Recurrent Central Nervous System Lymphoma Research Articles

10177-ML-5 HIGH-DOSE CHEMOTHERAPY FOLLOWED BY AUTOLOGOUS STEM CELL TRANSPLANT FOR RECURRENT CNS LYMPHOMA

Abstract BACKGROUND The prognosis of relapsed central nervous system lymphoma (CNSL) is poor, and effective standard treatment has not been established. The BTK inhibitor or HD-MTX-based chemotherapy is re-administered if the patient responds to HD-MTX-based therapy at initial treatment, but durable remission is difficult to achieve. Thiotepa (TT) was approved in Japan as a pre-treatment for autologous hematopoietic stem cell transplantation in malignant lymphoma, and autologous stem cell transplantation (ASCT)-assisted high-dose chemotherapy (HDC) can be performed. TBC (TT, busulfan, and cyclophosphamide) and BCNU+TT are used in Europe and the US, but treatment-related mortality (TRM) has been reported in about 10% of patients. The regimen approved in Japan is BuTT (busulfan and TT) and there is little information on its efficacy and safety in relapsed CNSL. In this study, we examined the efficacy and safety of HDC-ASCT at Saitama Medical University. Subjects: Nine patients with recurrent CNSL (primary CNSL: 6 cases, secondary CNSL: 3 cases) since May 2021, age ≤ 65 years, KPS ≥ 70, are included in this study. METHODS After response to induction (R)MPV regimen, peripheral blood stem cells were harvested after administration of G-CSF and plerixafol, pretreated with BuTT regimen (Bu: 3.2 mg/kg, day-8 to -5, TT: 5 mg/kg, day-4, -3), and transplanted on Day 0. RESULTS Adverse events of Grade 3 or higher were febrile neutropenia in 5 cases, neutropenia in 9 cases, thrombocytopenia in 9 cases, pharyngitis in 5 cases, oral candida in 1 case, pleuritis in 1case, abdominal pain in 1 case, nausea in 1 case, and sepsis 1 case, but all recovered, and no TRM was observed. Six patients with primary CNSL and two with secondary CNSL are currently alive without recurrence, and one with non-CR secondary CNSL died of progression in two months. CONCLUSION HDC-ASCT is an effective salvage treatment for relapsed CNSL.

Preclinical and clinical evaluation of Buparlisib (BKM120) in recurrent/refractory Central Nervous System Lymphoma

Central Nervous System (CNS) Lymphomas are aggressive brain tumors with limited treatment options. Targeting the phosphoinositide 3-kinase (PI3K) pathway yields promising responses across B-cell malignancies, but its therapeutic potential in CNS lymphomas remains unexplored. We present pre-clinical and clinical data on the pan-PI3K inhibitor Buparlisib in CNS lymphomas. In a primary CNS lymphoma-patient-derived cell line, we define the EC50. Four patients with recurrent CNS lymphoma were enrolled in a prospective trial. We evaluated Buparlisib plasma and cerebrospinal fluid pharmacokinetics, clinical outcomes, and adverse events. Treatment was well tolerated. Common toxicities include hyperglycemia, thrombocytopenia, and lymphopenia. The presence of Buparlisib in plasma and CSF was confirmed 2h post-treatment with a median CSF concentration below the EC50 defined in the cell line All four patients were evaluated for response and the median time to progression was 39 days. Buparlisib monotherapy did not lead to meaningful responses and the trial was prematurely stopped.Clinical Trial Registration: NCT02301364

Use of rituximab, temozolomide, and radiation in recurrent and refractory primary central nervous system lymphoma in the Philippines: a retrospective analysis (P13-13.006)

<h3>Objective:</h3> This study aimed to present the clinical course and outcomes of patients with recurrent or refractory disease who were given a combination of radiation, temozolomide, and rituximab. <h3>Background:</h3> Refractory disease in primary central nervous system lymphoma (PCNSL) may occur despite adequate initial treatment. There is currently no standard of care for relapsed and recurrent PCSNL. No study to date documents using a combined regimen of radiotherapy, temozolomide, and rituximab. <h3>Design/Methods:</h3> Retrospective analysis was employed to evaluate data from recurrent or refractory PCNSL patients who were treated with radiation, temozolomide, and rituximab in two tertiary hospitals in the Philippines. Baseline demographics, treatment regimen, and outcomes were analyzed. <h3>Results:</h3> Fifteen patients with a median age of 56 years were included, 11 with refractory disease and 4 with recurrent disease. Patients with bulky disease received either whole brain radiotherapy or partial field radiotherapy with rituximab and temozolomide given during radiation and for 6 months after radiation. Overall response rate to salvage therapy was 93.3% (14/15). Median overall survival from initial diagnosis was not reached (median follow-up: 84 months). Mortality rate was 33.3% (5/15), but only 2 out of 5 mortalities were from disease progression. There were only two reported cases of mild allergic reactions to rituximab, which did not result in treatment interruption. <h3>Conclusions:</h3> Rituximab, temozolomide, and radiotherapy can be considered as an effective and safe salvage therapy for relapsed and recurrent central nervous system lymphoma. <b>Disclosure:</b> Dr. Apor has nothing to disclose. Dr. Batara has nothing to disclose. Christianne Mojica has nothing to disclose. Mark Willy Mondia has nothing to disclose.

Use of rituximab, temozolomide, and radiation in recurrent and refractory primary central nervous system lymphoma in the Philippines: a retrospective analysis.

BackgroundRefractory disease in primary central nervous system lymphoma (PCNSL) may occur despite adequate initial treatment. There is currently no standard of care for relapsed and recurrent PCSNL. No study to date documents using a combined regimen of radiotherapy, temozolomide, and rituximab. This study aimed to present the clinical course and outcomes of patients with recurrent or refractory disease who were given a combination of radiation, temozolomide, and rituximab.MethodsRetrospective analysis was employed to evaluate data from recurrent or refractory PCNSL patients who were treated with radiation, temozolomide, and rituximab in two tertiary hospitals in the Philippines. Baseline demographics, treatment regimen, and outcomes were analyzed.ResultsFifteen patients with a median age of 56 years were included, 11 with refractory disease and 4 with recurrent disease. Patients with bulky disease received either whole brain radiotherapy or partial field radiotherapy with rituximab and temozolomide given during radiation and for 6 months after radiation. Overall response rate to salvage therapy was 93.3% (14/15). Median overall survival from initial diagnosis was not reached (median follow-up: 84 months). Mortality rate was 33.3% (5/15), but only 2 out of 5 mortalities were from disease progression. There were only two reported cases of mild allergic reactions to rituximab, which did not result in treatment interruption.ConclusionRituximab, temozolomide, and radiotherapy can be considered as an effective and safe salvage therapy for relapsed and recurrent central nervous system lymphoma.

Relationship between vitreoretinal lymphoma and the site of lymphoma development in the central nervous system.

To investigate diffuse large B-cell lymphoma lesions with central nervous system (CNS) involvement in patients with vitreoretinal lymphoma (VRL) during long-term clinical courses. Multicenter, retrospective, and observational research. Seventy-one patients participated in this study, 45 were newly diagnosed VRL patients with CNS involvement initially or during follow-up of at least 12months. We identified the CNS lesions in the patients that had VRL and investigated whether the onset sites of the CNS lesions were associated with the VRL lesions or optic pathways. There were 42 patients with bilateral ocular lesions; 29 had unilateral lesions; 26 had incidental CNS lymphomas. Twenty patients developed recurrent CNS lymphoma 1-73months after VRL diagnosis; 25 patients had no CNS lesions during the follow-up period. Most CNS lesions were in forebrain-originating tissues (95 lesions/total 124 CNS lesions total), followed by hindbrain-originating tissues, especially the cerebellum. Sixty-seven lesions were found in the non-optic pathway or non-visual cortex. Over 60% of the VRL patients had CNS lesions. CNS involvement was not associated with the optic pathway or visual cortex, suggesting that clinicians should carefully examine CNS lesions occurring in both forebrain- and hindbrain-originating tissues during a patient's clinical course. Moreover, the CNS lymphomas that manifest as VRL show multifocal tumor development.

Stereotactic Radiation Therapy With Concurrent Immune Checkpoint Inhibitor Therapy in Patients With Relapsed or Refractory Central Nervous System Lymphoma

Relapsed or refractory central nervous system lymphoma (CNSL) after high-dose methotrexate-based therapy is a challenging clinical entity with limited treatment options. Salvage systemic therapy and whole brain radiation therapy (WBRT) are commonly employed but are associated with significant toxicity and poor outcomes. Prior studies have shown that primary CNSLs frequently exhibit increased expression of PD-L1, and immune checkpoint inhibitor (ICI) therapy may be active in this setting. We assessed the safety and efficacy of concurrent ICI therapy and hypo-fractionated stereotactic radiation therapy (SRT) in patients with relapsed or refractory CNSL.We retrospectively analyzed the records of patients with relapsed or refractory CNSL treated with SRT + ICI at our institution from 2017 to 2020. ICI therapy included pembrolizumab 200 mg IV q3weeks or nivolumab 3 mg/mg IV q2weeks. Linac-based SRT was delivered in 5 daily fractions of 5 Gy. CTVs included all grossly enhancing disease on T1 weighted post-contrast MR scans, with 3 mm uniform PTV expansions. Patients were followed for symptomatic and radiographic response. Progression-free survival (PFS) and overall survival (OS) were calculated via Kaplan-Meier analysis.Seven consecutive patients with relapsed or recurrent CNSL were analyzed: 6 with primary CNSL, 1 with secondary CNSL. Patients presented at a median age of 72.2 years (range: 40.9 - 89.9) after a median of 2 prior courses of systemic therapy. Five patients had a solitary intracranial lesion and 2 had multiple lesions. None had active extracranial disease. Median pre-SRT Karnofsky Performance Status (KPS) was 60 (range 50 - 90). All 7 patients completed SRT and received concurrent and adjuvant ICI therapy. Median follow-up after completion of SRT was 9.1 months. Acute toxicities of SRT and ICI therapy were minimal, including fatigue (3 patients), diarrhea (2), and adrenal insufficiency requiring oral steroids (1). Five patients (71.4%) achieved symptomatic improvement after SRT including 2 patients (28.5%) with a clinical complete response (CR). Median post-SRT KPS was 70 (range: 60 - 100). Six patients had follow-up imaging, and all had an objective response including 3 (50%) with a radiographic CR. The median time to best radiographic response was 2.0 months (range 0.3 - 3.7 months), and all treated lesions remained controlled on all subsequent imaging. Three patients (42.9%) experienced out-of-field intracranial recurrence. Median PFS was 7.7 months (95% CI: 4.0 - 11.4 months) and median OS was 12.6 months (95% CI: 7.5 - 12.7 months) post-SRT.Among patients with relapsed or refractory CNSL, SRT + ICI appears to be well tolerated and offers excellent symptomatic and radiographic local control. Further studies are needed to identify appropriate candidates for salvage SRT + ICI, and to evaluate the clinical efficacy and neurocognitive impact of this approach.

Tumor metabolism and neurocognition in CNS lymphoma.

The mechanistic basis for neurocognitive deficits in central nervous system (CNS) lymphoma and other brain tumors is incompletely understood. We tested the hypothesis that tumor metabolism impairs neurotransmitter pathways and neurocognitive function. We performed serial cerebrospinal fluid (CSF) metabolomic analyses using liquid chromatography-electrospray tandem mass spectrometry to evaluate changes in the tumor microenvironment in 14 patients with recurrent CNS lymphoma, focusing on 18 metabolites involved in neurotransmission and bioenergetics. These were paired with serial mini-mental state examination (MMSE) and MRI studies for tumor volumetric analyses. Patients were analyzed in the setting of the phase I trial of lenalidomide/rituximab. Associations were assessed by Pearson and Spearman correlation coefficient. Generalized estimating equation (GEE) models were also established, adjusting for within-subject repeated measures. Of 18 metabolites, elevated CSF lactate correlated most strongly with lower MMSE score (P < 8E-8, ρ = -0.67). High lactate was associated with lower gamma-aminobutyric acid (GABA), higher glutamate/GABA ratio, and dopamine. Conversely, high succinate correlated with higher MMSE scores. Serial analysis demonstrated a reproducible, time-dependent, reciprocal correlation between changes in lactate and GABA concentrations. While high lactate and low GABA correlated with tumor contrast-enhancing volume, they correlated more significantly with lower MMSE scores than tumor volumes. We provide evidence that lactate production and Warburg metabolism may impact neurotransmitter dysregulation and neurocognition in CNS lymphomas. We identify novel metabolomic biomarkers that may be applied in future studies of neurocognition in CNS lymphomas. Elucidation of mechanistic interactions between lymphoma metabolism, neurotransmitter imbalance, and neurocognition may promote interventions that preserve cognitive function.

Stereotactic Radiosurgery in the Treatment of Recurrent CNS Lymphoma

Central nervous system lymphoma (CNSL) is typically treated with chemotherapy and external beam radiation therapy (EBRT). Optimal management of recurrent CNSL is poorly defined. We aim to determine the effectiveness of stereotactic radiosurgery in the treatment of recurrent CNSL. We performed a retrospective analysis of patients having stereotactic radiosurgery (SRS) for recurrent intracranial CNSL between 1999 and 2011. Fourteen patients (20 tumors) underwent SRS. The median patient age was 71 years (range, 18-82 years). Seven patients (50%) had primary CNSL. All had received prior chemotherapy, and nine patients (64%) had undergone prior whole brain radiotherapy (WBRT) with a median dose of 40 Gy in 25 fractions. The median preoperative Karnofsky Performance Score was 80. The median tumor volume was 6.7 cm(3) (range, 0.5-37.7); the median margin dose was 15.5 Gy (range, 10-18). Eleven patients (79%) had tumor regression (n = 11) shown on MRI after SRS. The median overall survival after SRS was 9.5 months. No patient had a major radiation-related complication. Stereotactic radiosurgery for patients with recurrent CNSL is well tolerated and has a high rate of radiographic response. A marginal dose of 15.5 Gy or greater, a Karnofsky score of 80 or greater, and the absence of pre-SRS WBRT were associated with significantly longer overall survival. Stereotactic radiosurgery may be beneficial as an initial salvage therapy in the treatment of recurrent CNSL for properly selected patients.

Interim Results of a Phase I Study of Lenalidomide (CC-5013) Plus Intraventricular/Intravenous Rituximab for Recurrent/Refractory CNS and Intraocular Lymphoma

BACKGROUND: There is an unmet need for effective therapies for relapsed/refractory primary and secondary central nervous system (CNS) and intraocular lymphomas (IOL), complications that are increasing in frequency among patients age >60. Whole brain irradiation, broadly utilized in the relapsed setting, yields insufficient efficacy and considerable morbidity, particularly in older patients. Implementation of new agents that selectively target survival pathways upregulated in refractory CNS lymphoma would have significant impact. Lenalidomide (CC-5013) has established activity as a single agent in aggressive NHL, particularly in ABC-type DLBCL. We recently demonstrated the activity of lenalidomide, at modest doses, in the treatment of recurrent/refractory intraocular and CNS lymphoma (J. Clin Oncol, 2011). We also provided evidence of cereblon-dependent efficacy of lenalidomide in preclinical models of patient-derived CNS DLBCL (ASH, 2013). These observations are the basis for this first trial of IMiD® immunomodulatory compound therapy in CNS NHL, as monotherapy, and in patients with inadequate responses to lenalidomide, in combination with combined intravenous plus intraventricular rituximab. (NCT01542918).METHODS: The primary objective of this phase I study is to evaluate the safety and efficacy of lenalidomide at three dose levels (10, 20, and 30mg) in relapsed/refractory CD20+ CNS NHL, with staging evaluations involving brain, CSF and intraocular compartments. Key secondary endpoints include: (1) determination of extent of CSF penetration by lenalidomide; (2) feasibility and activity of combined intraventricular and intravenous rituximab plus lenalidomide in patients with recurrent CNS lymphoma, not responsive to lenalidomide monotherapy; (3) evaluation of the effects of lenalidomide on the tumor microenvironment, including effects on tumor metabolism and immune cell infiltration and phenotypes.RESULTS: Thus far, seven subjects with relapsed CNS DLBCL (6 PCNSL, 1 SCNSL) have been treated on protocol at UCSF (median age 63, range 46-77). Each had methotrexate-resistant disease and 4 had lymphoma refractory to high-dose chemotherapy. In general, lenalidomide has been well-tolerated in the CNS lymphoma population with one DLT (non-hematologic) noted at the 20 mg dose level: fatigue and memory loss. Clinical benefit has been noted in 3 out of 4 patients with IOL, with 1 PR > 6 months duration and 1 SD > 10 months duration, each to lenalidomide monotherapy. Brain parenchymal responses to lenalidomide monotherapy (20 mg) have been demonstrated at restaging MRI, including 1 CR and 1 PR. There has been 1 CR in the leptomeninges with resolution of B-cell lymphoma in CSF, quantified by serial flow-cytometry. Combined intraventricular (20 mg) plus intravenous infusion of rituximab was well-tolerated in 3/3 patients and, with 10 mg lenalidomide, resulted in 1 PR in highly refractory IOL. Using GC/MS, we demonstrated lenalidomide penetration in ventricular CSF (0.6-7.9 ng/ml) in each of 4 patients, 12-15 hours after dosing at the 20 mg level, but trough lenalidomide concentrations >0.5 ng/ml were detected in only 1 of 3 patients receiving 10 mg lenalidomide. Serial metabolomic profiling revealed that CSF lactate correlated with clinical response to lenalidomide. Finally, we demonstrated that lenalidomide is reproducibly associated with a rapid and reversible effect on peripheral blood macrophage polarization to an M1, iNOS+ phenotype.CONCLUSIONS: These preliminary results provide evidence that lenalidomide is well-tolerated at 10 and 20 mg dose levels in CNS lymphoma. We demonstrate for the first time lenalidomide penetration in ventricular CSF, with higher trough concentrations detected at 20 mg compared to the 10 mg dose level. Encouraging evidence of lenalidomide efficacy in relapsed CNS DLBCL has been demonstrated in intraocular, CSF and brain compartments. Combined intraventricular and intravenous infusion of rituximab is feasible and represents a novel strategy to the potentiation of immunotherapeutic strategies in brain tumors. Studies are in progress to further elucidate the safety, pharmacokinetics and mechanisms involved in this biological approach to the treatment of refractory CNS lymphomas.Supported by NCI, Leukemia and Lymphoma Society, UCSF Helen Diller Comprehensive Cancer Center, Celgene and Genentech DisclosuresOff Label Use: Intrathecal administration of rituximab. Wang:Celgene: Employment. Chen:Celgene: Employment.

A 46‐year‐old woman with chin pain and a fainting spell

History of the present illness The patient had a history of primary central nervous system (CNS) lymphoma that had recurred in the past but had been in remission for 2 years. She was admitted to the hospital in August 2008, following a syncopal episode. For several weeks prior to her syncope, she had experienced generalized malaise and the sensation of total body weakness. On the day of admission, she was nauseated and had one episode of non-bloody emesis. As the day progressed, she felt lightheaded and eventually lost consciousness while walking to the bathroom. In the emergency department, she was suspected of dehydration. However, an electrocardiogram revealed complete heart block (CHB). A temporary transjugular pacing wire was placed, intravenous fluids were started, and she was admitted to the Cardiac Unit. The patient stated that she had been completely well until 2 months before admission, when she began to experience easy fatigability. One month before admission, she developed a series of episodes of myalgias that involved her shoulders and neck. These symptoms responded to acetaminophen. She had also experienced periodic night sweats during this time. Two weeks before admission, the patient presented to her oncologist with the symptom of chin pain that radiated bilaterally toward the angle of her mandible. The pain was described as “sharp and shooting.” It sometimes appeared to be worsened by jaw movement. The patient indicated that chewing exacerbated the pain, starting with the first bite. Her oncologist had obtained a brain magnetic resonance imaging (MRI) study to exclude a lymphoma recurrence. The MRI study was interpreted as showing no new lesions. The pain did not respond to nonsteroidal antiinflammatory drugs and had been present for 2 weeks at the time of her syncope.

Temozolomide plus rituximab in the treatment of recurrent central nervous system lymphoma: Case report and literature review

Objective The aim of our study was to investigate the treatment of recurrent central nervous system lymphoma.

Complement Activation and Resistance within the Cerebrospinal Fluid Following Intraventricular Administration of Anti-CD20 in the Treatment of Recurrent CNS Lymphoma.

We recently conducted the first phase I dose escalation study of intraventricular rituximab (anti-CD20 antibody) in patients with recurrent central nervous system (CNS) non-Hodgkin's lymphoma (NHL). The goals of this study have been to define the safety and pharmacokinetics of intraventricular rituximab monotherapy and to gain insight into the molecular basis of rituximab efficacy and resistance in the treatment of high-grade lymphomas. We observed a rapid lymphocytotoxic effect of intraventricular rituximab administration in six out of ten subjects treated, resulting in four complete responses at the completion of five weeks of therapy. Cytologic responses were evident within one hour of rituximab treatment and were not likely related to the action of corticosteroids as these were held stable, tapered or withheld in the week before intrathecal therapy. Three potential mechanisms have been proposed to explain the basis for rituximab efficacy in the treatment of NHL:1.direct induction of apoptosis;2.complement-dependent cytotoxicity (CDC);3.antibody dependent cellular cytotoxicity (ADCC).Given the rapid rate of response detected in the leptomeningeal compartment and the relative paucity of Fc-receptor bearing natural killer cells detected in the CSF, we tested the hypothesis that complement activation is responsible for the rapid rituximab-mediated tumor cell lysis which we observed. Pretreatment gene expression profile analysis of meningeal lymphoma cells isolated from CSF demonstrated that RNA levels of expression of CD46, CD55, and CD59 were similar in both responding and non-responding patients. However microarray analysis suggested a possible correlation between low levels of complement receptor 2 (CD21) and immediate rituximab resistance. We focused on the potential generation of C3a anaphylatoxin in the CSF after rituximab administration as C3 is the central component in the classical and alternative complement pathways. Quantitative measurement of C3a concentration in CSF by ELISA demonstrated rapid activation of the complement cascade within one hour of intrathecal anti-CD20 antibody administration. C3a concentrations increased between three-to-eight-fold up to peak concentrations greater than 300 ng/ml. These findings were confirmed by immunoblot analysis of C3a in CSF. Acquired rituximab resistance was associated with marked decreases in the magnitude of complement activation in two patients who initially had exhibited complete responses to intraventricular rituximab monotherapy. These results suggest a mechanistic basis for the rapid lymphocytoxic effects observed and provide a possible explanation for the development of acquired rituximab resistance.