Central Nervous System Relapse Research Articles

Outcomes of children treated for relapsed or refractory acute lymphoblastic leukemia: A single tertiary care center experience.

Acute lymphoblastic leukemia (ALL) is one of the most common malignancies among children. Despite success in frontline treatment, 20% of children will relapse or show resistance to treatment. The aim of this study is to evaluate the clinical characteristics of children diagnosed and treated for refractory or relapsed ALL and determine 3-year overall survival (OS) outcomes. This study involved a retrospective chart review of patients aged 1-14 years diagnosed with ALL during January 2002 to December 2018. Data were extracted for baseline characteristics at diagnosis and at relapse. A total of 347 newly diagnosed children with ALL were identified, among whom there were three induction failures (IF) and 28 relapses, resulting in a cohort of 31 patients with a relapse rate of 9%. The male-to-female ratio was 4.16:1, and the mean duration of first complete remission (CR1) was 26 months. Fifteen (48%) patients relapsed ≤18 months, 7 (23%) during 18-36 months, and 9 (29%) relapsed >36 months of IF or CR1. Nineteen patients (61%) had isolated bone marrow (BM) relapse, 7 (23%) patients experienced isolated extramedullary relapse (5 isolated CNS relapse and 2 isolated testicular relapse), and 5 (16%) patients experienced BM involvement with other sites (4 BM + CNS and 1 BM + testis). The 3-year OS of the cohort was 62.3%, while in patients with CR post first-salvage therapy, a 3-year OS of 79.5% was observed (p value <.05 compared with patients who did not achieve remission post first-salvage therapy, 3-year OS: 46.4%). The same statistical difference was observed in 3-year OS when comparing the duration of remission of CR prior to relapse: ≤18 months, 33.2%; 18-36 months, 66.7%; and >36 months, 87.5%. The same trend continued when comparing 3-year OS based on risk stratification at relapse: low risk (LR), 83.3%; intermediate risk (IR), 80%; and high risk (HR), 44.8%. The incidence and outcomes reported are comparable to internationally reported data regarding the duration of CR1. Risk stratification at relapse and remission status post-salvage therapy were identified as significant prognostic factors for survival. No survival difference was observed among patients who received hematopoietic stem cell transplantation after induction compared with those who received chemotherapy, which could be attributed to the smaller sample size, warranting a multi-institutional observational study. These findings corroborate the need for novel therapies and treatment approaches.

Comparative Study on the Clinicopathologic and Molecular Characteristics of Primary and Secondary Diffuse Large B-cell Lymphoma in the Central Nervous System.

Diffuse large B-cell lymphoma of the central nervous system (CNS-DLBCL) is an aggressive B-cell lymphoma with clinical and molecular heterogeneity. Primary CNS-DLBCL (PCNSL) affects the brain, eyes, leptomeninges, or spinal cord without systemic involvement. Secondary CNS-DLBCL (SCNSL) manifests concurrently with systemic lymphoma or as an isolated CNS relapse with poor prognosis. Next-generation sequencing (NGS) was used to identify genomic alterations in 32 PCNSL and 9 SCNSL cases. Single nucleotide variants and copy number variations in addition to the clinicopathologic data and proposed risk predictive values were compared to aid in diagnostic differentiation between the two types of lymphomas. The MCD genotype, characterized by mutations in MYD88 and CD79B, is the most common alteration in PCNSL and is associated with lower survival rates. The frequency of MYD88 mutation was significantly higher in PCNSL compared to SCNSL (75.0% vs. 33.3%; p=0.042). Recurrent copy number loss of 6p21 occurred in 56.1% of cases, more often in PCNSL (65.6%) than in SCNSL (22.2%) (p=0.028). Diagnostic positive predictive values (PPV) of MYD88 mutation and 6p21 loss for PCNSL were 89% and 91%, respectively. PPV of both alterations was 93% for the diagnosis of PCNSL. MYD88 mutation and 6p21 loss were significantly higher in PCNSL than in SCNSL, and novel risk prediction models based on these distinct genomic profiles can aid in the clinical differentiation of PCNSL and SCNSL.

Philadelphia-chromosome positive acute lymphoblastic leukemia: ten frequently asked questions.

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) constitutes a distinctive cytogenetic entity associated with challenging outcomes, particularly in adult patients. Current upfront chemotherapy-tyrosine kinase inhibitor (TKI)-based therapies include first, second and third-generation TKIs that have revolutionized patient outcomes including molecular remission and overall survival. Chemotherapy-free regimens such as blinatumomab-dasatinib or blinatumomab-ponatinib offer exciting possibilities, yet challenges arise, particularly in preventing central nervous system relapse. Monitoring measurable residual disease is now a cornerstone particularly using next-generation sequencing (NGS)-Clonoseq for accurate assessment. Controversy regarding the ability to omit consolidation with allogeneic stem cell transplantation, specifically for patients achieving early molecular remission, is related to the excellent survival achieved with novel combinations in the upfront setting, however challenged by the lower disease control when transplant is utilized beyond first remission. Post-transplant maintenance introduces new dilemmas: the optimal TKI, dosing, and duration of therapy are open questions. Meanwhile, a myriad of new combinations and cellular therapies are used for relapsed Ph+ ALL, prompting us to unravel the optimal sequencing of these promising regimen. In this review, we delve into the breakthroughs and controversies in Ph+ ALL with ten commonly asked questions.

Safety and Feasibility of Hippocampal Sparing Cranial Radiation in Pediatric and Adolescent Acute Lymphoblastic Leukemia Patients: A Prospective Study.

Introduction Acute lymphoblastic leukemia (ALL) constitutes a significant portion of pediatric malignancies, with central nervous system (CNS) relapse posing a considerable threat to patient outcomes. While cranial radiation therapy (CRT)has been utilized to mitigate CNS relapse, it is associated with neurocognitive (NC) side effects. This study explores the feasibility and safety of using volumetric arc therapy (VMAT) with hippocampal sparing (HS) during cranial radiation therapy for ALL patients, aiming to reduce these side effects. Methodology This prospective observational study included pediatric and young adult patients with ALL who werein remission. HS was achieved using VMAT, and NC assessments were performed at baseline, six months, one year, and, to a limited extent, four years posttreatment. Results VMAT enabled precise hippocampal-sparing CRT with minimal dose to the hippocampus. Dosimetric analysis revealed that patients receiving 18 Gy had mean doses to planning target volume (PTV) and bilateral hippocampus of 18.9 and 9 Gy, respectively. Those receiving 12 Gy had corresponding doses of 13.3 and 7 Gy, respectively. Conformity and homogeneity indices were 0.9 and 0.1, and no brain relapses were observed among the patients in this study. NC assessments demonstrated no decline in intelligence quotient (IQ) scores over time, while only a subset of patients could be assessed at the four-year mark; telephone interviews suggested no significant cognitive decline. Conclusions This study highlights the potential of VMAT with HS as a promising approach to CRT for ALL patients in reducing the risk of NC side effects. The absence of brain relapses and preservation of NC function are encouraging findings, though larger studies are necessary to establish conclusive evidence.

CNS bridging radiotherapy achieves rapid cytoreduction before CAR T-cell therapy for aggressive B-cell lymphomas

AbstractChimeric antigen receptor (CAR) T-cell therapy (CART) for central nervous system lymphoma (CNSL) is a promising strategy, yet responses are frequently not durable. Bridging radiotherapy (BRT) is used for extracranial lymphoma in which it can improve CART outcomes through cytoreduction of high-risk lesions. We hypothesized that BRT would achieve similar, significant cytoreduction before CART for CNSL (CNS-BRT). We identified patients with CNSL with non-Hodgkin B-cell lymphoma who received CNS-BRT before commercial CART. Cytoreduction from CNS-BRT was calculated as change in lesion size before CART. Twelve patients received CNS-BRT, and the median follow-up among survivors is 11.8 months (interquartile range, 8.5-21.9). Ten patients had CNSL (9 secondary, 1 primary) and 2 patients had epidural disease (evaluable for toxicity). All 10 patients with CNSL had progressive disease at the time of CNS-BRT. Of 12 patients, 1 experienced grade ≥3 cytokine release syndrome, and 3 of 12 patients experienced grade ≥3 immune effector cell–associated neurotoxicity syndrome. CNS-BRT achieved a 74.0% (95% confidence interval, 62.0-86.0) mean reduction in lesion size from baseline (P = .014) at a median of 12 days from BRT completion and before CART infusion. Best CNS response included 8 complete responses, 1 partial response, and 1 progressive disease. Three patients experienced CNS relapse outside the BRT field. Preliminary data suggest CNS-BRT achieves rapid cytoreduction and is associated with a favorable CNS response and safety profile. These data support further study of BRT as a bridging modality for CNSL CART.

Incidence of central nervous system relapse in primary mediastinal B-cell lymphoma: Implications for central nervous system prophylaxis.

7080 Background: Primary mediastinal large B-cell lymphoma (PMBCL) is an uncommon type of aggressive B-cell non-Hodgkin lymphoma. PMBCL has distinct clinicopathologic features compared to diffuse large B-cell lymphoma but shares some clinical and biologic features with nodular sclerosis classic Hodgkin lymphoma (cHL). Central nervous system (CNS) relapse is exceedingly rare in cHL, therefore one may expect that CNS relapse in PMBCL is also uncommon. Herein, we examined the incidence of CNS relapse in patients with PMBCL. Methods: Patients with newly diagnosed PMBCL seen at Mayo Clinic between 1/2002 and 4/2023 were identified from the Mayo Clinic Lymphoma Database. Clinical features, treatment details and outcomes were abstracted from medical records. The CNS relapse rate was calculated using a competing risk model, with death considered as a competing risk. Results: A total of 154 PMBCL cases were identified. The median age at diagnosis was 38 years (range 18-77) and 60.4% were female. The distribution of CNS-IPI was low-risk in 80 (51.9%) patients, intermediate-risk in 43 (27.9%), and high-risk in 3 (1.9%), and data were missing for 28 patients (18.2%). 78 patients (50.6%) received R-CHOP and 76 patients (49.4%) received R-DA-EPOCH as frontline therapy. High-dose methotrexate (HD-MTX) for CNS prophylaxis was administered to 5 patients (all treated with R-CHOP). 20 patients received intrathecal (IT) chemotherapy (methotrexate and/or cytarabine) for CNS prophylaxis (4 with R-CHOP [1 received HD-MTX too],16 with R-DA-EPOCH). The median follow-up was 39 months (95% CI 28.2-49.8). Only 3 patients had CNS relapse, all associated with systemic relapse (1 concurrent, 1 had CNS relapse 8.8 months after systemic relapse, 1 had CNS relapse 2 months before systemic relapse). The cumulative incidence of CNS relapse for the entire cohort was 1.43% (95% CI 0.3%-4.6%) at 1 year and 2.21% (95% CI 0.6%-5.8%) at both 2 and 5 years. For those who did not receive CNS prophylaxis (n=130), the incidence was 0.86% (95% CI 0.1%-4.3%) at 1 year and 1.82% (95% CI 0.4%-5.8%) at both 2 and 5 years. All 3 patients who experienced CNS relapse had R-CHOP as frontline therapy; two patients did not receive any CNS prophylaxis, while 1 patient received IT CNS prophylaxis. Conclusions: The risk of isolated CNS relapse in PMBCL appears to be very low, even in patients who did not receive CNS prophylaxis. While some patients may experience CNS relapse associated with systemic relapse, the overall incidence was low (1.43% at 1 year and 2.21% at 2 and 5 years). The rarity of isolated CNS relapse in PMBCL suggests that routine CNS prophylaxis may not be necessary as part of initial therapy.

MRI compared to 123I-MIBG scan for detection of central nervous system relapse in neuroblastoma.

10040 Background: Neuroblastoma (NB) relapsing in the central nervous system (CNS), though uncommon, is historically incurable. However, a multimodality approach has improved long term survival (1). Timely detection of CNS relapse may reduce or prevent morbidity and mortality. In most centers, surveillance for NB includes whole-body MIBG scans but does not require dedicated anatomical brain imaging. At Memorial Sloan Kettering Cancer Center (MSK), head MRI at regular intervals is standard. The objective of this retrospective study was to determine the optimal imaging modality for detecting CNS relapse in NB. Methods: After MSK IRB approval, records of patients with CNS NB seen at MSK from 2004-2023 were evaluated. In most cases, relapse was diagnosed at other institutions before referral to MSK. Analyzed data included symptoms and findings on brain CT/MRI and MIBG scans. Results: Of 206 patients with MIBG-avid CNS NB, 7 were excluded because they had CNS disease at diagnosis. For the remaining 199 patients, median time to CNS relapse from diagnosis was 18 months. 132 (66%) patients had CNS relapse at a median of 9.8 months after achieving complete remission. In 67 patients with prior systemic progression, median time to CNS relapse was 10.9 months from the last relapse. Relapse was isolated to CNS in 130/199 (65%) patients. 118 (59%) patients had neurological symptoms at time of CNS disease; 81(41%) were asymptomatic, relapse being detected on surveillance scans. Multiple (&gt;1) parenchymal lesions were noted in 74 (37%), diffuse leptomeningeal disease without parenchymal involvement in 15 (7%) and solitary lesions in 110 (55%) patients. Median diameter of the largest lesion was 2.7 (range &lt;0.5-6.8) cm. Anatomical imaging was performed with MRI (65%), CT (14%) or both (34%). Of those undergoing both scans, CNS relapse was missed on CT in 4/67 (6%) patients. 137 patients had MIBG scans before resection of CNS relapse. All sites of CNS disease noted on MRI/CT were positive by MIBG in 46 (33%) patients. However, MIBG scan was either totally or partly negative in 69 (50%) and 22 (16%) patients, respectively. Even for lesions ≥2cm in diameter, MIBG was completely negative in 27/57 (47%). MIBG positivity did not correlate with age, size &gt;2cm, MYCN amplification or ALK mutation status (p&gt;0.05 for each). Lesions &lt;1cm and infratentorially located were more likely to be negative on MIBG scan (p&lt;0.05). Lesions in symptomatic patients, dural lesions and hemorrhagic lesions were more likely to be positive on MIBG scan (p&lt; 0.05). Conclusions: CNS relapse is isolated to the brain in most patients. MIBG scan has poor sensitivity for the detection of CNS NB, regardless of size or location. Although CT or MRI are both effective in detecting CNS relapse, the former can miss some lesions. We recommend brain MRI for surveillance of high-risk NB for ≥2 years after initial diagnosis or last systemic relapse. 1. J. Neurooncology 97:409, 2010.

Prevalence of somatic PIK3CA mutations in hormone receptor-positive metastatic breast cancer: The Indian experience.

e13047 Background: The phosphatidylinositol 3-kinase (PI3K) inhibitors have been found to improve survival outcomes in hormone receptor-positive metastatic breast cancer (MBC) and are FDA-approved in this setting after progression on hormonal therapy. However, real-world data from India on the prevalence of PIK3CA mutations is scarce. Methods: This is a retrospective study including patients with hormone receptor-positive breast cancer registered at our center between January 2017- and December 2023 who developed metastatic disease on follow-up after getting appropriate treatment (adjuvant /neoadjuvant) as per institutional protocol. The PIK3CA mutation testing was done on the biopsy specimen. FDA-approved therascreen PIL3CA RGQ PCR kit from Qiagen was used and the assay is a real-time qualitative PCR test for the detection of 11 mutations phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) gene (Exon 7: C420R; Exon 9: E542K, E545A, E545D [1635G&gt;T only], E545G, E545K, Q546E, Q546R; and Exon 20: H1047L, H1047R, H1047Y) using genomic DNA (gDNA) extracted from formalin-fixed, paraffin-embedded (FFPE) breast tumor tissue. The clinical demographics of patients with PIK3CA mutations were extracted from the hospital database and represented descriptively. Results: A total of 80 consecutive patients with hormone-positive breast cancer at relapse were screened and 26 were found to have PIK3CA mutations (32.5%) of which 24 were female (92.3%). The median age of patients with mutated PIK3CA cases was 50 years (range: 31 to 72 years). The clinical stage of disease at presentation was: stage II in 11.5%, IIIA in 23.1%, and IIIB in 65.4% of cases. The median time of relapse was 21 months from diagnosis (range: 10 to 42 months). The disease sites at relapse were multiple in 23 patients (88.46%) [including central nervous system (CNS) relapse in 3 patients) and CNS (brain) only in 3 patients (11.54%). The mutations detected included H1047R (3140A&gt;G at exon 20) in 8 cases, E545K (1633 G&gt;A at exon 9) in 5 cases, Q546R (1637 A&gt;G at exon 9) in 4 cases, E542K (1624 G&gt;A at exon7) in 3 cases and synchronous mutations (E542K/E545K at Exon 7) in 3 cases and (H1047R/H1047L at exon 20 ) in 3 cases. Only eight patients received alpelisib with fulvestrant due to financial constraints. Conclusions: This is the first Indian study that describes the prevalence of PIK3CA mutations in hormone-positive breast cancer at relapse. Around one-third of patients harbor this mutation and 23.1% of cases have CNS involvement at relapse. The most common PIK3CA mutation detected was H1047R (exon 20) followed by E545K (exon 9).

Evolution of tisagenlecleucel use for the treatment of pediatric and young adult relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL): Center for International Blood &amp; Marrow Transplant Research (CIBMTR) registry results.

10016 Background: Tisagenlecleucel is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell immunotherapy indicated for patients (pts) up to 25 y of age with B-ALL that is refractory or in second or later relapse. Since the pivotal ELIANA trial, pt characteristics now include pts &lt; 3 y, pts with isolated central nervous system relapse, and pts with leukemia burden &lt; 5%. Here we examine the impact of tisagenlecleucel on the pt treatment journey since FDA approval in 2017. Methods: Data were collected as a part of a noninterventional, prospective, longitudinal study using the CIBMTR registry. Pts were treated in the United States, Canada, Korea, or Taiwan. Results: As of May 4, 2023, 974 pts received tisagenlecleucel. Primary disease history has evolved since 2017. Notably, disease burden prior to infusion has decreased (≥50% blasts: 18% in 2018, 4% in 2022) and a higher proportion of pts received tisagenlecleucel while in morphological complete remission (34% in 2018, 51% in 2022). Between 2018 and 2022, the proportion of pts who were in third or greater relapse decreased (14% vs 2%, respectively). Pts ≥18 y had more prior exposure to blinatumomab and inotuzumab compared with pts &lt; 18 y: 27% vs 16% and 17% vs 7%, respectively. The proportion of pts undergoing ≥1 hematopoietic stem cell transplantation (HSCT) before tisagenlecleucel infusion decreased (37% in 2018, 15% in 2022), coinciding with the use of tisagenlecleucel in earlier lines of therapy. Reporting of B-cell recovery was suboptimal. In total, 34.5% (314/911) of pts received postinfusion HSCT (reasons for HSCT were not captured for most pts); 8.5% (77/911) of pts received postinfusion HSCT to treat relapse, persistent/progressive disease, or positive minimal residual disease. Although the overall rate of postinfusion HSCT did not change, pts with high-risk cytogenetics showed a decrease in HSCT frequency. Previously, most pts &lt; 3 y with KMT2A rearrangement received a HSCT. Since 2017, only 16% (12/75) of pts &lt; 3 y received a prior HSCT despite 72% (54/75) having a KMT2A rearrangement. Furthermore, of the pts with rearrangement, only 43% (23/53) received a HSCT postinfusion. With censoring for HSCT, median RFS improved: 18 mo in 2018, 27 mo in 2020, and not estimable in 2021. OS was not substantially affected by HSCT censoring; 36-mo probabilities (95% CI) with and without censoring were 66 (61-71) and 62 (57-66), respectively. Conclusions: Pediatric and young adult pts with r/r B-ALL are receiving tisagenlecleucel earlier in the course of their disease treatment, reducing the use of HSCT for r/r disease, and prolonging RFS. As both real-world and clinical trial data supporting the curative potential of tisagenlecleucel grow, the use of HSCT in pts with remission after CAR-T should be carefully evaluated.

N9: Pilot study of novel shortened induction for high-risk neuroblastoma.

10052 Background: N9 induction for high-risk neuroblastoma was designed to limit non-hematological toxicity (especially ototoxicity) and to prevent relapse in the central nervous system (CNS). N9 builds on 2 novel regimens: high-dose cyclophosphamide-topotecan-vincristine (CTV) and ifosfamide-carboplatin-etoposide (ICE), each with good penetration across the blood-brain barrier. Methods: N9 is a pilot study (Clinicaltrials.gov.NCT04947501) to assess feasibility and safety. Secondary/exploratory objectives include response, collection of peripheral blood stem cells (PBSCs; ≥5x106/kg CD34(+) cells sufficient for ≥2 rescues), tumor resection, and assessment of central nervous system relapse. Early stopping rules centered on excessive delay in timing of chemotherapy. Eligibility criteria included age &gt;1-to-&lt;13 years; 1 prior chemotherapy cycle was allowed. CTCAE Version 5.0 and International Neuroblastoma Response Criteria are used.N9 comprises 4 cycles of chemotherapy. Cycles start after absolute neutrophil count is &gt;500/μL, platelets &gt;100,000/μL, and non-hematologic toxicities grade ≤2. Intervals of 21-28 days between start of cycles are foreseen. PBSC collection and surgery follow &gt;3 cycles. Cycles #1 and #4 (CTV): cyclophosphamide 70mg/kg/day, days 1-2, topotecan 2mg/m2/day, days 1-4, and vincristine 0.067mg/kg, day 1. Cycle #2 (ICE): ifosfamide 1500mg/m2/day, days 1-5, carboplatin 400mg/m2/day, days 1-2, and etoposide 100mg/m2/day, days 1-5. Cycle #3: cyclophosphamide (as in CTV) and 72-hr infusions of doxorubicin 75mg/m2 and vincristine 0.067mg/kg. Results: The target number of 15 patients were enrolled: 10/2021-9/2023; age 1.5–9.8 (median 3.3) years; 14 stage M, 1 stage L2; and 10 post-1 cycle of other chemotherapy. They completed N9 without undue toxicity: all cycles started on time, organ functions remained intact, 11/11 patients tested had no ototoxicity, and acute toxicities were typical for myelosuppression (including uncomplicated fever/neutropenia). Responses were complete (n=6), partial (n=5), and stable disease (n=4). The target number of PBSCs was collected in 12 patients (9-75, median 14 x106/kg CD34(+) cells), 4x106/kg in 2 patients, and pending in 1. All patients had gross total resections of the primary tumor. Post-N9, patients did not undergo transplant, but proceeded to immunotherapy (naxitamab) or chemoimmunotherapy (naxitamab+irinotecan-temozolomide). Of 9 with residual disease post-N9, 7 achieved CR (median of 5.6 months from study entry) and 1 achieved metabolic CR (16 months), though 3 subsequently relapsed (no CNS). Conclusions: N9 shows promise for reducing chemotherapy and long-term toxicity. Less chemotherapy without compromising survival is a realistic goal by virtue of the advances with anti-GD2 monoclonal antibodies which, in combination with GM-CSF+low-dose chemotherapy, are highly effective against chemo-resistant disease in bone/bone marrow. Clinical trial information: NCT04947501 .

The CNS relapse in T-cell lymphoma index predicts CNS relapse in patients with T- and NK-cell lymphomas

AbstractLittle is known about risk factors for central nervous system (CNS) relapse in mature T-cell and natural killer cell neoplasms (MTNKNs). We aimed to describe the clinical epidemiology of CNS relapse in patients with MTNKN and developed the CNS relapse In T-cell lymphoma Index (CITI) to predict patients at the highest risk of CNS relapse. We reviewed data from 135 patients with MTNKN and CNS relapse from 19 North American institutions. After exclusion of leukemic and most cutaneous forms of MTNKNs, patients were pooled with non-CNS relapse control patients from a single institution to create a CNS relapse–enriched training set. Using a complete case analysis (n = 182), including 91 with CNS relapse, we applied a least absolute shrinkage and selection operator Cox regression model to select weighted clinicopathologic variables for the CITI score, which we validated in an external cohort from the Swedish Lymphoma Registry (n = 566). CNS relapse was most frequently observed in patients with peripheral T-cell lymphoma, not otherwise specified (25%). Median time to CNS relapse and median overall survival after CNS relapse were 8.0 and 4.7 months, respectively. We calculated unique CITI risk scores for individual training set patients and stratified them into risk terciles. Validation set patients with low-risk (n = 158) and high-risk (n = 188) CITI scores had a 10-year cumulative risk of CNS relapse of 2.2% and 13.4%, respectively (hazard ratio, 5.24; 95% confidence interval, 1.50-18.26; P = .018). We developed an open-access web-based CITI calculator (https://redcap.link/citicalc) to provide an easy tool for clinical practice. The CITI score is a validated model to predict patients with MTNKN at the highest risk of developing CNS relapse.

Clinical implications of CSF-ctDNA positivity in newly diagnosed diffuse large B cell lymphoma.

The clinical implications of CSF-ctDNA positivity in newly diagnosed diffuse large B cell lymphoma (ND-DLBCL) remains largely unexplored. One hundredND-DLBCL patients were consecutively enrolled as training cohort and another 26 ND-DLBCL patients were prospectively enrolled in validation cohort. CSF-ctDNA positivity (CSF(+)) was identified in 25 patients (25.0%) in the training cohort and 7 patients (26.9%) in the validation cohort, extremely higher than CNS involvement rate detected by conventional methods. Patients with mutations of CARD11, JAK2, ID3, and PLCG2 were more predominant with CSF(+) while FAT4 mutations were negatively correlated with CSF(+). The downregulation of PI3K-AKT signaling, focal adhesion, actin cytoskeleton, and tight junction pathways were enriched in CSF(+) ND-DLBCL. Furthermore, pretreatment CSF(+) was significantly associated with poor outcomes. Three risk factors, including high CSF protein level, high plasma ctDNA burden, and involvement of high-risk sites were used to predict the risk of CSF(+) in ND-DLBCL. The sensitivity and specificity of pretreatment CSF-ctDNA to predict CNS relapse were 100% and 77.3%. Taken together, we firstly present the prevalence and the genomic and transcriptomic landscape for CSF-ctDNA(+) DLBCL and highlight the importance of CSF-ctDNA as a noninvasive biomarker in detecting and monitoring of CSF infiltration and predicting CNS relapse in DLBCL.

CAR T-cell therapy in mantle cell lymphoma with secondary CNS involvement: a multicenter experience

Secondary central nervous system (CNS) involvement in Mantle cell lymphoma has poor outcomes, with limited data for efficacy of CAR-T therapy. This study reports encouraging response with reasonable safety profile, but risk of CNS relapse remains high in such patients.

Abstract PS11-02: Clinical risk factors of Central Nervous System (CNS)-related death in patients with HER2-positive metastatic breast cancer

Abstract Background: Central nervous system (CNS) relapse represents a challenge in the management of patients with HER2-positive (+) metastatic breast cancer. Data regarding the impact of brain metastases (BrM) and CNS involvement on mortality are sparse. In this study we sought to determine the proportion of HER2+ MBC patients in which CNS disease is the cause of death and identify risk factors associated with CNS-related mortality. Methods: We reviewed medical records of 294 consecutive patients with HER2+ MBC and diagnosis of CNS disease including parenchymal BrM, leptomeningeal disease (LMD) or dural metastases (DM), treated at Memorial Sloan Kettering Cancer Center between August 2010 and April 2022. HER2-positivity was assessed at the first diagnosis of metastatic disease (any site). Clinicopathologic characteristics including disease burden at presentation, timing of CNS disease and extracranial metastases (ECM), neurologic complications, and local and systemic treatments were collected. CNS-related death was defined as any death caused by BrM or LMD or DM progression or CNS treatment-associated complications. CNS-related death was estimated using cumulative incidence in the competing risks setting (with death due to other causes as a competing event) and overall survival (OS) was estimated using Kaplan Meier methodology. Risk factors associated with CNS-related death were assessed using sub-distribution hazards regression modeling. Treatments given after CNS disease diagnosis were treated as time-varying variables. Tests were two-sided with statistical significance &amp;lt; 0.05. Results: After excluding 19 patients (11 for discordant HER2 status, 5 for concomitant second solid tumor, and 3 for missing data), 275 patients were included in these analyses (258 patients with parenchymal BrM +/- LMD, 8 patients with DM only, 2 patients with DM concomitantly with LMD, and 6 patients with LMD only). Overall, 63/275 (23%) presented with CNS as first and only site of metastasis, 210 (76%) patients developed CNS disease synchronously with or following ECM, and 2 had unknown timing. 125/275 (45%) had de novo MBC, and nearly all patients were treated with CNS local therapies (92% ≥1 radiation treatment and 28% underwent ≥1 BrM resection). The median number of lines of systemic therapy after CNS disease diagnosis was 1 (range: 0-14); 105/275 (38%) patients received a HER2 tyrosine kinase inhibitor (lapatinib: 21%, neratinib: 4.4%, and tucatinib: 12%). The median follow-up was 3.6 years for survivors (range: 0.22 years-12 years). 193/275 (70%) patients died, of whom 105 (54%) died of CNS-related cause. The 3-year OS rate was 40% (95% CI=34%-46%), which varied for patients with BrM only at the diagnosis of metastatic disease [56% (95% CI=43%-69%] compared to patients with ECM +/- BrM [35% (95% CI=28%-42%] (p=0.05). The cumulative incidence of CNS-related death at 3 years was 33% (95% CI=27%-39%). Upon univariable modeling, LMD and CNS radiation treatment (RT) were associated with CNS-related death, and these associations remained statistically significant in a multivariable model [LMD: HR=2.49 (95% CI=1.62-3.83), p&amp;lt; 0.0001, and RT: HR=2.91 (95% CI=1.27-6.64), p=0.01]. Conclusions: Greater than half of patients with HER2+ with CNS involvement suffered of CNS-related death, with greatest risk among patients with LMD. We hypothesize that the association between radiotherapy and CNS-related death may reflect upfront response to systemic cancer-directed treatments of those in patients with DM only or limited CNS disease extension. CNS-only relapse at metastatic presentation portended improved survival than intra- plus extracranial progression, supporting an approach of aggressive local therapy for selected patients. Multimodality approaches using HER2-directed agents effective against parenchymal BrM, LMD along with extracranial metastases, in combination with local CNS-directed therapies need to be optimized. Citation Format: Emanuela Ferraro, Rabih Bou Nassif, Anne Reiner, Samantha Brown, Umberto Tosi, Katherine Panageas, Chau Dang, Andrew D Seidman, Nelson Moss. Clinical risk factors of Central Nervous System (CNS)-related death in patients with HER2-positive metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS11-02.

Acute Lymphoblastic Leukemia with Central Nervous System Relapse: Case series of unusual presentation

Acute Lymphoblastic Leukemia with Central Nervous System Relapse: Case series of unusual presentation

Prevalence of Central Nervous System Relapse in Diffuse Large B-Cell Lymphoma: A Comprehensive Review

Central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) is a rare but serious complication associated with poor outcomes. The prevalence of CNS relapse in DLBCL varies widely in the literature, ranging from 1% to 30%, depending on several risk factors and diagnostic methods. This article provides a comprehensive review of the current literature on the prevalence of CNS relapse in DLBCL, focusing on risk factors, diagnostic approaches, and treatment strategies. Understanding the epidemiology and clinical characteristics of CNS relapse in DLBCL is crucial for the development of effective preventive and therapeutic strategies.

Diagnostic significance of cerebrospinal fluid flow cytometry in Chinese children with B lineage acute lymphoblastic leukemia

BackgroundCentral nervous system leukemia (CNSL) is one of the major causes of the poor prognosis of childhood leukemia. We aimed to compare the sensitivity of cytomorphology (CM) and flow cytometry (FCM) in diagnosing CNSL, emphasizing the importance of FCM in the diagnosis process.MethodsOne-hundred-sixty-five children with newly diagnosed B-cell Acute Lymphoblastic Leukemia (B-cell ALL) were included in this study. Cerebrospinal fluid (CSF) samples were taken for routine CSF analysis, CM analysis, and FCM examination. Computed tomography scans and/or magnetic resonance imaging were performed at diagnosis. Patients with CNS2, CNS3, and traumatic lumbar puncture (TLP) at diagnosis received two additional courses of triple intrathecal injections during induction treatment. We compared the sensitivity of FCM and CM in the diagnosis of children with CNSL.ResultsOne hundred and twenty-eight (77.58%) CSF samples were negative by either CM or FCM (CM−/FCM−), four (2.42%) were positive by both CM and FCM (CM+/FCM+), and thirty-three (20%) displayed a single positive finding by FCM (CM−/FCM+) (p = 0.044). By adding two intrathecal injections in the induction treatment, ten children with TLP+ had no CNS relapse, like those with TLP−. However, compared to CNS1 and TLP, the event-free survival (EFS) did not significantly improve in patients with CNS2 and CNS3. Moreover, CNSL status was associated with worse 3-year EFS (p < 0.05).ConclusionsWe have validated that FCM is more accurate in stratifying the status of the CNS compared to CM analysis. However, to improve the EFS rate of childhood leukemia, it is necessary to combine CM examination, FCM, and cranial imaging for the early diagnosis of CNSL.

Efficacy of intravenous high-dose methotrexate in preventing relapse to the central nervous system in R-CHOP(-like)-treated, high-risk, diffuse large B-cell lymphoma patients and its effect on mortality: a systematic review and meta-analysis.

Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) carries a dismal prognosis and most clinical guidelines recommend CNS prophylaxis to patients deemed at high risk of CNS relapse. However, results from observational studies investigating the effect of CNS prophylaxis have yielded conflicting results. The aims of this study were to evaluate: (i) whether addition of prophylactic intravenous high-dose methotrexate (HD-MTX) reduces the risk of CNS relapse in high-risk DLBCL patients treated with R-CHOP or similar, and (ii) whether HD-MTX prophylaxis confers an overall survival benefit, irrespective of CNS relapse. We performed a systematic search of MEDLINE/PubMed and EMBASE for data on DLBCL patients at high risk of CNS relapse treated with R-CHOP or similar who received HD-MTX as an intervention and a comparator arm of patients who did not receive prophylaxis and/or intrathecal prophylaxis. A risk of bias was estimated using the ROBINS-I tool and the quality of the evidence was assessed by the GRADE approach. Finally, a meta- analysis based on the systematic review was conducted. A total of 1,812 studies were screened. No randomized controlled trials were identified. Seven observational studies comprising 1,661 patients met the inclusion criteria. We found a statistically non-significant relative risk of 0.54 (95% confidence interval: 0.27-1.07) of CNS relapse for patients receiving HD-MTX versus controls. The meta-analysis investigating mortality demonstrated a relative risk of death of 0.70 (95% confidence interval: 0.44-1.11) for patients treated with HD-MTX versus controls. The overall risk of bias was adjudged as "serious" and the quality of the evidence was rated as "low". In conclusion, our data indicate that HD-MTX does not prevent or, at best, only slightly reduces the risk of CNS relapse and confers no survival benefit.

Predicting central nervous system relapse in primary breast diffuse large B-cell lymphoma using the stage-modified IPI score: A retrospective cohort study

ObjectiveThe existing Central Nervous System-International Prognostic Index (CNS-IPI) provides insufficient guidance for predicting central nervous system (CNS) relapse in individuals with primary breast diffuse large B-cell lymphoma (DLBCL). This retrospective cohort study sought to examine the potential of the stage-modified IPI in predicting CNS relapse within this specific patient population. Patients and methodsWe examined the baseline characteristics of 76 consecutive patients diagnosed with primary breast DLBCL, calculating the stage-modified IPI score for each individual. Utilizing a competing risk regression (CRR) model, we conducted both univariate and multivariate analyses to explore the relationship between potential prognostic factors and the occurrence of CNS relapse. ResultsIn our cohort, the rates of CNS disease at 2 and 5 years since the diagnosis of primary breast DLBCL are 3.9% and 7.8%, respectively. Among patients experiencing CNS relapse, 80% presented with a parenchymal brain mass. Individuals with a high stage-modified IPI score (1–3 points) had a significantly higher incidence of CNS relapse (p = 0.031), a shorter time from the initial diagnosis of primary breast DLBCL to the first CNS relapse (p = 0.010), as well as relapse at any site (p = 0.012), compared to those with a low score (0 points). Univariate analysis identified stage (Hazard Ratio (HR): 4.098, p = 0.024), stage-modified IPI score (HR: 11.582, p = 0.012), and radiation therapy (HR: 5.784, p = 0.026) as significant risk factors. In multivariate analysis, in addition to radiation therapy (HR: 7.258, p = 0.012), the stage-modified IPI score (1–3 points versus 0 points) emerged as an independent and reliable predictor for CNS relapse (HR: 12.945, p = 0.016). ConclusionOur study underscores the significance of stage-modified IPI scores in predicting CNS relapse for patients with primary breast DLBCL. Validation of these findings through further research is essential, along with exploring potential prevention and intervention approaches.

Efficacy and Safety of Dose-Escalated Alectinib in Patients With Metastatic ALK-Positive NSCLC and Central Nervous System Relapse on Standard-Dose Alectinib

IntroductionCentral nervous system (CNS) metastases remain a common challenge in patients with ALK-positive NSCLC. We previously reported reinduction of CNS responses using dose-intensified alectinib in two patients with CNS progression on standard-dose alectinib. Nevertheless, this strategy has not been assessed in larger cohorts. MethodsPatients were eligible for this retrospective study if they had metastatic ALK-positive NSCLC with CNS relapse on alectinib 600 mg twice daily dosing and subsequently received escalated dosing (900 mg twice daily) of alectinib. CNS efficacy was assessed per the modified Response Evaluation Criteria in Solid Tumors version 1.1. ResultsAmong 27 patients, median duration of dose-escalated alectinib was 7.7 months (95% confidence interval [CI]: 4.8–10.9), with median overall time-to-progression (TTP) of 7.1 months (95% CI: 4.4–9.6). Among 25 CNS response-assessable patients, CNS objective response rate was 12.0% (95% CI: 2.5–31.2) and CNS disease control rate was 92.0% (95% CI: 74.0–99.0), with median CNS duration of disease control of 5.3 months (95% CI: 3.4–8.3) and median CNS TTP of 7.1 months (95% CI: 4.4–9.6). Among four patients with measurable CNS disease at baseline, three experienced a best intracranial response of stable disease and one experienced intracranial partial response with CNS TTP ranging from 4.1 to 7.7 months. No patient required drug discontinuation due to treatment-related adverse event or experienced grade 3 or higher treatment-related adverse events. ConclusionsDose-intensified alectinib was found to have tolerability and activity in patients with ALK-positive NSCLC who experienced CNS relapse on standard-dose alectinib and represents one clinically viable strategy for this population.