Protocol Modifications Decrease Toxicity, Increase Event-Free Survival in Children With Down Syndrome Treated for ALL

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Kelly W. Maloney, MD

A. Kim Ritchey, MD

We have a similar event-free survival in the Down syndrome children and non–Down syndrome children. We can deliver this therapy safely, but we do have to be mindful [that the children with Down syndrome] need additional supportive care and probably additional attention.

—Kelly W. Maloney, MD

Protocol modifications to address increased risk of toxicity and excess early mortality among children with Down syndrome being treated for B-cell acute lymphoblastic leukemia (ALL) proved safe for patients with Down syndrome, and these patients had event-free survival similar to those without Down syndrome. Overall survival, however, was still significantly inferior among children with Down syndrome. The results of a study comparing two Children’s Oncology Group (COG) clinical trials were summarized by lead author Kelly W. Maloney, MD, Associate Professor, Pediatrics-Hematology/Oncology, Children’s Hospital Colorado in Aurora, at the 27th Annual Meeting of the American Society of Pediatric Hematology Oncology ­(ASPHO) in Chicago.

The study was one of two “particularly outstanding” abstracts chosen from among 400 submitted abstracts for presentation at the meeting’s Plenary Session, noted ASPHO’s then-President, A. Kim Ritchey, MD. He is Vice Chair of Clinical Affairs, Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center.

More Therapy-Related Toxicities

“Children with Down syndrome and acute lymphoblastic leukemia have more toxicities related to their therapy, and this has been pretty well documented and published,” Dr. Maloney noted. These include grade 2–4 gastrointestinal toxicities, grade 3–4 hematologic toxicities, and infections. “In general most of the protocols have shown an increase in infections, sometimes significantly increased over those without Down syndrome undergoing comparable treatment,” Dr. Maloney continued.

Children with Down syndrome and ALL have “increased mortality during induction, but they are also more likely to suffer death after obtaining remission,” Dr. Maloney said. The mortality rate “can be as high as 28% vs a more standard 2% to 3%, and perhaps even lower in those children who do not have Down syndrome. There is an increased risk of death from relapse as well.”

Excessive Induction Mortality

COG trial ALL0232, a phase III trial for patients with high-risk ALL, was a randomized comparison of 28 days of prednisone vs 14 days of dexamethasone during induction, and high-dose methotrexate with leucovorin rescue vs escalating intravenous methotrexate without rescue plus pegaspargase (Oncaspar) using the Capizzi schedule in interim maintenance.

“As planned from the beginning, patients with Down syndrome participated in the induction steroid randomization, but were not randomly assigned to high-dose methotrexate, but were nonrandomly assigned to Capizzi methotrexate,” Dr. Maloney said. This trial enrolled 3,084 patients, 39 with Down syndrome.

COG trial ALL0331 enrolled 5,311 patients with standard-risk ALL, 140 with Down syndrome. The trial used a three-drug induction with dexamethasone for 28 days, vincristine, and pegaspargase. Children with Down syndrome participated in the postinduction randomization to intensified vs standard consolidation, with Capizzi methotrexate as interim maintenance.

“Both studies experienced excessive induction mortality for children with [Down syndrome] initially and were modified with expanded supportive care guidelines and leucovorin rescue after intrathecal methotrexate. These modifications successfully eliminated excessive mortality on AALL0331. However, excessive mortality persisted in [high-risk Down syndrome] ALL on AALL0232 and enrollment to this protocol was halted in 2008,” according to the abstract.

Collective Results

Looking at the studies collectively shows that children with Down syndrome had lower 5-year event-free survival and higher morality. Event-free survival for both studies was 80% ± 4% for patients with Down syndrome vs 84.3% ± 0.6% (P = .059) for those without Down syndrome, and overall survival was 82.8% ± 3.8% vs 92.2% ± 0.4% (< .0001), respectively.

Looking at the studies individually confirms that children with Down syndrome had lower event-free and overall survival than those without Down syndrome, but also shows that children with Down syndrome receiving the modified protocol had better 5-year event-free survival than those in the original protocol (86.1% ± 4.2% vs 57.8% ± 8.4%), and better 5-year overall survival (89.2% ± 3.8% vs 60.3% ± 8.3%). With the modified protocol, the 5-year event-free survival was similar for children with and without Down syndrome (86.1% ± 4.2% vs 89.5% ± 0.6%, P  = .102), but overall survival was significantly inferior (89.2% ± 3.8% vs 96.1% ± 0.4%, P  < .0001).

On trial AALL0331, “the induction mortality dropped to 1.7%, which was in line with all the past standard-risk trials and we felt was very acceptable, and postinduction, we did not have any remission deaths,” Dr. Maloney said. “We have a similar event-free survival in the Down syndrome children and non–Down syndrome children. We can deliver this therapy safely, but we do have to be mindful [that the children with Down syndrome] need additional supportive care and probably additional attention,” she noted. ■

Disclosure: Dr. Maloney reported no potential conflicts of interest.


1. Maloney K, Larsen E, Devidas M, et al: Event free (EFS) and overall survival (OS) for children with Down syndrome (DS) and B-lymphoblastic leukemia (B-ALL) in Children’s Oncology Group (COG) clinical trials AALL0232 and AALL0331. ASPHO Annual Meeting. Abstract 4009. Presented May 15, 2014.