GRAALL 2005: Age 55 years may be limit for pediatric regimens in ALL

SAN DIEGO — Patients with Philadelphia-negative acute lymphoblastic leukemia aged 55 years or older experienced poorer survival outcomes than younger patients, even when treated with an adjusted dose of cyclophosphamide, according to findings presented at the ASH Annual Meeting and Exposition.

Thus, age 55 years may be the upper age limit for using a pediatric-like strategy in younger adults with ALL, according to Françoise Huguet, MD, of the department of hematology at Institut Universitaire du Cancérologie de Toulouse in France, and colleagues.

“Adolescents have better outcomes if treated with pediatric as opposed to adult protocols,” Huguet said. “Pediatric or pediatric-like protocols have been proposed to treat adults aged 35 to 59 years. We are raising the question of the appropriate age threshold.”

In the GRAALL-2005 study, Huguet and colleagues aimed to address the issue of age cutoff for use of pediatric regimens and to randomly evaluate a reinforced hyper-fractionated vs. standard dose of cyclophosphamide during induction and late intensification.

The standard-of-care dose consisted of 750 mg/m² on day 1 followed by 750 mg/m² on day 15, whereas the hyper-fractionated cyclophosphamide dose consisted of 300 mg/m² every 12 hours on days 15 to 17.

EFS served as the primary endpoint. Compliance to therapy served as the secondary outcome.

“We planned to detect a 10% increase in EFS,” Huguet said.

The median follow-up was 5.25 years.

There were 813 patients included in the analysis, of whom 787 (median age, 37 years) were evaluable. This included 200 patients aged 18 to 24 years, 172 aged 25 to 34 years, 171 aged 35 to 44 years, 151 aged 45 to 54 years, and 93 aged older than 55 years.

Overall, complete response rate was 92%, with an induction mortality rate of 5.5%. Five-year EFS was 52% and 5-year OS was 58%, which was similar between the two arms, Huguet said.

The standard-dosing regimen was associated with a complete response rate of 90.2%, compared with 93.6% in the hyper-dose arm. After one course, the complete response rate was 87.5% for the standard-dose arm and a 91.8% for the hyper-dose arm.

Five-year EFS was 26% for patients aged older than 55 years, which was significantly lower than the EFS rate of the other age groups (18-24 years, 60%; 25-34 years, 58%; 35-44 years, 54%; 45-54 years, 50%: HR = 2.2; 95% CI, 1.7-2.8).

Most of this disparity came from a greater cumulative incidence of non-refractoriness/relapse mortality — which included toxic death during induction and death in first complete remission — at 5 years among patients aged older vs. younger than 55 years (40% vs. 14%; HR = 3.4; 95% CI, 2.3-5).

“Poor tolerance of therapy was observed in patients aged 55 years or older,” Huguet said. “This was not observed in patients aged younger than 55 years.”

Overall, hyper-dose treatment had no impact on EFS (HR = 0.89; 95% CI, 0.7-1.1). However, post-hoc subgroup analyses revealed that patients aged 55 years and older significantly benefited from hyper-dose treatment (5-year EFS, 38% vs. 12%; HR = 0.51; 95% CI, 0.3-0.8), whereas younger patients did not (5-year EFS, 57% vs. 55%; HR = 0.95; 95% CI, 0.8-1.2).

Five-year cumulative incidence of failure among patients aged older than 55 years was 40% among those treated on the standard-dose arm compared with 27% among those treated on the hyper-dose arm, the latter of which was comparable to that observed in younger patients (standard dose, 31%; hyper dose, 30%).

“This observation might be related to the inferior treatment compliance observed in patients aged 55 years and older at each treatment phase, suggesting that the benefit associated with hyper-dose cyclophosphamide reinforcement became apparent because these patients could not tolerate the planned pediatric-inspired therapy,” the researchers wrote.

The older age subgroup received less asparaginase during induction, along with less cytarabine, less vincristine, doxorubicin and cyclophosphamide during intensification, according to Huguet.

“Treatment tolerability and survival were worse in older patients despite dose reductions,” she said.

These results suggest that age 55 years “is likely to be the upper age limit to tolerate pediatric-like therapy for younger adults with Philadelphia-negative ALL,” Huguet concluded.

Patients in this age range are likely to benefit from alternative front-line strategies such as blinatumomab (Blincyto, Amgen) or inotuzumab ozogamicin (CMC-544, Pfizer), she added. – by Rob Volansky

Reference:

Huguet F, et al. Abstract 762. Presented at: The ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.

Disclosure: Huguet reports no relevant financial disclosures. Please see the abstract for a list of all other researchers’ relevant financial disclosures.