Key Points
Question
Is sirolimus effective for vascular malformations in children?
Findings
This observational-phase randomized clinical trial of 59 children aged 6 to 18 years found no evidence on magnetic resonance imaging of the efficacy of sirolimus for reducing the volume of slow-flow vascular malformations. Overall, sirolimus was efficient for painful symptoms, especially among patients with combined malformations, and for bleeding, oozing, and quality of life associated with the malformations.
Meaning
This study allows for clarifying the goals of the patient and family when starting sirolimus therapy: reducing pain, bleeding, oozing, and volume only for those with pure lymphatic malformations.
Abstract
Importance
Sirolimus is increasingly being used to treat various vascular anomalies, although evidence of its efficacy is lacking.
Objective
To assess the efficacy and safety of sirolimus for children with slow-flow vascular malformations to better delineate the indications for treatment.
Design, Setting and Participants
This 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.
Interventions
Patients 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 Measures
The 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.
Results
Among 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 Relevance
This 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 Registration
ClinicalTrials.gov Identifier: NCT02509468; clinicaltrialsregister.eu Identifier: 2015-001096-43
This randomized clinical trial assesses the efficacy and safety of sirolimus among children with slow-flow vascular malformations to better delineate the indications for treatment.
Introduction
Vascular anomalies include a heterogeneous group of disorders divided into vascular tumors (characterized by vascular cell hyperplasia) and vascular malformations (due to defective embryologic vasculogenesis).1 Slow-flow vascular malformations include capillary malformations, venous malformations (VMs), lymphatic malformations (LMs), or combinations of these malformations. Several pathogenic, somatic, activating variants in the genes involved in vascular angiogenesis and lymphangiogenesis have been identified in vascular malformations, such as in PIK3CA (OMIM 171834) and TEK (OMIM 600221). PIK3CA variants have been identified mainly in combined vascular malformations associated with overgrowth, such as CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevis, spinal or skeletal anomalies or scoliosis) or Klippel-Trenaunay syndrome, but also in several cases of pure LMs and VMs,2,3,4,5 whereas TEK variants are more commonly found in VMs.6,7
Venous malformations and LMs are usually present at birth, although they are not always apparent at this stage. Apart from macrocystic LMs, which may resolve spontaneously after common infections of infancy,8 the natural history of VMs and LMs consists mainly of slow progressive increases in size and the occurrence of complications, such as pain, bleeding, and oozing,9,10 which are associated with functional impairment and have a negative impact on quality of life (QoL).11
Management of VMs and LMs includes observation, physiotherapy, sclerotherapy, complete or partial resection, and medical therapies, such as mammalian target of rapamycin (mTOR) inhibitors.12,13,14,15,16,17,18 However, the literature on these therapies is difficult to interpret because of the inconsistent use of nomenclature and the lack of clinical trials.
The mTOR inhibitors, especially sirolimus (rapamycin), usually indicated as immunosuppressive agents for preventing rejection of a transplanted organ,19 have been increasingly used for treating complicated vascular anomalies.17,18 They directly inhibit mTOR, which is regulated by phosphoinositide-3-kinase and acts as a master switch in numerous cellular processes, such as cell growth and proliferation and angiogenesis and lymphangiogenesis.20,21,22 Contrary to high-flow vascular malformations, for which sirolimus seems poorly effective as treatment,23 slow-flow vascular malformations showed promising although mixed results in previous observational reports, but with heterogeneous sirolimus doses and outcomes.18,24,25,26 All of the authors highlighted the need for randomized clinical trials to better delineate indications for sirolimus therapy and to be able to clarify the goals with the patient and family when starting sirolimus therapy. We performed a observational-phase randomized clinical trial (PERFORMUS [Superficial Slow-Flow Vascular Malformations Treated With Sirolimus]) to assess the efficacy and safety of sirolimus for children with complicated slow-flow vascular malformations.
Methods
This multicenter, open-label, observational-phase randomized clinical trial recruited children aged 6 to 18 years with a slow-flow vascular malformation between September 28, 2015, and March 22, 2018, in 11 French tertiary hospital centers. Details of the trial protocol were previously published (trial protocol in Supplement 1).27 Children and both parents gave written and oral consent to participate. The protocol was approved by the institutional review board of the University Hospital Centre of Tours and received authorization from ANSM (Agence Nationale de Sécurité du Médicament et des Produits de Santé).
Trial Design and Setting
This was a phase 2 trial that involved 11 French tertiary hospital centers for vascular anomalies, with a randomized observational-phase design derived from the design described by Feldman et al.28 Participants first underwent an observational period (OP) with no treatment and then switched to an interventional period (IP) when they received sirolimus. The switch time was randomized from month 4 to month 8, and the whole study period lasted 12 months for each patient (eFigure 1 in Supplement 2). This individually randomized, stepped-wedge design29 (in which participants are randomly allocated to sequences) allows for taking into account the duration of time, which may be a confounding factor. At the end of the protocol, the physician could continue sirolimus if needed.
Participants
Criteria for eligibility were pediatric patients, aged 6 to 18 years, with a complicated slow-flow vascular malformation (VM, LM apart from pure macrocystic LM, and combined venolymphatic malformations, including syndromic forms) extending to underlying tissues (subcutaneous tissue and muscles), confirmed by magnetic resonance imaging (MRI). We did not include children younger than 6 years of age because MRI requires sedation for children of this age. We excluded children with a vascular malformation that required immediate medical treatment or individuals who had contraindications to MRI or sirolimus (allergy, immunosuppression, chronic infectious disease or cancer, liver insufficiency, cytopenia, hypercholesterolemia, pregnancy, and women of childbearing age not using birth control).
Interventions
Sirolimus was administered from the randomized switch time after the OP until month 12. Treatment was in oral solution or tablets, starting with 0.08 mg/kg/d twice a day, with dose adjustments (6 mg/d maximum) based on serum levels of sirolimus (target of 4-12 ng/mL) at day 15, then almost once a month. Concomitant treatments interacting with sirolimus and interventions that could modify the course of the vascular malformation were not allowed during the study period.
Outcomes
Patients underwent MRI 3 times: at baseline (M0), at the time of switch from the OP to the IP (MS), and at the end of follow-up (M12). The MRI scans were centralized and interpreted by the same radiologist (B.M.), with blinding to participants’ names and protocol sequence time. The primary outcome was the change per unit of time in the volume of the malformation as measured by MRI, during the IP compared with during the OP, calculated as follows: [(VM12 – VMS)/VMS]/(M12 – MS) – [(VMS – VM0)/VM0]/(MS – M0), where VM0, VMS, and VM12 are the MRI volumes assessed at M0, MS, and M12, respectively; (MS-M0) is the duration of the OP and (M12-MS) is the duration of the IP.
The study also had several secondary outcomes. Global efficacy was assessed at each visit beginning at MS by the physician and self-assessed by the participant and proxy (parents) on a 0 to 10 visual analog scale (where 0 indicates no efficacy and 10 indicates complete resolution). This outcome was a global perception of efficacy that was the result of different outcomes also assessed separately. Pain was self-assessed at each visit on a 0 to 10 visual analog scale (where 0 indicates no pain and 10 indicates the worst pain imaginable), reported along with period duration. Efficacy was assessed by 2 independent experts (C.L. and J.P.) who had to identify, for each participant, which 1 of 3 photographs taken at M0, MS, and M12, respectively was the one showing the participant after sirolimus treatment (M12) (1 chance in 3 to identify the exact photograph). Quality of life was assessed by the validated Children–Dermatological Life Quality Index (C-DLQI).30 Evolution of cutaneous bleeding and oozing was considered a secondary outcome. Safety was assessed based on physical signs and monitoring of monthly laboratory test values.
Ancillary Study
When consent was given, we performed genetic analysis of TEK and PIK3CA genes to allow for a phenotype-genotype association description. We performed ultradeep targeted sequencing on DNA extraction from both blood and skin samples of the impacted lesion tissue. A whole coding sequence of genes was covered at a minimum of 1000× to detect pathogenic variants with a minimal allelic fraction of 1%. Bioinformatic analyses were performed by using an internal pipeline dedicated to the detection of mosaic disorder–related variants.
Sample Size
In the absence of any previous data on sample size, we planned to recruit 50 patients. Considering a correlation of 0.5 between the outcomes assessed under the OP and IP, this sample size provided the same power as a sample size of 200 in a 2-parallel group randomized trial (ie, 80% power to detect an effect size of 0.4, with a 2-sided type I error of 5%).
Randomization
Randomization was handled by a biostatistician not involved in patient management. A blocked randomization sequence with a block size of 5 was generated by using a discrete uniform-probability distribution, considering 5 possible values (months 4, 5, 6, 7, and 8). The allocation sequence was implemented by means of an electronic case report form: once a patient was included, the investigator was informed of the treatment switch date.
Blinding
The trial was an open-label trial. However, the primary outcome was based on an objective outcome (ie, MRI scans interpreted by a radiologist blinded to treatment periods).
Statistical Analysis
Statistical analysis was performed on an intent-to-treat basis from December 4, 2019, to November 10, 2020. Relative change in volume per unit of time of the vascular malformations as detected on MRI scans was compared by use of the paired t test. Changes in assessments of efficacy were analyzed by mixed linear regression with a patient random effect and time as a fixed effect. Changes in assessments of pain were analyzed by mixed linear regression with a patient random effect and time and intervention as fixed effects, with an interaction between time and intervention. Scores on the C-DLQI were dichotomized between values of 0 and 1 (no decrease in QoL) and values of more than 1, and they were analyzed in a logistic regression model with a patient random effect, time and treatment as fixed effects, and an interaction between time and treatment. For efficacy on photographs, the proportion of good responses was compared with a theoretical proportion of 1 of 3 by use of the χ2 test.31
The primary outcome was analyzed in the population of children who switched from the OP to the IP. We used multiple imputations for missing data. We performed subgroup analyses by type of malformation (VMs, LMs, or combined malformations). All P values were from 2-sided tests, and results were deemed statistically significant at P < .05.
Results
Patients were recruited from September 28, 2015, to March 22, 2018. A total of 63 participants were enrolled; 59 were included in the main analysis (Figure 1). The mean (SD) age of participants was 11.6 (3.8) years, and 35 (59.3%) were girls (Table 1). In total, 22 participants (37.3%) had a VM, located mostly on the upper limbs (11 [50.0%]); 18 participants (30.5%) had an LM, located mostly on the head and neck (8 [44.4%]); and 19 participants (32.2%) had a combined malformation, with the most frequent location on the lower limbs (14 [73.7%]). Previous therapies included mainly partial surgical resection (19 patients [32.2%]) and sclerotherapy (18 patients [30.5%]).
Figure 1. Flowchart of Patients Included in the Study, From Enrollment to Analysis.
Table 1. Demographic and Morphologic Characteristics of Patients Included and Their Vascular Malformations.
| Variables | Patients, No. (%) | |||
|---|---|---|---|---|
| Total (N = 59) | Malformations | |||
| Venous (n = 22) | Lymphatic (n = 18) | Combined (n = 19) | ||
| Age, mean (SD), y | 11.6 (3.8) | 10.3 (3.9) | 11.7 (3.3) | 12.9 (3.7) |
| Sex | ||||
| Female | 35 (59.3) | 13 (59.1) | 13 (72.2) | 9 (47.4) |
| Male | 24 (40.7) | 9 (40.9) | 5 (27.8) | 10 (52.6) |
| Height, mean (SD), cm | 147.3 (19.8) | 141.3 (20.4) | 146.5 (16.8) | 154.9 (20.0) |
| Weight, mean (SD), kg | 42.9 (18.7) | 37.9 (17.1) | 43.5 (16.7) | 48.0 (21.6) |
| Topographya | ||||
| Head and neck | 17 (28.8) | 6 (27.3) | 8 (44.4) | 3 (15.8) |
| Limbs | ||||
| Upper | 19 (32.2) | 11 (50.0) | 2 (11.1) | 6 (31.6) |
| Lower | 22 (37.3) | 3 (13.6) | 5 (27.8) | 14 (73.7) |
| Trunk | 22 (37.3) | 9 (40.9) | 5 (27.8) | 8 (42.1) |
| Genitals | 5 (8.5) | 0 | 2 (11.1) | 3 (15.8) |
| Gluteal area | 18 (30.5) | 2 (9.1) | 5 (27.8) | 11 (57.9) |
| Previous therapiesa | ||||
| Surgery | ||||
| Partial resection | 19 (32.2) | 4 (18.2) | 4 (22.2) | 11 (57.9) |
| Epiphysiodesis | 3 (5.1) | 0 | 0 | 3 (15.8) |
| Sclerotherapy | 18 (30.5) | 6 (27.3) | 8 (44.4) | 4 (21.1) |
| Carbon dioxide laser | 4 (6.8) | 0 | 3 (16.7) | 1 (5.3) |
| Radiofrequencies | 1 (1.7) | 0 | 1 (5.6) | 0 |
| Pulsed dye laser | 2 (3.4) | 0 | 0 | 2 (10.5) |
| Propranolol | 2 (3.4) | 0 | 2 (11.1) | 0 |
| Anticoagulation | 6 (10.2) | 5 (22.7) | 0 | 1 (5.3) |
Several answers might be possible for each patient.
Eighteen patients underwent genetic analyses, which identified somatic variants of PIK3CA in 11 patients, TEK variants in 5 patients, and no variants in 2 patients (eTable 1, eTable 2, and eFigure 2 in Supplement 2). The phenotype of VM was associated with TEK variants; among the 11 patients with PIK3CA variants, 7 had a phenotype of CLOVES syndrome, 1 of Klippel-Trenaunay syndrome, and 3 were pure LMs. The 2 participants with no identified variants had combined malformations of a lower limb with no overgrowth.
Primary Outcome
The median volumes of the vascular malformations detected on MRI scans were highly heterogeneous at baseline, tended to increase until MS, then decreased from IP until M12 for LMs and combined malformations, but not for VMs (Table 2; eFigure 4 in Supplement 2). Variations in volume of vascular malformations between IP and OP per unit of time were not statistically significant when considering vascular malformations overall (mean [SD] difference, –0.001 [0.007]), nor was it significant for both subgroups of VMs (mean [SD] difference, 0.001 [0.004]) and combined malformations (mean [SD] difference, 0.001 [0.009]). However, for pure LMs, results showed a significant difference of relative changes in volume of vascular malformations per unit of time between IP and OP (mean [SD] difference, –0.005 [0.005]).
Table 2. Variations in Volume of the Vascular Malformations by Time and Relative Variation in Volume Related to the Period Duration.
| Time | Volume, mm3 | Primary outcome | Difference between periods | P valuea | |||
|---|---|---|---|---|---|---|---|
| M0 | MS | M12 | Observational period | Interventional period | |||
| All vascular malformations | |||||||
| Median (IQR) | 164 (49 to 485) | 158 (48 to 510) | 151 (31 to 420) | 0 (−0.001 to 0.002) | −0.001 (−0.003 to 0.001) | −0.002 (−0.004 to 0.001) | .24 |
| Mean (SD) | 654 (1379) | 660 (1328) | 538 (1166) | NA | NA | NA | |
| No. | 59 | 58 | 58 | 58 | 58 | 59 | 59 |
| Venous malformations | |||||||
| Median (IQR) | 128 (24 to 276) | 110 (23 to 327) | 135 (23 to 311) | 0 (−0.001 to 0.001) | 0 (−0.001 to 0.001) | 0 (−0.002 to 0.002) | .73 |
| Mean (SD) | 497 (1062) | 469 (966) | 384 (639) | NA | NA | NA | |
| No. | 22 | 22 | 22 | 22 | 22 | 22 | 22 |
| Lymphatic malformations | |||||||
| Median (IQR) | 173 (47 to 343) | 308 (50 to 510) | 145 (17 to 373) | 0.002 (0 to 0.003) | −0.003 (−0 to 004 to −0.001) | −0.004 (−0.006 to −0.002) | <.001 |
| Mean (SD) | 465 (979) | 607 (1256) | 496 (1314) | NA | NA | NA | |
| No. | 18 | 17 | 17 | 17 | 17 | 17 | 17 |
| Combined malformations | |||||||
| Median (IQR) | 189 (79 to 832) | 217 (72 to 672) | 151 (49 to 800) | 0 (−0.001 to 0.003) | −0.001 (−0.002 to 0.002) | −0.001 (−0.004 to 0.003) | .70 |
| Mean (SD) | 1006 (1916) | 920 (1714) | 757 (1480) | NA | NA | NA | |
| No. | 19 | 19 | 19 | 19 | 19 | 19 | 19 |
Abbreviations: IQR, interquartile range; M0, inclusion time; MS, time of switch from the observational period to sirolimus period; M12, end of the study, at month 12; NA, not applicable.
The t test was used for all vascular malformations and Wilcoxon tests were used for venous, lymphatic, and combined malformations.
Assessment of Global Efficacy, Pain, Bleeding, and Oozing
Whoever the assessor (physician, participant, or parents), the mean scores of global efficacy significantly increased over time for vascular malformations overall and for each subgroup, with a good correlation of assessment values between assessors (eTable 3 in Supplement 2). Regarding pain, the mean (SD) score (range, 0-10) at baseline was 3.6 (3.0) for VMs, 1.5 (2.5) for LMs, and 3.7 (3.1) for combined malformations. The mean (SD) pain score per unit of time significantly decreased between OP and IP for vascular malformations overall (3.5 [3.2] vs 1.8 [2.3]; P = .004) and for combined malformations (5.1 [3.2] vs 2.1 [2.6]; P = .009), but the decrease was not significant for LMs and VMs (Figure 2; eTable 4 in Supplement 2). The proportion of bleeding and oozing, which occurred at baseline for 23 patients (39.0%) for bleeding (12 LMs and 11 combined malformations) and for 18 patients (30.5%) for oozing (8 LMs and 10 combined malformations), was globally similar at MS and then highly decreased after sirolimus treatment at M12 (bleeding, 3 [5.1%]; oozing, 8 [13.6%]; eTable 5 in Supplement 2).
Figure 2. Patient-Assessed Pain and Physician-Assessed Efficacy.
Pain was assessed by patients on a visual analog scale of 0 to 10 (where 0 indicates no pain and 10 indicates the worst pain imaginable) during the observational period and interventional period for all vascular malformations (A), venous malformations (B), lymphatic malformations (C), and combined malformations (D). Global efficacy was assessed on a visual analog scale of 0 to 10 (where 0 indicates no efficacy and 10 indicates complete resolution) by investigator physicians, patients, and parents, starting from the time of switch to sirolimus to the end of the study for all vascular malformations (A), venous malformations (B), lymphatic malformations (C), and combined malformations (D).
Assessment of Efficacy Based on Photographs
Photographs at M0, MS, and M12 were available for 47 patients (18 VMs, 13 LMs, and 16 combined malformations) (eFigure 3 in Supplement 2). Agreement between both experts was good (Cohen κ = 0.58; P < .001). The experts successfully identified the LM at M12 in 10 of 13 patients (76.9%; 95% CI, 46.0%-93.8%; P = .002) and 8 of 13 patients (61.5%; 95% CI, 32.3%-84.9%; P = .06). For VMs and combined malformation, 1 reviewer failed in doing better than hazard.
Effect on QoL
At baseline, for 16 of 59 children (27.1%), the vascular malformation had no effect on QoL (C-DLQI score, 0 or 1). At M12, the number of children with a C-DLQI score of 0 or 1 reached 32 (54.2%). When considering changes in the C-DLQI score over time, we observed significant positive interactions between time and sirolimus treatment, both globally and in VMs and LMs, but not for combined malformations (eTable 6 in Supplement 2).
Safety
During this study, 56 patients experienced 231 adverse events (AEs) during the IP, and 28 patients experienced 54 AEs during the OP (Table 3). Of the 231 AEs during the IP, 89 were probably associated with sirolimus treatment; 5 were serious AEs, including 1 case of viral ileitis, 1 case of septic arthritis of a toe, 1 case of sepsis due to Pseudomonas aeruginosa, 1 case of fecaloma, and 1 deep vein thrombosis of the leg affected by Klippel-Trenaunay syndrome that occurred 6 weeks after beginning sirolimus treatment. There were no pneumocystis infections, although no patients received pneumocystis prophylaxis during the study. Among nonserious AEs likely associated with sirolimus treatment, the most frequent were oral ulcers (29 of 59 patients [49.2%]), upper respiratory infections (22 of 59 patients [37.3%]), and headaches (16 of 59 patients [27.1%]). Most of the nonserious AEs resolved spontaneously. In total, 5 patients discontinued treatment because of AEs. Laboratory test results found a slight transitory elevation of liver enzyme activity in 2 patients and hypercholesterolemia in 2 patients; none required withdrawal from treatment.
Table 3. Serious and Nonserious Adverse Events Reported During the Study.
| Adverse events | Observational period | Interventional period | ||
|---|---|---|---|---|
| Nonseriousa adverse events | Serious adverse events | Nonseriousa adverse events | Serious adverse events | |
| No. of events/No. of patients who experienced an adverse eventb | 54/28 | NA | 231/56 | NA |
| Not related to sirolimus | ||||
| No. of events | 20 | 5 | 14 | 3 |
| No. of patients who experienced an adverse event | 14 | 3 | 10 | 3 |
| Age, median (IQR), y | 13 (11-18) | 17 (17-17) | 11 (7-13) | 13 (12.5-13.5) |
| Not related to sirolimus but to the vascular malformation | ||||
| No. of events | 25 | 4 | 14 | 5 |
| No. of patients who experienced an adverse event | 16 | 1 | 12 | 3 |
| Age, median (IQR), y | 14 (10-16) | 18 | 14 (11-17) | 15 (10-19) |
| Possibly related to sirolimus | ||||
| No. of events | 0 | 0 | 101 | 5 |
| No. of patients who experienced an adverse event | 0 | 0 | 43 | 5 |
| Age, median (IQR), y | NA | NA | 12 (8-15) | 17 (16-17) |
| Probably related to sirolimus | ||||
| No. of events | 0 | 0 | 89 | 0 |
| No. of patients who experienced an adverse event | 0 | 0 | 35 | 0 |
| Age, median (IQR), y | 0 | 0 | 12 (8-14) | 0 |
Abbreviations: IQR, interquartile range; NA, not applicable.
Six nonserious adverse events were not assessable because of too few details.
One patient could experience several adverse events.
End of Study
After the 12-month study period, treatment was maintained for 27 of 59 patients (45.7%). These patients included 8 of 22 with VMs (36.4%), 11 of 18 with LMs (61.1%), and 8 of 19 with combined malformations (42.1%).
Discussion
The study shows that sirolimus treatment had no effect on volume changes detected on MRI scans of slow-flow vascular malformations overall associated with the duration period in slow-flow vascular malformations but significantly decreased the volume of LMs when analyzing subgroups. In no case was complete regression observed. Sirolimus treatment also had positive effects on end points associated with symptoms such as pain (especially in combined malformations), bleeding, oozing, and QoL.
These data are consistent with the study by Adams et al,24 which included 61 individuals aged 21 days to 28.5 years with heterogeneous VMs treated with approximately the same dosage of sirolimus as in our study. In most cases (83%), a partial response was observed after 6 courses of treatment, with no complete resolution detected on imaging.24 Sirolimus treatment seemed more effective for LMs than for VMs, and the sirolimus treatment profile seemed safe. Also, data from the 19 patients in the monocentric observational study by Hammer et al26 similarly showed the positive effects of sirolimus treatment on pain and QoL of patients with slow-flow vascular malformations. Therefore, an international project (Outcome Measures for Vascular Malformations [OVAMA]) involving a large panel of physicians and patients was initiated to develop a core set of outcome measures for vascular malformations, with goals not just focused on reducing the volume of malformations but also improving symptoms and QoL.32
Another study by Parker et al33 tested a low regimen of sirolimus for 39 patients with well-identified entities of PIK3CA-related overgrowth spectrum. The authors found a significant mean reduction in volume of 7.2% after a 26-week treatment period in the affected tissues—fatty tissues and not vascular tissue—which is different from our study. The rates of toxic effects seemed higher than in our study (18% discontinued treatment), although the sirolimus dosage was lower. This finding may be associated with the study population (severe PIK3CA-related overgrowth spectrum and participants older than in our study).
The effect of sirolimus are due to the inhibition of the mTOR pathway, with subsequent effects on angiogenesis and lymphangiogenesis.20,34 Huber et al34 evidenced the antilymphangiogenic properties of sirolimus by showing that, in animal models, mTOR inhibition impairs downstream signaling of vascular endothelial growth factor A and vascular endothelial growth factor C in lymphatic endothelial cells. Therefore, inhibiting mTOR may help decrease the volume and the symptoms associated with lymphatic anomalies, even with no evidence of PIK3CA variants. Somatic variants of the gene TEK were identified only in patients with VMs in our study. TEK is also upstream of mTOR action. We found that pain was higher among patients with VMs and combined malformations than those with with LMs. This finding is probably associated with intramalformation thrombosis and localized intravascular coagulopathy within venous malformative vessels.10,35,36 A decrease in pain per unit of time was significant with combined malformations only. These results echo the study by Mack et al37 of 12 patients with combined malformations, which suggested that sirolimus treatment improves coagulopathy (as evidenced by a reduced d-dimer level) and decreases pain likely associated with localized intravascular coagulopathy. Also, Limaye et al38 demonstrated that dysregulation of coagulation cascade components in the endothelium may be associated with TEK and PIK3CA variants. Our study included too few genetic data to allow for comparing pain according to likely causal genes.
The question of the optimal age for initiating sirolimus treatment remains to be answered. Earlier age (corresponding to a precocious stage of development of the vascular malformation) may be associated with increased efficacy. In fact, in the series by Adams et al,24 younger patients seemed to exhibit a more substantial response. A few publications also reported cases of very young infants with cervical or orbital LMs39,40 with very good results on volume reduction and prevention of volume increase with sirolimus.
Rates of toxic effects do not seem to be higher for children from 6 to 12 years of age vs older children. In our study, serious AEs occurred among children at a median age of 17 years (interquartile range, 17-17 years). Safety data in the literature (almost all in the short or medium term) are even quite reassuring for very young infants with Kasabach-Merritt phenomenon treated with sirolimus.41 In our study, AEs were consistent with those described in the literature,18,24,26 with the most frequent being oral ulcers in 49.2% of patients. Oral ulcers are reported in the literature in 3% to 60% of patients and usually do not require treatment withdrawal.18,24,42,43 Oral ulcers probably result from direct toxic effects of mTOR inhibitors on mucosal membranes and might be dose dependent.44 The other classic AEs are digestive symptoms, asthenia, upper respiratory tract infections, cytopenia, and an increase in serum levels of cholesterol, triglycerides, and, rarely, glucose.18,24,26,33,42
Limitations
Our study has some limitations. First, children younger than 6 years were not included in the study. Second, the study was not blinded, but we overcame the risk of bias by using an objective primary outcome. Third, our study design did not allow for controlling for time as a possible confounding factor when analyzing the primary outcome, contrary to the pain outcome, because we had only 3 measurements per patient.29
Conclusions
This study allows for clarifying the goals of patients and families when starting sirolimus therapy for children older than 6 years. Lymphatic malformations seem to be the best indication because we found evidence of an effect of sirolimus treatment on decreasing LM volume, oozing, and bleeding and improving QoL. In combined malformations, sirolimus treatment significantly reduced pain, oozing, and bleeding. Benefits, also based on symptoms only, seemed lower with pure VMs than the 2 other subgroups. Questions remain on the optimal age to initiate sirolimus therapy to potentially prevent an increase in the volume of vascular malformations and on how long treatment must be maintained.
Trial Protocol
eFigure 1. The Randomized Observational-Phase Design: Data Collection for the Primary Outcome (on MRI)
eTable 1. Correlation Between Post-Zygotic Mutations and Phenotype of Vascular Malformations
eTable 2A. Assessment of Pain
eFigure 2. Evolution of Pain During the Study According to Genotypes
eTable 2B. Proportion of Patients With C-DLQI=0 or 1 (No Decrease of Quality of Life Due to the Malformation) According to Genotypes
eTable 3. Global Assessment of Efficacy of Sirolimus According to the Investigator Physicians, Patients and Parents
eTable 4. Effect of Sirolimus on Pain, Self-Assessed by Patients
eTable 5. Evolution of Bleeding and Oozing
eTable 6. Effect of Sirolimus on Quality of Life by Using the C-DLQI
eFigure 3. Photos of Capillaro-Veno-Lymphatic Malformation of the Back With Overgrowth at M0 (Baseline), MS (Time of Switch to Sirolimus) and M12 (End of Study); Gluteal Microcystic Lymphatic Malformations at M0, MS, and M12; Cervical Venous Malformation at M0, MS, and M12
eFigure 4. TSE T2 Axial Slices With Fat Signal Saturation With 4-mm Thickness Performed With a Siemens 1.5T MRI
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol
eFigure 1. The Randomized Observational-Phase Design: Data Collection for the Primary Outcome (on MRI)
eTable 1. Correlation Between Post-Zygotic Mutations and Phenotype of Vascular Malformations
eTable 2A. Assessment of Pain
eFigure 2. Evolution of Pain During the Study According to Genotypes
eTable 2B. Proportion of Patients With C-DLQI=0 or 1 (No Decrease of Quality of Life Due to the Malformation) According to Genotypes
eTable 3. Global Assessment of Efficacy of Sirolimus According to the Investigator Physicians, Patients and Parents
eTable 4. Effect of Sirolimus on Pain, Self-Assessed by Patients
eTable 5. Evolution of Bleeding and Oozing
eTable 6. Effect of Sirolimus on Quality of Life by Using the C-DLQI
eFigure 3. Photos of Capillaro-Veno-Lymphatic Malformation of the Back With Overgrowth at M0 (Baseline), MS (Time of Switch to Sirolimus) and M12 (End of Study); Gluteal Microcystic Lymphatic Malformations at M0, MS, and M12; Cervical Venous Malformation at M0, MS, and M12
eFigure 4. TSE T2 Axial Slices With Fat Signal Saturation With 4-mm Thickness Performed With a Siemens 1.5T MRI
Data Sharing Statement
