Background:

Rituximab has been studied and incorporated into the treatment of primary and secondary CNS lymphoma (Grommes 2017; Bobillo 2023). Systemic rituximab, a CD20-targeting monoclonal antibody, is widely used in the treatment of various B-cell malignancies (Klein 2021); however penetration into the central nervous system (CNS) is limited (Petereit 2009; Harjunpää 2001). Although there are conflicting data regarding the efficacy of IV rituximab in primary CNS lymphoma (Schmitt 2019; Ferrari 2022; Bromberg 2019), its role in other B-cell malignancies with CNS involvement has not been adequately described. In particular, its role in treating the cerebrospinal fluid (CSF) space is unclear. The rationale for direct administration of rituximab into the CSF via lumbar puncture or Ommaya reservoir is to allow for consistent treatment of this compartment in order to effectively clear the CSF of lymphoma cells (Kadoch 2014). Limited data exist regarding the efficacy and safety of intrathecal rituximab (Bonney 2011 Aslan 2022; van de Fling 2008; Santiago 2021; Soares 2019). Current intrathecal armamentarium for leptomeningeal lymphoma is very limited and more data on the efficacy and safety of intrathecal rituximab is needed in these patients.

Methods:

This is a retrospective, single center study of adult patients with a diagnosis of leukemia or lymphoma who received intrathecal (IT) rituximab between 1/1/2016 and 12/31/2022 at Hackensack Meridian Health. Rituximab 25 mg IT was administered weekly either via lumbar puncture or into an Ommaya reservoir. The primary objective of this study was to evaluate the efficacy and safety of IT rituximab. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan Meier method. Descriptive statistics were used to summarize data for categorical and continuous variables.

Results:

Twelve patients were identified to have received IT rituximab at our institution between 1/1/2016 and 12/31/2022. Median age was 60 years (range 45-81), 54% were male, and 69% white. Disease types included primary CNS lymphoma (67%), diffuse large B-cell lymphoma (17%), PTLD of the CNS (8%), and chronic lymphocytic leukemia (8%). In regards to CNS disease involvement, 58% of patients presented with parenchymal and leptomeningeal disease, 33% with leptomeningeal disease only, and 8% with parenchymal disease only.

There were 12 patients who received IT rituximab for the treatment of malignant CNS disease with characteristics and outcomes as shown in Table 1. The median number of IT rituximab treatments administered were 8 (range 2-9). Of the 10 patients evaluable for response, 92% of patients achieved complete response in the CSF following treatment with IT rituximab as evaluated by flow cytometry, cytology, cell count and protein levels in CSF. One patient that did not achieve CSF remission has an unusual case of relapsing/remitting CLL and leukemic meningitis. There were 2 patients unevaluable for response to IT rituximab: one patient received only 2 treatments prior to switching to hospice care; and the other patient had a severe adverse reaction (tightening of throat, flushing, toe numbness) after IT rituximab and was not continued on treatment. At a median follow-up of 19.7 months, median PFS was not reached (NR) (95% CI, 0.5-NR) ( Figure 1). Median OS was 70.1 months (95% CI, 1.2-NR).

Six (50%) patients experienced adverse reactions from IT rituximab treatment, including perioral numbness, headache, nausea, and flushing ( Table 1). No treatment-related deaths occurred. One (8%) patient experienced a severe adverse reaction following administration of IT rituximab. This patient developed tightening of the throat, flushing, and toe numbness after the first IT rituximab and symptoms resolved with administration of hydrocortisone and diphenhydramine. No further IT rituximab doses were administered. Another patient experienced a mild reaction consisting of headache, fatigue, nausea, diaphoresis, hypotension, and bradycardia following the fourth dose of IT rituximab in combination with IV rituximab, but was able to complete his treatment course.

Conclusions:

The use of IT rituximab appears safe and showed promising activity in B cell malignancies, specifically as part of induction in patients with leptomeningeal disease and PCNSL as those patients achieved cytologic response.

Feldman:Juno: Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene, BMS: Research Funding, Speakers Bureau; Corvus: Research Funding; Janssen Biotech, Inc.: Speakers Bureau; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics LLC: Speakers Bureau; Poteligeo: Speakers Bureau; Portola: Research Funding; Kite, a Gilead Company: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genomic Testing Cooperative: Current equity holder in private company; Takeda: Speakers Bureau; Tessa: Research Funding; Eisai: Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; MorphoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kymera: Research Funding. Lee:MJH Life Sciences: Honoraria. Parmar:Sanofi: Consultancy, Honoraria; Cellectar Biosciences: Consultancy, Honoraria. Ip:Merck: Current holder of stock options in a privately-held company; COTA: Current holder of stock options in a privately-held company; MJH Life Sciences: Honoraria; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Speakers Bureau; Seattle Genetics: Speakers Bureau; Genomic Testing Cooperative: Current equity holder in private company. Leslie:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/ Bristol Myers Squibb: Other: Travel support, Speakers Bureau; LRF: Other: Educational role; LLS: Other: Educational role/ Leadership role in LLS light the night events (unpaid); Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen/ J&J: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Kite, a Gilead Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; SeaGen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; CLL: Other: Educational role; Eli Lilly: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Astrazeneca: Consultancy, Other: Travel support, Speakers Bureau; Janssen/PCYC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau. Goy:Clinical Advances in Hematology & Oncology: Consultancy; Michael J. Hennessey: Consultancy, Honoraria; Medscape: Consultancy; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee, Research Funding; OncLive Peer Exchange: Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Practice Update Oncology: Consultancy, Honoraria; Verastem: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Steering Committee, Research Funding; Hoffman la Roche: Consultancy, Honoraria, Research Funding; MorphoSys: Research Funding; Resilience: Current holder of stock options in a privately-held company; OMI: Current Employment; Vincerx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other; Physicians Education Resource, LLC: Consultancy, Honoraria, Other: travel, accommodations, and expenses; Seagen: Research Funding; Karyopharm: Research Funding; Infinity: Research Funding; Genentech: Research Funding; Acerta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee, Research Funding; Bristol Myers Squibb/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Novartis: Consultancy, Honoraria; Constellation: Research Funding; Xcenda: Consultancy, Honoraria; AbbVie/ Pharmacyclics LLC: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee, Research Funding; Alloplex: Current holder of stock options in a privately-held company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genomics Testing Cooperative LLC: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership Role; COTA Healthcare: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership Role; Regional Cancer Care Associates, OMI: Current Employment, Research Funding.

This study describes our institution's experience administering rituximab, a CD-20 monoclonal antibody, via the intrathecal route in B-cell malignancies. Administration via the intrathecal route is an off-label use of rituximab.

Figure 1
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2023
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