INNV-28. POTENTIAL EFFECTIVE CONSOLIDATION THERAPY WITH SINGLE AGENT IBRUTINIB FOR A CASE WITH PRIMARY CNS LYMPHOMA AFTER INITIAL HD-MTX AND RITUXIMAB INDUCTION THERAPY

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi111-vi111
Author(s):  
Steven Du ◽  
Uvin Ko ◽  
Daniela Bota ◽  
Xiao-Tang Kong
Keyword(s):  
Induction Therapy ◽  
Kinase Inhibitor ◽  
Brain Mri ◽  
Single Agent ◽  
Primary Cns Lymphoma ◽  
B Cell Lymphoma ◽  
Cns Lymphoma ◽  
High Dose ◽  
Consolidation Therapy ◽  
Left Lateral Ventricle

Abstract INTRODUCTION Primary CNS Lymphoma (PCNSL) is a rare and aggressive cancer that originates from lymphocytes and develops in the central nervous system. Standard induction therapy involves high-dose methotrexate (HD-MTX)-based chemotherapy, which achieves complete or partial response in most PCNSL patients. However, there is no standard consolidation therapy. We report one case in which ibrutinib, a Bruton’s tyrosine kinase inhibitor, replaced low-dose WBRT as consolidation therapy after induction by HD-MTX and rituximab. Ibrutinib treatment yielded good tolerance and further resolution of small residue lymphoma. CASE REPORT The patient is a 77-year-old female who presented with slurred speech, right-sided weakness, and difficulty word-finding in early 2020. Brain MRI found multifocal lesions, and biopsy of the largest lesion near the left lateral ventricle revealed diffuse large B cell lymphoma. The patient began HD-MTX at 6 g/m2 for the first cycle of induction therapy. She continued HD-MTX every two weeks, but dosage was reduced every cycle due to worsening renal function. Ultimately, MTX was discontinued after 6 cycles. Brain MRI showed significant response after HD-MTX except for small residue lymphoma at the biopsy area. 2nd line regimen rituximab and temozolomide was given to complete induction. Brain MRI was stable, but the small enhancing residue lymphoma at left peri-ventricle area was persistent after the induction therapy (uCR). Ibrutinib as consolidation therapy began after discussion with the patient. The patient tolerated 560 mg ibrutinib for 6 cycles initially, then switched to a reduced dose of 420 mg for cycles 7 and 8 due to neutropenia. Brain MRIs have been stable with resolution of the small lymphoma residue after 6 cycles of ibrutinib. The patient continues ibrutinib for the goal of one year of consolidation therapy. DISCUSSION Our case highlights the potential of single-agent ibrutinib as consolidation therapy for PCNSL after HD-MTX and rituximab/temzolomide induction therapy.

INNV-29. BILATERAL PARIETAL LYMPHOMA LESIONS RESPONDED DIFFERENTLY TO HD-MTX AND RITUXIMAB/TEMOZOLOMIDE THERAPY

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi111-vi112
Author(s):  
Xiao-Tang Kong ◽  
Steven Du ◽  
Yoon Jae Choi ◽  
Daniela Bota
Keyword(s):  
Treatment Regimen ◽  
Brain Mri ◽  
Single Agent ◽  
Specific Treatment ◽  
Primary Cns Lymphoma ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Cns Lymphoma ◽  
Induction Phase ◽  
Combination Regimen

Abstract INTRODUCTION Primary CNS lymphoma is a rare aggressive hematological malignancy. Current chemotherapy for induction phase is HD-MTX single agent or HD-MTX based combination regimen. We report a rare case whose left and right parietal lymphoma lesions in the brain responded to different induction therapy regimens during the induction phase. CASE REPORT A 43-year-old female presented with seizure and her brain MRI showed bilateral parietal brain lesions in January of 2020. Biopsy and work-up revealed primary CNS diffuse large B-cell lymphoma (DLBCL). The patient underwent HD-MTX therapy. Brain MRI showed clear progression of left parietal lymphoma but stable right parietal lymphoma after two cycles of HD-MTX at 8 g/m2. The treatment was switched to a rituximab 750 mg/m2 weekly and temozolomide 150 mg/m2 daily one-week-on and one-week-off regimen. After 8 weeks, her brain MRI showed nearly complete response of her left parietal lymphoma to rituximab/temozolomide but progression of her right parietal lymphoma. She was switched back to HD-MTX and completed total 8 cycles. Her right parietal lymphoma lesion showed complete response to HD-MTX. The patient is doing well and has been off the treatment over the past 10 months and is waiting for consolidation therapy with autologous stem cell transplantation that has been postponed due to the COVID pandemic. DISCUSSION Our case highlights the very rare heterogenous feature of primary CNS lymphoma responding to different treatment regimen. Biopsy of bilateral heterogeneous lesions may be indicated to compare the different molecular features of the lymphoma to find underlying mechanism if they respond to treatment differently. Specific treatment regimen should be selected based on the responsiveness of CNS lymphoma lesions or combination therapy is selected to cover the heterogeneous susceptibility to chemotherapy regimens.

scholarly journals Midostaurin in Combination with Intensive Induction and As Single Agent Maintenance Therapy after Consolidation Therapy with Allogeneic Hematopoietic Stem Cell Transplantation or High-Dose Cytarabine (NCT01477606)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 322-322 ◽  
Author(s):  
Richard Schlenk ◽  
Konstanze Döhner ◽  
Helmut Salih ◽  
Andrea Kündgen ◽  
Walter Fiedler ◽  
...  
Keyword(s):  
Stem Cell ◽  
Maintenance Therapy ◽  
Induction Therapy ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
High Dose ◽  
Consolidation Therapy ◽  
Hematopoietic Stem ◽  
High Dose Cytarabine ◽  
Induction Cycle

Abstract Background: Internal tandem duplications (ITD) in the receptor tyrosine kinase FLT3 occur in roughly 25% of younger adult patients (pts) with acute myeloid leukemia (AML), implicating FLT3 as a potential target for kinase inhibitor therapy. The multi-targeted kinase inhibitor midostaurin shows potent activity against FLT3 as a single agent but also in combination with intensive chemotherapy. Aims: To evaluate the feasibility and efficacy of midostaurin in combination with intensive induction therapy and as single agent maintenance therapy after allogeneic hematopoietic stem cell transplantation (alloHSCT) or high-dose cytarabine (HIDAC). Methods: The study includes adult pts (age 18-70 years (yrs)) with newly diagnosed FLT3-ITD positive AML enrolled in the ongoing single-arm phase-II AMLSG 16-10 trial (NCT: NCT01477606). Pts with acute promyelocytic leukemia are not eligible. The presence of FLT3-ITD is analyzed within our diagnostic study AMLSG-BiO (NCT01252485) by Genescan-based fragment-length analysis (allelic ratio >0.05 required to be FLT3-ITD positive). Induction therapy consists of daunorubicin (60 mg/m², d1-3) and cytarabine (200 mg/m², continuously, d1-7); midostaurin 50 mg bid is applied from day 8 onwards until 48h before start of the next treatment cycle. A second cycle is optional. For consolidation therapy, pts proceed to alloHSCT as first priority; if alloHSCT is not feasible, pts receive three cycles of age-adapted HIDAC in combination with midostaurin from day 6 onwards. In all pts maintenance therapy for one year is intended. This report focuses on the first cohort of the study (n=149) recruited between June 2012 and April 2014 prior to the amendment increasing the sample size; the amendment to the study is active since October 2014. Results: At study entry patient characteristics were median age 54 years (range, 20-70, 34% ≥ 60 yrs); median white cell count (WBC) 48.4G/l (range 1.1-178G/l); karyotype, n=103 normal, n=3 t(6;9), n=2 t(9;11), n=20 intermediate-2 and n=7 high-risk according to ELN recommendations, n=14 missing; mutated NPM1 n=92 (62%). Data on response to first induction therapy were available in 147 pts; complete remission (CR) 58.5%, partial remission (PR) 20.4%, refractory disease (RD) 15% and death 6.1%. A second induction cycle was given in 34 pts. Overall response after induction therapy was CR 75% and death 7.5%. Adverse events 3°/4° reported during the first induction cycle were most frequently gastrointestinal (n=34) and infections (n=81). During induction therapy midostaurin was interrupted, dose-reduced or stopped in 55% of the pts. Overall 94 pts received an alloHSCT, 85 in first CR (n=65 age<60 yrs, n=20 age ≥60 yrs) and 9 pts after salvage outside the protocol or after relapse (n=70 from a matched unrelated and n=24 from a matched related donor). In pts receiving an alloHSCT within the protocol in median 2 chemotherapy cycles were applied before transplant (range 1-4) and the cumulative incidence of relapse and death at 12 months were 9.2% (SE 3.3%) and 19.5% (SE 4.8%). Maintenance therapy was started in 52 pts, 40 pts after alloHSCT and 12 pts after HIDAC. Only 4 adverse events 3°/4° were attributed to midostaurin. First analyses revealed a low cumulative incidence of relapse irrespective of the FLT3-ITD mutant to wildtype ratio (<0.5 versus ≥0.5) in patients proceeding to alloHSCT with 12% and 5% as well as for those after HIDAC consolidation with 28% and 29%, respectively. Conclusions: The addition of midostaurin to intensive induction therapy and as maintenance after alloHSCT or HIDAC is feasible and compared to historical data may be most effective in those patients with a high FLT3-ITD mutant to wildtype ratio. Disclosures Schlenk: Novartis: Honoraria, Research Funding. Salwender:Celgene: Honoraria; Janssen Cilag: Honoraria; Bristol Meyer Sqibb: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Götze:Celgene Corp.: Honoraria; Novartis: Honoraria.

What is the role of whole brain radiation therapy (WBRT) and high-dose cytarabine (Ara-C) as consolidation treatment after initial chemotherapy for primary CNS lymphoma (PCNSL)?

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2013-2013
Author(s):  
M. Ekenel ◽  
F. M. Iwamoto ◽  
L. S. Ben Porat ◽  
K. S. Panageas ◽  
J. Yahalom ◽  
...  
Keyword(s):  
Combined Modality Therapy ◽  
Significant Risk ◽  
Primary Cns Lymphoma ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Cns Lymphoma ◽  
High Dose ◽  
Consolidation Therapy ◽  
Whole Brain Radiation ◽  
Significant Difference

2013 Background: Optimal management of PCNSL is not defined. To date the best outcomes have been achieved by combined modality therapy using methotrexate (MTX)-based chemotherapy and WBRT. However, WBRT carries a significant risk of neurotoxicity and may not be required in all patients. Methods: We retrospectively analyzed the data of 122 patients who had complete response (CR) after initial chemotherapy, from a total of 338 PCNSL patients treated in our institution since 1986. Descriptive variables including sex, age, KPS at diagnosis, histology, and extent of CNS involvement were reported. We specifically studied the benefit of consolidation therapy with WBRT and/or high dose Ara-C on OS and PFS. Results: The median age was 60 (19–89) years and a median KPS was 70. Men constituted 57% of the patients. Median follow up was 30 months. Histologically, 83% had diffuse large B cell lymphoma. Ocular and CSF involvements were 13%, and 27%, respectively. Most patients received MTX-based regimens (96%). Five-year OS was 43% and five-year PFS was 50% for all patients. There was no significant difference in OS, between patients who received consolidation therapy with Ara-C (n=35), WBRT (n=12), Ara-C + WBRT (n=28), or no consolidation (n=42) [data from 5 patients are missing]. There was a trend towards improved disease control for patients treated with WBRT; however, these patients were also younger than the other groups. Risk of neurotoxicity was significantly higher in patients who received WBRT (p=0.005). Conclusions: Consolidation therapy does not clearly improve survival in PCNSL patients with a CR to initial treatment. However other important prognostic factors including age and KPS may have been used in the decision making related to consolidation therapy. [Table: see text] No significant financial relationships to disclose.

scholarly journals Ibrutinib in primary central nervous system diffuse large B-cell lymphoma

CNS Oncology ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. CNS51 ◽  
Author(s):  
Justin T Low ◽  
Katherine B Peters
Keyword(s):  
Kinase Inhibitor ◽  
Cell Lymphoma ◽  
Primary Cns Lymphoma ◽  
B Cell Lymphoma ◽  
Cns Lymphoma ◽  
High Dose ◽  
Standard Regimen ◽  
Large B Cell Lymphoma ◽  
Dose Methotrexate ◽  
Bruton Tyrosine Kinase

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.

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

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 15-16
Author(s):  
Khe Hoang-Xuan ◽  
Roch Houot ◽  
Carole Soussain ◽  
Marie Blonski ◽  
Anna Schmitt ◽  
...  
Keyword(s):  
Objective Response ◽  
Primary Cns Lymphoma ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
Cns Lymphoma ◽  
High Dose ◽  
Moderate Activity ◽  
Multicentric Study ◽  
First Results ◽  
Duration Of Response

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>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.

scholarly journals Del(6)(q22) and BCL6 Rearrangements in Primary CNS Lymphoma Are Indicators of an Aggressive Clinical Course

2008 ◽  
Vol 26 (29) ◽  
pp. 4814-4819 ◽  
Author(s):  
Francois M. Cady ◽  
Brian Patrick O'Neill ◽  
Mark E. Law ◽  
Paul A. Decker ◽  
David M. Kurtz ◽  
...  
Keyword(s):  
Survival Data ◽  
Proportional Hazards ◽  
Deep Structure ◽  
Primary Cns Lymphoma ◽  
B Cell Lymphoma ◽  
Aggressive Lymphoma ◽  
Cns Lymphoma ◽  
High Dose ◽  
Putative Tumor Suppressor Gene ◽  
Thin Sections

Purpose Primary CNS lymphoma (PCNSL) is an aggressive lymphoma but clinically validated biologic markers that can predict natural history to tailor treatment according to risk are lacking. Several genetic changes including BCL6 rearrangements and deletion of 6q22, containing the putative tumor suppressor gene PTPRK, are potential risk predictors. Herein we determined the prevalence and survival impact of del(6)(q22) and BCL6, immunoglobulin heavy chain (IGH), and MYC gene rearrangements in a large PCNSL cohort treated in a single center. Patients and Methods Interphase fluorescence in situ hybridization was performed using two-color probes for BCL6, MYC, IGH-BCL6, and del(6)(q22) on thin sections of 75 paraffin-embedded samples from 75 HIV-negative, immunocompetent patients newly diagnosed with PCNSL. Survival data were analyzed using Kaplan-Meier survival curves, log-rank tests, and proportional hazards regression adjusting for age, deep structure involvement, and high-dose methotrexate (HDMTX) treatment. Results The prevalence of del(6)(q22) and BCL6, IGH, and MYC translocations was 45%,17%, 13%, and 3%, respectively. The presence of del(6)(q22) and/or a BCL6 translocation was associated with inferior overall survival (OS; P = .0097). The presence of either del(6)(q22) alone or a BCL6 translocation alone was also associated with inferior OS (P = .0087). Univariable results held after adjusting for age, deep structure involvement, and HDMTX. Conclusion Del (6)(q22) and BCL6 rearrangements are common in PCNSL and predict for decreased OS independent of deep structure involvement and HDMTX. Unlike systemic diffuse large B-cell lymphoma, del(6)(q22) is common and IGH translocations are infrequent and usually involve BCL6 rather than BCL2, suggesting a distinct pathogenesis.

scholarly journals PC3 - 128 Clinical Profile and Treatment Outcomes of Patients with Primary CNS Lymphoma in a Tertiary Hospital in the Philippines: An Eight-Year Retrospective Review

2016 ◽  
Vol 43 (S4) ◽  
pp. S20-S20
Author(s):  
M.C. Concepcion Sales
Keyword(s):  
Survival Rate ◽  
Combination Chemotherapy ◽  
Single Agent ◽  
Primary Cns Lymphoma ◽  
B Cell Lymphoma ◽  
The Philippines ◽  
Clinical Profile ◽  
Treatment Modalities ◽  
Cns Lymphoma ◽  
Female Ratio

Primary CNS Lymphoma (PCNSL) is an unusual extranodal form of Non-Hodgkin’s lymphoma with a locally aggressive course but a rare tendency to disseminate systemically. It has been documented in that the clinical characteristics and response to treatment among Asians is comparable to the Western population yet no studies done locally are available. Objectives: This study aims to determine the clinico-pathologic profile of patients diagnosed with PCNSL seen at Philippine General Hospital (PGH) from January 2006 to September, 2014 and to evaluate the patients’ response to the following treatment modalities: 1) Combination chemotherapy 2) Chemo-RT 3) Single agent chemotherapy and 4) no specific anti-lymphoma treatment. Methodology: This is a descriptive and retrospective study that included all cases of histologically-proven PCNSL seen at the PGH from January 2006 to September, 2014. The clinical profile, imaging studies and biopsy findings were obtained from the patient records. The survival rates at the end of one and two years of diagnosis were computed. Results and Conclusion. Among patients diagnosed with PCNSL at PGH, there is a higher incidence of PCNSL among males with a male to female ratio of 1.4:1 and have a younger onset with a median age of 50.2 years. Most patients presented with signs of increase ICP and majority had solitary cortical lesions with histopathologic diagnosis of diffuse large B cell lymphoma. Patients who did not undergo any form of treatment had a mean survival of 10 months. Immunocompromised patients had a shorter life-span with a mean survival of 7.5 months. Treatment of combination chemotherapy with HD-MTX and Rituximab had the most favorable outcome followed by HD-MTX only with a 2 year survival rate of 100% and 66% respectively while patients who underwent chemo-RT had a 2 year survival rate of 33% with a high incidence of neurocognitive delay.

Treatment of primary CNS lymphoma with induction high-dose methotrexate, temozolomide, rituximab followed by consolidation cytarabine/etoposide: A pilot study with biomarker analysis

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7595-7595 ◽  
Author(s):  
S. Issa ◽  
J. Hwang ◽  
J. Karch ◽  
J. Fridlyand ◽  
M. Prados ◽  
...  
Keyword(s):  
Induction Therapy ◽  
Primary Cns Lymphoma ◽  
Cns Lymphoma ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Whole Brain Irradiation ◽  
Whole Brain ◽  
Brain Irradiation ◽  
Dose Methotrexate ◽  
Biomarker Analysis

7595 Background: There is currently no consensus on the optimal treatment for patients diagnosed with primary CNS lymphoma (PCNSL). Between 2001–2004, UCSF PCNSL patients were treated with combination high-dose methotrexate, temozolomide, rituximab (MTR) as induction therapy. Patients in CR with this regimen were treated with high-dose cytarabine plus etoposide as consolidation. The purposes of this study were: (1) Pilot analysis to determine the safety and efficacy of intensive methotrexate-based induction therapy followed by high-dose consolidation with elimination of whole brain irradiation; (2) Analysis of molecular markers in PCNSL which predict sensitivity to chemotherapy and outcome. Methods: 21 untreated, CD20 +, immunocompetent PCNSL patients were treated with combination methotrexate (8 gm/m²), temozolomide (150 mg/m²/day)and rituximab (375 mg/m²). Patients in CR received consolidation cytarabine (2 g/ m² x 8 doses) plus etoposide (40 mg/kg over 96 hours). IHC analysis of potential biomarkers predictive of outcome was performed on paraffin sections from these patients. Candidate markers for validation were selected by gene expression analysis of an independent, multicenter dataset of 20 cases. Results: Mean age was 58.6 y (range 40–81). Median KPS was 60. MTR and cytarabine/etoposide consolidation was well-tolerated with no treatment-related mortality or evidence for neurotoxicity. One case of post-remission cytopenia occurred after consolidation and resolved spontaneously. Eleven patients (52.4%) attained CR with induction; eight received consolidation; three patients in CR deferred consolidation. Median PFS was 11.5 months. Median OS for all 21 patients has not yet been reached with median follow-up of 27.5 months. Expression of the apoptotic regulator DAP-1 by lymphoma cells as determined by IHC was associated with improved PFS (p<0.028) and OS (p<0.021). Conclusions: Combination MTR followed by intensive consolidation appears to be well tolerated in PCNSL. PFS appears at least similar to regimens that contain whole brain irradiation. A larger phase II study has been initiated to evaluate this regimen in a multicenter setting. [Table: see text]

Phase 1B of ibrutinib and high-dose methotrexate for recurrent/refractory CNS lymphoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7533-7533 ◽  
Author(s):  
Christian Grommes ◽  
Jacqueline Stone ◽  
Craig Nolan ◽  
Elina Tsyvkin ◽  
Julia Wolfe ◽  
...  
Keyword(s):  
Adverse Events ◽  
Systemic Disease ◽  
Single Agent ◽  
Primary Cns Lymphoma ◽  
Cns Lymphoma ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Newly Diagnosed ◽  
Dose Methotrexate ◽  
Phase 1B

7533 Background: Primary CNS Lymphoma (PCNSL) is an aggressive primary brain tumor. Outcome and treatment options for patients with recurrent/refractory (r/r) disease are poor. We have observed promising efficacy of single agent ibrutinib in r/r PCNSL and secondary CNS lymphoma (SCNSL). In this phase 1B trial, we investigate the toxicity of ibrutinib in combination with high-dose methotrexate (HD-MTX) in r/r PCNSL/SCNSL. Methods: Eligible patients had r/r PCNSL/SCNSL or newly diagnosed SCNSL, age≥18, ECOG≤2, normal end-organ function, and with any number and type of prior therapies. In patients with SCNSL disease, systemic disease needed to be absent. HD-MTX was given at 3.5g/m2 every 2 weeks for a total of 8 doses. To minimize adverse events, ibrutinib was stopped on days of HD-MTX infusion and was restarted 5 days after MTX infusion or after completion of MTX-clearance, if clearance of MTX required more than 5 days. Ibrutinib was continued daily after completion of 8 doses of MTX. Results: Six patients have been enrolled; 3 received 560mg and 3 received 840mg ibrutinib in combination with HD-MTX. Median age was 62 (range 43-74); median ECOG 1 (0:2; 1:3; 2:1). Two had r/r PCNSL and 4 SCNSL. Three had brain disease, one isolated cerebrospinal fluid (CSF) involvement and two parenchymal and CSF involvement. Three patients had recurrent (2 PCNSL; 1 SCNSL), two refractory (both SCNSL), and one newly diagnosed disease (SCNSL). There were no grade 4 adverse events. Grade 3 events were observed in 5 patients (lymphopenia in 3, ALT elevation in 2, diarrhea in 1, electrolyte changes in 1, hypertension in 1). The most common adverse events were hypokalemia, low WBC, hyperglycemia, ALT and AST elevation. There was no dose reduction of methotrexate or ibrutinib in any patient. After a median follow-up of 130 days, all patients were evaluated for response after 4 doses of HD-MTX, with 4/6 (67%) showing a response: 2 CR, 2 PR, and 1 SD, 1 PD; both non-responders were refractory SCNSL. Ibrutinib concentrations were measured in plasma and CSF. Conclusions: Patients with CNS lymphoma tolerate the combination of HD-MTX and Ibrutinib (at 560 and 840mg) well. Continued enrollment into a combination arm that includes rituximab, methotrexate and ibrutinib is ongoing. Clinical trial information: NCT02315326.

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