Advertisement

Event-Free Survival Benefit, Greater Toxicity of Augmented Postremission Therapy for Children/Young Adults With High-Risk Acute Lymphoblastic Leukemia

Advertisement

Key Points

  • Augmented postremission therapy was associated with significantly improved event-free survival and numerically improved overall survival.
  • Serious or severe asparaginase-related and intravenous methotrexate–related adverse events were more common with the augmented regimen.

In a UK phase III trial (UKALL 2003) reported in The Lancet Oncology, Vora et al found that augmented postremission therapy provided an event-free survival benefit at the cost of increased toxicity in children and young adults with clinical standard- or intermediate-risk but minimal residual disease–defined high-risk acute lymphoblastic leukemia (ALL).

Study Details

In the open-label trial, 533 patients aged 1 to 24 years with clinical standard- or intermediate-risk ALL with minimal residual disease ≥ 0.01% at day 29 of induction were randomly assigned between October 2003 and June 2011 to standard (n = 266) or augmented (n = 267) postremission therapy. Augmented therapy included an additional eight doses of pegylated asparaginase, 18 doses of vincristine, and escalated-dose intravenous (IV) methotrexate without leucovorin rescue during courses of interim maintenance treatment. The primary endpoints were event-free survival and overall survival in the intent-to-treat population.

The standard and augmented therapy groups were balanced for age (median, 5 years in both, 13% and 11% ≥ 16 years), sex (57% and 54% male), white blood cell count at diagnosis (median, 13 × 109/L in both), National Cancer Institute risk (standard in 62% and 63%), immunophenotype (B lineage/null in 87% and 85%), and cytogenetic risk (intermediate/poor in 34% and 33%).

Improved Event-Free Survival

Median follow-up was 70 months. Five-year event-free survival was 89.6% in the augmented therapy group vs 82.8% in the standard therapy group (odds ratio [OR] = 0.61, P = .04), and 5-year overall survival was 92.9% vs 88.9% (OR = 0.67, P = .16).

Five-year rates of any relapse (7.5% vs 14.2%, OR = 0.55, P = .03) and bone marrow relapse (4.6% vs 10.5%, OR = 0.42, P = .009) were significantly lower in the augmented therapy group. There was no significant difference between groups in 5-year nonmarrow relapse rate (3.1% vs 4.1%, OR = 0.95, P = .91) or rate of death during induction (2.7% vs 3.5%, OR = 0.76, P = .59).

Adverse Events

Serious adverse events were more common in the augmented therapy group (45% vs 34%, P = .02), including greater frequencies of asparaginase-related hypersensitivity (7% vs < 1%, P = .0003), asparaginase-related pancreatitis (3% vs < 1%, P = .04), and IV methotrexate–related mucositis (4% vs 1%, P = .05). Grade 3 or 4 adverse events occurred in 86% vs 84%, with greater frequencies of IV methotrexate–related stomatitis (18% vs 5%, P < .0001) and vomiting (8% vs 3%, P = .05) in the augmented therapy group.

The investigators concluded, “Our findings suggest that children and young people with acute lymphoblastic leukaemia and 0.01% or more [minimal residual disease] at the end of remission induction therapy could benefit from augmented post-remission therapy. However, the asparaginase and [IV] methotrexate used in the augmented treatment regimen is associated with more adverse events than is the standard post-remission treatment regimen.”

Ajay Vora, FRCPath, of Sheffield Children’s Hospital, is the corresponding author for The Lancet Oncology article.

The study was funded by the UK Medical Research Council and Leukaemia and Lymphoma Research. The study authors reported no potential conflicts of interest.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


Advertisement

Advertisement



Advertisement