Adolescents and Young Adults With ALL Benefit From Paediatric Protocols

Early results of the USA Intergroup clinical study

Results from a large, prospective clinical trial add to mounting evidence that adolescent and young adult patients, aged 16 to 39 with acute lymphoblastic leukaemia (ALL), tend to fare better when treated with high-intensity paediatric protocols than previous patients who were treated with standard adult regimens.

The Intergroup trial, presented at the 56th annual meeting of the American Society of Hematology (6-9 December 2014, San Francisco, USA), enrolled 318 adolescent and young adult patients with ALL, from whom 296 were evaluable. All participants were treated by adult hematologists-oncologists on a paediatric protocol, including four intensive courses of chemotherapy. After two years of follow-up, 78% of the patients achieved overall survival and 66% of patients maintained event-free survival (time after treatment without recurrence, progression or death).

Dr Wendy Stock, who is professor of medicine at the University of Chicago and the study's main author, said the 66% event-free survival rate was a significant improvement over previous studies for this age range, which showed an event-free survival rate of 34%.

"We showed that adolescents and young adults could tolerate an intensive pediatric regimen. The protocol resulted in low treatment-related mortality, less than two percent, and improved both disease-free and overall survival," Dr Stock said. "Our results are important because most adolescent and young adult patients with ALL are still treated with lower-intensity adult regimens and are not enrolled on clinical trials."

Still, she cautioned that these findings need to be confirmed with longer follow-up.

The evidence for better results from higher-intensity therapy dates back to 2000, when Dr Stock and University of Chicago paediatric oncologist, Dr James Nachman examined ALL trials conducted over the last 10 years by two cancer cooperative groups, one paediatric and one adult.

They found a stunning difference. ALL patients ages 16 to 21 who were enrolled in paediatric trials had a progression-free survival rate of 68%. Patients ages 16 to 21 who were enrolled in the adult trials had a progression-free survival rate of 34%, about the same as patients 22-39 years of age. Retrospective studies from France, the United Kingdom and the Netherlands had similar results. These data led the USA cooperative groups to perform the prospective C10403 study.

Biological disease factors other than the treatment also play a role, the researchers point out. High initial white blood cell counts, or the presence of minimal residual disease after the first month of therapy, were linked to poor outcomes.The nearly 30% of patients enrolled in the trial with a Ph-like gene expression signature, indicating aggressive disease, experienced markedly worse outcomes; 52% two-yearevent-free survivalvs. 81%event-free survivalamong those without the genetic alteration.

There were 5 (2%) treatment-related deaths during protocol therapy: liver failure in two cases, both during induction; one case of infection in induction and one in consolidation phase; and one case of ventricular arrhythmia in induction. Overall, treatment toxicities were similar to those reported in the standard arm of COG AALL0232 study reported at ASH 2013 by Advaniet al., with an increased thrombosis and early hyperbilirubinemia for C10403 patients.

"With these new insights, we can now focus future clinical trial research to build upon the C10403 regimen and evaluate new targeted agents to eradicate minimal residual disease in young adults with ALL and further improve their long-term survival," Dr Stock said.