Matching-adjusted indirect comparison of CPX-351 in secondary Acute Myeloid Leukemia between the registrative trial and a real-life study

Matching-adjusted indirect comparison of CPX-351 in secondary Acute Myeloid Leukemia between the registrative trial and a real-life study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Matching-adjusted indirect comparison of CPX-351 in secondary Acute Myeloid Leukemia between the registrative trial and a real-life study Luana Fianchi, Alfonso Piciocchi, Fabio Guolo, Francesco Marchesi, and 30 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5915486/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 May, 2025 Read the published version in Annals of Hematology → Version 1 posted 5 You are reading this latest preprint version Abstract A real-life study on CPX-351 and the standard arm (‘7 + 3’) of the CPX-351 registrative trial in adults with secondary Acute Myeloid Leukemia were compared by an unanchored Matching-adjusted indirect comparison (MAIC), in order to evaluate the efficacy and toxicity of CPX-351. Results of this study are important to confirm the role of CPX-351 in significantly improving survival and remission rates compared with ‘7 + 3’ with a good safety profile in AML patients with high-risk features, a target group traditionally with a very poor prognosis. Moreover, this pilot analysis underlines the potentiality of the statistical method to compare studies with strong differences. Secondary acute myeloid leukemia CPX-351 Matching-adjusted indirect comparison Figures Figure 1 Introduction Approximately a 25% of the total cases of acute myeloid leukemia (AML) are subsequent to previous hematological disorders (sAML) or developing after chemotherapy or radiotherapy (tAML) [ 1 ]. Furthermore, AML with myelodysplasia-related changes (MRC-AML) is defined by the history of a myelodysplastic syndrome (MDS), signs of MDS-related cytogenetic abnormalities and/or dysplasia [ 2 ]. All the above occur more frequently with advancing age and are associated with adverse genetics and multidrug resistance phenotype ([ 3 – 4 ]. In the last 40 years, the ‘7 + 3’ regimens have been a standard for AML induction therapy (5). In older adults and patients with secondary AML, ‘7 + 3’ induction is associated with lower remission rates, increased early mortality, and higher relapse rates than in younger adults and patients with de novo AML [ 5 ]. CPX-351 is a liposomal encapsulation of cytarabine and daunorubicin in a 5-to-1 molar ratio. The registration study with a trial comparing the classic ‘7 + 3’ Vs. CPX-351 has demonstrated the greater efficacy in the treatment of sAML [ 5 – 6 ]. CPX-351 has received Food and Drug Administration (FDA) in 2017 and European Medicine Agency (EMA) in 2018 approval for the treatment of adult patients with tAMLs, sAMLs, or MRC–AML. After the registration of CPX-351, several real-life studies have been performed to evaluate the efficacy and safety of this new formulation, and recently an Italian multicenter study demonstrated the low rate of infections and treatment-related mortality among 200 patients ]7]. In this analysis, a real-life study on the use of CPX-351 and the standard arm (‘7 + 3’) of the CPX-351 registrative trial in adults with sAML were compared by an unanchored Matching-adjusted indirect comparison (MAIC), in order to evaluate the efficacy and toxicity of CPX-351. Methods and Patients MAIC methodology use individual patient data (IPD) from trials of one treatment to match baseline summary statistics reported from trials of another treatment, while indirect comparisons based only on aggregate data can be limited by cross-trial differences in patient populations, differences in the definitions of outcome measures, and sensitivity to modelling assumptions. By combining IPD with published aggregate data, MAIC can reduce observed cross-trial differences that can be potentially either prognostic or treatment effect modifiers and provide decision makers with timely comparative evidence [ 8 ]. This analysis aimed to test the feasibility to compare individual patients’ data with aggregated published results and evaluate the rate of infections of CPX-351 in real life vs the ‘7 + 3’ regimen and their impact on the survival outcomes. Patients-level data from GIMEMA-SEIFEM real-life study on the use of CPX-351, including all consecutive patients with AML from 30 Italian hematologic centers who received at least 1 course of CPX-351 from July 2018 to June 2021 according to clinical practice (n = 200) was weighted for the aggregated patients’ characteristics from the standard arm of the CPX-351 trial (‘7 + 3’ arm, n = 156). The study was approved by the Ethics Committee of the coordinating center, Fondazione Policlinico Universitario Agostino Gemelli—IRCCS, Università Cattolica del Sacro Cuore of Rome, Italy (Study ID: 3405), and by the respective ethics committees of all participating centers. Written informed consent for data collection was obtained from each patient enrolled. The study was conducted according to the Declaration of Helsinki. Accordingly, weighted Overall Survival and Event-Free Survival (w-OS, w-EFS) estimates, as well as rates of febrile neutropenia, fever of unknown origin (FUO), pneumonia, complete recovery (CR), and the interval of polymorphonuclear neutrophil (PMN) recovery, were computed. Results Five potential effect modifiers were identified and used for adjustment: age, sex, AML subtype (tAML, sAML, MDR), prior hypomethylating agents (HMA) exposure and transplant. The study included 200 patients treated with CPX-351 in a real-life setting across 30 Italian hematologic centers. Table 1 describes these characteristics in the original real-life study and adjusted. Table 1 Potential effect modifiers identified and used for adjustment: age, sex, AML subtype (tAML, sAML, MDR), prior hypomethylating agents (HMA) exposure and transplant in the original real-life study and adjusted GIMEMA-SEIFEM CPX-351 real-life study CPX-351 trial (‘7 + 3’ arm) Adjusted GIMEMA-SEIFEM CPX-351 real-life study Age (median) 65yy 67yy 67yy Sex M/F 1.04 1.6 1.6 AML subtype (tAML) 26% 21% 22% AML subtype (sAML) 35% 54% 54% AML subtype (MDR) 39% 24% 25% Prior HMA 20% 46% 46% Transplant 47% 25% 25% The median age of the cohort was 65 years, with a range spanning from 18 to 80 years. The gender distribution was balanced, with 51% of patients being male. Regarding disease classification, 26% of patients were diagnosed with therapy-related acute myeloid leukemia (tAML), 35% with secondary AML (sAML), and 39% with AML with myelodysplasia-related changes (MDR-AML). A history of prior exposure to hypomethylating agents (HMA) was documented in 20% of cases. A significant proportion of patients, amounting to 47%, underwent hematopoietic stem cell transplantation (HSCT) as part of their treatment. To ensure comparability between the real-world CPX-351 cohort and the ‘7 + 3’ standard arm of the registrative trial, a Matching-Adjusted Indirect Comparison (MAIC) was performed. The adjustment process resulted in a more balanced patient distribution, aligning baseline characteristics between the two groups. After weighting, the median age increased from 65 to 67 years, while the percentage of patients with sAML rose from 35–54%. The proportion of patients with prior HMA exposure increased from 20–46%, and the rate of HSCT decreased from 47–25%, reflecting a population more similar to that of the registrative trial. In terms of treatment response, the unadjusted rate of complete remission (CR) following CPX-351 treatment in the real-world cohort was 65%, which decreased to 55% after weighting. In contrast, the CR rate in the ‘7 + 3’ arm of the registrative trial was 33.3%, demonstrating a higher response rate with CPX-351. The adjusted early mortality rate at 30 days and at 60 days was 3.8% and 11% respectively, compared to those observed in the registrative trial, where early mortality rates with CPX-351 and ‘7 + 3’ were 5.9% and 10.6% at day 30, and 13.7% and 21.2% at day 60, respectively. Survival outcomes were also analyzed pre- and post-weighting ( Fig. 1 ) . The observed median overall survival (OS) in the CPX-351 real-world cohort was 18 months, with a 95% confidence interval of 14 to 21 months. Following MAIC adjustment, the weighted median OS was 12 months, ranging from 8.5 to 14 months. In comparison, the median OS in the ‘7 + 3’ arm of the registrative trial was notably lower, at 5.9 months (95% CI: 5.0-7.7). Similarly, the median event-free survival (EFS) in the real-world CPX-351 cohort was 11 months (95% CI: 7.6–17), while the weighted EFS was reduced to 5.4 months (95% CI: 2.8–9.8). The EFS in the ‘7 + 3’ cohort remained markedly inferior at 1.3 months (95% CI: 1.0-1.6). The study also evaluated the hematologic recovery profile and the incidence of infectious complications. The median time to polymorphonuclear neutrophil (PMN) recovery in the CPX-351 real-world cohort was 19 days, with a weighted median of 17.8 days, indicating a prolonged period of neutropenia but one that remained within the expected range for CPX-351 treatment. Febrile neutropenia (FN), defined according to Infectious Diseases Society of America (IDSA) criteria, grade 1–4, was a frequent adverse event, with an incidence of 74% in the real-world setting, which increased slightly to 76% after MAIC adjustment. In the ‘7 + 3’ arm of the registrative trial, the FN rate was reported at 70.9%. The incidence of fever of unknown origin (FUO) in CPX-351-treated patients was 37% before weighting and 33% post-weighting, while pneumonia was recorded in 12% of patients before weighting and 15% post-weighting. Discussion In vitro studies showed that CPX-351 enhances drug synergy and extends the half-life of both drugs, improving their bone marrow penetration and accumulation [ 9 – 10 ]. However, its pharmacokinetics lead to prolonged post-chemotherapy cytopenia, with neutropenia recovery around 36 days (vs. 32 days with traditional chemotherapy) [ 5 ]. In the phase II trial, nonhematologic common grade 3/4 adverse events included febrile neutropenia (34%), pneumonia (23%), and sepsis (16%) [ 11 ]. In the randomized phase III trial, febrile neutropenia was the most frequent adverse event (68.0% vs. 70.9% in ‘7 + 3’), with infection-related grade 3 to 5 events occurring in 83.7% of CPX-351 patients vs. 86.1% in ‘7 + 3’ [ 5 ]. In a French cohort, 91% had febrile neutropenia, 36% had pulmonary infections, and 10% were treated for invasive pulmonary aspergillosis [ 12 ]. In an early access program for older patients, febrile neutropenia (31%) and infections (6%) were the most common treatment-emergent adverse events [ 13 ]. The SEIFEM study confirmed CPX-351’s safety profile in real-world settings, with infectious complications similar to pivotal trials. Despite prolonged neutropenia, fungal infections were low (5.5%) and infection-related mortality was 6% [ 7 ]. The MAIC method in this study allowed for a robust comparison of two clinical trials in AML treatment, demonstrating its potential for comparing studies with large differences in patient selection. Baseline characteristics showed no significant sex distribution differences between groups. The GIMEMA-SEIFEM cohort was slightly younger, with different secondary AML subtypes. Notably, fewer patients (20%) in the real-life study had prior hypomethylating agents compared to the adjusted group (46%), and more patients (47%) in the real-life study underwent transplants compared to the post-weighted group (25%). This disparity likely impacts survival outcomes, reflecting probably a greater real-world experience with the drug. Survival outcomes in the real-life cohort were better than the registration trial’s median values, even after adjustment. In this MAIC analysis, CPX-351 showed higher OS and EFS compared to ‘7 + 3’. Safety data indicated similar recovery times for PMN and comparable infectious outcomes, with febrile neutropenia being the main difference. Pneumonia risk was lower in the CPX-351 group than in the ‘7 + 3’ arm. Ultimately the data obtained by this MAIC gives us back the profile of an easy-to-handle drug; this can be considered of utmost importance, because the target population is mainly a fragile population, often with a history of a previous neoplasm or myelodysplasia which leads to an increased risk of complications. The Kaplan-Meier Survival curves, even adjusted, show better results of CPX-351 therapy compared to conventional cytarabine plus daunorubicin regimen. In conclusion, results of this study are important to confirm the role of CPX-351 in significantly improving survival and remission rates compared with ‘7 + 3’ with a good safety profile in AML patients with high-risk features, as sAML or therapy-related AML, a target group traditionally with a very poor prognosis. Declarations Authorship and Conflict-of-Interest Statements LF, AP and LP conceived and designed the work that led to the submission, acquired data, and played an important role in interpreting the results; drafted the manuscript, approved the final version, agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolve; AP and GM performed also the statistical analysis. FG, FM, CC, MG, FR, AC, EOLB, RF, CP; OF, NF, MD, FL, MD, VB, MIDP, PZ, MP, CB, MP, PM, PC, LP, CB, LM, DZ, FF, VM, MR, AB acquired data, played an important role in interpreting the results the manuscript and approved the final version. The authors declare that they have no conflict of interest. Acknowledgments This study was not supported by research funding or grant. Data Availability declaration Data sharing will be available upon request to the Corresponding Author. 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Cite Share Download PDF Status: Published Journal Publication published 24 May, 2025 Read the published version in Annals of Hematology → Version 1 posted Editorial decision: Accepted 22 Apr, 2025 Reviewers agreed at journal 31 Mar, 2025 Reviewers invited by journal 28 Mar, 2025 Submission checks completed at journal 28 Mar, 2025 First submitted to journal 17 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5915486","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":436455799,"identity":"d46dae45-9fb0-4e3e-bf34-7ffee473cf60","order_by":0,"name":"Luana Fianchi","email":"data:image/png;base64,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","orcid":"","institution":"Fondazione Policlinico Universitario A. 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Ospedale Santa Chiara, Pisa","correspondingAuthor":false,"prefix":"","firstName":"Rita","middleName":"","lastName":"Fazzi","suffix":""},{"id":436455810,"identity":"a89233a0-5e57-4115-8b30-96269676525f","order_by":11,"name":"Crescenza Pasciolla","email":"","orcid":"","institution":"Istituto Tumori Bari","correspondingAuthor":false,"prefix":"","firstName":"Crescenza","middleName":"","lastName":"Pasciolla","suffix":""},{"id":436455811,"identity":"580e89f9-4ab8-4e2f-9950-d3476c00a50e","order_by":12,"name":"Olimpia Finizio","email":"","orcid":"","institution":"Ospedale Antonio Cardarelli, Napoli","correspondingAuthor":false,"prefix":"","firstName":"Olimpia","middleName":"","lastName":"Finizio","suffix":""},{"id":436455812,"identity":"92057d2f-1fed-489b-ba83-0c0ecfa68091","order_by":13,"name":"Nicola Fracchiolla","email":"","orcid":"","institution":"Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano","correspondingAuthor":false,"prefix":"","firstName":"Nicola","middleName":"","lastName":"Fracchiolla","suffix":""},{"id":436455813,"identity":"a663187a-efd6-45b1-bb28-123c75c5526a","order_by":14,"name":"Mario Delia","email":"","orcid":"","institution":"Azienda Universitaria Ospedaliera Consorziale - Policlinico Bari","correspondingAuthor":false,"prefix":"","firstName":"Mario","middleName":"","lastName":"Delia","suffix":""},{"id":436455814,"identity":"a8fb284c-68e4-4432-8db8-f6fcb66c21a5","order_by":15,"name":"Federica Lessi","email":"","orcid":"","institution":"Azienda Ospedaliera di Padova","correspondingAuthor":false,"prefix":"","firstName":"Federica","middleName":"","lastName":"Lessi","suffix":""},{"id":436455815,"identity":"e94e1407-6560-4277-90cf-40e39a5a1c3a","order_by":16,"name":"Michela Dargenio","email":"","orcid":"","institution":"Ospedale Vito Fazzi, Lecce","correspondingAuthor":false,"prefix":"","firstName":"Michela","middleName":"","lastName":"Dargenio","suffix":""},{"id":436455816,"identity":"409009ce-c5d6-495f-b2eb-0570a9a0227b","order_by":17,"name":"Valentina Bonuomo","email":"","orcid":"","institution":"Dipartimento di Scienze Cliniche e Biologiche, Università di Torino,","correspondingAuthor":false,"prefix":"","firstName":"Valentina","middleName":"","lastName":"Bonuomo","suffix":""},{"id":436455817,"identity":"9cae37fa-a25d-42c4-9f5c-6b21a2d51cf4","order_by":18,"name":"Maria Ilaria Del Principe","email":"","orcid":"","institution":"Policlinico Tor Vergata, Roma","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Ilaria Del","lastName":"Principe","suffix":""},{"id":436455818,"identity":"01ff14b3-7c46-4993-8473-3c4743ae5c64","order_by":19,"name":"Patrizia Zappasodi","email":"","orcid":"","institution":"Policlinico San Matteo Fondazione, Pavia","correspondingAuthor":false,"prefix":"","firstName":"Patrizia","middleName":"","lastName":"Zappasodi","suffix":""},{"id":436455819,"identity":"9be9c191-d829-48d6-869d-fdd27c2dfb30","order_by":20,"name":"Marco Picardi","email":"","orcid":"","institution":"Federico II University Hospital, Napoli","correspondingAuthor":false,"prefix":"","firstName":"Marco","middleName":"","lastName":"Picardi","suffix":""},{"id":436455820,"identity":"64364755-f456-4431-9221-da6531450d6e","order_by":21,"name":"Claudia Basilico","email":"","orcid":"","institution":"Azienda Socio Sanitaria Territoriale dei Sette Laghi, Varese","correspondingAuthor":false,"prefix":"","firstName":"Claudia","middleName":"","lastName":"Basilico","suffix":""},{"id":436455821,"identity":"85e2f897-1327-445a-bb78-ba66a07cfd05","order_by":22,"name":"Monica Piedimonte","email":"","orcid":"","institution":"Azienda Ospedaliera Sant'Andrea, Roma","correspondingAuthor":false,"prefix":"","firstName":"Monica","middleName":"","lastName":"Piedimonte","suffix":""},{"id":436455822,"identity":"41c263fb-3da4-4af8-9fc8-7107c6933fa2","order_by":23,"name":"Paola Minetto","email":"","orcid":"","institution":"Ospedale Policlinico San Martino, Genova","correspondingAuthor":false,"prefix":"","firstName":"Paola","middleName":"","lastName":"Minetto","suffix":""},{"id":436455823,"identity":"dbbb53fe-7f85-4b7f-b82c-4c7f2c1810b9","order_by":24,"name":"Patrizia Chiusolo","email":"","orcid":"","institution":"Fondazione Policlinico Universitario A. Gemelli, IRCCS, Università Cattolica del Sacro Cuore Roma","correspondingAuthor":false,"prefix":"","firstName":"Patrizia","middleName":"","lastName":"Chiusolo","suffix":""},{"id":436455824,"identity":"bb1a5bad-ba1a-49d3-9385-f50265af5cda","order_by":25,"name":"Lucia Prezioso","email":"","orcid":"","institution":"Ospedale di Parma","correspondingAuthor":false,"prefix":"","firstName":"Lucia","middleName":"","lastName":"Prezioso","suffix":""},{"id":436455825,"identity":"480b9c69-e4c2-417f-aa52-39345a903057","order_by":26,"name":"Caterina Buquicchio","email":"","orcid":"","institution":"Sc ematologia con trapianto, Ospedale Dimiccoli, Barletta","correspondingAuthor":false,"prefix":"","firstName":"Caterina","middleName":"","lastName":"Buquicchio","suffix":""},{"id":436455826,"identity":"cf09504a-d91d-4e8f-9a00-60a5eb6adb83","order_by":27,"name":"Lorella Melillo","email":"","orcid":"","institution":"Ematologia, Policlinico OU Foggia","correspondingAuthor":false,"prefix":"","firstName":"Lorella","middleName":"","lastName":"Melillo","suffix":""},{"id":436455827,"identity":"dbe66fe3-7669-41d5-8139-6fe512077c2e","order_by":28,"name":"Daniele Zama","email":"","orcid":"","institution":"Policlinico S.Orsola-Malpighi, Bologna","correspondingAuthor":false,"prefix":"","firstName":"Daniele","middleName":"","lastName":"Zama","suffix":""},{"id":436455828,"identity":"e382439a-867b-477e-8475-0d2161bdeec1","order_by":29,"name":"Francesca Farina","email":"","orcid":"","institution":"IRCCS Ospedale San Raffaele, Milano","correspondingAuthor":false,"prefix":"","firstName":"Francesca","middleName":"","lastName":"Farina","suffix":""},{"id":436455829,"identity":"20b05cc3-0324-4b21-9de4-39fb299e50a1","order_by":30,"name":"Valentina Mancini","email":"","orcid":"","institution":"Ospedale Niguarda Ca' Granda, Milano","correspondingAuthor":false,"prefix":"","firstName":"Valentina","middleName":"","lastName":"Mancini","suffix":""},{"id":436455830,"identity":"10262d06-1235-41fd-a009-5624cfa33ebe","order_by":31,"name":"Michela Rondoni","email":"","orcid":"","institution":"Azienda Unità Sanitaria Locale Della Romagna, Ravenna","correspondingAuthor":false,"prefix":"","firstName":"Michela","middleName":"","lastName":"Rondoni","suffix":""},{"id":436455831,"identity":"9acd02c4-cb88-40bc-974e-b735c8b44472","order_by":32,"name":"Alessandro Busca","email":"","orcid":"","institution":"Azienda Ospedaliera Citta' della Salute e della Scienza di Torino","correspondingAuthor":false,"prefix":"","firstName":"Alessandro","middleName":"","lastName":"Busca","suffix":""},{"id":436455832,"identity":"0f53ef18-e505-4f47-bbf2-77c2b961dc0d","order_by":33,"name":"Livio Pagano","email":"","orcid":"","institution":"Fondazione Policlinico Universitario A. Gemelli, IRCCS, Università Cattolica del Sacro Cuore Roma","correspondingAuthor":false,"prefix":"","firstName":"Livio","middleName":"","lastName":"Pagano","suffix":""}],"badges":[],"createdAt":"2025-01-28 01:08:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5915486/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5915486/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00277-025-06381-3","type":"published","date":"2025-05-24T15:58:43+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":79660033,"identity":"aa9089f3-232c-4202-b21f-3b68650fdb6e","added_by":"auto","created_at":"2025-04-01 09:29:27","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":251263,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curves for overall survival (OS) and event-free survival (EFS) in the real-life CPX-351 study (unweighted) versus its weighted estimates\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5915486/v1/4c77f601a60e6badcf7042fb.jpg"},{"id":83460149,"identity":"b869b122-3f46-4f12-9fe4-83197677986d","added_by":"auto","created_at":"2025-05-26 16:11:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":854049,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5915486/v1/9188681c-1b2e-45dc-be9f-bc1dd3e5e9be.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Matching-adjusted indirect comparison of CPX-351 in secondary Acute Myeloid Leukemia between the registrative trial and a real-life study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eApproximately a 25% of the total cases of acute myeloid leukemia (AML) are subsequent to previous hematological disorders (sAML) or developing after chemotherapy or radiotherapy (tAML) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Furthermore, AML with myelodysplasia-related changes (MRC-AML) is defined by the history of a myelodysplastic syndrome (MDS), signs of MDS-related cytogenetic abnormalities and/or dysplasia [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. All the above occur more frequently with advancing age and are associated with adverse genetics and multidrug resistance phenotype ([\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the last 40 years, the \u0026lsquo;7\u0026thinsp;+\u0026thinsp;3\u0026rsquo; regimens have been a standard for AML induction therapy (5). In older adults and patients with secondary AML, \u0026lsquo;7\u0026thinsp;+\u0026thinsp;3\u0026rsquo; induction is associated with lower remission rates, increased early mortality, and higher relapse rates than in younger adults and patients with de novo AML [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCPX-351 is a liposomal encapsulation of cytarabine and daunorubicin in a 5-to-1 molar ratio. The registration study with a trial comparing the classic \u0026lsquo;7\u0026thinsp;+\u0026thinsp;3\u0026rsquo; Vs. CPX-351 has demonstrated the greater efficacy in the treatment of sAML [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e CPX-351 has received Food and Drug Administration (FDA) in 2017 and European Medicine Agency (EMA) in 2018 approval for the treatment of adult patients with tAMLs, sAMLs, or MRC\u0026ndash;AML.\u003c/p\u003e \u003cp\u003eAfter the registration of CPX-351, several real-life studies have been performed to evaluate the efficacy and safety of this new formulation, and recently an Italian multicenter study demonstrated the low rate of infections and treatment-related mortality among 200 patients ]7].\u003c/p\u003e \u003cp\u003eIn this analysis, a real-life study on the use of CPX-351 and the standard arm (\u0026lsquo;7\u0026thinsp;+\u0026thinsp;3\u0026rsquo;) of the CPX-351 registrative trial in adults with sAML were compared by an unanchored Matching-adjusted indirect comparison (MAIC), in order to evaluate the efficacy and toxicity of CPX-351.\u003c/p\u003e"},{"header":"Methods and Patients","content":"\u003cp\u003eMAIC methodology use individual patient data (IPD) from trials of one treatment to match baseline summary statistics reported from trials of another treatment, while indirect comparisons based only on aggregate data can be limited by cross-trial differences in patient populations, differences in the definitions of outcome measures, and sensitivity to modelling assumptions. By combining IPD with published aggregate data, MAIC can reduce observed cross-trial differences that can be potentially either prognostic or treatment effect modifiers and provide decision makers with timely comparative evidence [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis analysis aimed to test the feasibility to compare individual patients\u0026rsquo; data with aggregated published results and evaluate the rate of infections of CPX-351 in real life vs the \u0026lsquo;7\u0026thinsp;+\u0026thinsp;3\u0026rsquo; regimen and their impact on the survival outcomes.\u003c/p\u003e \u003cp\u003e Patients-level data from GIMEMA-SEIFEM real-life study on the use of CPX-351, including all consecutive patients with AML from 30 Italian hematologic centers who received at least 1 course of CPX-351 from July 2018 to June 2021 according to clinical practice (n\u0026thinsp;=\u0026thinsp;200) was weighted for the aggregated patients\u0026rsquo; characteristics from the standard arm of the CPX-351 trial (\u0026lsquo;7\u0026thinsp;+\u0026thinsp;3\u0026rsquo; arm, n\u0026thinsp;=\u0026thinsp;156). The study was approved by the Ethics Committee of the coordinating center, Fondazione Policlinico Universitario Agostino Gemelli\u0026mdash;IRCCS, Universit\u0026agrave; Cattolica del Sacro Cuore of Rome, Italy (Study ID: 3405), and by the respective ethics committees of all participating centers. Written informed consent for data collection was obtained from each patient enrolled. The study was conducted according to the Declaration of Helsinki.\u003c/p\u003e \u003cp\u003eAccordingly, weighted Overall Survival and Event-Free Survival (w-OS, w-EFS) estimates, as well as rates of febrile neutropenia, fever of unknown origin (FUO), pneumonia, complete recovery (CR), and the interval of polymorphonuclear neutrophil (PMN) recovery, were computed.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eFive potential effect modifiers were identified and used for adjustment: age, sex, AML subtype (tAML, sAML, MDR), prior hypomethylating agents (HMA) exposure and transplant.\u003c/p\u003e \u003cp\u003eThe study included 200 patients treated with CPX-351 in a real-life setting across 30 Italian hematologic centers.\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e describes these characteristics in the original real-life study and adjusted.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePotential effect modifiers identified and used for adjustment: age, sex, AML subtype (tAML, sAML, MDR), prior hypomethylating agents (HMA) exposure and transplant in the original real-life study and adjusted\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGIMEMA-SEIFEM CPX-351\u003c/p\u003e \u003cp\u003ereal-life study\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCPX-351 trial (\u0026lsquo;7\u0026thinsp;+\u0026thinsp;3\u0026rsquo; arm)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdjusted\u003c/p\u003e \u003cp\u003eGIMEMA-SEIFEM CPX-351\u003c/p\u003e \u003cp\u003ereal-life study\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (median)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65yy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67yy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e67yy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex M/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAML subtype (tAML)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAML subtype (sAML)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e54%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAML subtype (MDR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior HMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e46%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTransplant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe median age of the cohort was 65 years, with a range spanning from 18 to 80 years. The gender distribution was balanced, with 51% of patients being male. Regarding disease classification, 26% of patients were diagnosed with therapy-related acute myeloid leukemia (tAML), 35% with secondary AML (sAML), and 39% with AML with myelodysplasia-related changes (MDR-AML). A history of prior exposure to hypomethylating agents (HMA) was documented in 20% of cases. A significant proportion of patients, amounting to 47%, underwent hematopoietic stem cell transplantation (HSCT) as part of their treatment.\u003c/p\u003e \u003cp\u003eTo ensure comparability between the real-world CPX-351 cohort and the \u0026lsquo;7\u0026thinsp;+\u0026thinsp;3\u0026rsquo; standard arm of the registrative trial, a Matching-Adjusted Indirect Comparison (MAIC) was performed. The adjustment process resulted in a more balanced patient distribution, aligning baseline characteristics between the two groups. After weighting, the median age increased from 65 to 67 years, while the percentage of patients with sAML rose from 35\u0026ndash;54%. The proportion of patients with prior HMA exposure increased from 20\u0026ndash;46%, and the rate of HSCT decreased from 47\u0026ndash;25%, reflecting a population more similar to that of the registrative trial.\u003c/p\u003e \u003cp\u003eIn terms of treatment response, the unadjusted rate of complete remission (CR) following CPX-351 treatment in the real-world cohort was 65%, which decreased to 55% after weighting. In contrast, the CR rate in the \u0026lsquo;7\u0026thinsp;+\u0026thinsp;3\u0026rsquo; arm of the registrative trial was 33.3%, demonstrating a higher response rate with CPX-351. The adjusted early mortality rate at 30 days and at 60 days was 3.8% and 11% respectively, compared to those observed in the registrative trial, where early mortality rates with CPX-351 and \u0026lsquo;7\u0026thinsp;+\u0026thinsp;3\u0026rsquo; were 5.9% and 10.6% at day 30, and 13.7% and 21.2% at day 60, respectively.\u003c/p\u003e \u003cp\u003eSurvival outcomes were also analyzed pre- and post-weighting \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. The observed median overall survival (OS) in the CPX-351 real-world cohort was 18 months, with a 95% confidence interval of 14 to 21 months. Following MAIC adjustment, the weighted median OS was 12 months, ranging from 8.5 to 14 months. In comparison, the median OS in the \u0026lsquo;7\u0026thinsp;+\u0026thinsp;3\u0026rsquo; arm of the registrative trial was notably lower, at 5.9 months (95% CI: 5.0-7.7). Similarly, the median event-free survival (EFS) in the real-world CPX-351 cohort was 11 months (95% CI: 7.6\u0026ndash;17), while the weighted EFS was reduced to 5.4 months (95% CI: 2.8\u0026ndash;9.8). The EFS in the \u0026lsquo;7\u0026thinsp;+\u0026thinsp;3\u0026rsquo; cohort remained markedly inferior at 1.3 months (95% CI: 1.0-1.6).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe study also evaluated the hematologic recovery profile and the incidence of infectious complications. The median time to polymorphonuclear neutrophil (PMN) recovery in the CPX-351 real-world cohort was 19 days, with a weighted median of 17.8 days, indicating a prolonged period of neutropenia but one that remained within the expected range for CPX-351 treatment. Febrile neutropenia (FN), defined according to Infectious Diseases Society of America (IDSA) criteria, grade 1\u0026ndash;4, was a frequent adverse event, with an incidence of 74% in the real-world setting, which increased slightly to 76% after MAIC adjustment. In the \u0026lsquo;7\u0026thinsp;+\u0026thinsp;3\u0026rsquo; arm of the registrative trial, the FN rate was reported at 70.9%. The incidence of fever of unknown origin (FUO) in CPX-351-treated patients was 37% before weighting and 33% post-weighting, while pneumonia was recorded in 12% of patients before weighting and 15% post-weighting.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn vitro studies showed that CPX-351 enhances drug synergy and extends the half-life of both drugs, improving their bone marrow penetration and accumulation [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, its pharmacokinetics lead to prolonged post-chemotherapy cytopenia, with neutropenia recovery around 36 days (vs. 32 days with traditional chemotherapy) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the phase II trial, nonhematologic common grade 3/4 adverse events included febrile neutropenia (34%), pneumonia (23%), and sepsis (16%) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In the randomized phase III trial, febrile neutropenia was the most frequent adverse event (68.0% vs. 70.9% in \u0026lsquo;7\u0026thinsp;+\u0026thinsp;3\u0026rsquo;), with infection-related grade 3 to 5 events occurring in 83.7% of CPX-351 patients vs. 86.1% in \u0026lsquo;7\u0026thinsp;+\u0026thinsp;3\u0026rsquo; [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In a French cohort, 91% had febrile neutropenia, 36% had pulmonary infections, and 10% were treated for invasive pulmonary aspergillosis [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In an early access program for older patients, febrile neutropenia (31%) and infections (6%) were the most common treatment-emergent adverse events [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe SEIFEM study confirmed CPX-351\u0026rsquo;s safety profile in real-world settings, with infectious complications similar to pivotal trials. Despite prolonged neutropenia, fungal infections were low (5.5%) and infection-related mortality was 6% [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe MAIC method in this study allowed for a robust comparison of two clinical trials in AML treatment, demonstrating its potential for comparing studies with large differences in patient selection. Baseline characteristics showed no significant sex distribution differences between groups. The GIMEMA-SEIFEM cohort was slightly younger, with different secondary AML subtypes. Notably, fewer patients (20%) in the real-life study had prior hypomethylating agents compared to the adjusted group (46%), and more patients (47%) in the real-life study underwent transplants compared to the post-weighted group (25%). This disparity likely impacts survival outcomes, reflecting probably a greater real-world experience with the drug.\u003c/p\u003e \u003cp\u003eSurvival outcomes in the real-life cohort were better than the registration trial\u0026rsquo;s median values, even after adjustment. In this MAIC analysis, CPX-351 showed higher OS and EFS compared to \u0026lsquo;7\u0026thinsp;+\u0026thinsp;3\u0026rsquo;. Safety data indicated similar recovery times for PMN and comparable infectious outcomes, with febrile neutropenia being the main difference. Pneumonia risk was lower in the CPX-351 group than in the \u0026lsquo;7\u0026thinsp;+\u0026thinsp;3\u0026rsquo; arm.\u003c/p\u003e \u003cp\u003eUltimately the data obtained by this MAIC gives us back the profile of an easy-to-handle drug; this can be considered of utmost importance, because the target population is mainly a fragile population, often with a history of a previous neoplasm or myelodysplasia which leads to an increased risk of complications.\u003c/p\u003e \u003cp\u003eThe Kaplan-Meier Survival curves, even adjusted, show better results of CPX-351 therapy compared to conventional cytarabine plus daunorubicin regimen.\u003c/p\u003e \u003cp\u003eIn conclusion, results of this study are important to confirm the role of CPX-351 in significantly improving survival and remission rates compared with \u0026lsquo;7\u0026thinsp;+\u0026thinsp;3\u0026rsquo; with a good safety profile in AML patients with high-risk features, as sAML or therapy-related AML, a target group traditionally with a very poor prognosis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthorship and Conflict-of-Interest Statements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLF, AP\u0026nbsp;and\u0026nbsp;LP\u0026nbsp;conceived and designed the work that led to the submission, acquired data, and played an important role in interpreting the results; drafted the manuscript, approved the final version, agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolve;\u0026nbsp;AP\u0026nbsp;and GM performed also the statistical analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFG, FM, CC, MG, FR, AC, EOLB, RF, CP; OF, NF, MD, FL, MD, VB, MIDP, PZ, MP, CB, MP, PM, PC, LP, CB, LM, DZ, FF, VM, MR, AB\u0026nbsp;acquired data, played an important role in interpreting the results the manuscript and approved the final version.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was not supported by research funding or grant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData sharing will be available upon request to the Corresponding Author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGuolo F, Fianchi L, Minetto P, Clavio M, Gottardi M, Galimberti S, et al. CPX-351 treatment in secondary acute myeloblastic leukemia is effective and improves the feasibility of allogeneic stem cell transplantation: results of the Italian compassionate use program. Blood Cancer J [Internet]. 2020 Oct 1 [cited 2024 Mar 31];10(10). Available from: https://pubmed.ncbi.nlm.nih.gov/33024084/\u003c/li\u003e\n\u003cli\u003eArber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood [Internet]. 2016 May 19 [cited 2024 Mar 31];127(20):2391\u0026ndash;405. Available from: https://pubmed.ncbi.nlm.nih.gov/27069254/\u003c/li\u003e\n\u003cli\u003e\u0026Oslash;stg\u0026aring;rd LSG, Medeiros BC, Sengel\u0026oslash;v H, N\u0026oslash;rgaard M, Andersen MK, Dufva I, et al. Epidemiology and Clinical Significance of Secondary and Therapy-Related Acute Myeloid Leukemia: A National Population-Based Cohort Study. J Clin Oncol [Internet]. 2015 Nov 1 [cited 2024 Mar 31];33(31):3641\u0026ndash;9. Available from: https://pubmed.ncbi.nlm.nih.gov/26304885/\u003c/li\u003e\n\u003cli\u003eNagel G, Weber D, Fromm E, Erhardt S, L\u0026uuml;bbert M, Fiedler W, et al. Epidemiological, genetic, and clinical characterization by age of newly diagnosed acute myeloid leukemia based on an academic population-based registry study (AMLSG BiO). Ann Hematol [Internet]. 2017 Dec 1 [cited 2024 Mar 31];96(12):1993\u0026ndash;2003. Available from: https://pubmed.ncbi.nlm.nih.gov/29090343/\u003c/li\u003e\n\u003cli\u003eLancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, et al. CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia. J Clin Oncol [Internet]. 2018 Sep 10 [cited 2024 Mar 31];36(26):2684\u0026ndash;92. Available from: https://pubmed.ncbi.nlm.nih.gov/30024784/\u003c/li\u003e\n\u003cli\u003eLancet JE, Uy GL, Newell LF, Lin TL, Ritchie EK, Stuart RK, et al. CPX-351 versus 7+3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial. Lancet Haematol [Internet]. 2021 Jul 1 [cited 2024 Mar 31];8(7):e481\u0026ndash;91. Available from: https://pubmed.ncbi.nlm.nih.gov/34171279/\u003c/li\u003e\n\u003cli\u003eFianchi L, Guolo F, Marchesi F, Cattaneo C, Gottardi M, Restuccia F, et al. Multicenter Observational Retrospective Study on Febrile Events in Patients with Acute Myeloid Leukemia Treated with Cpx-351 in \u0026ldquo;Real-Life\u0026rdquo;: The SEIFEM Experience. Cancers (Basel) [Internet]. 2023 Jul 1 [cited 2024 Mar 31];15(13). Available from: https://pubmed.ncbi.nlm.nih.gov/37444567/\u003c/li\u003e\n\u003cli\u003eSignorovitch JE, Sikirica V, Erder MH, Xie J, Lu M, Hodgkins PS, et al. Matching-adjusted indirect comparisons: a new tool for timely comparative effectiveness research. Value Health [Internet]. 2012 Sep [cited 2024 Mar 31];15(6):940\u0026ndash;7. Available from: https://pubmed.ncbi.nlm.nih.gov/22999145/\u003c/li\u003e\n\u003cli\u003eCortes JE, Goldberg SL, Feldman EJ, Rizzeri DA, Hogge DE, Larson M, et al. Phase II, multicenter, randomized trial of CPX-351 (cytarabine:daunorubicin) liposome injection versus intensive salvage therapy in adults with first relapse AML. Cancer [Internet]. 2015 Jan 15 [cited 2024 Mar 31];121(2):234\u0026ndash;42. Available from: https://pubmed.ncbi.nlm.nih.gov/25223583/\u003c/li\u003e\n\u003cli\u003eLancet JE, Cortes JE, Hogge DE, Tallman MS, Kovacsovics TJ, Damon LE, et al. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood [Internet]. 2014 May 22 [cited 2024 Mar 31];123(21):3239\u0026ndash;46. Available from: https://pubmed.ncbi.nlm.nih.gov/24687088/\u003c/li\u003e\n\u003cli\u003eIssa GC, Kantarjian HM, Xiao L, Ning J, Alvarado Y, Borthakur G, et al. Phase II trial of CPX-351 in patients with acute myeloid leukemia at high risk for induction mortality. Leukemia 2020 34:11 [Internet]. 2020 Jun 16 [cited 2024 Sep 5];34(11):2914\u0026ndash;24. Available from: https://www.nature.com/articles/s41375-020-0916-8\u003c/li\u003e\n\u003cli\u003eChiche E, Rahme R, Bertoli S, Dumas PY, Micol JB, Hicheri Y, et al. Real-life experience with CPX-351 and impact on the outcome of high-risk AML patients: a multicentric French cohort. Blood Adv [Internet]. 2021 Jan 12 [cited 2024 Sep 5];5(1):176\u0026ndash;84. Available from: https://dx.doi.org/10.1182/bloodadvances.2020003159\u003c/li\u003e\n\u003cli\u003eRoboz GJ, Larson ML, Rubenstein SE, Solomon SR, Schiller GJ, An Q, et al. Final safety and efficacy results from the CPX-351 early access program for older patients with high-risk or secondary acute myeloid leukemia. Leuk Lymphoma [Internet]. 2020 Apr 15 [cited 2024 Sep 5];61(5):1188\u0026ndash;94. Available from: https://www.tandfonline.com/doi/abs/10.1080/10428194.2020.1725503\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Secondary acute myeloid leukemia, CPX-351, Matching-adjusted indirect comparison","lastPublishedDoi":"10.21203/rs.3.rs-5915486/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5915486/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eA real-life study on CPX-351 and the standard arm (\u0026lsquo;7\u0026thinsp;+\u0026thinsp;3\u0026rsquo;) of the CPX-351 registrative trial in adults with secondary Acute Myeloid Leukemia were compared by an unanchored Matching-adjusted indirect comparison (MAIC), in order to evaluate the efficacy and toxicity of CPX-351.\u003c/p\u003e \u003cp\u003eResults of this study are important to confirm the role of CPX-351 in significantly improving survival and remission rates compared with \u0026lsquo;7\u0026thinsp;+\u0026thinsp;3\u0026rsquo; with a good safety profile in AML patients with high-risk features, a target group traditionally with a very poor prognosis. 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