Treatment Options for Recurrent Primary CNS Lymphoma

Curr Treat Options Oncol. 2022 Nov;23(11):1548-1565. doi: 10.1007/s11864-022-01016-5. Epub 2022 Oct 7.


Primary CNS lymphoma (PCNSL) constitutes a rare extranodal variant of non-Hodgkin lymphoma (NHL) with an annual incidence of 0.45/100,000. Given the paucity of large prospective clinical trials, there is no consensus treatment for refractory or relapsed (r/r) PCNSL, and available strategies are largely based on retrospective analyses. Patient age, performance status, previously administered treatment, duration of response, and molecular characteristics guide selection of salvage therapy. Patients with a good performance status (KPS >70), particularly ≤65 years, and adequate organ function should be considered for salvage polychemotherapy. Based on its high overall response rate even in the relapsed setting, we choose high-dose (≥ 3.5g/m2) methotrexate (HD-MTX) based regimens, e.g., R-MPV (rituximab, HD-MTX, procarbazine, and vincristine), for remission re-induction as long as patients were sensitive to first line HD-MTX-based regimens, especially when duration of previous response was ≥ 1 year. Following successful remission induction, we choose myeloablative chemotherapy (e.g., thiotepa, busulfan, cyclophosphamide) and subsequent autologous stem cell transplant in curative intent whenever feasible. Alternatively, conventional chemotherapy regimens (for example, monthly HD-MTX) or low-dose whole-brain radiation therapy (WBRT) are selected for consolidation in non-transplant candidates in complete remission. In cases of HD-MTX refractory disease or contraindications, we use pemetrexed; temozolomide/rituximab; high-dose cytarabine; or whole brain radiation for remission induction. Clinical trial participation is considered as well. Emerging therapies for upfront or salvage therapy under ongoing investigation include bruton tyrosine kinase inhibition (e.g., ibrutinib), immunomodulatory drugs (e.g., lenalidomide), immune checkpoint inhibitors (ICI, e.g., nivolumab), and chimeric antigen receptor T (CAR-T) cell therapy.

Keywords: CAR-T cell therapy; Immunotherapy; Methotrexate; Non-Hodgkin lymphoma; Primary CNS lymphoma; Recurrence.

Publication types

  • Review

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Brain Neoplasms* / etiology
  • Busulfan / therapeutic use
  • Central Nervous System Neoplasms* / diagnosis
  • Central Nervous System Neoplasms* / etiology
  • Central Nervous System Neoplasms* / therapy
  • Cranial Irradiation
  • Cyclophosphamide / therapeutic use
  • Cytarabine / therapeutic use
  • Humans
  • Immune Checkpoint Inhibitors
  • Lenalidomide / therapeutic use
  • Lymphoma, Non-Hodgkin* / drug therapy
  • Lymphoma, Non-Hodgkin* / therapy
  • Methotrexate / therapeutic use
  • Nivolumab / therapeutic use
  • Pemetrexed / therapeutic use
  • Procarbazine / therapeutic use
  • Prospective Studies
  • Receptors, Chimeric Antigen*
  • Retrospective Studies
  • Rituximab / therapeutic use
  • Temozolomide / therapeutic use
  • Thiotepa / therapeutic use
  • Vincristine / therapeutic use


  • Thiotepa
  • Busulfan
  • Rituximab
  • Agammaglobulinaemia Tyrosine Kinase
  • Receptors, Chimeric Antigen
  • Methotrexate
  • Vincristine
  • Lenalidomide
  • Pemetrexed
  • Nivolumab
  • Temozolomide
  • Immune Checkpoint Inhibitors
  • Procarbazine
  • Cytarabine
  • Cyclophosphamide