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

Considerations include1:
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 factors1-4

  • 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

chemotherapy sign icon

HD-MTX rechallenge is commonly considered, but not all patients are eligible1

  • HD-MTX rechallenge is appropriate for patients who responded to HD-MTX and relapse later (>12 months)2
  • However, patients who receive first-line HD-MTX and relapse early may be inherently chemo-resistant, limiting further treatment options1
Factors that impair the ability to receive HD-MTX include5:
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.6

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 to4,6:

  • 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.2,4,6

  • Delayed neurotoxicity affects up to 47% of patients and is a serious problem that impacts cognitive function and quality of life7

Additional regimens, including targeted and immune-based therapies, have been studied in R/R PCNSL clinical trials as single agents or in combination2,6,8

BTKi sign icon

BTKis: Target the BCR pathway2

IMiDs sign icon

IMiDs: Targeted agents that use multiple mechanisms, including the BCR and PI3K/AKT pathways and inhibit the activity of NF-κB2

mAbs sign icon

mAbs: Those that have been studied in R/R PCNSL bind targets such as CD20 and PD-12,8

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In general, use of novel agents is recommended within the context of clinical trials6

No accepted standard of care

No therapy has been FDA-approved for
R/R PCNSL1,2

The management of patients with R/R PCNSL remains poorly defined and is a major area of unmet clinical need9
  • Although the treatment of PCNSL has evolved during the past few decades, there is no accepted standard of care in R/R PCNSL10
Many regimens have been studied; however, there are still no therapies that are FDA-approved for R/R PCNSL1,6
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 vary4,9:
  • 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 PCNSL6

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.

Obstacles to advancing 
R/R PCNSL treatment remain

Future Outlook

*Also a type of chemotherapy.

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

AKT=serine/threonine protein kinase; ASCT=autologous stem cell transplantation; BCR=B-cell receptor; BTKi=Bruton tyrosine kinase inhibitor; CD20=cluster of differentiation 20; CSF=cerebrospinal fluid; 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; NF-κB=nuclear factor-kappa B; PD-1=programmed death-1; PI3K=phosphoinositide 3-kinase; R/R PCNSL=relapsing or refractory primary central nervous system lymphoma; WBRT=whole brain radiation therapy.

References: 1. 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 2. 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 3. 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 4. 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 5. 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 6. 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 7. 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 8. 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 9. 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 10. 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 11. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Central Nervous System Cancers V.3.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed October 8, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org.