Chemotherapy-Free Salvage Therapy with Rituximab, Lenalidomide, and Poseltinib in Relapsed or Refractory Primary Central Nervous System Lymphoma: A Multi-center, Phase II Study

Dong Hyun Kim; Sanyeowool An; Hongyul Ahn; Han Song; Ka-Won Kang; Sang Eun Yoon; Seok Jin Kim; Hyo Jung Kim; Youngil Koh; Deok-Hwan Yang; Consortium for Improving Survival of Lymphoma (CISL)

doi:10.4143/crt.2025.977

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Original Article Chemotherapy-Free Salvage Therapy with Rituximab, Lenalidomide, and Poseltinib in Relapsed or Refractory Primary Central Nervous System Lymphoma: A Multi-center, Phase II Study: Dong Hyun Kim^1,2, Sanyeowool An³, Hongyul Ahn⁴, Han Song⁴, Ka-Won Kang⁵, Sang Eun Yoon⁶, Seok Jin Kim⁶, Hyo Jung Kim⁷, Youngil Koh^1,3,4, Deok-Hwan Yang⁸, Consortium for Improving Survival of Lymphoma (CISL); DOI: https://doi.org/10.4143/crt.2025.977
Published online: November 12, 2025

¹Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea

²Department of Translational Medicine, Seoul National University College of Medicine, Seoul, Korea

³Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea

⁴NOBO Medicine Inc, Seoul, Korea

⁵Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea

⁶Department of Medicine, Samsung Medical Center, Sungkyunkwan University College of Medicine, Seoul, Korea

⁷Department of Internal Medicine, Hallym University Sacred Heart Hospital, Anyang, Korea

⁸Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea

Correspondence: Sang Eun Yoon, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea
Tel: 82-2-3410-1210 E-mail: starload0326@gmail.com

Co-correspondence: Deok-Hwan Yang, Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, 322 Seoyang-ro, Hwasun 58128, Korea
Tel: 82-61-379-7636 E-mail drydh1685@hotmail.com

• Received: September 6, 2025 • Accepted: November 11, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract

Purpose
Relapsed or refractory (R/R) primary central nervous system lymphoma (PCNSL) is an aggressive malignancy for which salvage chemotherapy has limited efficacy. We conducted an investigator-initiated, single-arm, multicenter phase II trial to evaluate the efficacy and safety of a chemotherapy-free salvage regimen comprising rituximab, lenalidomide, and poseltinib (R2P) in patients with R/R PCNSL.
Materials and Methods
The R2P regimen consisted of two phases: six cycles of induction with rituximab, lenalidomide, and poseltinib, followed by three cycles of consolidation with lenalidomide and poseltinib. The primary endpoints were complete response rate (CRR) and overall response rate (ORR). Secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS).
Results
A total of 10 patients were enrolled (one withdrew before cycle 1; nine were evaluable for efficacy). The median age was 70 years (range, 53 to 75 years), and all had received methotrexate-based first-line chemotherapy. The ORR was 55.6%, and the CRR was 33.3%. The median PFS was 5.6 months, and the median OS was not reached. Next-generation sequencing was performed in four patients (three responders and one non-responder). CD79B missense mutations were identified in all three responders. A total of 11 adverse events (AEs) were observed in six patients. The most common AE was neutropenia (30.0%). The only grade ≥ 3 AE was a single case of grade 3 neutropenia. No dose modifications were required due to toxicity.
Conclusion
Poseltinib in combination with lenalidomide and rituximab showed activity in patients with R/R PCNSL, warranting further investigation in larger studies.
Key words: Primary central nervous system lymphoma, Relapsed or refractory, Poseltinib, Lenalidomide+Rituximab, Chemotherapy-free regimen, Clinical trial

Introduction

Primary central nervous system lymphoma (PCNSL) is a rare subtype of non-Hodgkin lymphoma characterized by its confinement to the central nervous system (CNS) and an unfavorable prognosis due to its aggressive progression [1,2]. The treatment of newly diagnosed PCNSL typically involves induction therapy with high-dose methotrexate-based combination chemotherapy, often including rituximab [3,4]. For consolidation therapy, autologous stem cell transplantation (ASCT) is considered for fit patients, while whole-brain radiotherapy or lenalidomide maintenance is employed for those who are not candidates for ASCT [5,6]. Salvage chemotherapy for relapsed or refractory (R/R) PCNSL is limited in efficacy, with various regimens showing generally poor outcomes [7,8]. Moreover, salvage chemotherapy is challenging due to the high risk of toxicities and mortality [9].

The B-cell receptor (BCR) signaling pathway, Toll-like pathway, and JAK/STAT pathway are associated with the pathogenesis of PCNSL [10]. Targeted therapies and immunomodulatory agents have been investigated in R/R PCNSL to inhibit these activated pathways. The combination of lenalidomide and rituximab has demonstrated significant activity in R/R PCNSL [11]. In addition, Bruton’s tyrosine kinase (BTK) inhibitors have shown favorable outcomes as monotherapy in R/R PCNSL [12,13].

Lenalidomide and BTK inhibitors, as chemotherapy-free regimens developed based on the pathogenesis of PCNSL, have demonstrated favorable efficacy and safety profiles in R/R PCNSL, suggesting the potential benefits of their combination therapy. Poseltinib is a potent and selective BTK-TEC dual inhibitor [14] and exhibits efficacy in R/R lymphoma [15]. To this end, we conducted a prospective phase II trial to evaluate the efficacy and safety of a chemotherapy-free salvage regimen comprising rituximab, lenalidomide, and poseltinib in patients with R/R PCNSL.

Materials and Methods

1. Participants and study design

This is an investigator-initiated, prospective, open-label, single-arm, multicenter phase II clinical trial started in December 2022 at four university-affiliated hospitals in South Korea (KCT0008105). Patients with a histopathological diagnosis of PCNSL were eligible. Eligible patients were aged 19-80 years and had confirmed disease progression or treatment resistance after remission induction therapy, radiotherapy, or ASCT; an Eastern Cooperative Oncology Group (ECOG) performance score of 0-2; adequate organ function; and measurable disease. Patients with newly diagnosed PCNSL, ocular lymphoma without brain lesions, or secondary CNS lymphoma were excluded. The complete eligibility criteria are outlined in the Supplementary Methods.

2. Treatment protocol

This regimen consists of a total of nine cycles, comprising two phases: six cycles of induction therapy (rituximab, lenalidomide, poseltinib; R2P) followed by three cycles of consolidation therapy (lenalidomide, poseltinib; RP), with each cycle lasting 28 days. Rituximab was administered at a dose of 375 mg/m² intravenously during the induction phase. It was given on days 1, 8, and 15 of cycle 1, and on day 1 of cycles 2 through 6. Lenalidomide (15 mg daily) and poseltinib (40 mg twice daily) were administered orally from day 1 to day 21 of each cycle for a total of nine cycles. Considering the favorable safety profile of this regimen observed in the safety cohort (n=6) of the present study and in previous phase I trial of poseltinib, the protocol was amended in February 2024 to increase the poseltinib dose to 60 mg twice daily. Dose modification for rituximab was not permitted, while dose adjustments for lenalidomide and poseltinib were performed based on the worst grade of toxicity, according to the approved protocol. All patients received neutropenia prophylaxis with pegteograstim (Neulapeg, GC Biopharma Corp.) at a dose of 6 mg in each treatment cycle. In addition, single-strength trimethoprim/sulfamethoxazole (TMP/SMZ) and acyclovir 200 mg twice daily were administered as prophylactic antimicrobial agents throughout the study treatment. The rationale for the dose selection of this regimen is outlined in the Supplementary Methods.

3. Outcomes

The primary endpoints were the complete response (CR) rate and the overall response rate (ORR), which is defined as the proportion of patients who achieved a CR or partial response (PR). The secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and toxicity. Response evaluation was performed according to the magnetic resonance imaging (MRI) response criteria [16], utilizing brain MRI. Baseline assessments were conducted, followed by evaluations after cycle 3, cycle 6, and within 4 weeks after the completion of treatment. Adverse events (AEs) were assessed according to the National Cancer Institute Common Terminology Criteria for AE v5.0. AEs were assessed up to 28 days after the last administration of the study drug.

4. Next-generation sequencing

Formalin-fixed paraffin-embedded tumor tissues from four patients were deeply sequenced with a next-generation sequencing (NGS). NGS was performed using SureSelect Cancer CGP assay (Agilent Technologies) after informed written consent was obtained from the patients. The procedures for NGS are detailed in Supplementary Methods.

5. Statistical analysis

This trial was designed with 80% power to reject the null hypothesis that the ORR is 35% or less, at a one-sided significance level of 0.05, assuming the true ORR to be 60% or higher. These hypotheses were based on the response rates of the R2 regimen (rituximab and lenalidomide) for R/R PCNSL previously reported in a phase II study [11]. Considering an expected dropout rate of 10%, a total of 29 patients were required.

Descriptive statistics are presented as median values with ranges or numbers with percentages. All efficacy and safety analyses were conducted on patients who completed cycle 1. The Clopper-Pearson method was used for calculating the 95% confidence interval (CI) for the response rate. Median follow-up duration was calculated by the reverse Kaplan-Meier method. PFS and OS were defined as the time from enrollment to progressive disease (PD) or death from any cause, and time from enrollment to death from any cause, respectively. Survival outcomes were estimated using the Kaplan-Meier method. The statistical software R ver. 4.4.2 (http://www.r-project.org) was used for all statistical analyses. p-values of < 0.05 were considered statistically significant.

Results

1. Patient and disease characteristics

Overall, 10 patients were enrolled in the study from April 2023 to May 2024; follow-up continued until June 2025. Enrollment was terminated before reaching the target number to facilitate a registrational trial of poseltinib with an optimized dosing regimen. The decision was made by NOBO Medicine, the company holding the development rights for poseltinib, based on clinical data from the present study and the glofitamab/poseltinib/lenalidomide study (NCT05335018), another investigator-initiated trial targeting R/R diffuse large B-cell lymphoma.

The baseline characteristics of the 10 patients are presented in Table 1. The median age was 70 years (range, 53 to 75 years), and four patients (40.0%) were male. Three patients had an ECOG performance status of 2. The median number of prior chemotherapy lines was 2 (range, 1 to 3). All patients received methotrexate-based chemotherapy as first-line treatment, and six were exposed to cytarabine. Seven patients had received prior radiotherapy, and one had undergone ASCT.

2. Efficacy outcomes

Overall, seven patients were able to complete the treatment protocol; three completed the induction phase (up to cycle 6), and one patient completed all nine cycles. Nine patients received poseltinib at a dose of 40 mg twice daily, while the last enrolled patient received 60 mg twice daily according to the amended protocol. Of the 10 patients enrolled, one who received poseltinib 40 mg twice daily withdrew consent prior to completing cycle 1 in the absence of disease progression and was subsequently lost to follow-up. Consequently, efficacy analyses were conducted on the remaining nine patients.

Based on the best response, three patients achieved a CR (33.3%), and two achieved a PR (22.2%), resulting in an ORR of 55.6% (95% CI, 21.2 to 86.3) (Table 2). Four patients were confirmed to have PD after cycle 3 and were therefore withdrawn from the trial after receiving treatment up to cycle 3. Among the two patients who achieved a PR after cycle 3, one withdrew consent after completing cycle 5 without evidence of PD, while the other developed PD after cycle 5. Among the three patients who achieved a CR after cycle 3, one maintained CR, completed treatment up to cycle 9, and remained in CR at the time of analysis. Another patient developed PD after cycle 6. The remaining patient discontinued treatment after cycle 7 due to withdrawal of consent but has continued follow-up and remains in CR. For responders, the median DoR was 3.5 months (95% CI, 2.0 to not reached) (Fig. 1A). Among patients who achieved a CR, the median DoR was not reached, whereas it was 2 months in those with a PR (S1 Fig.).

During a median follow-up of 20.1 months (95% CI, 8.4 to not reached), a total of six patients experienced PD, and three patients died due to disease progression. The median PFS was 5.6 months, with 6-month and 12-month PFS rates of 41.7% (95% CI, 18.5 to 94.0) and 27.8% (95% CI, 8.9 to 86.9), respectively (Fig. 1B). The median OS was not reached, with 6-month and 12-month OS rates of 76.2% (95% CI, 52.1 to 100.0) and 61.0% (95% CI, 34.1 to 100.0), respectively (Fig. 1C).

3. Safety outcomes

Safety analysis was conducted in all 10 patients who received at least one dose of study treatment. During treatment, a total of 11 treatment-emergent AEs were observed in six patients (Table 3). No AEs occurred in the patient who received poseltinib at a dose of 60 mg twice daily. The most common AE of all grade was neutropenia (4 events, 3/10), followed by urticaria (2 events, 1/10). The remaining AEs each occurred once in a single patient. The only AE of grade 3 or higher was a single case of grade 3 neutropenia observed in one patient. Among treatment-related AEs, neutropenia and anemia were considered possibly related to poseltinib, while urticaria was reported to be associated with lenalidomide and rituximab. No dose adjustments were required due to toxicity. One patient discontinued treatment during cycle 2 due to hemoptysis and pulmonary aspergillosis, which were assessed as possibly related to the study treatment; however, the patient recovered and was able to resume treatment. No patients withdrew from the trial due to AEs. No serious AEs were reported, and no treatment-related deaths occurred.

4. Genomic analysis

NGS using SureSelect Cancer CGP assay was conducted on the pre-treatment archival tissue samples in four out of the 10 patients (3 responders and 1 non-responder). Integrated genomic analysis of mutations is shown in Fig. 2 and S2 Table. The most frequently identified mutations were in PIM1 (4/4, 100%), followed by CD79B (3/4, 75%). Missense mutations in CD79B were identified in all three responders but were absent in the non-responder. The MYD88 L265P mutation was identified in two patients—one who achieved a best response of CR, and the other who exhibited PD.

Discussion

In this study, we evaluated the clinical outcomes of a cytotoxic chemotherapy-free regimen consisting of rituximab, lenalidomide, and poseltinib (R2P) in patients with R/R PCNSL, which included six cycles of an induction phase with all three agents followed by three cycles of a consolidation phase with lenalidomide and poseltinib. The ORR was 55.6%, with a CR rate of 33.3%. In addition, the toxicity profile was manageable, with no AEs requiring dose modifications or study withdrawal. The findings of this study suggest that poseltinib, in combination with rituximab and lenalidomide, may serve as an effective and safe treatment approach for patients with R/R PCNSL.

BTK is highly expressed in B-cells, where it serves as a key regulator of BCR-mediated activation and survival [17]. Poseltinib is a selective, potent BTK-TEC dual inhibitor that suppresses BCR signaling and cytokine production. Poseltinib inhibits BTK and other TEC kinases by over 80%, with more than twofold greater selectivity for BTK than other kinase inhibitors [14]. In the NGS finding of this study, all three responders harbored CD79B mutations. The CD79B mutation, located in the BCR, is known to enhance “chronic active” BCR signaling [17]. This mechanism provides a plausible biological basis for increased sensitivity to BTK inhibitor [18]. In addition, MYD88 mutations activates nuclear factor кB and often co-occur with CD79B mutations [19]. The coexistence of CD79B and MYD88 mutations indicates strong BCR pathway dependency, providing a mechanistic rationale for efficacy of BTK inhibitor in this setting. In our study, one patient who achieved a CR harbored both the CD79B mutation and MYD88 L265P, whereas the non-responder carried MYD88 L265P alone without CD79B mutation. These findings collectively align with prior studies and highlight the need to interpret CD79B and MYD88 alterations in an integrated manner rather than in isolation [20].

Salvage treatment options for patients with R/R PCNSL are limited and have not been well established [21]. Various salvage chemotherapy regimens have been attempted; however, most data are derived from investigator-initiated trials, with ORRs ranging from 14.3% to 63.6% (Table 4). Salvage cytotoxic chemotherapy has shown limited efficacy, with response rates ranging from 10% to 30% [22-24]. Even in patients who achieve response, a substantial proportion of older adults experience cognitive impairment [9]. Furthermore, in elderly patients, the incidence of both hematologic and non-hematologic toxicities is higher, limiting the available therapeutic options. Monotherapies with targeted agents or immunomodulatory drugs have also been investigated, with response rates ranging from 30% to 50% [8,25-27]. However, PFS was generally short, with a median of approximately 2 months. A phase II study by Ghesquieres et al. [11] reported that R2 achieved an ORR of 35.6% and a PFS of 7.8 months. Given the relative frequency of MYD88 mutations and other alterations affecting the BCR signaling pathway in PCNSL [28], targeted therapies against this pathway have been investigated. Temsirolimus, a mammalian target of rapamycin inhibitor, demonstrated an ORR of 54.1% [26]. Ibrutinib, a BTK inhibitor targeting upstream components of the BCR signaling pathway, showed an ORR of 51.9% as monotherapy in a phase II study [12]. Narita et al. [13] reported that tirabrutinib, a second-generation, potent, and irreversible BTK inhibitor, was active in R/R PCNSL, with an ORR of 63.6%. However, AEs occurred in 86.4% of patients, with grade ≥ 3 events reported in approximately half of the cohort. In this trial, R2P showed favorable outcomes, with an ORR of 55.6% and a median PFS of around 6 months. Although the median DoR was relatively short at 3.5 months, this likely reflects early treatment discontinuation in responding patients who withdrew consent while still achieving responses, rather than a loss of therapeutic efficacy. Although comparisons across studies on R/R PCNSL are challenging due to cohort heterogeneity and the lack of detailed information, the favorable antitumor activity observed in the present study supports further investigation of the BTK inhibitor+R2 regimen.

Based on this potency, poseltinib is currently being investigated in patients with R/R diffuse large B-cell lymphoma. In the interim analysis of a phase II trial evaluating the combination of glofitamab, lenalidomide, and poseltinib at a dose of 40 mg twice daily, no safety issues were observed in the safety cohort. An ORR of 89.3% and a CR rate of 42.9% were reported [15]. In the present study, no safety concerns were observed in the safety cohort, and phase I data showed more effective BTK inhibition at 60 mg twice daily (Supplementary Methods) [14]. Pharmacokinetic simulation also indicated that long-term administration of poseltinib 60 mg twice daily did not result in significant pharmacokinetic changes (data not shown). Accordingly, the last enrolled patient received an escalated dose of 60 mg twice daily without safety concerns. Considering these findings and the favorable CNS penetration profile of poseltinib [29], the 60 mg twice-daily regimen is expected to provide improved efficacy. Based on these results, a registrational trial (NCT06737250) is currently underway to evaluate the R2P regimen with poseltinib administered at 60 mg twice daily.

The toxicity observed with this chemotherapy-free regimen was minimal. AEs of any grade occurred in 60% of patients, with neutropenia being the most common AE (30%). Only one case of grade ≥ 3 neutropenia was reported, and no dose modifications were required. Prophylactic use of pegteograstim suggests that neutropenia associated with the R2P regimen can be adequately managed. The only treatment-discontinuing AE was associated with aspergillosis. The patient recovered and was able to resume treatment. The use of BTK inhibitors may affect both innate and adaptive immunity, potentially increasing the risk of fungal infections [12]. This risk may be further increased in patients with PCNSL who are receiving concomitant corticosteroid therapy. Therefore, in addition to the use of TMP/SMZ for Pneumocystis jirovecii pneumonia prophylaxis, continuous monitoring and appropriate management of infectious episodes are needed [30].

This study had several limitations, the primary one being the small sample size resulting from the trial’s early termination. However, given the aggressive nature of R/R PCNSL and the rapid deterioration in patients’ performance status, which often limits enrollment into clinical trials, the study retains its clinical and scientific significance despite the small sample size. Moreover, the observed ORR of 55.6% is compelling enough to justify a follow-up trial. Another limitation is the short follow-up duration. While the toxicity profile was assessed during the treatment period, further studies are needed to evaluate the long-term survival outcomes of this regimen. Lastly, this trial was conducted as a single-arm study, highlighting the need for large-scale comparative studies to validate our findings.

Despite these limitations, this is the first prospective trial of a combination therapy with BTK inhibitor, lenalidomide, and rituximab in R/R PCNSL. Given the demonstrated efficacy of both the R2 regimen and BTK inhibitors in R/R PCNSL, the combination of R2 with poseltinib—a novel and potent BTK-TEC dual inhibitor—represents a biologically rational, chemotherapy-free treatment approach based on the molecular pathogenesis of PCNSL. In addition, based on the favorable efficacy and safety profile observed in this trial, a registrational trial of the R2P regimen in R/R PCNSL is currently underway, using a dosage optimized to maximize the therapeutic potential of poseltinib.

In conclusion, our study demonstrated that the combination of a BTK inhibitor with the R2 regimen may serve as a promising treatment option for patients with R/R PCNSL. An ORR of 55.6% and a CR rate of 33.3% were observed. All AEs were manageable, demonstrating a favorable toxicity profile. The use of poseltinib can be a promising therapeutic approach for R/R PCNSL, and further studies with larger sample sizes are warranted to validate this combination.

Electronic Supplementary Material

Supplementary materials are available at Cancer Research and Treatment website (https://www.e-crt.org).

crt-2025-977_S1_Fig.pdf

crt-2025-977_S2_Table.pdf

crt-2025-977_Supplementary_Methods.pdf

NOTES

Ethical Statement

This trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines. The study protocol was approved by the Institutional Review Board of Chonnam National University Hwasun Hospital (IRB No: CNUHH-2022-170). Written informed consent was obtained from all patients prior to their participation.

Author Contributions

Conceived and designed the analysis: Kim DH, Yoon SE, Koh Y, Yang DH.

Collected the data: Kim DH, Ahn H.

Contributed data or analysis tools: An S, Song H, Kang KW, Yoon SE, Kim SJ, Kim HJ, Koh Y, Yang DH.

Performed the analysis: Kim DH, An S, Ahn H.

Wrote the paper: Kim DH, An S, Ahn H.

Reviewed and revised the manuscript: Kim DH, An S, Ahn H, Song H, Kang KW, Yoon SE, Kim SJ, Kim HJ, Koh Y, Yang DH.

Conflicts of Interest

YK holds share of NOBO Medicine.

Acknowledgments

We thank the participating patients and their families, all study coinvestigators, and research coordinators.

Funding

Lenalidomide and financial support were provided by Boryung Corp., rituximab and financial support by Celltrion, and poseltinib by Hanmi Pharmaceutical and NOBO Medicine. Pegteograstim was provided by GC Biopharma Corp. This study was an investigator-initiated trial conducted independently of the funder. The funder had no role in the study design, data collection, data analysis, or interpretation.

Fig. 1.

Kaplan-Meier curve of treatment outcomes. (A) Duration of response. (B) Progression-free survival. (C) Overall survival.

Fig. 2.

Integrated genomic profiling data (n=4; each column represents one patient). CR, complete response; PD, progressive disease; PR, partial response; SNV, single-nucleotide variant.

Table 1.

Baseline characteristics of study subjects

	Value (n=10)
Age (yr)	70 (53-75)
> 60	9 (90.0)
Sex
Male	4 (40.0)
Female	6 (60.0)
BMI (kg/m²)	24.0 (15.8-27.8)
ECOG performance-status score
0	0
1	7 (70.0)
2	3 (30.0)
LDH levels
Within reference range	7 (70.0)
Beyond reference range (elevated)	3 (30.0)
Deep brain involvement	2 (20.0)
IELSG score
0	0
1	4 (40.0)
2	4 (40.0)
3	2 (20.0)
4 or 5	0
No. of previous chemotherapy lines
1	2 (20.0)
2	7 (70.0)
3	1 (10.0)
Prior radiotherapy to brain	7 (70.0)
Prior autologous stem cell transplantation	1 (10.0)
Laboratory results at inclusion
Hemoglobin (g/dL)	12.3 (10.7-13.1)
Platelet (×10⁹/L)	247 (126-301)
White blood cell (×10⁹/L)	7.1 (2.7-9.6)
Absolute neutrophil count	4.56 (1.63-8.26)
Absolute lymphocyte count	1.00 (0.41-3.27)

Values are presented as median (range) or number (%). BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; IELSG, international extranodal lymphoma study group; LDH, lactate dehydrogenase.

Table 2.

Efficacy outcomes

	Value (n=9)
Best objective response, n (%)
CR	3 (33.3)
PR	2 (22.2)
SD	0
PD	4 (44.4)
Overall response rate (95% CI, %)	55.6 (21.2 to 86.3)
PFS (mo), median (95% CI)	5.6 (2.7 to not reached)
6-Month PFS rate (95% CI, %)	41.7 (18.5 to 94.0)
12-Month PFS rate (95% CI, %)	27.8 (8.9 to 86.9)
OS (mo), median (95% CI)	Not reached (11.8 to not reached)
6-Month OS rate (95% CI, %)	76.2 (52.1 to 100)
12-Month OS rate (95% CI, %)	61.0 (34.1 to 100)

CI, confidence interval; CR, complete response; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.

Table 3.

Safety outcomes

	Any	Grade ≥ 3	Treatment-related
Hematologic adverse events
Neutropenia	3 (30.0)	1 (10.0)	3 (30.0)
Anemia	1 (10.0)	0	1 (10.0)
Thrombocytopenia	0	0	0
Non-hematologic adverse events
Urticaria	1 (10.0)	0	1 (10.0)
Fatigue	1 (10.0)	0	0
Dizziness	1 (10.0)	0	0
Hemoptysis	1 (10.0)	0	0
Infection (pulmonary aspergillosis)	1 (10.0)	0	1 (10.0)

Values are presented as number (%).

Table 4.

Compendium of publications on treatment options for relapsed or refractory primary central nervous system lymphoma

Study	Regimen	Study design	No. of patients	Age (yr), median (range)	Response (%)	Median PFS (mo)	Median OS (mo)
Our study	Poseltinib+R2	Prospective, phase II	10	70 (53-75)	ORR 55.6 (CR 33.3, PR 22.2)	5.6	Not reached
Fischer et al. (2006) [22]	Topotecan	Prospective, phase II	27	51 (26-77)	ORR 33.3 (CR 18.5, PR 14.8)	2.0	8.4
Reni et al. (2007) [23]	Temozolomide	Prospective, phase II	36	60 (34-81)	ORR 30.6 (CR 25.0, PR 5.6)	2.8	3.9
Wong et al. (2012) [24]	Temozolomide	Retrospective	7	60 (41-75)	ORR 14.3 (CR 0, PR 14.3)	2.0	4.0
Batchelor et al. (2011) [25]	Rituximab	Prospective, pilot study	12	64 (31-81)	ORR 41.7 (CR 33.3, PR 8.3)	1.9	20.9
Nayak et al. (2013) [8]	Rituximab+temozolomide	Prospective, phase II	16	63 (42-79)	ORR 35.7 (CR 14.3, PR 21.4)	1.6	Not reached
Korfel et al. (2016) [26]	Temsirolimus	Prospective, phase II	37	70 (22-83)	ORR 54.1 (CR 21.6, PR 32.4)	2.1	3.7
Tun et al. (2018) [27]	Pomalidomide+dexamethasone	Prospective, phase I	25	≥ 60, 18 (7.2%)	ORR 48.0 (CR 32.0, PR 16.0)	5.3	-
Ghesquieres et al. (2019) [11]	R2	Prospective, phase II	45	69 (46-86)	ORR 35.6 (CR 28.9, PR 6.7)	7.8	17.7
Soussain et al. (2019) [12]	Ibrutinib	Prospective, phase II	52	67.5 (47-82)	ORR 51.9 (CR 19.2, PR 32.7)	4.8	19.2
Narita et al. (2021) [13]	Tirabrutinib	Prospective, phase I/II	44	60 (29-86)	ORR 63.6 (CR 34.1, PR 29.5)	2.9	Not reached

CR, complete response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; R2, lenalidomide+rituximab.

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Chemotherapy-Free Salvage Therapy with Rituximab, Lenalidomide, and Poseltinib in Relapsed or Refractory Primary Central Nervous System Lymphoma: A Multi-center, Phase II Study

DOI: https://doi.org/10.4143/crt.2025.977

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Abstract
Introduction
Materials and Methods
Results
Discussion
Electronic Supplementary Material
NOTES
REFERENCES

Nivolumab in Relapsed or Refractory Primary Central Nervous System Lymphoma: Multicenter, Retrospective Study

Chemotherapy-Free Salvage Therapy with Rituximab, Lenalidomide, and Poseltinib in Relapsed or Refractory Primary Central Nervous System Lymphoma: A Multi-center, Phase II Study

Fig. 1. Kaplan-Meier curve of treatment outcomes. (A) Duration of response. (B) Progression-free survival. (C) Overall survival.

Fig. 2. Integrated genomic profiling data (n=4; each column represents one patient). CR, complete response; PD, progressive disease; PR, partial response; SNV, single-nucleotide variant.

Fig. 1.

Fig. 2.

Chemotherapy-Free Salvage Therapy with Rituximab, Lenalidomide, and Poseltinib in Relapsed or Refractory Primary Central Nervous System Lymphoma: A Multi-center, Phase II Study

	Value (n=10)
Age (yr)	70 (53-75)
> 60	9 (90.0)
Sex
Male	4 (40.0)
Female	6 (60.0)
BMI (kg/m²)	24.0 (15.8-27.8)
ECOG performance-status score
0	0
1	7 (70.0)
2	3 (30.0)
LDH levels
Within reference range	7 (70.0)
Beyond reference range (elevated)	3 (30.0)
Deep brain involvement	2 (20.0)
IELSG score
0	0
1	4 (40.0)
2	4 (40.0)
3	2 (20.0)
4 or 5	0
No. of previous chemotherapy lines
1	2 (20.0)
2	7 (70.0)
3	1 (10.0)
Prior radiotherapy to brain	7 (70.0)
Prior autologous stem cell transplantation	1 (10.0)
Laboratory results at inclusion
Hemoglobin (g/dL)	12.3 (10.7-13.1)
Platelet (×10⁹/L)	247 (126-301)
White blood cell (×10⁹/L)	7.1 (2.7-9.6)
Absolute neutrophil count	4.56 (1.63-8.26)
Absolute lymphocyte count	1.00 (0.41-3.27)

	Value (n=9)
Best objective response, n (%)
CR	3 (33.3)
PR	2 (22.2)
SD	0
PD	4 (44.4)
Overall response rate (95% CI, %)	55.6 (21.2 to 86.3)
PFS (mo), median (95% CI)	5.6 (2.7 to not reached)
6-Month PFS rate (95% CI, %)	41.7 (18.5 to 94.0)
12-Month PFS rate (95% CI, %)	27.8 (8.9 to 86.9)
OS (mo), median (95% CI)	Not reached (11.8 to not reached)
6-Month OS rate (95% CI, %)	76.2 (52.1 to 100)
12-Month OS rate (95% CI, %)	61.0 (34.1 to 100)

	Any	Grade ≥ 3	Treatment-related
Hematologic adverse events
Neutropenia	3 (30.0)	1 (10.0)	3 (30.0)
Anemia	1 (10.0)	0	1 (10.0)
Thrombocytopenia	0	0	0
Non-hematologic adverse events
Urticaria	1 (10.0)	0	1 (10.0)
Fatigue	1 (10.0)	0	0
Dizziness	1 (10.0)	0	0
Hemoptysis	1 (10.0)	0	0
Infection (pulmonary aspergillosis)	1 (10.0)	0	1 (10.0)

Study	Regimen	Study design	No. of patients	Age (yr), median (range)	Response (%)	Median PFS (mo)	Median OS (mo)
Our study	Poseltinib+R2	Prospective, phase II	10	70 (53-75)	ORR 55.6 (CR 33.3, PR 22.2)	5.6	Not reached
Fischer et al. (2006) [22]	Topotecan	Prospective, phase II	27	51 (26-77)	ORR 33.3 (CR 18.5, PR 14.8)	2.0	8.4
Reni et al. (2007) [23]	Temozolomide	Prospective, phase II	36	60 (34-81)	ORR 30.6 (CR 25.0, PR 5.6)	2.8	3.9
Wong et al. (2012) [24]	Temozolomide	Retrospective	7	60 (41-75)	ORR 14.3 (CR 0, PR 14.3)	2.0	4.0
Batchelor et al. (2011) [25]	Rituximab	Prospective, pilot study	12	64 (31-81)	ORR 41.7 (CR 33.3, PR 8.3)	1.9	20.9
Nayak et al. (2013) [8]	Rituximab+temozolomide	Prospective, phase II	16	63 (42-79)	ORR 35.7 (CR 14.3, PR 21.4)	1.6	Not reached
Korfel et al. (2016) [26]	Temsirolimus	Prospective, phase II	37	70 (22-83)	ORR 54.1 (CR 21.6, PR 32.4)	2.1	3.7
Tun et al. (2018) [27]	Pomalidomide+dexamethasone	Prospective, phase I	25	≥ 60, 18 (7.2%)	ORR 48.0 (CR 32.0, PR 16.0)	5.3	-
Ghesquieres et al. (2019) [11]	R2	Prospective, phase II	45	69 (46-86)	ORR 35.6 (CR 28.9, PR 6.7)	7.8	17.7
Soussain et al. (2019) [12]	Ibrutinib	Prospective, phase II	52	67.5 (47-82)	ORR 51.9 (CR 19.2, PR 32.7)	4.8	19.2
Narita et al. (2021) [13]	Tirabrutinib	Prospective, phase I/II	44	60 (29-86)	ORR 63.6 (CR 34.1, PR 29.5)	2.9	Not reached

Table 1. Baseline characteristics of study subjects

Values are presented as median (range) or number (%). BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; IELSG, international extranodal lymphoma study group; LDH, lactate dehydrogenase.

Table 2. Efficacy outcomes

CI, confidence interval; CR, complete response; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.

Table 3. Safety outcomes

Values are presented as number (%).

Table 4. Compendium of publications on treatment options for relapsed or refractory primary central nervous system lymphoma

CR, complete response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; R2, lenalidomide+rituximab.