High-dose methotrexate improves outcomes in children with B-ALL

High-dose methotrexate appeared superior to Capizzi methotrexate without increasing toxicity in children and young adults with high-risk B-acute lymphoblastic leukemia, according to a randomized, controlled study conducted by the Children’s Oncology Group.

Dexamethasone administered during induction conferred benefit to younger children but provided no benefit and increased toxicity among older children, results showed.

ALL is the most common form of childhood cancer, and has a cure rate of approximately 90%. However, between 20% and 25% of children with B-acute lymphoblastic leukemia (B-ALL) — which comprises approximately 85% of pediatric ALL cases — remain uncured.

“The improvement in cure rates for ALL over the last few decades, for the most part, has not come through the introduction of new medicines, but through using existing medications in new ways, in terms of their dose and schedule,” William L. Carroll, MD, Julie and Edward J. Minskoff professor of pediatrics and director of the Stephen D. Hassenfeld Children’s Center for Cancer and Blood Disorders at NYU Langone Medical Center, said in a press release. “One of the improvements in outcome for ALL overall has been using methotrexate in a more intense fashion, by giving higher doses.”

Combined treatment with steroids and methotrexate has been a common treatment strategy for patients with ALL.

Carroll and colleagues from the Children’s Oncology Group sought to determine best treatment practices for children with B-ALL deemed at high risk for relapse.

The study included data from 2,914 children and young adults (age range, 1-30 years; 54% male) newly diagnosed with B-ALL from 2004 to 2011.

The researchers used a 2 x 2 factorial design and randomly assigned patients to dexamethasone (14 days) or prednisone (28 days) during induction with high-dose methotrexate or dose-escalating Capizzi methotrexate plus pegaspargase during interim maintenance.

Thus, patients received either prednisone and Capizzi methotrexate (n = 926), prednisone and high-dose methotrexate (n = 926), dexamethasone and Capizzi methotrexate (n = 535) or dexamethasone and high-dose methotrexate (n = 527).

Trial enrollment closed in January 2011, when planned interim monitoring showed the high-dose methotrexate regimens exceeded predefined superiority boundaries.

At the time of closure, a greater proportion of patients assigned high-dose methotrexate achieved 5-year EFS than patients assigned Capizzi methotrexate (82% vs. 75.4% P = .006).

The mature final data showed a 5-year EFS trend in favor of high-dose methotrexate (79.6% vs. 75.2%; P = .008).

Patients assigned high-dose methotrexate had nonsignificant decreases in marrow and central nervous system recurrences.

Patients aged 1 year to 9 years assigned dexamethasone and high-dose methotrexate had superior 5-year EFS rates (91.2%) compared with any other regimen (dexamethasone/Capizzi, 83.2%; prednisone/high-dose methotrexate, 80.8%; prednisone/Capizzi, 82.1%; P = .015).

The dexamethasone and high-dose methotrexate cohort also had a nonsignificant trend toward improved 5-year OS.

Younger patients assigned dexamethasone and high-dose methotrexate also had the lowest rates for marrow relapse (3.2%; P = .024).

Corticosteroid enrollment for patients 10 years or older ended in June 2008, due to excess rates of osteonecrosis with dexamethasone compared with prednisone in this cohort (24.3% vs. 15.9%; P = .001).

The 5-year EFS rates for older children randomly assigned dexamethasone (n = 523) or prednisone (n = 525) before enrollment closed were virtually identical (73.1% vs. 73.9%).

More patients assigned Capizzi methotrexate experienced febrile neutropenia than those assigned high-dose methotrexate (8.3% vs. 5.1%; P = .003). Five patients assigned high-dose methotrexate and no patients assigned Capizzi methotrexate had ischemic cerebrovascular toxicity (P = .03).

Dexamethasone was associated with higher rates of febrile neutropenia (18.2% vs. 11%; P < .001) and infections or infestations (29.4% vs. 20.3%; P < .001) during induction. However, both arms had nearly identical death rates (1.9% vs. 1.8%).

“This clinical trial illustrates that despite what seem to be remarkable outcomes for kids with ALL, we have not reached a plateau,” Carroll said. “The outcomes are getting better and better.” – by Cameron Kelsall

Disclosure: Carroll reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.