International 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.

Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in Secondary Central Nervous System Large B-Cell Lymphoma (SCNSL): A Multicenter Retrospective Analysis

Introduction Secondary central nervous system (CNS) involvement develops in 2-10% of large B-cell lymphoma (LBCL) cases. Current treatment approaches for relapsed or refractory CNS disease generally do not provide durable responses. Limited data suggest efficacy and feasibility of CAR-T therapy in SCNSL. We report here the largest multicenter retrospective analysis of the safety and efficacy of CD19-directed CAR-T therapy in SCNSL patients. Methods This study included SCNSL patients who received commercial CD19-directed CAR-T therapy at 9 academic institutions in the United States between 2016 and 2022. SCNSL was defined as history of parenchymal and/or leptomeningeal/cerebrospinal fluid (CSF) involvement by lymphoma at any time prior to receiving CAR-T therapy. Systemic response was assessed using the Lugano criteria while CNS response was assessed as per International PCNSL Collaborative Group criteria. Kaplan-Meier curves were generated for progression-free survival (PFS) and overall survival (OS) for entire cohort, as well as subsets of patients with and without active CNS disease at the time of CAR-T infusion. Results Ninety patients were included in the analysis, with baseline characteristics shown in Table 1. CAR-T products utilized include axicabtagene ciloleucel (n= 38, 42%), tisagenlecleucel (n=37, 41%) and lisocabtagene maraleucel (n= 15, 14%). Fludarabine/cyclophosphamide was used as lymphodepletion in 84 patients (93%). 28 patients received CNS directed radiation therapy (RT) prior to CAR-T infusion (31%) within a median time of 28.5 days (range 5 - 906) from last day of RT. Amongst all patients at the time of CAR-T infusion 82 (91.1%) had active CNS and/or systemic involvement while 8 (8.9%) had no evidence of disease; 68 (75.5%) had active CNS involvement while 22 (24.5%) had a prior history of CNS involvement but no active at the time of CAR-T infusion. ( Table 1) Median follow up all patients was 0.5 year (range 0.01 - 4.7). 71 patients (79%) developed cytokine release syndrome (CRS; median time to onset 3 days) with 3.3% patients developing Grade 3-4. Immune effector cell-associated neurotoxicity syndrome (ICANS; median time to onset 5 days) was reported in 55 patients (61%), with 28.8% developing Grade 3-4. No patients died due to CRS or ICANS. At 1-month post CAR-T, 80 patients were evaluable for CNS response and 71 patients in the entire cohort were evaluable for systemic response. Similarly, at 3-months these numbers were 66 and 60, respectively. Objective response rates (ORR) were 75% and 80% at 1-month for CNS and systemic disease respectively, while corresponding ORRs at 3-months were 68% and 76.7%. At 1- and 3-months timepoint 36 (45%) and 33 (50%) patients, respectively achieved CNS complete remission (CR), while 44 (62%) and 42 (70%) patients respectively achieved systemic CR. 1- and 2-year PFS for entire cohort were 25% (95%Cl 15% - 34%) and 16% (95%Cl 8.5% - 28%) respectively, while 1- and 2-year OS were 46% (95%Cl 36% - 59%) and 31% (95%Cl 22% - 46%). Non-relapse mortality (NRM) were 4.6% (95%CI, 1.8% -12%) and 7.2% (95%CI 2.9% - 18%) at 1- and 2-year. Cumulative incidence of relapse at 1- and 2-year were 73% (95%Cl 63% - 83%) and 77% (95%Cl 68% - 88%), respectively. ORRs for CNS response in patients with active CNS disease at 1-month and 3-month interval were 71% (n=45) and 60% (n=31). Similarly, ORR for systemic response with active CNS disease at 1-month and 3-month interval were 85% (n=43) and 74.3% (n=32).The 2-year PFS for patients with and without active CNS disease at CAR-T infusion were 12% (95%Cl 5.4% - 27%) and 28% (95%Cl 12% - 65%) respectively, with a corresponding OS of 25% (95%Cl 15% - 41%) and 58% (95%Cl 37% - 91%). ( Figure 1) The 2-year NRM rates for patients with and without active CNS disease at CAR-T infusion were 4.6% (95%Cl 1.5% - 14%) and 14% (95%Cl 3.6% - 53%) respectively, while the cumulative incidence of relapse in similar order were 83% (95%Cl 73% - 95%) and 58% (95%Cl 39% - 88%). Conclusion In this largest known case series to date, CAR-T therapy appeared safe and feasible in patients with SCNSL, but is associated with high rates of treatment failure, particularly in patients with active CNS disease at CAR-T infusion. This warrants further study of optimal CNS-directed treatment strategies prior to CAR-T, development of novel cellular therapy platforms or consideration of post CAR-T maintenance therapy in these high-risk patients.

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.

Impact on Tumour Treatment and Outcome of Sars-Cov-2 Infection in 91 Patients with Primary CNS Lymphoma: A Real-Life Study of the International PCNSL Collaborative Group

Impact on Tumour Treatment and Outcome of Sars-Cov-2 Infection in 91 Patients with Primary CNS Lymphoma: A Real-Life Study of the International PCNSL Collaborative Group

Impact of severe acute respiratory syndrome coronavirus-2 infection on the outcome of primary central nervous system lymphoma treatment: A study of the International PCNSL Collaborative Group.

SummaryTo optimise management of severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection identifying high‐risk patients and maintaining treatment dose intensity is an important issue in patients with aggressive lymphomas. In the present study, we report on the presentation, management, and outcome of an international series of 91 patients with primary central nervous system lymphoma and SARS‐CoV‐2 infection. SARS‐CoV‐2 was diagnosed before/during first‐line treatment in 64 patients, during follow‐up in 21, and during salvage therapy in six. Among the 64 patients infected before/during first‐line chemotherapy, 38 (59%) developed pneumonia and 26 (41%) did not clear the virus. Prolonged exposure to steroids before viral infection and/or treatment with high‐dose cytarabine favoured pneumonia development and virus persistence and were associated with poorer survival; 81% of patients who did not clear virus died early from coronavirus disease 2019 (COVID‐19). Vaccination was associated with lower pneumonia incidence and in‐hospital mortality. Chemotherapy was initiated/resumed in 43 (67%) patients, more commonly among patients who did not develop pneumonia, cleared the virus, or did not receive steroids during infection. Chemotherapy resumption in patients with viral persistence should be indicated cautiously as it was associated with a poorer survival (6‐month, 70% and 87%, p = 0.07). None of the 21 patients infected during follow‐up died from COVID‐19, requiring similar measures as infected subjects in the general population.

Tisagenlecleucel Demonstrates Safety, Efficacy and CNS Trafficking in Primary CNS Lymphoma

Tisagenlecleucel Demonstrates Safety, Efficacy and CNS Trafficking in Primary CNS Lymphoma

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.

ML-05 One-year follow-up data of phase I/II study of tirabrutinib in patients with relapsed or refractory primary central nervous system lymphoma

In March 2020, Tirabrutinib (TIR), a second-generation oral Bruton’s tyrosine kinase inhibitor, was approved for the indication of relapsed or refractory PCNSL (r/rPCNSL) based on the results of a phase I/II study in Japan. In this study, 44 Japanese patients with r/rPCNSL were treated with TIR QD at 320 mg, 480 mg, or 480 mg in the fasted condition (480 mg fasted QD). The primary endpoint was overall response rate (ORR) assessed by an independent review committee according to International PCNSL Collaborative Group criteria. We previously reported the results of this study with data cutoff in June 2019 (Narita et al. Neuro Oncol. 2020). In the report, 17 of 44 patients were treated with TIR at 480 mg fasted QD which is an approved dose, and had ORR of 52.9%, median progression-free survival of 5.8 months, and median overall survival of not reached (median follow-up: 3.8 months). In 44 patients, ORR was similar among patients harboring either of the oncogenic mutants CARD11, MYD88, CD79B, or wild type. Throughout the whole patients, most common adverse events (AEs) at any grade were rash (31.8%), neutropenia (22.7%), leukopenia (18.2%), and lymphopenia (15.9%), and grade ≥3 AEs were neutropenia (9.1%), lymphopenia, leukopenia, and erythema multiforme (6.8% each). One patient with 480 mg QD had grade 5 AEs (pneumocystis jirovecii pneumonia and interstitial lung disease). We will present one-year follow-up data of this study at the meeting. As of data cutoff (February 2020), 11 of 44 patients continued to receive TIR, including 6 patients with 480 mg fasted QD. Updated data for overall survival, duration of response, and time to onset of AEs will also be presented. TIR is a promising new treatment for r/rPCNSL.

CTNI-66. ONE-YEAR FOLLOW-UP DATA OF PHASE I/II STUDY OF TIRABRUTINIB IN PATIENTS WITH RELAPSED OR REFRACTORY PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA

Abstract Primary central nervous system lymphoma (PCNSL) is known as one of the incurable brain tumors. In March 2020, Tirabrutinib (TIR), a second-generation oral Bruton’s tyrosine kinase inhibitor, was approved for the indication of relapsed or refractory PCNSL (rrPCNSL) based on the results of a phase I/II study in Japan (Trial registration: JapicCTI-173646). In this study, 44 Japanese patients with rrPCNSL were treated with TIR QD at 320 mg, 480 mg, or 480 mg in the fasted condition (480 mg fasted QD). The primary endpoint was overall response rate (ORR) assessed by an independent review committee according to International PCNSL Collaborative Group criteria. We previously reported the results of this study with data cutoff on June 13, 2019 (Nagane et al., the 61st American Society of Hematology Annual Meeting and Exposition in 2019). In the report, 17 of 44 patients were treated with TIR at 480 mg fasted QD which is an approved dose, and had ORR of 52.9%, median progression-free survival of 5.8 months, and median overall survival of not reached (median follow-up: 3.8 months). In 44 patients, ORR was similar among patients harboring either of the oncogenic mutants CARD11, MYD88, CD79B, or wild type. Throughout the whole patients, most common adverse events (AEs) at any grade were rash (32%), neutropenia (23%), leukopenia (18%), and lymphopenia (16%), and grade ≥3 AEs were neutropenia (9.1%), lymphopenia, leukopenia, and erythema multiforme (6.8% each). One patient with 480 mg QD had grade 5 AEs (pneumocystis jirovecii pneumonia and interstitial lung disease). We will present one-year follow-up data of this study at the meeting. As of data cutoff (February 25, 2020), 11 of 44 patients continued to receive TIR, including 6 patients with 480 mg fasted QD. Updated data for OS, duration of response, and time to onset of AEs will also be presented.

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.

Treatment with Temozolomide and Ibrutinib in Recurrent/Refractory Primary (PCNSL) and Secondary CNS Lymphoma (SCNSL)

I ntroduction Despite recent therapeutic progress in this field, the prognosis of elderly patients with Primary (PCNSL) and Secondary Central Nervous System Lymphoma (SCNSL) remains poor, with a median OS of less than two years in most prospective studies. Patients with chemo refractory relapsed PCNSL within the first year from diagnosis have a median OS of 2-4 months. Activated B cell like subtype of Diffuse Large B Cell Lymphoma (DLBCL) and PCNSL relies on a chronically active B-cell receptor (BCR) signaling. Ibrutinib achieves CNS penetrance and has a high overall response rate in CNS lymphomas, but duration of response is short and curative potential is limited. A novel regimen that combines ibrutinib with temozolomide, etoposide, liposomal doxycycline, dexamethasone, and rituximab (Teddi-R) seems to be promising for this population but its tolerance is an issue in patients with advanced age and poor general condition, common features of many PCNSL patients., calling for an alleviated regimen of broader use. Patients and methods We evaluated a combination of temozolomide and ibrutinib in immunocompetent adult with recurrent/refractory (PCNSL) and (SCNSL) treated in five French centers between June 2015 and January 2020. The treatment consisted of 560 mg ibrutinib orally once daily (28-day cycles) and temozolomide 100 mg/m2 or 150 mg/m2 orally day 1 to 5 for cycle 1, increased to 200mg/m2 day 1 to 5 from cycle 2, until disease progression or unacceptable toxicity occurred. The evaluations were performed using Magnetic resonance imaging (MRI) and the responses were assessed according to the International PCNSL Collaborative Group Response Criteria. The lymphoma diagnoses were all confirmed by expert pathologists in the framework of the national program "lymphopath", based on the criteria of the World Health Organization 2008 classification. Results 22 immunocompetent adults with recurrent/refractory (PCNSL n=13) and (SCNSL n=9) were evaluable for safety and efficacy. Median age was 71 years (range, 44 - 89 years). All patients had relapsed (n=6) or refractory (n=16) disease, after a median of two lines of therapy (range, 1-3). Overall, 18 patients (82%) and 14 (64%) patients had previously received high dose methotrexate or both high dose methotrexate with high dose cytarabine, respectively. Among the four patients who did not receive Methotrexate, one had a chronic kidney disease secondary to diabetic nephropathy and experienced major toxicity after cytarabine infusion. The three others (72, 79 and 89 years old) were SCNSL experiencing comorbidities and toxicities from their previous treatment lines. Ten patients had a poor performance status according to Eastern Cooperative Oncology Group [ECOG] ⩾ 2. Patients received a median of 3.2 cycles (1-19 cycles). One patient received whole brain radiotherapy consolidation after obtaining a partial response under treatment. Best overall response rate was 55% (12/22) including 3 (13.6%) complete responses and 9 (40.9%) partial responses. After a median follow-up of 18.2 months (range, 5.1 - 61.7), the median progression-free survival was 5.3 months (95% confidence interval [CI]; 3.10 - NA) and overall survival 8.9 months (95% CI; 5.2 - NA). Eight patients (36%) received temozolomide and ibrutinib for more than 6 months, four patients were still on treatment at the end of the follow-up including one on ibrutinib only. Twelve patients (55%) stopped treatment due to progressive disease. Three (14%) patients stopped treatment for toxicity: Two (9%) due to grade 2 atrial fibrillation and one patient after 18 months in RC due to grade 1 muscle cramps, which did not stop after treatment discontinuation. three (14%) patients stopped temozolomide only due to recurrent grade 2 microcrystalline arthritis, grade 3 fall and one patient after 15 months in RC due to recurrent grade 2 bronchial infection, asthenia and nausea. Two patients temporary stopped treatment for grade 1 tumor hemorrhage and grade 3 tumor hemorrhage with grade 3 seizure. Micro-bleedings were seen at the MRI in four patients. Four patients (18%) experienced serious infectious complications including: two grade 3 febrile neutropenia, one grade 3 urinary tract infection and one grade 3 sepsis. None of the patients developed aspergillosis during the follow-up. Conclusion Temozolomide combined with ibrutinib showed clinical activity with manageable side effects in R/R CNS lymphomas. Disclosures Morschhauser: Novartis: Honoraria; JANSSEN-CILAG: Honoraria; Pharmacyclics LLC: Honoraria; Gilead: Honoraria; Roche: Honoraria; Celgene: Honoraria; Abbvie: Honoraria; Servier: Honoraria.

Outcomes in Primary CNS Lymphoma Post BEAM Autologous Stem Cell Transplantation: A Single-Center Analysis.

<h3>Background</h3> Primary CNS lymphoma (PCNSL) is a variant of NHL, involving the brain, leptomeninges, spinal cord, and/or the eyes without any evidence of systemic disease. Optimal therapy in PCNSL is yet to be determined. High dose methotrexate (HD-MTx) forms the mainstay of treatment. Consolidation strategies include radiation, non-myeloablative chemotherapy or myeloablative chemotherapy followed by stem cell rescue (ASCT). Thiotepa-based conditioning is preferred for ASCT based on evidence of superiority over BEAM conditioning. These studies however, are small in size and mostly single center. Typical drug costs for thiotepa exceed $100,000 and may be 3-4 times that of BEAM. We describe our experience at the Mayo Clinic of PCNSL patients who underwent BEAM conditioning. <h3>Methods</h3> We identified patients with a diagnosis of PCNSL that received BEAM conditioning for ASCT. Baseline characteristics were collected. All the patients were diagnosed before the year 2010 (thiotepa based conditioning preferred clinical practice after). MRI brain before transplant and day +100 were reviewed, and disease status was categorized based on international PCNSL collaborative group consensus (IPCG) guidelines. Overall survival (OS) from the time of diagnosis was estimated using the Kaplan Meier method and compared using the Log-Rank test. <h3>Results</h3> 25 patients with PCNSL underwent BEAM conditioning for ASCT. The median age at diagnosis was 50 (26-67) years. There was slight male preponderance (n =15; 60%); 22 (88%) had diffuse large B-cell lymphoma with 1 case each of PTCL-NOS, HGBL-NOS, and ALK-negative ALCL. All patients received HD-MTx, and since ASCT consolidation was not standard practice at the time, some patients also received rituximab (n =9), temozolomide (n =5) and radiation therapy (n = 3). Median time to transplant from diagnosis was 6 (2-73) months. 76% patients had achieved CR (n =18) or CRU (n =1) before transplant and 24% (n = 6) had partial response. Day +100 MRI evaluation demonstrated findings consistent with progressive disease in 20% (n = 5). These were patients not in CR prior to ASCT. Median OS for the entire cohort was 144 months (Figure 1). There was a statistically significant difference in OS based on remission status prior to transplant; median OS was 164 vs 31 months (p< 0.001) for patients in CR vs PR, respectively. After a median follow-up of 186 months, 14 patients were in CR, 10 had relapsed disease and 1 had stable disease at the time of death or last follow up. <h3>Discussion</h3> BEAM conditioning resulted in a prolonged median OS, especially in the patients achieving CR prior to transplant. Although thiotepa-based regimens are currently preferred over BEAM conditioning for ASCT, there are significant financial implications. There remains a need for more robust clinical trial data comparing the efficacy and safety between these alternative regimens and their pharmacoeconomic impact.

Patterns of response and relapse in primary CNS lymphomas after first-line chemotherapy: imaging analysis of the ANOCEF-GOELAMS prospective randomized trial

Our aim was to review MRI characteristics of patients with primary CNS lymphoma (PCNSL) enrolled in a randomized phase II trial and to evaluate their potential prognostic value and patterns of relapse, including T2 fluid attenuated inversion recovery (FLAIR) MRI abnormalities. Neuroimaging findings in 85 patients with PCNSL enrolled in a prospective trial were reviewed blinded to outcomes. MRI characteristics and responses according to International PCNSL Collaborative Group (IPCG) criteria were correlated with progression-free survival (PFS) and overall survival (OS). Multivariate analysis showed that objective response at 2 months (P < .001) and at end of treatment (P = .015) were predictors of prolonged OS. Infratentorial location (P = .008) and large (>11.4 cm3) enhancing tumor volume (P = .006) were associated with poor OS and PFS, respectively. Ratio of change in product of largest diameters at early MRI evaluation but not timing of complete response achievement (early vs delayed) was prognostic for OS. Sixty-nine patients relapsed. Relapse in the brain (n = 52) involved an initial enhancing site, a different site, or both in 46%, 40%, and 14% of patients, respectively. At baseline, non-enhancing T2-FLAIR hypersignal lesions distant from the enhancing tumor site were detected in 18 patients. These lesions markedly decreased (>50%) in 16 patients after chemotherapy, supporting their neoplastic nature. Of these patients, 10/18 relapsed, half (n = 5) in the initially non-enhancing T2-FLAIR lesions. Baseline tumor size and infratentorial localization are of prognostic value in PCNSL. Our findings provide evidence that non-enhancing FLAIR abnormalities may add to overall tumor burden, suggesting that response criteria should be refined to incorporate evaluation of T2-weighted/FLAIR sequences.

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.

RARE-39. INTRAVASCULAR LYMPHOMA AFFECTING THE CENTRAL NERVOUS SYSTEM: FEATURES AND OUTCOMES IN A CASE SERIES OF THE PRIMARY CNS LYMPHOMA COLLABORATIVE GROUP (IPCG)

Intravascular lymphoma (IVL) is a rare subtype of extranodal lymphoma, usually of the large B-cell type. It constitutes a subtype of primary central nervous system (CNS) diffuse large B-cell lymphoma (PCNSL) when it is confined to the vascular lumina of the CNS. In this International PCNSL Collaborative Group (IPCG) effort, we describe the clinical features and treatment outcomes of patients diagnosed with IVL affecting the CNS. We present a retrospective case series of 72 adults with IVL from 16 cancer centers in 6 countries. IVL was present in the CNS in 55 cases, with a mean age of 61.6 years and more than 90% of patients having neurological deficits at the time of diagnosis. There was a mean diagnostic delay of 20 weeks after presentation of stroke-like symptoms or myelopathy. Eighty-five percent had a poor functional status with an Eastern Cooperative Oncology Group (ECOG) performance status ≥2 with another eight percent diagnosed post-mortem. Serum LDH was elevated in 87% of available patients with no correlation with treatment outcome. Frontline treatment with intravenous high-dose methotrexate-based combination therapy was the most common first line treatment in the presence of CNS disease. Seventy-two percent of patients receiving any regimen reached one-year survival. There is improved one-year survival for patients having received a regimen containing high-dose methotrexate therapy with or without rituximab vs. non-methotrexate containing combination therapy (OR = 0.0667 95% CI 0.006-0.7451, P=0.028). The median progression free survival in patients treated with combination methotrexate and rituximab is at least 52 months. Multivariate analysis examining prognostic factors for outcome will be updated at time of presentation. This is the first case series to report improved prognosis in intravascular lymphoma with CNS involvement using combination high-dose methotrexate with rituximab.

Diffusion-Weighted Imaging for Predicting and Monitoring Primary Central Nervous System Lymphoma Treatment Response.

Whether ADC value predicts the therapy response and outcomes of primary central system lymphoma remains controversial. This study assessed the minimum ADC correlated with treatment response in patients with primary central nervous system lymphoma undergoing methotrexate-based chemotherapy. Thirty-five patients with primary central nervous system lymphoma underwent conventional MR imaging and DWI before chemotherapy and after 1 and 5 cycles of chemotherapy. Treatment response was determined according to the International PCNSL Collaborative Group criteria and was classified as a complete response, partial response, or progressive disease. Pretreatment minimum ADC, minimum ADC after 1 cycle, minimum ADC after 5 cycles, and change in minimum ADC were compared among the different response groups. The Pearson correlation test was calculated between these ADC parameters and tumor response. The pretreatment minimum ADC of the progressive disease group was lower than that of the complete response and partial response groups, but there was no significant difference among them. The minimum ADC after 1 cycle and minimum ADC after 5 cycles were statistically significantly higher than the pretreatment minimum ADC. A comparison among groups showed that minimum ADC after 1 cycle, minimum ADC after 5 cycles, minimum ADC change, and the percentage of minimum ADC change were all significantly different among the 3 groups. A significant positive correlation was observed between the percentage of minimum ADC after 1 cycle of chemotherapy and the size reduction percentage after 5 cycles of chemotherapy. The minimum ADC change and the percentage of minimum ADC change performed better in the differentiation of the final treatment response, specifically in complete response and partial response from progressive disease. The minimum ADC after 1 cycle and minimum ADC changes were better correlated with the treatment response than the pretreatment minimum ADC. Minimum ADC after early therapy may potentially to be used to predict and monitor the response of primary central nervous system lymphoma to chemotherapy.

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.

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.