High-dose methotrexate or standard interim maintenance in young patients with ALL? 

High-dose methotrexate was not associated with a reduction in the risk for CNS relapse compared with standard interim maintenance therapy in children and young adults with acute lymphoblastic leukaemia (ALL) who were enrolled in the phase 3 UKALL 2011 trial.

The UKALL 2011 trial (ISRCTN64515327) included children and young adults up to 25 years of age with ALL. Investigated were the difference between a short (14 days) versus a standard (28 days) induction course of dexamethasone, the CNS relapse risk for high-dose methotrexate compared with a standard interim maintenance regimen, and the difference between the effect of vincristine/dexamethasone pulses or no pulses on bone marrow relapse rate. At ASH 2017, the results of the dexamethasone induction courses were presented [1]. At ASH 2022, Ms Amy Kirkwood (University College London, UK) presented the maintenance results [2].

In total, 1,570 participants, receiving a backbone therapy according to the risk group they were stratified to, were randomised to 1 of 4 maintenance arms:

• High-dose methotrexate with pulses
• High-dose methotrexate without pulses
• Standard interim maintenance with pulses
• Standard interim maintenance without pulses

After a median follow-up of 72 months, there was no difference between high-dose methotrexate and standard interim maintenance with regard to CNS relapse (HR 0.99; 95% CI 0.65–1.51; P=0.97), with 5-year rates of 5.6% for both treatment regimens. Interestingly, participants who received a short course of induction dexamethasone followed by high-dose methotrexate and no pulses had an inferior event-free survival compared with participants who received short-duration induction dexamethasone followed by either high-dose methotrexate with pulses or standard interim maintenance with or without pulses (survival rate 75.9% vs 83.2–86.0%; P-value for interaction=0.006).

Furthermore, ‘no pulses’ was non-inferior to ‘pulses’ regarding bone marrow relapse rates (HR 1.22; 95% CI 0.89–1.67). The corresponding 5-year bone marrow relapse rates were 12.2% for participants who did not receive pulses and 10.2% for those who did receive pulses. Ms Kirkwood added that the 5-year event-free survival rate was slightly higher in participants who received pulses than those who did not (86.0% vs 81.7%; P=0.010).

In conclusion, high-dose methotrexate maintenance therapy did not reduce the risk for CNS relapse in young patients with ALL enrolled in the UKALL 2011 trial. Omitting pulses did not result in a higher rate of bone marrow relapse in this population.

1. Goulden NJ, et al. Blood. 2017;130(supplement_1):141.
2. Kirkwood AA, et al. High Dose Methotrexate Does Not Reduce the Risk of CNS Relapse in Children and Young Adults with Acute Lymphoblastic Leukaemia and Lymphoblastic Lymphoma. Results of the Randomised Phase III Study UKALL 2011. Abstract 214, ASH 64^th Annual Meeting, 10–13 December 2022, New Orleans, LA, USA.

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Posted on 20 February 2023