Dr Katherine Lewis
High dose methotrexate (HD-MTX) prophylaxis is not associated with a reduction in CNS relapse in high risk patients with aggressive B-cell lymphoma.
Speaking at ASH 2021, Dr Katharine Lewis said CNS relapse was an uncommon but devastating complication of aggressive B-cell lymphoma with a median overall survival (OS) of less than six months.
Dr Lewis, from the Sir Charles Gairdner Hospital in WA, said there was currently no consensus regarding who was at high risk, what CNS directed prophylaxis should be, or how to incorporate CNS prophylactic therapy into systemic therapy.
Meanwhile, she noted HD-MTX was widely used to mitigate CNS risk but required in-hospital stays, may lead to toxicities, or result in delay to frontline systemic lymphoma treatment.
She said the literature on HD-MTX was mixed, prompting the multi-centre retrospective study of 2,267 adults with DLBCL with a CNS-IPI score of 4-6, patients with double and triple hit lymphoma, or primary breast or testicular DLBCL irrespective of CNS-IPI.
The study recruited consecutive patients from 21 sites in North America, Europe, Asia and Australia.
Dr Lewis said the CNS relapse rate was 9.0% in the 1,875 patients who did not receive HD-MTX. In the 392 patients who received CNS prophylaxis with HD-MTX, the CNS relapse rate was 7.9% over a median follow-up of 5.8 years.
She said the HD-MTX group of patients was enriched with males, patients under 60 years, and a favourable ECOG of 0-1. They also had a higher number of extranodal sites and more high-risk extranodal sites.
The cumulative incidence of CNS relapse was 9.2% in the untreated group and 8.1% with HD-MTX; the median time to CNS relapse was 6.7 months versus 8.5 months respectively.
“The difference in 5-year CNS relapse risk between those who revived HD-MTX and those who did not was 1.1%. In other words, in our cohort, 91 patients would need to receive HD-MTX over a 5-year period in order to prevent one CNS relapse.”
Subgroup analysis
In a subgroup of 1,468 patients in complete response (CR), and with a median follow-up of 5.4 years, CNS relapse was 5.8% in those without prophylaxis and 5.4% in the HD-MTX group.
Most HD-MTX patients (71%) had received at least one cycle of treatment ≥3 g/m2; while 31% had HD-MTX during chemoimmunotherapy and about half (53%) after completion of chemoimmunotherapy.
The cumulative incidence of CNS relapse in the CR patient cohort was 6.3% without HD-MTX and 4.8% with prophylaxis; median time to CNS relapse was 10.3 versus 11.5 months.
Exploratory analyses showed no difference in CNS relapse rates in any high-risk subgroup including the double and triple hit lymphoma patients, isolated versus synchronous /systemic relapse, higher CNS-IPI scores, or high-risk extranodal sites.
“Acknowledging the caveats of a retrospective study and in the absence of a RCT, our study provides further substantial evidence that high-dose methotrexate may be ineffective at preventing CNS relapse in high risk patients,” Dr Lewis concluded.
“Careful consideration should be given as to whether its use in this setting remains justified.”
All of us in Oz are more than a little bit proud of Katherine Lewis and @chanyooncheah for their work on the now very doubtful role of methotrexate for CNS prophylaxis in lymphoma #lymsm #ash21 https://t.co/khRl9laiIj pic.twitter.com/G75OUAIXWI
— Michael Dickinson (@mike_dickinson1) December 11, 2021