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Clinical differences in sirolimus treatment with low target levels between children and adults with vascular malformations - A nationwide trial.

ABSTRACT: The clinical presentation of patients with slow-flow vascular malformations is very heterogeneous. High clinical burden and subsequent reduced health-related quality of life is something they have in common. There is an unmet medical need for these patients for whom regular treatments like surgery and embolization are either insufficient or technically impossible. Sirolimus has been reported to be effective and overall well-tolerated in most patients. However, the main limitation of sirolimus is the reported high toxicity, especially when target levels of 10-15 ng/mL are being used. We report the results of a phase IIB single-arm open-label clinical trial consisting of 68 (67 in the challenge phase and 68 in the rechallenge phase) evaluable patients (children n = 33 and adults n = 35) demonstrating that treatment with low sirolimus target levels (4-10 ng/mL) is effective in 79.1% of the patients. When sirolimus treatment was stopped, the majority of patients experienced a recurrence of symptoms, supporting prolonged or even lifelong treatment requirement. Adults experienced a higher baseline pain score compared with children, having an estimated marginal mean of 6.2 versus 4.1, p < 0.05; however, they showed a similar decrease to children. Furthermore, the pediatric population experienced less often a sirolimus-related grade I-IV adverse event (35.9% vs. 64.1%, p > 0.05) compared with adults. Additionally, response rates were higher in children compared with adults (93.8% vs. 65.7%, p < 0.05), and children responded faster (28 vs. 91 days, p < 0.05). These results suggest benefits of sirolimus in patients with slow-flow vascular malformations and support its initiation as young as possible.

SUBMITTER: Harbers VEM

PROVIDER: S-EPMC10176016 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Clinical differences in sirolimus treatment with low target levels between children and adults with vascular malformations - A nationwide trial.

Harbers Veroniek E M VEM Zwerink Lilly G J M LGJM Rongen Gerard A GA Klein Willemijn M WM van der Vleuten Carine J M CJM van Rijnsoever Ingrid M P IMP Gerdsen-Drury Lynda L Flucke Uta E UE Verhoeven Bas H BH de Laat Peter C J PCJ van der Horst Chantal M A M CMAM Schultze Kool Leo J LJ Te Loo D Maroeska W M DMWM

Clinical and translational science 20230223 5

The clinical presentation of patients with slow-flow vascular malformations is very heterogeneous. High clinical burden and subsequent reduced health-related quality of life is something they have in common. There is an unmet medical need for these patients for whom regular treatments like surgery and embolization are either insufficient or technically impossible. Sirolimus has been reported to be effective and overall well-tolerated in most patients. However, the main limitation of sirolimus is ...[more]

PMID: 36824030

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Project description:IntroductionPatients with congenital vascular malformations often suffer from an impaired quality of life (QoL) because of pain and functional disabilities. Previous studies have shown that the mTOR inhibitor sirolimus can reduce complaints and improve QoL in some patients. High target levels of sirolimus of 10-15 ng/ml were well tolerated; however, in a relative high percentage of patients sirolimus caused serious adverse events (AEs).MethodsA case series of 12 patients with therapy-resistant low-flow vascular malformations was treated with sirolimus, using low target levels of 4-10 ng/ml. Efficacy of sirolimus was evaluated in regard to pain symptoms using the visual analogue scale/numeric rating scale and patients reported QoL. To rule out a placebo effect of sirolimus, sirolimus was stopped after a certain time point and reintroduced as soon as complaints returned. Adverse events were closely monitored and graded using the Common Terminology Criteria for Adverse Events (CTCAE) grading.ResultsAn improvement in symptoms was seen in 92% (n = 11/12) of patients. In nine patients pain complaints returned. Seven out of nine of them (78%) again experienced a reduction of symptoms after restarting sirolimus treatment. Despite low target levels, these response rates are comparable to those found in the literature using higher target levels of sirolimus. However, significantly less serious AEs were observed with low dose sirolimus, suggesting low dose sirolimus might be safer. Unfortunately, young adolescent female patients developed serious menstrual disturbances during treatment with low dose sirolimus. We describe this adverse event for the first time in patients with congenital vascular malformations and this might be specifically related to low dose sirolimus.ConclusionsLow dose sirolimus showed a high efficacy in patients with therapy-resistant and low-flow malformation, with a lower incidence of serious adverse events. At the same time a new adverse event, namely menstrual cycle disturbance, was observed in young adolescents, indicating the need for caution when sirolimus is given. This is extremely relevant to patients with low-flow vascular malformation, who are likely to require lifelong treatment for their condition.

Project description:BACKGROUNDSlow-flow vascular malformations frequently harbor activating mutations in the PI3K/AKT/mTOR cascade. Phase II trials pinpointed sirolimus effectiveness as a drug therapy. Efficacy and safety of sirolimus thus need to be evaluated in large prospective phase III trials.METHODSThe Vascular Anomaly-Sirolimus-Europe (VASE) trial, initiated in 2016, is a large multicentric prospective phase III trial (EudraCT 2015-001703-32), which evaluates efficacy and safety of sirolimus for 2 years in pediatric and adult patients with symptomatic slow-flow vascular malformations. In this interim analysis, we studied all patients enrolled up to October 2021 who received sirolimus for 12 or more months or who prematurely stopped the treatment.RESULTSThirty-one pediatric and 101 adult patients were included in this analysis; 107 completed 12 or more months of sirolimus, including 61 who were treated for the whole 2-year period. Sirolimus resulted in a clinical improvement in 85% of patients. The efficacy appeared within the first month for the majority of them. Grade 3-4 adverse events were observed in 24 (18%) patients; all resolved after treatment interruption/arrest. Sirolimus increased feasibility of surgery or sclerotherapy in 20 (15%) patients initially deemed unsuitable for intervention. Among the 61 patients who completed the 2-year treatment, 33 (54%) reported a recurrence of symptoms after a median follow-up of 13 months after sirolimus arrest. While there was no difference in efficacy, clinical improvement was faster but subsided more rapidly in PIK3CA-mutated (n = 24) compared with TIE2-mutated (n = 19) patients.CONCLUSIONSirolimus has a high efficacy and good tolerance in treatment of slow-flow vascular malformations in children and adults.TRIAL REGISTRATIONClinicalTrials.gov NCT02638389 and EudraCT 2015-001703-32.FUNDINGThe Fonds de la Recherche Scientifique (FNRS grants T.0247.19, P.C005.22, T.0146.16, and P.C013.20), the Fund Generet managed by the King Baudouin Foundation (grant 2018-J1810250-211305), the Walloon Region through the FRFS-WELBIO strategic research programme (WELBIO-CR-2019C-06), the MSCA-ITN network V.A. Cure no. 814316, the Leducq Foundation Networks of Excellence Program grant "ReVAMP" (LFCR grant 21CVD03), the European Union's Horizon 2020 research and innovation programme under grant agreement no. 874708 (Theralymph), the Swiss National Science Foundation under the Sinergia project no. CRSII5_193694, and a Pierre M. fellowship.

Project description:ImportanceSirolimus is increasingly being used to treat various vascular anomalies, although evidence of its efficacy is lacking.ObjectiveTo assess the efficacy and safety of sirolimus for children with slow-flow vascular malformations to better delineate the indications for treatment.Design, setting and participantsThis multicenter, open-label, observational-phase randomized clinical trial included 59 children aged 6 to 18 years with a slow-flow vascular malformation who were recruited between September 28, 2015, and March 22, 2018, in 11 French tertiary hospital centers. Statistical analysis was performed on an intent-to-treat basis from December 4, 2019, to November 10, 2020.InterventionsPatients underwent an observational period, then switched to an interventional period when they received oral sirolimus (target serum levels, 4-12 ng/mL). The switch time was randomized from month 4 to month 8, and the whole study period lasted 12 months for each patient.Main outcomes and measuresThe primary outcome was change in the volume of vascular malformations detected on magnetic resonance imaging scan (with centralized interpretation) per unit of time (ie, between the interventional period and the observational period). Secondary outcomes included subjective end points: pain, bleeding, oozing, quality of life, and safety.ResultsAmong the participants (35 girls [59.3%]; mean [SD] age, 11.6 [3.8] years), 22 (37.3%) had a pure venous malformation, 18 (30.5%) had a cystic lymphatic malformation, and 19 (32.2%) had a combined malformation, including syndromic forms. Variations in the volume of vascular malformations detected on magnetic resonance imaging scans associated with the duration period were not overall significantly different between the interventional period and the observational period (all vascular malformations: mean [SD] difference, -0.001 [0.007]; venous malformations: mean [SD] difference, 0.001 [0.004]; combined malformations: mean [SD] difference, 0.001 [0.009]). However, a significant decrease in volume was observed for children with pure lymphatic malformations (mean [SD] difference, -0.005 [0.005]). Overall, sirolimus had positive effects on pain, especially for combined malformations, and on bleeding, oozing, self-assessed efficacy, and quality of life. During sirolimus treatment, 56 patients experienced 231 adverse events (5 serious adverse events, none life-threatening). The most frequent adverse event was an oral ulcer (29 patients [49.2%]).Conclusions and relevanceThis observational-phase randomized clinical trial allows for clarifying the goals of patients and families when starting sirolimus therapy for children older than 6 years. Pure lymphatic malformations seem to be the best indication for sirolimus therapy because evidence of decreasing lymphatic malformation volume per unit of time, oozing, and bleeding and increasing quality of life was found. In combined malformations, sirolimus significantly reduced pain, oozing, and bleeding. Benefits seemed lower for pure venous malformations than for the 2 other subgroups, also based on symptoms.Trial registrationClinicalTrials.gov Identifier: NCT02509468; clinicaltrialsregister.eu Identifier: 2015-001096-43.

Project description:IntroductionVascular malformations are rare congenital anomalies of the vascular system, which can involve the capillaries, veins, arteries, lymphatics, or a combination of vessel types. Patients with vascular malformations experience an impaired health-related quality of life (HRQoL) because of their symptoms (e.g., pain, swelling, and bleeding) and psychosocial distress. Sirolimus is an effective drug used in the medical treatment of these patients; however, relatively little is known about the effect of sirolimus on specific changes in the HRQoL domains and its magnitude.MethodsThe magnitude of change (effect size) following intervention is more informative to clinical practitioners than statistically significant but clinically unimportant changes; therefore, this study aimed to examine the magnitude and meaningfulness of change in the HRQoL of children and adults with vascular malformations following sirolimus treatment using low target levels.ResultsIn total, 50 patients with vascular malformations (19 children, 31 adults) were included in this study. These patients experienced a lower HRQoL than the general population, with the adults reporting a significantly lower score in almost all domains. A 6-month sirolimus treatment improved the HRQoL in 29 patients, including 77.8% of the children (Pediatric Quality of Life Inventory score [PedsQL]) and 57.7% of the adults (Short Form 36 [SF-36]). The effect sizes of sirolimus for each SF-36/PedsQL domain ranged from 0.19 to 1.02. The clinically relevant moderate magnitude of changes was seen in the domains of the children's reports: "Physical functioning" and "Social functioning" and in the domains of the parent reports: "Social functioning," "School functioning," and "Psychosocial." A high-magnitude change was seen in the domains "Emotional functioning" and "Psychosocial" in the children's reports and "Physical functioning" in the parent reports. In addition, the moderate magnitude of changes was also seen in the adults SF-36: in all domains except for "Role limitations-physical problems," "Role limitations-emotional problems," and "General health perception."ConclusionWe believe this is the first study showing the magnitude of change in HRQoL after sirolimus treatment in patients with vascular malformations. Before treatment, these patients experienced an impaired HRQoL compared with the general Dutch population. A 6-month sirolimus treatment with low target levels led to moderate-to-high clinically relevant changes in multiple domains, which significantly improved the HRQoL.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT03987152?cond=Vascular+Malformations&cntry=NL&city=Nijmegen&draw=2&rank=1, identifier: NCT03987152.

Project description:BackgroundLingual microcystic lymphatic malformations (LMLMs) are rare congenital vascular malformations presenting as clusters of cysts filled with lymph fluid or blood. Even small well-limited lesions can be responsible for a heavy burden, inducing pain, aesthetic prejudice, or oozing, bleeding, infections. The natural history of LMLMs is progressive worsening punctuated by acute flares. Therapeutic options include surgery, laser excision, and radiofrequency ablation but all are potentially detrimental and expose to local relapse. Therefore, the management frequently relies on a "watchful waiting" approach. In complicated LMLMs, treatment with oral sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is often used. Topical applications of sirolimus on the buccal mucosae have been reported in other oral diseases with good tolerance and none to slight detectable blood sirolimus concentrations. We aim to evaluate the efficacy and safety of a 1 mg/mL sirolimus solution applied once daily on LMLM of any stage in children and adults after 4, 8, 12, 16, 20, and 24 weeks of treatment compared to usual care (no treatment).MethodsThis is a randomized, multicentric study using an individually randomized stepped-wedge design over 24 weeks to evaluate topical application of a 1 mg/mL sirolimus solution once daily, on LMLM, versus usual care (no treatment), the control condition. Participants begin with an observational period and later switch to the intervention at a randomized time (week 0, 4, 8, or 12). Visits occur every 4 weeks, either in the study center or by teleconsulting. The primary outcome will be the evaluation of global severity of the LMLM on monthly standardized photographs by 3 independent blinded experts using the physical global assessment (PGA) 0 to 5 scale. Secondary outcomes will include lesion size measurement and quality of life assessment, investigator, and patient-assessed global disease and specific symptoms (oozing, bleeding, sialorrhea, eating impairment, taste modification, aesthetic impairment, pain, and global discomfort) assessment. A biological monitoring will be performed including residual blood sirolimus concentration and usual laboratory parameters.DiscussionGiven the disappointing state of current treatment options in LMLMs, topical sirolimus could become firstline therapy in treating LMLMs if its efficacy and safety were to be demonstrated.Trial registrationClinicalTrials.gov NCT04128722 . Registered on 24 September 2019. EudraCT: EUCTR2019-001530-33-FR Sponsor (University Hospital Center of Tours - CHRU Tours): DR190041-TOPGUN French regulatory authorities: ID RCB: 2019-001530-33.

Project description:Two behavioral experiments assessed the plasticity and short-term improvement of task switching in 215 children and adults. Specifically, we studied manipulations of cued attention to different features of a target stimulus as a way to assess the development of cognitive flexibility. Each experiment had multiple levels of difficulty via manipulation of number of cued features (2-4) and number of response options (2 or 4). Working memory demand was manipulated across the two experiments. Impact of memory demand and task level manipulations on task accuracy and response times were measured. There were three overall goals: First, these task manipulations (number of cued features, response choices, and working memory load) were tested to assess the stability of group differences in performance between children ages 6-16 years and adults 18-27 years, with the goal of reducing age group differences. Second, age-related transitions to adult-level performance were examined within subgroups of the child sample. Third, short-term improvement from the beginning to the end of the study session was measured to probe whether children can improve with task experience. Attempts to use task manipulations to reduce age differences in cued task switching performance were unsuccessful: children performed consistently worse and were more susceptible to task manipulations than adults. However, across both studies, adult-like performance was observed around mid-adolescence, by ages 13-16 years. Certain task manipulations, especially increasing number of response options when working memory demand was low, produced differences from adults even in the oldest children. Interestingly, there was similar performance improvement with practice for both child and adult groups. The higher memory demand version of the task (Experiment 2) prompted greater short-term improvement in accuracy and response times than the lower memory demand version (Experiment 1). These results reveal stable differences in cued switching performance over development, but also relative flexibility within a given individual over time.

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Clinical differences in sirolimus treatment with low target levels between children and adults with vascular malformations - A nationwide trial.

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Clinical differences in sirolimus treatment with low target levels between children and adults with vascular malformations - A nationwide trial.

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