Abstract only
2011
Background: Leptomeningeal metastasis (LM) involves seeding of tumor cells to the cerebrospinal fluid (CSF) and the leptomeninges. Proton craniospinal irradiation (pCSI) has been ...shown to be potentially effective for patients with solid tumor LM. We evaluated whether CSF circulating tumor cells (CSF-CTC) and neuroimaging correlate with outcomes in patients with LM treated with pCSI. Methods: We reviewed a single-institution retrospective database of patients treated with pCSI for LM between 2018-2020 who had ≥ 3 months (mos.) follow-up and identified 58 patients. Pre-pCSI CSF-CTC using CellSearch and magnetic resonance imaging (MRI) data, and post-pCSI CSF-CTC nadir before initiation of new cancer-directed therapy were assessed. The optimal cutoff for pre-pCSI CSF-CTC was determined using maximally selected rank statistics. Kaplan Meier analysis was used to identify univariate correlates with CNS progression free survival (CNS PFS) and overall survival (OS), calculated from start of pCSI. Multivariate Cox proportional hazards modeling was used to test independence of univariate associations. Results: The median follow-up for patients who were censored (n = 15, 26%) was 15 mos. (interquartile range (IQR): 9 -21). Most patients were diagnosed with lung (n = 27, 47%) or breast cancer (n = 22, 38%). The median CNS PFS and OS were 6 mos. (IQR: 3 – 9) and 8 mos. (IQR: 5 – 18), respectively. Of the 49 patients with pre-pCSI CSF-CTCs analyzed, CSF-CTCs were identified in 43 (88%). Pre-pCSI CSF-CTC
< 53/3mL was associated with improved CNS PFS (11.8 vs 6.0 mos., p = 0.01), and a trend toward improved OS (16.7 vs 7.7 mos., p = 0.08). On pre-pCSI MRI, patients with parenchymal brain metastases (n = 33, 57%) had worse OS (6.7 vs 12.7 mos., p = 0.01) but not CNS PFS. Patients with both brain and spine LM (n = 42, 72%) compared to those only one site or no visible disease (n = 16, 28%) showed worse CNS PFS (5.8 vs 7.5 mos., p = 0.03) and OS (7.7 vs 16.7 mos., p = 0.05). In a multivariate model, pre-pCSI CSF-CTC was significantly associated with CNS PFS (p = 0.03) while brain and spine LM on MRI was not (p = 0.20) No patient had an increase in CSF-CTC immediately post-pCSI, and in those with both detectable pre-pCSI CSF-CTCs
and a post-pCSI
measurement
(n = 29, 50%), the median decrease at nadir was 37/3mL (range: 0-200) occurring at a median of 1.6 mos. (range: 0.5 -5.2). A decrease in CSF-CTC > 37/3mL was associated with improved CNS PFS (7.1 vs 4.4 mos., p = 0.04) but not OS (12.5 vs.7.7 mos., p = 0.2). Conclusions: Proton CSI is an effective treatment for patients with solid tumor LM and can result in prolonged disease control in some patients. Lower CSF-CTC count prior to pCSI and larger changes after pCSI are predictive of survival outcomes, arguing for early pCSI intervention for solid tumor LMD. Early treatment escalation after pCSI can be considered for patients with high pre-pCSI CSF-CTC and a smaller nadir post-pCSI.
Abstract
BACKGROUND
CSF-CTC analysis through the CellSearch® platform has been studied as a diagnostic and prognostic tool for LM from solid tumors. CSF-ctDNA can be detected in LM and/or BM, with ...unclear significance. We aimed to evaluate CSF-CTCs and CSF-ctDNA as predictors of LM diagnosis and survival in LM and BM.
METHODS
We retrospectively reviewed charts of patients with solid tumors who underwent CSF-CTC and ctDNA evaluation from the same lumbar puncture between 2016-2021 at Memorial Sloan Kettering Cancer Center. LM was diagnosed by MRI and/or CSF cytology; CSF-ctDNA was considered “positive” if next-generation sequencing (NGS) detected ≥ 1 mutations using clinically validated thresholds. Associations with newly diagnosed LM were performed using logistic regression, and with development of LM using cause-specific competing risks models. Survival analyses were performed using Cox proportional hazards modeling from date of first CSF collection, and adjusted by LM as a time-dependent variable.
RESULTS
Out of 151 total patients, 99 had LM at the time of CSF analysis (58/99 with newly diagnosed LM, within 30 days of first CSF collection), and 52 had BM only, of which 8/52 (15%) developed LM later (median time from CSF to LM=235 days, range 57-364). CSF-CTCs and CSF-ctDNA were predictive of newly diagnosed LM (OR=1.006, 95% CI:1.002-1.01, p=0.002 for continuous CSF-CTCs; OR=3.60, 95% CI:1.65-7.87, p=0.001 for positive CSF-ctDNA). In a small cohort of patients without LM, CSF-ctDNA was almost statistically significant in predicting later development of LM (HR=4.14, 95% CI: 0.98-17.57, p=0.054) while continuous CSF-CTCs were not (HR=1.02, 95% CI: 0.99-1.04, p=0.21). In all patients, both CSF-CTCs (OR=1.004, 95% CI: 1.001-1.006, p=0.002) and CSF-ctDNA (OR=2.49, 95% CI: 1.51-4.15, p=0.0004) predicted survival.
CONCLUSION
CSF-ctDNA could predict development of LM in patients with BM. Presence of CTCs and ctDNA in CSF were associated with poor survival in patients with central nervous system metastases.
Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We ...performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Clinical responses to ibrutinib occurred in 10 of 13 (77%) patients with PCNSL, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of CARD11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-cell antigen receptor-associated protein CD79B.
-mutant PCNSLs showed enrichment of mammalian target of rapamycin (mTOR)-related gene sets and increased staining with PI3K/mTOR activation markers. Inhibition of the PI3K isoforms p110α/p110δ or mTOR synergized with ibrutinib to induce cell death in
-mutant PCNSL cells.
Ibrutinib has substantial activity in patients with relapsed or refractory B-cell lymphoma of the CNS. Response rates in PCNSL were considerably higher than reported for diffuse large B-cell lymphoma outside the CNS, suggesting a divergent molecular pathogenesis. Combined inhibition of BTK and PI3K/mTOR may augment the ibrutinib response in
-mutant human PCNSLs.
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Abstract
BACKGROUND
Recurrent gliomas are universally fatal with few adequate treatment options. IDH-mutant gliomas may be susceptible to PARP inhibition, thus combination therapy using alkylating ...agents and checkpoint inhibition could be synergistic.
METHODS
This is an open label, phase II study of olaparib, temozolomide, and pembrolizumab for patients with recurrent IDH-mutant glioma, grade 2 or 3, with measurable enhancing disease per RANO. Patients received pembrolizumab 200mg IV on day 1 of each 21-day cycle. Oral olaparib 200mg twice daily and temozolomide 50mg/m2 daily were given days 1-7 of cycles 3-11. Here, we report the results of our safety lead in, consisting of the first 6 patients to complete cycle 3.
RESULTS
A total of seven patients were enrolled to the safety lead-in: 2 women; 5 patients with astrocytoma, 2 oligodendroglioma. Patients had a median age of 45 (range 29-63) and median KPS 90 (range 80-100). Median number of recurrences was 3.5 (range 1-5). All had received prior alkylating therapy and all but 1 patient had received prior RT. No patients were taking steroids at the time of enrollment. Six patients completed the dose-limiting toxicity (DLT) period without any DLTs. One patient experienced clinical progression on pembrolizumab monotherapy prior to the start of combination therapy and was thus replaced. No grade 3 or 4 toxicities were seen through the DLT period. The most common clinical toxicities at least possibly related to treatment were grade 1 and 2 fatigue (n = 4), nausea (n = 3) and constipation (n = 2). Hematological toxicities include grade 1 anemia (n = 2) and decreased platelet count (n = 1).
CONCLUSIONS
The combination of olaparib, temozolomide, and pembrolizumab was well tolerated in this cohort. Following completion of the safety lead-in, the trial was redesigned to minimize the length of pembrolizumab monotherapy and introduce combination therapy in cycle 1. Enrollment is ongoing. NCT05188508.
Primary CNS Lymphoma (PCNSL) is an aggressive primary brain tumor. Outcome and treatment options for patients with recurrent/refractory (r/r) disease are poor. We have observed promising efficacy of ...single-agent ibrutinib in r/r PCNSL and secondary CNS lymphoma (SCNSL). We hypothesize that combing ibrutinib with the immunomodulatory imide lenalidomide and theanti-CD20 antibody rituximab would be adding clinical efficacy. In this phase 1b trial, we investigate the toxicity of ibrutinib in combination with rituximab and lenalidomide in r/r PCNSL/SCNSL.
Eligible patients had r/r PCNSL/SCNSL or newly diagnosed SCNSL, age≥18, ECOG≤2, normal end-organ function, and with any number and type of prior therapies. Enrollment followed the 3+3 design. Ibrutinib was dosed at 560mg daily (dose level 1) and 840mg (level 2, 3, 4); lenalidomide was dosed at 10mg daily (day 1-21) (level 1, 2), 15mg daily (day 1-21) (level 3) and 20mg daily (day 1-21) (level 4); rituximab was dosed at 500mg/m2 (all dose levels). Rituximab was given for 6 cycles, lenalidomide for 12 cycles, and ibrutinib ongoing.
Fifteen patients have been enrolled; 3 at dose level 1-3 and 6 at level 4. Median age was 69 years (range 56-82); 4 were women. Median ECOG was 1 (0: 5, 1: 7, 2: 3). Eleven had r/r PCNSL. Eleven had recurrent parenchymal disease; two had additional cerebrospinal fluid (CSF) involvement; two had both. Nine patients had recurrent and 6 refractory disease. No DLT occurred. One grade 4 lymphopenia was observed. The following grade 3 events occurred: rash (in 3 patients); lymphopenia (in 2); AST, ALT, lung infection, and elevated aPTT (in 1). The most common adverse events were thrombocytopenia, lymphopenia, and rash. No Aspergillosis infection was observed. After a median follow-up of 6.9 months, 14/15 were evaluated for response with 13/15 (73%) showing a response: 4 CR, 7 PR, and 2 SD, 1 PD. Median PFS was 3.03 months; not yet reached for Dose level 4 (only 1/6 has developed progression with a median follow up of 5 months).
Patients with CNS lymphoma tolerate the combination of rituximab, lenalidomide and ibrutinib well. No dose limiting toxicities were observed. No Aspergillosis infection occurred with this combination regimen. Continued enrollment is ongoing.
Grommes:BTG: Consultancy; Ono: Consultancy; Kite: Consultancy. Schaff:Debiopharm: Consultancy.
Full text
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
BACKGROUND
CSF-CTC testing using the CellSearch® platform is a validated diagnostic tool for leptomeningeal metastases (LM) from solid tumors. CSF-CTCs can also be detected in patients with ...brain metastases (BM), but their significance is unclear. Our objective was to evaluate the utility of CSF-CTC quantification in predicting outcomes in CNS metastases.
METHODS
We retrospectively reviewed charts of patients with solid tumors who underwent CSF-CTC measurement between 2016–2019 at Memorial Sloan Kettering Cancer Center. Information on neuroaxis imaging, CSF results, systemic cancer status, tumor molecular profile and survival was collected. LM was diagnosed by MRI and/or CSF cytology. Survival analyses were performed using Cox proportional hazards modeling, and CSF-CTC splits associated with survival were identified through recursive partitioning analysis (RPA).
RESULTS
A total of 407 patients (38% lung primary, 34% breast, 28% other tumor types) were included; of these, 144 had LM and 233 had BM diagnosed before or around the time of CSF tests (97 had both). For a subgroup of 101 patients with LM diagnosed within 30 days of CSF sampling, mean CSF-CTCs were 127.3/3ml, compared to 44.6/3ml in the overall cohort. CSF-CTCs predicted survival in these patients, with optimal cutoff at 61 CSF-CTCs/3ml, above which the risk of death doubled (HR=2.09, 95% CI: 1.13–3.87, p=0.02). For 53 patients with BM diagnosed 1–6 months prior to CSF tests, CSF-CTCs (mean 54.1/3ml) also determined higher risk of death when above the optimal cutoff of 94 (HR=5.15, 95% CI: 2.08–12.78, p=0.004). For both groups, positive/suspicious cytology was associated with higher risk of death as well, but these results were not statistically significant (LM group: HR=1.79, 95% CI: 0.95–3.35, p=0.07; BM group: HR=1.86, 95%CI: 0.82–4.22, p=0.14).
CONCLUSION
In newly diagnosed LM and BM, quantification of CSF-CTCs predicts survival. CSF-CTC analysis can be used as a prognostic tool in patients with CNS metastases.
The genomic landscape of gliomas has been characterized and now contributes to disease classification, yet the relationship between molecular profile and disease progression and treatment response ...remain poorly understood.
We integrated prospective clinical sequencing of 1,004 primary and recurrent tumors from 923 glioma patients with clinical and treatment phenotypes.
Thirteen percent of glioma patients harbored a pathogenic germline variant, including a subset associated with heritable genetic syndromes and variants mediating DNA repair dysfunctions (29% of the total) that were associated with somatic biallelic inactivation and mechanism-specific somatic phenotypes. In astrocytomas, genomic alterations in effectors of cell-cycle progression correlated with aggressive disease independent of IDH mutation status, arose preferentially in enhancing tumors (44% vs. 8%,
< 0.001), were associated with rapid disease progression following tumor recurrence (HR = 2.6,
= 0.02), and likely preceded the acquisition of alkylating therapy-associated somatic hypermutation. Thirty-two percent of patients harbored a potentially therapeutically actionable lesion, of whom 11% received targeted therapies. In
-mutant gliomas, response to agents targeting the RAF/MEK/ERK signaling axis was influenced by the type of mutation, its clonality, and its cellular and genomic context.
These data reveal genomic correlates of disease progression and treatment response in diverse types of glioma and highlight the potential utility of incorporating genomic information into the clinical decision-making for patients with glioma.
The Macdonald criteria and the Response Assessment in Neuro-Oncology (RANO) criteria define radiologic parameters to classify therapeutic outcome among patients with malignant glioma and specify that ...clinical status must be incorporated and prioritized for overall assessment. But neither provides specific parameters to do so. We hypothesized that a standardized metric to measure neurologic function will permit more effective overall response assessment in neuro-oncology.
An international group of physicians including neurologists, medical oncologists, radiation oncologists, and neurosurgeons with expertise in neuro-oncology drafted the Neurologic Assessment in Neuro-Oncology (NANO) scale as an objective and quantifiable metric of neurologic function evaluable during a routine office examination. The scale was subsequently tested in a multicenter study to determine its overall reliability, inter-observer variability, and feasibility.
The NANO scale is a quantifiable evaluation of 9 relevant neurologic domains based on direct observation and testing conducted during routine office visits. The score defines overall response criteria. A prospective, multinational study noted a >90% inter-observer agreement rate with kappa statistic ranging from 0.35 to 0.83 (fair to almost perfect agreement), and a median assessment time of 4 minutes (interquartile range, 3-5).
The NANO scale provides an objective clinician-reported outcome of neurologic function with high inter-observer agreement. It is designed to combine with radiographic assessment to provide an overall assessment of outcome for neuro-oncology patients in clinical trials and in daily practice. Furthermore, it complements existing patient-reported outcomes and cognition testing to combine for a global clinical outcome assessment of well-being among brain tumor patients.
Abstract
Background
Leptomeningeal metastases (LM) are associated with limited survival and treatment options. While involved-field radiotherapy is effective for local palliation, it lacks ...durability. We evaluated the toxicities of proton craniospinal irradiation (CSI), a treatment encompassing the entire central nervous system (CNS) compartment, for patients with LM from solid tumors.
Methods
We enrolled patients with LM to receive hypofractionated proton CSI in this phase I prospective trial. The primary endpoint was to describe treatment-related toxicity, with dose-limiting toxicity (DLT) defined as any radiation-related grade 3 non-hematologic toxicity or grade 4 hematologic toxicity according to the Common Terminology Criteria for Adverse Events that occurred during or within 4 weeks of completion of proton CSI. Secondary endpoints included CNS progression-free survival (PFS) and overall survival (OS).
Results
We enrolled 24 patients between June 2018 and April 2019. Their median follow-up was 11 months. Twenty patients were evaluable for protocol treatment–related toxicities and 21 for CNS PFS and OS. Two patients in the dose expansion cohort experienced DLTs consisted of grade 4 lymphopenia, grade 4 thrombocytopenia, and/or grade 3 fatigue. All DLTs resolved without medical intervention. The median CNS PFS was 7 months (95% CI: 5–13) and the median OS was 8 months (95% CI: 6 to not reached). Four patients (19%) were progression-free in the CNS for more than 12 months.
Conclusion
Hypofractionated proton CSI using proton therapy is a safe treatment for patients with LM from solid tumors. We saw durable disease control in some patients.
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