Nathalie Auger

PURPOSE: Intermediate-risk neuroblastoma patients older than 18 months, with non– MYCN amplified, International Neuroblastoma Risk Group Staging System localized, unresectable or International Neuroblastoma Staging System stage 3 tumors, and unfavorable histology have inferior outcomes compared with other intermediate-risk patients. This study aimed to identify genetic prognostic biomarkers within this rare subgroup. METHODS: We conducted a large, international study including chromosomal copy number in all cases, next-generation DNA sequencing in most, and telomere maintenance mechanisms and gene expression in a subset, and correlated results with patient survival. RESULTS: Among 98 tumors, 9/98 (9.2%) had oncogene amplifications ( CDK4/MDM2/TERT coamplification (n = 1), CDK4/MDM2 coamplification (n = 4), CDK4 (n = 2), TERT (n = 1), and MYC (n = 1)), while 63/98 (64.3%) had typical segmental chromosomal aberrations (tSCAs). Patients with tumors with oncogene amplification had the worst 5-year event-free survival (EFS; 0%; P < .0001 log-rank test) and 5-year overall survival (OS; 44.4% [95% CI, 21.4 to 92.3]; P < .01 log-rank test). Patients with tumors harboring tSCAs had inferior EFS compared with those with numerical chromosomal aberrations only (51.7% [95% CI, 40.6 to 65.8] v 93.3% [95% CI, 81.5 to 100]; P < .01). Patients with p53 pathway tumor alterations (n = 10) had worse EFS than those without (0% v 61.1% [95% CI, 50.3 to 74.3]; P < .0001, log-rank test) and worse OS (26.7% [95% CI, 8.9 to 80.3] v 80.9% [95% CI, 71.8 to 91.3]; P < .001 log-rank test). Multivariable analysis identified tSCAs as an independent prognostic variable for EFS and oncogene amplification or p53 pathway abnormalities as independent prognostic variables for EFS and OS. CONCLUSION: Oncogene amplification and/or p53 pathway abnormalities and/or typical SCAs identify patients with intermediate-risk neuroblastoma with inferior outcome for whom intensified or alternative treatments should be considered.

We report a large cohort of 95 adult patients with acute myeloid leukemia (AML) harboring NUP98 rearrangements (NUP98r). Patient characteristics included a young age (median 50 years [IQR 38-64]), 20% of therapy-related AML, a high WBC count (median 52×10⁹/L), normal karyotype in 32%, FLT3-ITD in 48% and WT1 mutations in 34%. NUP98::NSD1 fusion was the most common (54%), and these patients were significantly younger (41 y vs. 61 y), had more de novo AML (94% vs. 64%), higher rates of normal karyotypes (56% vs. 4.5%), FLT3-ITD (76% vs. 18%) and WT1 mutations (50% vs. 16%) than other NUP98r AML. The median overall survival (OS) for the entire cohort was 15.2 months (95% CI, 11.9-20.8) and event-free survival was 5.8 months (2-7.5). Among patients treated intensively (n = 73), age (HR = 2.7), FLT3 inhibitor therapy (HR = 0.45) and hematopoietic stem cell transplant (HR = 0.5) influenced OS in univariate analysis. Compared with NUP98 wild-type (WT) AML, NUP98r patients had a prognosis more similar to that of NUP98 WT ELN adverse patients whether initially classified as intermediate (20.3 months [11.7-30.2]) or adverse (15.7 months [13.5-42.9]). However, treatment with FLT3 inhibitors improved prognosis, with median OS not reached and 5-year OS of 53.3%, approaching that of intermediate-risk patients.

PURPOSE: Fanconi anemia (FA) is a genetic disorder typically characterized by progressive bone marrow failure (BMF) during childhood, leading to diagnosis at that stage. In adolescence or adulthood, patients are predisposed to myelodysplastic syndrome (MDS), acute myeloid leukemia, and solid tumors. However, some individuals present atypically, delaying FA recognition and resulting in life-threatening complications. This study describes the distinctive phenotype associated with biallelic FANCM pathogenic variants. PATIENTS AND METHODS: Clinical and biologic data were analyzed from eight patients carrying biallelic germline FANCM pathogenic variants within a French cohort of 411 patients with FA (2.0%). Clinical outcomes were compared with those of patients with FA carrying non- FANCM variants. RESULTS: None of the eight FANCM patients developed BMF, contrasting with a 93.5% cumulative incidence among other FA genotypes ( P < .0001). This absence of marrow failure resulted in delayed FA diagnosis (median age 23.5 v 6.8 years, P < .01). Instead, six patients initially presented with malignancy and exhibited marked toxicity to conventional cancer therapies, prompting FA testing. Malignancies included four oral cancers and, unexpectedly, two ALL: a ZNF384-rearranged B-cell precursor ALL and a BCL11B::HOXA13 early T-cell precursor ALL. No ALL cases occurred among the 403 non- FANCM patients with FA ( P < .0001). The treatment courses of the two FANCM -related ALL cases are reported. CONCLUSION: Biallelic FANCM variants define a distinct FA subtype lacking early BMF, leading to missed diagnoses and severe toxicity upon malignancy. Recognizing this presentation is crucial for timely FA detection and for implementing adapted therapeutic and follow-up strategies.

Commutation plot visualizing the mutated genes in t-MN after OC according to PARPi treatment.

TP53 mutations characteristics among t-MN PARPi national cohort.

Flow chart of the study displaying the three cohorts.

Waffle chart (%) of patients addressed for cytopenia exploration after OC exposed to a PARPi treatment from cytopenia diagnosis (A) and cytopenia diagnosis based on NGS results (B). Dot plots (C) showing the median WBC, hemoglobin, and platelet counts from patients referred for cytopenia exploration after OC exposed to a PARPi treatment according to t-MN diagnosis (“t-MN”) or not (“Cytopenia”).

Blood smear and bone marrow aspiration of patient referred for cytopenia post PARPi.

Patient characteristics of the national cohort according to the type of PARPi received (olaparib vs. other PARP inhibitors).

Univariate analysis for overall survival from t-MN diagnosis of patients from the national cohort.