scholarly journals Preliminary Evaluation of Zanubrutinib-Containing Regimens in DLBCL and the Cerebrospinal Fluid Distribution of Zanubrutinib: A 13-Case Series

2021 ◽  
Vol 11 ◽  
Author(s):  
Yan Zhang ◽  
Yanan Li ◽  
Zhe Zhuang ◽  
Wei Wang ◽  
Chong Wei ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Kinase Inhibitor ◽  
Primary Cns Lymphoma ◽  
Case Series ◽  
B Cell Lymphoma ◽  
Fluid Distribution ◽  
Cns Lymphoma ◽  
Preliminary Evaluation ◽  
Retrospective Case ◽  
Liquid Chromatography Tandem Mass

Zanubrutinib is a second-generation Bruton’s tyrosine kinase inhibitor. Its safety and effectiveness in central nervous system (CNS) lymphoma along with its distribution in the brain and ability to cross the blood–brain barrier (BBB) remain unknown. This retrospective case series involved patients with diffuse large B-cell lymphoma (DLBCL) treated with zanubrutinib-containing regimens from August to December 2020 in PUMCH. The amounts of zanubrutinib in the plasma and brain were assessed by liquid chromatography–tandem mass spectrometry in paired plasma and cerebrospinal fluid (CSF) samples. In total, 13 patients were included: eight primary CNS lymphoma cases and five systemic DLBCL cases with 61.5% (8/13) refractory/relapsed and 84.6% (11/13) showing CNS involvement. The overall response rates were 84.5% in the entire population and 81.8% in the CNS-involved cases. A total of 23 time-matched plasma-CSF sample pairs were collected. The mean peak concentration of zanubrutinib in CSF was 2941.1 pg/ml (range, 466–9032.0 pg/ml). The corrected mean CSF/plasma ratio determined based on 94% protein binding was 42.7% ± 27.7% (range, 8.6%–106.3%). This preliminary study revealed the effectiveness of zanubrutinib-containing regimens in DLBLC, especially CNS-involved cases, for the first time. The excellent BBB penetration of zanubrutinib supports its further investigation for the treatment of CNS lymphoma.

scholarly journals Preliminary Results of Zanubrutinib-Containing Regimens in DLBCL and Cerebrospinal Fluid Distribution of Zanubrutinib

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4556-4556
Author(s):  
Yan Zhang ◽  
Yanan Li ◽  
Zhe Zhuang ◽  
Wei Wang ◽  
Chong Wei ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Tyrosine Kinase ◽  
Primary Cns Lymphoma ◽  
Fixed Time ◽  
Fluid Distribution ◽  
Cns Lymphoma ◽  
Liquid Chromatography Tandem Mass ◽  
Penetration Ability ◽  
Btk Inhibitor ◽  
Cns Lymphomas

Abstract Background: Zanubrutinib is a second-generation Bruton's tyrosine kinase (BTK) inhibitor. The safety and efficacy of zanubrutinib in CNS lymphoma are unknown, as well as its brain distribution through the blood-brain barrier. Objective: A retrospective study of zanubrutinib-containing regimens was performed in patients with DLBCL to evaluate the efficacy of zanubrutinib. Paired plasma and cerebrospinal fluid (CSF) samples were collected to assess zanubrutinib's permeability through the BBB. Methods: Consecutive DLBCL patients treated with zanubrutinib-containing regimens from August to December 2020 in PUMCH were recruited. Paired plasma and CSF samples were collected at a fixed time point after zanubrutinib administration. Plasma and brain zanubrutinib quantification was performed by liquid chromatography-tandem mass spectrometry. Results: Totally 13 patients were enrolled, including primary CNS lymphoma (n=8) and systemic DLBCL (n=5). 53.8% (7/13) were refractory/relapsed, 84.6% (11/13) had CNS involvement. Overall response rates (ORRs) were 84.5% and 81.8% in the whole population and CNS involved cases, respectively. A total of 23 time-matched plasma-CSF sample pairs were collected. The mean peak concentration of zanubrutinib in the CSF was 2941.1 pg/ml (range, 466-9032.0). The corrected mean CSF/plasma ratio by protein binding of 94.0% was 42.7±27.7% (range, 8.6-106.3%), indicating the good penetrating ability through the BBB of free drug. The CSF/plasm ratio was not influenced by sex, DLBCL subtype, co-administrated BBB penetrating drugs or plasma drug concentration. Conclusion: This preliminary study revealed the efficacy of zanubrutinib-containing regimens in DLBLC, especially CNSL, for the first time. The excellent BBB penetration of zanubrutinib supports its further investigation in CNS lymphomas. Disclosures Li: Astellas Pharma, Inc.: Research Funding. OffLabel Disclosure: Zanubrutinib is a selective Bruton Tyrosine kinase(BTK) inhibitor and is approved for WM, MCL and CLL/SLL in the Unite States and China. BTK inhibitors such as ibrutinib and tirabrutinib are highly effective in CNS lymphoma and have good penetration ability of brain-blood-barrier. We supposed that zanubrutinib should be effective in DLBCL and CNS lymphomas just as other BTKi,so we prescribed zanubrutinib in this study.

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.

Efficacy and Safety of DepoCyte® (Liposomal Cytarabine) in Patients with CNS Involvement from Non-Hodgkin’s Lymphoma (NHL): A Report on 32 Patients Treated in Spain.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2451-2451 ◽  
Author(s):  
José A. García-Marco ◽  
B. Navarro ◽  
E. Ruiz Sanz ◽  
L. Palomera ◽  
F.J. Capote ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Effects ◽  
Primary Cns Lymphoma ◽  
Case Series ◽  
B Cell Lymphoma ◽  
Cns Lymphoma ◽  
Liposomal Cytarabine ◽  
Time To Progression ◽  
Large B Cell Lymphoma ◽  
Neurological Progression

Abstract Lymphomatous meningitis (LM) occurs in approximately 7–15% of patients with lymphoma and carries an extremely poor prognosis (Chamberlain et al. CNS Drugs1998;10:25; Chowdary & Chamberlain J Natl Compr Canc Netw2005;3:693). Intrathecal (IT) chemotherapy with standard agents (cytarabine, methotrexate and thiotepa) is limited by the need for multiple injections per week via lumbar puncture or an Ommaya reservoir. Liposomal cytarabine (DepoCyte®) has an extended half-life in cerebrospinal fluid that permits fortnightly administration, improving convenience and reducing the potential for injection-related trauma and infections. Thirty-two Spanish patients (median age 43.5 years [range 19–78]; 22 male) with NHL received IT liposomal cytarabine for the treatment of LM between 2004 and 2006 at 21 treatment centers. Half of the patients had diffuse large B-cell lymphoma (DLBCL; n = 16); the remainder had Burkitt’s lymphoma (n = 4), T-cell NHL (n = 3), mucosa-associated lymphoid tissue lymphoma (n = 3), lymphoblastic lymphoma (n = 2), follicular lymphoma (n = 2) or primary CNS lymphoma (n = 1). A full histological diagnosis was not available for 1 patient. The dosage of liposomal cytarabine was 50 mg per cycle, with a median of 4 cycles (range 1–10). All patients received oral dexamethasone (4 mg 2–4 × daily for 4–7 days per cycle) as prophylaxis for chemical arachnoiditis. Neurological and cytological responses were obtained in 20 (62%; 16 complete responses, 4 partial responses; Figure 1) and 25 (78%) patients, respectively. Neurological progression was subsequently reported in 23 (72%) patients, with a median time to progression of 45 days (range 7–570). Twelve patients were still alive at the time of reporting, including 5 of 16 patients with DLBCL and 2 of 3 patients with T-cell NHL. Eighteen patients reported no adverse effects from treatment. The most commonly reported adverse effects were headache (n = 11), nausea (n = 4) and vomiting (n = 4). Data from this case series show that IT liposomal cytarabine is effective and well tolerated in the treatment of LM; the less intensive administration schedule of the agent may offer additional benefits to patients and their carers during the final months of life. Figure Figure

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.

Primary CNS lymphoma after CLIPPERS: a case series

2021 ◽  
pp. jnnp-2020-325759
Author(s):  
Sofia Doubrovinskaia ◽  
Felix Sahm ◽  
Marc Christian Thier ◽  
Martin Bendszus ◽  
Wolfang Wick ◽  
...  
Keyword(s):  
Primary Cns Lymphoma ◽  
Case Series ◽  
Cns Lymphoma

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 P.108 Diffuse large B-cell Lymphoma secondary to iatrogenic immunosuppression with unusual MRI findings and literature review

2016 ◽  
Vol 43 (S2) ◽  
pp. S45-S45 ◽  
Author(s):  
AH Naeem ◽  
MD Staudt ◽  
B Wang ◽  
D Lee ◽  
A Parrent
Keyword(s):  
Literature Review ◽  
B Cell ◽  
Cell Lymphoma ◽  
Immunosuppressive Agents ◽  
Primary Cns Lymphoma ◽  
B Cell Lymphoma ◽  
Cns Lymphoma ◽  
Mri Findings ◽  
Axial Mass ◽  
Large B Cell

Background: Immunosuppressive therapy is a risk factor for lymphoproliferative disorders. We present a case of primary CNS B-cell lymphoma in the setting of iatrogenic immunosuppression from azathioprine usage. A literature review is provided. Methods: Case report Results: 64-year-old male presents with several weeks of cognitive decline, impaired speech, and headache with a history of ulcerative colitis (on azathioprine and 5-ASA) with no radiological evidence of systemic malignancy. MR showed left frontal extra-axial mass (4.0 x 2.4 x 4.0 cm) with heterogeneous enhancement of a solid component with local dural thickening. The enhancing mass had solid and cystic components. Radiological differential included dural metastasis, atypical meningioma or unusual intra-axial mass including GBM with some dural involvement. He underwent surgical resection, which showed a primary CNS lymphoma, diffuse large B-cell, CD 20 + and EBV +. Post-operatively his cognition improved. Azathioprine was stopped and 5-ASA was increased. He proceeded with MPVC (methotrexate, procarbazine, vincristine, and cytarabine) chemotherapy. Conclusions: Our case shows isolated extra-nodal CNS manifestation of lymphoma in the context of immunosuppressive medications with strikingly atypical MR findings leading to a pre-operative diagnostic dilemma. Treatment is challenging and needs to be individually tailored due to a need for stopping immunosuppressive agents in conjunction with CNS lymphoma treatment.

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