February 2016, Vol. 5, No. 1

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Another Study Shows Benefit with a Pediatric Regimen in Young Adults with ALL

Daniel DeAngelo, MD, PhD

ASH 2015, ASH Highlights

daniel_DeAngelo98pxA pediatric regimen achieves superior outcomes compared with adult regimens in adolescents and young adults with acute lymphoblastic leukemia (ALL). Several studies have already shown this outcome, and a multicenter phase 2 study presented at the meeting adds further confirmatory evidence in support of this approach. The multicenter phase 2 trial enrolled patients with ALL aged 18 to 50 years, whereas other trials evaluating “pediatric” or “pediatric inspired” regimens had an upper age limit of 30 or 40 years.

Three-year overall survival (OS) with the Dana-Farber pediatric ALL regimen was 75% and 3-year disease-free survival was 73% in this trial, which was better than expected. “The take-home point from trials of pediatric regimens to date is that overall survival and disease-free survival are improved compared with historical controls treated on prior adult regimens,” said lead author Daniel DeAngelo, MD, PhD, Dana-Farber Cancer Institute, Boston, MA.

“The regimen is tolerable in young adults with ALL and represents a major therapeutic advance,” he said.

Thus far, all the trials of pediatric regimens in younger adults with ALL have been phase 2 trials. DeAngelo said it is unlikely that a phase 3 trial will be conducted.

The Dana-Farber regimen used in this trial employed weekly pegylated asparaginase, which is thought to be safer and longer lasting than E coli asparaginase, which this group of investigators used in previous trials.

The study included 110 high-risk young adult ALL patients treated with induction therapy; patients who achieved remission went on to 30 weeks of consolidation and 2 years of maintenance therapy. They were treated with central nervous system prophylaxis consisting of intrathecal chemotherapy and radiation starting on day 1, high doses of asparaginase, and non–cross-resistant drugs with different side effect profiles that allow use of a number of drugs.

The dose of pegylated asparaginase was adjusted because of toxicity concerns during consolidation therapy; the interval between doses was lengthened to every 3 weeks for a total of 10 doses instead of 15. Prophylactic anticoagulation with low-molecular-weight heparin was used during treatment with asparaginase, which reduced the incidence of thrombosis, DeAngelo said.

Of the 110 patients accrued to the trial, 65 were on higher-dose pegylated asparaginase and 45 on the amended protocol. Median age was 32 years; 61% were male. Eighty percent had B-cell ALL and 20% had T-cell ALL.

The rate of complete remission was 89%; 21 patients went on to transplant. Three deaths occurred due to transplant-related complications.

Subgroup analysis showed that patients under age 30 had a 4-year OS of 80% to 85%, which was significantly better than the other age groups. Also, patients with T-cell ALL did particularly well on this protocol, with an OS of 80% and 70% for B-cell Philadelphia chromosome–negative ALL.

“A surprising finding was the association between poor OS based on body mass index. Underweight and normal weight patients did much better than obese patients,” DeAngelo said.

Minimal residual disease (MRD)-negative patients had improved outcomes compared with MRD-positive patients, but no data were provided at press time.

Adjusting the dosing of pegylated asparaginase reduced the rate of grades 3 and 4 hyperbilirubinemia, ALT elevations, and risk of thrombosis. The investigators noted that pegylated asparaginase had greater toxicity in older adults as well as in those with high body mass index (>30). DeAngelo said that these patients have psychosocial needs that require attention. “We need a unified approach to make progress in ALL, and this means more cooperative group trials in adolescents and young adults with ALL,” he stated.

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