Long term treatment of sirolimus for pediatric vascular anomaly

Long term treatment of sirolimus for pediatric vascular anomaly | 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 Long term treatment of sirolimus for pediatric vascular anomaly Jueun Park, Hyunhee Kwon, Dae Yeon Kim, Seong Chul Kim, Jung-Man Namgoong, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9084188/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background Although sirolimus has emerged a safe and effective treatment modality for unresectable vascular anomlaies, comprehensive long-term follow-up data remain scarce in the current literature. This study aims to evaluate the long-term clinical experience of pediatric patients with vascular anomalies who received sirolimus treatment over five years. Methods We retrospectively analysed 17 pediatric patients with vascular anomalies treated with sirolimus over five years in Asan Medical Center. Lesion volumes were measured via 3D volumetric MRI and normalized to body surface area (BSA). Adverse drug effects and therapeutic responses were periodically assessed. Longitudinal response was modeled using generalized additive mixed-effects models (GAMM). Tapering protocols were initiated after 24 months of stability, and alpelisib switch was considered for sirolimus-refractory cases with documented PIK3CA mutations. Results With a median follow-up of 78 months, the overall response rate was 81.3%. GAMM analysis demonstrated a significant non-linear volume reduction (p < 0.0001), characterized by a rapid initial response within 12–24 months followed by a sustained plateau. Tapering was successful in 70.6% of patients without disease progression. Three patients with suboptimal responses transitioned to alpelisib; those with sufficient follow-up achieved additional volume reduction within 12 months. Long-term sirolimus use was well-tolerated, with no Grade ≥ 3 adverse events reported. Conclusion Sirolimus provides sustained long-term efficacy and safety in pediatric vascular anomalies. The observed treatment plateau suggests that dose tapering is a viable strategy for sustained responders. Furthermore, genotype-guided transition to alpelisib offers an effective alternative for refractory PIK3CA-mutant cases. Pediatrics Vascular anomaly Medical Genetics Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Pediatric vascular anomalies (VAs) are a heterogeneous group of conditions ranging from benign hemangiomas to life-threatening malformations.[1] Complex or infiltrating vascular anomalies can cause significant functional impairment and morbidity. Traditional interventions, including surgery and sclerotherapy, often face limitations due to the diffuse nature of these lesions and high recurrence rates.[2] The identification of the PI3K/AKT/mTOR signaling pathway as a key driver in VA pathogenesis has revolutionized therapeutic approaches.[3] Sirolimus (Rapamycin), an mTOR inhibitor, has subsequently emerged as a standard medical therapy, with clinical trials demonstrating its safety and significant short-term volumetric responses.[2, 4–8] Despite these advancements, the existing literature primarily focuses on short-to-intermediate follow-up periods [8–10]. Crucial data regarding long-term durability of response, relapse patterns after cessation, and cumulative safety profiles remain scarce. Furthermore, management strategies for patients exhibiting suboptimal responses to prolonged sirolimus monotherapy are not well-defined. This study reports our institutional experience with sirolimus treatment over an extended follow-up period, exceeding five years. We evaluate sustained volumetric responses, long-term safety, and clinical outcomes of transition to Alpelisib in sirolimus-refractory cases, aiming to optimize the long-term management algorithm for complex pediatric VAs. Methods Study Design and Patient Selection This retrospective cohort study was conducted at Asan Medical Center. We included pediatric patients with complicated vascular anomalies who initiated sirolimus treatment since January 2018 and completed at least 5 years of follow-up. Complicated vascular anomalies were defined as lesions that were unresectable, had failed conventional therapies (sclerotherapy or surgical intervention), or posed significant functional or cosmetic concerns. The study protocol was approved by the Institutional Review Board of Asan Medical Center. Treatment Protocol Sirolimus was administered orally at an initial dose of 0.8 mg/m² body surface area (BSA) twice daily. Dosing was adjusted to achieve target trough levels of 8–12 ng/mL. Trough levels were monitored every 2–4 weeks during the initial 3 months, then every 3 months once stable levels were achieved. Initially, tissue biopsy was not routinely performed as the diagnosis was primarily established through clinical and radiologic evaluation. However, biopsy was indicated in specific cases to exclude malignancy when radiologic features were inconclusive or to facilitate molecular profiling in patients exhibiting a suboptimal response to sirolimus. In cases of limited response to sirolimus after 24–36 months of treatment, particularly when PIK3CA mutations were identified on tissue biopsy, switching to alpelisib (PI3Kα-specific inhibitor) was considered. For patients demonstrating sustained treatment response and stable lesion volumes for at least 24 months, medication tapering was initiated. The tapering protocol consisted of reducing from twice-daily to once-daily dosing while maintaining the same single-dose amount, followed by a thrice-weekly regimen. Patients were closely monitored with clinical assessments and imaging during the tapering period. Imaging Assessment and Response Evaluation Magnetic resonance imaging (MRI) was performed at baseline and every 12 months thereafter. Lesion volumes were measured on T2-weighted fat-suppressed sequences by a blinded pediatric surgeon using 3D volumetric analysis. To adjust for pediatric growth, all volumes were normalized to the patient’s body surface area (BSA) at each scan. Treatment response was defined by the percentage change in normalized volume from baseline. Complete Response (CR) was defined as a reduction ≥ 95%. Partial Response (PR) was subcategorized as Significant (≥ 50%), Moderate (20–50%), or Modest (< 20%) reduction. Progressive Disease (PD) was defined as any volume increase. The overall response rate (ORR) represented the proportion of patients achieving CR or PR at the final follow-up. Safety Assessment Adverse events were monitored through clinical assessment at each outpatient visit (every 3 months) and laboratory testing including complete blood count, liver function tests, lipid profile, and renal function tests. Adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Statistical Analysis Continuous variables were expressed as median (IQR) or mean (SD), and categorical variables as frequencies (%). Longitudinal changes in normalized volumes were analyzed using generalized additive mixed-effects models (GAMM) with random intercepts to account for individual variability and non-linear trajectories. Sensitivity analyses were conducted with and without these two patients to assess the robustness of the observed trends, given that they demonstrated marked volumetric increases that disproportionately influenced the overall model fit. The primary findings are presented based on models that best reflected the dominant response pattern in the cohort, while acknowledging heterogeneity of trajectories. For patients switching to alpelisib, only MRI data obtained during sirolimus therapy were included. One patient (Patient 16) was excluded from normalized volume analysis due to missing baseline BSA data. Interaction terms were interpreted cautiously and no adjustments for multiple comparisons were applied, as the subgroup analyses (age at initiation and lesion location) were exploratory in nature. Statistical significance was defined as p < 0.05 using R version 4.2.1. Results Patient Demographics and Baseline Clinical Characteristics A total of 17 patients (9 females, 8 males) with complicated vascular anomalies were included in this study. The median follow-up duration was 78 months (IQR: 73–84 months), with a median sirolimus treatment duration of 42 months (IQR: 37–48 months). The median age at treatment initiation was 57 months (IQR: 13–110 months). The presenting symptom was a mass in 13 patients (76.5%), airway obstruction in 2 patients (11.8%), and pain in 2 patients (11.8%). Regarding timing of diagnosis, 12 patients (70.6%) were diagnosed prenatally by ultrasound, 2 (11.8%) at birth, and 3 (17.6%) during the growth period. The primary lesion locations were head and neck in 9 patients (52.9%), extremities in 6 patients (35.3%), and trunk in 2 patients (11.8%). The most common diagnosis was lymphatic malformation (LM) in 11 patients (64.7%), followed by lymphaticovenous malformation (LVM) in 4 patients (23.5%), venous malformation (VM) in 1 patient (5.9%), and Kaposiform hemangioendothelioma in 1 patient (5.9%). PIK3CA mutation analysis was performed in 7 patients (41.2%). Among these, mutations were detected in 5 patients, including H1047L (n = 1), H1047R (n = 1), E545K (n = 1), and E542K (n = 1). Two patients had negative mutation results, and 10 patients did not undergo genetic testing. Detailed patient characteristics are summarized in Table 1. Treatment Patterns and Response During follow-up of sirolimus therapy, 12 patients (70.6%) successfully underwent medication tapering without disease progression. One patient experienced relapse after complete discontinuation but responded well to reinitiation. Three patients (17.6%) were switched to alpelisib due to suboptimal response (n = 1), recurrent infections (n = 1), or cellulitis (n = 1). One patient ceased treatment after achieving a complete response (CR) without recurrence (Fig. 1–1). The overall response rate (ORR) was 81.3% (13/16 evaluated), with 2 patients achieving CR (12.5%) and 11 achieving a partial response (PR, 68.8%). Among those with PR, 6 demonstrated significant (≥ 50%), 3 moderate (20–50%), and 2 modest (< 20%) volume reduction. Three patients (18.8%) exhibited progressive disease (Fig. 1– 2 ). The median change in normalized lesion volume was − 45% (IQR: -69% to + 11%), reflecting a consistent trend toward volumetric reduction across the cohort. Figure 2 − 1 presents a spaghetti plot illustrating the longitudinal trajectories of normalized lesion volumes for the entire cohort (N = 17). The plot demonstrates substantial heterogeneity in individual responses, ranging from near-complete regression to progressive enlargement. An initial linear mixed-effects model did not adequately capture these longitudinal patterns (p = 0.9492), likely reflecting non-linearity in treatment trajectories. Therefore, a flexible additive mixed-effects framework was employed to better model these dynamics, and sensitivity analyses were conducted to evaluate the influence of extreme trajectories on model stability. The resulting model (Fig. 2 – 2 ) demonstrated a significant non-linear association between treatment duration and volume change (smooth term F = 18.57, p < .0001; edf = 2.71). The fitted curve indicates a rapid reduction in lesion volume during the first 12–24 months, followed by relative stabilization. Although a continued decline is visually suggested beyond 60 months, statistical certainty in this extended period is limited by reduced sample size. Overall, the most robust finding is the early therapeutic reduction and subsequent maintenance of treatment gains. Although no statistically significant difference was observed (interaction p = 0.428; Fig. 3 ), patients treated before 2 years of age demonstrated a more pronounced trend toward volume reduction over time compared with those treated at ≥ 2 years of age (slope = − 1.65 vs. −0.32). Lesion Location (head and neck, trunk, extremities) showed no statistically significant differences in treatment response trajectories among groups (interaction p = 0.612) (Fig. 4 ). However, visual examination of the fitted regression lines suggested a trend toward greater volume reduction in patients with head and neck lesions (slope = -1.23) and trunk lesions (slope = -0.87) compared to extremity lesions (slope = + 0.42), though these differences did not reach statistical significance in our limited sample size. Adverse events during sirolimus treatment were generally mild and manageable. No Grade 3 or higher adverse events related to sirolimus were documented. The most common adverse event was upper respiratory tract infection, occurring in 6 patients (35.3%). Oral ulcers developed in 3 patients (17.6%), and single occurrences of diarrhea, skin rash, and menstrual irregularity were observed (5.9% each). Patient 3's switch to alpelisib was motivated by both recurrent infections affecting daily activities and suboptimal disease control rather than severe toxicity. Response to Alpelisib Switch Three patients were switched from sirolimus to alpelisib after 44–48 months of sirolimus treatment. Patient 3 and Patient 16, who had adequate follow-up after the switch (> 12 months), demonstrated clinical improvement with reduction in lesion size on volumetric MRI, showing 42% and 38% decreases, respectively, within 12 months of alpelisib initiation. Discussion This study presents one of the longest follow-up experiences with sirolimus treatment for pediatric vascular anomalies, with a median follow-up of 78 months. Our findings demonstrate that sirolimus maintains a favorable safety profile with long-term use and achieves an overall response rate of 81%, consistent with previously reported short-term studies.[8–10] However, our longitudinal analysis reveals important insights into the temporal dynamics of treatment response and identifies clinical scenarios where alternative therapeutic strategies may be considered. In our study, most responding patients demonstrated lesion volume reduction during the initial 12–24 months of treatment, whereas subsequent measurements showed minimal additional change. As a result, the overall longitudinal model did not demonstrate a statistically significant trend in continued volume reduction (p = 0.949). This pattern may indicate that the therapeutic effect of sirolimus reaches a plateau after approximately two years of treatment, with important implications for treatment duration and monitoring strategies. The biological basis for this plateau effect remains unclear but may reflect several mechanisms. First, sirolimus is primarily cytostatic rather than cytolytic; it suppresses cell proliferation and angiogenesis without directly inducing cell death [11]. Consequently, volume reduction may reach a limit once maximal inhibition of these processes is achieved. Second, feedback activation of compensatory signaling pathways, such as PI3K/AKT reactivation through mTORC2 or receptor tyrosine kinase upregulation, may limit efficacy over time.[12, 13]. Finally, chronic vascular anomalies involve secondary structural changes – including fibrosis, adipose accumulation, and lymphatic congestion – that are irreversible by mTOR inhibition once tissue remodeling is established. These observations support a treatment strategy of intensive monitoring during the first 24 months, followed by consideration of medication tapering in responding patients or switch to alternative agents in those with minimal response. Our tapering protocol, successfully implemented in 71% of patients, allowed for reduced medication exposure while maintaining disease control in most cases. Based on the spaghetti plot, the heterogeneity in treatment response likely reflects diverse molecular pathogenesis and lesion-specific biology. Although PIK3CA mutation analysis was limited to 41.2% of our cohort, Venot et al. reported that specific PIK3CA mutation variants are associated with differential sensitivity to mTOR inhibitors versus PI3K inhibitors, suggesting a potential role for genotype-driven therapeutic selection [14]. These findings highlight the clinical relevance of molecular heterogeneity and support the importance of molecular profiling in the management of vascular anomalies. An important contribution of our study is the demonstration that patients with limited response to long-term sirolimus therapy may benefit from switching to alpelisib, particularly when PIK3CA mutations are identified. Two of three patients who switched to alpelisib achieved substantial clinical improvement after 24–36 months of minimal response to sirolimus. This observation aligns with emerging evidence that direct PI3K inhibition may overcome resistance mechanisms that limit mTOR inhibitor efficacy. [15, 16] Alpelisib, as a PI3Kα-specific inhibitor, directly targets the mutant PIK3CA enzyme, potentially providing more complete pathway suppression.[17] However, alpelisib use is associated with distinct toxicity profiles, most notably hyperglycemia due to inhibition of insulin signaling.[18] Patient 1's development of elevated HbA1C exemplifies this concern and necessitates careful metabolic monitoring and potentially earlier intervention. The substantially higher cost of alpelisib compared to sirolimus also represents a practical barrier to its widespread use, emphasizing the importance of patient selection and molecular confirmation before switching. Our findings support a treatment algorithm wherein sirolimus remains the preferred first-line agent for complicated vascular anomalies, with consideration of alpelisib switch after 24–36 months in patients with documented PIK3CA mutations who demonstrate minimal response to adequate sirolimus therapy. Tissue biopsy for molecular analysis should be strongly considered in cases of suboptimal response to guide subsequent therapeutic decisions. While our subgroup analyses by lesion location did not reveal statistically significant differences, trends observed in the data merit discussion. Patients with head and neck lesions and trunk lesions appeared to demonstrate better responses compared to extremity lesions. This observation may reflect differences in lesion biology by anatomic site, with extremity lesions potentially having greater involvement of muscular and connective tissue structures that respond less favorably to medical therapy. Alternatively, different developmental timing and vascular bed characteristics in various anatomic locations may influence treatment response. The trend toward better outcomes in patients starting treatment before 2 years of age, though not statistically significant in our cohort, aligns with previous suggestions that earlier intervention may prevent progressive expansion and anatomic complications.[19] Prospective studies with larger sample sizes are needed to definitively establish whether age at treatment initiation predicts long-term outcomes. This study has several limitations, including its retrospective single-center design, small sample size, and heterogeneity of lesion types, which limit generalizability and statistical power, particularly for subgroup analyses. Incomplete PIK3CA mutation analysis restricts robust genotype–phenotype correlations, and the absence of a control group precludes definitive attribution of volume changes solely to sirolimus, although prior randomized data have demonstrated its superiority over observation [9]. In addition, reliance on volumetric imaging may not fully capture clinically meaningful outcomes, and the limited experience with alpelisib, involving only three patients with short follow-up, prevents definitive conclusions regarding optimal switching strategies and long-term safety and efficacy. Larger multicenter collaborations are needed to establish evidence-based guidelines for managing sirolimus-resistant cases. Conclusion In conclusion, sirolimus demonstrated sustained long-term efficacy and acceptable safety in pediatric patients with complicated vascular anomalies. In patients with limited response, particularly those harboring PIK3CA mutations, transition to PI3K-targeted therapy may represent a reasonable consideration. Future multicenter prospective studies incorporating systematic molecular profiling are needed to refine long-term treatment algorithms. Abbreviations BSA Body surface area CR Complete response CTCAE Common Terminology Criteria for Adverse Events GAMM Generalized additive mixed-effects model LM Lymphatic malformation LVM Lymphaticovenous malformation MRI Magnetic resonance imaging ORR Overall response rate PD Progressive disease PR Partial response VAs Vascular anomalies VM Venous malformation mTOR Mechanistic target of rapamycin PIK3CA Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha Declarations Ethics approval and consent to participate This study was approved by the Institutional Review Board of Asan Medical Center and was conducted in accordance with the Declaration of Helsinki. The requirement for informed consent was waived due to the retrospective nature of the study. Consent for publication Not applicable. Availability of data and materials The datasets generated and/or analyzed during the current study are not publicly available due to patient privacy and institutional regulations but are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding This research received no external funding. Authors’ contributions YJ.C conceived and designed the study. J.P collected clinical data. J.P performed the statistical analysis. All authors contributed to manuscript drafting and critically revised the manuscript. All authors read and approved the final manuscript. Acknowledgements The authors thank the clinical staff of Asan Medical Center for their support in patient care and data collection. References Wassef, M., et al., [Classification of vascular tumours and vascular malformations. Contribution of the ISSVA 2014/2018 classification]. Ann Pathol, 2021. 41 (1): p. 58-70. Hammill, A.M., et al., Sirolimus for the treatment of complicated vascular anomalies in children. Pediatr Blood Cancer, 2011. 57 (6): p. 1018-24. Luks, V.L., et al., Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA. J Pediatr, 2015. 166 (4): p. 1048-54 e1-5. Ozeki, M., et al., The impact of sirolimus therapy on lesion size, clinical symptoms, and quality of life of patients with lymphatic anomalies. Orphanet J Rare Dis, 2019. 14 (1): p. 141. Mack, J.M., et al., Effect of sirolimus on coagulopathy of slow-flow vascular malformations. Pediatr Blood Cancer, 2019. 66 (10): p. e27896. Gabeff, R., et al., Efficacy and Tolerance of Sirolimus (Rapamycin) for Extracranial Arteriovenous Malformations in Children and Adults. Acta Derm Venereol, 2019. 99 (12): p. 1105-1109. Ji, Y., et al., Sirolimus for the treatment of progressive kaposiform hemangioendothelioma: A multicenter retrospective study. Int J Cancer, 2017. 141 (4): p. 848-855. Adams, D.M., et al., Efficacy and Safety of Sirolimus in the Treatment of Complicated Vascular Anomalies. Pediatrics, 2016. 137 (2): p. e20153257. Maruani, A., et al., Sirolimus (Rapamycin) for Slow-Flow Malformations in Children: The Observational-Phase Randomized Clinical PERFORMUS Trial. JAMA Dermatol, 2021. 157 (11): p. 1289-1298. Ji, Y., et al., A prospective multicenter study of sirolimus for complicated vascular anomalies. J Vasc Surg, 2021. 74 (5): p. 1673-1681 e3. Benjamin, D., et al., Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat Rev Drug Discov, 2011. 10 (11): p. 868-80. O'Reilly, K.E., et al., mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res, 2006. 66 (3): p. 1500-8. Rodrik-Outmezguine, V.S., et al., mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. Cancer Discov, 2011. 1 (3): p. 248-59. Venot, Q., et al., Targeted therapy in patients with PIK3CA-related overgrowth syndrome. Nature, 2018. 558 (7711): p. 540-546. Sun, S.Y., et al., Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res, 2005. 65 (16): p. 7052-8. Rozengurt, E., H.P. Soares, and J. Sinnet-Smith, Suppression of feedback loops mediated by PI3K/mTOR induces multiple overactivation of compensatory pathways: an unintended consequence leading to drug resistance. Mol Cancer Ther, 2014. 13 (11): p. 2477-88. Canaud, G., et al., Alpelisib for treatment of patients with PIK3CA-related overgrowth spectrum (PROS). Genet Med, 2023. 25 (12): p. 100969. Andre, F., et al., Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med, 2019. 380 (20): p. 1929-1940. Balakrishnan, K., et al., Primary surgery vs primary sclerotherapy for head and neck lymphatic malformations. JAMA Otolaryngol Head Neck Surg, 2014. 140 (1): p. 41-5. Tables Table 1 is available in the Supplementary Files section. Supplementary Files Table1.xlsx Table 1. Baseline demographic and clinical characteristics of the study cohort (N=17) Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 21 Apr, 2026 Reviewers invited by journal 21 Apr, 2026 Editor invited by journal 23 Mar, 2026 Editor assigned by journal 19 Mar, 2026 First submitted to journal 18 Mar, 2026 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. 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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-9084188","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":626937546,"identity":"1184827f-8262-4aaa-8b3a-677e72abe835","order_by":0,"name":"Jueun Park","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0UlEQVRIiWNgGAWjYBACxgYwZSPHD6ISCojXkmYsCWIkGBBv2eHEDQdANDFamGckH5Mu3HGYcfP51YkfHhgwyPOLHSDgsBlpadIzz6Qzm914u1kC6DDDmbMTCGnJMZPmbbNmM7txdgNIS4LBbYJa8r8BtTDzGM84u/kHkVpy2IBanCUM+Hu3EWlLzzNja94zaQYSN3i3WSQYSBD2i2F78sPbvDts6vv7z26++aPCRp5fmpCWBgZofEqAVUrgVw4C8gwwLfwHCKseBaNgFIyCkQkA7u5DEIOmaOsAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-4609-0502","institution":"Inje University Busan Paik Hospital","correspondingAuthor":true,"prefix":"","firstName":"Jueun","middleName":"","lastName":"Park","suffix":""},{"id":626937547,"identity":"e306508d-b52d-465e-9726-6c087615dbf8","order_by":1,"name":"Hyunhee Kwon","email":"","orcid":"","institution":"Asan Medical Center Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hyunhee","middleName":"","lastName":"Kwon","suffix":""},{"id":626937548,"identity":"da0bb3ff-0133-41cd-92e1-745ccc6786df","order_by":2,"name":"Dae Yeon Kim","email":"","orcid":"","institution":"Asan Medical Center Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Dae","middleName":"Yeon","lastName":"Kim","suffix":""},{"id":626937549,"identity":"c51fde9a-7ec7-4b0f-a47a-774291853307","order_by":3,"name":"Seong Chul Kim","email":"","orcid":"","institution":"Asan Medical Center Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Seong","middleName":"Chul","lastName":"Kim","suffix":""},{"id":626937551,"identity":"a2f6f5b8-2a24-4ab6-9b84-49f77dfd48a4","order_by":4,"name":"Jung-Man Namgoong","email":"","orcid":"","institution":"Asan Medical Center Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jung-Man","middleName":"","lastName":"Namgoong","suffix":""},{"id":626937553,"identity":"6de67661-3e17-4b1f-b5e8-3c9bbe498550","order_by":5,"name":"Yu Jeong Cho","email":"","orcid":"https://orcid.org/0000-0001-6823-2746","institution":"Hanyang University Guri Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yu","middleName":"Jeong","lastName":"Cho","suffix":""}],"badges":[],"createdAt":"2026-03-10 12:47:47","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9084188/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9084188/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108492918,"identity":"f568e6bb-d88b-44b9-a1d8-77552031e58c","added_by":"auto","created_at":"2026-05-05 09:58:59","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":30145,"visible":true,"origin":"","legend":"\u003cp\u003eFigure 1-1. Treatment patterns in patients with vascular anomalies (N=17).\u003c/p\u003e","description":"","filename":"image1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-9084188/v1/3741ccf092d1151746b3c5aa.jpeg"},{"id":108385742,"identity":"0af9c09f-30db-48e0-aaef-caf92692aa54","added_by":"auto","created_at":"2026-05-04 06:05:03","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":34760,"visible":true,"origin":"","legend":"\u003cp\u003eFigure 1-2. Overall treatment response based on volumetric analysis (N=16). One patient was excluded from this volumetric analysis due to the absence of baseline body surface area (BSA) data required for normalization.\u003c/p\u003e","description":"","filename":"image2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-9084188/v1/2458f90e3e354ca9fd31f5c5.jpeg"},{"id":108493188,"identity":"88ffb3e6-f67a-4fb1-9f60-2b1597aedb20","added_by":"auto","created_at":"2026-05-05 09:59:35","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":13470,"visible":true,"origin":"","legend":"\u003cp\u003eFigure 2-1. Spaghetti Plot of Response Profiles over Time\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-9084188/v1/d7b4eb2f7b1332cc440fd934.png"},{"id":108385745,"identity":"018a3da4-5c53-4e46-b244-496ad0621166","added_by":"auto","created_at":"2026-05-04 06:05:03","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":19176,"visible":true,"origin":"","legend":"\u003cp\u003eFigure 2-2. Results from analysis of generalized additive mixed-effects model with random intercept for each subject\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-9084188/v1/3ebe18f3856749fb14a640fe.png"},{"id":108492908,"identity":"82b6e53e-f1fd-417e-94fa-25963d6f0db3","added_by":"auto","created_at":"2026-05-05 09:58:57","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":16352,"visible":true,"origin":"","legend":"\u003cp\u003eFigure 3. Spaghetti Plot of Response Profiles over Time by Start over 2yrs\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-9084188/v1/d428baf78870239b22c6408a.png"},{"id":108493267,"identity":"3916114e-a703-4ca0-98d2-b4316e6aad0c","added_by":"auto","created_at":"2026-05-05 09:59:49","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":20534,"visible":true,"origin":"","legend":"\u003cp\u003eFigure 4. Spaghetti Plot of Response Profiles over Time by Lesion\u003c/p\u003e","description":"","filename":"image6.png","url":"https://assets-eu.researchsquare.com/files/rs-9084188/v1/51a4dac7920bd9b0f2eda5e7.png"},{"id":108804040,"identity":"75b63850-48d2-49a4-abde-272a9e52c256","added_by":"auto","created_at":"2026-05-08 15:14:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":354510,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9084188/v1/87089804-a585-44a1-b1f9-fcc45a420d1a.pdf"},{"id":108385741,"identity":"245b0ea9-8754-4c7e-909d-aad248e59496","added_by":"auto","created_at":"2026-05-04 06:05:03","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":12529,"visible":true,"origin":"","legend":"\u003cp\u003eTable 1. Baseline demographic and clinical characteristics of the study cohort (N=17)\u003c/p\u003e","description":"","filename":"Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-9084188/v1/df33b7452f324038b6d924cf.xlsx"}],"financialInterests":"","formattedTitle":"Long term treatment of sirolimus for pediatric vascular anomaly","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePediatric vascular anomalies (VAs) are a heterogeneous group of conditions ranging from benign hemangiomas to life-threatening malformations.[1] Complex or infiltrating vascular anomalies can cause significant functional impairment and morbidity. Traditional interventions, including surgery and sclerotherapy, often face limitations due to the diffuse nature of these lesions and high recurrence rates.[2]\u003c/p\u003e \u003cp\u003eThe identification of the PI3K/AKT/mTOR signaling pathway as a key driver in VA pathogenesis has revolutionized therapeutic approaches.[3] Sirolimus (Rapamycin), an mTOR inhibitor, has subsequently emerged as a standard medical therapy, with clinical trials demonstrating its safety and significant short-term volumetric responses.[2, 4\u0026ndash;8]\u003c/p\u003e \u003cp\u003eDespite these advancements, the existing literature primarily focuses on short-to-intermediate follow-up periods [8\u0026ndash;10]. Crucial data regarding long-term durability of response, relapse patterns after cessation, and cumulative safety profiles remain scarce. Furthermore, management strategies for patients exhibiting suboptimal responses to prolonged sirolimus monotherapy are not well-defined.\u003c/p\u003e \u003cp\u003eThis study reports our institutional experience with sirolimus treatment over an extended follow-up period, exceeding five years. We evaluate sustained volumetric responses, long-term safety, and clinical outcomes of transition to Alpelisib in sirolimus-refractory cases, aiming to optimize the long-term management algorithm for complex pediatric VAs.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Patient Selection\u003c/h2\u003e \u003cp\u003eThis retrospective cohort study was conducted at Asan Medical Center. We included pediatric patients with complicated vascular anomalies who initiated sirolimus treatment since January 2018 and completed at least 5 years of follow-up. Complicated vascular anomalies were defined as lesions that were unresectable, had failed conventional therapies (sclerotherapy or surgical intervention), or posed significant functional or cosmetic concerns. The study protocol was approved by the Institutional Review Board of Asan Medical Center.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTreatment Protocol\u003c/h3\u003e\n\u003cp\u003eSirolimus was administered orally at an initial dose of 0.8 mg/m\u0026sup2; body surface area (BSA) twice daily. Dosing was adjusted to achieve target trough levels of 8\u0026ndash;12 ng/mL. Trough levels were monitored every 2\u0026ndash;4 weeks during the initial 3 months, then every 3 months once stable levels were achieved.\u003c/p\u003e \u003cp\u003eInitially, tissue biopsy was not routinely performed as the diagnosis was primarily established through clinical and radiologic evaluation. However, biopsy was indicated in specific cases to exclude malignancy when radiologic features were inconclusive or to facilitate molecular profiling in patients exhibiting a suboptimal response to sirolimus.\u003c/p\u003e \u003cp\u003eIn cases of limited response to sirolimus after 24\u0026ndash;36 months of treatment, particularly when PIK3CA mutations were identified on tissue biopsy, switching to alpelisib (PI3Kα-specific inhibitor) was considered.\u003c/p\u003e \u003cp\u003eFor patients demonstrating sustained treatment response and stable lesion volumes for at least 24 months, medication tapering was initiated. The tapering protocol consisted of reducing from twice-daily to once-daily dosing while maintaining the same single-dose amount, followed by a thrice-weekly regimen. Patients were closely monitored with clinical assessments and imaging during the tapering period.\u003c/p\u003e\n\u003ch3\u003eImaging Assessment and Response Evaluation\u003c/h3\u003e\n\u003cp\u003eMagnetic resonance imaging (MRI) was performed at baseline and every 12 months thereafter. Lesion volumes were measured on T2-weighted fat-suppressed sequences by a blinded pediatric surgeon using 3D volumetric analysis. To adjust for pediatric growth, all volumes were normalized to the patient\u0026rsquo;s body surface area (BSA) at each scan.\u003c/p\u003e \u003cp\u003eTreatment response was defined by the percentage change in normalized volume from baseline. Complete Response (CR) was defined as a reduction\u0026thinsp;\u0026ge;\u0026thinsp;95%. Partial Response (PR) was subcategorized as Significant (\u0026ge;\u0026thinsp;50%), Moderate (20\u0026ndash;50%), or Modest (\u0026lt;\u0026thinsp;20%) reduction. Progressive Disease (PD) was defined as any volume increase. The overall response rate (ORR) represented the proportion of patients achieving CR or PR at the final follow-up.\u003c/p\u003e\n\u003ch3\u003eSafety Assessment\u003c/h3\u003e\n\u003cp\u003eAdverse events were monitored through clinical assessment at each outpatient visit (every 3 months) and laboratory testing including complete blood count, liver function tests, lipid profile, and renal function tests. Adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eContinuous variables were expressed as median (IQR) or mean (SD), and categorical variables as frequencies (%). Longitudinal changes in normalized volumes were analyzed using generalized additive mixed-effects models (GAMM) with random intercepts to account for individual variability and non-linear trajectories.\u003c/p\u003e \u003cp\u003eSensitivity analyses were conducted with and without these two patients to assess the robustness of the observed trends, given that they demonstrated marked volumetric increases that disproportionately influenced the overall model fit. The primary findings are presented based on models that best reflected the dominant response pattern in the cohort, while acknowledging heterogeneity of trajectories.\u003c/p\u003e \u003cp\u003eFor patients switching to alpelisib, only MRI data obtained during sirolimus therapy were included. One patient (Patient 16) was excluded from normalized volume analysis due to missing baseline BSA data.\u003c/p\u003e \u003cp\u003eInteraction terms were interpreted cautiously and no adjustments for multiple comparisons were applied, as the subgroup analyses (age at initiation and lesion location) were exploratory in nature. Statistical significance was defined as \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 using R version 4.2.1.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePatient Demographics and Baseline Clinical Characteristics\u003c/h2\u003e \u003cp\u003eA total of 17 patients (9 females, 8 males) with complicated vascular anomalies were included in this study. The median follow-up duration was 78 months (IQR: 73\u0026ndash;84 months), with a median sirolimus treatment duration of 42 months (IQR: 37\u0026ndash;48 months). The median age at treatment initiation was 57 months (IQR: 13\u0026ndash;110 months).\u003c/p\u003e \u003cp\u003eThe presenting symptom was a mass in 13 patients (76.5%), airway obstruction in 2 patients (11.8%), and pain in 2 patients (11.8%). Regarding timing of diagnosis, 12 patients (70.6%) were diagnosed prenatally by ultrasound, 2 (11.8%) at birth, and 3 (17.6%) during the growth period.\u003c/p\u003e \u003cp\u003eThe primary lesion locations were head and neck in 9 patients (52.9%), extremities in 6 patients (35.3%), and trunk in 2 patients (11.8%). The most common diagnosis was lymphatic malformation (LM) in 11 patients (64.7%), followed by lymphaticovenous malformation (LVM) in 4 patients (23.5%), venous malformation (VM) in 1 patient (5.9%), and Kaposiform hemangioendothelioma in 1 patient (5.9%).\u003c/p\u003e \u003cp\u003ePIK3CA mutation analysis was performed in 7 patients (41.2%). Among these, mutations were detected in 5 patients, including H1047L (n\u0026thinsp;=\u0026thinsp;1), H1047R (n\u0026thinsp;=\u0026thinsp;1), E545K (n\u0026thinsp;=\u0026thinsp;1), and E542K (n\u0026thinsp;=\u0026thinsp;1). Two patients had negative mutation results, and 10 patients did not undergo genetic testing. Detailed patient characteristics are summarized in Table\u0026nbsp;1.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTreatment Patterns and Response\u003c/h3\u003e\n\u003cp\u003eDuring follow-up of sirolimus therapy, 12 patients (70.6%) successfully underwent medication tapering without disease progression. One patient experienced relapse after complete discontinuation but responded well to reinitiation. Three patients (17.6%) were switched to alpelisib due to suboptimal response (n\u0026thinsp;=\u0026thinsp;1), recurrent infections (n\u0026thinsp;=\u0026thinsp;1), or cellulitis (n\u0026thinsp;=\u0026thinsp;1). One patient ceased treatment after achieving a complete response (CR) without recurrence (Fig.\u0026nbsp;1\u0026ndash;1).\u003c/p\u003e \u003cp\u003eThe overall response rate (ORR) was 81.3% (13/16 evaluated), with 2 patients achieving CR (12.5%) and 11 achieving a partial response (PR, 68.8%). Among those with PR, 6 demonstrated significant (\u0026ge;\u0026thinsp;50%), 3 moderate (20\u0026ndash;50%), and 2 modest (\u0026lt;\u0026thinsp;20%) volume reduction. Three patients (18.8%) exhibited progressive disease (Fig.\u0026nbsp;1\u0026ndash;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The median change in normalized lesion volume was \u0026minus;\u0026thinsp;45% (IQR: -69% to +\u0026thinsp;11%), reflecting a consistent trend toward volumetric reduction across the cohort.\u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u0026thinsp;\u0026minus;\u0026thinsp;1 presents a spaghetti plot illustrating the longitudinal trajectories of normalized lesion volumes for the entire cohort (N\u0026thinsp;=\u0026thinsp;17). The plot demonstrates substantial heterogeneity in individual responses, ranging from near-complete regression to progressive enlargement. An initial linear mixed-effects model did not adequately capture these longitudinal patterns (p\u0026thinsp;=\u0026thinsp;0.9492), likely reflecting non-linearity in treatment trajectories. Therefore, a flexible additive mixed-effects framework was employed to better model these dynamics, and sensitivity analyses were conducted to evaluate the influence of extreme trajectories on model stability. The resulting model (Fig.\u0026nbsp;\u0026lt;link rid=\"fig5\"\u0026gt;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e2\u0026lt;/link\u0026gt;\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e2\u003c/span\u003e) demonstrated a significant non-linear association between treatment duration and volume change (smooth term F\u0026thinsp;=\u0026thinsp;18.57, p \u0026lt; .0001; edf\u0026thinsp;=\u0026thinsp;2.71). The fitted curve indicates a rapid reduction in lesion volume during the first 12\u0026ndash;24 months, followed by relative stabilization. Although a continued decline is visually suggested beyond 60 months, statistical certainty in this extended period is limited by reduced sample size. Overall, the most robust finding is the early therapeutic reduction and subsequent maintenance of treatment gains.\u003c/p\u003e \u003cp\u003eAlthough no statistically significant difference was observed (interaction p\u0026thinsp;=\u0026thinsp;0.428; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e3\u003c/span\u003e), patients treated before 2 years of age demonstrated a more pronounced trend toward volume reduction over time compared with those treated at \u0026ge;\u0026thinsp;2 years of age (slope\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;1.65 vs. \u0026minus;0.32).\u003c/p\u003e \u003cp\u003eLesion Location (head and neck, trunk, extremities) showed no statistically significant differences in treatment response trajectories among groups (interaction p\u0026thinsp;=\u0026thinsp;0.612) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e4\u003c/span\u003e). However, visual examination of the fitted regression lines suggested a trend toward greater volume reduction in patients with head and neck lesions (slope = -1.23) and trunk lesions (slope = -0.87) compared to extremity lesions (slope\u0026thinsp;=\u0026thinsp;+\u0026thinsp;0.42), though these differences did not reach statistical significance in our limited sample size.\u003c/p\u003e \u003cp\u003eAdverse events during sirolimus treatment were generally mild and manageable. No Grade 3 or higher adverse events related to sirolimus were documented. The most common adverse event was upper respiratory tract infection, occurring in 6 patients (35.3%). Oral ulcers developed in 3 patients (17.6%), and single occurrences of diarrhea, skin rash, and menstrual irregularity were observed (5.9% each). Patient 3's switch to alpelisib was motivated by both recurrent infections affecting daily activities and suboptimal disease control rather than severe toxicity.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eResponse to Alpelisib Switch\u003c/h2\u003e \u003cp\u003eThree patients were switched from sirolimus to alpelisib after 44\u0026ndash;48 months of sirolimus treatment. Patient 3 and Patient 16, who had adequate follow-up after the switch (\u0026gt;\u0026thinsp;12 months), demonstrated clinical improvement with reduction in lesion size on volumetric MRI, showing 42% and 38% decreases, respectively, within 12 months of alpelisib initiation.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study presents one of the longest follow-up experiences with sirolimus treatment for pediatric vascular anomalies, with a median follow-up of 78 months. Our findings demonstrate that sirolimus maintains a favorable safety profile with long-term use and achieves an overall response rate of 81%, consistent with previously reported short-term studies.[8\u0026ndash;10] However, our longitudinal analysis reveals important insights into the temporal dynamics of treatment response and identifies clinical scenarios where alternative therapeutic strategies may be considered.\u003c/p\u003e \u003cp\u003eIn our study, most responding patients demonstrated lesion volume reduction during the initial 12\u0026ndash;24 months of treatment, whereas subsequent measurements showed minimal additional change. As a result, the overall longitudinal model did not demonstrate a statistically significant trend in continued volume reduction (p\u0026thinsp;=\u0026thinsp;0.949). This pattern may indicate that the therapeutic effect of sirolimus reaches a plateau after approximately two years of treatment, with important implications for treatment duration and monitoring strategies.\u003c/p\u003e \u003cp\u003eThe biological basis for this plateau effect remains unclear but may reflect several mechanisms. First, sirolimus is primarily cytostatic rather than cytolytic; it suppresses cell proliferation and angiogenesis without directly inducing cell death [11]. Consequently, volume reduction may reach a limit once maximal inhibition of these processes is achieved. Second, feedback activation of compensatory signaling pathways, such as PI3K/AKT reactivation through mTORC2 or receptor tyrosine kinase upregulation, may limit efficacy over time.[12, 13]. Finally, chronic vascular anomalies involve secondary structural changes \u0026ndash; including fibrosis, adipose accumulation, and lymphatic congestion \u0026ndash; that are irreversible by mTOR inhibition once tissue remodeling is established.\u003c/p\u003e \u003cp\u003eThese observations support a treatment strategy of intensive monitoring during the first 24 months, followed by consideration of medication tapering in responding patients or switch to alternative agents in those with minimal response. Our tapering protocol, successfully implemented in 71% of patients, allowed for reduced medication exposure while maintaining disease control in most cases.\u003c/p\u003e \u003cp\u003eBased on the spaghetti plot, the heterogeneity in treatment response likely reflects diverse molecular pathogenesis and lesion-specific biology. Although PIK3CA mutation analysis was limited to 41.2% of our cohort, Venot et al. reported that specific PIK3CA mutation variants are associated with differential sensitivity to mTOR inhibitors versus PI3K inhibitors, suggesting a potential role for genotype-driven therapeutic selection [14]. These findings highlight the clinical relevance of molecular heterogeneity and support the importance of molecular profiling in the management of vascular anomalies.\u003c/p\u003e \u003cp\u003eAn important contribution of our study is the demonstration that patients with limited response to long-term sirolimus therapy may benefit from switching to alpelisib, particularly when PIK3CA mutations are identified. Two of three patients who switched to alpelisib achieved substantial clinical improvement after 24\u0026ndash;36 months of minimal response to sirolimus. This observation aligns with emerging evidence that direct PI3K inhibition may overcome resistance mechanisms that limit mTOR inhibitor efficacy. [15, 16] Alpelisib, as a PI3Kα-specific inhibitor, directly targets the mutant PIK3CA enzyme, potentially providing more complete pathway suppression.[17]\u003c/p\u003e \u003cp\u003eHowever, alpelisib use is associated with distinct toxicity profiles, most notably hyperglycemia due to inhibition of insulin signaling.[18] Patient 1's development of elevated HbA1C exemplifies this concern and necessitates careful metabolic monitoring and potentially earlier intervention. The substantially higher cost of alpelisib compared to sirolimus also represents a practical barrier to its widespread use, emphasizing the importance of patient selection and molecular confirmation before switching.\u003c/p\u003e \u003cp\u003eOur findings support a treatment algorithm wherein sirolimus remains the preferred first-line agent for complicated vascular anomalies, with consideration of alpelisib switch after 24\u0026ndash;36 months in patients with documented PIK3CA mutations who demonstrate minimal response to adequate sirolimus therapy. Tissue biopsy for molecular analysis should be strongly considered in cases of suboptimal response to guide subsequent therapeutic decisions.\u003c/p\u003e \u003cp\u003eWhile our subgroup analyses by lesion location did not reveal statistically significant differences, trends observed in the data merit discussion. Patients with head and neck lesions and trunk lesions appeared to demonstrate better responses compared to extremity lesions. This observation may reflect differences in lesion biology by anatomic site, with extremity lesions potentially having greater involvement of muscular and connective tissue structures that respond less favorably to medical therapy. Alternatively, different developmental timing and vascular bed characteristics in various anatomic locations may influence treatment response.\u003c/p\u003e \u003cp\u003eThe trend toward better outcomes in patients starting treatment before 2 years of age, though not statistically significant in our cohort, aligns with previous suggestions that earlier intervention may prevent progressive expansion and anatomic complications.[19] Prospective studies with larger sample sizes are needed to definitively establish whether age at treatment initiation predicts long-term outcomes.\u003c/p\u003e \u003cp\u003eThis study has several limitations, including its retrospective single-center design, small sample size, and heterogeneity of lesion types, which limit generalizability and statistical power, particularly for subgroup analyses. Incomplete PIK3CA mutation analysis restricts robust genotype\u0026ndash;phenotype correlations, and the absence of a control group precludes definitive attribution of volume changes solely to sirolimus, although prior randomized data have demonstrated its superiority over observation [9]. In addition, reliance on volumetric imaging may not fully capture clinically meaningful outcomes, and the limited experience with alpelisib, involving only three patients with short follow-up, prevents definitive conclusions regarding optimal switching strategies and long-term safety and efficacy. Larger multicenter collaborations are needed to establish evidence-based guidelines for managing sirolimus-resistant cases.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, sirolimus demonstrated sustained long-term efficacy and acceptable safety in pediatric patients with complicated vascular anomalies. In patients with limited response, particularly those harboring PIK3CA mutations, transition to PI3K-targeted therapy may represent a reasonable consideration. Future multicenter prospective studies incorporating systematic molecular profiling are needed to refine long-term treatment algorithms.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBSA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBody surface area\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eComplete response\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCTCAE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCommon Terminology Criteria for Adverse Events\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGAMM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGeneralized additive mixed-effects model\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLymphatic malformation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLVM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLymphaticovenous malformation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMRI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMagnetic resonance imaging\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eORR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eOverall response rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eProgressive disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePartial response\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eVAs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eVascular anomalies\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eVM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eVenous malformation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003emTOR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMechanistic target of rapamycin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePIK3CA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePhosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\u003cp\u003eThis study was approved by the Institutional Review Board of Asan Medical Center and was conducted in accordance with the Declaration of Helsinki. The requirement for informed consent was waived due to the retrospective nature of the study.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials\u003c/p\u003e\u003cp\u003eThe datasets generated and/or analyzed during the current study are not publicly available due to patient privacy and institutional regulations but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\u003cp\u003eThis research received no external funding.\u003c/p\u003e\n\u003cp\u003eAuthors’ contributions\u003c/p\u003e\u003cp\u003eYJ.C conceived and designed the study. J.P collected clinical data. J.P \u0026nbsp;performed the statistical analysis. All authors contributed to manuscript drafting and critically revised the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\u003cp\u003eThe authors thank the clinical staff of Asan Medical Center for their support in patient care and data collection.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWassef, M., et al., \u003cem\u003e[Classification of vascular tumours and vascular malformations. Contribution of the ISSVA 2014/2018 classification].\u003c/em\u003e Ann Pathol, 2021. \u003cstrong\u003e41\u003c/strong\u003e(1): p. 58-70.\u003c/li\u003e\n\u003cli\u003eHammill, A.M., et al., \u003cem\u003eSirolimus for the treatment of complicated vascular anomalies in children.\u003c/em\u003e Pediatr Blood Cancer, 2011. \u003cstrong\u003e57\u003c/strong\u003e(6): p. 1018-24.\u003c/li\u003e\n\u003cli\u003eLuks, V.L., et al., \u003cem\u003eLymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA.\u003c/em\u003e J Pediatr, 2015. \u003cstrong\u003e166\u003c/strong\u003e(4): p. 1048-54 e1-5.\u003c/li\u003e\n\u003cli\u003eOzeki, M., et al., \u003cem\u003eThe impact of sirolimus therapy on lesion size, clinical symptoms, and quality of life of patients with lymphatic anomalies.\u003c/em\u003e Orphanet J Rare Dis, 2019. \u003cstrong\u003e14\u003c/strong\u003e(1): p. 141.\u003c/li\u003e\n\u003cli\u003eMack, J.M., et al., \u003cem\u003eEffect of sirolimus on coagulopathy of slow-flow vascular malformations.\u003c/em\u003e Pediatr Blood Cancer, 2019. \u003cstrong\u003e66\u003c/strong\u003e(10): p. e27896.\u003c/li\u003e\n\u003cli\u003eGabeff, R., et al., \u003cem\u003eEfficacy and Tolerance of Sirolimus (Rapamycin) for Extracranial Arteriovenous Malformations in Children and Adults.\u003c/em\u003e Acta Derm Venereol, 2019. \u003cstrong\u003e99\u003c/strong\u003e(12): p. 1105-1109.\u003c/li\u003e\n\u003cli\u003eJi, Y., et al., \u003cem\u003eSirolimus for the treatment of progressive kaposiform hemangioendothelioma: A multicenter retrospective study.\u003c/em\u003e Int J Cancer, 2017. \u003cstrong\u003e141\u003c/strong\u003e(4): p. 848-855.\u003c/li\u003e\n\u003cli\u003eAdams, D.M., et al., \u003cem\u003eEfficacy and Safety of Sirolimus in the Treatment of Complicated Vascular Anomalies.\u003c/em\u003e Pediatrics, 2016. \u003cstrong\u003e137\u003c/strong\u003e(2): p. e20153257.\u003c/li\u003e\n\u003cli\u003eMaruani, A., et al., \u003cem\u003eSirolimus (Rapamycin) for Slow-Flow Malformations in Children: The Observational-Phase Randomized Clinical PERFORMUS Trial.\u003c/em\u003e JAMA Dermatol, 2021. \u003cstrong\u003e157\u003c/strong\u003e(11): p. 1289-1298.\u003c/li\u003e\n\u003cli\u003eJi, Y., et al., \u003cem\u003eA prospective multicenter study of sirolimus for complicated vascular anomalies.\u003c/em\u003e J Vasc Surg, 2021. \u003cstrong\u003e74\u003c/strong\u003e(5): p. 1673-1681 e3.\u003c/li\u003e\n\u003cli\u003eBenjamin, D., et al., \u003cem\u003eRapamycin passes the torch: a new generation of mTOR inhibitors.\u003c/em\u003e Nat Rev Drug Discov, 2011. \u003cstrong\u003e10\u003c/strong\u003e(11): p. 868-80.\u003c/li\u003e\n\u003cli\u003eO'Reilly, K.E., et al., \u003cem\u003emTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt.\u003c/em\u003e Cancer Res, 2006. \u003cstrong\u003e66\u003c/strong\u003e(3): p. 1500-8.\u003c/li\u003e\n\u003cli\u003eRodrik-Outmezguine, V.S., et al., \u003cem\u003emTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling.\u003c/em\u003e Cancer Discov, 2011. \u003cstrong\u003e1\u003c/strong\u003e(3): p. 248-59.\u003c/li\u003e\n\u003cli\u003eVenot, Q., et al., \u003cem\u003eTargeted therapy in patients with PIK3CA-related overgrowth syndrome.\u003c/em\u003e Nature, 2018. \u003cstrong\u003e558\u003c/strong\u003e(7711): p. 540-546.\u003c/li\u003e\n\u003cli\u003eSun, S.Y., et al., \u003cem\u003eActivation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition.\u003c/em\u003e Cancer Res, 2005. \u003cstrong\u003e65\u003c/strong\u003e(16): p. 7052-8.\u003c/li\u003e\n\u003cli\u003eRozengurt, E., H.P. Soares, and J. Sinnet-Smith, \u003cem\u003eSuppression of feedback loops mediated by PI3K/mTOR induces multiple overactivation of compensatory pathways: an unintended consequence leading to drug resistance.\u003c/em\u003e Mol Cancer Ther, 2014. \u003cstrong\u003e13\u003c/strong\u003e(11): p. 2477-88.\u003c/li\u003e\n\u003cli\u003eCanaud, G., et al., \u003cem\u003eAlpelisib for treatment of patients with PIK3CA-related overgrowth spectrum (PROS).\u003c/em\u003e Genet Med, 2023. \u003cstrong\u003e25\u003c/strong\u003e(12): p. 100969.\u003c/li\u003e\n\u003cli\u003eAndre, F., et al., \u003cem\u003eAlpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer.\u003c/em\u003e N Engl J Med, 2019. \u003cstrong\u003e380\u003c/strong\u003e(20): p. 1929-1940.\u003c/li\u003e\n\u003cli\u003eBalakrishnan, K., et al., \u003cem\u003ePrimary surgery vs primary sclerotherapy for head and neck lymphatic malformations.\u003c/em\u003e JAMA Otolaryngol Head Neck Surg, 2014. \u003cstrong\u003e140\u003c/strong\u003e(1): p. 41-5.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Pediatrics, Vascular anomaly, Medical Genetics","lastPublishedDoi":"10.21203/rs.3.rs-9084188/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9084188/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAlthough sirolimus has emerged a safe and effective treatment modality for unresectable vascular anomlaies, comprehensive long-term follow-up data remain scarce in the current literature. This study aims to evaluate the long-term clinical experience of pediatric patients with vascular anomalies who received sirolimus treatment over five years.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe retrospectively analysed 17 pediatric patients with vascular anomalies treated with sirolimus over five years in Asan Medical Center. Lesion volumes were measured via 3D volumetric MRI and normalized to body surface area (BSA). Adverse drug effects and therapeutic responses were periodically assessed. Longitudinal response was modeled using generalized additive mixed-effects models (GAMM). Tapering protocols were initiated after 24 months of stability, and alpelisib switch was considered for sirolimus-refractory cases with documented PIK3CA mutations.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eWith a median follow-up of 78 months, the overall response rate was 81.3%. GAMM analysis demonstrated a significant non-linear volume reduction (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), characterized by a rapid initial response within 12\u0026ndash;24 months followed by a sustained plateau. Tapering was successful in 70.6% of patients without disease progression. Three patients with suboptimal responses transitioned to alpelisib; those with sufficient follow-up achieved additional volume reduction within 12 months. Long-term sirolimus use was well-tolerated, with no Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 adverse events reported.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eSirolimus provides sustained long-term efficacy and safety in pediatric vascular anomalies. The observed treatment plateau suggests that dose tapering is a viable strategy for sustained responders. Furthermore, genotype-guided transition to alpelisib offers an effective alternative for refractory PIK3CA-mutant cases.\u003c/p\u003e","manuscriptTitle":"Long term treatment of sirolimus for pediatric vascular anomaly","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-04 06:04:58","doi":"10.21203/rs.3.rs-9084188/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2026-04-21T10:07:51+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-21T09:10:30+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"Orphanet Journal of Rare Diseases","date":"2026-03-23T16:26:22+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-19T13:03:46+00:00","index":"","fulltext":""},{"type":"submitted","content":"Orphanet Journal of Rare Diseases","date":"2026-03-18T22:01:23+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"82366b4b-7665-4c5d-8fab-62cb47d972a7","owner":[],"postedDate":"May 4th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-04T06:04:58+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-04 06:04:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9084188","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9084188","identity":"rs-9084188","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}