Primary CNS Lymphoma Collaborative Group Research Articles

CNS Radiotherapy As Bridging Prior to CAR T-Cell Therapy for Non-Hodgkin B-Cell Lymphoma

Introduction: Up to 80% of patients who receive CAR T-cell therapy (CAR T) for central nervous system lymphoma (CNSL) require bridging therapy, yet optimal regimens remain undefined. Radiotherapy is an established strategy for extracranial lymphoma that provides beneficial cytoreduction. However, CNS bridging radiotherapy (CNS-BRT) prior to CAR T is controversial due to concerns of potential enhanced neurotoxicity. We explored the safety and response profiles in patients treated with CNS-BRT prior to CAR T. Methods: We identified patients with non-hodgkin B-cell lymphoma who received CNS-BRT at our institution prior to commercial CAR T infusion. CNS-BRT was defined as treatment delivered between apheresis and CAR T infusion or within 30 days prior to apheresis, targeting the CNS parenchyma, leptomeninges, or epidural spine. Patients with epidural spine disease were included since the adjacent spinal cord is part of the treatment field. Safety was evaluated by rate of cytokine release syndrome (CRS) and immune effector associated neurotoxicity syndrome (ICANS) after CAR T. Best CNS response post CAR T was evaluated using the International Primary CNS Lymphoma Collaborative Group (IPCG) or Response Assessment in Neuro-Oncology (RANO) for parenchymal or leptomeningeal lesions, respectively. Cytoreduction from CNS-BRT was estimated by calculating the change in lesion size (sum of product diameter) from before and after CNS-BRT, but before CAR T infusion. Risk of any CNS relapse after CAR T was estimated using the Gray's method with death as a competing risk. Patients with epidural spine disease were not evaluate for CNS response or relapse. Results: 12 patients received CNS-BRT with median follow up of 8.5 months (range: 3.2 - 30.2), median age of 60 (30-76), median Karnofsky Performance Status (KPS) of 80 (range: 50 - 90). Histologies included diffuse large B cell (DLBCL) (n = 9), mantle cell (n = 2), and Burkitt lymphoma (n = 1), with disease localizing to the brain parenchyma (n = 6), leptomeninges (n = 4), and epidural spine (n = 2). 9 patients had secondary CNSL and 1 patient had primary CNSL. Prior to CNS-BRT, 11/12 patients had progressive disease. 5/12 patients had disease outside of the CNS. 5/12 patients received prior autologous hematopoietic stem cell transplantation. 9/12 patients received prior high dose methotrexate with median 46-day interval to CNS-BRT (range: 0 - 393). RT targets included whole brain (n = 3), involved site (partial) brain (n = 4), involved site spine (n = 4), and orbits (n = 1) with median dose 24 Gy (range: 15 - 33). CAR T products included Tisagenlecleucel (n = 4), Lisocabtagene maraleucel (n = 7), and Axicabtagene ciloleucel (n = 1). Among 10 patients with available toxicity grading, 6/10 experienced CRS (n = 1 grade (G) 1, n = 4 G2, and n = 1 G3), and 3/10 experienced ICANS (n = 1 G1, n = 1 G3, n = 1 G4). 6/10 patients required tocilizumab and/or steroids. CNS-BRT achieved a 74.4% (95% CI, 62.9 - 85.9) mean reduction in lesion size prior to CAR T infusion. Best CNS response after CAR T infusion included 3 complete responses (CR), 6 partial responses (PR), and 1 progressive disease (PD). The patients who achieved PR remained in PR at last follow up. The 12-month estimated risk of CNS progression after CNS-BRT and CAR T infusion was 20.0% (95% CI, 3- 49). CNS progression was not observed in patients who received involved site brain RT. Conclusion: Preliminary data suggest CNS-BRT achieves rapid cytoreduction prior to CAR T therapy and is associated with a favorable CNS response profile. While overall numbers are limited to date, the rate of severe CRS and ICANS is similar to that of historical series of CNSL patients treated with CAR T. However, a larger cohort will be required to determine the safety of CNS-BRT. These data support further study of RT, and exploration of involved site brain RT, as an effective bridging modality for CAR T-cell therapy in CNSL.

Radiotherapy As an Effective Bridge for Relapsed/Refractory Secondary CNS Lymphoma

Introduction: Secondary CNS lymphoma (SCNSL) is observed in 2-5% of patients with diffuse large B cell lymphoma (DLBCL). Progression of SCNSL after first line CNS-directed systemic therapy is particularly challenging to treat, without a clear standard of care. Brain radiotherapy (RT) is used for progressive SCNSL in either the chemo-refractory or palliative setting. Historically, the RT field included the whole brain due to concerns about diffuse intracranial involvement. However, treatment fields limited to just involved site(s) (partial brain RT) may provide a favorable balance of disease control and reduced treatment toxicity, particularly in an era of improved CNS-directed systemic therapies. We hypothesized that RT would confer a high rate of intracranial response among patients with chemo-refractory SCNSL. Methods: We identified DLBCL patients with SCNSL who received brain RT at our institution for radiographic or clinical progression after at least 1 line of SCNSL-directed therapy. SCNSL-directed therapy was defined as systemic therapy for active SCNSL (as opposed to prophylaxis). Overall survival (OS) was determined from RT start to death from any cause using the Kaplan-Meier method. OS comparing subsequent therapy was landmarked 2 months post RT to minimize immortal time bias. RT response was evaluated with contrast MRI or CT using International Primary CNS Lymphoma Collaborative Group (IPCG) or Response Assessment in Neuro-oncology (RANO) radiographic criteria for parenchymal or leptomeningeal disease (LMD), respectively. LMD was assessed by cytology and/or imaging. Results: Between 1999-2023, 55 patients received brain RT for progressive SCNSL with median follow up of 3.2 months. At the time of RT, median age was 64 (interquartile range (IQR) 49 - 71), median Karnofsky Performance Status was 70 (IQR, 60 - 80), and 85% had neurologic symptoms. Patients had received a median of 2 lines of SCNSL-directed therapy prior to RT (IQR, 1 - 3), 91% received a methotrexate-based regimen with median interval of 21 days (IQR, 10 - 67) between methotrexate and RT. Median RT dose was 30 Gy in 10 fractions delivered to whole brain (n = 44), partial brain (n = 9), or craniospinal axis (n = 2). 38 patients were evaluable for response; the remainder were lost to follow up/hospice (n = 8), lacked suitable imaging (n = 4), died with progressive neurologic symptoms (n = 4) or other cause (n = 1). The overall response rate was 79%, including a 24% complete response rate. Median time to best response was 60 days (IQR, 30 - 145). 32/55 patients (58%) were successfully bridged to subsequent systemic therapy (n = 22), hematopoietic stem cell transplantation (autologous n = 4, allogeneic n = 1), or CAR T (n = 5), after a median of 34 days from RT (IQR, 20 - 57). Median OS for the entire cohort was 3.5 months, and was improved for those who were bridged to subsequent therapy (no subsequent therapy 0.7 months, subsequent systemic therapy 4.0 months, subsequent cell therapy 8.9 months, p = 0.006). Among patients who received partial brain RT, 7/7 evaluable patients had at least a partial response and 7/9 patients were successfully bridged to subsequent therapy. Conclusion: Patients referred to RT for progressive SCNSL represent a high-risk cohort characterized by rapidly progressive, symptomatic, treatment-resistant disease. RT confers a high response rate in this chemo-resistant population, and can facilitate bridging to subsequent therapy. Preliminary data suggest that partial brain radiotherapy may be an effective bridging strategy among select patients, however a larger sample size will be required to determine this.

CNS radiotherapy as bridging prior to CAR T‐cell therapy for hematologic malignancies

Introduction: Up to 80% of patients who receive CAR T-cell therapy for central nervous system lymphoma (CNSL) require bridging therapy, yet optimal regimens remain undefined. Bridging radiotherapy (BRT) is an established strategy for extracranial lymphoma that provides beneficial cytoreduction. However, BRT for CNSL (CNS-BRT) is controversial due to concerns of potential enhanced neurotoxicity. We explored the safety and response profiles for CNS-BRT prior to CAR T therapy. Methods: We identified CAR T patients with hematologic malignancy at MSKCC who received CNS-BRT, defined as treatment delivered between cell collection and infusion to targets in CNS parenchyma, leptomeninges, or epidural space. Safety was evaluated by cytokine release syndrome (CRS), immune effector associated neurotoxicity syndrome (ICANS), and immune effector cell encephalopathy (ICE) scores, as documented by primary physician. Response was evaluated within the RT field for patients with baseline measurable disease using the International Primary CNS Lymphoma Collaborative Group (IPCG), Response Assessment in Neuro-Oncology (RANO), and Response Evaluation Criteria in Lymphoma (RECIL) radiographic criteria for parenchymal, leptomeningeal, and epidural lesions, respectively. Results: 11 patients received CNS-BRT with median follow up of 10.1 months (range: 1.1–25.9). At RT, median age was 51 (25–79), median KPS was 80 (50–90), and 9/11 patients had progressive CNS disease. 8/11 patients received prior methotrexate (high dose n = 7, intrathecal n = 1) with median 39-day interval to RT (0–179). Disease was localized to the brain parenchyma (n = 6), leptomeninges (n = 2), and epidural spine (n = 3). RT targets included whole brain (n = 3), involved site (partial) brain (n = 4), and involved site spine (n = 4), with median dose 24 Gy (20–30). Patient and CAR T cell characteristics are shown in Table 1. 4/10 patients experienced ICANS (n = 1 grade (G) 1, n = 1 G2, n = 1 G3, and n = 1 G4). 8/10 patients experienced CRS (n = 2 G1, n = 5 G2, and n = 1 G3). 6/11 patients required tocilizumab and/or steroids. Patients with G3/4 ICANS had decreased baseline ICE scores of 5 and 6, respectively. Median change in lesion size prior to CAR T infusion was -43.6% (-3.1% to -74.5%) among 7 evaluable patients. Best response included 6 partial responses (PR) and 4 complete responses (CR) at median 4.2 months (0.5–10.4). There were 3 CNS treatment failures, 1 in the leptomeninges and 2 in the paraspinal/epidural space. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cellular therapies, Radiation Therapy Conflicts of interests pertinent to the abstract. R. Shouval Other remuneration: Medexus Pharmaceuticals, Inc., MyBiotics P. B. Dahi Other remuneration: Curio Science LLC, Kite Pharmaceuticals, OncLive, Targeted Oncology R. J. Lin Consultant or advisory role: Kite, A Gilead Company M. L. Palomba Other remuneration: BeiGene, Ltd., Mustang Bio, Novartis, Synthekine, Inc. M. Perales Stock ownership: NexImmune, Omeros, Orca Biosystems, Inc. Other remuneration: ADC Therapeutics, Bristol-Myers Squibb, Cidara Therapeutics, Inc., CoImmune, Inc., Equillium, Inc., Incyte, Jazz Pharmaceuticals, Karyopharm, Kite Pharmaceuticals, Merck & Co Inc., Miltenyi Biotec Incorporated, MorphoSys AG, Novartis, Partners Therapeutics Inc., VectivBio AG, Vor Biopharma Inc. G. Salles Stock ownership: Owkin, Inc. Other remuneration: AbbVie, Aptitude Health, Bayer, BeiGene, Ltd., Bio Ascend, Bristol-Myers Squibb, Celgene, Epizyme, Everest Clinical Research Corporation, GenMab, Genentech, Gilead Pharmaceutical, Incyte, Ipsen, Janssen Pharmaceuticals, Inc., Loxo Oncology, Miltenyi Biotec Incorporated, MorphoSys AG, Nordic Nanovector ASA, Novartis, Physicians' Education Resource, RAPT Therapeutics, Regeneron Pharmaceuticals, Inc., Roche, Scientific Education Support Ltd., Takeda Millennium L. Falchi Consultant or advisory role: Genmab, Abbvie, Genentech, ADC therapeutics, Astrazeneca, Seagen, Roche Research funding: Genmab, Abbvie, Roche, Genentech Educational grants: Genmab C. Grommes Other remuneration: BTG International, Ono Pharma, Roche M. Scordo Consultant or advisory role: McKinsey & Company, Angiocrine Bioscience, Inc., Omeros Corporation, Kite – A Gilead Company Honoraria: i3Health, Medscape Research funding: Angiocrine Bioscience, Inc., and Omeros Corporation J. Yahalom Other remuneration: Convergent R.N.R Ltd. B. S. Imber Other remuneration: GT Medical Technologies, Inc.

CLRM-15 TRIAL IN PROGRESS: A PHASE 1B/2 STUDY OF GB5121, A NOVEL, HIGHLY SELECTIVE, POTENT, AND CNS-PENETRANT INHIBITOR OF BRUTON’S TYROSINE KINASE (BTKI) FOR RELAPSED/REFRACTORY PRIMARY/SECONDARY CNS LYMPHOMA (R/R PCNSL/SCNSL) AND PRIMARY VITREORETINAL LYMPHOMA (PVRL)

BTK plays an important role in B cell receptor and Toll-like receptor signaling pathways, which are constitutively active in primary CNS lymphomas, and hence represents an excellent therapeutic target. Ibrutinib, a first-generation BTKi, was evaluated in phase 1/2 trials for R/R PCNSL, SCNSL, and PVRL, showing limited survival benefit. GB5121 is a novel, orally available, covalent BTKi with superior specificity, CNS penetration, and CNS target occupancy in preclinical testing versus other BTKis including ibrutinib. GB5121 is well-suited for evaluation in CNS lymphoma. This is a phase 1b/2 open-label study of GB5121 in adults with R/R PCNSL, isolated SCNSL or PVRL and will be conducted in three parts: phase 1b dose-escalation, expansion, and phase 2. Eligibility criteria for phase 1b dose-escalation and expansion (N≈30 for each) include age ≥18 years, ECOG≤2, R/R PCNSL, R/R SCNSL with CNS-only relapse, or R/R PVRL. Patients with newly diagnosed PCNSL who cannot tolerate standard high-dose methotrexate-based therapies are also eligible. Patients with prior allogeneic stem cell transplant are excluded. A Bayesian optimal interval design will be employed to perform dose escalation to determine the recommended phase 2 dose (RP2D). In the absence of dose-limiting toxicity (DLT), dose levels will increase sequentially according to a modified Fibonacci approach. Safety, tolerability, PK/PD, DLT, maximum tolerated dose, and preliminary therapeutic activity will be assessed to determine the optimal biological dose informing the RP2D. Phase 1b expansion will further explore therapeutic activity and characterize safety and tolerability of GB5121 at the RP2D. Phase 2 will initiate following RP2D determination. This is a single-arm, open-label study to investigate GB5121 safety and efficacy in patients with R/R PCNSL. Adverse events will be graded per CTCAE v5.0. Clinical response will be determined using International Primary CNS Lymphoma Collaborative Group criteria. Progression-free and overall survival will be evaluated. Enrollment begins May 2022 (NCT05242146).

Consensus recommendations for MRI and PET imaging of primary central nervous system lymphoma: guideline statement from the International Primary CNS Lymphoma Collaborative Group (IPCG).

Advanced molecular and pathophysiologic characterization of primary central nervous system lymphoma (PCNSL) has revealed insights into promising targeted therapeutic approaches. Medical imaging plays a fundamental role in PCNSL diagnosis, staging, and response assessment. Institutional imaging variation and inconsistent clinical trial reporting diminishes the reliability and reproducibility of clinical response assessment. In this context, we aimed to: (1) critically review the use of advanced positron emission tomography (PET) and magnetic resonance imaging (MRI) in the setting of PCNSL; (2) provide results from an international survey of clinical sites describing the current practices for routine and advanced imaging, and (3) provide biologically based recommendations from the International PCNSL Collaborative Group (IPCG) on adaptation of standardized imaging practices. The IPCG provides PET and MRI consensus recommendations built upon previous recommendations for standardized brain tumor imaging protocols (BTIP) in primary and metastatic disease. A biologically integrated approach is provided to addresses the unique challenges associated with the imaging assessment of PCNSL. Detailed imaging parameters facilitate the adoption of these recommendations by researchers and clinicians. To enhance clinical feasibility, we have developed both “ideal” and “minimum standard” protocols at 3T and 1.5T MR systems that will facilitate widespread adoption.

A Radiomic Machine Learning Model to Predict Treatment Response to Methotrexate and Survival Outcomes in Primary Central Nervous System Lymphoma (PCNSL)

Introduction: Primary CNS lymphomas (PCNSL) are heterogeneous, aggressive, extra-nodal non-Hodgkin lymphomas limited to the neuraxis. Published response rates to high-dose methotrexate (MTX) based induction regimens for PCNSL range from 35-78%. However, >50% of patients relapse and have a median survival of 2 months without additional treatment. Our ability to prognosticate outcomes is limited to clinical models like the International Extranodal Lymphoma Study Group (IELSG) score and Memorial Sloan-Kettering Cancer Center (MSKCC) classifier. There is an urgent need to develop improved biologic and radiologic predictive models for PCNSL to facilitate therapeutic advances. We hypothesize that a machine learning model using advanced magnetic resonance imaging (MRI) tumor characteristics will improve the accuracy of clinical models to predict response to MTX and survival outcomes. Methods: Data from patients with PCNSL treated at UT Southwestern and Parkland Health and Hospital System hospitals from 2008-2020 (n=95) were collected. An analytical dataset of 61 patients was selected based on the availability of T1 postcontrast (T1c) and T2w FLAIR MR images. A subset of 47 patients was used to evaluate MTX treatment response. Expert neuroradiologists drew regions of interest (ROIs) on the multiparametric MR images including whole tumor (consisting of edema + enhancing tumor + necrosis), enhancing tumor and necrosis (Figure 1). Response to methotrexate-based induction was defined per the International Primary CNS Lymphoma Collaborative Group (IPCG) criteria. For overall- and progression-free survival (OS and PFS) analysis, short (≤1 year) and long-term (>1 year) survivor groups were defined. A support vector machine (SVM) network was used for predicting treatment response to MTX and for predicting the OS groups. A Multinomial Naive Bayes (MNB) network was used for predicting the PFS groups. PyRadiomics package was used to extract 106 texture-based features from the combination of each MR image and tumor ROI. A total of 642 features were extracted from the imaging parameters. Clinical features including age, race, performance status, MSKCC class, IELSG score, histology, delay from 1st MRI to start of treatment, induction and consolidation treatments used were included in the analysis. Feature reduction methodology based on the feature importance derived from the gradient boost model was applied to reduce the number of features. 17 features (imaging = 14, clinical = 3) were used for predicting OS/PFS and 7 features (imaging = 5, clinical = 2) were used for predicting treatment response to MTX. Networks utilizing only clinical features were analyzed for comparison. The sklearn package in python was used for the machine learning analysis. 5-Fold cross validation was performed to generalize the network performance. Results: Baseline wclinical characteristics of the study population is shown in Table 1. Table 2 lists the accuracy, F1 score, sensitivity, specificity, positive predictive value, negative predictive value and area under the curve (AUC) values averaged for the 5-fold cross validation. The SVM network achieved a mean testing accuracy of 81.1 ± 12.3% for predicting the treatment response to MTX-based induction. Sensitivity, specificity and AUC values were 90.5 ± 13.1%, 63.3 ± 22.1% and 0.81 ± 0.14 respectively. The SVM and the MNB network achieved mean testing accuracies of 80.3 ± 11.4% and 83.3 ± 11.8% for predicting the long and short survival groups in OS and PFS respectively. Sensitivity, specificity and AUC values for the SVM and MNB networks were 79.3 ± 6.5%, 80.5 ± 16.5% and 0.86 ± 0.12 and 85.3 ± 12.9%, 81.9 ± 11.8% and 0.86 ± 0.13 respectively. The accuracy values for predicting treatment response to MTX, OS and PFS using only the clinical features were 61.6 ± 9.2%, 59.1 ± 16.4% and 62.1 ± 17.5% respectively. Conclusion: This machine learning model boosted the accuracy (≥20%) over currently validated clinical models alone in predicting response to methotrexate-based therapies and survival outcomes in PCNSL. The current analysis is limited by the small sample size, and we plan to statistically test this model across a larger dataset and report results at the meeting. Our preliminary results suggest that machine learning based radiomic analysis may predict biologic aggressiveness in PCNSL and has the potential to be integrated in clinical predictive tools and design of clinical trials. Disclosures Awan: Blueprint medicines: Consultancy; Celgene: Consultancy; Sunesis: Consultancy; Karyopharm: Consultancy; MEI Pharma: Consultancy; Astrazeneca: Consultancy; Genentech: Consultancy; Dava Oncology: Consultancy; Kite Pharma: Consultancy; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy; Janssen: Consultancy; Abbvie: Consultancy. Desai:Boston Scientific: Consultancy, Other: Trial Finding.

Rituximab-Lenalidomide (REVRI) in Relapse or Refractory Primary Central Nervous System (PCNSL) or Vitreo Retinal Lymphoma (PVRL): Results of a "Proof of Concept" Phase II Study of the French LOC Network

BackgroundPrimary CNS lymphoma (PCNSL) is a diffuse large B-cell lymphoma (DLBCL), predominantly of non-germinal center (non-GC) subtype. Despite improvement of therapeutic results since the introduction of high-dose methotrexate (MTX) in first-line treatment, improvements of therapeutic results are needed in PCNSL, both in first-line treatment and at relapse. The roles of consolidation and maintenance therapy need to be addressed as well. The association of Rituximab and Lenalidomide has shown activity in non-CNS non-GC DLBCL, but its activity in PCNSL was unknown.MethodsIn this prospective, multicenter open-label phase II study, we enrolled patients over 18 with a refractory or relapse PCNSL or primary vitreo-retinal lymphoma (PVRL) of DLBCL type. The treatment consisted in an induction phase with 8 cycles of 28 days with R2 (Rituximab 375/m2 IV D1; Lenalidomide 20 mg/D D1-D21 for the first cycle then 25 mg/D D1-D21 for the subsequent cycle in the absence of hematologic toxicity), followed, in responder patients by a maintenance phase with 12 cycles of 28 days with Lenalidomide alone (10 mg/D, D1-D21). Corticosteroids were allowed during the first induction cycle in case of a threatening or symptomatic edema. Deep vein thrombosis prophylaxis was mandatory. Patient who received a complete month of treatment were evaluable for response. The primary end-point was the objective response rate (ORR) at the end of the induction phase, according to the international primary CNS lymphoma collaborative group (IPCG) criteria. The analysis was based of a Fleming's two-step design (P0 = 10 %; P1= 30%). A pilot exploration of circulating NK and T cells before and after treatment and correlation with therapeutic response was conducted. This study is registered with ClinicalTrials.gov, number NCT01956695ResultsBetween September 17, 2013 and September 29, 2015, fifty patients (median age: 69, range 46-86) were recruited from 10 centers. All the patients had previously received high-dose (HD) MTX. Median number of previous lines of chemotherapy was 2 (range, 1-4). Nine patients had previous received an HD chemotherapy followed by hematopoetic stem cell rescue. Initial diagnoses were PCNSL (n = 42) and PVRL (n = 8). At time of inclusion in the study, diagnoses were PCNSL (n = 41) and PVRL or isolated intra-ocular (IO) relapse of PCNSL (n=9). Seven patients had concomitant involvement of the cerebrospinal fluid (CSF). Patients were included either for a relapse after last treatment (80 %; median time to relapse = 5.5 months), or for a refractory disease (20 %). Thirty-four patients received concomitant corticosteroids during the first month of treatment. Forty-five patients were evaluable for response after the first cycle of treatment. Median number of induction cycles was 7 (range, 1-8). Grade 3 or 4 adverse events were reported in 11 patients (infection: n = 10, cutaneous rash: n =1). A second cancer (melanoma) occurred in one patient. Two patients withdrew their consent. During the induction phase, best observed responses were CR (n = 16), PR (n = 11), stable disease (n = 5) and progressive disease (n = 11) for an ORR of 63% (27/43). . At the end of the induction phase, 43 patients were evaluable for the primary objective. ORR was 39 % (17/43) including 13 CR (30%). A response has been observed in patients included for a PCNSL (n = 13, 32%) and for an IO relapse or PVRL (n = 4, 44%). Seventeen patients started the maintenance phase. With a median follow-up of 9 months (range, 1.1-15.4), median overall and progression-free survivals of the whole population were 15.3 months (95 % CI, 9.6 - non reached) and 8.1 months (95 % CI, 4.2 - non reached) respectively. Median duration of response in the responder patients was 8.9 months (95 % CI, 7.6- non reached). The results of the maintenance phase are pending. Results will be further updated.ConclusionThis phase II study demonstrates a significant activity of the rituximab-lenalidomide regimen in relapse or refractory PCNSL or PVRL. Updated results with a longer follow-up are awaited to better evaluate the PFS and the median duration of response. This regimen warrants to be added in the armamentarium drugs for PCNSL and further explored in combination with other chemotherapies in first-line treatment, as maintenance therapy, or as a chemo-free regimen for patients unfit for high-dose methotrexate.Funding: Celgne, Roche [Display omitted] DisclosuresGhesquieres:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche France: Research Funding; Mundipharma: Consultancy. Choquet:Celgene: Consultancy; Janssen: Consultancy. Morschhauser:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Janssen: Honoraria; Servier: Consultancy, Honoraria. Soussain:Roche: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding.

Ibrutinib Monotherapy in Relapse or Refractory Primary CNS Lymphoma (PCNSL) and Primary Vitreo-Retinal Lymphoma (PVRL). Result of the Interim Analysis of the iLOC Phase II Study from the Lysa and the French LOC Network

RATIONALPrimary CNS lymphoma (PCNSL) is a diffuse large B-cell lymphoma (DLBCL), predominantly of non-germinal center (non-GC) subtype, carrying a pejorative prognosis. Constitutive activation of the NF-kB pathway via mutations in B cell receptor (BCR) pathway (CD79B) and mutation of MYD 88 and TBL1XR1 plays an important role in PCNSL. Ibrutinib, an inhibitor of BCR signaling, has been found to have significant therapeutic activity in relapsed or refractory non-CNS non-GC DLBCL.METHODSIn this prospective, multicenter, open-label phase II, we enrolled immuno-competent patients over 18 with a refractory or relapse of PCNSL or primary vitreo-retinal lymphoma (PVRL) of DLBCL type. The treatment consisted in ibrutinib monotherapy given orally at 560 mg daily until disease progression or unacceptable toxicity. Additional corticosteroids treatment was allowed during the first 4 weeks of treatment in case of a threatening or symptomatic edema. Therapeutic responses were assessed according to the international primary CNS lymphoma collaborative group (IPCG) criteria. The primary objective of the study was the disease control (DC) rate (CR + CRu + PR + SD) after two months of treatment. This study is a two-stage Simon’s design. Patients were evaluable for response if they received > 90 % of the expected dose during the first month of treatment. An interim analysis for futility was planned when 18 patients were evaluable for response. P0 and P1 hypotheses were < 10 % and > 30 % respectively. A total of 35 evaluable patients are required for the final analysis. Exploratory ancillary studies are planned and consist in dosage of ibrutinib in the cerebrospinal fluid after one cycle of treatment, and correlation of therapeutic response with mutational status of the disease. This study is registered with ClinicalTrials.gov, number NCT02542514.RESULTSBetweenSeptember 25, 2015 and June 30, 2016, 52 patients were recruited in 10 French centers of the French LOC network for PCNSL. The interim analysis was done on the first 18 patients evaluable for response (median age: 70 y, range 49-80). At initial diagnosis, diagnoses were PCNSL (n = 12) and PVRL (n = 6). Patients were included in the study for a relapse (n = 13) or a progressive disease (n = 5). At time of inclusion in the study, disease status was PCNSL (n = 11) and PVRL or isolated intra-ocular relapse of a PCNSL (n = 7). ECOG performance status was 0, 1 and 2 in 4, 10 and 4 patients respectively. All the patients had previously received high-dose methotrexate-based chemotherapy. Four patients had previously received high-dose chemotherapy followed by autologous stem cell transplantation. Patients had received 1, 2 or 3 prior treatments in 12, 5 and 1 cases respectively. Three patients had a concomitant meningeal involvement. Five patients received concomitant corticosteroids during the first month of treatment. At the time of analysis (median follow-up = 6.6 months), nine patients discontinued ibrutinib after a median duration of 3 months (range, 0.9 -6.4) because of a disease progressive(n = 8) or a concurrent illness (n=1). Median number of treatment cycles was 5 (range, 1-9). One patient experienced a pulmonary aspergillosis with a favorable outcome. No hemorrhagic complication was reported. Five patients died due to disease progression (n = 4), and concurrent illness (n = 1). After two months of treatment, a DC was achieved in 15/18 patients (83 %, IC 95 %, [59-96%]) (complete and unconfirmed complete response: n =3; partial response: n = 7; stable disease: n =5).CONCLUSIONIn this interim analysis, Ibrutinib monotherapy demonstrated a high DC rate of 83%, including 56% objective responses in patients with relapse/refractory PCNSL or PVRL. Regarding safety, Ibrutinib might be a risk factor for aspergillosis in this population of PCNSL patients, otherwise not exposed to fungal infection. A security warning was sent to all the investigators for a close monitoring of infections. The second cohort of patients has been recruited. Thirty-three patients are currently on study treatment. The final analysis of the iLOC study is awaited to confirm these encouraging results and better define the positioning of ibrutinib in the therapeutic strategy of PCNSL and PVR patients. DisclosuresChoquet:Janssen: Consultancy; Celgene: Consultancy. Ghesquieres:Mundipharma: Consultancy; Roche France: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Soussain:Celgene: Research Funding; Roche: Research Funding; Pharmacyclics: Research Funding.

OS5.8 Intravascular lymphoma affecting the central nervous system: features and outcomes in a case series of the Primary CNS Lymphoma Collaborative Group (IPCG)

OS5.8 Intravascular lymphoma affecting the central nervous system: features and outcomes in a case series of the Primary CNS Lymphoma Collaborative Group (IPCG)

Primary leptomeningeal lymphoma

To evaluate clinical presentation, optimal diagnostic evaluation and treatment, and outcome in primary leptomeningeal lymphoma, a rare form of primary CNS lymphoma without parenchymal or systemic involvement. The International Primary CNS Lymphoma Collaborative Group, a multidisciplinary group of physicians with a particular interest in primary CNS lymphoma, retrospectively identified cases of lymphoma isolated to the leptomeninges as diagnosed by CSF cytology, flow cytometry, or biopsy, without systemic or parenchymal brain/spinal cord lymphoma or immunodeficiency. Forty-eight patients were identified, with median age at diagnosis of 51 years and median Eastern Cooperative Oncology Group performance status of 2. Presenting symptoms were multifocal in 68%. Leptomeningeal enhancement was seen in 74% and CSF profile was abnormal in all cases. CSF cytology detected malignant lymphocytes in 67%. Flow cytometry identified monoclonal population in 80%, as did receptor gene rearrangement studies in 71%. Sixty-two percent had B-cell lymphoma, 19% T-cell, and 19% unclassified. Treatment varied and included fractionated radiotherapy (36%), systemic chemotherapy (78%), and intra-CSF chemotherapy (66%), with 66% receiving ≥ 2 modalities. Seventy-one percent had a favorable clinical response; ultimately, 44% received salvage treatment. Median overall survival was 24 months, with 11 patients still alive at 50 months follow-up. Primary leptomeningeal lymphoma is a rare form of primary CNS lymphoma. Patients usually present with multifocal symptoms, with evidence of leptomeningeal enhancement and diagnostic CSF analysis. Although treatment is highly variable, patients have a better prognosis than previously reported and a subset may be cured.

Ten Years of International Primary CNS Lymphoma Collaborative Group Studies

Ten Years of International Primary CNS Lymphoma Collaborative Group Studies

A Multicentric Prospective Phase 2 Study of Intravenous Rituximab and Intrathecal Liposomal Cytarabine in Combination with C5R Protocol Followed by Brain Radiotherapy for Immunocompetent Patients with Primary CNS Lymphoma: A Lymphoma Study Association (LYSA) Trial

AbstractAbstract ▪796▪This icon denotes a clinically relevant abstract Background:The LNHCP93 trial is an intensive high-dose methotrexate and cytarabine containing chemotherapy (CT) derived from CT regimens used for Burkitt lymphomas (C5R protocol) followed by brain radiotherapy (RT) showing favourable long-term survival in Primary CNS Lymphoma (PCNSL) patients younger than 60 years: the complete response (CR) rate was 33%, the 5-year progression-free survival (PFS) and overall survival (OS) rates were 31% and 42%, respectively with however 9% of toxic death. Rituximab improves outcome of systemic Diffuse Large B-Cell Lymphoma (DLBCL) but it is unclear if its addition is useful in PCNSL with DLBCL histology. Intrathecal (IT) liposomal cytarabine (Depocyt) which shows a long-CSF half-life and better efficacy compared to IT methotrexate and free cytarabine in lymphomatous meningitis is also an attractive treatment for PCNSL. Methods:In order to improve antitumor activity of C5R protocol, we prospectively evaluated the addition of intravenous rituximab and IT liposomal cytarabine to CT before RT for 18 to 60 years old immunocompetent patients with PCNSL. The primary objective of this study is the complete and unconfirmed complete response rate (CR/CRu) after immuno-CT, according to International Primary CNS Lymphoma Collaborative Group response criteria. The number of patients was calculated in order to improve the 30% CR/CRu rate of LNHCP93 study up to 50%. The secondary objectives were side effect profile including acute and late neurological toxicities, PFS and OS. Patients received two courses of methotrexate, cyclophosphamide, doxorubicin, vincristine, prednisone (COPADEM) followed by two courses of methotrexate, cytarabine (CYM) administred at 21-day intervals from day 1 to day 21. At each day 1, intravenous rituximab 375mg/m2and at each day 3 IT liposomal cytarabine 50mg were infused. After immuno-CT, a brain RT was planned for all patients. A new response assessment was performed after RT. Patients were followed every 4 months for the first two years and then every 6 months. Neurotoxicity was evaluated by a Mini-Mental State Examination (MMSE) test. Results:Fifty-three PCNSL patients with a confirmed diagnosis of CD20 positive DLBCL were included between August 2007 and September 2011: median age was 55 years (range, 36–60), 57% were male, 42% had a performance status >1, 55% had an involvement of deep structures of brain, 45% a high CSF protein level and 36% a high LDH level. Median MMSE score assessed for 42 patients at baseline was 26 (range 3–30). After immuno-CT, 22 patients achieved a CR and 13 a CRu (CR + CRu, 66%), 7 a partial response (13%), 6 had a stable or progressive disease (11%) and 5 (10%) were not evaluated due to early death (n=2) or toxicities (n=3). For 45 patients who completed the fourth cycles, CR/CRu rate was 75.6%. Thirty-one patients (58%) presented at least one serious adverse event, mainly infections (25 patients, 47%). At least one red blood cell and platelet transfusions were given in 94% and 68% of patients, respectively and 57% of patients experienced a febrile neutropenia. Forty-two patients (79%) underwent RT, 23 of them with a reduced whole brain RT (median 26 Gy) and a boost to the tumor bed. With a median follow-up of 22 months, 15 patients progressed or relapsed (28.3%) and 13 patients died (24.5%), 3 (5.7%) of them from acute toxicity. The 2-year PFS and OS rates are 67% (95%CI, 50.0% to 79.4%) and 82% (95%CI, 67.0% to 90.7%), respectively. Median MMSE score was 27 (range, 26–30) for the 7 patients evaluated between 12 and 18 months after the beginning of treatment. Conclusions:With the addition of intravenous rituximab and intrathecal liposomal cytarabine, C5R protocol provided higher CR/CRu rate and promising outcome results with a 2-year PFS of 67% as compared to historical controls. No additional severe toxicities were observed compared to C5R protocol and with short follow-up no neurocognitive decline was observed. Disclosures:Off Label Use: Depocyt (intrathecal liposomal cytarabine) is off-label used in first line therapy of Primary CNS Lymphoma but approval for treatment of lymphomatous meningitis. Morschhauser:Roche: Honoraria. Blay:Roche: Honoraria, Research Funding.

FDG-PET Is An Independent Predictor for Survival in Primary Central Nervous System Lymphoma

Abstract▪2687▪This icon denotes a clinically relevant abstract Background:Primary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin lymphoma confined to the CNS compartment at presentation. Treatment strategies mainly comprise high-dose methotrexate (HD-MTX) based protocols. The value of [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) for the evaluation of PCNSL has only sparsely been investigated so far. Aim of this retrospective study was to investigate the prognostic value of pretreatment FDG-PET in PCNSL patients regarding tumor response and patient survival. Patients and Methods:Immunocompetent patients with biopsy proven PCNSL who received an FDG-PET before start of treatment were included. All patients had contrast-enhanced brain magnet resonance imaging scans for baseline and tumour response evaluation as recommended by the International Primary CNS Lymphoma Collaborative Group (Abrey et al. 2005). PET examinations were carried out using a Siemens ECAT EXACT 922/47 scanner after iv-injection of 366+55 MBq FDG. Tumor mean and maximum standardized uptake values (SUV) were assessed by volume of interest (VOI) analyses employing an automatic isocontour definition (80% of VOI maximum; PMOD software, PMOD Technologies Ltd.). In addition, a visual grading system was used to linearly grade tumor uptake by means of a simple, custom-made 6-step colour-scale: The maximum threshold of this colour-scale was individually adjusted to display physiological cerebellar uptake (reference region) as white (range 10%-20% of maximum; grade 1). FDG uptake below cerebellar uptake is colour-coded as black (<10% of maximum; grade 0), whereas FDG uptake above cerebellar uptake was colour-coded in four discrete steps (20–40%, 40–60%, 60–80% and >80% of maximum, grade 2–5). We used the chi-square test for contingency table tests, the log-rank test to compare survival probabilities, and multivariable Cox regression models to investigate the prognostic impact of pretreatment tumor grades on overall and progression free survival (OS and PFS). Results:42 immunocompetent patients (23/19 female/male, median age 65 [range 38–83]) were included. All patients were treated according to HD-MTX based protocols. Median maximum SUV of the lymphomas was 10.48 (range 3.1–22.8). Distribution of patients according to FDG uptake: grade 1 N=13 (31%); grade 2 N=17 (40.5%); grade 3 N=8 (19%); grade 4 N=3 (7.1%); grade 5 N=1 (2.4%). 90% of patients responded to therapy; distribution of response according to FDG uptake: grade 1 31%, grade 2 33%; grade 3 19%; grade 4 7.1% and grade 5 0%. Overall, response was inversely associated with FDG uptake (p=0.012). Median OS and PFS of the entire cohort were 59 and 22.5 months, respectively. Patients with FDG uptake grade ≥3 had a significantly shorter OS and PFS (median both 11 months) compared to patients with lower FDG uptake (median OS and PFS not reached; p= 0.0441 and p=0.0219, respectively). After adjustment for age and performance status, FDG uptake was still independently associated with decreased OS (Hazard ratio [HR] 1.77, p=0.028) and PFS (HR 1.83, p=0.016). Conclusions:The present study demonstrates that higher pretreatment PCNSL glucose metabolism is inversely correlated with treatment response and, thus, represents an independent negative outcome predictor with respect to OS and PFS. Disclosures:No relevant conflicts of interest to declare.

Primary CNS Lymphoma in Children and Adolescents: A Descriptive Analysis from the International Primary CNS Lymphoma Collaborative Group (IPCG)

To describe the demographic and clinical features and outcomes for children and adolescents with primary CNS lymphoma (PCNSL). A retrospective series of children and adolescents with PCNSL was assembled from 10 cancer centers in 3 countries. Twenty-nine patients with a median age of 14 years were identified. Sixteen (55%) had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or greater. Frontline therapy consisted of chemotherapy only in 20 patients (69%), while 9 (31%) had chemotherapy plus cranial radiotherapy. Most patients received methotrexate (MTX)-based regimens. Overall response rate was 86% (complete remission 69%, partial remission 17%). The 2-year progression-free survival (PFS) and overall survival (OS) rates were 61% and 86%, respectively; the 3-year OS was 82%. Univariate analyses were conducted for age (≤ 14 vs. >14 years), PS (0 or 1 vs. >1), deep brain lesions, MTX dose, primary treatment with chemotherapy alone, intrathecal chemotherapy, and high-dose therapy. Primary treatment with chemotherapy alone was associated with better overall response rates with an odds ratio (OR) of 0.125 (P = 0.02). There was a marginally significant relationship between higher doses of MTX and response (OR = 1.5, P = 0.06). ECOG-PS of 0 to 1 was the only factor associated with better outcome with hazard ratios of 0.136 (P = 0.017) and 0.073 (P = 0.033) for PFS and OS, respectively. This is the largest series collected of pediatric PCNSL. The outcome of children and adolescents seems to be better than in adults. PS of 0 to 1 is associated with better survival.

Neurolymphomatosis: an International Primary CNS Lymphoma Collaborative Group report

AbstractNeurolymphomatosis (NL) is a rare clinical entity. The International Primary CNS Lymphoma Collaborative Group retrospectively analyzed 50 patients assembled from 12 centers in 5 countries over a 16-year period. NL was related to non-Hodgkin lymphoma in 90% and to acute leukemia in 10%. It occurred as the initial manifestation of malignancy in 26% of cases. The affected neural structures included peripheral nerves (60%), spinal nerve roots (48%), cranial nerves (46%), and plexus (40%) with multiple site involvement in 58%. Imaging studies often suggested the diagnosis with 77% positive magnetic resonance imaging, and 84% (16 of 19) positive computed tomography-positron emission tomography studies. Cerebrospinal fluid cytology was positive in 40%, and nerve biopsy confirmed the diagnosis in 23 of 26 (88%). Treatment in 47 patients included systemic chemotherapy (70%), intra-cerebrospinal fluid chemotherapy (49%), and radiotherapy (34%). Response to treatment was observed in 46%. The median overall survival was 10 months, with 12- and 36-month survival proportions of 46% and 24%, respectively. NL is a challenging diagnosis, but contemporary imaging techniques frequently detect the relevant neural invasion. An aggressive multimodality therapy can prevent neurologic deterioration and is associated with a prolonged survival in a subset of patients.

Isolated Brain Parenchyma Relapse of Non-Hodgkin's Lymphoma (NHL): A Descriptive Analysis from the International Primary CNS Lymphoma Collaborative Group (IPCG).

Background: Isolated brain parenchyma relapse as initial site of relapse is a rare complication of NHL and carries a poor prognosis. Few large series focus on treatment characteristics and outcomes of isolated brain parenchyma relapse of NHL.Methods: The IPCG conducted a retrospective review of patient and treatment characteristics and outcomes of this complication. Following initial diagnosis and treatment of NHL (1980–2004), cases with brain parenchyma relapse as initial relapse site, with no evidence of lymphoma elsewhere in the body at the time of brain relapse, were eligible. Cases with brain, spine or leptomeningeal involvement at NHL diagnosis were not eligible.Results: 113 cases were assembled from 13 investigators in 8 countries. Preliminary data summaries are: 94 (83%) cases had diffuse large B-cell NHL, 5 (4%) follicular lymphoma, 3 (3%) Burkitt's lymphoma, other NHL subtypes (11) . Median age at NHL diagnosis was 61yrs (16–85 yrs). 55% were male. Median ECOG at NHL diagnosis was 1. Median time from NHL diagnosis to isolated brain relapse was 1.8 yrs (3 months–15.9 yrs). 76 (67%) relapsed in brain less than 3 yrs after NHL diagnosis. Symptoms at brain relapse included mental status changes in 37%, gait/balance disturbance (27%), motor/sensory symptoms (23%). Median ECOG at brain relapse was 2. Parenchyma relapse was documented by brain imaging plus biopsy in 54 (48%), or imaging without biopsy in 58 (52%); not reported (1). 53 (48%) cases had one brain lesion; 56 (50%) had two or more lesions; not reported (4). Site of relapse was cerebral hemispheres in 53 (48%) cases, deep brain structures (brain stem/cerebellum) in 30 (27%), cerebral hemispheres and deep brain structures in 23 (21%); not reported (7). At brain relapse, CSF was positive in 11 (10%) cases, negative in 56 (50%); not reported (46[40%]). Treatment for brain relapse was chemotherapy alone in 52 (46%) cases, WBRT alone in 34 (30%), chemotherapy followed by RT in 26 (23%), and brain surgery alone (1). 78 (69%) cases are deceased. Median survival from brain parenchyma relapse to death was 1.6 yrs (95% CI: 11 months–2.6 yrs). Effect of treatment type at brain relapse on survival, will be reported. Brain lymphoma was the cause of death in 49 (63%) cases; CNS toxicity was the cause in 6 (8%) cases.Conclusion: Though a rare relapse site, prospective studies are needed to improve understanding and outcomes of isolated brain parenchyma relapse of NHL.

Primary intraocular lymphoma (PIOL): An International Primary CNS Lymphoma Collaborative group report

1534 Background: PIOL is a hemopoietic tumor that arises in the retina, vitreous or optic nerve head, and carries a high risk of ocular and CNS relapse. The natural history and optimal management are unknown. Methods: A retrospective series of 81 patients with PIOL was assembled from 15 centers in 7 countries. Only patients with isolated ocular lymphoma were included; none had brain, spinal cord, or systemic lymphoma at diagnosis. Results: The median age at diagnosis was 65 (24–85). 58% were women. The median ECOG performance status was 0, and only three had a score &gt; 1. The median latency from symptom onset to diagnosis was 6 months (0– 36). Slit lamp exam was positive in 51, negative in 6, and not reported in 24. Vitrectomy was positive in 72 and negative in 2. 6 had a positive choroidal or retinal biopsy and 1 had no ocular surgery. CSF cytology was positive in 10 (17%), negative in 48, and unknown in 23. 21 received local therapy at diagnosis: 6 intra-ocular methotrexate (400 ug), 14 ocular radiation (median 3600 cGy), and 1 both modalities. 52 received more extensive therapy including systemic chemotherapy alone in 20 and a combination of chemotherapy and radiotherapy in 32. 5 received no treatment and details are unknown in 3. 47 patients (58%) relapsed a median of 19 months (0.5–180) after initial therapy. Sites of relapse included brain 47%, eyes 30%, brain and eyes 15%, and systemic 8%. Patients treated with ocular therapy alone did not have an increased risk of failing in the brain (p = 0.6). Progression free survival (PFS) and overall survival (OS) were 29.6 and 57 months respectively and were unaffected by the choice of therapy. CNS disease was the cause of death in 19/33 (58%). Conclusions: In this series, treatment type did not affect sites of relapse, PFS or OS in patients with PIOL. To minimize toxicity, the best initial therapy should be limited to intraocular chemotherapy or focal radiotherapy. Prospective clinical trials are needed to improve our understanding and treatment of this disease. No significant financial relationships to disclose.

Primary CNS Lymphoma of T-Cell Origin: A Descriptive Analysis From the International Primary CNS Lymphoma Collaborative Group

To describe the demographic and tumor related characteristics and outcomes for patients with primary T-cell CNS lymphoma (TPCNSL). A retrospective series of patients with TPCNSL was compiled from twelve cancer centers in seven countries. We identified 45 patients with a median age of 60 years (range, 3 to 84 years). Twenty (44%) had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Twenty-six (58%) had involvement of a cerebral hemisphere and sixteen (36%) had lesions of deeper sites in the brain. Serum lactate dehydrogenase was elevated in 7 (32%) of 22 patients, and CSF protein was elevated in 19 of 24 patients (79%) with available data. The median disease-specific survival (DSS) was 25 months (95% CI, 11 to 38 months). The 2- and 5-year DSS were 51% (95% CI, 35% to 66%) and 17% (95% CI, 6% to 34%), respectively. Univariate and multivariate analyses were conducted for age (</= 60 v > 60 years), PS (0 or 1 v 2, 3, or 4), involvement of deep structures of the CNS (no v yes), and methotrexate (MTX) use in the primary treatment (yes v no). Only PS and MTX use were significantly associated with better outcome with hazard ratios of 0.2 (95% CI, 0.1 to 0.4) and 0.4 (95% CI, 0.2 to 0.8), respectively. This is the largest series ever assembled of TPCNSL. The presentation and outcome appear similar to that of B cell PCNSL. PS 0 or 1 and administration of MTX are associated with better survival.