group. 70s, 1970s therapy; 80sHR, 1980s high-risk therapy; 80sSR, 1980s standard-risk therapy; 90sHR, 1990s high-risk therapy; 90sSR, 1990s standard-risk therapy; R/BMT, relapse or with hematopoietic cell transplantation.