Cerebrospinal Fluid Involvement Research Articles

Efficacy and Safety of TLR2 Co-Stimulated CAR T Cells in CD19-Positive Lymphoid Malignancies with Central Nervous System Involvement

Background CD19 chimeric antigen receptor (CAR) T cell therapy showed remarkable remission rates in patients with refractory or relapsed (R/R) non-Hodgkin's lymphoma (NHL) and acute lymphoblastic leukemia (ALL). However, data on outcomes of CAR T cell therapy for patients with central nervous system (CNS) involvement are limited, as most of them have been excluded from most pivotal CAR-T studies because of concerns about treatment-related neurotoxicity. Here, we show results of a third generation of CD19 CAR T cells for patients with R/R B cell cancers with CNS involvement in a single-center cohort study. Methods A total of 21 patients with R/R B cell malignancies (including ALL and NHL) with CNS involvement were included in this study. Patients derived peripheral lymphocytes were collected through apheresis and lentivirally transduced with a 3 rd generation CAR containing CD28 and TLR2 co-stimulatory domains. The cells were expanded ex vivo and administered in a single infusion (1×10 6 or 2×10 6 CAR T cells per kilogram of body weight) after a conditioning regimen of cyclophosphamide and fludarabine. Results Of the 21 patients with CNS involvement, 11 patients with ALL and 10 with NHL were included in this study, with a data cutoff of July 2023. All 11 patients with ALL had both bone marrow (BM) and cerebrospinal fluid (CSF) involvement. Of the 10 patients with NHL, 5 of the 10 lymphoma patients had parenchyma involvement, 6 patients (6/10) had CSF infiltration and 1 had oculus sinister involvement; the majority of patients (8/10) were diagnosed with secondary CNS lymphoma, whereas 2 patient was primary CNS lymphoma. Of the 21 patients who were treated, the overall response rate (ORR) was 71% (15/21), with 73% (8/11) in ALL and 70% (7/10) in NHL. 67% of patients with ALL (7/11) had a complete remission in both BM and CSF, while 40% of NHL patients (4/10) had a complete response and 30% (3/10) received a partial response. The median overall survival (OS) of ALL was 14.3 months, with a median follow-up of 20.3 months, while the median OS of NHL was not reached with a median follow-up of 14.2 months. Median progression-free survival (PFS) of ALL and NHL were 11.1 months (95% CI, 0.7-29.9 months) and 4.8 months (95% CI, 1.0-15.3 months), respectively (P = 0.84). In the total CNS cohort, cytokine release syndrome (CRS) of any grade was seen in 20 patients (95%), grade 3 in 3 patients (14%). ICANS occurred in 9 patients (42.8%, including 5 ALL and 4 NHL patients), grade 3 in 5 patients (23.8%), and there was no grade 4 event. Median time to ICANS was 5 days (range, 2-10 days) after CAR-T infusion. All the CRS or ICANS were manageable. No significant difference in occurrence of and time to ICANS was seen between ALL and NHL patients (P = 0.22 and 0.96). CAR T cells were identified in CSF of patients following infusion, and the median time to peak CAR T cells in CSF of ALL and NHL were 6.5 days and 10 days post-infusion, respectively (P = 0.141). Median time to last documented follow-up of all patients (alive or dead) was 18.1 months (range 1.0-31.2 months). At the end point of observation, 5 of the 11 ALL patients and 5 of 10 NHL patients were still alive with sustained CR of CNS disease and systemic disease (Figure 1). Conclusion TLR2-costimulated CAR T cell therapy for patients with R/R B cell malignancies with CNS involvement is safe, feasible, and results in high response rates and durable remission in both ALL and NHL patients with CNS disease. The clinical trial was registered at www.clinicaltrials.gov as # NCT04605666.

P14.08.A PROGNOSTIC VALUE OF CSF IL-10 AT THE 2-MONTH ASSESSMENT AFTER THE START OF INDUCTION CHEMOTHERAPY IN PRIMARY CNS LYMPHOMAS. A LOC NETWORK STUDY

Abstract BACKGROUND Despite a high rate of objective response at first evaluation of ongoing high dose methotrexate (hd MTX) based induction chemotherapy, the risk of early relapse remains high and unpredictable in patients suffering from primary CNS lymphomas (PCSNL). Since cerebrospinal fluid (CSF) IL-10 level has been shown prognostic in PCNSL, both before and at the end of the treatment, it is used in routine in some centers. The objective of the present study was to assess the prognostic value of early CSF IL-10 level (e-IL-10), performed 2 months after the beginning of the induction chemotherapy. MATERIAL AND METHODS We retrospectively selected the immunocompetent patients treated at Pitié-Salpêtrière hospital and Institut Curie for a PCNSL diagnosed between January 2019 and July 2022 according to the following criteria : histological diagnosis of diffuse large B-cell lymphoma ; hd MTX-based chemotherapy as induction in first line treatment; complete response (CR) or partial response (PR) according to the IPCG criteria at the 2-month evaluation; availibility of dosage of e-IL-10. CSF IL-10 was classified as detectable (≥2.5 pg/ml) or undetectable (<2.5 pg/ml) RESULTS Thirty patients (median age 63 years, median KPS 70, 17 men) met the selection criteria. At initial diagnosis, all patients presented with brain lymphoma, associated with CSF (N=10) and/or intraocular involvement (N=2). Before treatment, 22 of them had a dosage of CSF IL-10, which was detectable in 21 cases (median 27.5 pg/mL, range 3-1844 pg/mL), with a ratio IL-10/IL-6>1 in 21 cases. At the 2-month evaluation after the beginning of the treatment, 25 patients were in PR and 5 were in CR and e-IL-10 was undetectable in 22 patients and detectable in 8 patients, with the following values: 105, 30, 20, 16, 14, 10, 6, 3 pg/mL . For the patients with detectable e-IL-10, e-IL-10 was superior to initial IL-10 level in 1 case and inferior in 5 cases (no data at baseline for 2 patients) and the ratio CSF e-IL-10/e-IL-6 was superior to 1 in 8/8 cases. At the end of induction treatment, all but one patient (the one with an e-IL-10 value of 3 pg/ml) had experienced progressive disease in the group with detectable e-IL-10 (2 progression in the brain, 5 in the CSF) vs 4/22 patients in the group with undetectable e-IL-10 (p=0.001). The median follow-up was 16 months. Median PFS was 5.8 months in the group with detectable e-IL-10 and 28.6 months in the group with undetectable e-IL-10 (p=0.0001). 1-year OS was 71% in the group with detectable e-IL-10 and 86% in the group with undetectable e-IL-10 (p=0.36). CONCLUSION Our results suggest that detectable CSF IL-10 at 2 months after the start of first line induction chemotherapy in PCNSL is associated with a high risk of early relapse and that closer follow-up of these patients is warranted. Further studies are needed to confirm these results and to assess whether the therapeutic strategy should be adapted accordingly in these cases.

Initial and follow-up evaluations on cerebrospinal fluid involvement by hematologic malignancy.

Central nervous system (CNS) involvement is a serious complication in hematologic malignancy, and early detection and management of CNS involvement in these cases significantly impact the prognosis. Currently, there is no consensus on the use of multiparametric flow cytometry (MFC) and conventional cytology (CC) testing for initial and follow-up cerebrospinal fluid (CSF) specimens to diagnose CNS involvement by hematologic malignancy. In our institution, after initial MFC and CC, two subsequent negative MFCs are required before discontinuing MFC. The aim of this study is to evaluate the outcome of this approach. CSF cytology and MFC reports were retrieved from Laboratory Information System, and data was reviewed. Between January 2020 and December 2021, 1789 CSF samples from 280 patients were submitted for CSF analysis. For those 517 CSF samples tested by both MFC and CC, 97 cases tested positive by both MFC and CC with 95% concordance. Eighteen cases were MFC + /CC - and 7 were MFC - /CC + . Thirty-six cases had initially positive MFCs followed by more than one MFC evaluation. Among those 36 cases, 22 cases (61.1%) converted to negative after the second follow-up sample, 9 cases (25%) were continuously positive for at least three samples, and 5 cases (13.9%) exhibited negative to positive conversion. Compared to negative CSF cases, positive CSFs had higher total nucleated cell count and higher total protein levels while red blood cells, glucose, and lactate dehydrogenase levels remained at comparable levels. The concordance between MFC and CC was excellent. The high incidence of positive MFCs on two or more follow-up samples and the high frequency of negative MFC to positive conversion indicate the necessity of repeated negative MFCs before discontinuing MFC. The fact that more than half of the positive cases converted to negative after the second CSF specimen and most follow-up positive cases can be detected by CC alone suggests it is adequate to use CC alone for follow-up CSF study after two consecutive negative MFCs.

Real-world use of tisagenlecleucel in children and young adults with relapsed or refractory B-cell lymphomas.

10031 Background: Survival for pediatric B-cell lymphomas (BCL) exceeds 90% with modern regimens, however outcomes remain poor for patients with relapsed or refractory (R/R) disease. Tisagenlecleucel is a CD19-directed CAR T-cell therapy (CART) that is FDA approved for adults with R/R BCL. No data exists for use of tisagenlecleucel in R/R pediatric BCL. Methods: We surveyed 48 sites in the Pediatric Real-World CAR Consortium to retrospectively describe use and outcomes of tisagenlecleucel for pediatric patients with R/R BCL. This cohort included 10 patients from 7 centers aged ≤25 years who were infused between 2019-2022 and were ≥3 months from CART. We aimed to describe response rates, as determined by each institution based on positron emission tomography, bone marrow evaluation, and/or cerebrospinal fluid (CSF) studies, along with toxicity and outcomes in this population. Results: Ten patients received CART with a median age at infusion of 19 (range, 7-24) years. Five patients had B-lymphoblastic lymphoma (B-LLy), 2 had primary mediastinal BCL, and 1 each had Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), and post-transplant lymphoproliferative disorder related DLBCL. Five patients had primary refractory disease, and 5 were in ≥2nd relapse. Three had received prior hematopoietic stem cell transplant (HSCT). Two had CSF involvement, and 1 had central nervous system parenchymal disease at time of infusion. CART was well tolerated with 1 patient experiencing grade 3 cytokine release syndrome and 2 patients experiencing neurotoxicity (grade 2 n = 1, grade 3 n = 1), both of whom had CSF involvement at time of CART infusion. Best overall response was complete response (CR) for 6, partial response (PR) for 2, and refractory disease for 2. Two patients, both with B-LLy, underwent allogeneic HSCT while in CART-mediated CR with B-cell aplasia. Both patients with PR (1 DLBCL, 1 Burkitt) subsequently relapsed with CD19-negative disease; the patient with DLBCL subsequently achieved CR with salvage immuno-chemotherapy and HSCT. All 6 CR patients remain in remission at a median time to follow-up of 31 (range, 14-47) months. Conclusions: This multicenter case series of CD19-directed CART for R/R pediatric BCL suggests that tisagenlecleucel may be safe and active in this population with all CR patients currently in sustained remission. Larger studies are needed to understand how best to incorporate CART into treatment for R/R pediatric BCL. [Table: see text]

Diffuse large B-cell lymphoma at risk of secondary CNS involvement: The inefficacy of intravenous high-dose methotrexate CNS prophylaxis and the importance of baseline cerebrospinal fluid analysis.

High-dose intravenous methotrexate (HD-MTX) CNS prophylaxis in high-risk diffuse large B cell lymphoma (DLBCL) remains controversial. We describe real-world CNS relapse incidence following baseline cerebrospinal fluid (CSF) analysis to exclude asymptomatic leptomeningeal involvement in newly diagnosed high-risk DLBCL patients with versus without single-route HD-MTX CNS prophylaxis. Consecutively diagnosed high-risk systemic DLBCL patients without leptomeningeal involvement by CSF analysis (noCNS) were identified retrospectively. Five-year CNS relapse incidence and survival outcomes were examined, as stratified by receipt of HD-MTX prophylaxis. Secondary analysis of survival outcomes in patients with synchronous leptomeningeal involvement (CNSinv) by CSF analysis at diagnosis were compared with the noCNS group. No significant difference in 5-year CNS relapse incidence was observed following HD-MTX prophylaxis versus no prophylaxis (total n = 445) despite similar CNS-IPI risk; 6.2% versus 5.6%, adjusted HR 1.08 (95% CI 0.41-2.85), p = .88; nor in 5-year progression free survival (PFS) or overall survival (OS) risk. Of CNSinv patients, 93.3% had ≥1 extranodal site. Increased CNS relapse/progression risk (5-year risk; HR 10.7 [95% CI 5.35-21.37], p < .0001) and inferior PFS and OS were observed in CNSinv versus all noCNS patients. The CNSinv group had superior OS compared with noCNS patients who later experienced CNS relapse (HR 0.55, p = .052). HD-MTX prophylaxis does not reduce CNS relapse risk in high-risk systemic DLBCL without leptomeningeal involvement by CSF analysis at diagnosis. Asymptomatic patients with synchronous leptomeningeal involvement on baseline CSF examination are at increased risk of further CNS disease events and inferior survival compared to patients without CSF involvement.

Metastatic retinoblastoma at presentation: Clinical presentation, treatment, and outcomes.

The aim of this study was to retrospectively determine clinical features, treatment outcomes, and overall survival in four patients with metastatic retinoblastoma at presentation. The mean age at diagnosis was 63 months (range: 24-108 months). Three patients had overt orbital disease of at least one eye and one patient had microscopic orbital disease with scleral infiltration on histopathology. Metastatic sites included regional lymph nodes (RLN) (n = 4), bone marrow (BM) (n = 2), and cerebrospinal fluid (CSF) (n = 1). The most common sites of RLN were ipsilateral preauricular nodes (two patients) and contralateral parotid gland involvement (one patient). The treatment administered included primary enucleation (n = 1), high-dose intravenous chemotherapy (n = 4), secondary enucleation (n = 2), orbital external beam radiotherapy (n = 3), and intrathecal chemotherapy (n = 1). High-risk features included massive choroidal and microscopic scleral infiltration in the eye that underwent primary enucleation. At a mean follow-up of 33 months (range, 4-68 months), one patient with CSF involvement deceased in 4 months. The remaining three patients were alive and disease-free at the last mean follow-up period of 43 months (range, 18-68 months). The results of our study showed that RLN and BM metastasis respond well to treatment while CSF metastasis is associated with poor prognosis.

Diagnosis, treatment, and outcome of primary CNS lymphoma—a single-center experience

Primary CNS lymphoma (PCNSL) is a highly aggressive non-Hodgkin lymphoma (NHL) that occurs in the CNS (e.g. brain, meninges, spinal cord, cerebrospinal fluid, or intraocular involvement) in the absence of systemic NHL. Tumor resection does not improve survival, and neurosurgical intervention is generally limited to stereotactic biopsy to provide a histopathological diagnosis. The objective of this single-center study was to evaluate the management and outcome of PCNSL patients diagnosed by biopsy, using overall survival and progression-free survival as endpoints. At our department of neurosurgery, 140 patients were diagnosed with PCNSL by biopsy between January 1, 2009, and December 31, 2018. Of these, 37 patients were included in the study and were divided into three groups according to their postoperative therapy. Median OS was 35.7months for the intensive treatment group, 29.5months for the moderate treatment group, and 8.6months for the palliative treatment group. The intensive and moderate treatment groups had similar progression-free survival, while the palliative treatment group had poor overall and progression-free survival. Six patients were long-term survivors (> 80months). Age under 65years was the main significant parameter affecting overall survival. In this cohort, patients with PCNSL had an overall fair prognosis if they (1) were under 65years old, (2) had a performance score < 2 at the time of diagnosis, and (3) received either intensive or moderate chemotherapeutic treatment. Biopsy is still the primary diagnostic tool; other methods have been investigated but are not yet recommended.

Value of cerebrospinal fluid white cell count and protein level in predicting leptomeningeal involvement by systemic aggressive B‐cell lymphoma

Diagnostic cerebrospinal fluid (CSF) analysis for patients with newly diagnosed aggressive B-cell lymphoma at risk of secondary central nervous system involvement typically includes multiparametric flow cytometry (MFC), cytology (CC), white cell count (WCC) and total protein. The strength of relationships between MFC results and the remaining variables has been disputed in small studies. We explored these relationships in a large homogeneous cohort of patient samples, aiming to establish the relationship between WCC and protein level and MFC results. Adult patients with aggressive B-cell lymphoma at risk of CNS involvement who underwent staging CSF analysis by MFC were identified retrospectively from institutional electronic records between October 2011 and December 2020. Three hundred and seventy eight samples, including 45 (11.9%) MFC+ samples, were analysed. The relative sensitivity of CC for MFC positivity was 0.38, with PPV of 0.68. Significantly higher median WCC (p<.001) and protein levels (p=.011) were seen in MFC+ vs. MFC- samples. MFC+CC+ (vs. MFC+CC- samples) demonstrated higher median neoplastic events and neoplastic cell concentration. WCC ≥36×106 /L and protein ≥1.12g/L cut-off values demonstrated the highest PPVs for MFC positivity (0.67 and 0.88, respectively). Statistically significant associations exist between elevated WCC and protein and MFC positivity, and selected WCC and protein cut-off values have PPVs comparable to that of cytological assessment. Whilst routine WCC and protein analysis may be unnecessary, WCC/protein values above these levels could be regarded as reasonable evidence of CSF involvement in the appropriate setting.

CSF Involvement by Nonhematolymphoid Malignancies: A Descriptive Study with Emphasis on Cytomorphological Clues.

Introduction:Detection of malignant cells in cerebrospinal fluid (CSF) samples in suspected cases of malignancy is critical for the management of patients. CSF involvement by nonhaematolymphoid malignancies is less common. We aimed to study the cytomorphologic characteristics of various nonhaematolymphoid malignancies in CSF.Methods:A retrospective cytomorphological analysis of 27 CSF cytology smears reported as positive or suspicious for nonhematolymphoid malignancies from January 2010 to April 2020 over 10 years was carried out. Smears in all cases were prepared by cytospin technique and stained with May-Grunwald-Giemsa (MGG) and papanicolaou (Pap) staining procedures. Cell immunohistochemistry/immunocytochemistry was done wherever cell block/extra slides were available.Results:Twenty-four of 27 cases were interpreted as “positive,” while three were reported as “suspicious” of malignancy. Nineteen of 27 cases were metastatic adenocarcinomas including three suspicious malignancy cases with the primary sites of origin being the breast (10), stomach (2), rectum (1), gall bladder (1), lung (1), and four cases of unknown primary. Of the remaining positive cases, there were five cases of metastatic medulloblastoma, two cases of metastatic pineoblastomas, and one case of metastatic extraskeletal Ewings sarcoma. Each of these metastatic malignancies had at least a single diagnostic cytomorphological clue, similar to those observed in other body cavities and primary malignancy sites.Conclusion:Nonhematolymphoid malignancies are readily diagnosable on CSF cytology, most of them are metastatic. Identification of malignant cells in CSF is critical, as it has therapeutic and prognostic implications.

Cerebrospinal fluid cytology in a toddler with a posterior fossa space-occupying lesion.

An atypical teratoid rhabdoid tumour (AT/RT) is an extremely rare malignant neoplasm. Cerebrospinal fluid (CSF) involvement at presentation indicates intracranial dissemination and is associated with an aggressive course and worse outcomes. We present the characteristic cytomorphological features of AT/RT in the cerebrospinal fluid from a toddler presenting with a posterior fossa space-occupying lesion.

Characteristics, Management and Outcome of DLBCL Patients Presenting with Simultaneous Systemic and CNS Disease at Diagnosis - a Retrospective Multicenter Study

▪Background: The incidence of lymphoma concurrently involving the central nervous system (CNS) and systemic organs is very rare. Data regarding this clinical setting are based on case reports and relatively small retrospective series, precluding the establishment of solid recommendation regarding prognosis and treatment.Objectives: The current retrospective multi-center study investigated the characteristics, treatment protocols and outcome of patients with B cell non-Hodgkin lymphoma (B-NHL), diagnosed with concomitant systemic and CNS involvement, between the years 2004 to 2017.Results: All consecutive patients with B- NHL, presenting with concomitant systemic and CNS involvement at diagnosis were reviewed. Thirty five patients were included (24 male; 11 females). Median age at diagnosis was 59 years (34-86). Histological subtype was diffuse large B-cell lymphoma in almost all patients (n=34; 97%). The International prognostic index was greater than 2 in 70% of the patients (n=24). The median number of extra nodal sites was 1 (range: 0-4), with bone being the most common extra nodal site (n=14).Concurrent indolent and aggressive lymphoma were reported in 2 out of 30 patients for which these data were available (6.7%). Twenty two patients had paranchymal involvement (63%). Eight patients had meningeal involvement per imaging (23%) and 4 had spinal disease. Cerebrospinal fluid (CSF) involvement, defined by a positive CSF cytology or immunophenotyping, was detected in 59% (13/22 patients).The most common induction chemotherapy was anthracycline-based (RCHOP / RCHOP like regimen) in combination with high-dose methotrexate (MTX), with or without cytarabine (23 of 35 patients, 66%). Seven patients were ineligible for intensive chemotherapy due to poor performance status. Overall, 14 patients died from the disease (40%). Six of them during induction and 8 due to relapsed/refractory disease. 2 patients died from other causes.Overall response rate following induction treatment was 80%, including 60% complete remissions (CRs) and 20% partial remissions (PRs). Most patients achieved CNS and systemic CR (evaluated by nervous system MRI/CT and PET/CT).14 patients were treated with high dose chemotherapy followed by autologous stem cell transplantation (ASCT) (12 in CR and 2 in PR). ASCT did not improve depth of response in any of the patients transplanted in less than CR.Nine patients (33.3%) relapsed within less than 2 years from diagnosis. Disease-free survival (DFS) and overall survival (OS) of the entire cohort were 50.4% and 70.2%, respectively (Figure 1), similar to patients receiving anthracycline-based / high-dose MTX regimen (47.8% and 79.2% respectively). ASCT did not improve the outcome of patients treated with anthracycline-based / high-dose MTX chemotherapy (figure 2). Paravertebral mass (HR=14.8, p=0.002) rather than brain disease (parenchyma, intraventricular or both), meningeal or cranial nerve involvement and an increased LDH level (HRfor100unit=1.11, p=0.006) were found to be associated with shorter OS.Restricted analysis, including patients receiving anthracycline-based / high-dose MTX regimen only , found paravertebral mass (HR=38.265, p=0.011) and meningeal disease (HR=10.463, p=0.059) to be associated with an increased risk of relapse. Of note, brain involvement (HR=0.08, p=0.036) was associated with a decrease risk of relapse.Conclusion: Combination therapy with RCHOP-HD MTX provides encouraging outcome in DLBCL patients presenting with systemic and CNS disease, with half remain free of disease at 2 years post diagnosis. Patients presenting with brain involvement had better survival than patients diagnosed with paravertebral involvement. Our study did not demonstrate clear survival benefit for patients undergoing ASCT, and given the relatively good outcome of our cohort, the benefit of ASCT in this group of patients needs to be further validated in prospective studies. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Issue Highlights — May 2021

Issue Highlights — May 2021

RARE-16. SEVEN CASES OF RETINOBLASTOMA WITH CNS INVOLVEMENTS

Treatment strategy for trilateral retinoblastoma (TRb: very rare RB with brain tumor) or retinoblastoma with central nervous system (CNS) involvement is not established yet. We retrospectively reviewed our seven cases of these rare almost fatal tumors. Their ages at diagnosis are 0y3m-1y10m (median 1y3m) (Male 4, Female 3). Only one had RB family history. Their affected eyes were bilateral 3, unilateral 3 and no 1. Their CNS involvements were suprasellar tumor 4, pineal tumor 1 and cerebrospinal fluid (CSF) cytology positive 2. Three of the suprasellar tumor patients had spinal metastasis. Four of the seven patients were TRb and one were genetically classified suprasellar retinoblastoma. All of them were treated with chemotherapy and four received high-dose chemotherapy. Three brain tumors of four TRb almost disappeared with chemotherapy. Two of them also received radiotherapy but relapsed. Although one radiation-free long-term TRb survivor developed secondary osteosarcoma, he got remission again and live 5 more years. One CSF positive Rb patient with chiasm invasion died of disease 11 months later. The other patient had no chiasm invasion nor CSF involvement at diagnosis, but his CSF cytology turned to positive after his second cycle of chemotherapy. He got remission with radiotherapy and high-dose chemotherapy, and alive without disease for 4 years. 2-year RFS and 2-year OS of all patients were 40% and 60%. Although our TRb patients responded to chemotherapy, it was difficult to avoid radiotherapy except one. Data accumulation is necessary for better treatment of these cancer-predisposed patients.

Phase Ib Trial with Dose Expansion of the Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Combination with Rituximab and Lenalidomide in Patients with Refractory/Recurrent Primary Central Nervous System Lymphoma (PCNSL) and Refractory/Recurrent Secondary Central Nervous System Lymphoma (SCNSL)

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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. Disclosures Grommes: BTG: Consultancy; Ono: Consultancy; Kite: Consultancy. Schaff:Debiopharm: Consultancy.

Bing-Neel Syndrome – A Challenging Diagnosis: Case Report

Bing-Neel syndrome is a rare neurologic complication of Waldenström’s macroglobulinemia, characterized by infiltration of the central nervous system by clonal lymphoplasmacytes. We present a rare clinical case of a patient, who one year after the diagnosis of Waldenström’s macroglobulinemia, progressed with diverse neurologic presentation and cerebrospinal fluid involvement. The diagnosis was based on magnetic resonance imaging and flow cytometry detection of clonal B-cells in the cerebrospinal fluid. Bing-Neel syndrome should be considered in patients with neurologic symptoms and a history of Waldenström’s macroglobulinemia.

Cerebrospinal fluid cytokines in metastatic group 3 and 4 medulloblastoma

BackgroundMetastatic medulloblastoma (MB) portends a poor prognosis. Amongst the 4 molecular subtypes, Group 3 and Group 4 patients have a higher incidence of metastatic disease, especially involving the neuroaxis. At present, mechanisms underlying MB metastasis remain elusive. Separately, inflammation has been implicated as a key player in tumour development and metastasis. Cytokines and their inflammation-related partners have been demonstrated to act on autocrine and, or paracrine pathways within the tumour microenvironment for various cancers. In this study, the authors explore the involvement of cerebrospinal fluid (CSF) cytokines in Group 3 and 4 MB patients with disseminated disease.MethodsThis is an ethics approved, retrospective study of prospectively collected data based at a single institution. Patient clinicpathological data and corresponding bio-materials are collected after informed consent. All CSF samples are interrogated using a proteomic array. Resultant expression data of selected cytokines are correlated with each individual’s clinical information. Statistical analysis is employed to determine the significance of the expression of CSF cytokines in Group 3 and 4 patients with metastatic MB versus non-metastatic MB.ResultsA total of 10 patients are recruited for this study. Median age of the cohort is 6.6 years old. Based on Nanostring gene expression analysis, 5 patients have Group 3 as their molecular subtype and the remaining 5 are Group 4. There are 2 non-metastatic versus 3 metastatic patients within each molecular subtype. Proteomic CSF analysis of all patients for both subtypes show higher expression of CCL2 in the metastatic group versus the non-metastatic group. Within the Group 3 subtype, the MYC-amplified Group 3 MB patients with existing and delayed metastases express higher levels of CXCL1, IL6 and IL8 in their CSF specimens at initial presentation. Furthermore, a longitudinal study of metastatic Group 3 MB observes that selected cytokines are differentially expressed in MYC-amplified metastatic Group 3 MB, in comparison to the non-MYC amplified metastatic Group 3 MB patient.ConclusionThis study demonstrates higher expression of selected CSF cytokines, in particular CCL2, in metastatic Group 3 and 4 MB patients. Although our results are preliminary, they establish a proof-of-concept basis for continued work in a larger cohort of patients affected by this devastating disease.

Outcomes of Burkitt lymphoma (BL) managed in academic (Acad) or community (Comm) centers: real-world evidence (RWE) from 30 US sites.

8043 Background: Prior analyses have suggested better overall survival (OS) of cancer patients (pts) treated in Acad rather than Comm hospitals, but these disparities may reflect different patient characteristics. We examined outcomes of pts with BL in a large RWE cohort from 30 US healthcare systems (Evens, ASH 2019) with a mix of Acad and affiliated Comm sites. Methods: We collected clinical data on adults with BL diagnosed in 2009-2018, individually assigned to Acad or Comm principal setting of care. We compared duration of chemotherapy (CTx, incl. standard CODOX-M/IVAC, hCVAD/MA, DA-EPOCH), rates of complete response (CR), progression-free survival (PFS), and OS adjusting for age, sex, HIV, performance status (PS), stage, LDH &gt; 3x upper limit of normal (ULN), involvement of bone marrow or cerebrospinal fluid (CSF), reporting adjusted risk (RR) or hazard ratio (HR) with 95% CI. Results: Among 641 BL pts, 77 (12%) were managed in Comm setting. Comm pts had lower median age (45 vs 48 in Acad, P= .049), less frequent HIV (13% vs 23%, P= .039), less marrow (21% vs 36%, P= .009) or detected CSF involvement (8% vs 15%, P= .11), and less LDH &gt; 3xULN (21% vs 41%, P= .013), with no significant differences in sex, PS, stage, hemoglobin, or receipt of CTx (97% vs 99%). Acad sites more often applied standard intensive CTx regimens (93% vs 85%, P= .03) and rituximab (92% vs 79%, P= .001), without significant difference in median time to CTx ( P= .69) or treatment-related mortality (TRM, P= .16). Pts managed in Comm (vs Acad) sites were less likely to achieve CR (61% vs 75%, P= .03; RR = 0.79 [0.65-0.95]) and had worse 3-year PFS (46% vs 67%, log-rank P= .003; HR = 2.17 [1.51-3.14]) and OS (53% vs 72%, P= .006; HR = 2.20 [1.48-3.25]). There was no significant interaction with age, sex, HIV, PS, or CSF involvement. Excess mortality concentrated in the 1st year of follow-up. CR, PFS, and OS appeared similar between Acad and Comm settings for pts receiving hCVAD or DA-EPOCH, but outcomes were significantly worse in Comm setting for pts receiving CODOX-M/IVAC. Median number of cycles did not differ between Comm or Acad sites, but median duration of CODOX-M/IVAC delivery was significantly longer in Comm setting (113 vs 101 days, P= .023). Conclusions: In this large RWE analysis, superior outcomes of adults with BL in Acad setting were not explained by baseline patient characteristics or TRM. Differences in the use of standard CTx regimens, rituximab, duration of Ctx, and CR rates suggest need for further research on potential barriers to delivery of intensive CTx for BL in a broader Comm setting.

Phosphatidylcholine PC ae C44:6 in cerebrospinal fluid is a sensitive biomarker for bacterial meningitis

BackgroundThe timely diagnosis of bacterial meningitis is of utmost importance due to the need to institute antibiotic treatment as early as possible. Moreover, the differentiation from other causes of meningitis/encephalitis is critical because of differences in management such as the need for antiviral or immunosuppressive treatments. Considering our previously reported association between free membrane phospholipids in cerebrospinal fluid (CSF) and CNS involvement in neuroinfections we evaluated phosphatidylcholine PC ae C44:6, an integral constituent of cell membranes, as diagnostic biomarker for bacterial meningitis.MethodsWe used tandem mass spectrometry to measure concentrations of PC ae C44:6 in cell-free CSF samples (n = 221) from patients with acute bacterial meningitis, neuroborreliosis, viral meningitis/encephalitis (herpes simplex virus, varicella zoster virus, enteroviruses), autoimmune neuroinflammation (anti-NMDA-receptor autoimmune encephalitis, multiple sclerosis), facial nerve and segmental herpes zoster (shingles), and noninflammatory CNS disorders (Bell’s palsy, Tourette syndrome, normal pressure hydrocephalus).ResultsPC ae C44:6 concentrations were significantly higher in bacterial meningitis than in all other diagnostic groups, and were higher in patients with a classic bacterial meningitis pathogen (e.g. Streptococcus pneumoniae, Neisseria meningitidis, Staphylococcus aureus) than in those with less virulent or opportunistic pathogens as causative agents (P = 0.026). PC ae C44:6 concentrations were only moderately associated with CSF cell count (Spearman’s ρ = 0.45; P = 0.009), indicating that they do not merely reflect neuroinflammation. In receiver operating characteristic curve analysis, PC ae C44:6 equaled CSF cell count in the ability to distinguish bacterial meningitis from viral meningitis/encephalitis and autoimmune CNS disorders (AUC 0.93 both), but had higher sensitivity (91% vs. 41%) and negative predictive value (98% vs. 89%). A diagnostic algorithm comprising cell count, lactate and PC ae C44:6 had a sensitivity of 97% (specificity 87%) and negative predictive value of 99% (positive predictive value 61%) and correctly diagnosed three of four bacterial meningitis samples that were misclassified by cell count and lactate due to low values not suggestive of bacterial meningitis.ConclusionsIncreased CSF PC ae C44:6 concentrations in bacterial meningitis likely reflect ongoing CNS cell membrane stress or damage and have potential as additional, sensitive biomarker to diagnose bacterial meningitis in patients with less pronounced neuroinflammation.

PEDT-04 SIX CASES OF RETINOBLASTOMA WITH CNS INVOLVEMENT

Although the survival rate of intraocular retinoblastoma (RB) is nearly 100%, the outcome of central nervous system (CNS) involvement or Trilateral retinoblastoma (TRb: very rare RB which associated with brain tumor) is dismal. We retrospectively reviewed our six cases of these rare tumors. Their ages at diagnosis are 0y3m-1y10m (median 1y3m) (Male 4, Female 2). Only one had RB family history. Their affected eyes were bilateral 2, unilateral 3 and no 1. Their CNS diseases were suprasellar tumor 3, pineal tumor 1 and cerebrospinal fluid (CSF) cytology positive 2. Two of the suprasellar tumor patients had spinal metastasis. Three of the six patients were TRb. One TRb patient was treated with chemotherapy and high-dose chemotherapy without radiotherapy. Although he suffered with secondary osteosarcoma seven years later, he got complete remission and alive 5 years more without any tumor recurrence. The second TRb patient was treated with chemotherapy and local radiotherapy but relapsed 20 months later. The third TRb patient was chemotherapy resistant. Two CSF positive patients had optic nerve invasion. One patient with chiasm invasion died 11 months later because of treatment resistance. The other patient with optic nerve invasion before optic canal had no CNS tumor nor CSF involvement at diagnosis. Chemotherapy before enucleation was given to avoid dissemination. However, CSF cytology became positive after enucleation and remained even with intensified chemotherapy. Finally, he got remission with radiotherapy and high-dose chemotherapy, and alive without disease for 3.8 years. The last patient had suprasellar genetically classified retinoblastoma tumor and cerebrospinal metastasis. This patient showed good chemotherapy response and is still under treatment. Even with "so called° fatal RB cases, some case could survive with intensified therapy. Data accumulation is necessary for better survival of these tumors.

A Comprehensive Study of Human Integrins in Pediatric Lymphoblastic Leukemia Supports a Role of CD49f (Integrin α6) in the Localization to Bone Marrow but Not Spinal Fluid

Introduction: The overall survival of children with ALL (Acute Lymphoblastic Leukemia) has improved markedly over the last decade, yet relapse occurs in about 20% of patients. The spread of leukemic blasts to the Central Nervous System (CNS) and increased resistance to therapy due to cell adherence within the Bone Marrow (BM) or CNS constitutes major challenges to treatment. For these reasons, adhesion molecules governing the homing and adhesion of leukemic cells are perceived to be of extraordinary importance, both as potential biomarkers and therapeutic targets. Integrins constitute a large family of heterodimeric receptors composed of alpha and beta subunits, which play important roles during homing and migration of normal leucocytes by facilitating adhesion to both stromal cells and components of the extracellular matrix. Increased expression of CD49d (integrin subunit α4) is a marker for adverse prognosis in ALL and recently, CD49f (integrin subunit α6) was shown to facilitate metastasis of ALL xenografts to the central nervous system in mice (Yao H et al., Nature 2018). Methods Previous studies of integrins in BCP-ALL have focused on individual alpha integrins in xenograft models and were based on limited numbers of clinical samples. The present study was based on a large number of Danish pediatric BCP-ALL patients stratified between 2012-2018 using Minimal Residual Disease (MRD) according to the Nordic NOPHO-2008 protocol (Toft N et al., Eur J Haematol 2013). Diagnostic BM samples were subjected to flowcytometric analysis (FCM) of CD49f (n=246) and CD49d (n=135), using a backbone of lineage-specific B-cell markers (CD45, CD10, CD19, CD20). Leukemic blasts were detected in Cerebrospinal Fluid (CSF) using high-sensitivity FCM and the following markers CD45, CD10, CD19, CD20, CD34 and CD38 (n = 246, with matching BM and CSF samples). Results Our data provided us with a unique possibility to identify the role of CD49d and CD49f with respect to minimal residual disease (MRD) at the end of induction therapy (day 29), which is considered the most important prognostic factor in paediatric lymphoblastic leukemia. We found that CD49f was more highly expressed in patients with MRD ≥ 0,1% at day 29 than patients with MRD &lt; 0,1% (p = 0,01), whereas no difference was seen with respect to CD49d. We also investigated the correlation between white blood cell (WBC) and surface expression of CD49d and CD49f in diagnostic BM blasts with respect to different cytogenetic subtypes. A Kruskall-Wallis test showed that the expression varies according to genetic subtypes (p‹0.0001). We found that the expression of CD49d was highest among the high hyperdiploid and iAMP21 (intrachromosomal amplification of chromosome 21) patients, whereas the expression of CD49f was highest among the t12,21 and iAMP21 patients. Notably, the expression of CD49f was inversely correlated to WBC (r=0,17, p=0.01), which was most pronounced among the patients in the B-other cytogenetic subgroup defined as leukaemia that could not be classified into the existing cytogenetic groups (r=0,42, P‹0.0001). In case of strong adherence to BM, lower levels of leukemic blasts might be expected in circulation resulting in high MRD but low WBC. Therefore, both MRD and WBC data are consistent with a prominent adhesive role of CD49f within BM. In contrast, we found significantly lower CD49f surface expression in diagnostic BM samples in patients with leukemic blasts within CSF (p=0.0297). Conclusions: Recently, Yao et al. (2018) showed that ALL cells in circulation are unable to breach the blood-brain barrier in mice and instead employ CD49f (integrin α6) to migrate into the CNS along vessels that connect vertebral or calvarial bone marrow and the subarachnoid space. Potentially, this mechanism could account for cases of ALL relapse within CNS. Our work shows a strong association between high MRD and the expression of CD49f which is a function that would have been anticipated for CD49d due to previous works with ALL and CLL. Furthermore, we found significantly lower CD49f surface expression in leukemic blasts within the BM in patients with CSF involvement and therefore no support for the recently proposed role of CD49f in facilitating the spread of leukemic cells to the CNS. Disclosures No relevant conflicts of interest to declare.