NEW ORLEANS — A survey with the worthwhile extremity of attempting to further amended outcomes and trim toxicity of attraction for children and young adults with acute lymphoblastic leukemia (ALL) oregon lymphoblastic lymphoma recovered that, contrary to long-held assumptions, high-dose methotrexate does not trim the hazard for cardinal tense strategy (CNS) relapse.
The aforesaid survey besides addressed 2 different questions astir modular attraction for these patients, astir the dose of dexamethasone utilized during the archetypal signifier of attraction (results for which had already been reported immoderate years ago), and besides tested omitting monthly pulses of dexamethasone and vincristine aft archetypal treatment.
"The proceedings did not springiness america the answers we were looking for, but that's wherefore we bash randomized trials, and astatine slightest we person 1 wide answer, which is that high-dose methotrexate does not look to person payment successful reducing the hazard of CNS relapse," reported survey researcher Ajay Vora, MSc, from Great Ormond Street Hospital successful London, UK.
Among 1570 patients randomly assigned successful 1 radical of the UKALL2011 trial, 5-year rates of CNS relapse were identical astatine 5.6% for patients treated with either high-dose methotrexate oregon modular interim attraction with oral mercaptopurine and oral and intrathecal methotrexate.
There was a hint, however, that high-dose methotrexate could person a beneficial effect astatine reducing relapses successful bony marrow for immoderate subgroups of patients with B-lineage illness aft dexamethasone induction, Vora commented.
He was speaking astatine a property briefing present astatine the American Society of Hematology yearly meeting, anterior to the presumption of the information by Amy A. Kirkwood, MSc, from the University College London Cancer Institute.
Reacting to the results, Cynthia E. Dunbar, MD, main of the Translational Stem Cell Biology Branch astatine the National Heart, Lung, and Blood Institute successful Bethesda, Maryland, emphasized that "in patients treated with the UKALL regimen, precocious doses of methotrexate did not trim the complaint of CNS relapse, contrary to our long-standing beliefs."
"Going forward, patients tin beryllium spared the hazard of high-dose methotrexate without expanding their hazard of recurrence successful the cardinal tense system," she said.
"As researchers successful hematology, we look astatine it arsenic our work to question the modular approaches that we usage to dainty patients, adjacent those that we thought of arsenic tried-and-true," said briefing moderator Mikkael Sekeres, MD, of the Sylvester Comprehensive Cancer Center astatine the University of Miami Miller School of Medicine. This is 1 of the abstracts that "challenge immoderate of those standards and successful information uncover that successful galore cases, giving little therapy and being little restrictive is really amended for patients, oregon astatine slightest nary worse."
Complex Design
The UKALL2011 proceedings had a byzantine design, with the overarching extremity of answering the question astir which attraction and attraction strategy finds the sweetest spot betwixt efficacy and toxicity successful children and young adults (up to property 25) with ALL and lymphoblastic lymphoma.
One question that was already answered, arsenic investigators reported astatine the 2017 ASH yearly meeting, came from the archetypal randomization successful the study, which was designed to spot whether a shorter people of dexamethasone — 14 days vs the modular 28 days — could trim induction toxicity; it did not.
Now astatine ASH 2022, the investigators reported outcomes from the 2nd signifier of the proceedings which included 2 randomizations: 1 comparing high-dose methotrexate with modular interim attraction to trim CNS relapse risk, and 1 to spot whether forgoing pulses of vincristine/dexamethasone could trim attraction morbidity.
Patients were stratified by National Cancer Institute minimal residual illness (MRD) hazard categories, cytogenetics, and end-of-induction MRD to person 1 of 3 attraction regimens. Patients with MRD precocious risk, defined arsenic MRD greater than 0.5% astatine the extremity of consolidation, were not eligible for second-phase randomization and alternatively received off-protocol therapies.
The 2nd randomization was factorial, stratified by NCI and MRD hazard groups, resulting successful 4 arms: high-dose methotrexate with oregon without pulses, and modular interim attraction with our without pulses.
Standard interim attraction successful this proceedings was 2 months of oral mercaptopurine/methotrexate monthly pulses and azygous intrathecal methotrexate successful 2 of the regimens, and 5 doses of escalating intravenous methotrexate positive vincristine and 2 doses of pegylated asparaginase successful the third.
High-dose methotrexate was fixed astatine a dose of 5 g/m2 for 4 doses 2 weeks apart, debased dose 6-mercaptopurine, positive 2 doses of pegylated asparaginase successful 1 regimen only.
Equivocal Conclusions
As noted above, CNS relapse, the superior endpoint for the interim attraction randomization, did not disagree betwixt the groups, with identical 5-year relapse rates. Similarly, 5-year event-free endurance (EFS) rates were 90.3% successful the high-dose radical and 89.5% successful the modular group, a quality that was not statistically important (P = .68).
There was, however, an enactment betwixt the archetypal (short- vs standard-course dexamethasone) and the interim attraction randomizations, indicating importantly inferior EFS outcomes for patients who had received the abbreviated dose of dexamethasone followed by high-dose methotrexate, particularly among patients who did not person pulses (P = .006).
An investigation of patients treated with modular dexamethasone showed that those who received high-dose methotrexate had a little hazard for bony marrow relapse, with a hazard ratio of 0.62 (P = .029), and trends, albeit nonsignificant, toward amended EFS and wide survival.
In addition, the wide results suggested that steroid pulses could beryllium safely omitted without starring to an summation successful bony marrow relapses: the 5-year rates of bony marrow relapse were 10.2% with pulses and 12.2% without, though omitting pulses was associated with a flimsy but important alteration successful EFS wide (P = .01). The effect was attenuated among patients who had received standard-course dexamethasone and high-dose methotrexate. Leaving retired the pulses besides reduced rates of people 3 oregon 4 adverse events, including febrile neutropenia, Kirkwood noted successful her presentation.
The investigators program to analyse quality-of-life outcomes related to dexamethasone-vincristine pulses to spot whether doing truthful could extremity the equilibrium successful favour of leaving them retired of therapy, and they volition proceed to travel patients to spot whether their findings hold.
UKALL2011 was funded by Children with Cancer UK, Blood Cancer UK, and Cancer Research UK. Kirkwood disclosed consulting for and receiving honoraria from Kite. Vora reported nary applicable fiscal relationships.
American Society of Hematology (ASH) 2022 Annual Meeting: Abstract 214. Presented December 10, 2022.
Neil Osterweil, an award-winning aesculapian journalist, is simply a long-standing and predominant contributor to Medscape.
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