Lanino L, Hunter AM, Gagelmann N
… +48 more, Robin M, Dall'Olio D, Flamigni A, Sala C, Gurnari C, Wang YH, Pleyer L, Xicoy B, Montalban-Bravo G, Shih LY, Alsugair A, Fathima S, Gregorio C, Rollo C, Palomo L, Platzbecker AS, Asti G, Itzykson R, Sallman DA, Fariselli P, Kern W, Garcia-Manero G, Platzbecker U, Solé F, Diez-Campelo M, Maciejewski J, Bejar R, Thol F, Kroger N, Savona M, Fenaux P, Sanz G, Kordasti S, Santini V, Fontenay M, Zeidan AM, Komrokji RS, Haferlach T, Germing U, Castellani G, D'Amico S, Patnaik M, Ieva F, Solary E, Tefferi A, Padron E, Della Porta MG, iCPSS Alliance
J Clin Oncol
· 2026 Jun · PMID 41894646
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PURPOSE: Chronic myelomonocytic leukemia (CMML) is a rare myeloid neoplasm characterized by clinical heterogeneity and is associated with poor outcomes. To date, limited molecular information has been incorporated into d...PURPOSE: Chronic myelomonocytic leukemia (CMML) is a rare myeloid neoplasm characterized by clinical heterogeneity and is associated with poor outcomes. To date, limited molecular information has been incorporated into disease classification and risk stratification. We aimed to integrate genomic features into the clinical decision-making process for CMML. PATIENTS AND METHODS: We analyzed a retrospective cohort of 3013 patients with CMML (training set) and a prospective population of 516 patients (validation set). Using an innovative framework for multimodal data analysis, we developed molecular-based disease taxonomy and prognostication. RESULTS: Unsupervised clustering identified nine entities with distinct genomic features and outcomes ( < .001), including splicing machinery, transcription factors, signal transduction and tyrosine kinase pathways aberrations, and high-risk molecular signatures. Notably, 15% of patients showed molecular/clinical overlap with other myeloid neoplasms. We integrated molecular and clinical information to build the international CMML Prognostic Scoring System (iCPSS), incorporating mutations in nine genes together with hematologic parameters and cytogenetic abnormalities. The iCPSS identified five groups with distinct probability of overall and leukemia-free survival in both training and validation cohorts ( < .001), outperforming existing prognostic models. Importantly, 55% of patients were reassigned to higher or lower risk groups by the iCPSS. Decision analysis demonstrated that iCPSS could refine the optimal timing of allogeneic transplantation at the individual level; compared with conventional prognostic tools, iCPSS-based decision modeling changed transplantation strategy in 31% of cases, resulting in a significant gain-in-life expectancy for eligible patient population ( < .001). A federated learning platform was implemented to enable continuous, privacy-preserving model update across multiple centers. CONCLUSION: Molecular information improves CMML classification and prognostication, supports more effective clinical decision making, and potentially refines the design of clinical trials.
Besse B, Subbiah V, Curigliano G
… +28 more, Bowles DW, Doebele RC, Mansfield AS, Baik CS, de Lima Lopes G, Paz-Ares L, Taylor MH, Tan DSW, Alonso G, Gadgeel SM, Kalemkerian GP, Ou SI, van der Wekken AJ, Becerra CR, Evangelist M, Griesinger F, Liu SV, Lou Y, Mazières J, Melear JM, Narang M, Saxena A, Thomas M, Wang S, Thomassen A, Lee DH, Kim DW, Gainor JF
J Clin Oncol
· 2026 May · PMID 41886723
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fusions appear in 1%-2% of non-small cell lung cancers (NSCLCs). The results from the ARROW study (ClinicalTrials.gov identifier: NCT03037385) supported US Food and Drug Administration approval of pralsetinib, an oral se...fusions appear in 1%-2% of non-small cell lung cancers (NSCLCs). The results from the ARROW study (ClinicalTrials.gov identifier: NCT03037385) supported US Food and Drug Administration approval of pralsetinib, an oral selective RET inhibitor, for metastatic -altered NSCLC and fusion-positive thyroid cancers. ARROW was a phase I/II open-label study of pralsetinib 400 mg once daily in fusion-positive NSCLCs. Coprimary end points were overall response rate (ORR) and safety. Key secondary end points included duration of response, progression-free survival, and overall survival (OS). At data lock (May 20, 2024), 281 patients initiated pralsetinib (median treatment duration, 15.0 months). ORR (measurable disease patients; n = 259) was 78% (95% CI, 69 to 86) for treatment-naïve patients and 63% (95% CI, 54 to 71) for prior platinum-based chemotherapy patients. Median OS was 44.3 months (95% CI, 30.9 to 53.1), 50.1 months (95% CI, 28.3 to not reached) in treatment-naïve patients, and 39.7 months (95% CI, 27.8 to 53.2) in prior platinum patients. Common grade ≥3 treatment-related adverse events were anemia (21%), hypertension (15%), and decreased neutrophils (13%). Three treatment-related deaths occurred (pneumonia, n = 2; interstitial lung disease and rhabdomyolysis, n = 1 each). Safety was consistent with previous ARROW reports; no hypersensitivity was reported in patients receiving prior immunotherapies. Pralsetinib produced robust, durable responses with manageable safety in treatment-naïve and previously treated patients with fusion-positive NSCLCs, confirming previous findings with longer follow-up.
PURPOSE: Cascade genetic testing in families with hereditary cancer syndromes is an important strategy to reduce the burden of cancer, but testing of relatives is low. Direct engagement of relatives through cancer surviv...PURPOSE: Cascade genetic testing in families with hereditary cancer syndromes is an important strategy to reduce the burden of cancer, but testing of relatives is low. Direct engagement of relatives through cancer survivors is a promising approach to bridge this gap. METHODS: We conducted a population-based cluster-randomized clinical trial (Genetic Information and Family Testing [GIFT]) of an online, direct-to-family, cancer genetic education and communication tool including the offer of home testing to adult relatives of cancer survivors diagnosed in 2018-2019 who carried a pathogenic variant. We selected patients through SEER and surveyed them for eligibility followed by a trial invitation. Two features were randomized: assistance from a human navigator (yes, no) and testing cost (free $50). We hypothesized that the fraction of relatives tested in a family (primary outcome) would be higher with a navigator and free testing. RESULTS: Four thousand three hundred patients were surveyed and 2,285 responded (53.1%); 2,006 eligible respondents were invited (87.8%) and 414 enrolled (20.6%). Enrolled patients reported a total of 4,946 first- and second-degree relatives (mean, 12.3; standard deviation [SD], 8.6); they invited 948 relatives (19.2%) and 303 enrolled (32.0%). Most enrolled relatives ordered testing (267, 91.3%); more than double were tested in the free versus $50 arm (odds ratio [OR], 2.5 [1.6-3.9]), but the baseline fraction tested was low at 0.03 and thus the absolute increase was modest (0.04 [95% CI, 0.02 to 0.05]). We did not find evidence for increased testing in the navigation arm (OR, 1.3 [0.8-2.1]). CONCLUSION: GIFT is a promising blueprint for online cascade genetic education and testing. Results suggest that a low-cost, population-level intervention could be deployed without a human navigator. Additional intervention strategies are needed to increase the modest invitation and testing uptake observed in this study.
PURPOSE: Acute radiation dermatitis (ARD) is a common debilitating toxicity in patients with head and neck cancer receiving radiotherapy. Current evidence-based strategies for preventing ARD remain limited, and alternati...PURPOSE: Acute radiation dermatitis (ARD) is a common debilitating toxicity in patients with head and neck cancer receiving radiotherapy. Current evidence-based strategies for preventing ARD remain limited, and alternative approaches are needed to optimize care. METHODS: In this double-blind, randomized, controlled phase II trial, eligible patients with head and neck cancer undergoing radiotherapy were randomly assigned in a 1:1 ratio to receive either fullerene or trolamine at West China Hospital, Sichuan University, from August 2024 to March 2025. Participants were instructed to apply the assigned cream three times daily starting from the 3 days before radiotherapy and continuing for 14 days after completion of radiotherapy. ARD was evaluated weekly during radiotherapy and for 4 weeks after radiotherapy. The primary end point was the incidence of grade ≥2 ARD, assessed in the intention-to-treat population. RESULTS: A total of 132 patients were randomly assigned, with 66 allocated to the fullerene group and 66 to the trolamine group. The patients had a mean age of 58.0 years (standard deviation, 11.1), and 39 (29.5%) were female. The incidence of grade ≥2 ARD was significantly lower in the fullerene group than in the trolamine group. In the fullerene group, 34.8% of patients (95% CI, 24.5 to 46.9) developed grade ≥2 ARD, compared with 83.3% of patients in the trolamine group (95% CI, 72.6 to 90.4). CONCLUSION: In this prospective, randomized clinical trial, fullerene significantly reduced the incidence of ARD compared with trolamine.
PURPOSE: The CALYPSO study demonstrated activity of savolitinib and durvalumab in -driven papillary renal cancer (PRC). We report final efficacy outcomes and exploratory circulating tumor DNA (ctDNA) biomarker analysis....PURPOSE: The CALYPSO study demonstrated activity of savolitinib and durvalumab in -driven papillary renal cancer (PRC). We report final efficacy outcomes and exploratory circulating tumor DNA (ctDNA) biomarker analysis. METHODS: This single-arm phase II study evaluated savolitinib and durvalumab in treatment-naïve or pretreated PRC. End points included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). FoundationOne CDx assessed DNA alterations and /PD-L1 or /tumor mutational burden (TMB) copositivity. ctDNA collected at baseline and on treatment was correlated with outcomes. RESULTS: At 41-months median follow-up, ORR was 34% (95% CI, 20.0 to 51.0) in the intention-to-treat (ITT) population (N = 41) and 53% (95% CI, 28.0 to 77.0) in -driven patients (n = 17). Median PFS was 6.5 (95% CI, 2.7 to 12.0) versus 13.9 months (95% CI, 2.9 to 23.8), and OS was 18.3 (95% CI, 7.3 to 30.7) versus 27.4 months (95% CI, 9.3 to 37.4), in the ITT population and the -driven population, respectively. PD-L1 (66% positive) and TMB (median 2.5 mut/Mb) status did not correlate with response. Baseline ctDNA positivity (10/21) correlated with shorter OS (median 7.3 33.3 months), while ctDNA clearance and mean variant allele frequency reduction correlated with improved OS (median 31.3 7.2 and 31.3 15.5 months, respectively). CONCLUSION: Savolitinib plus durvalumab shows OS in -driven PRC, supporting the ongoing SAMETA RIII trial (ClinicalTrials.gov identifier: NCT05043090). ctDNA may be a useful predictive biomarker.
Furtwängler R, Dandis R, van Tinteren H
… +19 more, Welter N, Vokuhl C, Vujanic G, Coulomb-L'Hermine A, Godzinski J, Schenk JP, Brisse H, Gessler M, Kager L, Melchior P, Warmann SW, Verschuur A, de Camargo B, Ramirez-Villar G, Spreafico F, Brok J, Chowdhury T, van den Heuvel-Eibrink MM, Graf N
PURPOSE: The International Society of Paediatric Oncology-Renal Tumour Study Group (SIOP-RTSG) classifies blastemal-type Wilms tumor (WT) after preoperative chemotherapy as high-risk (HRWT). It remains unresolved whether...PURPOSE: The International Society of Paediatric Oncology-Renal Tumour Study Group (SIOP-RTSG) classifies blastemal-type Wilms tumor (WT) after preoperative chemotherapy as high-risk (HRWT). It remains unresolved whether residual absolute volume of blastema (AVB) functions as an independent prognostic factor across WT subtypes. MATERIALS AND METHODS: AVB was calculated from preoperative tumor volume, necrosis percentage, and viable blastema using prospectively collected data from 3,459 patients with unilateral WT treated in the SIOP WT 2001 study between 2001 and 2018. Martingale residual plots defined AVB thresholds discriminating survival in localized HRWT, intermediate-/low-risk WT (IRWT/LRWT), and metastatic WT (stage IV). Complete AVB data were available for 1,802 patients (51.2%); 298 (16.5%) had stage IV disease. Of 1,504 patients with localized WT, 265 (17.6%) had HRWT, 1,203 (79.9%) had IRWT, and 36 (2.4%) had LRWT. RESULTS: Multivariable Cox regression adjusted for age, sex, and local stage confirmed significantly worse survival for patients exceeding these AVB thresholds: (1) IRWT (≥20 mL): Hazard ratio for event-free survival (EFS) 2.93 (95% CI, 2.08 to 4.12) and overall survival (OS) 2.76 (95% CI, 1.32 to 5.77); (2) HRWT (≥100 mL): EFS 2.89 (95% CI, 1.59 to 5.26) and OS 3.25 (95% CI, 1.45 to 7.27); and (3) stage IV (≥10 mL): EFS 5.78 (95% CI, 3.65 to 9.17) and OS 4.59 (95% CI, 2.57 to 8.17). Patients above these thresholds had significantly lower 2-year EFS ( < .0001). In stage II to III IRWT patients with AVB ≥20 mL, those treated with doxorubicin had superior EFS versus those without (87.6%, 95% CI, 81.5 to 94.1 69.2%, 95% CI, 59.8 to 80.1; = .0064). CONCLUSION: AVB after preoperative chemotherapy is a strong, independent predictor of both EFS and OS in WT across risk groups. An AVB of ≥20 mL identifies a clinically relevant subset of patients with IRWT who may benefit from intensified therapy with doxorubicin. These findings support the use of AVB as a stratification criterion in future SIOP-RTSG protocols.