High-Dose MTX Does Not Reduce CNS Relapse in Pediatric ALL

High-Dose MTX Does Not Reduce CNS Relapse in Pediatric ALL

NEW ORLEANS — A research with the worthwhile purpose of trying to additional enhance outcomes and scale back toxicity of therapy for kids and younger adults with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma discovered that, opposite to long-held assumptions, high-dose methotrexate doesn’t scale back the chance for central nervous system (CNS) relapse.

The identical research additionally addressed two different questions on customary look after these sufferers, in regards to the dose of dexamethasone used in the course of the first section of therapy (outcomes for which had already been reported some years in the past), and likewise examined omitting month-to-month pulses of dexamethasone and vincristine after preliminary therapy.

“The trial didn’t give us the solutions we have been in search of, however that is why we do randomized trials, and at the very least we have now one clear reply, which is that high-dose methotrexate doesn’t appear to have profit in lowering the chance of CNS relapse,” reported research investigator Ajay Vora, MSc, from Nice Ormond Road Hospital in London, UK.

Amongst 1570 sufferers randomly assigned in a single group of the UKALL2011 trial, 5-year charges of CNS relapse have been equivalent at 5.6% for sufferers handled with both high-dose methotrexate or customary interim upkeep with oral mercaptopurine and oral and intrathecal methotrexate.

There was a touch, nevertheless, that high-dose methotrexate may have a helpful impact at lowering relapses in bone marrow for some subgroups of sufferers with B-lineage illness after dexamethasone induction, Vora commented.

He was talking at a press briefing right here on the American Society of Hematology annual assembly, previous to the presentation of the information by Amy A. Kirkwood, MSc, from the College School London Most cancers Institute.

Reacting to the outcomes, Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Department on the Nationwide Coronary heart, Lung, and Blood Institute in Bethesda, Maryland, emphasised that “in sufferers handled with the UKALL routine, excessive doses of methotrexate didn’t scale back the speed of CNS relapse, opposite to our long-standing beliefs.”

“Going ahead, sufferers might be spared the chance of high-dose methotrexate with out growing their threat of recurrence within the central nervous system,” she mentioned.

“As researchers in hematology, we have a look at it as our obligation to query the usual approaches that we use to deal with sufferers, even people who we considered tried-and-true,” mentioned briefing moderator Mikkael Sekeres, MD, of the Sylvester Complete Most cancers Heart on the College of Miami Miller College of Drugs. This is among the abstracts that “problem a few of these requirements and actually reveal that in lots of instances, giving much less remedy and being much less restrictive is definitely higher for sufferers, or at the very least no worse.”

Complicated Design

The UKALL2011 trial had a byzantine design, with the overarching purpose of answering the query about which therapy and upkeep technique finds the sweetest spot between efficacy and toxicity in youngsters and younger adults (as much as age 25) with ALL and lymphoblastic lymphoma.

One query that was already answered, as investigators reported on the 2017 ASH annual assembly, got here from the primary randomization within the research, which was designed to see whether or not a shorter course of dexamethasone — 14 days vs the usual 28 days — may scale back induction toxicity; it didn’t.

Now at ASH 2022, the investigators reported outcomes from the second section of the trial which included two randomizations: one evaluating high-dose methotrexate with customary interim upkeep to cut back CNS relapse threat, and one to see whether or not forgoing pulses of vincristine/dexamethasone may scale back upkeep morbidity.

Sufferers have been stratified by Nationwide Most cancers Institute minimal residual illness (MRD) threat classes, cytogenetics, and end-of-induction MRD to obtain one in all three therapy regimens. Sufferers with MRD excessive threat, outlined as MRD higher than 0.5% on the finish of consolidation, weren’t eligible for second-phase randomization and as a substitute acquired off-protocol therapies.

The second randomization was factorial, stratified by NCI and MRD threat teams, leading to 4 arms: high-dose methotrexate with or with out pulses, and customary interim upkeep with our with out pulses.

Customary interim upkeep on this trial was 2 months of oral mercaptopurine/methotrexate month-to-month pulses and single intrathecal methotrexate in two of the regimens, and 5 doses of escalating intravenous methotrexate plus vincristine and two doses of pegylated asparaginase within the third.

Excessive-dose methotrexate was given at a dose of 5 g/m­2 for 4 doses 2 weeks aside, low dose 6-mercaptopurine, plus two doses of pegylated asparaginase in a single routine solely.

Equivocal Conclusions

As famous above, CNS relapse, the first endpoint for the interim upkeep randomization, didn’t differ between the teams, with equivalent 5-year relapse charges. Equally, 5-year event-free survival (EFS) charges have been 90.3% within the high-dose group and 89.5% in the usual group, a distinction that was not statistically important (P = .68).

There was, nevertheless, an interplay between the primary (short- vs standard-course dexamethasone) and the interim upkeep randomizations, indicating considerably inferior EFS outcomes for sufferers who had acquired the brief dose of dexamethasone adopted by high-dose methotrexate, particularly amongst sufferers who didn’t obtain pulses (P = .006).

An evaluation of sufferers handled with customary dexamethasone confirmed that those that acquired high-dose methotrexate had a decrease threat for bone marrow relapse, with a hazard ratio of 0.62 (P = .029), and developments, albeit nonsignificant, towards higher EFS and total survival.

As well as, the general outcomes urged that steroid pulses could possibly be safely omitted with out resulting in a rise in bone marrow relapses: the 5-year charges of bone marrow relapse have been 10.2% with pulses and 12.2% with out, though omitting pulses was related to a slight however important lower in EFS total (P = .01). The impact was attenuated amongst sufferers who had acquired standard-course dexamethasone and high-dose methotrexate. Leaving out the pulses additionally decreased charges of grade Three or four adversarial occasions, together with febrile neutropenia, Kirkwood famous in her presentation.

The investigators plan to investigate quality-of-life outcomes associated to dexamethasone-vincristine pulses to see whether or not doing so may tip the stability in favor of leaving them out of remedy, and they’re going to proceed to observe sufferers to see whether or not their findings maintain.

UKALL2011 was funded by Kids with Most cancers UK, Blood Most cancers UK, and Most cancers Analysis UK. Kirkwood disclosed consulting for and receiving honoraria from Kite. Vora reported no related monetary relationships.

American Society of Hematology (ASH) 2022 Annual Assembly: Summary 214. Offered December 10, 2022.

Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.

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