Refractory Primary CNS Lymphoma Research Articles

A Phase II study assessing Long-Term Response to Ibrutinib Monotherapy in recurrent or refractory CNS Lymphoma.

Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK). We previously reported the safety and short-term antitumor activity of ibrutinib in 20 patients with relapsed or refractory (r/r) primary (PCNSL) or secondary CNS lymphoma (SCNSL). We enrolled 26 additional patients with r/r PCNSL/SCNSL into the dose-expansion cohort of the trial into a combined cohort of 46 patients (31 PCNSLs, 15 SCNSLs). Patients received ibrutinib at 560mg or 840mg daily in the dose-escalation and 840mg daily in the expansion cohort. Median follow up was 49.9 and 62.1 months for patients with PCNSL and SCNSL, respectively. We sequenced DNA from available tumor biopsies and cerebrospinal fluid (CSF) collected before and during ibrutinib therapy. Tumor responses were observed in 23/31 (74%) PCNSLs and 9/15 (60%) SCNSLs, including 12 complete responses in PCNSL and 7 in SCNSL. Median progression-free survival (PFS) for PCNSL was 4.5 months (95%CI: 2.8-9.2) with 1y-PFS at 23.7% (95%CI: 12.4%-45.1%). Median duration of response (DOR) in the 23 PCNSL responders was 5.5 months. Median PFS in SCNSL was 5.3 months (95%CI: 1.3-14.5) with a median DOR 8.7 months for the 9 responders. Exploratory biomarker analysis suggests that mutations in TBL1XR1 may be associated with a long-term response to ibrutinib in PCNSL (p=0.0075). Clearance of circulating tumor DNA from CSF was associated with complete and long-term ibrutinib response. Our study confirms single-agent activity of ibrutinib in r/r CNS lymphoma and identifies molecular determinants of response based on long-term follow up. NCT02315326.

Survival, prognostic factors, hospitalization time and clinical performance status after first cerebral relapse or progression in 54 patients with primary CNS lymphoma not eligible for high dose chemotherapy: a retrospective analysis

BackgroundTreatment of relapsed or refractory primary CNS lymphoma (r/r PCNSL) is difficult, particularly in patients not eligible for high dose chemotherapy with autologous stem cell transplantation (HDC-ASCT). No standard treatment has been defined for these patients yet.MethodsWe retrospectively analyzed survival, prognostic factors, hospitalization time and Karnofsky performance score (KPS) before and after treatment in 54 r/r PCNSL patients with isolated cerebral relapse or progression (n = 23 refractory, n = 31 relapsed) not eligible for HDC-ASCT, who received heterogenous salvage treatments.ResultsTreatments were temozolomide (+ rituximab) (n = 21), high dose methotrexate (HD-MTX)-based therapy (n = 11), whole brain radiotherapy (WBRT)/focal radiotherapy (n = 11), other systemic treatments (n = 2) and best supportive care (BSC, n = 9). Median progression free survival (PFS) and overall survival (OS) were 2.6 months (95% CI 1.0–4.2 months) and 4.8 months (95% CI 3.3–6.3 months), respectively. Eight patients survived for ≥ 3 years (13.1%, n = 3 received temozolomide, n = 3 WBRT, n = 2 HD-MTX-based treatment). Application of any salvage treatment (vs. BSC), younger age at relapse and asymptomatic (vs. symptomatic) relapse were positive prognostic factors. No significant differences in OS were found for the different salvage treatments. Median hospitalization time for treatment was 15/13 days for temozolomide (+ rituximab)/radiotherapy compared to 55 days for HD-MTX-based therapy. Median KPS in assessable patients (n = 41) was 60 (range 30–100) before treatment and 50 (range 20–90) after treatment. In patients with response to treatment (n = 16) KPS improved from 60 (range 40–90) before treatment to 70 (range 50–90) after treatment, while patients with PD (n = 25) deteriorated from 60 (range 30–100) to 40 (range 20–70).ConclusionSurvival for this cohort of r/r PCNSL patients with isolated cerebral relapse or progression was poor. Considering long hospital stays associated with HD-MTX-based chemotherapy and neurotoxicity associated with WBRT, temozolomide might be worth considering with a chance of prolonged survival and avoidance of long hospitalization. Novel therapeutic agents are urgently needed to improve survival in r/r PCNSL patients.

Karnofsky Performance Status and quality of life in patients with relapsed or refractory primary CNS lymphoma from a phase I/II study of tirabrutinib.

Tirabrutinib, a second-generation inhibitor of Bruton's tyrosine kinase, was approved in March 2020 for the treatment of relapsed or refractory primary central nervous system lymphoma (r/r PCNSL) based on phase I/II studies in Japan. We previously reported the overall response rate and safety profile. We describe Karnofsky Performance Status (KPS) and the quality of life (QoL) in patients with r/r PCNSL receiving tirabrutinib based on more than 1-year follow-up data. Patients with r/r PCNSL, age ≥20 years, and KPS ≥70 were treated with tirabrutinib once daily at a dose of 320, 480, or 480 mg under fasted conditions. QoL was assessed using questionnaires issued by the European Organization for Research and Treatment of Cancer (EORTC), namely EORTC QLQ-C30, EORTC QLQ-BN20, and EuroQol 5 dimensions 3-level (EQ-5D-3L) along with KPS. Forty-four patients (mean age, 60 years [range 29-86]) were enrolled. The median follow-up period was 14.9 months (range, 1.4-27.7). The median KPS of the patients at baseline was 80.0 (range, 70-100), and this remained constant during the treatment. The global health status/QoL in the QLQ-C30 showed significant improvements from baseline through cycles 3-17 and remained relatively constant thereafter until cycle 23. Improvements were also seen in emotional functioning and constipation in the QLQ-C30 segments. Other items of QLQ-C30 and QLQ-BN20, EQ-5D visual analog scales, and EQ-5D index were maintained during the treatment. Tirabrutinib generally maintains KPS and QoL scores with some improvements in specific QoL items in patients with r/r PCNSL.

INNV-18. PROLONGED REMISSION AFTER TREATMENT WITH SINGLE-AGENT IBRUTINIB AS MAINTENANCE THERAPY FOLLOWING SALVAGE RADIATION THERAPY FOR REFRACTORY/RELAPSE PRIMARY CNS LYMPHOMA

Abstract INTRODUCTION Primary central nervous system lymphoma (PCNSL) is a rare and aggressive disease. Standard induction therapy for PCNSL consists of a high-dose methotrexate-based (HD-MTX) regimen. For relapsed or refractory primary CNS lymphoma (r/r PCNSL), most of the non-standard treatment regimens including additional chemotherapy, stem cell transplant, or whole brain radiation therapy (WBRT) may not reach long-term remission due to intolerance of the treatment by the patients or lack of effects. Here we report a case with r/r PCNSL reached more than 50-month remission after salvage WBRT followed by single agent ibrutinib maintenance therapy. CASE REPORT: a 75-year-old female with PCNSL, experienced disease recurrence, despite undergoing multiple lines of treatment including initial HD-MTX, second-line rituximab and temozolomide, repeated HD-MTX, and a clinical trial. Because her disease was refractory to these treatment options, we decided to start WBRT as salvage therapy, which resulted in significant reduction of tumor burden. Prior studies, however, showed that r/r PCNSL patients who underwent salvage WBRT alone had a median survival of only 1-2 years. Therefore, to extend the remission after salvage WBRT, she opted to try ibrutinib, a Bruton’s tyrosine kinase inhibitor with past success in treating r/r PCNSL patients, as maintenance therapy after salvage WBRT. She tolerated well and decided to be off the treatment after 18 month-maintenance therapy. The patient has been stable clinically. She has since survived for more than 50 months after the completion of salvage WBRT plus maintenance therapy with ibrutinib. DISCUSSION Compared to prior reports of 11 to 16 months of median survival after salvage WBRT alone for r/r PCNSL, our case has had prolonged survival, which supports the potential positive effect of ibrutinib as maintenance therapy for r/r PCNSL after salvage WBRT

Treatment Options for Recurrent Primary CNS Lymphoma.

Primary CNS lymphoma (PCNSL) constitutes a rare extranodal variant of non-Hodgkin lymphoma (NHL) with an annual incidence of 0.45/100,000. Given the paucity of large prospective clinical trials, there is no consensus treatment for refractory or relapsed (r/r) PCNSL, and available strategies are largely based on retrospective analyses. Patient age, performance status, previously administered treatment, duration of response, and molecular characteristics guide selection of salvage therapy. Patients with a good performance status (KPS >70), particularly ≤65 years, and adequate organ function should be considered for salvage polychemotherapy. Based on its high overall response rate even in the relapsed setting, we choose high-dose (≥ 3.5g/m2) methotrexate (HD-MTX) based regimens, e.g., R-MPV (rituximab, HD-MTX, procarbazine, and vincristine), for remission re-induction as long as patients were sensitive to first line HD-MTX-based regimens, especially when duration of previous response was ≥ 1 year. Following successful remission induction, we choose myeloablative chemotherapy (e.g., thiotepa, busulfan, cyclophosphamide) and subsequent autologous stem cell transplant in curative intent whenever feasible. Alternatively, conventional chemotherapy regimens (for example, monthly HD-MTX) or low-dose whole-brain radiation therapy (WBRT) are selected for consolidation in non-transplant candidates in complete remission. In cases of HD-MTX refractory disease or contraindications, we use pemetrexed; temozolomide/rituximab; high-dose cytarabine; or whole brain radiation for remission induction. Clinical trial participation is considered as well. Emerging therapies for upfront or salvage therapy under ongoing investigation include bruton tyrosine kinase inhibition (e.g., ibrutinib), immunomodulatory drugs (e.g., lenalidomide), immune checkpoint inhibitors (ICI, e.g., nivolumab), and chimeric antigen receptor T (CAR-T) cell therapy.

High-Dose Chemotherapy with Autologous Hematopoietic Stem Cell Transplantation in Relapsed or Refractory Primary CNS Lymphoma: A Retrospective Monocentric Analysis of Long-Term Outcome, Prognostic Factors, and Toxicity.

Simple SummaryNo standard treatment is defined for relapsed or refractory (r/r) primary CNS lymphoma (PCNSL). However, high-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT), an efficient first line treatment in younger PCNSL patients, is commonly applied in relapsed or refractory disease, if tolerable. Here, we retrospectively analyzed 59 patients with r/r PCNSL focusing specifically on differences in long-term outcome and toxicity in patients <65 years (n = 33) and ≥65 years (n = 26) of age.High-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) is reportedly an effective treatment strategy in relapsed or refractory primary CNS lymphoma (r/r PCNSL); however, only selected patients are eligible for this treatment. We retrospectively analyzed outcome, prognostic factors, and toxicity in 59 patients with r/r PCNSL planned to receive HCT-ASCT at our institution between January 2005 and December 2021 (n = 33 < 65 years; n = 26 ≥ 65 years). Median follow-up was 65 months (95% CI 21–109). Median age was 63 years (range 29–76), median Karnofsky performance score (KPS) was 80 (range 30–100). In the entire cohort of 59 patients, median overall survival (OS) was 14 months (95% CI 0–37). In 50/59 (84.7%) patients who completed HCT-ASCT, median progression free survival (PFS) was 12 months (95% CI 3–21) and median OS 30 months (95% CI 0–87). 1-year, 2-year, and 5-year OS rates of 61.2%, 52.3% and 47.1%, respectively, were observed. Six patients (10.2%) died related to treatment (1 during induction treatment, 5 post HCT-ASCT). Age was not prognostic. On univariate analysis, KPS ≥ 80 (p = 0.019) and complete or partial remission before HCT-ASCT (p = 0.026) were positive prognosticators of OS; on multivariate analysis, KPS (p = 0.043) and male gender (p = 0.039) had an impact on OS. The 5-year OS rate in patients with progressive or stable disease after induction treatment was 32.7%. In summary, HCT-ASCT was effective and feasible in this cohort of r/r PCNSL patients. Clinical state, remission status before HCT-ASCT, and gender influenced survival, whereas age did not influence outcome in this study.

ML-10 Tirabrutinib, a second-generation BTK inhibitor in relapsed and refractory primary CNS lymphoma: A single institute study

BACKGROUND: The prognosis of relapsed and refractory (r/r) primary CNS lymphoma (PCNSL) is poor, and the development of new therapeutic agents is desirable. Comprehensive genetic analysis of PCNSL has shown that MYD88 and CD79B are frequently mutated and are oncogenic drivers, suggesting that Bruton’s tyrosine kinase (BTK), which is located downstream of MYD88 and CD79B, may be a reasonable therapeutic target. Tirabrutinib is a second-generation oral BTK inhibitor recently approved in Japan for the treatment of r/r PCNSL. In this study, we evaluated the efficacy and safety of tiraburtinib treatment of r/r PCNSL at Saitama Medical University. MATERIAL AND METHODS: Eighteen patients with r/r PCNSL to HD-MTX-based regimens were treated with 480 mg tiraburtinib daily under fasting conditions until disease progression. RESULTS: The median age was 63.5 years, and the median KPS was 70. Nine patients (50%) achieved a CR, 2 (11%) had a partial response, 3 (17%) had stable disease, and 4 (22%) had progressive disease. After a median follow-up of 17.3 months, the median progression-free survival was 7.9 months, and the median overall survival was 23.6 months. There were four cases of long-term treatment lasting more than one year. Grade 3 or higher adverse events were observed in 1 case of maculopapular rash, 1 case of cardiac failure, 1 case of neutropenia, and 1 case of lymphopenia. CONCLUSION: Tiraburtinib can be administered relatively safely to patients with relapsed or refractory PCNSL, and a certain degree of efficacy can be expected. Which patients can be treated with tiraburtinib over the long term, when can stop tirabrutinib treatment for patients with long-term CR, and the mechanism of tiraburtinib resistance needs to be determined.

ML-18 High-dose chemotherapy supported by autologous stem cell transplant in relapsed and refractory primary CNS lymphoma

While whole brain radiation therapy (WBRT) has been performed as consolidation therapy in primary central nervous system lymphoma (PCNSL), high-dose chemotherapy supported by autologous stem cell transplant (HDC/ASCT) is widely investigated today as an alternative treatment strategy, given the high risk for radiation-induced neurotoxicity in WBRT. Various conditioning regimens have been investigated in phase II trials, which report non-inferiority of HDC/ASCT in efficacy and preservation of neurocognitive function in comparison with WBRT. Besides its promising efficacy, treatment-related deaths are reported in 11% in patients treated by a conditioning regimen using thiotepa, busulfan and cyclophosphamide (TBC), which raises a concern for safety. Among several conditioning regimens, analysis using registry data of Japan Society for Hematopoietic Cell Transplantation has revealed that the use of conditioning regimens containing thiotepa was a positive factor for longer PFS. According to the result of a phase I trial in Japan which investigated HDC/ASCT using thiotepa and busulfan (BuTT), thiotepa was approved by the pharmaceuticals and medical devices agency (PMDA) on March 2020. In comparison with the TBC regimen, cyclophosphamide is omitted, and the dose of thiotepa is lower (250 mg/m2, 3 days in TBC; 5 mg/kg, 2 days in BuTT) in BuTT, therefore BuTT could be less toxic in comparison with TBC, and no treatment-related deaths were observed in the phase I study in Japan. Further investigation on the efficacy and safety of BuTT in actual clinical practice is warranted. We have constituted a multi-disciplinary team in our institution in order to perform HDC/ASCT using BuTT in relapsed/refractory PCNSL. Treatment indications are as follows; 65 years old or younger, previously treated by rituximab, methotrexate, procarbazine and vincristine (R-MPV), good organ function and neurological status. Future directions along with preliminary treatment results will be discussed at the meeting.

Treatment of Patients with Relapsed or Refractory Primary CNS Lymphoma (rrPCNSL) Enrolled in the Randomized Trials of the International Extranodal Lymphoma Study Group (IELSG)

Treatment of Patients with Relapsed or Refractory Primary CNS Lymphoma (rrPCNSL) Enrolled in the Randomized Trials of the International Extranodal Lymphoma Study Group (IELSG)

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

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

Relapsed and refractory primary CNS lymphoma: treatment approaches in routine practice

Despite recent therapeutic progress and improved survival for many patients with primary central nervous system lymphoma (PCNSL), up to 50% of patients will experience refractory or relapsed disease following first-line treatment with high dose methotrexate (HD-MTX) based regimens. The majority of such events occur within 2 years of diagnosis although, unlike their systemic counterpart, the risk of PCNSL relapse remains, even for patients in radiologic complete response at 10 years following diagnosis. Currently, there are no approved therapies, and no widely accepted ‘standard-of-care’ approaches for the treatment of refractory or recurrent primary central nervous system lymphoma (rrPCNSL). Re-treatment with HD-MTX based regimens, use of non-cross resistant chemotherapy regimens, high-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT), and brain irradiation all remain important therapeutic approaches for rrPCNSL. However, the survival outcomes for patients with rrPCNSL remain extremely poor and the vast majority of patients will die of their disease. Increasingly, novel treatment approaches are being investigated in early phase clinical studies. Importantly, such therapies need to be evaluated in the context of both refractory and relapsed disease; in older patients and those with co-morbid conditions; and those with neurocognitive dysfunction. A deeper understanding of the molecular genetic mechanisms underpinning rrPCNSL and its unique tumor microenvironment is urgently needed to inform biologically rational and effective therapies. rrPCNSL remains a clear unmet clinical need and a high priority area for clinical research that will require national and international collaborative studies with embedded translational science in order to improve outcomes for patients.

ML-02 Chemotherapy for patients with relapsed or refractory primary CNS lymphoma

BACKGROUNDS: Standard of care for patients with primary CNS lymphoma (PCNSL) has been high-dose methotrexate (HD-MTX)-based multiagent immunochemotherapy, particularly with R-MPV-A with or without whole-brain radiotherapy (WBRT), however, the optimal treatment for relapsed/refractory (r/r)PCNSL has not been established yet. Approval of a second-generation BTK inhibitor, tirabrutinib, for r/rPCNSL in Japan in March 2020, prompted us to evaluate retrospectively efficacy of R-MPV-A for r/rPCNSL to compare their activities. PATIENTS: Histologically proven PCNSL patients treated at relapse in our institution from April 2000 to November 2019 were analyzed. Outcomes were compared between those treated with RMPVA or other regimens. RESULTS: Among 148 PCNSL patients identified, 73 had at least one relapse, of whom 47 received salvage chemotherapy including 23 treated with RMPVA, 14 with HD-MTX monotherapy, and 11 with DeVIC (DEX, etoposide, ifosfamide, CDBCA). Median age/KPS were 69 yo (20–87)/ 80 (40–100), 27 patients had received prior WBRT. RMPVA was given at the first relapse in 11 patients, median number of RMPV cycles was 8 (1–4 cycles: 10; 8 cycles 13). CR/CRu were achieved in 19 (83%), response rate was 87%, while there were two PDs (9%). After median follow-up of 21.9 months, the median PFS after salvage RMPVA was 13.0 m (95%CI: 9.1–16.9), 1-year overall survival (OS) was 82%, median OS was 70.0 m (95%CI: 12.9–127.1), which were longer than those in 24 patients with salvage treatment other than RMPVA (mPFS 4.4 m, P=0.054; mOS 13.6 m, P=0.009). Median PFS and OS for HD-MTX monotherapy were 5.1m and 36.6 m, while those for DeVIC were 4.4 m and 9.1 m, respectively. Treatment was generally well-tolerated but there was one treatment-related death. CONCLUSIONS: Salvage RMPVA at relapses was active and associated with longer survival compared with other regimens, necessitating further development of salvage regimens incorporating tirabrutinib in the future studies.

First Results of the Acsé Pembrolizumab Phase II in the Primary CNS Lymphoma (PCNSL) Cohort

Background: AcSé Pembrolizumab is a Phase 2, open-label, single-arm, multi-cohort, multicentric study investigating the efficacy and safety of pembrolizumab monotherapy in patients with advanced rare cancers (NCT03012620). Here, we report the first results of Pembrolizumab in the cohort of Primary Central Nervous System Lymphoma (PCNSL). Methods: Main inclusion criteria were: relapsed or refractory PCNSL after one or several lines of treatment including high dose Methotrexate based chemotherapy, pathologically confirmed diffuse large B cell lymphoma, age&amp;gt;18, HIV negative, concurrent steroid medication at a dose no greater than prednisone 20 mg/day or equivalent. Patients received pembrolizumab 200 mg IV as a 30-minute infusion on Day 1 of every 21-day cycles for a maximum of 2 years. The primary endpoint was the confirmed objective response rate according to IPCG at 84 day after the start of treatment. Secondary endpoints included best response (ORR), duration of response, progression-free survival (PFS), overall survival (OS), and safety. Analysis used all enrolled patients. Results: 50 patients suffering from PCNSL, including 9 primary vitreoretinal lymphoma (PVRL) were included from July, 2017 to October, 2019. Median age was 72 years (range: 43 to 83), Median PS (ECOG) was 1 (range 0-1). The median number of cycles was 4 (range 1-35). At 84 days from start of treatment, 6 patients responded (4 CR+2PR). Overall, 3 patients whose response was not assessed were considered as failures, and the rates of ORR (CR+PR), stable disease (SD), progressive disease (PD) were 26% (13/50, 8 CR + 5 PR), 10% (5/50), 58% (29/50), respectively. ORR was 29% (12/41) and 11% (1/9) in primary cerebral lymphoma and PVRL respectively. After a median follow-up of 6.7 months (range 0.2-27.4), median PFS was 2.6 months, with 6-month PFS of 29.8% and 6-month OS of 60.4%. In responders, median duration of response was estimated at 10 months (95%CI, 2.7 to 12.5). Grade III and IV toxicities related to the drug were observed in 4 patients (8%) and one patient (2%) respectively. No related toxic death was reported. Conclusion: Pembrolizumab shows moderate activity in relapsed/ refractory PCNSL with acceptable toxicity, supporting further studies evaluating its use in combination therapies. Disclosures Hoang-Xuan: BTG: Consultancy, Research Funding. Houot:Bristol-Myers Squibb: Honoraria; MSD: Honoraria; Gilead: Honoraria; Kite: Honoraria; Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Schmitt:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche, Janssen: Honoraria. Ahle:Roche: Honoraria; Novartis: Honoraria; Biogene: Honoraria; Abbvie: Honoraria; Sanofi: Honoraria. Bories:Abbvie: Consultancy; Celgen: Consultancy; Gilead: Consultancy; BMS: Honoraria; Novartis: Honoraria. Houillier:BTG: Consultancy.

Efficacy of High Dose Chemotherapy with Autologous Transplantation for Primary CNS Lymphoma Treatment

Introduction: Primary CNS lymphoma (PCNSL) is a highly aggressive non-Hodgkin lymphoma (NHL) variant limited to the CNS with rare evidence of systemic spread. It constitutes 4% of all CNS malignancies. Owing to the impenetrable blood-brain barrier to routine chemo-immunotherapy, the efficacy of such treatment is less than optimal. The combination of chemoradiotherapy has substantial associated risk of late neurotoxicity and increased disease recurrence. High dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) as rescue has been shown to be effective. We performed a systematic review of literature to explore the efficacy of HDT and ASCT in patients with PCNSL. Methods: We performed a comprehensive literature search (following PRISMA guidelines) on May 28, 2020 on Pubmed, Cochrane Library and Clinicaltrials.Gov by using the MeSH terms related to high-dose chemotherapy, autologous transplantation and primary CNS lymphoma which yielded 561 relevant articles. Following subsequent screening by 2 reviewers, we selected 16 published trials (n=745) and included data from these studies in our systematic review. We manually extracted data summarized the results. Results: 405/745 patients eventually underwent sequential HDT+ASCT the results of which are illustrated in table 1 and 2 stratified on the basis of newly diagnosed (ND) (n=641) and relapsed, refractory (RR) PCNSL patients (n=104) respectively. ND PCNSL: Among ND PCNSL patients, carmustine and thiotepa based regimens were the most widely studied HDT regimens (n= 351). Illerhaus et al. (2016, n= 81) in a phase 2 trial used HDT of intravenous (IV) combinations of rituximab, thiotepa and carmustine followed by ASCT on 73 patients which yielded partial response (PR) 13.9 %, complete response (CR) 77.2% and overall survival (OS) 81% at 36 months. 4 patients suffered transplant related mortality (TRM), mucositis (8%) and arrhythmias (2%) were the most common nonhematologic &amp;gt;grade 4 adverse effects. Ferreri et al. (2017) [n=122] in a phase 2 trial (n=59) used ASCT following Carmustine + Thiotepa HDT and reported 2-year OS of 71% and CR of 93% with a modest toxicity profile (infections (8%), mucositis (5%) and 2 (3%) treatment related deaths). IV thiotepa, busulfan and cyclophosphamide (TBC) combination was used as HDT / ASCT in ND PCNSL patients (n=208). Omuro et al. (2015) (n=32) used HDT with TBC followed by ASCT in 26 patients. Whole brain radiation therapy (WBRT) was not given to any patient regardless of recurrence or relapse. At 5 years, the study reported PR=11%, CR=81%, and OS=81%. In a phase 2 trial, Houillier et al. (2019, n=140) used TBC combination as HDT followed by either WBRT or ASCT (2 separate arms), 44 patients of the latter arm exhibited a CR of 38% and OS of 66% at 5 years with 5 treatment related deaths. An IV combinations of carmustine, etoposide, cytarabine and melphalan (BEAM) have also been used as HDT with ASCT in 3 phase 2 trials (n=59). Abrey et al. (2003, n=28) in a phase 2 trial used high-dose BEAM therapy followed by ASCT which yielded PR of 14%, CR of 57% and OS of 55% at 28 months. Only 1 treatment related mortality occurred. RR PCNSL: TBC combination has been the most extensively used HDT regimen for RR PCNSL patients undergoing ASCT (n=65). Soussain et al. (2008, n=43) conducted a phase 2 trial in which high-dose TBC sequentially followed by ASCT was studied in 27 RR PCNSL patients. The results showed median PFS of 41.1 months with OS of 45% at 2 years however, 3 toxicity related deaths were observed. Kasenda et al. (2017, n=39) in a phase 2 trial used high-dose combination of rituximab, carmustine and thiotepa coupled with ASCT on RR PCNSL patients which yielded PR of 15.4%, CR of 56% and median PFS of 12.4 months with an OS of 56.4% at 2 years. However, there were 4 treatment related deaths and an extensive toxicity spectrum with widespread pancytopenia (thrombocytopenia =96.9%, leukopenia =100%, anemia =65.6%) and nonhematologic infections (65.6%) observed. Conclusion: HDT followed by ASCT rescue has exhibited favorable outcomes and can be used an alternative to WBRT especially in ND PCNSL patients. Evidence is limited by mainly phase II non randomized data. Although, hematologic adverse effects due to HDT were observed on a widespread basis, transplant related mortality was however minimal. There is need to carry out prospective randomized phase III trials to access the safety and efficacy profile of HDT / ASCT for ND and RR PCNSL. Table Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Nivolumab in Primary CNS Lymphoma and Primary Testicular Lymphoma with CNS Involvement: Single Center Experience

Background.Most patients with primary CNS lymphoma (PCNSL), an aggressive extranodal lymphoma confined to the CNS, have a poor prognosis in spite of development of chemotherapy regimens. First-line treatment consists of high-dose methotrexate-based (HD-MTX) regimen followed by consolidation with autologous stem cell transplantation or whole brain radiotherapy. Given that this tumor manifests predominantly in older patients with median age of 65 years, many patients are unable to tolerate intensive chemotherapy. Moreover, most patients eventually present with relapsed or refractory (r/r) disease. Relapse or refractory (r/r) PCNSL has a poor prognosis with median overall survival not exceeding 3.5 months (Langner-Lemercier et al, 2016) and these patients should be offered a clinical trial whenever possible. These groups are in need of safe, tolerable and effective therapeutic approaches. Primary testicular lymphoma (PTL) shares biological and clinical similarities with PCNSL and often present with CNS involvement. Such patients are also in need of new approaches, especially if they are refractory or not suitable to HD-MTX. Given high PD-1/PD-L1 expression in tumor microenvironment (Berghoff, 2014), immune checkpoint inhibitors were successfully tested in r/r PCNSL and PTL setting. However, data are still scarce and limited to case series (Nayak et al., 2017; Graber et al. 2020). Here we present Pavlov University experience of the treatment of PCNSL and PTL with CNS involvement with PD-1 inhibitor nivolumab. Methods.Eight patients, 2 men and 6 women, with PCNSL and one patient with PTL with CNS involvement treated at the Pavlov University between 2017 and 2020 were included into analysis. Median age at a diagnosis was 62 (28-66) years. Two patients (22%) had ECOG score 3-4 and therefore could not be considered for intensive MTX containing frontline treatment. In all of the cases the tumor histological type was diffuse large B-cell lymphoma. All patients had parenchymal involvement: 7 patients had multifocal disease; deep structures were involved in 2 patients. One patient had leptomeningeal involvement. Nivolumab was used in a first-line setting in 2 patients (22%). In 7 (78%) patients with relapsed/refractory disease, the median number of treatment lines prior to nivolumab was 1 (1-7). Nivolumab was given every 2 weeks in the 100 mg dose. Adverse events were defined according to NCI CTC-AE 5.0. Results.At the time of analysis, the median follow-up was 18 (3-44) months. Median number of nivolumab cycles was 10 (2-23). Seven (78%) patients had an objective response: complete response in 3 patients (33.3%) and partial response in 4 patients (44.4%). Two patients (22.2%) were refractory to treatment. Two-year overall survival (OS) was 44% with median OS of 12 months. Two-year progression-free survival (PFS) was 26% with median of PFS 12 months. Оne responder had a moderate increase of tumor volume on MRI after two months of therapy followed by complete disappearance of brain lesions on sequential imaging at 4 months after treatment initiation. Nivolumab therapy appeared safe with only one patient (11%) having severe adverse event, namely grade 3 alanine aminotransferase and aspartate aminotransferase increase. Conclusion.Nivolumab appears to be safe and effective therapy in PCNSL and PTL with CNS involvement both in first-line and r/r setting. However, in our cohort majority of patients relapsed that suggest that consolidation therapy after remission induction with nivolumab may be crucial for long-term remissions. We also demonstrate that pseudoprogression might be also observed in PCNSL during immunotherapy. Large-scale trials are needed to generate strong evidence for the use of PD-1 inhibitors in PCNSL. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Nivolumab is an anti-PD-1 inhibitor approved for classical Hodgkin lymphoma. There is early clinical data suggesting the efficiency of nivolumab in PCNS lymphoma (Nayak, 2017)

Ibrutinib in primary central nervous systemdiffuse large B-cell lymphoma.

The standard regimen for the treatment of newly diagnosed primary CNS lymphoma (PCNSL) remains regimens that contain high-dose methotrexate (MTX). While these regimens can provide control for some patients, there is a dearth of options for the treatment of patients with PCNSL who cannot tolerate MTX-containing regimens, or whose cancers are refractory to MTX. In this article, we review a promising new option; ibrutinib, a Bruton tyrosine kinase inhibitor, for patients with relapsed and refractory PCNSL.

Expanding the Indications for Ibrutinib: Complete Remission Obtained By Induction with Ibrutinib Followed By Consolidative Ahsct in Refractory Primary CNS Lymphoma

Introduction Primary central nervous system lymphoma (PCNSL) is an exceedingly rare and aggressive sub-type of Non-Hodgkin's Lymphoma. Despite initial polychemotherapy that includes High-Dose Methotrexate (HD-MTX), over half of patients will develop recurrent or refractory disease that requires salvage therapy.1 Ibrutinib, a Bruton's tyrosine kinase inhibitor, has become an alternative for salvage treatment in relapsed or refractory PCNSL (RR-PCNSL) that is particularly useful in patients who are ineligible for re-induction with HD-chemo. In RR-PCNSL, Ibrutinib led to a progression free survival (PFS) of roughly 5 months when used as monotherapy2,3 and 15 months when used as add-on therapy.4 While its role as salvage treatment has been documented, its use to facilitate consolidative autologous hematopoietic stem cell transplant (AHSCT) in RR-PCNSL is not currently known. The following case describes the first known report of a patient with RR-PCNSL who achieved persistent complete remission following Ibrutinib salvage treatment and consolidative AHSCT. Case Description A 64-year-old male presented to the emergency department with a two-week history ptosis, visual abnormalities, confusion, and increasing fatigue. On physical exam, he was found to have bilateral mydriasis, left third nerve cranial palsy, severe left-sided ptosis, and restricted upwards and downward gaze of the right eye. A contrast-CT was performed which showed multiple areas of abnormal enhancement throughout the frontal lobes, corpus callosum, and midbrain associated with significant vasogenic edema. These findings were confirmed on MRI. He underwent a stereotactic guided burr hole biopsy which was consistent with diffuse large B-cell lymphoma (DLBCL). Immunohistochemistry performed on the tissue showed that the neoplastic cells were CD3(-), CD5(-), CD20(+), CD10(-), BCL2(subset +), BCL6(+), MUM1(+) and Cyclin D1(-). Staging CT and bone marrow biopsy showed no evidence of systemic disease. He was diagnosed with PCNSL and went on to receive induction therapy with Rituximab, Methotrexate, Procarbazine, and Vincristine (R-MPV) with curative intent and received a total of 7 cycles. Initially, he had a significant radiographic response with a repeat MRI post cycle 4 showing only a few small areas of residual enhancement. However, after completion of the 7 cycles of R-MPV, his MRI showed evidence of disease progression with both new and enlarging intra-axial lesions. Given his ECOG of 0 and lack of comorbidities, it was decided that he would proceed with salvage treatment with Cytarabine and Etoposide with curative intent for refractory PCNSL. Unfortunately, after only four weeks of receiving cycle one of Cytarabine and Etoposide, a repeat MRI showed evidence of disease progression. He was then transitioned to palliative therapy with prednisone up until December 2017, at which point he was able to obtain Ibrutinib on a compassionate basis. He was started on Ibrutinib salvage therapy and achieved radiographic evidence of complete remission after four months of treatment. There were minimal adverse effects of Ibrutinib therapy, most notably a severe neutropenia requiring a temporary discontinuation of therapy for two weeks. He underwent consolidative AHSCT with Thiotepa, Busulfan and Melphalan conditioning in August 2018. His post-transplant course was complicated by culture negative febrile neutropenia with a subsequent source determined to be Clostridium difficile for which he was treated. An MRI head performed 3 months after his AHSCT showed no evidence of recurrent or residual disease. He continues to be followed by the Hematology Service in Newfoundland and has remained in complete remission since. Conclusions This case demonstrates the feasibility of a salvage approach using Ibrutinib followed by AHSCT when standard salvage options have been exhausted in refractory PCNSL. OffLabel Disclosure: Ibrutinib's indications do not currently include use as a induction treatment prior to AHSCT in refractory/recurrent PCNSL.

Ibrutinib monotherapy for relapse or refractory primary CNS lymphoma and primary vitreoretinal lymphoma: Final analysis of the phase II ‘proof-of-concept’ iLOC study by the Lymphoma study association (LYSA) and the French oculo-cerebral lymphoma (LOC) network

BackgroundPrimary central nervous system lymphomas (PCNSLs) are mainly diffuse large B-cell lymphomas (DLBCLs) of the non-germinal centre B-cell subtype, with unmet medical needs. This study aimed to evaluate the efficacy and toxicity of ibrutinib in DLBCL-PCNSL Patients and methodsThis prospective, multicentre, phase II study involved patients with relapse or refractory(R/R) DLBCL-PCNSL or primary vitreoretinal lymphoma. The treatment consisted of ibrutinib (560 mg/day) until disease progression or unacceptable toxicity occurred. The primary outcome was the disease control (DC) rate after two months of treatment (P0 < 10%; P1 > 30%). ResultsFifty-two patients were recruited. Forty-four patients were evaluable for response. After 2 months of treatment, the DC was 70% in evaluable patients and 62% in the intent-to-treat analysis, including 10 complete responses (19%), 17 partial responses (33%) and 5 stable diseases (10%). With a median follow-up of 25.7 months (range, 0.7–30.5), the median progression-free and overall survivals were 4.8 months (95% confidence interval [CI]; 2.8–12.7) and 19.2 months (95% CI; 7.2-NR), respectively. Thirteen patients received ibrutinib for more than 12 months. Two patients experienced pulmonary aspergillosis with a favourable (n = 1) or fatal outcome (n = 1). Ibrutinib was detectable in the cerebrospinal fluid (CSF). The clinical response to ibrutinib seemed independent of the gene mutations in the BCR pathway. ConclusionIbrutinib showed clinical activity in the brain, the CSF and the intraocular compartment and was tolerated in R/R PCNSL. The addition of ibrutinib to standard methotrexate-base induction chemotherapy will be further evaluated in the first-line treatment. Clinical trial numberNCT02542514.

Dose-Adjusted Teddi-R Induces Durable Complete Remissions in Relapsed and Refractory Primary CNS Lymphoma

Background: Primary CNS lymphoma (PCNSL) is an aggressive B-cell lymphoma that relies on chronic active B-cell receptor (BCR) signaling. Patients with chemo-refractory PCNSL or relapsed < 1y have a median OS of only 2-4 mos. Ibrutinib targets BCR signaling through inhibition of BTK. In a phase 1 study, we showed tumor reductions after a 14-day ibrutinib window in 94%, including complete remissions (CR) (Lionakis et al. Cancer Cell 2017). Further, ibrutinib added to anthracycline-based chemotherapy (DA-TEDDi-R) achieved CR in 86% of evaluable patients. Routine use of DA-TEDDi-R, however, is limited by our observation of 7 presumed or proven cases of Aspergillus when no fungal prophylaxis was given and in conjunction with high dose steroids. Herein, we report the durability of CR and PFS in relapsed/refractory patients with extended follow-up.Methods: Patients with untreated or relapsed/refractory PCNSL, age >18, and adequate organ function were enrolled. Previous BTK inhibitor, EBV+, and active pregnancy were excluded. Patients had baseline MRI brain, PET/CT brain and body, Ommaya placed, CSF analysis with flow cytometry, and ophthamologic evaluation. A window of ibrutinib x 14d was given in 3 cohorts at escalating doses (560mg, 700mg, 840mg) then repeat MRI to assess activity. After ibrutinib window, patients received up to 6 cycles of ibrutinib + TEDD-R (temozolamide, etoposide, doxil, dexamethasone, rituximab) with ICV or IT cytarabine. No pt received maintenance or consolidation. All remissions by MRI were confirmed with PET/CT brain and repeat CSF analysis. Surveillance brain MRI after treatment q3mos for 1y, q4mos x 1y, q6mos x 1y, then annually.Results:18 PCNSL patients with a median age 66 (range 49-87) were enrolled between August 2014 and March 2016. 5 patients were untreated, 2 relapsed, and 11 chemo-refractory. After a median potential f/u of 38.9m, the median PFS for all patients who received DA-TEDDi-R is 15.2m (95% CI:3.8-undefined) and the 2-yr PFS is 43.8% (95% CI: 19.8-65.6). Of 13 relapsed/refractory patients, 2 died from Aspergillus infection during the ibrutinib window; neither had fungal prophylaxis and both had high-dose steroids. 11 patients received a median of 5 cycles (range 1-6) of DA-TEDDi-R. Nine (82%) of these patients achieved CR/CRu. Notably, none of the 6 patients with relapsed/refractory PCNSL (1 relapsed, 5 refractory) in CR at the time of publication have relapsed or died. The median duration of CR in relapsed/refractory PCNSL has not yet been reached (range 2-43m) and the 2-year durable CR rate is 66.7% (95% CI: 28.2-87.8) (Figure 1). Of the 11 relapsed/refractory patients who received DA-TEDDi-R, the median PFS has not yet been reached and the 2-yr PFS is 54.5% (95% CI: 22.9-78.0) (Figure 2).Conclusions: Ibrutinib + anthracycline-based chemotherapy (TEDDi-R) induces durable complete remissions in PCNSL without maintenance or consolidation, including patients with disease refractory to chemotherapy. Risk of Aspergillus infections mandates use of fungal prophylaxis and judicious use of steroids. Phase 1 study of escalating ibrutinib doses with concurrent isavuconazole is currently enrolling patients with relapsed and refractory PCNSL (NCT02203526).This work was supported by the Intramural Research Program of NCI at NIH [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

R-CHOP Preceded By Engineered Tumor Necrosis Factor (TNF) in Patients with Relapsed or Refractory (r/r) Primary CNS Lymphoma (PCNSL): Results of Antitumor Activity, Safety and Blood-Brain Barrier (BBB) Permeabilization in the “Ingrid” Phase II Trial

Background: Almost all PCNSL belong to the category of DLBCL. However, affected pts are treated with high-dose methotrexate-based combinations that are not currently used in other DLBCL and require hospitalization and extensive expertise to manage toxicity. The use of R-CHOP could overcome these difficulties, but CNS availability of related drugs is poor. TNF induces BBB permeabilization and enhances CNS access of anticancer drugs. Coupling TNF with NGR, a peptide that targets CD13+ tumor vessels, improves its biological effects and therapeutic index. Thus, we tested the hypothesis that this conjugate (called NGR-hTNF) can break the BBB, thereby improving CNS access and activity of R-CHOP in pts with r/rPCNSL enrolled in a phase II trial (NCT03536039). Herein, we report results of activity, safety and BBB permeabilization.Methods: HIV-neg adults with PCNSL failed after methotrexate-based chemo and measurable disease were enrolled and treated with 1 course of R-CHOP, followed by 5 courses of R-CHOP21 preceded by NGR-hTNF (0.8 μg/m², 1-h inf). Overall response rate (ORR) was the primary endpoint. The two-stage Simon Minimax design was used; sample size estimated to demonstrate an improvement from 30% ORR (P0) to 50% (P1) (one-sided test; α 10%; β 90%) was 28 pts. NGR-hTNF/RCHOP would be declared active if ≥12 responses were recorded.As secondary endpoints, changes in vessel permeability, CD13 expression and anticancer drugs pharmacokinetics were assessed in the first 10 pts. Changes in BBB permeability were assessed by Dynamic Contrast Enhanced MRI (DCE-MRI) and 99mTc-DTPA-SPECT in tumor lesions, perilesional areas and normal appearing brain. DCE-MRI findings recorded before/after the 1st course (RCHOP alone - baseline) and before/after the 2nd and 6th courses (NGR-hTNF/RCHOP) were compared to establish the effect of TNF, and results were expressed as Ktrans values normalized using contralateral white matter. SPECT was performed before and after the 3rd course, and results were expressed as changes in the volume of ≥30% 99mTc-DTPA uptake (cm3). CD13 expression was assessed by immunohistochemistry on diagnostic tissue samples. Rituximab, cyclophosphamide and doxorubicin concentrations on matched CSF/plasma samples collected before/after the 1st, 2nd and 6th courses were tested to exclude a non-specific effect of NGR-hTNF on pharmacokinetics.Results: 22 pts (median age: 58 yo, range 26-78; 11 males) were enrolled; 18 pts had intermediate-high IELSG score. Pts were heavily pretreated: 13 had received ASCT, WBRT or both; 13 had refractory disease. Twenty pts were evaluable for the primary endpoint.NGR-hTNF/RCHOP combination was active: the predetermined activity threshold (≥12 responses) was achieved, with confirmed tumor response in 13 pts (65%; 95%CI= 45-85%), which was complete in 9. At a median follow-up of 8 months (2-26), 9 pts remain relapse free and 12 pts are alive.Treatment was well tolerated; toxicities were quickly solved without dose reductions or interruptions. G4 toxicities were neutropenia (49% of courses) and thrombocytopenia (15%), anemia (1%), and FN (1%). Ten SAEs were recorded in 8 pts: g2 seizures (n= 2), g2 DVT (2), g3 infections (2), g3 syncope (2), g4 FN and g2 LVEF reduction. There were 3 cases of g1-2 TNF infusion reaction.DCE-MRI studies showed an increase of vascular permeability after NGR-hTNF infusion as median (range) Ktrans of tumor and perilesional areas raised from baseline values of 23.5 (6.8-98.8) and 2.5 (0.4-3.9) to 35.3 (23.9-887.7; p= 0.39) and 4.7 (2.2-37.7; p= 0.01), respectively. Likewise, SPECT studies showed a significant enlargement of the volume ≥30% 99mTc-DTPA uptake, with median (range) values before and after NGR-hTNF infusion of 26 cm3 (5 - 67) and 40 cm3 (10 - 92), respectively (p= 0.02), with a median volume increase of 45% (14-87%). As important features supporting the specificity of the effect of NGR-hTNF, CD13 was expressed in all diagnostic samples, and drug levels in CSF/plasma samples were not influenced by NGR-hTNF.Conclusions: NGR-hTNF/RCHOP is active and safe in pts with r/rPCNSL. NGR-hTNF enhances vascular permeability specifically in tumor lesions and perilesional areas, which was consistently demonstrated by DCE-MRI, SPECT and plasma/CSF pharmacokinetics studies and was in line with CD13 expression. Accrual completion is warranted. This innovative approach deserves to be addressed as first-line treatment in PCNSL pts. DisclosuresAngelucci:Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol; Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC; Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board; Roche Italy: Other: Local (national) advisory board; Celgene: Honoraria, Other: Chair DMC.