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.
Study Highlights.
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
Sirolimus is an effective treatment option for patients with vascular malformations. High target sirolimus levels of 10–15 ng/mL were well‐tolerated, although serious toxicities were regularly observed.
WHAT QUESTION DID THIS STUDY ADDRESS?
This trial addresses the question whether low target levels of sirolimus are as effective as reported higher target levels and whether there is a difference in response in children compared with adults.
WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
The trial proved that in vascular malformations, based on exploratory analysis, sirolimus was effective and safe at low target levels. This was comparable with reported high target levels, but resulted in significant less serious adverse events.
HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
These data show that trials are needed to investigate whether drugs used for repurposing are used in the right dose. This trial indicates that low target levels of sirolimus are comparably effective for treatment of vascular malformations, as is shown in studies performed previously with high target levels.
INTRODUCTION
Slow‐flow vascular malformations comprise a group of congenital defects that occur during angiogenesis in the embryological phase. Depending on type and location of the vascular lesion, patients can experience pain, hypertrophy, functional impairment, lymph leakage, and infections. Local thrombo‐embolic events in the vascular malformation in combination with inflammation may cause the pain. Due to symptoms, many patients experience a high disease burden and subsequently a reduced health‐related quality of life (HRQOL). 1 Little is known whether children with a vascular malformation present themselves differently from adults; however, it seems that pain is the most common complaint in both groups. 2 , 3 , 4
Current treatment options may be conservative (compression bandage), medication‐based (analgesics, anti‐inflammatory, or anti‐coagulation drugs) or invasive (sclerotherapy, embolization, or surgery). 5 Unfortunately, these methods are not sufficient in all patients. For example, only one half of the patients reported improvement after treatment (e.g., sclerotherapy). 6
In the past decade, several studies have demonstrated that sirolimus led to a (partial) reduction of vascular‐malformation‐related symptoms. 7 , 8 , 9 , 10 , 11 Response to sirolimus was seen in patients who were resistant to standard therapy or had no other treatment options. 7 , 8 , 9 , 10 , 11 In vascular malformations, a somatic or germline (e.g., phosphatase and tensin homolog gene) genetic mutation led to an activation of the phosphoinositide 3‐kinases/serine/threonine kinase/mammalian target of rapamycin‐pathway (PI3K/AKT/mTOR‐pathway). Sirolimus is an inhibitor of mTOR, which has antiproliferative and anti‐angiogenic/lymphangiogenic properties. By sirolimus inhibition of the pathway, patients experienced improvement of their pain and other vascular‐malformation‐related symptoms, such as oozing, HRQOL and even in some patients a reduction of vascular malformation size.
Sirolimus can give severe side effects especially when blood levels of sirolimus are high (>10 ng/mL). 12 , 13 , 14 The reported adverse events (AEs) are diverse and can be life threatening (e.g., infections and interstitial pneumonitis). 12 , 15 , 16 , 17 Kahan et al. showed a significant relation between the occurrence of some side effects and the steady‐state concentration (C ss) value of sirolimus. 18 These Aes did not occur when the C ss was below 10 ng/L. Recently, our group described a case series of 12 patients (children and adults) that showed that C ss concentrations below 10 ng/L sirolimus was therapeutically effective, but was accompanied with a low incidence of Aes. 19
Therefore, a clinical trial was designed to investigate the efficacy and toxicity of sirolimus using low target levels. These objectives were investigated in respect to the age of patients, as pharmacological aspects can be age‐dependent and might influence pharmacokinetic (PK) and pharmacodynamic outcome. 20
METHODS/DESIGN
A nationwide prospective phase IIB open‐label single‐arm clinical trial was conducted in patients with therapy‐resistant slow‐flow vascular malformation. All patients were enrolled in a single tertiary referral center between September 2017 and February 2021.
The protocol was approved by the Central Committee on Research Involving Human Subjects (CCMO) in the Netherlands. The clinical trial (NCT03987152; EudraCT 2016‐002157‐38) was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Informed consent was obtained from all patients and/or their legal representatives.
Patients
The main inclusion criteria in this trial consisted of a diagnosis of a slow‐flow vascular malformation that was refractory/resistant to standard care and an age above 1 year (Table S1). To exclude patients who may have other treatment alternatives, each patient was discussed in a multidisciplinary team. All case‐series patients were included in the clinical trial as they were treated according to a similar protocol. 19
Treatment
For children, sirolimus (Rapamune) was prescribed with a start dose of 0.8 mg/m2 in two doses, and for adults, a standard start dose of 1 mg twice daily. Dose adjustments were based on plasma levels of sirolimus at each visit to reach target levels of 4–10 ng/mL.
Co‐trimoxazole was prescribed as prophylaxis (Table S2).
Clinical trial design
Patients were included in the single‐arm open‐label trial following the challenge–dechallenge–rechallenge (CDR) trial design. Patients were started with a 6‐month treatment period with sirolimus (challenge phase). After completion of the 6‐month challenge phase, patients were no longer treated with sirolimus in the dechallenge phase, consisting of monthly follow‐up, with a maximum duration of 12 months. Treatment was resumed if pain or other symptoms of the vascular malformation were noted and continued for a treatment period of 12 months (rechallenge phase). See Table S2 for additional information.
Outcomes
Primary outcome: Change in pain and health‐related quality of life
The primary outcome of the trial was either reduction of pain related to the vascular malformation or improvement of HRQOL or both. Therefore, patients recorded a daily pain score starting 2 months before trial medication was given (baseline) until the end of the clinical trial. Pain was recorded using the Children and Infants Postoperative Pain Scale for children aged 0–3 years, visual analog scale (VAS) clinical pictures for children aged 4–7 years, VAS for patients aged 8–17 years and numeric pain rating scale (NRS) for adults. 21 , 22 , 23 These measurement tools are frequently used for patient global assessment and are internationally recognized as being adequate. Pain symptoms were evaluated in each patient (also in patients who did not experience pain at baseline), during the entire trial. The pain symptoms evaluation (no change/improvement/worsening) was based on the information given by the patient and/or parents.
Before and after each phase, the HRQOL was assessed by Research and Development‐36 (RAND‐36) questionnaires for adults. 24 , 25 The TNO‐AZL (Nederlandse Organisatie voor toegepast‐natuurwetenschappelijk onderzoek van het Academisch Ziekenhuis in Leiden) Preschool Children Quality of Life Questionnaire 26 , 27 was used for parents of 1‐year‐old children. The parents' version of the Pediatric Quality of Life Inventory 4.0 Generic Core Scales was used for the parents of children aged 2–17 years and the children's PedsQL version for children aged 5–17 years.
Primary outcomes results were expressed by the number of patients with a response after the challenge phase as a percentage (N response/N total evaluable patients). During the whole trial, changes in assessments of pain scores were analyzed by mixed linear regression with a patient random effect and trial phase as fixed effect. Bonferroni correction was used for multiple testing.
Secondary outcomes: Clinical symptoms and imaging
Secondary outcomes were clinical symptoms, change of the size of the vascular malformation on two‐dimensional magnetic resonance imaging (2D‐MRI), and safety.
Clinical symptoms at baseline were evaluated and classified in three categories at each visit: worsening, stabilization, or improvement.
Overall symptoms and size of the vascular malformation were expressed by the number of patients with a response during the challenge phase as a percentage (N responded patients/N total evaluable patients).
The size of the vascular malformation was evaluated (before and after each phase) using 2D‐MRI with a standardized protocol, and changes were noted on 2D‐MRI scans by experienced radiologists.
Secondary outcome: Safety
AEs were reported and assessed according to the Common Terminology Criteria for Adverse Events 4.03.
The percentages of Aes attributable to sirolimus were calculated (N Aes/N total number of Aes). The percentage per AE category (specified by grades II–IV) was calculated by the number of Aes of the category divided by the total number of Aes.
Exploratory analysis
The following exploratory analyses were performed: patient characteristics; time (days) until first response, recurrence of pain after stopping and restarting of sirolimus; and disease response to sirolimus. Additional exploratory analyses were carried out to explore the differences per trial phase and disease response: patient characteristics (e.g., child/adult and vascular malformation type) and sirolimus PK level.
The optimal assessment of disease response in patients with slow‐flow malformation has not been established; therefore, the overall benefit/risk assessment after the challenge phase was determined on four items: pain evaluation, HRQOL, clinical symptoms assessment, and MRI results. 7 , 28 , 29 If pain symptoms and HRQOL had not changed, clinical symptoms and the vascular anomaly on MRI were evaluated on difference to determine total response (Table 1). Patients were classified as responder to sirolimus in case of complete remission (CR; no evidence of disease) or partial remission (PR; reduction in one or more items), or did not respond (nonresponder) to sirolimus in case of stable disease (SD; no change in one of the items) or progressive disease (PD; worsening in one or more items; Table 1).
TABLE 1.
Exploratory analysis: categorized responses.
| Total response of sirolimus | ||
|---|---|---|
Disease response will be established by changes in at least one item, according to the following criteria:
| ||
| Responder | CR | No evidence of disease symptoms clinically or on radiologic imaging and normalization of HRQOL |
| PR |
|
|
| Non‐responder | PD |
|
| SD | No change on pain, HRQOL, vascular lesion, clinical symptoms, or size or amelioration on MRI | |
Note: Based on Adams et al., 7 Horbach et al., 28 and Frendl et al. 29 The overall benefit/risk assessment was determined either by improvement of pain and/or HRQOL. Symptoms and the MRI were a secondary outcome as described in the main text, if pain and HRQOL did not change, a change of the vascular anomaly on clinical symptoms and MRI were evaluated to determine the total response. In children, if the HRQOL score of children differed with the HRQOL of their parents, then it was classified as stable disease. If PCS or MCS differed, the preference of PCS was used to classify the change.
Abbreviations: CR, complete remission; HRQOL, health‐related quality of life; MCS, Mental Component Summary; MRI, magnetic resonance imaging; NRS, numeric pain rating scale; PCS, Physical Component Summary; PD, progressive disease; PedsQL, Pediatric Quality of Life Inventory; PR, partial remission; SD, stable disease; SF‐36, Medical Outcomes Study 36‐Item Short Form; VAS, visual analog scale.
Descriptive statistics were used for the results of patients’ demographic characteristics, laboratory results, and the number of patients needed to restart.
The Kaplan–Meier (KM) analysis was used for the calculation of the time until first response, recurrence of symptoms, and time before restart sirolimus. The differences between children and adults in these items were calculated by KM analyses and Cox regression analyses.
Chi‐square analyses were performed to analyze differences among children/adults, gender, vascular malformation types, mutation type, and sirolimus PK groups in terms of primary, secondary, and exploratory outcomes (pain, HRQOL, overall symptoms, imaging results, safety, laboratory values, and disease response).
To evaluate the differences in pain scores between adults and children, a mixed linear regression was used. Pain scores were presented using estimated marginal means (EMMs) with 95% confidence interval (CI).
T‐tests were used to analyze the differences between laboratory values and patient characteristics; in case of skewed data, nonparametric tests (Mann–Whitney U test) were used.
Spearman's and Pearson's correlations were calculated for correlation of sirolimus target trough level and PK groups in relation to toxicity and disease response. PK groups were defined as (group 1 very low mean level sirolimus <7 ng/mL and group 2 low mean level sirolimus ≥7 ng/mL).
The analyses of disease response of treatment were performed with inclusion and exclusion of case‐series patients.
Statistical analysis
Power analysis
Before starting the trial, a power analysis was performed, estimating the number of patients to be included. Based on the literature and verified in the first 12 patients (of the case series), we expect that pain can be reduced in at least 80% of patients. To estimate an 80% response rate in patients treated with sirolimus with a 10% accuracy and an alpha of 5%, 61 patients were needed. To be able to perform subgroup analysis (child/adult) and accounting for an estimated dropout rate of 10%–20%, the goal was to include 75 patients.
Data were analyzed in SPSS. In case of missing data, patients were excluded from analysis. Means and standard deviations or 95% CI for continuous variables and proportions for nominal variables were given. In case of skewed data, medians with interquartile ranges or 95% CI for median for these variables were presented. All p values depicted two‐sided tested. Results were considered statistically significant if p ≤ 0.05.
RESULTS
In total, 74 patients (mean age 23 years, range 1–60 years) were enrolled at the Radboud University Medical Center between September 2017 and February 2021. Seven patients did not complete the challenge phase. Reasons for not completing the challenge phase were related to the patients’ (and/or parents’) request (n = 3), noncompliance (n = 2), lost to follow‐up (n = 1), and not following the challenge phase according to protocol (n = 1; Figure 1). Table 2 shows patient characteristics of the evaluable patients.
FIGURE 1.
Patient distribution and inclusion in analysis. In total, 67 patients were included in the challenge phase and one extra patient was included in the rechallenge phase, resulting in a total of 68 patients who were evaluable for the evaluation of the trial. In total, 11 case‐series patients were included. One case‐series patient did not complete the challenge phase and was left out of the analysis. Clinical trial surveys were not sent out to the first 12 patients (described in the case series); due to a different protocol, the remaining 56 patients received the HRQOL questionnaires. In total 44, questionnaires (response rate = 78.6% (n = 44/56), n = 19 children, n = 25 adults) before and after the challenge phase were completed. Despite repeated requests, data of 12 patients were missing: four patients (3 children, of whom 1 child due to TAPQL, and 1 adult) at baseline and eight patients (3 children and 5 adults) at the end of the challenge phase. For the analysis of recurrence, 84.6% (n = 44/52) of the responders were evaluable. Patients were left out of analysis for several reasons (medical reasons for continuing sirolimus n = 2, only response by imaging and no response in symptoms n = 2, case‐series patients n = 3, and end of the clinical trial n = 1). HRQOL, health‐related quality of life; MRI, magnetic resonance imaging.
TABLE 2.
Demographic characteristics of included patients.
| Characteristic | Total (n = 68) | Children (n = 33, 48.5%) | Adults (n = 35, 51.4%) | Descriptives results |
|---|---|---|---|---|
| Age, years, mean ± standard deviation | 23.0 ± 16.4 | 9.3 ± 4.78 | 36.0 ± 12.37 | p < 0.001 |
| Age groups, years, n (%) | p < 0.0012 | |||
| Under 2 | 3 (4.4) | 3 (9.1) | – | |
| 2–4 | 4 (5.9) | 4 (12.1) | – | |
| 5–7 | 4 (5.9) | 4 (12.1) | – | |
| 8–12 | 14 (20.6) | 14 (42.4) | – | |
| 13–17 | 8 (11.8) | 8 (24.2) | – | |
| 18 and older | 35 (51.5) | – | 35 (100) | |
| Gender, n (%) | p = 0.17733 | |||
| Male | 24 (35.3) | 9 (27.3) | 15 (42.9) | |
| Female | 44 (64.7) | 24 (72.7) | 20 (57.1) | |
| Vascular malformation type, n (%) | p = 0.0412 | |||
| Lymphatic malformation a | 26 (38.2) | 17 (51.5) | 9 (25.7) | |
| Venous malformation b | 29 (42.6) | 13 (39.4) | 16 (45.7) | |
| Combined malformation c | 11 (16.2) | 2 (6.1) | 9 (25.7) | |
| Other d | 2 (2.9) | 1 (3.0) | 1 (2.9) | |
| Vascular malformation location, n (%) | ||||
| Head and neck | 18 (26.5) | 13 (39.4) | 5 (14.3) | p = 0.0462 |
| Thorax | 4 (5.9) | 0 (0.0) | 4 (11.4) | |
| Abdominal | 4 (5.9) | 1 (3.0) | 3 (8.6) | |
| Upper extremity | 5 (7.4) | 1 (3.0) | 4 (11.4) | |
| Lower extremity | 27 (39.7) | 12 (36.4) | 15 (42.9) | |
| Multiple locations | 10 (14.7) | 6 (18.2) | 4 (11.4) | |
| Type of mutation, n (%) e | ||||
| Activating PIK3CA mutation | 20 (29.4) | 13 (39.4) | 7 (20.0) | p = 0.1462 |
| Activating TEK mutation | 3 (4.4) | 1 (3.0) | 2 (5.7) | |
| Activating PTEN mutation | 1 (1.5) | 1 (3.0) | 0 (0.0) | |
| Activating mutation IDH1 | 1 (1.5) | 1 (3.0) | 0 (0.0) | |
| Combined activating mutation f | 1 (1.5) | 0 (0.0) | 1 (2.9) | |
| No mutation found | 9 (13.2) | 3 (9.1) | 6 (17.1) | |
| Measurement failed (e.g., low quantity of tissue) | 2 (2.9) | 2 (6.1) | 0 (0.0) | |
| No tissue available (n = 27) or diagnostics done (n = 4) | 31 (45.6) | 12 (36.4) | 19 (54.3) |
Note: Significant differences were seen in age, age groups, vascular malformation type, and location (frequently more children had a lymphatic malformation and a vascular malformation in the head and neck region compared to adults). No other significant differences (gender, vascular malformation type, and mutation type) were seen between children and adults. Vascular malformation type and location had no influence in response.
1Independent Samples test, 2Fisher's Exact test, 3Likelihood Ratio.
Lymphatic malformation, including Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevis, Spinal/Skeletal Anomalies/Scoliosis [CLOVES] syndrome (n = 1), lymphangiomatosis (n = 3).
Venous malformation including Blue Rubber Bleb Nevus syndrome (n = 1) and angio‐osteohypertrophy syndrome with venous malformation (n = 1).
Combined malformation: n = 7 Klippel Trenaunay Syndrome [KTS], n = 3 veno‐lymphatic malformation, and n = 1 capillary and venous malformation.
Other vascular malformations: fibro adipose vascular malformation [FAVA] (n = 1), multiple spindle‐cell hemangioma (n = 1).
Retrospective data, because this was not standardly performed by protocol.
Combined activating mutation = NRAS and TEK mutation.
Outcomes
Primary outcome: Change in pain and health‐related quality of life
In total, 67 patients were evaluable to investigate the challenge phase (Figure 1). For analysis of the pain diary (VAS/NRS scores), 47 patients with pain (45 patients in the challenge phase and two patients in the rechallenge phase) were eligible for evaluation of all phases. In total, 14 patients did not experience pain at baseline, and the remaining six patients (case series) with pain did not fill in the pain diary due to a different protocol (Table S3). Of the 45 evaluable patients during the challenge phase, 39 patients filled in diary scores at baseline and at the end of the challenge phase. The baseline EMM VAS/NRS score in these patients was 5.4 (95% CI 4.5 to 6.2); this significantly decreased by −1.8 (95% CI −2.8 to −0.8) after the challenge phase to an EMM VAS/NRS score of 3.6 (95% CI 2.8 to 4.4; Figure 2, Table 3).
FIGURE 2.
Daily pain scores of children and adult per phase. Estimated marginal mean (EMM) pain scores during the challenge phases and all phases of responders who restarted with sirolimus per patient group child/adult. Number of patients per phase is showed in boxes. Baseline includes data of 2 months before the challenge phase, the challenge phase has a duration of 6 months of treatment, the dechallenge phase has a duration of maximum of 12 months, and the rechallenge phase had a total duration of 12 months (data of the first 4 months are presented). *EMM pain scores of patients who completed the dechallenge phase in the diary and did not restart during the rechallenge phase are presented at month 18. EMM pain scores of 1 month before restart in patients who restarted are given at month 19.
TABLE 3.
Primary and secondary outcome results after challenge.
| Results after the challenge phase (6 months sirolimus using low target levels of 4–10 ng/mL) | ||||
| Primary outcomes | ||||
| Pain scores diary | ||||
| Pain diary completion | All patients | Children | Adults | Difference children/adults |
| Baseline (n) | 39 | 14 | 25 | NA |
| Challenge (n) | 45 | 19 | 26 | |
| After challenge (n) | 39 | 15 | 24 | |
| Pain | All patients | Children | Adult | Difference children/adults |
|
Baseline EMM [95% CI] |
5.4 [4.5; 6.2] | 4.1 [2.9; 5.4] | 6.2 [5.2; 7.2] |
−2.1 [−3.7 to −0.5], p = 0.011b |
| After challenge EMM [95% CI] | 3.6 [2.8; 4.4] | 2.7 [1.4; 4.0] | 4.3 [3.2; 5.4] | After challenge: NA* |
|
Difference EMM [95%CI] |
−1.8 [−2.8 to −0.8], p < 0.001a |
−1.5 [−3.1 to 0.08], p > 0.05a |
−1.9 [−3.2 to −0.5], p < 0.001a |
|
| Change in pain symptoms1 | ||||
| Item | All patients | Children | Adult | Difference children/adults |
| Pain evaluation (n) | 67 | 32 | 35 | NA |
| Item | All patients | Children | Adult | Difference children/adults |
| No change in pain, n (%) | 29 (43.3) | 13 (40.6) | 16 (45.7) | p > 0.05c |
| Improvement of pain, n (%) | 37 (55.2) | 19 (59.4) | 18 (51.4) | |
| Worsening of pain, n (%) | 1 (1.5) | 0 (0.0) | 1 (2.9) | |
| Change in HRQOL | ||||
| Item | All patients | PedsQL (children/parents) | SF‐36 (adults2 ) | Difference children/adults |
| Baseline (n) | 51 | 20 | 31 | NA |
| After challenge (n) | 49 | 22 | 27 | |
| Baseline and after challenge phase (n) | 44 | 18 | 26 | |
| Not possible to perform HRQOL analysis due to missing data (n) | 23 | 14 | 9 | |
| Item | All patients | Children | Adult | Difference children/adults |
| No change, n (%) | 11 (25.0) | 3 (16.7) | 8 (30.8) | p > 0.05c |
| Improved HRQOL, n (%) | 29 (65.9) | 15 (83.3) | 14 (53.8) | |
| Worsening of HRQOL, n (%) | 4 (9.1) | 0 (0.0) | 4 (15.4) | |
| Secondary outcomes | ||||
| Change of symptoms related to the vascular malformation (with the exclusion of pain) | ||||
| Item | All patients | Children | Adult | Difference children/adults |
| Evaluation of symptoms (n) | 67 | 32 | 35 | NA |
| Item | All patients | Children | Adult | Difference children/adults |
| No change, n (%) | 17 (25.4) | 4 (12.5) | 13 (37.1) | p = 0.018d |
| Improvement of symptoms, n (%) | 50 (74.6) | 28 (87.5) | 22 (62.9) | |
| Worsening of symptoms, n (%) | 0 (0.0) | 0 (0) | 0 (0) | |
| Change in size of the vascular malformation at 2D‐MRI | ||||
| Item | Item | Children | Adult | Difference children/adults |
| Baseline MRI (n) | 65 | 32 | 34 | NA |
| End of challenge MRI (n) | 64 | 32 | 32 | |
| Possible for evaluation change | 62 | 31 | 31 | |
| Measurement not possible or missing MRI | 5 | 1 | 4 | |
| Item | All patients | Children | Adult | Difference children/adults |
| No change in volume, n (%) | 39 (62.9) | 19 (61.3) | 20 (64.5) | p > 0.05c |
| Decreased volume, n (%) | 22 (35.5) | 12 (38.7) | 10 (32.3) | |
| Increased volume, n (%) | 1 (1.6) | 0 (0) | 1 (3.2) | |
| Safety AEs attributable to sirolimus | ||||
| Item | Total AEs | AEs in children | AEs in adults | Difference children/adults |
| Evaluation of AEs (n) | 67 | 32 | 35 | NA |
| Item | Total AEs | AEs in children | AEs in adults | Difference children/adults |
| Grade I (n, %) | 202 (73.2) | 72 (72.7) | 130 (73.4) | p > 0.05c |
| Grade II (n, %) | 67 (24.3) | 22 (22.2) | 45 (25.4) | |
| Grade III (n, %) | 6 (2.2) | 4 (4.0) | 2 (1.1) | |
| Grade IV (n, %) | 1 (0.4) | 1 (1.0) | 0 (0.0) | |
| Occurrence of grade I–IV AEs (n) (% of total AEs) | 276 | 99 (35.9) | 177 (64.1) | p > 0.05 e |
| Serious AEs attributable to sirolimus (n) | 3 | 3 | 0 | NA |
Note: Total number of patients in the challenge phase = 67 (child n = 32, adult n = 35). 1The pain diary presents the daily NRS/VAS pain score, in addition, pain symptoms are evaluated without the use of the daily NRS/VAS scores. 2The SF‐36 questionnaire was sent to adult patients and patients who reached the age of 18 years during the challenge phase (n = 1 child). aMixed linear regression with a patient random effect and trial phase as fixed effect, with Bonferroni correction to account for multiple testing. bMixed linear regression was used with a patient random effect and trial phase and child/adult as fixed effects. cFisher–Freeman–Halton Exact test. dLikelihood ratio. eIndependent t‐test.
Abbreviations: 2D‐MRI, two‐dimensional magnetic resonance imaging; AE, adverse event; CI, confidence interval; EMM, estimated marginal mean; HRQOL, health‐related quality of life; MRI, magnetic resonance imaging; NA, not applicable; NRS, numeric pain rating scale; PedsQL, pediatric quality of life; SF‐36, Short Form Health Survey‐36; VAS, visual analog scale.
Due to interaction between phases, no difference between challenge phase could be calculated.
For evaluation of change in pain symptoms at the end of the challenge phase, all patients were evaluable (n = 67). During the challenge phase, 43.3% (29/67) of patients experienced no change in pain (including all patients who did not experience pain at baseline), 55.2% (37/67) of patients experienced improvement of pain, and 1.5% (1/67) of patients experienced worsening of pain (Table 3).
For analysis of HRQOL, 56 patients were evaluable. Due to different protocol case‐series patients did not receive the HRQOL surveys. There were 78.6% (44/56) of the patients who completed the HRQOL surveys at baseline and at the end of the challenge phase (Figure 1). In total, 65.9% of (n = 29/44) patients experienced an improved HRQOL at the end of the challenge phase. In adults (n = 26 including one child who reached the age of 18 years during the challenge phase), the mean scores of the Mental Component Summary significantly increased by a mean of 3.6 points (standard deviation 8.3). The mean scores of the Physical Component Summary significantly increased by 6.2 (standard deviation 9.5). Total scale scores of children and parents significantly increased by 9.9 (standard deviation 12.6) and 10.9 (standard deviation 10.7), respectively. Remarkably, there is a numeric difference between children and adults regarding improved HRQOL (children n = 15/18, 83.3% vs. adults n = 14/26, 53.8%). Worsening of HRQOL occurred in 0.0% of the children (n = 0/18) and 15.4% (n = 4/26) of the adults (Table 3).
Secondary outcomes: Clinical symptoms and imaging
All 67 patients were evaluable for the analysis of evaluation of symptoms after the challenge phase.
In total, 74.6% (50/67) of patients experienced an improvement of clinical symptoms. Improvement of clinical symptoms was defined as clinical size decrease (21 patients), improvement of activities/functioning (15 patients), and improvement of energy/condition/endurance (9 patients). Examples of other symptoms were reduction in inflammation/infection, less frequent thrombophlebitis, and more strength (Table 3; Table S3). Some patients experienced that their multiple symptoms improved.
In total, in 62 patients, 2D‐MRI images were made at baseline and at the end of the challenge phase and therefore were evaluable for change (Figure 1). In three case‐series patients, no 2D‐MRI images were evaluable for change due to a different protocol, and for the remaining two patients, no evaluation was possible due to medical/technical reasons. No change of the vascular malformation size or amelioration/progression was seen in the majority of patients (62.9%, n = 39/62). In 35.5% (n = 22/62) of the patients, an amelioration/decrease in size was noticed; 1.6% (n = 1/62) of the patients showed progression (Table 3; Figures S1 and S2). The 2D‐MRI images of the patients are given in Figure S1.
Secondary outcome: Safety
All patients (n = 67) were evaluable for evaluation of AEs. During the challenge phase, 38 patients (15 children and 23 adults) experienced sirolimus‐related grade II–IV AEs.
The most observed grade II–IV AEs were infections, neurologic toxicities (e.g., headaches), metabolic/laboratory toxicities, gastrointestinal toxicities (e.g., mucositis), pulmonary/upper respiratory infections, and general symptoms (e.g., hypertension/tiredness; Table 4). None of the patients experienced interstitial lung disease or severe blood/bone marrow toxicities attributable to sirolimus.
TABLE 4.
Grade II–IV adverse events attributed to sirolimus.
| Attribution to sirolimus | |||||
|---|---|---|---|---|---|
| Toxicity category | Severity of AE | Total, n (%) | Possible | Probable | Definitely |
| Blood/bone marrow toxicity | Grade II | 3 (4.5) | 3 (4.5) | 0 (0) | 0 (0) |
| Grade III | 0 (0) | 0 (0) | 0 (0) | 0 (0) | |
| Gastrointestinal toxicity | Grade II | 10 (14.9) | 4 (6.0) | 4 (6.0) | 2 (3.0) |
| Grade III | 0 (0) | 0 (0) | 0 (0) | 0 (0) | |
| Metabolic/laboratory toxicity | Grade II | 6 (9.0) | 5 (7.5) | 1 (1.5) | 0 (0) |
| Grade III | 4 (6.0) | 3 (4.5) | 1 (1.5) | 0 (0) | |
| Infection (e.g., flu and fever) | Grade II | 12 (17.9) | 11 (16.4) | 1 (1.5) | 0 (0) |
| Grade III | 0 (0) | 0 (0) | 0 (0) | 0 (0) | |
| Grade IV | 1 (1.5) | 1 (1.5) | 0 (0) | 0 (0) | |
| Endocrine toxicity (e.g., menstruation abnormalities) | Grade II | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Grade III | 0 (0) | 0 (0) | 0 (0) | 0 (0) | |
| Dermatologic toxicity | Grade II | 3 (4.5) | 3 (4.5) | 0 (0) | 0 (0) |
| Grade III | 0 (0) | 0 (0) | 0 (0) | 0 (0) | |
| Neurologic toxicity (e.g., headache) | Grade II | 11 (16.4) | 7 (10.5) | 4 (6.0) | 0 (0) |
| Grade III | 0 (0) | 0 (0) | 0 (0) | 0 (0) | |
| Pulmonary/upper respiratory toxicity | Grade II | 6 (9.0) | 5 (7.5) | 1 (1.5) | 0 (0) |
| Grade III | 1 (1.5) | 1 (1.5) | 0 (0) | 0 (0) | |
| Musculoskeletal/soft tissue toxicity | Grade II | 2 (3.0) | 2 (3.0) | 0 (0) | 0 (0) |
| Grade III | 0 (0) | 0 (0) | 0 (0) | 0 (0) | |
| General symptoms (hypertension, pain, tiredness, psychologic (e.g., headache) | Grade II | 7 (10.5) | 7 (10.5) | 0 (0) | 0 (0) |
| Grade III | 0 (0) | 0 (0) | 0 (0) | 0 (0) | |
| Lymphedema | Grade II | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Grade III | 0 (0) | 0 (0) | 0 (0) | 0 (0) | |
Note: Total participants = 67, according to the CTCAE 4.03 criteria. Only one grade IV AE occurred. Percentage presents the frequency of adverse events per category and grade divided by the included patients (n = 67).
Abbreviations: AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events.
Numerically, more grade II–IV AEs occurred in adults 64.1% (177/276) compared with children 35.9% (99/276; Table 3).
Exploratory analyses
Results of the exploratory analyses are shown in Table 5. A first response was seen after a median of 39.0 days (95% CI 0.0 to 86.0), analyzed in all patients. Children had a median response time of 28 days (95% CI 4.4 to 51.5), whereas in adults a median first response after 84 days (95% CI 17.9 to 150.1) was seen (p < 0.05).
TABLE 5.
Exploratory results: differences per children and adults.
| Variable | Children (n = 32) | Adults (n = 35) | Difference children adults p value, test |
|---|---|---|---|
| First response | |||
| First response – time – estimated median days [95% CI] | 28 days [4.4–51.5] | 84 days [17.9–150.1] |
HR 0.58 ([0.33–1.0], p = 0.046) child vs. adults a |
| First response – category – n (%) | |||
| Pain reduction | 14 (43.8) | 14 (40.0) | p > 0.05b |
| Improvement of clinical symptoms | 6 (18.8) | 2 (5.7) | |
| Clinical size reduction | 9 (28.1) | 7 (20.0) | |
| Improvement of laboratory results | 1 (3.1) | 0 (0.0) | |
| No response | 2 (6.3) | 12 (34.3) | |
| Recurrence of symptoms | |||
| Time of recurrence of symptoms – estimated median days [95% CI] | 57 [21.1–92.9] | 76 [0.0–216.8] | p > 0.05c |
| Restart | |||
| Patients restarted – n (% of all 68 patients) | 24 (35.3) | 11 (16.2) | p < 0.001d |
| Laboratory results | |||
| PK level μg/mL median [IQR] | 5.0 [4.0–6.7] | 5.4 [4.5–6.7] | p > 0.05e |
| D‐dimer level (ng/mL) > 500 ng/ml at baseline [median 95% CI] |
Baseline: 1345 [620–2770] After challenge: 1070 [860–2580] |
Baseline: 1315 [820–2300] After challenge: 1030 [600–2280] |
Baseline: p > 0.05e After challenge: p > 0.05e |
| Disease response* | |||
| Overall result after challenge – n (%) | |||
|
Complete remission (all patients 0, 0.0) |
0 (0.0) | 0 (0.0) | p = 0.013b |
|
Partial remission (all patients 53, 79.1) |
30 (93.8) | 23 (65.7) | |
|
Stable disease (all patients 11, 16.4) |
2 (6.3) | 9 (25.7) | |
|
Progressive disease (all patients 3, 4.5) |
0 (0.0) | 3 (8.6) | |
|
Responder (all patients 53, 79.1) |
30 (93.8) | 23 (65.7) | p = 0.006d |
|
Non‐responder (all patients 14, 20.9) |
2 (6.3) | 12 (34.3) | |
Abbreviations: CI, confidence interval; HR, hazard ratio; IQR, inter‐quartile range; p, value of significance; PK, pharmacokinetic.
aMantel–Cox and Cox regression analyses; bFisher–Freeman–Halton Exact test; Chi‐square (Mantel–Cox); dLikelihood ratio; eMann–Whitney U test.
Criteria for response are described in Table 1. Patient may have responded in multiple items.
Children (n = 14) experienced a significant lower EMM pain score compared with adults (n = 25) at baseline, with a mean difference of −2.1 (95% CI –3.7 to −0.5; children EMM 4.1 [95% CI 2.9; 5.4] vs. adults EMM 6.2 [95% CI 5.2; 7.2]; Figure 2, Table 3). When corrected for this difference before the start, no significant difference in EMM pain score was observed between children and adults in the other phases (Figure 2).
After the challenge phase, a decrease in EMM of VAS/NRS scores by −1.8 (95% CI –2.8 to –0.8) was seen: children −1.5 (95% CI –3.1 to –0.08, p > 0.05); and adults −1.9 (95% CI –3.2 to –0.5, p < 0.05; Figure 2, Table 3).
Before the rechallenge phase, patients (n = 14) experienced an EMM pain score of 5.5 (95% CI 4.4 to 6.5); after 4 months (n = 12), the EMM pain score had decreased to an EMM of 3.7 (95% CI 2.7 to 4.8), with a mean decrease of −1.7 (95% CI –3.5 to 0.07, p > 0.05; Figure 2).
After the challenge phase, significantly more children experienced an improvement of symptoms compared with adults (87.5% [28/32] children vs. 62.9% [22/35] adults). After the challenge phase, a PR was observed in 79.1% (n = 53/67), PD in 4.5% (n = 3/67), and SD in 16.4% (n = 11/67) of the patients (Figure 1, Table 3). None of the patients had a CR (Table 3).
There was no difference in response per different vascular malformation type, location, mutation, or different gender (all p > 0.05). The fact that more children had a lymphatic malformation did therefore not influence response rates. A PIK3CA mutation was found in 52.6% (n = 20/38) of the patients; however, it did not influence the response to sirolimus. In addition, subanalysis of different sirolimus plasma levels and group (group 1 [<7 ng/mL, n = 53] and group 2 [≥7 ng/mL, n = 14]) revealed that there were no differences in response. Additionally, no significant difference was seen between the occurrence and quantity of AEs and (PK levels, or between the low or high PK group [4–7 ng/mL vs. 7–10 ng/mL]).
More children responded to sirolimus compared with adults, 93.8% (n = 30/32) versus 65.7% (n = 23/35 adults), χ 2 test <0.05 (Table 3).
DISCUSSION
For rare diseases, such as vascular malformations, repurposing of drugs that intervene on pathways involved provides new therapeutic options and a new perspective. For these new indications, target levels will have to be re‐determined and may be different.
The present clinical trial demonstrates that sirolimus treatment using low target levels in patients with slow‐flow vascular malformations reduces pain, improves HRQOL, and is safe. The disease response (change in pain, HRQOL, symptoms, or size of the malformation) is similar to what is described in the literature for higher target levels (10–15 ng/mL). 7 , 8 As vascular anomalies belong to the rare diseases, it is essential that clinical trials being performed include the same clinical outcome parameters to finally compare results and draw conclusions relevant for clinical practice (EudraCT: 2015–001703‐32). 7 No response in patients may be related to a lower target level, however, the described efficacy is comparable with previous studies using higher target levels. The primary outcome (pain) and secondary outcomes (clinical symptoms and safety) may interact with the secondary outcome, as pain and clinical symptoms reduction can lead to an improved HRQOL, and toxicity may decrease HRQOL. Nevertheless, the HRQOL measures multiple domains besides these aspects.
The case series previously published demonstrated that sirolimus treatment in a small group of children is safe and effective. 19 These results were subsequently confirmed in the present study. The positive results of the 11 responded case‐series patients did not influence the outcome results.
In most patients, a recurrence of symptoms occurred after stopping sirolimus, indicating that lifelong treatment might be necessary. During the 6‐month sirolimus treatment, a very low incidence of greater than or equal to grade III AEs attributable to sirolimus was noted in the current trial. This is in contrast to studies performed previously with high‐dose sirolimus: 10.4% (n = 7/67 patients) in our trial versus 21.1–38.3% greater than or equal to grade III AEs (Table 3). 7 , 8 In the current trial, no significant differences were seen in very low and low target levels, which is possibly due to the small target range or due to the lower occurrence of AEs under 10 ng/ml compared with the reported AEs of high target levels (>10 ng/mL).
As sirolimus (4–10 ng/mL) is well‐tolerated, treatment may be prolonged for a longer time period whereby a persistent further decrease in pain, improved HRQOL, and reduction in symptoms and vascular lesion size may be obtained.
The advantage of a linear mixed model is the possibility to take dependencies between the observations into account. The observations of the same patient have been measured at several times. In this way, the observations are no longer independent, and therefore it is possible to take this into account in the statistical analysis. Moreover, a linear mixed model analyzes all data at once. It is not a problem when a measurement moment is missed, the rest will be included. With linear mixed models it is feasible to specify fixed and random effects.
At baseline, higher pain scores were seen in adults compared with children. This may suggest that pain increases with age and is experienced differently compared with childhood. In respect to this, it might be possible that previous treatments, complications, or development of fibrous tissue in the vascular malformation may cause the difference. This difference in pain between children and adults was observed previously in a study of 2199 patients, which showed that the frequency of pain symptoms in venous malformations increased with age. 2 Another factor that could influence the degree of pain experienced is the size of the vascular malformation: vascular malformations are growing as the child grows, and this might be related to a higher incidence of pain symptoms. 2 Finally, it cannot be excluded that adults may develop a chronic pain syndrome due to a lifelong exposure to pain in the vascular malformation. 30 This could influence pain scores, which we not expect to occur in children.
Although results in respect to pain are promising, these results have to be interpreted with some precaution. One of the primary outcome parameters, pain, is a subjective tool, although VAS/NRS scores were used to quantify changes in pain as far as possible. Furthermore, pain scores might be influenced by other pain symptoms not related to vascular malformations (e.g., headache, muscle ache, or by activities). However, at the same time, previous studies have demonstrated that the VAS/NRS scores can be used in children and adults. 31 , 32
After the challenge phase, some patients had a size reduction of the vascular malformation at 2D‐MRI or a reduction in physical size during physical examination. Therefore, it is of interest to notice that, in the vascular malformation tissue, obvious histopathologic changes of collapse of cavernous vessels were observed, with fibrosis and proliferation of fibroblasts (Figure S2).
In addition, our data show that children responded more often and earlier to sirolimus, compared with adults (Table 3; Figure S3). A good explanation for this difference in response is not available; however, this is an interesting observation as this can lead to clinical consequences. Especially if looking to disease response, response rates in adults were significantly lower than in children. These data are in favor of starting sirolimus at a young age. This difference might be caused by previous treatments and the irreversible consequences or complications thereof, as well as development of fibrous tissue in the vascular malformation. The quantity of treatments may be higher in adults compared with children. Reactive fibrous tissue probably does not bear the genetic alteration that is seen in the vascular lesion that, however, may cause mechanical complaints. Sirolimus will only have a positive effect on the tissue with the genetic alteration leading to activation of the mTOR pathway.
Even though response rates in adults are lower than in children, they are still high, as patients included in the present trial had no other treatment options and were resistant to standard therapy. It would be of interest to investigate, whether, due to treatment with sirolimus, other treatment options such as surgery may become available. Especially in children, it is questionable whether early start of medical treatment with sirolimus would improve future outcome, due to the condition becoming treatable with other therapies as surgery or embolization.
The present trial has some limitations. First, the open‐label single‐arm design might have introduced bias in the outcome measures. Ideally, however, a randomized placebo clinical trial (RCT) design should be performed. Recently, it has been proposed that a CDR design can be used in rare diseases. 33 This design is based on the concept of challenge, dechallenge, and rechallenge to proof the efficacy (or AEs) caused by a single drug. CDR designs are typically used for N‐of‐1 clinical trials to investigate efficacy or verify causality when an adverse drug reaction is suspected. 33 As vascular malformations are rare and heterogeneous, the use of a CDR design offers the opportunity to generate interpretable data on efficacy and safety by analyzing each patient as its own control. We consider this design suitable to investigate the efficacy of new treatments in those rare diseases, for which RCTs are less feasible due to the low numbers of patients affected. 33
The second limitation could be the (initial) missing data of the genetic alterations causing the vascular malformation in our patients, as one would expect that only mutations in the mTOR pathway will benefit of treatment with sirolimus, 34 , 35 Interestingly, the presence of a PIK3CA mutation (52.6% n = 20/38) in patients was not directly related to sirolimus response. In the changing landscape in which more and more targeted therapy becomes available, the clinical urge to know the genetic alteration is increasing, although it remains questionable whether this is the most important factor for response or whether other aspects might play a role. Interestingly, more pharmacologic treatment options are under development, like the drug alpelisib (a phosphatidylinositol‐3‐kinase inhibitor) and especially for those patients with a PIK3CA mutation. 36 , 37 However, clinical trials are underway, and for those not carrying a specific PIK3CA mutation, sirolimus seems to be the best alternative.
Careful target level determination is required to achieve the intended effect without developing serious toxicity. For example, low target levels (2–4 ng/mL) may be sufficient in other vascular anomalies as Kaposiform hemangioendothelioma. Furthermore, especially in neonates and young infants in whom liver enzymes (e.g., CYP3A5), still have to maturate, the determination of target levels is essential. 20 , 38
In conclusion, the effectivity of low target level sirolimus in patients with slow‐flow malformation was comparable with the results described in literature, with a lower incidence of (severe) AEs. In addition, our results suggest that when sirolimus is started at a young age, it is more effective compared with treatment afterward. It would be of interest to analyze this in more detail by an international collaborative initiative giving the opportunity to include patients at different ages worldwide; of course, the long‐term effect and toxicity of sirolimus must also be considered and weighed up.
AUTHOR CONTRIBUTIONS
V.E.M.H., L.G.J.M.Z., G.A.R., W.M.K., C.J.M.V., I.M.P.R., L.G.‐D., U.E.F., B.H.V., P.C.J.L., C.M.A.M.H., L.J.SK., and D.M.W.M.L. wrote the manuscript. D.M.W.M.L. designed the research. V.E.M.H., L.G.J.M.Z., W.M.K., I.M.P.R., L.G.‐D., U.E.F., and D.M.W.M.L. performed the research. V.E.M.H. analyzed the data.
FUNDING INFORMATION
ZonMW funded the clinical trial (grant number: 848015013). Pfizer supported this clinical trial by providing sirolimus (Rapamune).
CONFLICT OF INTEREST STATEMENT
The authors declared no competing interests for this work.
Supporting information
Table S1
Table S2
Table S3
Figure S1
Figure S2
Figure S3
Harbers VEM, Zwerink LGJM, Rongen GA, et al. Clinical differences in sirolimus treatment with low target levels between children and adults with vascular malformations – A nationwide trial. Clin Transl Sci. 2023;16:781‐796. doi: 10.1111/cts.13488
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Supplementary Materials
Table S1
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