5-year PFS Research Articles

Third-generation anti-CD19 CAR T cells for relapsed/refractory chronic lymphocytic leukemia: a phase 1/2 study

Third-generation chimeric antigen receptor T cells (CARTs) for relapsed or refractory (r/r) chronic lymphocytic leukemia (CLL) may improve efficacy compared to second-generation CARTs due to their enhanced CAR design. We performed the first phase 1/2 investigator-initiated trial evaluating escalating doses of third-generation CARTs (HD-CAR-1) targeting CD19 in patients with r/r CLL and B-cell lymphoma. CLL eligibility criteria were failure to two therapy lines including at least one pathway inhibitor and/or allogeneic hematopoietic cell transplantation. Nine heavily pretreated patients received HD-CAR-1 at dose levels ranging from 1 × 106 to 200 × 106 CART/m2. In-house HD-CAR-1 manufacturing was successful for all patients. While neurotoxicity was absent, one case of grade 3 cytokine release syndrome was observed. By day 90, six patients (67%) attained a CR, five of these (83%) with undetectable MRD. With a median follow-up of 27 months, 2-year PFS and OS were 30% and 69%, respectively. HD-CAR-1 products of responders contained significantly more CD4 + T cells compared to non-responders. In non-responders, a strong enrichment of effector memory-like CD8 + T cells with high expression of CD39 and/or CD197 was observed. HD-CAR-1 demonstrated encouraging efficacy and exceptionally low treatment-specific toxicity, presenting new treatment options for patients with r/r CLL. Trial registration: #NCT03676504.

Cyclin-dependent kinase 4/6 inhibitors combined with stereotactic ablative radiotherapy in oligometastatic HR-positive/HER2-negative breast cancer patients.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have significantly improved the survival of patients with hormone receptor-positive HER2-negative advanced breast cancer (ABC). Although stereotactic ablative radiotherapy (SABR) is used more often in routine clinical practice, data on the safety and efficacy of combining SABR with CDK4/6i are lacking. Herein, we present the results of SABR combined with CDK4/6i in ABC. Patients with ABC who received CDK4/6i and SABR between 2018 and 2023 were analysed. Among 384 patients treated with CDK4/6i, 34 patients received 44 courses of SABR. Two-year progression-free survival (PFS) was 63.6% (95% CI, 45.8-88.3), and the median PFS was 32 months. Three-year overall survival (OS) was 88.9% (95% CI, 77.7-100). Two-year local control (LC) was 92.7% (95% CI, 83.4-100). Median OS and LC were not reached. The subgroup analysis showed the difference in survival between oligometastatic patients (OMD) and non-OMD subgroup. Two-year PFS was 69.2% (95% CI, 44.5-100) in OMD compared with 57.4% (95% CI, 36-91.7) in the non-OMD (P = .042). Three-year OS was 90% (95% CI, 73.2-100) in OMD compared with 86.2% (95% CI, 70-100) in the non-OMD (P = .67). Median PFS and OS in the non-OMD were 26 and 56 months, respectively, and were not reached in OMD. Fifteen patients required CDK4/6i dose reduction, and 2 discontinued treatment due to toxicity. No difference in high-grade toxicity was observed between the sequential and concurrent SABR. The addition of SABR to CDK4/6i seems to be safe and effective, especially in patients with oligometastatic disease. In advanced breast cancer patients treated with CDK4/6i, SABR provides a high local control and may provide additional benefit in an oligometastatic setting.

Primary Extranodal Diffuse Large B-Cell Lymphoma in the Rituximab Era: a Single-Center Retrospective Analysis

To investigate the clinical features and prognostic factors of patients with primary extranodal diffuse large B-cell lymphoma (DLBCL) in the rituximab era. The continuous data of newly diagnosed DLBCL patients with complete case data and first-line treated with rituximab, cyclophosphamide, epirubicin, vincristine, prednisone (R-CHOP) or R-CHOP treatment admitted to the Affiliated Hospital of Inner Mongolia Medical University from January 2013 to November 2023 were retrospectively analyzed. The clinical and molecular immunological features and prognosis of extranodal DLBCL were analyzed, Logistics regression model was used to analyzed the influencing factors of patients prognosis. A total of 237 patients were enrolled, of which 54.4% (129 cases) were primary extranodal sources of DLBCL, and the most common extranodal sites were as follows: stomach (19.4%), colon (14.7%), tonsils (12.4%), skin/muscle (9.3%), central (7.7%), nasal/nasopharynx (6.2%), bone marrow (5.4%), testes (4.7%). The 3-year PFS and OS of DLBCL patients with extranodal involvement of bone marrow, central, liver, gastrointestinal or pulmonary origin were significantly lower than those of other patients with extranodal DLBCL of non-special site origin, and the difference was statistically significant (PFS: 65.2% vs 76.7%, P =0.008; OS: 82.6% vs 88.3%, P =0.04). Multivariate analysis showed that the prognostic factors affecting OS included NCCN-IPI score >3 (OR : 0.142, 95%CI : 0.041-0.495, P =0.002), non-germinal center source (OR : 2.675，95%CI :1.069-6.694，P =0.036), and DEL patients (OR : 0.327, 95%CI : 0.129-0.830, P =0.019). An NCCN-IPI score >3 was the only independent adverse prognostic factor for PFS (OR : 0.235, 95%CI : 0.116-0.474, P < 0.001). Patients with primary extranodal source DLBCL are more common in gastrointestinal involvement, and the overall prognosis is worse than that of patients with lymph node origin. NCCN-IPI score is an important independent adverse prognostic factor for predicting overall survival and progression-free survival in patients with primary extranodal diffuse large B-cell lymphoma.

Efficacy and survival outcome of allogeneic stem-cell transplantation in multiple myeloma: meta-analysis in the recent 10 years.

Allogeneic hematopoietic cell transplantation (alloHCT) possessed direct cytotoxicity and graft-versus-multiple myeloma effect (GvMM). Growing trials have shown survival benefits of performing alloHCT in both newly diagnosed and relapsed MM. We aimed to provide a comprehensive analysis in the recent 10 years to verify the efficacy and survival outcome of alloHCT in MM patients. A total of 61 studies which provide data between 14/04/2013 and 14/04/2023 and a total of 15,294 data from MM patients who had undergone alloSCT were included in our study. The best response rates (CR, VGPR, PR) and survival outcomes (1-, 2-, 3-,5-, and 10-year OS, PFS, NRM) were assessed. We further conducted meta-analysis in the NDMM/frontline setting and RRMM/salvage setting independently. The pooled estimate CR, VGPR, and PR rates were 0.45, 0.21, and 0.24, respectively. The pooled estimates of 1-, 2-, 3-, 5-, and 10-year OS were 0.69, 0.57, 0.45, 0.45, and 0.36, respectively; the pooled estimates of 1-, 2-, 3-, 5-, and 10-year PFS were 0.47, 0.35, 0.24, 0.25, and 0.28, respectively; and the pooled estimates of 1-, 2-, 3-, 5-, and 10-year NRM were 0.16, 0.21, 0.16, 0.20, and 0.15, respectively. In the NDMM/upfront setting, the pooled estimate CR rate was 0.54, and those for 5-year OS, PFS, and NRM were 0.69, 0.40, and 0.11, respectively. In a relapsed setting, the pooled estimate CR rate was 0.31, and those for 5-year OS, PFS, and NRM were 0.24, 0.10, and 0.15, respectively. Our results showed constant OS, PFS, and NRM from the third year onwards till the 10th year, suggesting that alloSCT has sustained survival benefits. Good response rate and promising survival outcome were observed in the NDMM/ frontline setting. Although comparing with other treatments, alloSCT had a lower response rate and poorer short-term survival outcome, long-term follow-up could reveal survival benefits of alloSCT in MM patients.

Efficacy and Safety of Gilteritinib versus Sorafenib as Post-Transplant Maintenance in Patients With FLT3-ITD Acute Myeloid Leukemia

BackgroundFLT3-ITD AML is associated with an increased risk of relapse, leading many patients to receive an allogeneic hematopoietic stem cell transplantation (alloHCT) after induction. Unfortunately, relapse rate after alloHCT remains high and strategies are needed to improve outcomes. Materials and MethodsWe performed a retrospective analysis of adult patients with FLT3-ITD AML who received alloHCT from 6/1/2016 to 12/31/2020 and received gilteritinib (GILT) or sorafenib (SORA)as post-transplant maintenance, outside of a clinical trial. ResultsA total of 55 patients were treated with either GILT (n = 27) or SORA (n = 29) for post-HCT maintenance. One patient was treated with SORA after first alloHCT and GILT after second alloHCT. Patient characteristics were comparable between groups. FLT3 inhibitors were utilized in pre-alloHCT therapy in all but 1 patient. The median duration of time that patients remained on GILT was 385 days (range, 10-804) and on SORA 315 days (range, 3-1777). 1-year PFS and relapse incidence were similar between GILT and SORA; PFS was 66% versus 76% (P = .4) and relapse incidence was 19% versus 24% (P = .6), respectively.Both groups had high incidence of Grade 3-4 hematological toxicity, including neutropenia (45% GILT and 34% SORA) and thrombocytopenia (30% GILT and 52% SORA). Only 44% and 14% patients who received GILT and SORA did not discontinue maintenance, respectively. ConclusionOur results revealed comparable PFS and a similar toxicity profile when SORA and GILT are used as post- HCT maintenance therapy.

Effect of Online Clinic on Follow-Up Compliance and Survival Outcomes in Nasopharyngeal Carcinoma: Real-World Cohort Study from Endemic Area.

Nasopharyngeal carcinoma (NPC) requires regular follow-up to detect recurrence as early as possible. However, many patients are unable to regularly follow up due to the inconvenience of the conventional approach. Therefore, this study was designed to investigate the impact of the online clinic on follow-up compliance and prognosis in NPC patients. Patients who were first diagnosed with NPC between April 2019 and November 2019 were enrolled. Good follow-up compliance was defined as having at least one follow-up visit every 6 months within 2 years after treatment completion. Sensitivity analyses were performed using a propensity score matching model. A total of 539 (42%) patients used online follow-up while 731 (58%) used traditional follow-up. The median age of patients in the online cohort was lower than that in the traditional cohort (44 vs. 47, p < 0.001). Compared with the traditional cohort, the online cohort had significantly better follow-up compliance (57.3% vs. 17.1%, p < 0.001) and a higher 2-year PFS rate (98.1% vs. 94.4%, p = 0.003). Survival analysis showed that online follow-up was an independent factor for better survival prognosis (HR 0.39, 95%CI 0.20-0.74, p = 0.004). Sensitivity analysis further confirmed these results. Our study found that the online clinic increased follow-up compliance and improved prognosis in NPC patients.

Clinical application of FIGO 2023 staging system of endometrial cancer in a Chinese cohort

ObjectiveThe International Federation of Gynecology and Obstetrics (FIGO) 2023 staging system for endometrial cancer (EC) was released with incorporating histology, lympho-vascular space invasion, and molecular classification together. Our objective is to further explore the clinical utility and prognostic significance of the 2023 FIGO staging system in China.MethodsA retrospective analysis was conducted for patients who received standard surgeries and underwent genetic testing using multigene next-generation sequencing (NGS) panels between December 2018 and December 2023 at Fudan University Shanghai Cancer Center, Shanghai, China. The genomic and clinical data of all patients were analyzed, and stages were determined by both the 2009 and 2023 FIGO staging systems. Kaplan–Meier estimators and Cox proportional hazards models were used for survival analysis.ResultsA total of 547 patients were enrolled in the study. After the restaged by the FIGO 2023 staging system, stage shifts occurred in 147/547 (26.9%) patients. In patients with early stages in FIGO 2009 (stage I-II), 63 cases were rearranged to IAmPOLEmut and 53 cases to IICmp53abn due to the molecular classification of POLEmut and p53abn. Altogether 345 cases were in stage I, 107 cases in stage II, 69 cases in stage III, and 26 cases in stage IV according to the FIGO 2023 staging criteria. For stage I diseases, the 3-year PFS rate was 92.7% and 95.3% in 2009 and 2023 FIGO staging systems, respectively. The 3-year PFS of stage II in 2023 FIGO was lower than that of FIGO 2009 (3-year PFS: 85.0% versus 90.9%), especially in substage IIC and IICmp53abn. Three cases (12%) of stage IIIA in FIGO 2009 were shifted to stage IA3 FIGO 2023, with 3-year PFS rates of 90.9% versus 100%, respectively. In NGS analysis, the most prevalent gene alterations were observed in PTEN and PIK3CA.ConclusionThe FIGO 2023 staging system was proved to be a good predictor of survival for EC patients with enhanced precision compared to FIGO 2009. Predominant stage shifts were observed in early-stage diseases. Distinct gene alterations of different subtypes may help to explore more accurate target therapies.

Locoregional Radiotherapy in Patients with Advanced Breast Cancer Treated with Cyclin-Dependent Kinase 4/6 Inhibitors Based on Real-World Data.

The use of locoregional radiotherapy (RT) in patients with advanced ER-positive, HER2-negative breast cancer remains a topic of ongoing debate. In this study, we aimed to evaluate the efficacy of locoregional RT in advanced breast cancer patients treated with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in a first-line setting. We conducted a retrospective analysis of patients diagnosed with advanced breast cancer between 2018 and 2023 who received treatment with CDK4/6i and underwent locoregional radiotherapy. Among the 371 patients treated with CDK4/6i as part of their first-line therapy, 23 received locoregional RT either concurrently or sequentially with CDK4/6 inhibitors. Disease progression within the breast occurred in 19 patients (5.1%). Among these cases, five patients had previously undergone breast RT (5/23, 21.7%), while 14 did not (14/348, 4.0%, p = 0.004). All cases of local progression after RT followed palliative doses and were accompanied by early systemic progression. The 2-year PFS in the entire cohort of patients treated with locoregional RT was 65.7% (95% CI: 40.5-82.3%). Notably, patients who received higher RT doses had longer 2-year PFS (83.3%, 95% CI: 27.3-97.5%) than those with palliative RT doses (59.3%, 95% CI: 30.7-79.3%); however, the results were not statistically significant (p = 0.58). Furthermore, the 2-year local control in the entire cohort with locoregional RT was 73.0% (95% CI: 46.5-87.9%). Importantly, no local progression was observed after RT when using high doses. The addition of locoregional radiotherapy to first-line CDK4/6 inhibitors warrants further investigation across various clinical scenarios in advanced breast cancer. Palliative radiation regimens delivered early in breast oligoprogression may not always suffice, emphasizing the need for comprehensive studies in this context.

Alectinib vs. Lorlatinib in the Front-Line Setting for ALK-Rearranged Non-Small-Cell Lung Cancer (NSCLC): A Deep Dive into the Main Differences across ALEX and CROWN Phase 3 Trials.

Various next-generation ALK TKIs are available as first-line options for ALK-positive NSCLC, with alectinib and lorlatinib being commonly preferred. However, no direct comparison between them has been conducted, making it impossible to pick a winner. We performed an analytic, 'non-comparative' assessment of the two phase 3 pivotal clinical trials showing superiority of alectinib (ALEX) and lorlatinib (CROWN) in comparison to crizotinib. Overall, the two studies were very similar in the study design and patient characteristics, with the exception of the selection and evaluation of brain metastases. PFS hazard ratios numerically favored lorlatinib, both according to the investigator and to BICR. Notably, the 3-year PFS rate was numerically higher with lorlatinib (64%) than with alectinib (46.4%). Despite similar response rates and overall intracranial response, the rate of complete intracranial response was higher with lorlatinib, with a cumulative incidence risk of CNS disease progression at 12 months of 9.4% with alectinib and 2.8% with lorlatinib. The peculiar toxicities of lorlatinib were related to lipidic profile alterations, peripheral oedema and cognitive effects, with no impact on cardiovascular risk nor impairment in quality of life versus crizotinib. Furthermore, the rate of permanent treatment discontinuation due to adverse events was numerically higher with alectinib (26%) than with lorlatinib (7%). In conclusion, despite the immature OS data for both drugs, the efficacy of lorlatinib appears higher than alectinib while maintaining a manageable toxicity profile.

Прогностическое значение цитотоксических CD8-позитивных Т-лимфоцитов реактивного микроокружения опухоли при диффузной В-крупноклеточной лимфоме

AIM. To assess the prognostic value of cytotoxic CD8-positive Т-lymphocytes of the reactive tumor microenvironment in diffuse large B-cell lymphoma (DLBCL). MATERIALS &amp; METHODS. The study enrolled 124 patients with newly diagnosed DLBCL. All patients received the standard R-CHOP first-line immunochemotherapy. Immunochemistry and morphometry were used to assess the relative count of CD8-positive Т-lymphocytes in the biopsy samples of lymph nodes or other tumor tissues. In each biopsy sample, 20 fields of view were analyzed to assess the mean relative count of CD8-positive Т-lymphocytes in the reactive tumor microenvironment. Т-cells were counted by double-blind technique. Patients were aged 23–80 years (median 59 years); there were 62 women and 62 men. RESULTS. Obtained by ROC-analysis, the threshold value of the CD8-positive Т-lymphocyte count in the reactive tumor microenvironment was 13 %. The subthreshold relative count of cytotoxic CD8-positive Т-lymphocytes (≤ 13 %) was associated with extranodal lesions in DLBCL patients as well as with the lack of complete response to the R-CHOP first-line therapy and worse progression-free (PFS) and overall survival (OS) rates. In the group with the above-threshold (&gt; 13 %) count of CD8-positive Т-lymphocyte, the 5-year PFS was 60 % (median not reached), in the group with the subthreshold count it was 45.3 % (median 39 months; p = 0.036); the 5-year OS was 78.3 % (median not reached) and 45.3 % (median 40 months) in the groups with the above- and subthreshold CD8+ T-cell counts, respectively (p = 0.001). CONCLUSION. The results of the present study clearly indicate the need to assess the count of cytotoxic CD8-positive Т-lymphocytes of the reactive tumor microenvironment in DLBCL patients as early as on diagnosis verification. It is likely that this approach will allow clinicians to more accurately predict the course of DLBCL.

Intensity Modulated Carbon Ion Radiation Therapy Using Pencil Beam Scanning Technology for Patients With Unresectable Sacrococcygeal Chordoma

ObjectivesTo investigate the safety and efficacy of intensity modulated carbon ion radiotherapy (IM-CIRT) using pencil beam scanning technology for patients with unresectable sacrococcygeal chordoma (SC). Methods and MaterialsA total of 35 unresectable SC patients were retrospectively analyzed, including 54.3% (19/35) recurrent cases. 68.6% (24/35) cases’ tumor located in S2 or above, and all cases were treated with hypofractionated IM-CIRT. The median dose was 70.4 (range 69 - 80) Gy (RBE) in 16 (range 16 - 23) fractions, typically delivered over 5 fractions per week. ResultsThe 3-year OS, CSS, PFS, LRFS and DMFS rates with a median follow-up time of 42 (12∼91) months for the entire cohort were 93.2%, 96.3%, 61.8%, 80% and 77.3%, respectively. Multivariate analysis revealed that GTV volume (HR, 3.807; 95% CI: 1.044 - 13.887, p = 0.043) was the only significant prognostic factor for PFS and the dose for the GTV ≥ 70.4 Gy (RBE) was relevant with significantly better LRFS (HR, 0.190; 95% CI: 0.038 – 0.940, p = 0.042). No significant prognostic factor for OS, CSS and DMFS and no severe (i.e., grade ≥ 3) acute toxicity were identified. Severe late toxicities occurred in 3 patients (8.57 %): pain (1 patient), motor neuropathy (1 patient) and skin ulcer (1 patient). Furthermore, no severe toxicity related to urinary function or defecation was observed following IM-CIRT. Pain grades improved or remained unchanged in 85.7% of patients. ConclusionIM-CIRT produced acceptable 3-year outcomes without substantial late adverse effects, especially urinary and anorectal complications for SC, and did not appear to increase pain. IM-CIRT at high doses using hypofractionated RT may improve outcomes for local control and seems to be feasible even for postoperative recurrent SC.

Impact of Dosimetric Compromises on Early Outcomes of Chordomas and Chondrosarcomas Treated With Image-guided Pencil Beam Scanning Proton Beam Therapy

PurposeTo critically review the clinical factors, dosimetry, and their correlation with early outcomes in patients with chordomas and chondrosarcomas treated with pencil beam scanning proton beam therapy (PBS-PBT). MethodsConsecutive 64 patients diagnosed with chordoma, or chondrosarcoma treated at our centre were studied. Patient, tumor and treatment-related factors including dosimetry were captured. Early and late toxicities and early outcomes were evaluated and correlated with clinical and dosimetric factors using standard statistical tools. ResultsThe median age of patients was 39(4-74 years) and most common site was skullbase (47%) followed by sacrum(31%) and mobile spine(22%). The median prescription dose to the high-risk CTV for chordoma and chondrosarcoma was 70.4CGE(Cobalt Gray equivalent) and 66CGE at 2.2CGE per fraction respectively. At presentation to our centre, 55% presented after a recurrence/progression of which 17% received prior radiation and 32% had a significant neural compression. At the time of PBT, 25% of patients had suboptimal neural separation. Three-fourths of patients had at least an acceptable target coverage. While 11% had a tier-1 compromise (GTVD98<90%), 14% had a tier-2 compromise (GTVD98<59CGE). With a median follow-up of 27.5 months, 2-year local control and PFS was 86.7% and 81.8% for chordomas and 87.5% and 77.1% for chondrosarcomas respectively. Residual GTV>25cc and a tier-2 compromise were associated with inferior local control (HR-0.19,p=0.019; HR-0.061,p=0.022 respectively) and progression-free survival (HR-0.128,p=0.014; HR-0.194,p=0.025 respectively) on multivariate analysis. Despite multiple surgeries, a majority with recurrent disease and prior radiations, grade-3 acute and late toxicities were limited and comparable to others in the literature. ConclusionDespite multiple surgeries, adequate neural separation was challenging to achieve. Severe dosimetric compromise(GTVD98<59CGE) led to inferior early outcomes. Adequate neural separation is key to avoiding dosimetric compromise and achieving optimal local control.

IDH1 mutation is associated with improved resection rates, progression-free survival and overall survival in patients with anaplastic astrocytomas.

The introduction of molecular markers in to the diagnosis of gliomas has changed the therapeutic approach to this tumors. The aim of this study was to examine the impact of surgery on anaplastic astrocytomas (AA), which has not previously been fully elucidated. This was a retrospective study involving a total of 143 patients who underwent surgery for primary AA in our department between 1995 and 2020. Total tumor resection was achieved more often in patients with IDH-mutant tumors (41.09%) than in patients with IDH-wildtype tumors (30.76%). The median PFS was 1876 days for patients with IDH1 mutations and 238 days for patients with IDH-wildtype tumors. The 1-, 3-, 5- and 10-year PFS were longer in patients with total tumor resection and IDH-mutant AA (86.2%, 69%, 65.5% and 44.8%, respectively) than in patients with subtotal tumor resection and IDH-mutant AA (83.3%, 55.6%, 41.7% and 25%, respectively) and even longer compared to all IDH-wildtype tumors. The median OS was 2472 days for patients with IDH1 mutations and 434 days for patients with IDH-wildtype tumors. The 3-, 5- and 10-year OS times were longer in patients with total tumor resection and IDH-mutant AA (89.2%, 85.2% and 72.6%, respectively) than in patients with subtotal tumor resection and IDH-mutant AA (85.9%, 73.7% and 52.6%, respectively) and were even longer compared to all IDH-wildtype tumors. Total tumor resection is more common with IDH-mutant AA than with IDH-wildtype tumors. Patients with IDH-mutant AA had significantly better PFS and OS after total tumor resection than after subtotal tumor resection and biopsy.

TRLS-02. SAFETY AND EFFICACY OF BRAF INHIBITOR PLIXORAFENIB (FORE8394; PLX8394) IN CHILDREN AND ADULTS WITH RECURRENT, BRAF-ALTERED PRIMARY CENTRAL NERVOUS SYSTEM TUMORS (PCNST)

Abstract BACKGROUND Plixorafenib is a selective, potent BRAFi that inhibits V600 and non-V600 alterations by disrupting BRAF monomers/dimers. Plixorafenib evades paradoxical MAPK pathway activation, eliminating the need for MEKi combination, and is potentially less prone to toxicities and resistance typical of approved BRAFis. METHODS Phase 1/2a study (NCT02428712) in children (n=5, aged 4-17 years) and adults (n=108) with BRAF-altered solid tumors assessing safety, PK, and efficacy of oral plixorafenib 900-3600mg/day ± cobicistat (PK enhancer). RESULTS Five children, 3 LGG (1 V600E, 1 fusion, 1 amplification), 1 neuroblastoma (G469A) and 1 ND-LCH (V600E), 4-8 prior therapies, received plixorafenib 300-1200 mg/day without cobicistat. Four received BSA-adjusted dosing, which delivered lower exposures than RP2D. All had SD, with duration 66.9+ months for ND-LCH. The fifth (neuroblastoma, 1200 mg/day) had PD. No DLTs, dose reductions, or LFT elevations. One had possibly related Grade 3 headache. Of 9 evaluable MAPKi-naïve adults with V600E PCNST, 4/5 with HGG and 2/4 with LGG/GNT responded; ORR 67% (95% CI: 29.9-92.5), mDOR 13.9 months. Responses in patients with only non-enhancing lesions and/or pilocytic astrocytoma indicate clinically relevant CNS penetration. Responses occurred across V600 solid tumors, ORR 42% (10/24); 1-year PFS 54.4%, 2-year PFS 48.4% in the MAPKi-naïve (non-CRC) subgroup. Of 14 evaluable adults with fusions, 2 responses (melanoma: CR, DOR 62.6+ months; PTC: PR, DOR 4.0+ months), 8 SD (5 with PCNST), 5 PD (3/5 with co-occurring driver mutations). Safety, efficacy, and PK in adults and children and insight into factors affecting plixorafenib exposure (not age or weight dependent) determined the optimal RP2D of plixorafenib as 900 mg QD with cobicistat for ages ≥10 years. CONCLUSIONS Plixorafenib had low rates of symptomatic TEAEs with a manageable safety profile, and high ORR in MAPKi-naïve BRAFV600 PCNST. A phase 2 study in children and adults is ongoing (NCT05503797).

MDB-58. REDUCED CRANIOSPINAL DOSE FOR NEWLY DIAGNOSED HIGH-RISK MEDULLOBLASTOMA IN CHILDREN YOUNGER THAN 5 YEARS OLD: RETROSPECTIVE EXPERIENCE FROM SFCE

Abstract BACKGROUND High Risk medulloblastoma (MB) treatment strategy is based on an intensive multimodal treatment including surgery, chemotherapy and radiotherapy. French adapted PNET HR +5 is based on high-dose chemotherapy and age-stratified (18 Gy &amp;lt; 3 yo, 23 for 3-5 yo, 36 Gy for &amp;gt; 5 yo) craniospinal dose irradiation to reduce long-term side-effects of radiotherapy. METHODS To estimate progression-free (PFS) in a national multi-institutional retrospective study, we enrolled children younger than 5 yo with newly diagnosed high-risk MB treated according to adapted PNET HR +5 trial. RESULTS Thirty-seven children from 15 French hospitals (median age, 3.4 yo; range, 0.7-4.8) with confirmed high-risk MB were included. 15 patients (39%) were less than 3 years old. 29 patients (81%) had metastatic disease. Group 3 was the most represented molecular subgroup. 5-year PFS and OS was 59 % and 77 %, respectively. According to dose of craniospinal irradiation, PFS for 18 Gy, 23.4 Gy and 36 Gy patient groups were 100 %, 75 % and 45%, respectively. Treatment was well tolerated. One toxic death was declared. Analysis of longitudinal neurocognitive performance is ongoing. CONCLUSIONS the French strategy comprising high-dose chemotherapy and age-adapted craniospinal irradiation is promising with a high rate of survival in young children and must be confirmed by a prospective trial.

MDB-62. SUBGROUP AND SUBTYPE-SPECIFIC OUTCOMES IN METASTATIC INFANT MEDULLOBLASTOMA

Abstract BACKGROUND Metastatic infant medulloblastoma (MB) is a major challenge given the devastating long-term effects of craniospinal irradiation to the developing brain. However large cohorts of metastatic infant medulloblastoma have not been analysed to date. METHODS A multicentre molecularly informed international cohort of children &amp;lt;6 years old with metastatic medulloblastoma was assembled and analysed. RESULTS Eighty-four patients with a median age of 2.95 (0.66-6.58) years were identified. 48.8% were Group3-MB, 23.8% Group4-MB and 27.4% SHH-MB. 78% of Group3-MB were subtype II (40.4%) and IV (38.1%), 50% of Group 4 were subtype VII, and within SHH, SHHß and SHHγ were 52.2% and 43.5% respectively. 28.5% of all Group3-MB harboured MYC amplification. A multivariable analysis incorporating subgroup, MYC amplification and upfront craniospinal irradiation revealed that survival was superior for SHH patients compared to Group 3 irrespective of MYC status (Group3-veMYCamp: HR 3.05 95%-CI 1.05-8.87 p=0.04, Group3+veMYCamp HR 7.87 95%-CI 2.49-24.87 p=0.00044). Group 4 had a trend to a poor outcome (HR 2.63 95%-CI 0.82-8.39 p=0.1). SHH subjects had a superior outcome with 5-year PFS of 0.657 (95%-CI 0.47-0.92), without a significant difference between SHHß and SHHγ. High-dose chemotherapy regimens portended to a superior outcome for both subtypes of SHH-MB. 5-year PFS for non-radiated SHH-MB was 61% (95%-CI 40.8-91.4), compared to non-radiated Group3-MB (18.5%; 95%-CI 5.4-62.8) and Group4-MB (20%; 95%-CI 3.4-100). SHH-MB patients had more local than metastatic relapses compared to non-SHH-MB (p=0.01). CONCLUSIONS In the largest study dedicated to metastatic infant medulloblastoma assembled to date, outcomes for infants with Group 3- and 4-MB with metastatic disease treated with radiation sparing approaches is dismal despite intensified regimens. MYC amplification portends to a near uniformly fatal prognosis with current treatment irrespective of upfront radiotherapy. Novel radiation sparing approaches are urgently needed for this group. Infants with both metastatic SHHß and SHHγ benefit from intensified therapy.

HGG-08. DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT: A MULTI-INSTITUTIONAL EXPERIENCE

Abstract BACKGROUND Diffuse hemispheric glioma (DHG), H3 G34-mutant, is a rare, aggressive brain tumor molecularly defined by mutations in the H3-3A gene. Our study explored the association between patient outcomes and key molecular findings, resection extent, and temozolomide (TMZ) use. METHODS Multi-institutional chart and molecular analysis of 32 patients with H3 G34-mutant DHG. RESULTS The median patient age was 14 (10-28 years), with a M/F ratio of 1.4. The 1-year, 2-year, and 5-year PFS were 40.4% (23.7%, 57.1%), 22.1% (9.0%, 38.7%), and 11.0% (1.9%, 33.7%), respectively. The 1-year, 2-year, and 5-year OS were 82.5% (63.2%, 92.3%), 49.3% (28.7%, 66.3%), and 29.6% (9.1%, 50.6%), respectively. Patients who underwent a gross total resection (GTR) had improved PFS (p=0.0105) and OS (p=0.0184) compared to non-GTR patients. 22 patients (68.8%) received concurrent and/or adjuvant TMZ and had improved PFS (p=0.0278) compared to patients who did not receive front-line TMZ. Disease recurrence in relation to the radiation therapy (RT) field was analyzed in 17 patients; 5 recurred locally within the high-dose RT field, 5 recurred distantly, and 7 had both local and distant recurrences. There was no significant association between MGMT promoter methylation status (18 evaluable cases), PDGFRA amplification (N=6), and CDKN2A homozygous deletion (N=10) and survival outcomes. MGMT promoter methylation was not associated with increased TMZ efficacy (N=8 with MGMT silencing, N=4 without). CONCLUSIONS In our cohort, MGMT promoter methylation was not a favorable prognostic factor, in distinction from prior reports in adult and pediatric high-grade gliomas. Resection extent and the use of TMZ were associated with improved survival outcomes. As most treatment failures occurred within the high-dose RT field, extended fields do not appear warranted. Our findings may guide prognostic and therapeutic decisions in patients with H3 G34-mutant DHG and support the need for prospective efforts to improve outcomes in this patient population.

LGG-58. A MULTI-CENTER RETROSPECTIVE CASE SERIES OF SURGICAL OUTCOMES FOR INTRAVENTRICULAR JUVENILE PILOCYTIC ASTROCYTOMA

Abstract INTRODUCTION Juvenile pilocytic astrocytoma (JPA) is a common pediatric grade I astrocytoma. Prognosis is excellent with gross total resection (GTR) and 10-year survival rates of up to 95%. However, undesirable outcomes may occur, such as when tumors are in poorly accessible locations. Intraventricularly tumors present a unique surgical challenge due to their midline location in a fluid filled space with any intraparenchymal invasion involving critical neurologic structures. Here we retrospectively describe the clinical features of intraventricular JPA neoplasms from two centers to highlight the challenges in caring for this uncommon presentation. METHODS We retrospectively searched the electronic medical record from 2000-2023 for patients with neurosurgical treatment for intraventricular JPA at two centers. Intraventricular location was verified by a neuroradiologist. Data were collected on demographics, pathology, tumor location, extent of resection, adjuvant therapies, reoccurrence, progression, and neurological deficit. RESULTS We identified 28 surgical treated patients with intraventricular JPA. Females were 15/28 (54%) of patients with a mean age of 11.2±6.4 years. Most tumors presented in the 4th ventricle 15/28 (53.5%), followed by 9/28 (32%) in 3rd ventricle locations, and 4/28 (14%) in lateral ventricles. GTR was achieved in 12/28 patients (43%) and STR in 16/28 patients (57%). Progression/recurrence was noted in 8/28 (29%) and the 5-year PFS was 56% (10/18). Adjuvant treatment was used in 11/28 (39%) patients and repeat surgery was required in 4/28 patients (14%). Chemotherapy in 8/28 (29%) patients and radiation in 4/28 (14%) patients. A pre/post-operative neurological deficit was noted in 10/28 (36%) patients. A BRAF protein fusion was noted in 7 patients and 1 patient demonstrated a v600E mutation (some molecular data not available). Average follow up was 92 months with no deaths. CONCLUSION We observed that intraventricular JPA tumors commonly undergo subtotal resection with frequent progression/recurrence. Subsequently, recurrent surgeries and adjuvant therapies can be necessary.

EPEN-03. THE MANAGEMENT OF PEDIATRIC AND ADOLESCENT SPINAL EPENDYMOMA; A 20-YEAR NATIONAL EVALUATION INVOLVING UNITED KINGDOM PEDIATRIC ONCOLOGY PRIMARY TREATMENT CENTERS ON BEHALF OF THE UK CHILDREN’S CANCER AND LEUKAEMIA GROUP (CCLG)

Abstract INTRODUCTION Pediatric spinal ependymomas account for approximately 1% of childhood CNS tumors. Most are myxopapillary ependymomas (MPEs). For symptomatic cases, maximal safe surgical resection is the accepted therapeutic standard. However, a role for adjuvant therapy is unclear, underpinned by low incidence rates, inadequate trial data and recent WHO upgrading of the MPE variant. This retrospective national service evaluation aimed to provide safety and outcome data, from which future management guidance could be developed. METHOD Children, teenagers and young adults diagnosed with a spinal ependymoma of any WHO grade since 2000 across 17 UK CCLG centres were evaluated. Patient demographics, therapies, adverse events, and outcomes were captured. RESULTS 102 patients were evaluated. Ten children had NF2 (median age 11 (7.6 – 14) years) with nine located in the cervicomedullary region. All ten patients were alive following surveillance (n=3) or surgical intervention (n=7) with an estimated median PFS of 5.4 (1.7 – 9.1) years. For the remaining 92 patients (median age 12 (0.7 – 19) years), 63% of tumors were lumbosacral, 73% demonstrated MPE morphology and 16% were metastatic. The median symptom interval was 4 (0 - 36) months. Progression or relapse was reported in 30/92 (33%), with a 5-year PFS of 62(+ 6)%, yet only 4 disease-related deaths occurred (mean follow-up 6.8 years; no MPEs). Across this non-NF2 cohort, gross/near total resection and upfront adjuvant radiotherapy independently reduced disease progression risk (p &amp;lt; 0.05). However, improved local control from early irradiation was not statistically proven when localized disease or MPEs were exclusively scrutinized. No radiotherapy-related high-grade toxicity was reported. DISCUSSION Pediatric spinal ependymomas are rare tumors demonstrating excellent survival, particularly MPEs. Maximal safe surgery and early adjuvant radiotherapy can improve local control rates, but European collaboration will be required to evaluate efficacy for certain tumor and clinical subgroups. Conclusions could support future national management guidelines.

EPEN-14. MOLECULAR MARKERS AND PREDICTORS OF OUTCOME FOR PAEDIATRIC INTRACRANIAL EPENDYMOMA IN THE PROSPECTIVE, MULTICENTRE E-HIT2000 TRIAL AND SUBSEQUENT HIT-REGISTRIES: A POOLED ANALYSIS OF 244 PATIENTS

Abstract BACKGROUND Throughout the past decade, molecular tools have revolutionised ependymoma classification, yet their application has been limited in clinical trial cohorts. METHODS We present the molecular analysis of paediatric ependymoma patients from the E-HIT2000 trial (n = 165), or subsequent HIT2000-interim and I-HIT-MED registries (n = 79) based on DNA-methylation profiling with multi-level classification using the Heidelberg Brain Tumor Classifier v12.5 and the analysis of chromosome 1q, 6q, and CDKN2A copy number status. Prior to further analysis, cases without ependymoma group prediction were excluded (n = 16/244). RESULTS 5-year PFS and OS rates varied by group: EPN-PFA (n=146/228) 45±4% and 76±4%; EPN-PFB (n=19/228) 90±7% and 100%; EPN-ZFTA (n=59/228) 63±7% and 87±5%; and EPN-YAP1 (n=4/228) 50±25% and 100%. EPN-PFA was subclassified into nine subtypes. Poor median PFS was observed for PFA1c (n=22, 5-yr-PFS 32±10%/5-yr-OS 77±9%), PFA1d (n=13, 35±14%/72±14%), PFA1e (n=15, 47±13%/59±13%), and PFA2a (n=16, 27±12%/50±14%). Presence of 1q gain was associated with inferior survival (n = 39/146, 29±8%/65±8%). 6q loss impacted PFS, but not OS (n=8, 25±14%/100%). Among 59 EPN-ZFTA cases, 46 clustered with EPN ZFTA-RELA fused, and 12 clustered within recently described subgroups of EPN-ZFTA (EPN-ZFTA alt., Cluster 1: 1/12, Cluster 2: 11/12). Strikingly, 6/11 EPN ZFTA-alt. (Cluster 2) cases showed infratentorial (4/6) or supratentorial midline location (2/6). Homozygous deletion of CDKN2A (CDKN2A-/-; n=8) was only observed in EPN ZFTA-RELA. Presence of EPN ZFTA-alt. (cluster 2) (5-yr-PFS: 36±15%; p&amp;lt;0.001), and CDKN2A-/- (19±16%; p&amp;lt;0.0001) was associated with inferior PFS compared to EPN ZFTA-RELA CDKN2A-wt (81±6%). OS was only impacted for patients with EPN ZFTA-RELA CDKN2A-/- (5-yr-OS: 38±20%, p&amp;gt;0.0001). CONCLUSIONS We present strong evidence supporting the inclusion of molecular criteria into the next generation of clinical trials for children with ependymoma.