The COG A2971 trial enrolled 132 patients with DS and AML (n = 91) or MDS (n = 41) from 98 participating COG institutions between 1999 and 2003. This included 18 children who were enrolled initially on the TMD arm, all of whom had prior resolution of their TMD before they developed ML-DS. Two patients with prior TMD required intervention with low-dose cytarabine therapy. Eighty-five percent of the children with DS were enrolled initially with de novo ML-DS. Institutions reported that 39 patients in this de novo ML-DS group had a prior history of TMD but had not been enrolled on the TMD arm. The median length of follow-up in all patients was 4.8 years (range, 0.8–8.6 years).
The demographic characteristics of the patients with ML-DS on COG A2971 are summarized in and are comparable to those in the historic control group on the CCG 2891 trial. The median age at diagnosis was 1.7 years (range, 0.3–13.6 years), including 85 patients who were aged <2 years (birth to 2-year age group), 41 patients were between ages 2 years and 4 years (2 to 4-year age group), and 6 patients were aged >4 years (>4-year age group). In the COG A2971 study, there were statistically significant, smaller percentages of children with hepatomegaly (33.6% vs 50.9% on CCG 2891; P = .003) and/or splenomegaly (29% vs 49.1% on CCG 2891; P =.001).
Clinical Characteristics of the Children’s Oncology Group A2971 and the Children’s Cancer Group 2891 Down Syndrome Cohorts
Among the 18 children who were previously enrolled on the TMD arm, in which a set screening schedule was used, the median age at diagnosis of subsequent ML-DS was significantly younger than among the 39 children with a history of TMD who were not enrolled on the TMD arm (median age, 1.2 years vs 1.9 years; P = .005) or among the 75 children with de novo ML-DS who had no prior history of TMD (median age, 1.2 years vs 1.7 years; P = .015). The entire cohort of 57 children who had a reported antecedent history of TMD had clinical and disease characteristics similar to those of the children with DS of similar ages without a reported history of TMD (P > .05) and, thus, described together.
summarizes the disease-related characteristics of the children in our study compared with the children enrolled on CCG 2891. Approximately 33% of the patients with AML in each group presented with a prior history of MDS (31% vs 25%, respectively; P = .289). Institutional FAB classification identified a lower than expected M7 prevalence and a higher than previously reported MDS prevalence, and many may have had M7 disease with low blast percentages. Unlike the 4.3% of children with CNS disease enrolled on CCG 2891, none of the children on COG A2971 had CNS disease at diagnosis or relapse (P = .018).
Disease Characteristics of Pediatric Patients With Down Syndrome and Acute Myeloid Leukemia/Myelodysplastic Syndrome: Cohorts Treated on Successive Children’s Oncology Group Trial A2971 and Children’s Cancer Group Trial 2891a
Toxicities were similar to the prior study (). Children with ML-DS on A2971 received a cumulative anthracycline dose of 320 mg/m2
with no excess cardiac toxicity detected (nonsignificant P
value compared with CCG 2891). The relatively higher percentages of nonhematologic toxicities observed during induction and intensification on COG A2971 were not different from those observed on CCG 2891. The high proportion of patients with pulmonary toxicity on COG A2971 is consistent with the finding from the CCG 2891 study16
and was most prevalent during the first 2 cycles of induction therapy. Only 1 postremission death was reported on the COG A2971 study (vs n = 4 on CCG 2891; nonsignificant P
value). This child with ML-DS died on day 11 of intensification therapy (at the end of high-dose cytarabine therapy) from neutropenic fever, pseudomembranous colitis, hyponatremia, and gastrointestinal hemorrhage.
Toxicity Comparison Between the Children’s Oncology Group Trial A2971 CI-TAD Regimen and the Children’s Cancer Group Trial 2891 DCTER Regimena–c
Remission was evaluable in 108 of the 132 study participants. Twenty-four patients were not evaluable for induction response, including 1 patient who withdrew before the third cycle of induction therapy because of toxicity, 1 patient who died of disease, 2 patients who did not have data submitted, and 20 patients who were not evaluable because of failure to obtain a BM sample at the end of the 4 cycles of induction therapy. CRs were achieved in 84% of patients, and PRs were achieved in 8% of patients. Most of the children (74%) with DS (, 82% of the patients with ML-DS who had a history of TMD but who had not birth to 4-year age group) had a good response (<5% blasts on morphologic evaluation) by day 14 of the first cycle of induction therapy (n = 77 of 104 evaluable patients) (). Similar to CCG 2891, only 6.4% of patients developed progressive ML-DS (P = .955). There were no statistically significant age-related differences between the CR rates in children aged ≤4 years (n = 89) and children aged >4 years (n = 6; P = .498). All 18 children who had previously enrolled on the TMD arm achieved CR by the end of induction therapy, including the 2 patients with TMD who had received prior chemotherapy. However previously enrolled on the TMD arm (n = 39) achieved CR (P = .163). These remission rates were not statistically different from those in the patients without antecedent TMD.
Early bone marrow response (induction day 14) and 5-year event-free survival are illustrated for young children (ages birth to 4 years) with Down syndrome and acute myeloid leukemia/myelodysplastic syndrome.
The 5-year survival rates (OS, 84% ± 6%; EFS, 79% ± 7%) from the time of enrollment among all treated patients were similar to those reported in the CCG 2891 study (OS, 79% ± 7%; EFS, 77% ± 7%; P > 0.3). The DFS rates from the time of induction remission were comparable between the 2 studies, with an 89% ± 6% 5-year DFS rate in the COG A2971 study and an 85% ± 6% 5-year DFS rate in the CCG 2891 study (P = .337). Among the children aged <4 years (), there was a trend toward better EFS among those who rapidly cleared their BM blasts at the day-14 BM examination (5-year EFS rate: 86% [<5% blasts; n = 77] vs 72% [≥5% blasts; n = 27]; P = .12).
The children who had ML-DS with antecedent TMD (n = 57) had survival outcomes similar to those of the children who had de novo ML-DS (n = 75; P = .814). The 8 children who had mosaic DS had the same outcome as the rest of the children who had fully expressed, constitutional trisomy 21.
Older age remained a statistically significant adverse risk factor, with a poor 5-year EFS rate of 33% ± 38% (n = 6) in children with ML-DS who were aged >4 years (median age, 8.5 years; range, 4.2–13.6 years). This is in contrast to the favorable 81% ± 7% 5-year EFS rate observed in children with ML-DS who were aged ≤4 years (median age, 1.7 years; range, 0.3–3.8 years; n = 126; P = .001). These results are consistent with the poor 33% ± 31% EFS rate observed in children aged >4 years on the CCG 2891 study. The 5-year EFS rate for children aged <2 years on the COG A2971 study was 82% ± 9% (n = 85), which was comparable to the 86% ± 7% rate (n = 94) observed on the prior CCG 2891 study (P = .504). The EFS rate for children ages 2 to 4 years on COG A2971 was 80% ± 13% (n = 41) compared with 68% ± 12% (n = 58) in the CCG 2891 study (P = .227). Unlike CCG 2891, the COG A2971 study revealed no significant difference in EFS between children aged <2 years versus the slightly older children who were in the group ages 2 to 4 years (P = .726) (). COG A2971 age-based comparisons of EFS were similar to DFS probabilities (5-year DFS in the group aged <2 years [n = 72] vs the group ages 2–4 years [n = 26]; P = .73; 5-year DFS in the group ages 2–4 years vs the group aged >4 years [n = 3]; P < .001; and 5-year DFS in the group ages birth to 4 years vs the group aged >4 years; P < .001). There were no overall differences observed in the TRM rate from study entry between COG 2971 (3% ± 3%) and the CCG 2891 study (4% ± 3%; P = .747).
Figure 3 Age-based event-free survival probabilities are illustrated for children with Down syndrome and acute myeloid leukemia/myelodysplastic syndrome who were treated on Children’s Oncology Group Trial A2971 (COG A2971): Five-year event-free survival (more ...)