Phase I Study of Dose-Adjusted-Teddi-R with Ibrutinib in Untreated and Relapsed/Refractory Primary CNS Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 472-472 ◽  
Author(s):  
Kieron Dunleavy ◽  
Catherine E. Lai ◽  
Mark Roschewski ◽  
Jennifer N Brudno ◽  
Brigitte Widemann ◽  
...  
Keyword(s):  
Protein Binding ◽  
B Cell ◽  
Brain Mri ◽  
Primary Cns Lymphoma ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
Cns Lymphoma ◽  
Csf Penetration ◽  
Mixed Response ◽  
Therapeutic Principles

Abstract Introduction: Primary central nervous system lymphoma (PCNSL) is a rare type of diffuse large B-cell lymphoma (DLBCL). It closely resembles activated B-cell (ABC) DLBCL and most cases have B cell receptor (BCR) and MyD88 mutations. Ibrutinib is an inhibitor of BTK that targets BCR signaling and is active in patients with relapsed/refractory (R/R) ABC DLBCL. Methods: Ibrutinib was incorporated into a novel regimen called DA-TEDDI-R (temozolomide, etoposide, doxil, dexamethasone, ibrutinib and rituximab) (with intraventricular cytarabine). DA-TEDDI-R was designed around therapeutic principles for systemic DLBCL and CNS penetration. Methotrexate was excluded due to potential antagonism with ibrutinib based on preliminary in vitro experiments. Untreated or R/R PCNSL patients were eligible and received ibrutinib in cohorts (560-1120 mg/day PO) for 14-days in a "window" prior to cycle 1 of DA-TEDDI-R (with pre and post-brain MRI/FDG-PET), followed by DA-TEDDI-R with ibrutinib (days 1-10) q21 days x 6. Plasma and CSF PKs of ibrutinib and its metabolite PCI-45227 were analyzed. CSF penetration (AUCCSF: AUCPLASMA) was corrected for human plasma protein binding: parent: 97.3%, metabolite: 91%. CSF PKs of TEDDI drugs and molecular analysis of FFPE biopsies are ongoing. Results: Eleven patients have enrolled; 6 were R/R (median 3 (1-5) prior treatments) and 5 were previously untreated. Eleven completed the ibrutinib window and 5 patients completed and 2 remain on DA-TEDDI-R; Ibrutinib dosing was 560 mg in patients 1-6; 700 mg in patients 7-10; and 840 mg in patient 11. No patient had dose limiting toxicity determined on cycle 1 of DA-TEDDI-R. There were 3 on-study deaths: from progressive disease, infection and ventricular arrhythmia. Ibrutinib PK was completed in patients 1-10 (Table). When corrected for protein binding, CSF penetration was 21.4-100% for ibrutinib and 48-120% for its metabolite. CSF concentrations > IC50were maintained for a median of 4 hours and 8.5 hours at the 560 mg and 700 mg doses, respectively. With ibrutinib alone, 7 of 8 evaluable patients achieved partial responses, and 1 patient had a mixed response. After DA-TEDDI-R, all 5 patients achieved complete remission of which 4 (all R/R) are in remission at 1+, 2+, 3+, and 6+ months, and 1 (previously untreated) patient relapsed at 3 months. Conclusions: Ibrutinib is active in PCNSL and achieves meaningful CSF concentrations. DA-TEDDI-R is a novel treatment for PCNSL and leverages molecular and therapeutic principles developed for the curative treatment of ABC DLBCL. Accrual continues. Table. Plasma Ibrutinib PK CSF Ibrutinib PK CSF penetration Hours above IC50(0.5nM) Dose 560 mg Cmax(nM) Tmax(h) AUC0-10 (nM•h) T½(h) Cmax(nM) Tmax(h) AUC0-last (nM•h) AUCCSF : AUCPlasma (%) AUCCSF :AUCPlasmaCorrected (%) Plasma CSF 1 502 1 1232 10.2 1.99 2 7.7 (10h) 0.6 23.7 24 4 2 145 2 471 4.6 0.69 2 2.4 (6h) 0.5 21.4 24 2 3 77 2 347 3.1 1.28 2 4.4(6hr) 1.3 55.8 24 4 4 72 1 202 2.6 1.54 4 5.5 (10hr) 2.7 100 24 8 5 162 2 624 8.5 2.0 2 9.2 (10hr) 1.5 54.9 24 10 6 99 1 404 6.3 0.71 2 3.4 (4hr) 1.2 45 24 4 Median 122 1.5 437 5.5 1.4 2 5 1.3 50 24 4 Range 75-502 1-2 202-1232 2.6-10.2 0.7-2 2-4 2.4 9.2 21.4-100 24 2-10 Dose 700mg 7 581 1 2340 5.3 11.1 2 48.6 (24) 1.7 (10) 63 (10) 24 10 8 411 2 1565 2.4 1.63 2 11.9 (10) 0.8 28.1 10 10 9 164 2 865 3.8 0.69 4 3.9(10) 0.45 16.7 24 3 10 577 2 1648 5.4 2.36 2 11.0(10) 0.67 24.8 24 7 Median 494 2 1606 4.6 1.98 2 11.5(10) 0.74 26.5 24 8.5 Range 164-581 1-2 865-2340 2.4-5.4 0.69-11.1 2-4 3.9-48.6 0.45-1.7 16.7-63 10-24 3-10 Disclosures Staudt: Pharmacyclics LLC, an AbbVie Company: Patents & Royalties, Research Funding; NIH: Patents & Royalties.

scholarly journals EBV-tissue positive primary CNS lymphoma occurring after immunosuppression is a distinct immunobiological entity

Blood ◽  
2020 ◽  
Author(s):  
Maher K Gandhi ◽  
Thanh Hoang ◽  
Soi C Law ◽  
Sandra Brosda ◽  
Kacey O'Rourke ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Primary Cns Lymphoma ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
Hla Class I ◽  
Cns Lymphoma ◽  
Copy Number Loss ◽  
Cell Of Origin ◽  
Systemic Spread

Primary central nervous system lymphoma (PCNSL) is confined to the brain, eyes, and cerebrospinal fluid without evidence of systemic spread. Rarely, PCNSL occurs in the context of immunosuppression, e.g. post-transplant lymphoproliferative disorders (PTLD) or HIV (AIDS-related PCNSL). These cases are poorly characterized, have dismal outcome and are typically Epstein-Barr virus (EBV)-tissue positive. We used targeted sequencing and digital multiplex gene expression to compare the genetic landscape and tumor microenvironment (TME) of 91 PCNSL tissues all with diffuse large B-cell lymphoma histology. 47 were EBV-tissue negative: 45 EBV(-) HIV(-) PCNSL, 2 EBV(-) HIV(+) PCNSL; and 44 were EBV-tissue positive: 23 EBV(+) HIV(+) PCNSL, 21 EBV(+) HIV(-) PCNSL. As with prior studies, EBV(-) HIV(-) PCNSL had frequent MYD88, CD79B and PIM1 mutations, and enrichment for the activated B-cell (ABC) cell-of-origin (COO) sub-type. In contrast, these mutations were absent in all EBV-tissue positive cases and ABC frequency was low. Furthermore, copy number loss in HLA-class I/II and antigen presenting/processing genes were rarely observed, indicating retained antigen presentation. To counter this, EBV(+) HIV(-) PCNSL had a tolerogenic TME with elevated macrophage and immune-checkpoint gene expression, whereas AIDS-related PCNSL had low CD4 gene counts. EBV-tissue positive PCNSL in the immunosuppressed is immunobiologically distinct from EBV(-) HIV(-) PCNSL, and despite expressing an immunogenic virus retains the ability to present EBV-antigens. Results provide a framework for targeted treatment.

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.

No Benefit from Rituximab Containing Regimens in Patients with Primary Extranodal Diffuse Large B-Cell Lymphoma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3615-3615
Author(s):  
Gonzalo Gutiérrez-García ◽  
Luis Colomo ◽  
Neus Villamor ◽  
Leonor Arenillas ◽  
Antonio Martínez ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Primary Cns Lymphoma ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Cns Lymphoma ◽  
Large B Cell Lymphoma ◽  
The Impact ◽  
Large B Cell

Abstract Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous category of lymphoid tumors that comprises different clinical forms not fully recognized in the WHO classification. In this regard, extranodal (EN) DLBCLs have particular clinicobiological features and outcome, sometimes related to the specific site where the lymphoma arises. Nowadays, rituximab plus chemotherapy (CT) is the gold-standard in the treatment of DLBCL. However, the superiority of rituximab-CT (R-CT) over CT alone has not been addressed for all the clinical subsets of the disease and, in fact, the clinical role of the new therapies might be different for primary nodal or EN DLBCLs. The aim of this study was to assess the impact of rituximab in patients suffering from nodal or EN DLBCL. Two-hundred and thirty non-immunocompromised patients (112M/118F; median age, 61 years) diagnosed with CD20+DLBCL in a single institution between 1997 and 2006 (five years before and after establishing R-CT as the standard treatment in DLBCL) and treated with adriamycin-containing regimens were the subject of the present study. The series included 148 primary nodal and 82 EN DLBCL. Patients with primary CNS lymphoma were excluded and lymphomas arising at Waldeyer ring were considered as nodal DLBCL. The main EN sites were GI (n=26), bone (n=13), soft tissue (n=13), lung/pleura (n=9), liver (n=9), and other (n=12). Main clinico-biological and evolutive variables were analyzed. One hundred nineteen patients received only CT and 111 R-CT. Eighty-seven cases with available information were assigned to germinal center B-cell-like (GCB) (41%) or non-GCB (59%) groups according to the Hans method (Blood2004;103:275–82) based on CD10, BCL6 and MUM1 expression. Main initial features, including the primary nodal or EN origin, international prognostic index (IPI), and GCB/non-GCB categories were similar for CT and R-CT groups. No correlation was observed between the GCB/non-GCB groups and the primary site of the tumor, although nodal lymphomas more frequently expressed MUM1 than EN (69% vs. 31%, respectively; p=0.01). CR rate and 5-year overall survival (OS) according to the treatment arm (CT vs. R-CT) is detailed for the whole series and for the nodal and EN groups in the table and OS curves depicted in the figure. In the whole series, variables predicting poor OS in the multivariate analysis were high-risk IPI (RR 2.5; p<0.001), primary nodal involvement (RR 1.6; p=0.04) and no R-CT treatment (RR 1.9; p=0.002). In the nodal group, IPI and no R-CT maintained the prognostic value, whereas in the primary EN only IPI predicted OS. Moreover, no difference in OS was observed according to the nodal or EN origin in those patients receiving R-CT. Biological subtypes GCB vs. non-GCB did not add predictive information neither in the whole series nor in the nodal or EN groups. In conclusion, patients with primary EN DLBCL seem to have little benefit from the use of R-CT. Nevertheless, this intriguing observation should be confirmed in further prospective studies. Complete response CR (%) 5-years OS (%) CT R-CT CT R-CT *p<0.002 R-CT vs. CT All cases (n=230) 59 79* 46 70* Primary nodal (n=148) 54 78* 34 71* Primary extranodal (n=82) 68 78 70 69 Figure Figure

scholarly journals Mutated MYD88 Regulates HCK Pro-Survival Signaling through JunB in MYD88 Mutated B-Lymphoma Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3778-3778
Author(s):  
Xia Liu ◽  
Jiaji G Chen ◽  
Manit Munshi ◽  
Lian Xu ◽  
Amanda Kofides ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
B Cell ◽  
Tyrosine Kinases ◽  
Research Funding ◽  
Primary Cns Lymphoma ◽  
B Cell Lymphoma ◽  
Cns Lymphoma ◽  
Lymphoma Cells ◽  
Cell Commitment ◽  
Myd88 Signaling

Hematopoietic cell kinase (HCK) is a member of the SRC family tyrosine kinases (SFKs) that is down-regulated in later stages of B-cell ontogeny. In MYD88 mutated B-cell lymphomas, HCK is aberrantly over-expressed and is activated and triggers multiple growth and survival pathways including BTK, PI3Kδ/AKT and ERK1/2 which are essential to tumor cell survival. Ibrutinib, a pleiotropic inhibitor of BTK, that produces remarkable responses in MYD88 mutated WM, ABC-DLBCL, and Primary CNS Lymphoma was found also potently inhibits HCK. Mutations that abolish ibrutinib-HCK binding greatly diminish anti-tumor activity in MYD88 mutated lymphoma cells, highlighting the importance of HCK as an essential target in MYD88 driven diseases. To clarify the transcriptional regulation of HCK in MYD88 mutated malignancies, we performed promoter binding TF profiling, PROMO weighted transcription factor (TF) consensus binding analysis, and chromatin immuno-precipitation (ChIP) studies. We identified PAX5, and mutated MYD88 downstream signaling mediators, STAT3, AP-1 and NF-kB as important drivers of HCK transcription. Knockdown of PAX5, a crucial regulatory factor required for B-cell commitment and identity, abrogated HCK transcription in MYD88 mutated lymphoma cells. Deletion of STAT3, AP-1 or NF-kB binding sites greatly reduced corresponding TFs binding and HCK promoter activity, indicating the importance of MYD88 directed signaling in the regulation of HCK transcription. Among AP-1 complex components, JunB but not c-Jun showed greatest relevance to TLR/MYD88 signaling and regulation of HCK transcription. Since STAT3 and NF-kB are known downstream mediators of mutated MYD88 signaling, we focused on the function of JunB. JunB phosphorylation increased following MYD88 pathway activation through TLR4 (with LPS-EB) or TLR9 (with ODN-2006), as well as lentiviral mediated expression of mutated MYD88 (L265P) but not wild type MYD88 (MYD88-WT) at Thr102 and Thr104 in either MYD88 mutated BCWM.1 cells or MYD88-WT Ramos cells. Conversely, c-Jun phosphorylation was not impacted by either intervention. Knockdown of MYD88 in BCWM.1 WM cells also reduced the phosphorylation of JunB, while c-Jun phosphorylation showed modest increase. Moreover, knockdown of JunB reduced HCK protein levels in MYD88 mutated WM and ABC-DLBCL cells. These data demonstrate that JunB is an important mediator of mutated MYD88 signaling among AP1 complex members and is directly involved in the regulation of HCK expression in MYD88 mutated B-cell lymphoma. The findings provide new insights into the transcriptional regulation of HCK by MYD88 driven TFs, and opportunities for further advancing targeted therapeutics in MYD88 driven B-cell malignancies. Disclosures Hunter: Janssen: Consultancy. Castillo:TG Therapeutics: Research Funding; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Abbvie: Research Funding. Treon:Pharmacyclics: Research Funding; BMS: Research Funding; Janssen: Consultancy.

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.

Treatment of Primary Central Nervous System Lymphoma with a Combination of Intraventricular Administration of Rituximab and Systemic Chemotherapy.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4695-4695
Author(s):  
Shujie Wang ◽  
Wei Zhang ◽  
Wei Lian ◽  
Yongji Wu ◽  
Nong Zou ◽  
...  
Keyword(s):  
Survival Time ◽  
Systemic Chemotherapy ◽  
Brain Mri ◽  
Combined Treatment ◽  
Primary Cns Lymphoma ◽  
Central Nervous System Lymphoma ◽  
Ommaya Reservoir ◽  
Intraventricular Injection ◽  
Cns Lymphoma ◽  
Intraventricular Administration

Abstract Primary CNS lymphoma (PCNSL) is an uncommon and progressive form of non-Hodgkin’s lymphoma. Since the majority of PCNSL cases are B-cell neoplasms expressing the CD20 surface antigen, treatment with Rituximab, the anti-CD20 antibody, might be a new therapeutic option. Since 2000, we have been performing a study on PCNSL patients with combined treatment of intraventricular immunochemotherapy and systemic chemotherapy. Ommaya reservoirs were placed in all these patients. The regimen of Intraventricular therapy is as follows: Methotrexate (MTX) 10mg plus Dexamethasone (Dex) 5mg followed by Cytosine arabinoside 25mg plus Dex 5mg via Ommaya reservoir in the first week, and Rituximab30mg plus Dex 2mg were given via Ommaya reservoir every other day for three times in the second week. Above treatments were finished 2 weeks a cycle until complete response (CR) was achieved and then the interval prolonged. Systemic chemotherapy includes regimen A and B. Regimen A: MTX 3~5g/m2 (D1), Vincristine 2mg (D1), Ifosfomide (IFO) 800mg/m2 (D2~4), and Dex. 10mg/m2 (D2~4). Serum MTX levels were monitored and Leucovin rescue began 24 hours after completion of MTX. Mesna rescue for IFO were also given conventionally; Regimen B: Carmustine 125 mg (D1), Teniposide 50mg (D1~3), Vindesine 4mg (D1), and Dex. 20mg (D1~4). Regimen A and B were given alternatively three weeks a cycle until CR was achieved, and then the interval prolonged. Brain MRI or PET was done every 2 or 3 months after treatment for evaluation of the response. Seven patients have been evaluated. The patients are 5 males and 2 females with the mean age of 51 years old (range: 32–82). One of the cases was a relapsed PCNSL who had achieved CR1 after whole-brain radiotherapy, systemic chemotherapy and autologous peripheral blood stem cell transplantation. He relapsed 33 months after CR1 and was enrolled in this study. After therapy he achieved CR2. But the second relapse occurred 18 months after CR2, and CR3 was achieved again after treatment with the same regimens, and total survival time has been 83 months. The other six cases were newly diagnosed PCNSL and all achieved CR after 2 to 3 months’ treatment. Among them only one patient experienced relapse after 26 months of remission, regimen A and intraventricular Rituximab were given but showed no remarkable response and died with survival time of 29 months. Other five patients are in continuing CR for 2, 12, 23, 25, and 40 months respectively. Two patients had nausea or vomiting after each intraventricular injection of Rituximab, but could relieve soon after. Ommaya reservoir infections occured in two patients, and cultures of the cerebrospinal fluid showed MRSCoN and MSSCoN, respectively. They were treated with vancomycin intravenously and via the reservoir. The infections were controlled quickly and their Ommaya reservoirs were kept. One 82 years old patient developed mild ulceration of the month and anus after treatment with regimen A. Hematological toxicities were mild, and could recover quickly with no need of transfusion or the use of G-CSF. In summary, the treatment of Intraventricular Rituximab via Ommaya reservoir combined with systemic chemotherapy for patients with PCNSL was safe and effective. This remedy is likely to improve the prognosis of such patients, but more cases need to be studied for the long-term result.

Enhanced Delivery of Rituximab In Combination with Methotrexate-Based Blood-Brain Barrier Disruption for Patients with Newly Diagnosed Primary CNS Lymphoma.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2792-2792 ◽  
Author(s):  
Nancy D. Doolittle ◽  
Dale F. Kraemer ◽  
Cynthia Lacy ◽  
Rose Marie Tyson ◽  
Edward A. Neuwelt
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Primary Cns Lymphoma ◽  
B Cell Lymphoma ◽  
Cns Lymphoma ◽  
Newly Diagnosed ◽  
Blood Brain Barrier Disruption ◽  
Brain Barrier Disruption ◽  
Grade 3

Abstract Abstract 2792 Introduction: Primary CNS lymphoma (PCNSL) is a rare, aggressive, primarily large B-cell lymphoma confined to the CNS and/or eyes at presentation. High-dose (HD) methotrexate (MTX) - based chemotherapy is standard of care in PCNSL and when combined with enhanced delivery results in extended survival without cognitive loss. The addition of rituximab to HD MTX regimens for B-cell PCNSL is widely used primarily by analogy to the positive results attained in systemic B-cell lymphomas. However, recent pre-clinical and clinical use of single agent rituximab provides stronger rationale. Efficacy has been shown using single agent rituximab in nude rats with intracerebrally implanted MC116 human B-cell lymphoma cells, and in patients with recurrent PCNSL by using 111In-ibritumomab to assess delivery and 90Y-ibritumomab to assess efficacy. Next, safety and efficacy of enhanced delivery of rituximab with MTX-based blood-brain barrier disruption (BBBD) was shown in patients with recurrent PCNSL. Based on these results, we treated patients with newly diagnosed PCNSL with rituximab in combination with MTX-based BBBD. Methods: IRB permission was obtained to retrospectively evaluate patients with newly diagnosed B-cell PCNSL, treated with rituximab in combination with MTX-based (intra-arterial [i.a.]) BBBD chemotherapy as first-line treatment. Treatment consisted of MTX (2500mg/day, i.a.) and carboplatin (200mg/m2/day, i.a.) with BBBD, for 2 consecutive days every 4 weeks for up to one year. Rituximab (375mg/m2, i.v.) was given every 4 weeks, 12 hours prior to the MTX with BBBD treatment. Objective response rate, progression free survival (PFS), overall survival (OS), and toxicities were evaluated. Results: Twelve patients (7 female, 5 male) were treated between April 2003 and October 2008. The median age was 65 years (min 49, max 75); 10 patients were older than 60 years. The median Karnofsky Performance Score (KPS) prior to treatment was 55 (min 20, max 80). All patients had brain parenchyma involvement at presentation. Additionally, CSF cytology was positive in 2 patients and one patient had ocular involvement. One patient with pre-existing cardiac disease died 2 weeks after initiation of MTX without BBBD due to myocardial infarction and was not evaluable for response. The overall response rate was 83% (7 CR, 1 CRU, 2 PR, 1 SD). The median PFS was 3.47 years (95% CI: 0.42, not yet attained) and the 2-year PFS in this cohort is 73%. The median OS was 4.42 years (95% CI: 0.28, not yet attained). Eight patients who attained CR or CRU were alive at data-cut-off; 6 of the 8 patients remain in CR 2 years or more after diagnosis. The most frequent toxicities were hematologic. Eight (67%) patients developed grade 3 or 4 hematologic toxicity and 7 (58%) developed grade 3 infection. Conclusions: We previously reported a 2-year PFS of 50% with 25% survival at 8.5 years in 149 newly diagnosed PCNSL patients treated with MTX-based BBBD without rituximab. The addition of rituximab shows manageable toxicity and provides sustained duration of CR in newly diagnosed PCNSL, with 10 of 12 patients over 60 years old and a median KPS of 55. These pilot data suggest the 2-year PFS may be increased to 70% or more with the addition of rituximab to MTX-based BBBD chemotherapy. A multi-center phase II prospective study is underway. Disclosures: No relevant conflicts of interest to declare.

Primary CNS Lymphoma in a HIV Negative Population: A Review of Clinicopathologic Characteristics, Therapy, and Outcomes of 59 Patients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4858-4858
Author(s):  
Michael V. Jaglal ◽  
Bijal D. Shah ◽  
Jennifer L. Cultrera ◽  
Eduardo M. Sotomayor ◽  
Michael B Tomblyn ◽  
...  
Keyword(s):  
Retrospective Analysis ◽  
Primary Cns Lymphoma ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
Cns Lymphoma ◽  
High Dose ◽  
Clinicopathologic Characteristics ◽  
Female Ratio ◽  
Common Location ◽  
Chi Square Analysis

Abstract Abstract 4858 Background Primary central nervous system lymphoma (PCNSL) is a rare aggressive variant of diffuse large B cell lymphoma (DLBCL) with a poor prognosis. Optimal therapeutic strategies have not been defined yet in primary CNS lymphoma. High dose Methotrexate (HD MTX) is an effective chemotherapeutic agent with superior outcomes compared to historical studies using whole brain radiation therapy (WBRT). The combination of HD MTX with WBRT showed improved response rates compared to chemotherapy (CT) alone, but was associated with greater risk of neurotoxicity in patients >60 years old. Purpose To review clinicopathologic characteristics, therapy and outcomes of 59 patients with primary CNS DLBCL without HIV. Methods This was a single center retrospective review of pts with confirmed diagnosis of primary CNS DLBCL from 1999 to 2012. Data was extracted from the Moffitt Cancer Center (MCC) electronic records. Baseline demographics, clinical, pathological and treatment data were collected and analyzed. Patients were stratified according to their treatment regimens including HD MTX (3g/m2) alone or in combinations and WBRT alone or in combination with CT. Descriptive statistical analyses were utilized. Chi square analysis and t- test were performed to compare categorical and continuous variables. Kaplan-Meier method was used to estimate OS and log rank test was used to compare the groups. All data was analyzed using SPSS version 19.0 statistical software. Results 59 patients who underwent CT and/or WBRT for PCNSL between 1999 and 2012 were identified. The age range at diagnosis was 17–85 years with median age of 64. 35 of 59 patients (59%) were ≥ 60 years old. Male to female ratio was 1.27:1 (33:26). The median ECOG PS was 1. A majority of patients presented with motor deficits, 29 out of 59. The most common location of lymphoma was in the cerebral hemispheres. The median survival of the entire cohort was 37 months. 18 of 59 pts (25%) survived ≥ 60 months. In the cohort of pts that survived ≥ 60 months, a majority 16 of 18 (89%) received HD MTX. Patients treated with initial WBRT and chemotherapy revealed inferior overall survival (OS) compare to patients treated with induction chemotherapy alone (OS 37 months vs. 66 months) (p=0.011). Patients over the age of 60 had worse outcomes compared to patients who were less than the age of 60 (OS 33 months versus 70 months) (p=0.023). Conclusions HD MTX was the most frequently utilized CT regimen in the cohort of patients surviving > 60 months. Administering WBRT combined with chemotherapy was associated with worse outcomes in this retrospective analysis. Patients with primary CNS lymphoma who are older than 60 have worse outcomes in this retrospective analysis compared to patients younger than 60. Disclosures: Sokol: Celgene: Honoraria, Speakers Bureau.

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