maze of pcnsl treatment options

Current Treatment Challenges
Many factors complicate treatment decisions in R/R PCNSL

Treatment Considerations

Many factors must be weighed when choosing a treatment

PCNSL relapse may occur at different intervals, with early/short relapse (<12 months from treatment initiation) distinct from primary refractory disease1,2*

Considerations include3:
Prior therapies icon

Prior therapies

Quality of response icon

Quality of response to prior therapies

Duration of remission icon

Duration of remission

Patient characteristics icon

Patient characteristics

Patients may be unable to receive further intensive therapy due to multiple factors3-6

  • Advanced age
  • Impaired performance status
  • Poor physiological fitness
  • Debilitating symptoms, such as cognitive impairment and paralysis
  • Renal, lung, bone marrow, and cardiac function 
  • Tolerability of initial treatment
  • Other comorbidities
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The availability of caregiver support and a patient's ability to travel for care may impact treatment decisions

Many patients with R/R PCNSL are ineligible for further intensive treatment, such as HD-MTX1-3*

chemotherapy sign icon

HD-MTX rechallenge is commonly considered, but not all patients are eligible3

  • HD-MTX rechallenge is appropriate for patients who responded to HD-MTX and relapsed after a year2*†
  • However, patients who receive first-line HD-MTX and relapsed early (<12 months from treatment initiation) may be inherently chemo-resistant, limiting further treatment options1-3*
Factors that impair the ability to receive HD-MTX include7:
Worsened renal function icon

Impaired renal function

(CrCl <50-60 mL/min)

 

Impaired LVEF icon

Impaired LVEF

Drug interactions icon

Drug interactions 
with certain prescription medications

Additional current treatments

For patients who relapse or are refractory following first-line PCNSL treatment, additional options that may be considered include HDC-ASCT, WBRT, or other single-agent and combination regimens.8

ASCT sign icon

More aggressive and potentially effective therapies such as HDC-ASCT may be an option for select chemosensitive and fit patients. However, the majority of patients at relapse are not eligible for HDC-ASCT due to6,8:

  • Comorbidities
  • Age
  • Performance status
  • Overall tolerability profile associated with initial treatment
WBRT sign icon

WBRT is an option for patients with multiple relapses or rapid disease progression if no better systemic therapy is available, but it is utilized less frequently because it can cause significant delayed neurotoxicity in patients >60 years.4,6,8

  • Delayed neurotoxicity affects up to 47% of patients and is a serious problem that impacts cognitive function and quality of life9
Car-T

The approval of CAR T-cell therapy in the US marks a step forward, even as an unmet need persists for effective and tolerable treatments for R/R PCNSL across certain patient groups.10

  • Based on safety results from 13 patients, 85% experienced neurological toxicities, with 31% experiencing Grade 3 neurological toxicities11
  • CAR T-cell therapies can take up to 2 months to develop. Patients may require bridging therapies‡ during this period to prevent disease progression and potentially fatal outcomes12,13

Additional regimens, including targeted and immune-based therapies, have been studied in R/R PCNSL clinical trials as single agents or in combination4,8,14

BTKi sign icon

BTKis: Target the BCR and TLR pathways4

IMiDs sign icon

IMiDs: Targeted agents that use multiple mechanisms, including the BCR and TLR pathways and inhibit the activity of NF-κB4

mAbs sign icon

mAbs: Those that have been studied in R/R PCNSL bind targets such as CD20 and PD-14,14

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In general, use of novel agents is recommended within the context of clinical trials8

No accepted standard of care

There are limited FDA-approved options for R/R PCNSL3,4,10

The management of patients with R/R PCNSL remains poorly defined and is a major area of unmet clinical need15
  • Although the treatment of PCNSL has evolved during the past few decades, there is no accepted standard of care in R/R PCNSL16
Many regimens have been studied; however, there are limited FDA-approved therapies for R/R PCNSL3,8,10
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

The primary recommendation of the NCCN Guidelines® for R/R PCNSL is clinical trial participation.11

  • There is no preferred regimen2,11
As a result, treatment approaches vary6,15:
  • Chemotherapy: HD-MTX rechallenge, other chemotherapy regimens
  • HDC-ASCT
  • WBRT
  • Targeted agents and immunomodulatory approaches
  • Clinical trials
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There is no clear choice in treatment options for the management of R/R PCNSL8

Obstacles to advancing 
R/R PCNSL treatment remain

Future Outlook

*NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

*The timeframe of <12 months or ≥12 months was a consensus opinion; there are no specific data to define length of time before development of recurrence that would indicate if retreatment with methotrexate should be attempted.2

†Bridge therapies may include steroids, chemotherapy, targeted therapy, or radiation therapy (RT).

‡Also a type of chemotherapy.

Not all drugs within the presented classes are used in the treatment of R/R PCNSL.

ASCT=autologous stem cell transplantation; BCR=B-cell receptor; BTKi=Bruton tyrosine kinase inhibitor; CAR-T=chimeric antigen receptor t-cell therapy; CD20=cluster of differentiation 20; CrCl=creatinine clearance; FDA=Food and Drug Administration; HD-MTX=high-dose methotrexate; HDC-ASCT=high-dose chemotherapy plus autologous stem cell transplantation; IMiDs=immunomodulatory drugs; LVEF=left ventricular ejection fraction; mAbs=monoclonal antibodies; MTX=methotrexate; NF-κB=nuclear factor-kappa B; PCNSL=primary central nervous system lymphoma; PD-1=programmed death-1; R/R PCNSL=relapsing or refractory primary central nervous system lymphoma; TLR=toll-like receptor; WBRT=whole brain radiation therapy.

References: 1. Birnbaum T, Bochmann K, von Baumgarten L, Straube A. Early relapses in patients with primary CNS lymphoma treated with methotrexate-based chemotherapy without consolidating whole brain irradiation. J Neurooncol. 2013;112(2):233-239. doi:10.1007/s11060-013-1052-3 2. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Central Nervous System Cancers V.1.2026. © National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed May 18, 2026. To view the most recent and complete version of the guideline, go online to NCCN.org 3. Ambady P, Doolittle ND, Fox CP. Relapsed and refractory primary CNS lymphoma: treatment approaches in routine practice. Ann Lymphoma. 2021;5:23. doi:10.21037/aol-21-20 4. Tao K, Wang X, Tian X. Relapsed primary central nervous system lymphoma: current advances. Front Oncol. 2021;11:649789. doi:10.3389/fonc.2021.649789 5. Kaulen LD, Baehring JM. Treatment options for recurrent primary CNS lymphoma. Curr Treat Options Oncol. 2022;23(11):1548-1565. doi:10.1007/s11864-022-01016-5 6. Seidel S, Kowalski T, Nilius-Eliliwi V, Schroers R, Schlegel U. Survival, prognostic factors, hospitalization time and clinical performance status after first cerebral relapse or progression in 54 patients with primary CNS lymphoma not eligible for high dose chemotherapy: a retrospective analysis. Neurol Res Pract. 2023;5(1):8. doi:10.1186/s42466-023-00234-y 7. Martinez-Calle N, Isbell LK, Cwynarski K, Schorb E. Treatment of elderly patients with primary CNS lymphoma. Ann Lymphoma. 2021;5(2):1-16. doi:10.21037/aol-20-30 8. Holdhoff M, Mrugala MM, Grommes C, et al. Challenges in the treatment of newly diagnosed and recurrent primary central nervous system lymphoma. J Natl Compr Canc Netw. 2020;18(11):1571-1578. doi:10.6004/jnccn.2020.7667 9. Yamanaka R, Morii K, Sano M, et al. Long-term survivors of primary central nervous system lymphoma. Jpn J Clin Oncol. 2017;47(2):101-107. doi:10.1093/jjco/hyw171 10. FDA approves label update for Kite’s Yescarta® for relapsed/refractory primary central nervous system lymphoma. News release. Gilead Sciences, Inc. February 6, 2026. Accessed April 23, 2026. https://www.gilead.com/news/news-details/2026/fda-approves-label-update-for-kites-yescarta-for-relapsedrefractory-primary-central-nervous-system-lymphoma 11. YESCARTA® (axicabtagene ciloleucel). Prescribing information. Kite Pharma, Inc.; 2026. 12. Pinnix CC, Gunther JR, Dabaja BS, et al. Bridging therapy prior to axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma. Blood Adv. 2020;4(13):2871-2883. doi:10.1182/bloodadvances.2020001837 13. Sheikh S, Migliorini D, Lang N. CAR T-based therapies in lymphoma: a review of current practice and perspectives. Biomedicines. 2022;10(8):1960. doi:10.3390/biomedicines10081960 14. Holdhoff M, Wagner-Johnston N, Roschewski M. Systemic approach to recurrent primary CNS lymphoma: perspective on current and emerging treatment strategies. Onco Targets Ther. 2020;13:8323-8335. doi:10.2147/OTT.S192379 15. Langner-Lemercier S, Houillier C, Soussain C, et al. Primary CNS lymphoma at first relapse/progression: characteristics, management, and outcome of 256 patients from the French LOC network. Neuro Oncol. 2016;18(9):1297-1303. doi:10.1093/neuonc/now033 16. Mendez JS, Grommes C. Treatment of primary central nervous system lymphoma: from chemotherapy to small molecules. Am Soc Clin Oncol Educ Book. 2018;38:604-615. doi:10.1200/EDBK_200829