Examining the Blood-Brain Barrier

The prognosis for patients with non-Hodgkin lymphoma (NHL) who develop central nervous system (CNS) relapse is dismal, and there are few clear answers about the best CNS relapse prevention strategies, including which patients should receive it and which agents and modalities should be used. New research presented at the 2020 American Society of Hematology (ASH) annual meeting even raises the question of whether CNS prophylaxis should be used at all.

A Poor Prognosis

CNS relapse is relatively uncommon, but its incidence depends partially on a patients’ lymphoma subtype. For example, around 5% of patients with high-risk diffuse large B-cell lymphoma (DLBCL) will experience CNS relapse, Christopher Flowers, MD, chair of the Department of Lymphoma/Myeloma at MD Anderson Cancer Center in Houston, Texas, told ASH Clinical News. In the pediatric setting, approximately 5% of patients will relapse, many of whom have Burkitt lymphoma, according to Lisa Giulino-Roth, MD, associate professor of pediatrics and director of the Adolescent and Young Adult Lymphoma Program at Weill Cornell Medicine in New York City.

However, for people with other aggressive forms of lymphoma such as Burkitt lymphoma and lymphocytic leukemia, the incidence rate jumps substantially and can exceed 30%, added Dr. Flowers, who is also chair of ASH’s Committee on Promoting Diversity.

Incidence varies with subtype, but the prognosis after CNS relapse is universally poor. Relapse most often occurs within the first year after the diagnosis of systemic disease and the median survival for these patients is typically only a few months.

Data from the RICOVER-60 trial showed that nearly one-third of patients who developed CNS relapse did so after achieving a complete remission.1 The median survival after CNS relapse was just 2.5 months.

Victor M. Orellana-Noia, MD, who presented results from a retrospective analysis of CNS prophylaxis strategies in patients with aggressive NHLs at the 2020 ASH Annual Meeting,2 told ASH Clinical News that, while CNS relapse in people with DLBCL is “technically curable,” few of these patients are able to recover from the intensive treatment.

“In our study, we found that these patients had a median overall survival of just over seven months from time of CNS relapse,” said Dr. Orellana-Noia, who also is an instructor in the Department of Hematology and Medical Oncology at Emory University School of Medicine in Atlanta, Georgia, and a member of the Discovery and Developmental Therapeutics Research Program at Winship Cancer Institute.

Who Is at Highest Risk?

There are numerous approaches to determine patients’ risk for experiencing CNS relapse. Children and adolescents typically are grouped using the Murphy Staging System. In adults, the most common risk stratification approach is derived from the National Comprehensive Cancer Network (NCCN) guidelines and is known as the CNS-International Prognostic Index (CNS-IPI).

The CNS-IPI evaluates patients based on six characteristics: age >60 years; elevated serum lactate dehydrogenase (LDH) level; performance status >1; stage III or IV disease; >1 extranodal site; and kidney or adrenal gland involvement.

Patients who are determined to have zero or one of these characteristics are considered low risk for relapse; the risk level grows to “intermediate” for those who meet two or three criteria; and those with four to six of the criteria are at the highest risk of CNS relapse.

Patients with high-risk sites of disease like testicular, renal, or adrenal involvement may also be at an increased risk of CNS relapse, as are individuals with double-hit lymphoma. Dr. Flowers referenced an MD Anderson Cancer Center study of 129 patients with double-hit lymphomas that found CNS involvement in 13% of patients at three years after diagnosis.3

To Treat or Not to Treat – and With What?

According to Dr. Flowers, CNS prophylaxis is “built automatically into therapy for adults with Burkitt lymphoma or lymphocytic lymphoma because the risk of isolated CNS relapse is so high.” Guidance around CNS prophylaxis strategies for patients with lower-risk disease subtypes is less well-defined.

“There is no standardized approach to managing prophylaxis and CNS relapse in patients with DLBCL,” he added, “and this stems from the fact that there are no definitive randomized controlled trials that provide information upon which we can base our practice.”

Instead, lymphoma specialists rely on expert opinions and observational studies.

Most of the time, when clinicians talk about CNS prophylaxis in the adult setting, they are referring to adding some type of methotrexate administration to chemotherapy regimens like R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone) or R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin). But they are not always referring to the same route of administration. Methotrexate is most often delivered intravenously or intrathecally, and the choice between them depends on several factors.

“When we are deciding which prophylaxis route or combination of routes to use for methotrexate, the choice comes down to the chemotherapy regimen being used, the patient’s age, and the patient’s renal function,” Dr. Orellana-Noia explained.

Intravenous administration is associated with more toxicity, as it penetrates the blood-brain barrier, and the related hematologic toxicities and renal failure could delay start of the next chemotherapy cycle. “When the dose density of R-CHOP is affected, we start to get into trouble with the disease overall,” Dr. Orellana-Noia warned.

Clinicians tend to prefer intrathecal administration because this route is associated with fewer systemic toxicities, but it also does not penetrate the brain tissue, where most relapses occur.

As Dr. Orellana-Noia reported at the 2020 ASH Annual Meeting, in a retrospective review of medical records from more than 1,000 patients with NHL, CNS relapse rates were not significantly different between patients who received methotrexate intravenously (7%) or intrathecally (5%).

So, how do clinicians decide on the route of administration? Dr. Orellana-Noia said there is “no consistent answer” to that question, but researchers have determined that administration route depends in part on the type of chemotherapy regimen a patient receives.

For example, if a patient is receiving R-EPOCH, intravenous high-dose methotrexate may be too toxic.

“This has made me feel more comfortable giving intrathecal prophylaxis when I am giving R-EPOCH,” Dr. Orellana-Noia said. “When it comes to R-CHOP, at this point, it’s dealer’s choice.”

“The intrathecal therapies and the intravenous methotrexate all have toxicities associated with the treatment and with the procedure,” he said. Dr. Flowers added that it is essential for clinicians to properly identify individuals at the greatest risk of CNS relapse to avoid overtreatment of lower-risk patients.

Is Methotrexate Necessary?

High-dose methotrexate is the most widely adopted strategy for preventing CNS relapse, but a retrospective analysis presented at the 2020 ASH Annual Meeting by Robert Puckrin, MD, a hematology resident at the University of Calgary in Alberta, Canada, calls its value into question.

Dr. Puckrin and colleagues evaluated the efficacy of high-dose methotrexate in more than 900 adults with DLBCL treated with curative intent – approximately one-third of whom had high risk according to CNS-IPI score, the presence of double-hit lymphoma, or testicular involvement. Overall, there was no significant difference in CNS relapse rates between those who received CNS prophylaxis with high-dose methotrexate and those who did not (11.2% vs. 12.2%, respectively).

Researchers reported, however, that patients who had received more intensive treatment – whether it was higher-intensity chemoimmunotherapy or consolidative hematopoietic cell transplantation – appeared to have lower rates of CNS relapse when high-dose methotrexate was used, about 6% compared with 12% for those who received standard R-CHOP, he added.

“We thought that our study didn’t demonstrate any benefit of high-dose methotrexate, but there is a potential benefit when intensive systemic therapies are used,” Dr. Puckrin said. “Controlling the systemic disease seems to be a more effective strategy to prevent relapse.”

He cautioned, however, that results from a single retrospective analysis like this do not definitively answer the question of whether CNS prophylaxis with high-dose methotrexate is useful in clinical settings. “We still need more data, ideally from a prospective study or at least from a much larger study, as to whether high-dose methotrexate is beneficial and whether it’s worth the risk of hospitalization and toxicity,” Dr. Puckrin told ASH Clinical News.

He added that gathering those data will be challenging because CNS relapse is such a rare outcome. However, a large international retrospective study is currently under way that should provide additional insight into this clinical scenario.

Prevention in the Pediatric Population

There is a similar lack of high-quality evidence guiding CNS prophylaxis in the pediatric lymphoma population, where aggressive subtypes like Burkitt lymphoma are more common.

“The upfront therapy for a pediatric patient with DLBCL is quite different from the upfront therapy for an adult with DLBCL,” Dr. Giulino-Roth said. “The pediatric regimen is much more aggressive, intensive therapy that was developed to treat Burkitt lymphoma.”

“There is a potential benefit [with methotrexate] when intensive systemic therapies are used. Controlling the systemic disease seems to be a more effective strategy to prevent relapse.”

—Robert Puckrin, MD

Because the biology between DLBCL and Burkitt lymphoma can be difficult to differentiate in children, it is not uncommon for pediatric patients to be diagnosed with B-cell NHL, not otherwise specified. Standard upfront treatment regimens for DLBCL and Burkitt lymphoma usually include CNS-directed therapy, such as high-dose methotrexate and intrathecal chemotherapy prophylaxis.

“The dilemma that we have in managing pediatric B-cell NHL is that we are able to cure most children’s disease [with upfront therapy],” Dr. Giulino-Roth explained. “However, for those 5% of children whose disease relapses, we have very few therapies and their survival is exceedingly poor.”

Exploring New Options

The dismal outcomes associated with CNS relapse in patients with lymphoma underscore the need for new therapeutic options.

“Maybe high-dose methotrexate on its own just isn’t enough, and we need to look at new agents or other types of systemic treatment to try to improve patient outcomes,” Dr. Puckrin suggested.

According to Dr. Flowers, other agents known to cross the blood-brain barrier, such as temozolomide, dexamethasone, and ibrutinib, have been incorporated into regimens to treat primary CNS lymphomas, but are not routinely used as forms of prophylaxis.

Dr. Orellana-Noia agreed that the field is now moving toward studying other agents known to cross the blood-brain barrier as potential alternatives, including chimeric antigen receptor T-cell therapy, lenalidomide, and Bruton tyrosine kinase inhibitors. “To improve upon how we are doing with methotrexate, we need to design prospective studies with CNS-penetrating agents,” he said.

As CNS relapse strategies evolve, clinicians also need better ways to identify patients who are at greatest risk for CNS relapse, he noted, citing the fact that, in his group’s study, CNS relapse rates for patients considered low risk were much higher than expected.

Given the lack of high-quality evidence from prospective, randomized trials, the unanswered questions are going to continue piling up. For now, the clinicians who spoke with ASH Clinical News said, treatment decisions must be made on a case-by-case basis, accounting for the clinician’s estimation of an individual’s risk and comorbid diseases. —By Jill Sederstrom


  1. Pfreundschuh M, Schubert J, Ziepert M, et al. German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008;9(2):105-16.
  2. Orellana-Noia V, Reed D, Sen J, et al. CNS prophylaxis during front-line therapy in aggressive non-Hodgkin lymphomas: real-world outcomes and practice patterns from 19 US academic institutions. Abstract #478. Presented at the 2020 American Society of Hematology Annual Meeting, December 5, 2020.
  3. Oki Y, Noorani M, Lin P, et al. Double hit lymphoma: the MD Anderson Cancer Center clinical experience. Br J Haematol. 2014;166(6):891-901.
  4. Puckrin R, Darsa HE, Ghosh S, Peters A, and Stewart DA. Lack of effectiveness of intravenous high-dose methotrexate for prevention of CNS relapse in patients with high-risk DLBCL: A retrospective analysis from Alberta, Canada. Abstract #477. Presented at the 2020 American Society of Hematology Annual Meeting, December 6, 2020.