J Hematol

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 000, Number 000, August 2025, pages 000-000

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

**Table 1.** Prospective Clinical Trials of Targeted Therapies: Endpoints
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.

Table 1. Prospective Clinical Trials of Targeted Therapies: Endpoints

Author

Date published

Agent

Phase

Subjects

Efficacy endpoints (evaluable patients)

Follow-up (median)

Survival outcomes (median)

BTKi

Grommes [38]

2017

Ibrutinib

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

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

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

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

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

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

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)

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

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.

**Table 2.** Prospective Clinical Trials of Targeted Therapies: Summary of Outcomes
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.

Table 2. Prospective Clinical Trials of Targeted Therapies: Summary of Outcomes

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.

**Table 3.** Ongoing Clinical Trials of Targeted Agents for PCNSL
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	Untreated^a 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 tesirine^b + 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

Table 3. Ongoing Clinical Trials of Targeted Agents for PCNSL

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

R/R PCNSL, R/R SCNSL

BTKi and BTKi-based combinations

Acalabrutinib

NCT04548648

R/R PCNSL, R/R SCNSL

Tirabrutinib

NCT04947319

112

R/R PCNSL

Zanabrutinib + rituximab + lenalidomide; zanabrutinib or lenalidomide maintenance

NCT04938297

100

Untreated^a and R/R PCNSL, R/R SCNSL

ICIs

Camrelizumab (anti-PD-1)

NCT04070040

R/R PCNSL

ICI + BTKi +/- anti-CD20

Sintilimab (anti-PD-1) + orelabrutinib

NCT04961515

1b/2

R/R PCNSL

Durvalumab + acalabrutinib + rituximab

NCT04688151

R/R PCNSL

Pembrolizumab + ibrutinib + rituximab

NCT04421560

1b/2

R/R PCNSL

IMiD-based combinations

Tafasitamab (Fc-modified anti-CD19 monoclonal antibody) + lenalidomide

NCT05351593

1/2

R/R PCNSL, R/R SCNSL

Poseltinib (BTKi)+ rituximab + lenalidomide

NCT06737250

R/R PCNSL

Anti-CD19 antibody drug conjugate (ADC)

Loncastuximab tesirine^b + rituximab

NCT06607549

R/R PCNSL, R/R SCNSL

IRAK4 inhibitor

Emavusertib

NCT03328078

1/2

152

R/R PCNSL

PI3K inhibitor

Paxalisib

NCT04906096

R/R PCNSL

BTK degrader

NX-2127

NCT04830137

248

R/R PCNSL