Citations

10008 Background: NTRK1/2/3 gene fusions (TRK fusions) occur in a range of pediatric cancers and are the canonical molecular alterations in IFS. Larotrectinib is a highly selective TRK inhibitor that is FDA-approved for TRK fusion solid tumors in patients with no satisfactory alternative treatments or whose cancer has progressed following initial treatment. ADVL1823 (NCT03834961) evaluated larotrectinib in children with newly diagnosed TRK fusion positive solid tumors in two histology-based cohorts. Cohort A enrolled patients with IFS and is the focus of this analysis. Methods: Newly diagnosed patients ≤30 years old with unresectable or metastatic IFS and a locally identified NTRK gene fusion were eligible for Cohort A utilizing a Simon 2-stage design. Patients received larotrectinib at a dose of 100 mg/m2/dose BID (max of 100 mg/dose) continuously in 28-day cycles until disease progression, unacceptable toxicity, the tumor becoming surgically resectable following a minimum of 6 cycles of therapy, or completion of 12 cycles (for those with CR) or 26 cycles (for those with PR) of therapy. The primary endpoint was the centrally confirmed objective response rate within 6 cycles according to RECIST 1.1; response assessment occurred every 2 cycles for the first 6 cycles. The data cutoff was December 31, 2022. Results: Between October 2019 and May 2022, 18 patients with IFS were enrolled from 14 centers. The median age was 2 months (range <1 month to 4.6 years). NTRK fusions included presumed/confirmed ETV6: NTRK3, n=15, NTRK3 (partner unconfirmed), TMP3: NTRK1 and DCTN1: NTRK1, n=1 each, and were identified by FISH (n=8), NGS (n=7), and PCR (n=3). 17 of 18 patients (94%) demonstrated confirmed objective responses (16 PR and 1 CR,) resulting in closure to enrollment after meeting the pre-specified efficacy threshold. The only patient without confirmed response demonstrated 79% tumor reduction after cycle 2, but no confirmatory scan was obtained within the first 6 cycles. No patient discontinued therapy within the first 6 cycles due to disease progression or toxicity. Four (22%) patients had dose limiting toxicities: 2 neutropenia (both CTCAE V5 grade (G)4) and 1 each G3 AST increase and G3 weight loss. All patients resumed therapy following a dose reduction. Treatment-related grade ≥ 3 toxicities occurred in 7 patients, most commonly neutropenia (n=5, 3 G3, 2 G4). Conclusions: Larotrectinib is highly active and well tolerated in newly diagnosed patients with IFS. Enrollment of this very rare molecularly defined patient population was feasible within the COG. Ongoing follow-up will evaluate durability of response after treatment discontinuation at protocol specified response-adapted timepoints with or without surgical resection of tumor. Clinical trial information: NCT03834961 .

11529 Background: To evaluate clinical characteristics and patterns of treatment failure in patients with localized Ewing sarcoma (ES) treated on AEWS1031 according to local control (LC) strategies, tumor size, and tumor site. Methods: AEWS1031 was a phase 3 randomized trial comparing two interval compressed chemotherapy regimens. Patients who completed LC on AEWS1031 were analyzed. LC was with surgery alone (S), definitive radiation therapy (RT), or surgery plus radiation (S+RT), and determined by the treating investigator. Local failure (LF) and distant failure (DF) were defined as recurrence at primary tumor site or distant site, respectively. Fine and Gray method was used to estimate cumulative incidence of LF and DF from time LC was completed. P-values were calculated using logrank or Gray’s test, as appropriate. A two-sided p-value of ≤0.05 was considered significant. Results: 588 patients completed LC. Median age at enrollment was 13.0 years (range: 0.6- 33.9 years). Tumor sites were categorized as extremity (230; 39%), axial (142; 24%), extraosseous (110; 19%), and pelvis (106; 18%). At diagnosis, tumor volume (TV) was ≥200 mL in 170 patients (31%) and maximum tumor dimension (MTD) was ≥8 cm in 289 patients (52%). LC was with S in 320 patients (54%), RT in 160 (27%), and S+RT in 108 (18%). Eight patients received preoperative RT. Fifty-three patients (13.1%) who received S±RT had an R1 resection. LC with S was more likely for extremity (58%), RT for pelvis (38%) and S+ RT for axial (36%) and extraosseous (34%) primary tumors (p <0.01). With median follow up of 67.6 months from LC, the 5-year cumulative incidences of LF and DF for the entire cohort were 6.0% (95% CI, 4.3-8.3%) and 11.0% (95% CI, 8.6-13.9%), respectively. Eleven patients experienced simultaneous LF and DF. LF incidence was 5.0% for S, 8.4% for RT, and 5.6% for S+RT (p=0.47). DF incidence was 11.8% for S, 6.4% for RT, and 15.1% for S+RT (p=0.16). LF incidence by tumor site was 3.6% for extremity, 8.7% for pelvis, 7.3% for axial, and 6.8% for extraosseous (p=0.08). LF incidence was higher for primary tumors ≥200 mL (11.3%) compared to tumors < 200 mL (3.9%; p<0.01) and for tumors ≥8 cm (7.8%) compared to tumors < 8 cm (4.4%; p=0.02). Tumor size was associated with a higher LF incidence for S and RT, but not for S+RT (Table). LF incidence was 4.0% for R0, 7.5% for R1 with RT, and 16.7% for R1 without RT (p=0.02). Conclusions: We report the lowest LF incidence to date for prospective ES trials conducted. Both larger TV and MTD were associated with higher LF. Future investigations will aim to evaluate the impact of chemotherapy dose-intensity on LC and identify risk-stratification variables for improved LC. Five-year LF incidence by LC and tumor size. Clinical trial information: NCT01231906 . [Table: see text]

PURPOSE Monoclonal antibodies directed against insulin-like growth factor-1 receptor (IGF-1R) have shown activity in patients with relapsed Ewing sarcoma. The primary objective of Children's Oncology Group trial AEWS1221 was to determine if the addition of the IGF-1R monoclonal antibody ganitumab to interval-compressed chemotherapy improves event-free survival (EFS) in patients with newly diagnosed metastatic Ewing sarcoma. METHODS Patients were randomly assigned 1:1 at enrollment to standard arm (interval-compressed vincristine/doxorubicin/cyclophosphamide alternating once every 2 weeks with ifosfamide/etoposide = VDC/IE) or to experimental arm (VDC/IE with ganitumab at cycle starts and as monotherapy once every 3 weeks for 6 months after conventional therapy). A planned sample size of 300 patients was projected to provide 81% power to detect an EFS hazard ratio of 0.67 or smaller for the experimental arm compared with the standard arm with a one-sided α of .025. RESULTS Two hundred ninety-eight eligible patients enrolled (148 in standard arm; 150 in experimental arm). The 3-year EFS estimates were 37.4% (95% CI, 29.3 to 45.5) for the standard arm and 39.1% (95% CI, 31.3 to 46.7) for the experimental arm (stratified EFS-event hazard ratio for experimental arm 1.00; 95% CI, 0.76 to 1.33; 1-sided, P = .50). The 3-year overall survival estimates were 59.5% (95% CI, 50.8 to 67.3) for the standard arm and 56.7% (95% CI, 48.3 to 64.2) for the experimental arm. More cases of pneumonitis after radiation involving thoracic fields and nominally higher rates of febrile neutropenia and ALT elevation were reported on the experimental arm. CONCLUSION Ganitumab added to interval-compressed chemotherapy did not significantly reduce the risk of EFS event in patients with newly diagnosed metastatic Ewing sarcoma, with outcomes similar to prior trials without IGF-1R inhibition or interval compression. The addition of ganitumab may be associated with increased toxicity.

The clinical and largely unpredictable heterogeneity of phenotypes in patients with mitochondrial disorders demonstrates the ongoing challenges in the understanding of this semi-autonomous organelle in biology and disease. Previously, we used the gene-breaking transposon to create 1200 transgenic zebrafish strains tagging protein-coding genes (Ichino et al., 2020), including the lrpprc locus. Here, we present and characterize a new genetic revertible animal model that recapitulates components of Leigh Syndrome French Canadian Type (LSFC), a mitochondrial disorder that includes diagnostic liver dysfunction. LSFC is caused by allelic variations in the LRPPRC gene, involved in mitochondrial mRNA polyadenylation and translation. lrpprc zebrafish homozygous mutants displayed biochemical and mitochondrial phenotypes similar to clinical manifestations observed in patients, including dysfunction in lipid homeostasis. We were able to rescue these phenotypes in the disease model using a liver-specific genetic model therapy, functionally demonstrating a previously under-recognized critical role for the liver in the pathophysiology of this disease.

Abstract Hepatic cysts are fluid‐filled lesions in the liver that are estimated to occur in 5% of the population. They may cause hepatomegaly and abdominal pain. Progression to secondary fibrosis, cirrhosis, or cholangiocarcinoma can lead to morbidity and mortality. Previous studies of patients and rodent models have associated hepatic cyst formation with increased proliferation and fluid secretion in cholangiocytes, which are partially due to impaired primary cilia. Congenital hepatic cysts are thought to originate from faulty bile duct development, but the underlying mechanisms are not fully understood. In a forward genetic screen, we identified a zebrafish mutant that developed hepatic cysts during larval stages. The cyst formation was not due to changes in biliary cell proliferation, bile secretion, or impairment of primary cilia. Instead, time‐lapse live imaging data showed that the mutant biliary cells failed to form interconnecting bile ducts because of defects in motility and protrusive activity. Accordingly, immunostaining revealed a disorganized actin and microtubule cytoskeleton in the mutant biliary cells. By whole‐genome sequencing, we determined that the cystic phenotype in the mutant was caused by a missense mutation in the furinb gene, which encodes a proprotein convertase. The mutation altered Furinb localization and caused endoplasmic reticulum (ER) stress. The cystic phenotype could be suppressed by treatment with the ER stress inhibitor 4‐phenylbutyric acid and exacerbated by treatment with the ER stress inducer tunicamycin. The mutant liver also exhibited increased mammalian target of rapamycin (mTOR) signaling. Treatment with mTOR inhibitors halted cyst formation at least partially through reducing ER stress. Conclusion : Our study has established a vertebrate model for studying hepatic cystogenesis and illustrated the contribution of ER stress in the disease pathogenesis.

Abstract With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. Although the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet, the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification, and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses, and epigenetic profiling will be discussed because these will likely become important future tools for implementing precision medicine approaches in clinical decision making for patients with lymphoid malignancies.

7566 Background: Parenteral limited-duration BR chemoimmunotherapy and continuous orally administered Ibr, a Bruton tyrosine kinase inhibitor, dominate the treatment landscape of WM, a rare B cell lymphoma. No trials have assessed the comparative effectiveness of these 2 vastly different approaches. We conducted a multiinstitutional, international, collaborative study to compare BR and single-agent Ibr in patients (pts) with treatment naïve (TN) WM. Methods: Data from 347 pts with active TN WM, seen between 2011 and 2021 in the US and Europe, were analyzed. The pts on rituximab maintenance were excluded. The modified IWWM-6 criteria (based on IgM alone) were used for response assessment. All time-to-event analyses were performed from the frontline therapy initiation, using the Kaplan-Meier method. Results: The median age of the pts treated with BR (n=208) and Ibr (n=139) was 66 (range 40-86) years (y) and 69 (39-97) y, respectively, (p=0.005). With a median follow up of 4.2 y (95% CI 3.8-4.5), the 4-y progression free survival (PFS) was 73% in each group, p=0.6, and 4-y overall survival (OS) was 94% (95% CI 91-98) in the BR group versus ( v) 82% (95% CI 75-90) in the Ibr group, p=0.01. In a bivariate analysis adjusting for age and the treatment type, only age emerged as a predictor for OS (HR 7.2, p=0.0001). Therefore, a 1:1 age-matched analysis of 246 pts who received Ibr (n=123) or BR (n=123) was performed. Pts with a known MYD88WT status who had received Ibr and their age matched controls on BR were excluded. The international prognostic scoring system (IPSS) WM was comparable between the 2 groups (Table). A higher proportion of pts on BR attained very good partial or deeper response (≥VGPR) as the best response in comparison to the pts on Ibr (Table). The 4-y PFS for the BR and Ibr groups was similar [72% (95% CI 63-82) v 78% (95% CI 70-87), p=0.14] and 4-y OS was 95% (95% CI 91-99) with BR v 86% (95% CI 80-93) with Ibr (p=0.3). Premature discontinuation, during active treatment, due to adverse effects (AEs) or lack of response was noted in 13% and 33% of pts on BR and Ibr, respectively. A detailed assessment of the AEs will be presented at the meeting. Conclusions: Both BR and Ibr lead to comparable outcomes in pts with TN WM, although deeper responses are attained with BR. These findings require confirmation in prospective studies. For pts who harbor MYD 88L265P mutation, selection between the 2 approaches should be dictated by their potential toxicities, pt comorbidities, pt/clinician preference (parenteral fixed-duration v continuous oral) and access to therapies. [Table: see text]

Abstract Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.