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No Difference in CNS Relapse Rates Between IT and IV Prophylaxis Routes in Non-Hodgkin Lymphomas

November 24, 2021

November 2021 Bonus ASH Annual Meeting Preview Edition


There was no significant difference in central nervous system (CNS) relapse rates between intrathecal (IT) or intravenous (IV) administration routes of prophylaxis administration for patients with aggressive non-Hodgkin lymphomas (NHLs), according to findings from a recent study published in Blood. Despite current recommendations for prophylactic IV high-dose methotrexate in patients with diffuse large B-cell lymphoma (DLBCL), high-dose methotrexate did not lower the risk of CNS relapse in this population.

To determine whether route of prophylaxis affected CNS relapse, researchers led by Victor M. Orellana-Noia, MD, from Emory University in Atlanta, Georgia, evaluated 1,162 adult patients with the following NHL subtypes (excluding Burkitt lymphoma):

  • DLBCL (n=782)
  • high-grade B-cell lymphoma (n=243)
  • transformation from follicular lymphoma (n=59)
  • other non-chronic lymphocytic leukemia indolent histologies (n=8)


All patients received single-route CNS prophylaxis as part of frontline chemotherapy between 2013 and 2019. Patients were a median of 62 years old (range = 18-86) and 60% were male. Three-quarters had an Eastern Cooperative Oncology Group Performance Status score of 0-1. At diagnosis, 79% had stage III/IV disease.

Overall, participants in the study underwent a median of six cycles of chemotherapy, receiving the following frontline chemotherapy regimens:

  • R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone; n=536, 47.5%)
  • R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin; n=509, 45.1%)
  • other regimens (n=85, 7.4%)


A total of 894 patients received IT prophylaxis and 236 received IV prophylaxis, with 32 switching routes because of toxicity. All patients in the study were treated prophylactically with methotrexate, with 20% receiving high-dose methotrexate. Out of 894 patients who received IT prophylaxis, 121 received cytarabine in addition to methotrexate.

No significant difference was found in CNS relapse rates by prophylaxis route. In patients who received IT prophylaxis, the rate was 5.4% compared with 6.8% for IV prophylaxis (odds ratio [OR] = 1.28; 95% CI 0.71-2.30; p=0.4). After adjusting for differences in number of doses received and backbone chemotherapy regimen (adjusted OR 1.38; 95% CI 0.74-2.57; p=0.31) there was still no significant difference between routes. Additionally, no difference was found between prophylactic agents.

According to the researchers, this lack of difference persisted across all subgroups, including age, stage, CNS International Prognostic Index (IPI) score, and double-hit status. The CNS-IPI predicted a relapse rate of 5.8% across the population, which was nearly identical to the observed rate of 5.7%.

“Relapse rates among high-risk subgroups remain elevated and reconsideration of prophylaxis strategies in DLBCL is of critical need,” the authors wrote. “Future studies should focus less on route of methotrexate administration, in favor of how to further leverage molecular features in risk stratification as well as the role of more biologically directed therapies in DLBCL.”

Researchers found that the following features correlated with increased risk of CNS relapse despite prophylaxis:

  • testicular involvement
  • non-Germinal center B-cell-like subtype DLBCL
  • high total burden of extranodal disease


During the study period, 194 patients in the IT group and 32 in the IV group died, with 36 and nine deaths in the respective groups following CNS relapse. Researchers performed a competing risk analysis with death as a competing event to CNS relapse and found no difference between prophylaxis routes.

“We do not consider the currently available data, including those presented here, as sufficient to forego the use of CNS prophylaxis in DLBCL altogether; however, given the scale and complexity needed to investigate a rare and heterogeneous outcome such as CNS relapse, further study to compare routes of methotrexate administration is likely of diminishing benefit compared to that of other key advances in this space,” the authors concluded.

Study authors report no relevant conflicts of interest.


Orellana-Noia, VM, Reed D, McCook AA, et al. Single-route CNS prophylaxis for aggressive non-Hodgkin lymphomas: real-world outcomes from 21 US academic institutions [published online ahead of print, 2021 Sep 27]. Blood. doi: 10.1182/blood.2021012888.


  January 2022


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