Rapid Response to Sirolimus in Patients with PIK3CA-Related Overgrowth Spectrum

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Vascular anomalies (VA) are a heterogenous group of rare vascular disorders that can pose a diagnostic and therapeutic challenge to physicians due to their diverse, yet overlapping, morphology. The International Society for the Study of Vascular Anomalies has divided VAs into vascular tumors and vascular malformations. The latter are defined as somatic mutations that occur during embryogenesis, with the vascular component further subclassified based on the type of vessel involved.¹ Some VAs have a pathognomonic presentation and are easily identified on clinical exam. However, the majority of these lesions require imaging to identify the abnormal vasculature and establish a diagnosis.

The introduction of next-generation sequencing in 2003 allowed for the subclassification of several vascular malformations and overgrowth syndromes based on the presence of pathogenic variants. Genomic analysis revealed that many of these syndromes contain postzygotic somatic gain-of-function pathogenic variants in the phosphatidylinositol-4, 5-bisphospate 3-kinase, catalytic subunit alpha (PIK3CA) gene.² Once phosphorylated, PI3K activates AKT, ultimately leading to increased cell proliferation and angiogenesis via mammalian target of rapamycin (mTOR; Figure 1).^2,3 The mosaic nature of this variant explains the phenotypic variability seen between some VAs, while still sharing overlapping features (Figure 2). In 2013, the umbrella term PIK3CA-related overgrowth spectrum (PROS) was proposed to consolidate this group of overgrowth disorders linked by a shared genetic cause.⁴ With this relatively new understanding of the proliferative genetic pathway, research has led to the creation and implementation of targeted medical therapy. Currently, sirolimus, an mTOR inhibitor, is the primary treatment for most nonhemangioma vascular tumors and malformations.^5,6

Figure 1. P13K/AKT/mTOR pathway.

Figure 2. Phenotypic spectrum of PROS: disorders have overlapping clinical features that vary by tissue distribution and severity of disease. BLK, benign lichenoid keratoes; CLOVES, congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/spine abnormalities; EN, epidermal nevus; FAO, fibroadadipose overgrowth; FAVA, fibroadipose vascular anomaly; FIL, facial infiltrating lipomatosis; HH, muscular hemihyperplasia; HMEG/DMEG, hemimegalencephaly/dysplastic megalencephaly; HMML, hemihyperplasia multiple lipomatosis; ILM, isolated lymphatic malformation; KTS, Klippel-Trenaunay syndrome; MCAP, megalencephaly-capillary malformation; SK, seborrheic keratoses.

In patients with a known, or suspected, PROS diagnosis, we have frequently observed a profound clinical improvement shortly after the initiation of oral sirolimus therapy. While sirolimus is a known treatment for many VAs, the following case series aims to highlight how precision medicine promotes a robust clinical response in patients with PROS.

A 16-year-old female patient presented to our clinic with a lymphatic and residual capillary malformation of her right lower leg, complaining of persistent drainage, pain, and swelling. As an infant, she underwent multiple rounds of sclerotherapy and laser ablation, followed by surgical debulking of the lymphatic malformation at the age of 3 years. She was active and played tennis 3 or 4 times per week. However, her symptoms worsened with activity, and she found herself frequently requiring breaks. Magnetic resonance imaging (MRI) of the right tibia and fibula revealed 2 lymphatic malformations and scattered regions of subcutaneous edema. She was given the diagnosis of PROS, more specifically Klippel-Trenaunay syndrome (KTS), based on clinical findings and was initiated on oral sirolimus therapy at a dose of 1.5 mg bid (1 mg/m²/dose). Four weeks later, she reported the drainage from her vascular malformation stopped completely and she no longer required breaks due to pain. After 6 weeks of therapy, her sirolimus trough level was 3.4 ng/mL. At baseline her D-dimer was slightly increased (0.60 mcg/mL) but normalized (0.44 mcg/mL) after 3 months of therapy. Furthermore, her MRI after 7 months of treatment demonstrated a 69% reduction in lymphatic volume. Although there was minimal change in the gross appearance of her malformation (Figure 3), her profound symptomatic improvement can likely be explained by her MRI findings.

Figure 3. Patient 1 (A) before oral sirolimus therapy and (B) after 4 weeks of 1.5 mg bid (1 mg/m²/dose) oral sirolimus.

A 10-month-old male patient presented to our clinic with significant unilateral leg and buttock swelling present as a newborn. His mother expressed concerns at this initial visit regarding his inability to meet motor developmental milestones due to the profound asymmetry of his lower extremities, as well as pain when in a seated position. An ultrasound revealed a macrocystic lymphatic malformation of the right buttock with interval intracystic bleeding coupled with localized overgrowth. The patient was given a presumptive diagnosis of PROS and initiated on 0.3 mL bid (0.8 mg/m²/dose) oral sirolimus. There was a remarkable decrease in his limb asymmetry after 4 weeks of therapy. This can be appreciated by the reduced depth of the skin folds and tautness of the skin of his right leg (Figure 4). Furthermore, the patient’s mother reported he could now sit without support. After 6 weeks of therapy, his sirolimus trough level was 2.1 ng/mL. In addition, his D-dimer showed marked improvement, from 10.18 mcg/mL at baseline to 1.7 mcg/mL after 3 months of therapy.

Figure 4. Patient 2 (A) before oral sirolimus therapy and (B) after 4 weeks of 0.3 mL bid (0.8 mg/m²/dose) oral sirolimus.

A 13-year-old male patient presented to our clinic with a right popliteal capillary malformation, extensive venous malformations of the pelvis and right lower extremity, and anemia. He complained of repeated bleeding from the vascular malformation on the back of his leg and intermittent hematochezia. MRI of the right lower extremity showed a low flow venous malformation and multiple dilated subcutaneous and intramuscular veins. Based on clinical findings, he met the criteria for a diagnosis of KTS and began 1.5 mg bid (1 mg/m²/dose) oral sirolimus therapy. At his 4-week follow-up appointment, the superficial blebs on his posterior knee had decreased in size, were no longer bleeding, and there were fewer satellite lesions (Figure 5). In addition, the hematochezia did not recur while on treatment and his hemoglobin improved from 10.8 g/dL to 12.0 g/dL after 4 months of therapy. After 6 weeks of treatment, his sirolimus trough level was 9.6 ng/mL. At baseline, the D-dimer level was normal, and these levels were maintained throughout treatment.

Figure 5. Patient 3 (A) before oral sirolimus therapy and (B) after 4 weeks of 1.5 mg bid (1 mg/m²/dose) oral sirolimus.

GLA, generalized lymphatic anomaly; KTS, Klippel-Trenaunay syndrome; MRI, magnetic resonance imaging; RLE, right lower extremity

The PROS umbrella includes several syndromes. KTS is a complex congenital VA consisting of capillary and venous malformations and limb overgrowth, with or without the presence of lymphatic malformations.^1,2 First described by Klippel and Trenaunay in 1900, KTS was initially recognized as a unique syndrome. However, a few years later Parkes Weber identified patients with arteriovenous malformations, as well as the triad present in KTS. Over the next century, other overgrowth syndromes were identified that displayed similar vascular malformations but still exhibited unique morphologic phenotypes. For example, lymphatic malformations are present in many PROS syndromes, but isolated lymphatic malformations do not demonstrate overgrowth of the effected anatomical structures. Congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/spine abnormalities (CLOVES) is another syndrome with a similar presentation to KTS. However, the involvement of the spine and presence of lipomatous overgrowth are distinguishing features of CLOVES.

The classification PROS allows for these overgrowth syndromes to be unified with the following diagnostic criteria: (1) congenital or early childhood onset, (2) sporadic and mosaic overgrowth, and (3) presence of a somatic PIK3CA pathogenic variant. However, due to the mosaicism of this genetic condition, genomic testing may not reveal the presence of a PIK3CA pathogenic variant and a presumptive PROS diagnosis can still be considered based on clinical features (Figure 6).⁴ Gross visual assessment is typically used to determine which tissue to biopsy. Although there is a greater likelihood of detecting a pathogenic variant in a larger, or more severe, malformation, this does not necessarily correlate with the load and distribution of the causative agent in the affected tissue.⁴

Figure 6. Diagnostic criteria for PROS.⁴

The previously described cases each highlighted a variety of complications that a patient with PROS can experience. The presentation of PROS is dependent on the location and severity of the vascular overgrowth.^4,6,7 Lymphatic malformations are at risk for chronic leakage of lymph or blood, along with secondary infection.⁵ Swelling of these malformations can cause pain, as described in case 1. In addition to this being an aesthetic problem, the size of the malformation can impose functional limitations as was observed in case 2. Bleeding severity generally correlates with the extent of venous disease and can range from minor episodes due to ectasias, as seen in case 3, to severe disseminated intravascular coagulation (DIC).⁷

In most studies evaluating the therapeutic effect of oral sirolimus on VAs in pediatric patients, therapy is initiated at a dose of 0.8 to 1.0 mg/m² bid and titrated to a goal of 5 to 15 ng/mL.^5,8 Notably, in cases 1 and 2 the patients reported considerable symptomatic improvements with subtherapeutic trough levels of sirolimus. This response, combined with their subsequent reduction in D-dimer levels, supports the argument that the clinical benefits of sirolimus correlate with a reduction in localized intravascular coagulopathy.^9,10

Furthermore, other studies have emphasized the role of sirolimus as an anti-lymphangiogenic agent via its inhibition of vascular endothelial growth factor activity.^11-14 The clinical improvement observed in our patients is consistent with current literature emphasizing the efficacy of sirolimus for the treatment of slow-flow vascular malformations.^9,10,15,16 Future research should explore if lower trough levels of sirolimus are sufficient for the treatment of PROS or some of its phenotypes. Reducing the dosage of sirolimus would minimize the risk of dose-dependent side effects and likely aid in patient adherence to therapy, especially since many patients require therapy long term.⁶

An alternative candidate for the treatment of PROS is alpelisib, a PIK3CA inhibitor.⁶ With 2 treatment options now available, the following debate arises—alpelisib versus sirolimus. There is not yet a published comparison between the 2 drugs, thus many providers are basing their decision on the individual presentation of a patient’s disease. The current data suggest selecting sirolimus to address symptoms related to lymphatic malformations or alpelisib for patients with overgrowth.^9,10,15-17 However, there are additional factors affecting this decision, such as drug availability, insurance status/ability to pay for drug, the presence of other non-VA medical conditions, and adherence with follow-up. Although rarely occurring, if patients do not tolerate sirolimus due to side effects, such as cytopenias, hypertriglyceridemia, renal impairment, or cannot accept the risk of immunosuppression, alpelisib presents a second therapy option.

This case series emphasizes how insight into the genetic origin of vascular overgrowth syndromes allowed for their successful treatment with the same medication. Despite their vastly different clinical presentations, each patient experienced marked symptomatic improvement within the first 4 to 6 weeks of sirolimus therapy. The prognosis of PROS is highly variable, and its complications are dependent on the site and extent of the vascular overgrowth.For these reasons, individualized treatments with a multidisciplinary team should focus on the management and prevention of patient pain and functional impairment, while aiming to provide the optimal quality of life.