Refractory Central Nervous System Research Articles

A Phase 1 Study of Intravenous EGFR-ErbituxEDVsMIT in Children with Solid or CNS Tumours Expressing Epidermal Growth Factor Receptor.

Recurrent or refractory solid and central nervous system (CNS) tumours in paediatric patients have limited treatment options and carry a poor prognosis. The EnGeneIC Dream Vector (EDV) is a novel nanocell designed to deliver cytotoxic medication directly to the tumour. The epidermal growth factor receptor is expressed in several CNS and solid tumours and is the target for bispecific antibodies attached to the EDV. To assess the safety and tolerability of EGFR-Erbitux receptor EnGeneIC Dream Vector with mitoxantrone (EEDVsMit) in children with recurrent / refractory solid or CNS tumours expressing EGFR. Patients aged 2-21 years with relapsed or refractory CNS and solid tumours, or radiologically diagnosed diffuse intrinsic pontine glioma (DIPG), were treated in this phase I open-label study of single agent EEDVsMit. Thirty-seven patients' tumours were screened for EGFR expression. EEDVsMit was administered twice weekly in the first cycle and weekly thereafter. Standard dose escalation with a rolling 6 design was employed. Dosing commenced at 5 × 108 EEDVsMit per dose and escalated to 5×109 EEDVsMit per dose. EGFR expression was detected in 12 (32%) of the paediatric tumours tested. Nine patients were enrolled and treated on the trial, including three patients with diffuse midline glioma. Overall, EEDVsMit was well tolerated, with no dose-limiting toxicities observed. The most common drug-related adverse events were grade 1-2 fever, nausea and vomiting, rash, lymphopaenia, and mildly deranged liver function tests. All patients had disease progression, including one patient who achieved a mixed response as the best response. EGFR-Erbitux receptor targeted EnGeneIC Dream Vector with mitoxantrone can be safely delivered in paediatric patients aged 2-21 years with solid or CNS tumours harbouring EGFR expression. The discovery of EGFR expression in a high proportion of paediatric gliomas means that EGFR may be useful as a target for other treatment strategies. Targeted therapeutic-loaded EDVs may be worth exploring further for their role in stimulating an anti-tumour immune response. NCT02687386.

Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in Secondary Central Nervous System Large B-Cell Lymphoma (SCNSL): A Multicenter Retrospective Analysis

Introduction Secondary central nervous system (CNS) involvement develops in 2-10% of large B-cell lymphoma (LBCL) cases. Current treatment approaches for relapsed or refractory CNS disease generally do not provide durable responses. Limited data suggest efficacy and feasibility of CAR-T therapy in SCNSL. We report here the largest multicenter retrospective analysis of the safety and efficacy of CD19-directed CAR-T therapy in SCNSL patients. Methods This study included SCNSL patients who received commercial CD19-directed CAR-T therapy at 9 academic institutions in the United States between 2016 and 2022. SCNSL was defined as history of parenchymal and/or leptomeningeal/cerebrospinal fluid (CSF) involvement by lymphoma at any time prior to receiving CAR-T therapy. Systemic response was assessed using the Lugano criteria while CNS response was assessed as per International PCNSL Collaborative Group criteria. Kaplan-Meier curves were generated for progression-free survival (PFS) and overall survival (OS) for entire cohort, as well as subsets of patients with and without active CNS disease at the time of CAR-T infusion. Results Ninety patients were included in the analysis, with baseline characteristics shown in Table 1. CAR-T products utilized include axicabtagene ciloleucel (n= 38, 42%), tisagenlecleucel (n=37, 41%) and lisocabtagene maraleucel (n= 15, 14%). Fludarabine/cyclophosphamide was used as lymphodepletion in 84 patients (93%). 28 patients received CNS directed radiation therapy (RT) prior to CAR-T infusion (31%) within a median time of 28.5 days (range 5 - 906) from last day of RT. Amongst all patients at the time of CAR-T infusion 82 (91.1%) had active CNS and/or systemic involvement while 8 (8.9%) had no evidence of disease; 68 (75.5%) had active CNS involvement while 22 (24.5%) had a prior history of CNS involvement but no active at the time of CAR-T infusion. ( Table 1) Median follow up all patients was 0.5 year (range 0.01 - 4.7). 71 patients (79%) developed cytokine release syndrome (CRS; median time to onset 3 days) with 3.3% patients developing Grade 3-4. Immune effector cell-associated neurotoxicity syndrome (ICANS; median time to onset 5 days) was reported in 55 patients (61%), with 28.8% developing Grade 3-4. No patients died due to CRS or ICANS. At 1-month post CAR-T, 80 patients were evaluable for CNS response and 71 patients in the entire cohort were evaluable for systemic response. Similarly, at 3-months these numbers were 66 and 60, respectively. Objective response rates (ORR) were 75% and 80% at 1-month for CNS and systemic disease respectively, while corresponding ORRs at 3-months were 68% and 76.7%. At 1- and 3-months timepoint 36 (45%) and 33 (50%) patients, respectively achieved CNS complete remission (CR), while 44 (62%) and 42 (70%) patients respectively achieved systemic CR. 1- and 2-year PFS for entire cohort were 25% (95%Cl 15% - 34%) and 16% (95%Cl 8.5% - 28%) respectively, while 1- and 2-year OS were 46% (95%Cl 36% - 59%) and 31% (95%Cl 22% - 46%). Non-relapse mortality (NRM) were 4.6% (95%CI, 1.8% -12%) and 7.2% (95%CI 2.9% - 18%) at 1- and 2-year. Cumulative incidence of relapse at 1- and 2-year were 73% (95%Cl 63% - 83%) and 77% (95%Cl 68% - 88%), respectively. ORRs for CNS response in patients with active CNS disease at 1-month and 3-month interval were 71% (n=45) and 60% (n=31). Similarly, ORR for systemic response with active CNS disease at 1-month and 3-month interval were 85% (n=43) and 74.3% (n=32).The 2-year PFS for patients with and without active CNS disease at CAR-T infusion were 12% (95%Cl 5.4% - 27%) and 28% (95%Cl 12% - 65%) respectively, with a corresponding OS of 25% (95%Cl 15% - 41%) and 58% (95%Cl 37% - 91%). ( Figure 1) The 2-year NRM rates for patients with and without active CNS disease at CAR-T infusion were 4.6% (95%Cl 1.5% - 14%) and 14% (95%Cl 3.6% - 53%) respectively, while the cumulative incidence of relapse in similar order were 83% (95%Cl 73% - 95%) and 58% (95%Cl 39% - 88%). Conclusion In this largest known case series to date, CAR-T therapy appeared safe and feasible in patients with SCNSL, but is associated with high rates of treatment failure, particularly in patients with active CNS disease at CAR-T infusion. This warrants further study of optimal CNS-directed treatment strategies prior to CAR-T, development of novel cellular therapy platforms or consideration of post CAR-T maintenance therapy in these high-risk patients.

Gene Panels for Intraocular Lymphoma Can Overcome Diagnostic Difficulties and Enable Precision Medicine

Background: Definitive diagnosis of intraocular lymphoma (IOL) is often challenging, at least partially due to limited accessibility to the lesion and the rarity of tumor cells, with pathologically false-negative results reportedly occurring in approximately 30% of cases. Delayed diagnosis is often an important clinical issue, and the average time to diagnosis is approximately 1.5 years.Because of delayed diagnosis, IOLs are often found only after central nervous system (CNS) invasion has occurred, possibly leading to worse treatment outcomes. In this study, we tried to overcome diagnostic difficulties by using gene panel diagnostics of IOL. Furthermore, genetic analysis of IOLs may be able to predict the risk of recurrence.in Japan, a second-generation Bruton's tyrosine kinase (BTK) inhibitor, tirabrutinib, has been approved for the treatment of relapsed/refractory CNS lympoma. Herein, we present a case of IOL and CNS lesion with MYD88 mutation treated with tirabrutinib as part of precision medicine. Methods: We have developed a digital polymerase chain reaction-based system for multiplex gene panel testing of cell-free DNA (cfDNA) obtained from intraocular liquid biopsies (patent number 7149000, 2022/9/30). Our system can detect specific gene mutations in minute cfDNA by amplifying specific gene loci in bubbles, even from an extremely small number of cells. Using this multiplex gene panel testing, we analyzed genetic mutations in nine regions of four genes, MYD88, CD79B, BTG2, and PIM1, using cfDNA obtained from intraocular liquid biopsies. The diagnostic performance of the novel system was evaluated in 86 samlpes of patients with IOL. We also retrospectively analyzed the prognostic potential of the genetic mutations for IOL. Lastly, in the case of CNS lymphoma and IOL, we presented the MYD88 mutation treated with tirabrutinib. Results: Among the four disease-specific genes, the MYD88 mutation was present in 55 of 86 cases (64%), and frequencies of the CD79B, BTG2, and PIM1 mutations were 47%, 38%, and 29%, respectively. At least one of these mutations was found in 83 of the 86 IOL cases examined (97%), making this assay highly sensitive (Fig. 1). The MYD88 mutation was not associated with recurrence in patients with recurrent and refractory CNS lymphoma and IOL. Conversely,patients with the CD79B mutation had high rates of relapse for CNS lymphoma: the 4-year rate of recurrence-free survival was 35%, compared to 79% in patients without the CD79B mutation (p=0.012). Patients with the BTG2 mutation also had high rates of relapse (Fig. 2). Furthermore, we present a case of CNS lynphoma and IOL. By testing IOL gene panel, only MYD88 mutation was detected in the vitreous sample of IOL patient. We have experienced this case in which the second-generation BTK inhibitor,tirabrutinib, was effective not only for central but also for intraocular lesions. Conclusion: Our panel enables rapid and accurate diagnosis of IOL with only a small sample of intraocular liquid. We believe that this multiplex gene panel testing may aid in the diagnosis of IOL in difficult-to-diagnose patients, including those with chronic uveitis, by preventing CNS invasion due to diagnostic delay. Moreover, genetic profiling panels of IOL can help to stratify clinical outcomes.CD79B and BTG2 mutation is a potent predictive marker for relapse. In the clinical setting, we experienced a case of IOL with MYD88 mutation in which tirabrutinib was effective. Potentially, tirabrutinib also penetrates directly into the eye in intraocular lesions. Oral drug, tirabrutinib as eye dripping drug, might be effective as a therapeutic option for IOL and should be assessed in future clinical trials of precision medicine for IOL.

A Phase I/II Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of BTK Inhibitor HZ-a-018 in Adult Patients with Relapsed and/or Refractory Central Nervous System Lymphoma

Background: HZ-A-018 is a highly selective and potent covalent BTK inhibitor with CNS-penetrating profile, which was previously reported (Abstract 5501, ASH 2022). Phase I/II study is ongoing in China, and here we present preliminary results of HZ-A-018 monotherapy of the phase I part in central nervous system lymphoma. Methods: HZ-A-018-102 is an ongoing phase I/II study (CTR20210181) to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of HZ-A-018 in central nervous system lymphoma. The primary objective for phase I monotherapy was to determine the safety and tolerability and the recommended phase 2 dose (RP2D), and secondary objectives included preliminary antitumor activity and pharmacokinetics in patients with relapsed/refractory primary/secondary CNS lymphoma (R/R PCNSL/SCNSL) and primary vitreoretinal lymphoma (PVRL) who had received ≥1 prior therapy. HZ-A-018 was administered orally once daily in 28-day cycles until disease progression or unacceptable toxicity. Results: At the data cutoff date of 30 May 2023, 21 pts from the phase I monotherapy were analyzed, including 18 R/R PCNSL and 3 R/R SCNSL. 3 pts received 300mg/d, 12 pts received 450mg/d and 6 pts received 600mg/d. 600mg was the highest dose pre-defined in the study and MTD was not reached. Pts were with a median age of 62 years (range: 36-80), median KPS 80 (range: 60-90) and a median of 2 prior systemic therapies (range: 1-5). 20 pts (95.2%) presented with brain parenchyma, and 1 pt (4.8%) presented with intraocular (IO) involvement. All patients had received HD-MTX based chemotherapy, 19 pts (90.5%) had received rituximab and 1 pt had received whole brain radiation therapy (WBRT). 16 of 21 pts (76.2%) experienced a treatment related adverse event (TRAE). The most common TRAEs (≥10%) were thrombocytopenia (42.9%), neutropenia (23.8%), leukopenia (23.8%), and hypokalemia (14.3%), majority of which were grade 1 to 2. DLTs occurred in 1 pt at 450 mg/d and 1 pt at 600 mg/d. 4 pts (19.0%) had dose interruption, no pts had dose reductions, and no pts discontinued from the study due to TRAEs. The plasma and cerebrospinal fluid (CSF) pharmacokinetics showed HZ-A-018 was rapidly absorbed and could cross the blood-brain barrier with CSF HZ-A-018 concentration ranged from 5.94 to 17.5 ng/mL two hours post-dose. Of 19 pts available for tumor assessment (16 PCNSL with brain parenchyma, 1 PCNSL with IO and 2 SCNSL with brain parenchyma) and 2 pts not evaluable (1 PCNSL with brain parenchyma, and 1 SCNSL with brain parenchyma), the overall response rate (ORR) was 52.4% (95%CI: 29.8, 74.3), including 23.8% (5 pts) complete response(CR)/unconfirmed complete response(CRu), 28.6% (6 pts) partial response (PR), and 19.0% (4 pts) stable disease (SD), contributing to an 71.4% (95%CI: 47.8, 88.7) disease control rate (DCR). At 600mg/d, all 6 pts had achieved high and deep responses, contributing to 100% ORR and 50% CRR, with the 3-month duration of response (DOR) rate not reached. Dose expansion was ongoing at 600mg QD. Conclusions: These results demonstrated that HZ-A-018 was efficacious and well-tolerated in CNS lymphoma patients with high CNS penetrating profile. The monotherapy RP2D for R/R PCNSL was determined as 600 mg QD and a phase 2 R/R PCNSL registration study in China is currently planned.

RARE-07. BONE MARROW ABLATIVE CHEMOTHERAPY ASSOCIATED WITH IMPROVED OUTCOMES AMONG PATIENTS WITH RELAPSED CENTRAL NERVOUS SYSTEM NON-GERMINOMATOUS GERM CELL TUMORS

Abstract PURPOSE Patients with relapsed/refractory central nervous system (CNS) non-germinomatous germ cell tumors (NGGCTs) have poor outcomes. There is no universal agreement on managing these patients secondary to the rarity of the disease and lack of prospective trials. We aim to explore prognostic factors that may help guide the management of patients with relapsed/refractory CNS NGGCTs. METHODS We performed a multinational retrospective study of relapsed/refractory CNS NGGCTs. We summarized all data using standard descriptive statistics. Overall survival (OS) was evaluated using Kaplan-Meier and Fisher’s exact test to estimate odds ratios (OR) and 95% confidence intervals (CI) using SPSS software. RESULTS We identified 28 patients from 7 centers. Twenty-three patients (82%) were males. The median age at initial diagnosis was 11 years (range: 8-15). Twelve patients (43%) suffered from relapse, and 16 patients (57%) had an initial refractory disease. The median time to first relapse/progression was 29 months (range: 5-26). Eight patients (29%) received bone marrow ablative chemotherapy (HDCx) at relapse/progression. Sixteen patients (57%) received re-irradiation at relapse/progression. Six patients (21%) achieved complete remission (CR) at relapse. Only eight patients (29%) were alive at the last follow-up. The median follow-up time since relapse/progression was 16 months (range: 1 -153 months). HDCx (OR=25, 95%CI: 2.9-2223) – not re-irradiation (OR=7.8 95%CI: 0.795-76.1) – was associated with being alive at the last follow-up. All patients who achieved CR at the end of relapse treatment survived. Only one patient with the refractory disease was alive at the last follow-up. CONCLUSIONS Patients with refractory CNS NGGCTs have dismal outcomes. HDCx and achieving CR at the end of relapse therapy are associated with improved survival. A multinational registry is needed to collate standardized data to inform future prospective clinical trials and improve the outcomes of patients with relapsed/refractory CNS NGCCTs.

A phase 2 study of sirolimus in combination with metronomic chemotherapy (CHOAnome) in children with recurrent and/or refractory solid and CNS tumors.

10024 Background: Multiple low-dose, anti-angiogenic (metronomic) chemotherapy regimens have demonstrated activity in pediatric solid and central nervous system (CNS) tumors. The mTOR pathway is activated in many human cancers and provides an attractive therapeutic target. We previously conducted a phase 1 trial establishing the dose (2 mg/m2), safety and tolerability of sirolimus in combination with metronomic chemotherapy. In the current study, we conducted a prospective, multi-institutional phase 2 trial to determine the objective response rate (ORR) in pediatric patients with recurrent and/or refractory (R/R) solid and CNS tumors treated with this regimen (NCT02574728); herein we report the results of the CNS tumor stratum. Methods: Patients aged 12 months to 30 years with R/R CNS tumors of all world health organization (WHO) grades were eligible. After completion of the trial’s first stage, patients with diffuse intrinsic pontine glioma (DIPG) were excluded due to lack of efficacy. Patients were required to have measurable disease and no known curative therapeutic options. Treatment consisted of continuous sirolimus (2 mg/m2/dose PO daily), celecoxib (100 mg PO BID), and oral etoposide (50 mg/m2/day; max dose: 100 mg) alternating every 21 days with oral cyclophosphamide (2.5 mg/kg/day; max dose: 100 mg) in 42-day cycles. Sirolimus was dose-adjusted to maintain a serum trough concentration of 10-15 ng/ml. Response was determined using a modified Response Assessment in Neuro-Oncology (RANO) criteria. Enrollment proceeded using a Fleming’s two-stage design based on best overall response (BOR), which required two objective disease status determinations. Results: Twenty-two CNS tumor patients were enrolled; 20/22 were evaluable for response. Median age was 11.2 years (range: 5.9 – 18.1); 6 (30%) were female. Diagnoses included DIPG (N = 5), medulloblastoma (N = 3), high-grade (HG) glioma (N = 5), HG/malignant neuroepithelial tumor (N = 3) and one each of diffuse midline glioma, atypical teratoid/rhabdoid tumor (ATRT), choroid plexus carcinoma, and pineoblastoma. Median number of cycles was 2 (range: 1-6). Best response after any cycle was partial response (PR) in 4 [medulloblastoma (N = 3); pineoblastoma (N = 1)], stable disease (SD) in 4, and progressive disease (PD) in 12 for an ORR of 20%; all patients with DIPG had PD at or before their first disease evaluation. BOR was PR in 3 (15%), SD in 2 (10%), PD in 14 (70%), and unknown in 1 (5%). Four patients had SD or response for ≥ 6 months [medulloblastoma (n = 1), pineoblastoma (N = 1), and HG glioma (N = 2)]. Conclusions: The combination of sirolimus with metronomic chemotherapy showed activity in pediatric patients with some R/R CNS tumors, producing objective responses in medulloblastoma and pineoblastoma. Patients with DIPG did not benefit from this regimen and should be offered alternative treatments. Clinical trial information: NCT02574728 .

Diagnosis and management of vitreoretinal lymphoma: present and future treatment perspectives.

Intraocular lymphoma (IOL) is a rare malignant intraocular lymphocytic tumor that mimics uveitis. IOL is anatomically classified into vitreoretinal lymphoma (VRL) and uveal lymphoma; most IOLs are VRLs, while uveal lymphoma is rare. VRL is highly malignant, with 60%-85% of patients developing central nervous system (CNS) lymphoma; primary VRL (PVRL) is an ocular disease with poor prognosis. We aimed to review the management and both current and future treatments for VRL. VRL diagnosis is based on the results of cytopathological examination using vitreous biopsy. However, the positive ratio of vitreous cytology remains 29%-70%. A combination of adjunctive tests may improve diagnostic accuracy, but as yet no gold-standard regimen has been established. Methotrexate intravitreal injections are effective in controlling ocular lesions; however, this treatment allows CNS dissemination. The efficacy of systemic chemotherapy in suppressing CNS dissemination has been recently debated. A multicenter prospective study with a unified treatment protocol is required to clarify this issue. In addition, establishing a treatment protocol for elderly patients and those with poor general health is necessary. Moreover, relapsed/refractory VRL and secondary VRL are more difficult to treat than PVRL because they are prone to recurrence. Ibrutinib, lenalidomide with or without rituximab, and temozolomide are promising treatments for relapsed/refractory VRL. In Japan, Bruton's tyrosine kinase (BTK) inhibitors have been approved for treating refractory CNS lymphoma. Furthermore, a randomized prospective study of tirabrutinib, a highly selective BTK inhibitor, is ongoing for evaluating the suppressing of CNS progression in patients with PVRL.

Efficacy and safety of bevacizumab, irinotecan, and temozolomide combination for relapsed or refractory pediatric central nervous system embryonal tumor: a single-institution study.

This study aimed to evaluate the efficacy and safety of combination therapy with bevacizumab (Bev), irinotecan (CPT-11), and temozolomide (TMZ) in children with central nervous system (CNS) embryonal tumor relapse. The authors retrospectively examined 13 consecutive pediatric patients with relapsed or refractory CNS embryonal tumors who received combination therapy comprising Bev, CPT-11, and TMZ. Specifically, 9 patients had medulloblastoma, 3 had atypical teratoid/rhabdoid tumor (AT/RT), and 1 had CNS embryonal tumor with rhabdoid features. Of the 9 medulloblastoma cases, 2 were categorized in the Sonic hedgehog subgroup and 6 in molecular subgroup 3 for medulloblastoma. The complete and partial objective response rates were 66.6% in patients with medulloblastoma and 75.0% in patients with AT/RT or CNS embryonal tumors with rhabdoid features. Furthermore, the 12- and 24-month progression-free survival rates were 69.2% and 51.9% for all patients with recurrent or refractory CNS embryonal tumors, respectively. In contrast, the 12- and 24-month overall survival rates were 67.1% and 58.7%, respectively, for all patients with relapsed or refractory CNS embryonal tumors. The authors observed grade 3 neutropenia, thrombocytopenia, proteinuria, hypertension, diarrhea, and constipation in 23.1%, 7.7%, 23.1%, 7.7%, 7.7%, and 7.7% of patients, respectively. Furthermore, grade 4 neutropenia was observed in 7.1% of patients. Nonhematological adverse effects, such as nausea and constipation, were mild and controlled with standard antiemetics. This study demonstrated favorable survival outcomes in patients with relapsed or refractory pediatric CNS embryonal tumors and thus helped to investigate the efficacy of combination therapy comprising Bev, CPT-11, and TMZ. Moreover, combination chemotherapy had high objective response rates, and all adverse events were tolerable. To date, data supporting the efficacy and safety of this regimen in the relapsed or refractory AT/RT population are limited. These findings suggest the potential efficacy and safety of combination chemotherapy in patients with relapsed or refractory pediatric CNS embryonal tumors.

Refractory Primary Vitreoretinal Lymphoma Involving the Spinal Cord with a Temporary Complete Response to Tirabrutinib.

Many patients with primary vitreoretinal lymphoma (PVRL) exhibit central nervous system (CNS) involvement either at the diagnosis or during follow-up. The prognosis in the patients of PVRL with relapsed or refractory CNS remains extremely poor. We herein report a patient with refractory PVRL who had recurrence in the spinal cord despite receiving high-dose methotrexate-based chemotherapy and whole-brain radiotherapy. The patient surprisingly responded to tirabrutinib temporarily. We believe that this case suggests the utility of this new target therapy.

Anti-IL-6 therapies in central nervous system inflammatory demyelinating diseases.

Current treatments for central nervous system (CNS) inflammatory demyelinating diseases (IDDs) include corticosteroids, plasma exchange, intravenous immunoglobulin, and immunosuppressant drugs. However, some patients do not respond well to traditional therapies. In recent years, novel drugs, such as monoclonal antibodies, targeting the complement component C5, CD19 on B cells, and the interleukin-6 (IL-6) receptor, have been used for the treatment of patients with refractory CNS IDDs. Among these, tocilizumab and satralizumab, humanized monoclonal antibodies against the IL-6 receptor, have shown beneficial effects in the treatment of this group of diseases. In this review, we summarize current research progress and prospects relating to anti-IL-6 therapies in CNS IDDs.

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.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Nimotuzumab therapy in the treatment of pediatric central nervous system tumors: single-center experience.

Relapsed or refractory central nervous system (CNS) tumors still have poor prognosis, and, therefore, new treatment options are required. We retrospectively researched treatment results of patients with CNS tumors treated with nimotuzumab from 2010 to 2015. The study included nine patients with the diffuse intrinsic pontine glioma; eight with medulloblastoma; three each with anaplastic ependymoma, glioblastoma multiforme, and central nervous system primitive neuroectodermal tumor (CNS PNET); two patients with gliomatosis cerebri; and one patient each with other tumor types, including atypical teratoid rhabdoid tumor, thalamic astrocytoma, low-grade glial tumor, high-grade glial tumor, and cribriform neuroepithelial tumor. An objective response was observed in 10 of 33 patients with four patients showing a complete response, three a partial response, and three patients had stable disease. The 2-year overall survival (OS) and progression-free survival (PFS) rates were 35 ±9% and 19 ±8%, respectively. Due to the objective response in medulloblastoma, CNS PNET, and anaplastic ependymoma (MED group), survival rates of this group were analyzed. The 2-year OS and PFS for the MED group were 71 ±12% and 30 ±13%, respectively. The treatment was well tolerated. The treatment responses for medulloblastoma, CNS PNET, and anaplastic ependymoma have been promising. Likewise, some patients with relapsed or progressive CNS tumors may benefit through nimotuzumab-containing regimen.

Hyperbaric oxygen treatment: Results in seven patients with severe bacterial postoperative central nervous system infections and refractory mucormycosis

Resistant bacterial infections following brain and spine surgery and spontaneous mucormycosis with central nervous system (CNS) involvement represent a serious treatment challenge and more efficient therapeutic approaches ought to be considered. Hyperbaric oxygen treatment (HBOT) has shown promise as a complementary therapy. This case series evaluated whether HBOT contributed to infection resolution in seven patients with refractory CNS infectious conditions. Clinical results for seven patients referred for HBOT between 2010 to 2018 to treat refractory postoperative brain and spine infections or spontaneously developing mucormycosis were retrospectively analysed. The patients' clinical files and follow-up consultations were reviewed to assess evolution and outcome. Seven patients were referred with a median age of 56 years. The median follow-up was 20 months. Four patients had postoperative infections and three had rhino-orbital-cerebral mucormycosis (ROCM). HBOT was used as an adjunctive treatment to antimicrobial therapy in all patients. Prior to HBOT, all patients had undergone an average of four operations due to infection refractoriness and had completed an average of five months of antimicrobial therapy. After HBOT, infection resolution was obtained in six patients without additional operations, while one patient with ROCM stopped HBOT after the third session due to intolerance. Three patients stopped antimicrobial therapy while four were maintained on prophylactic treatment. Infection resolution was reached in the six patients that completed HBOT as prescribed. HBOT may serve as an effective complementary treatment in CNS refractory postoperative and spontaneous infections.

Membrane Transporters and Their Regulatory Mechanisms at the Brain and Retinal Barriers to Establish Therapies for Refractory Central Nervous System Diseases

The central nervous system (CNS) is segregated from the circulating blood and peripheral tissues by endothelial and epithelial barriers. To overcome refractory CNS diseases, it is important to understand the membrane transport systems of drugs and the endogenous compounds that relate to the pathogenesis of CNS diseases at these barriers. The endothelial barrier in the brain is the blood-brain barrier (BBB). Our studies clarified the efflux transport of prostaglandin E2 (PGE2), a modulator of neural excitation and inflammatory responses, across the BBB via plasma membrane transporters such as organic anion transporter 3 (Oat3) and multidrug resistance-associated protein 4 (Mrp4). This efflux transport was attenuated by peripheral inflammation or cerebral treatment with neuroexcitatory l-glutamate, suggesting that BBB-mediated PGE2 elimination was altered under several pathological conditions. We also examined excitatory amino acid transporter (EAAT) 1 and 3 as l-glutamate efflux transporters of the inner blood-retinal barrier (BRB) and blood-cerebrospinal barrier. It was considered that these efflux membrane transporters participated in the homeostasis of neuroexcitatory and neuroinflammatory responses in the brain and retina. Moreover, we identified connexin 43 (Cx43) hemichannels as a new membrane transport system that is activated under pathological conditions and recognizes several monocarboxylate drugs, such as valproate. As it is expected that the action of these membrane transporters across the CNS barriers is of great importance in understanding the pathology of various neuroexcitatory diseases, our studies should contribute to the establishment of therapeutic strategies for refractory CNS diseases.

A pediatric and young adult phase I dose escalation study of BXQ-350 for solid and central nervous system tumors.

2541 Background: BXQ-350 is a novel agent composed of the multifunctional, lysosomal activator protein Saposin C (SapC) and dioleoyl- phosphatidylserine (DOPS) and has demonstrated antitumor effects in both in vitro and in vivo preclinical models. Many tumors, including high-grade glioma and diffuse intrinsic pontine glioma (DIPG), and cells of tumor vasculature have aberrantly exposed phosphatidylserine (PS)-rich domains on the cell surface. BXQ-350 is an anti-tumor agent in development from Bexion Pharmaceuticals, Inc. that selectively targets tumor cell PS, particularly those translocated to the outer leaflet of the plasma membrane in tumor cells. BXQ-350 activates and participates in various cellular processes, including apoptosis and necrosis, and may also exhibit novel mechanisms leading to cell death that require further investigation. Methods: Nine refractory solid (2) and central nervous system (7) tumor patients (5F:4M, age 4-23 years of age) were enrolled in a 2-site dose escalation phase I first-in-pediatric trial ( NCT03967093 ) which completed in 2019. All patients received at least one dose of BXQ-350 which was administered as an intravenous infusion. Dosing began at 1.8 mg/kg and escalated to the highest planned dose level of 3.2mg/kg. Results: There were no BXQ-350-related serious adverse events, dose limiting toxicities, or withdrawals. The highest planned dose of 3.2 mg/kg was achieved safely but a maximum tolerated dose was not established. One osteosarcoma patient had progressive disease prior to completing cycle one of treatment and was removed from trial. Eight patients (DIPG-3, HGG-1, GBM-1, Pineoblasotoma-1, Ependymoma-1, Osteosarcoma-1) completed at least one cycle, with one DIPG patient completing cycle five. Conclusions: BXQ-350 was well tolerated with no significant dose-limiting toxicities at the highest planed dose level. A pediatric phase I trial in newly diagnosed patients is planned for 2nd quarter 2020. Clinical trial information: NCT03967093 .

PATH-30. TARGETED THERAPIES FOR PEDIATRIC LOW-GRADE GLIOMAS: A CASE SERIES

Abstract Pediatric central nervous system (CNS) malignancies are the most common malignancies of childhood. The standard treatment plan for most CNS malignancies involves surgery, chemotherapy, radiation, and/or a combination of above therapies. Unresectable symptomatic low grade gliomas, such as pilocytic astrocytomas and gangliogliomas, are slow growing tumors that are typically responsive to a single course of intravenous chemotherapy, but in select patients these WHO grade I or II tumors can recur and be refractory to multiple courses. Molecular diagnostics can offer valuable insight into the tumor microenvironment, where targeted therapies can be offered for specific actionable mutations. Here we report a case series of 3 pediatric patients, with unique CNS malignancies, currently on targeted therapies for tumor-specific somatic mutations. Patient A is a 5 year old male with unresectable Neurofibromatosis-1 related plexiform neurofibroma of the nasopharyngeal space as well as optic pathway glioma, with a mutation of the MAPK/ERK pathway. Patient B is a 6 year old male with recurrent, refractory pilocytic astrocytoma of the optic pathway and hypothalamus, with progression through several courses of intravenous chemotherapy, noted to have somatic NACC2-NTRK mutation. Patient C is a 17 year old female with unresectable, pontomedullary ganglioglioma, noted to have BRAF-V600E mutation. Patient A is treated with Selumetinib, for about 6 months, with near resolution of nasopharyngeal mass. Patient B is treated with Larotrectinib, for about 3 months, with stability of clinical symptoms. Patient C is treated with Vemurafenib, for about 10 months, with stability of lesion size and patient-reported clinical improvement. No adverse events were noted for any of these patients and all medications were administered orally. Significant improvement in quality of life was reported, as they did not have central lines or bone marrow suppression. Targeted inhibitors provide a reasonable treatment option for relapsed, refractory CNS malignancies with actionable mutations.

CD19-Directed CAR T Cells Treatment in a Patient With Refractory DLBCL and CNS Involvement

ABSTRACT Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common neoplasm of the lymphatic system. Treatment and clinical management are difficult in the relapsed/refractory (R/R) setting. Chimeric antigen receptor (CAR) T cells are genetically engineered using autologous patient lymphocytes and have shown very promising results in the treatment of relapsed and refractory cases of DLBCL. Methods: A 64-year-old male patient with refractory DLBCL and central nervous system (CNS) involvement after 9 lines of therapy was treated with CD19-specific CAR T cell therapy at the Department of medical oncology and hematology at the University Hospital of Zurich and followed-up for 10 weeks. Results: Autologous lymphocytes were successfully harvested and transfected/expanded for CAR T cell production. Conditioning chemotherapy and CAR T infusion was well tolerated. Post-infusion side effects were mild (cytokine release syndrome [CRS] grade 1−2), with limited signs of neurotoxicity. Ten weeks after CAR T cell therapy, an excellent response could be documented via PET-CT. The CNS lesion disappeared as assessed via cranial MRI. Conclusion: CD19-targeted CAR T cell therapy is a revolutionary treatment option for heavily pre-treated R/R DLBCL even in the setting of CNS involvement.

Phase 1/1B trial to assess the activity of entrectinib in children and adolescents with recurrent or refractory solid tumors including central nervous system (CNS) tumors.

10009 Background: Entrectinib is a CNS-penetrant oral inhibitor of TrkA/B/C, ROS1 and ALK tyrosine kinases. We report the efficacy of entrectinib in children with recurrent/refractory solid or CNS tumors. Methods: Patients ≤ 20y old with recurrent/refractory solid tumors were eligible. After determination of the recommended dose in all-comers, disease-specific expansion cohorts of CNS and solid tumors harboring target aberrations in NTRK1/2/3, ROS1 or ALK, and neuroblastoma (NBL), regardless of mutation spectrum, were enrolled. Response, assessed by Investigator, was classified as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) using RANO for CNS tumors, RECIST for solid tumors, and Curie score for NBL. Results: Between May 2016 and October 2018, 29 patients aged 4.9m–20y (median 7y) were enrolled and 28 were evaluated for response. Entrectinib was well tolerated. Dose limiting toxicities were elevated creatinine, dysgeusia, fatigue and pulmonary edema. The recommended dose was 550 mg/m2 daily. All responses occurred at doses ≥ 400 mg/m2. In CNS tumors (n = 6), all high-grade with gene fusions: 1 achieved a CR ( ETV6-NTRK3); 3 achieved a PR ( TPR-NTRK1, EEF1G-ROS1, EML1-NTRK2); 1 achieved an unconfirmed PR ( GOPC-ROS1); and 1 has yet to be evaluated ( KANK1-NTRK2). In extracranial solid tumors (n = 8), 6 had a fusion of whom 1 achieved a CR ( DCTN1-ALK) and 5 achieved a PR ( TFG1-ROS1, EML4-NTRK3, ETV6-NTRK3, KIF5B-ALK, ETV6-NTRK3). In NBL (n = 15): 1 achieved a CR ( ALK F1174L). Median duration of therapy was 85d (6–592d) for all patients; 56d (6–338d) for non-responders; and 281d (56–592d) for responders. Median time to response was 57d (30–58d). Conclusions: Entrectinib produced striking, rapid and durable responses in all children with refractory CNS and solid tumors harboring NTRK1/2/3, ROS1 or ALK fusions (11 out of 11) as well as in an ALK-mutated NBL. No responses were seen in tumors lacking aberrations in target kinases. These results support the continued evaluation of entrectinib as a targeted therapeutic in solid tumors with NTRK1/2/3, ROS1 and ALK fusions, especially in high-grade CNS neoplasms. Clinical trial information: NCT02650401.

Efficacy of Donor and ‘Third Party’ (Tabelecleucel) EBV-Specific T Cells for Treatment of Central Nervous System (CNS) EBV-PTLD

Background EBV+PTLD is a life-threatening complication after hematopoietic cell transplantation (HCT) and solid organ transplantation (SOT). Introduction of EBV-specific T-cells (EBV+CTLs) as second line treatment after rituximab has reduced overall EBV+PTLD related mortality. Due to limited efficacy of rituximab for EBV+PTLD disease involving the CNS there remains a clear clinical need. We studied the ability of EBV+CTLs to mediate responses in CNS EBV+PTLD. Methods Patients with CNS EBV+PTLD, with or without systemic disease, after HCT or SOT were eligible to receive either donor-derived or ‘third party' Tabelecleucel between 1996 and 2016 on two IRB approved MSKCC protocols (95-024: NC2663 and 11-130: NCT01498484). Donor EBV+CTLs were generated from EBV seropositive HCT-donors, while Tabelecleucel were selected from a bank of 330 lines from volunteer HCT donors. Selection of Tabelecleucel lines was based on matching for > 2/10 recipient alleles and HLA restriction by at least one HLA allele shared by the patient's tumor. Patients received 3 weekly infusions of ∼1-2 × 106 T cells/kg. Responses were assessed 21-35 days after the start of each cycle of EBV+CTLs based on Lugano criteria with CNS disease being assessed by MRI, CSF (EBV-PCR) or thalium scan. Patients not achieving a complete response (CR) to an initial cycle of EBV+CTLs were eligible to receive a subsequent cycle. Main outcome of interest was response to EBV+CTLs. Other outcomes of interest were 1-year overall survival (OS) and infusion-related toxicities. Results Nineteen patients were treated: 12 after HCT (T-cell depletion 6, cord blood 3, T-replete 3) and 7 after SOT (renal 4, heart 1, liver 1, heart/liver 1). 7 patients received EBV+CTLs from their primary donor, 11 from a third-party donor and 1 from both donor types. Ten were treated for had isolated-CNS disease while 9 had CNS and systemic disease. All of these patients had received prior therapy including rituximab (N = 17), radiation therapy (N = 6), and/or systemic chemotherapy (N = 9). The overall response rate was 63% and the one-year OS was 60% (70% for isolated-CNS, 56% for combined). Two patients with combined disease had simultaneous radiation therapy and achieved response, and thus, the CNS specific response could not be attributed to cell therapy alone. Toxicities associated with infusions were limited; 8 patients experienced ≥ grade 3 events with one patient experiencing a possibly related grade 3 event. Interpretation This study demonstrates clear responses and promising survival among patients with otherwise refractory and lethal CNS EBV+PTLD. Adoptive therapy with EBV directed cellular therapy (either primary donor or third party derived Tabelecleucel is a promising treatment modality for CNS EBV+PTLD.