| Journal of Hematology, ISSN 1927-1212 print, 1927-1220 online, Open Access |
| Article copyright, the authors; Journal compilation copyright, J Hematol and Elmer Press Inc |
| Journal website https://jh.elmerpub.com |
Review
Volume 14, Number 5, October 2025, pages 241-252
Novel Agents and Immunotherapies for Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System: Innovating for Impact in a Disease With Unmet Needs
Tables
| Author | Date published | Agent | Phase | Subjects | Efficacy endpoints (evaluable patients) | Follow-up (median) | Survival outcomes (median) |
|---|---|---|---|---|---|---|---|
| BTKi | |||||||
| Grommes [38] | 2017 | Ibrutinib | 1 | 13 | ORR: 10/12 (83%); CR: 5/12 (42%); PR: 5/12 (42%) |
15.7 months | PFS: 4.6 months; OS: 15 months |
| Soussain [39] | 2019 | Ibrutinib | 2 | 52 | Intention-to-treat analysis: ORR: 27/44 (61%); CR/CRu:10/44 (22.7%); PR: 17/44 (38.6%) |
25.7 months | PFS: 4.8 months; OS: 19.2 months |
| Narita [40] | 2021 | Tirabrutinib | 1/2 | 44 | ORR: 28/44 (64%); 320mg: ORR: 12/20 (60.0%), 5 CR/CRu 480mg: ORR: 7/7 (100%), 4 CR/CRu 480, fasting: ORR 9/17 (53%), 6 CR/CRu |
9.1 months | PFS: 2.9 months 320mg: 2.1 months 480mg: 11.1 months 480mg, fasting: 5.8 months OS: not reached |
| Lionakis [37] | 2017 | Ibrutinib 14-day window, followed by TEDDi-R | 1b | Ibrutinib window: 18; TEDDi-R: 16 | Ibrutinib window: PR: 15/18 (83%) TEDDi-R: CR/CRu: 12/14 (86%); PR: 1/14 (7%) |
15.5 months | PFS: 15.3 months; OS: not reached |
| IMiDs | |||||||
| Tun [41] | 2018 | Pomalidomide + dexamethasone | 1 | 29 | ORR: 12/25 (48%); CR/CRu: 8/25 (32%); PR: 4/25 (16%) |
16.5 months | PFS: 5.3 months (whole study); 9 months (responders) |
| Ghesquieres [42] | 2019 | Lenalidomide + rituximab | 2 | 50 | ORR: 16/45 (36%); CR/CRu: 13/45 (29%); PR: 3/45 (7%) |
19.2 months | PFS: 7.8 months; OS: 17.7 months |
| ICIs | |||||||
| NCT02857426 (clinicaltrials.gov) | 2023 | Nivolumab | 2 | 47 (PCNSL cohort) | ORR: 6.4% (independent central review); ORR: 10.6% (investigator) | Followed up to 51 months | PFS: 1.41 months; OS: 6.8 months |
| Zhang [43] | 2022 | Orelabrutinib + sintilimab (anti-PD-1 monoclonal antibody) | 2 | 13 | ORR: 8/13 (62%); CR/CRu: 5/13 (38%); PR: 3/13 (23%) |
7 months | Median 1-year PFS: 67.7% |
| Anti-CD19 CAR T-cell | |||||||
| Frigault [44] | 2022 | Tisagenlecleucel | 1/2 | 12 | ORR: 7/12 (58%); CR: 6/12 (50%); PR: 1/12 (8%) |
12.2 months | At data cutoff, 7/12 patients were alive and 3/12 did not experience disease progression. |
| Pharmacologic mechanism | Clinical trial | Primary outcome interpretation | Other significant findings |
|---|---|---|---|
| ASCT: autologous stem cell transplantation; BTK: Bruton’s tyrosine kinase; CAR: chimeric antigen receptor; CR: complete response; CRS: cytokine release syndrome; CSF: cerebrospinal fluid; DLBCL: diffuse large B-cell lymphoma; EFS: event-free survival; ICANS: immune effector cell-associated neurotoxicity syndrome; IMiDs: immunomodulatory drugs; MTD: maximum tolerated dose; ORR: overall response rate; PCNSL: primary central nervous system lymphoma; R/R: relapsed or refractory; WBRT: whole-brain radiotherapy. | |||
| Anti-CD20 | |||
| Rituximab, methotrexate, carmustine, etoposide, and prednisone (R-MBVP) vs. MBVP, followed by Ara-c and (in patients younger than 60 years) reduced-dose WBRT [36] | Phase 3; HOVON 105/ALLG NHL 24 | No significant improvement in OS, PFS or EFS with the addition of rituximab. | Neurocognitive function improved across both treatment arms. |
| Methotrexate, cytarabine vs methotrexate, cytarabine, rituximab vs methotrexate, cytarabine, rituximab, thiotepa (MATRix), followed by a second randomization to WBRT vs ASCT [28] | Phase 2; IELSG32 | The addition of rituximab and thiotepa to methotrexate-cytarabine combination therapy was associated with significantly improved response and survival rates, with a minor increase in hematological toxicity. | Absence of a study group exclusively receiving thiotepa complicates the ability to determine the individual contributions of rituximab and thiotepa to the positive outcomes observed in this trial. |
| BTK inhibitor-based therapy | |||
| Ibrutinib [38] | Phase 1 | Ibrutinib demonstrated the ability to penetrate the CSF and showed a trend
to higher CSF concentrations after 1 month of therapy. Ibrutinib monotherapy demonstrated significant clinical activity in patients with R/R PCNSL. |
Resistance was detected in tumors with mutations in CD79B and
CARD11 genes. Potential benefit was identified in combined inhibition of BTK and
PI3K/mTOR. Treatment was discontinued in one patient due to a fungal infection. The patient received corticosteroids for 17 weeks prior to trial enrollment. The patient succumbed to disease progression 77 days after the last ibrutinib dose. |
| Ibrutinib [39] | Phase 2 | Ibrutinib showed clinical activity in the brain, CSF, and the intraocular compartment. | Two patients experienced pulmonary aspergillosis, one with a fatal outcome. |
| Tirabrutinib [40] | Phase 1/2 | Tirabrutinib demonstrated clinical efficacy in patients with R/R PCNSL. | ORR was similar among patients harboring CARD11, MYD88, CD79B mutations,
and corresponding wild types. PFS was significantly longer in the 480mg group (11 months vs 2.9 months overall) but limited by a small cohort (N=7). One patient experienced bronchopulmonary aspergillosis. |
| Ibrutinib window, followed by DA-TEDDi-R [37] | Phase 1b | Ibrutinib monotherapy demonstrated significant tumor reductions in patients with R/R PCNSL; clinical activity was augmented when used as part of DA-TEDDi-R. | Invasive aspergillosis was diagnosed in seven patients. Two cases arose during ibrutinib monotherapy, both of which were fatal; five cases developed during the DA-TEDDi-R treatment, with one patient dying from progressive disease, who also exhibited pulmonary/CNS aspergillosis at the time of death. |
| IMiDs | |||
| Pomalidomide and dexamethasone [41] | Phase 1 | Pomalidomide/dexamethasone combination demonstrated clinical activity in
heavily pretreated patients with PCNSL. Responses extending beyond 6 months were seen, suggesting single-agent therapeutic activity of pomalidomide (as dexamethasone was discontinued after two cycles). |
Limited CNS pomalidomide pharmacokinetic data as the analysis was undertaken in one patient (treated at the 3 mg dose level; MTD of pomalidomide was 5 mg daily for 21 days). |
| Lenalidomide and rituximab (R2) [42] | Phase 2 | R2 has clinical effects in patients with R/R PCNSL and PVRL. Maximum response was achieved during the first four cycles, suggesting limited benefit to maintenance lenalidomide. | The dose of lenalidomide was reduced in 19 patients due to hematological toxicity. |
| Immunotherapy | |||
| Orelabrutinib and sintilimab (anti-PD1 mAb) [43] | Phase 2 | Orelabrutinib and sintilimab demonstrated clinical activity in patients with R/R PCNSL. | Although the study had a cohort of only 13 patients, of those who demonstrated clinical response, no relapses were observed. |
| Anti-CD19 CAR T-cell | |||
| Tisagenlecleucel [44] | Phase 1/2 | Tisagenlecleucel demonstrated an ORR of 58%, a CR rate of 50%, sustained remission in 42.9% of responders with a median time of follow-up of 12 months. | Grade 1 CRS was observed in 7/12 subjects; low-grade ICANS was observed in 5/12, and grade 3 ICANS in 1/12. |
| Agents | Clinical trials | Phase | Estimated enrollment | Lymphoma |
|---|---|---|---|---|
| a65 years or older, unable to tolerate frontline treatment. bAnti-CD19 antibody conjugated to the cytotoxic pyrrolobenzodiazepine dimer SG3199. BTKi: Bruton’s tyrosine kinase inhibitor; ICIs: immune checkpoint inhibitors; IMiDs: immunomodulatory drugs; PCNSL: primary central nervous system lymphoma; R/R: relapsed or refractory; SCNSL: secondary central nervous system lymphoma | ||||
| T-cell redirecting antibody | ||||
| CD3×CD19×4-1BB×PD-L1 | NCT05485753 | 1b/2 | 33 | R/R PCNSL, R/R SCNSL |
| BTKi and BTKi-based combinations | ||||
| Acalabrutinib | NCT04548648 | 2 | 16 | R/R PCNSL, R/R SCNSL |
| Tirabrutinib | NCT04947319 | 2 | 112 | R/R PCNSL |
| Zanabrutinib + rituximab + lenalidomide; zanabrutinib or lenalidomide maintenance | NCT04938297 | 2 | 100 | Untreateda and R/R PCNSL, R/R SCNSL |
| ICIs | ||||
| Camrelizumab (anti-PD-1) | NCT04070040 | 2 | 21 | R/R PCNSL |
| ICI + BTKi +/- anti-CD20 | ||||
| Sintilimab (anti-PD-1) + orelabrutinib | NCT04961515 | 1b/2 | 48 | R/R PCNSL |
| Durvalumab + acalabrutinib + rituximab | NCT04688151 | 1 | 22 | R/R PCNSL |
| Pembrolizumab + ibrutinib + rituximab | NCT04421560 | 1b/2 | 37 | R/R PCNSL |
| IMiD-based combinations | ||||
| Tafasitamab (Fc-modified anti-CD19 monoclonal antibody) + lenalidomide | NCT05351593 | 1/2 | 35 | R/R PCNSL, R/R SCNSL |
| Poseltinib (BTKi)+ rituximab + lenalidomide | NCT06737250 | 2 | 33 | R/R PCNSL |
| Anti-CD19 antibody drug conjugate (ADC) | ||||
| Loncastuximab tesirineb + rituximab | NCT06607549 | 1 | 12 | R/R PCNSL, R/R SCNSL |
| IRAK4 inhibitor | ||||
| Emavusertib | NCT03328078 | 1/2 | 152 | R/R PCNSL |
| PI3K inhibitor | ||||
| Paxalisib | NCT04906096 | 2 | 25 | R/R PCNSL |
| BTK degrader | ||||
| NX-2127 | NCT04830137 | 1 | 248 | R/R PCNSL |