Sirolimus in the Treatment of Microcystic Lymphatic Malformations: A Systematic Review

Introduction

Lymphatic malformations (LMs) are nonmalignant, congenital, abnormal lymphatic vessels that result in enlarged fluid-filled lymphatic spaces. ¹ Clinical manifestations vary considerably, ranging from local enlargements to widespread diffuse lesions. ² Depending on their location, these malformations can lead to disfigurement, organ dysfunction, recurrent infection, and potentially life-threatening airway obstruction. ³

The International Society for the Study of Vascular Anomalies divides LMs into 3 types based on cyst size and distribution:

Macrocystic LMs: Typically large, smooth, translucent, multi-lobular lesions present at birth.

Regardless of form, the majority of LMs result from postzygotic mutations typically in PIK3CA that lead to an overgrowth of lymphatic vessels. Although they are histologically similar, macrocystic LMs and micro LMs are phenotypically different and often have different treatment paradigms and outcomes. ⁸

Unlike macrocystic LMs, micro LM vessels connect to the epidermis in the form of vesicles, papules, and plaques, which can leak at the surface (lymphorrhea). Hyperkeratosis often results during the healing process and can bleed spontaneously, particularly when overlying a capillary malformation or due to minor trauma. Since micro LMs appear to be caused by activating mutations in genes that control growth, these lesions enlarge, and with recurrent leaking and healing tend to become more papular and keratotic over time.

Treatment success for micro LMs remains low.^1–3 Though several treatment modalities exist, current interventional therapies are less than ideal, and none are Food and Drug Administration (FDA) approved for this disorder. ³ For example, surgical resection remains challenging, if not impossible, due to the infiltrative, diffuse nature of micro LMs. In addition, due to underline somatic mutation associated with micro LM, it is difficult to achieve accurate and clear surgical margins, resulting in high recurrence rates post resection. Moreover, the benefits of surgical interventions were not sustained. Recurrence rates for micro LM after surgical resection have been reported to range from 17% with complete resection and 40% with incomplete resection, thus increasing the risk for iatrogenic morbidity with repeat surgeries.

Sclerotherapy, the first-line treatment for macrocystic LMs, may not be effective or practical in patients with micro LMs due to a lack of accessible therapeutic targets, although positive results have been reported for several sclerotherapy agents, mainly bleomycin, especially in cases of large diffuse micro LMs.^1,9 Efficacy of other surgical interventions including radiotherapy and laser therapy remains to be determined. ⁷ The drawbacks associated with surgical approaches for micro LMs have spurred the search for treatment alternatives that target the underlying pathological mechanisms of this disorder.

Although the pathogenesis of LMs remains to be clearly elucidated, important insights gained over the last decade have implicated abnormal activation of the PI3K/AKT/mTOR signaling pathway. ³ Enhanced mTOR signaling has been shown to enhance the expression of the vascular endothelial growth factor, a key promoter of angiogenesis and lymphangiogenesis, and leads, in turn, to uncontrolled and disorganized vascular development. The mTOR inhibitor sirolimus (rapamycin) offers a biologically plausible mechanism as a targeted therapy in the management of LMs, especially difficult-to-treat micro LMs.^10,11 By directly targeting the PI3K/AKT/mTOR pathway within LMs, sirolimus has been shown to downregulate lymphangiogenesis and attenuate clinical complications including lymphorrhea, bleeding, infection, and pain.

This systematic review of the literature examined clinical data on the role of topical and systemic sirolimus in the treatment of children and adults with micro LMs.

Methods

Results

The search strategy yielded a total of 251 publications (Table 2).

After removing duplicates, the remaining publications were reviewed to ensure they contained clinical data related specifically to the use of topical or oral sirolimus in the treatment of patients with micro LMs. The review yielded a total of 16 relevant studies that included 52 subjects with micro LMs (Table 3).^7,13–27 Studies identified were mostly case studies (10) or retrospective hospital case reviews (3). The 3 prospective clinical trials identified included 13 subjects with micro LMs.^13–15

Discussion

Micro LMs represent therapeutically challenging congenital vascular lesions. ²⁸ There is no universally accepted gold standard of care and there are no FDA approved therapies. Current interventional treatment modalities such as surgery or sclerotherapy may be infeasible or have only transient efficacy for many patients with micro LM.^2,29 These clinical gaps in the management of micro LMs have spurred the search for novel treatments to improve outcomes and reduce symptom burden. Recent insights into the pathogenesis of micro LMs have provided an opportunity to examine treatments, such as mTOR inhibitors, that better target the underlying pathogenesis of this disorder.

This systematic review examined the published literature on the role of sirolimus in the treatment of micro LMs. Limited prospective clinical trials have been conducted to specifically examine the role of sirolimus in the treatment of micro LMs, and no trials have been identified that use a placebo control.

As of July 2021, ClinicalTrials.gov showed only 3 active clinical trials examining the role of sirolimus for the management of LM. Due to the paucity of prospective, controlled trials, our review relied primarily on case studies and case reviews. We identified 52 patients across 16 studies who were treated with sirolimus for the management of micro LMs. Most patients (90%) demonstrated a clinically meaningful response to sirolimus treatment, with notable reductions in, or elimination of, the micro LM lesions over time. Indeed, time to discernable onset of action was reported to occur as early as 2 weeks after the start of therapy in some studies. In addition, improvements continued during follow-up that ranged from 2 months to 3 years, implying long-term maintenance treatment may be needed to prevent disease progression. About half the studies reviewed reported changes in specific micro LM associated symptoms, with sirolimus treatment yielding improvements in such manifestations as lymphorrhea, bleeding, pain, and skin discoloration.

Our findings confirm and extend the results of broader retrospective reviews of sirolimus in micro LM and vascular malformations.^2,30–32 The findings of these previously published reviews also highlighted a potentially important therapeutic role for sirolimus in a broad array of vascular and LMs and tumors. As in our review, most patients in these reviews displayed a clinically relevant response to sirolimus therapy.

In our review, topical sirolimus was associated with transient application-site reactions. Yet the risk for an application-site reaction may not be uniform across all topical formulations. Individuals using the liquid formulation directly may experience greater irritation and skin breakdown due to the formulation's excipient content. In addition, topical formulations derived from sirolimus pills can contain an alcohol residue remaining from the dissolving process. This residue may promote skin irritation and degradation. Topical sirolimus derived from a powder formulation, however, possesses neither of these liabilities and thus may be less irritating when applied topically. Because of the potential variation in application-site reactions across formulations, it is important to use the least reactive topical products.

However, developing a commercial topical sirolimus formulation faces important challenges. The chemical instability and poor solubility of sirolimus present significant stability and penetration challenges for compounded sirolimus. Furthermore, the high molecular weight of the sirolimus molecule restricts transepidermal delivery to the diseased tissue. Sirolimus has a molecular weight of 914 Daltons, almost two-fold higher than the generally accepted value of the 500 Dalton Rule, which states that the molecular weight of a compound should be under 500 Daltons to penetrate the skin.^33,34 At least partially because of these challenges, topical sirolimus is not commercially available, thus requiring compounding at a local pharmacy or shipping from a retail compounding pharmacy. Local compounding may result in variability in the formulation's concentration, potency, stability, quality and perhaps, increased patient costs as compounding is not covered under most insurance. Yet, these drawbacks should be balanced against the risk for systemic side effects and the need for regular blood testing with the long-term use of oral sirolimus for micro LMs.

In all the studies using the oral formulation identified in our review, blood testing was conducted to maintain sirolimus blood levels within a pre-specified blood level range, most commonly 10–15 ng/mL. Adverse events identified in our review were generally mild or moderate, manageable, and consistent with those previously reported with sirolimus treatment.^35,36 Treatment discontinuations (permanent) resulting from adverse events were uncommon, occurring in only 4 patients (8%; 4/52) treated with oral sirolimus across 3 studies.^13,22,27

Nonetheless, due to the limited scope of our review, potential adverse events associated with sirolimus therapy require careful treatment monitoring. In 1 study reviewed, a significant number of oral sirolimus-treated patients experienced blood and bone marrow abnormalities. The sirolimus label warns of the potential for other serious adverse events such as angioedema, acute kidney injury, and interstitial lung disease.^13,36

Our review, and others using similar methodologies, has important inherent limitations that affect the generalizability of the findings. Most of the studies cited in this review were case studies and case reviews. Many authors and centers may be prone to publish only positive outcomes for such studies. In addition, these studies assessed efficacy broadly by tools such as, QoL, and recorded a response as complete or partial, so it is difficult to assess the magnitude and relevance of differences in clinical responses across studies because of variability in the outcome measures used. Even responses to topical sirolimus may be difficult to generalize since the quality of compounded products was not standardized and likely varied considerably. Importantly, the overall sample size was small—a total of 52 patients with micro LMs. This small sample size may have resulted from the relative paucity of studies directly and specifically investigating mTOR inhibitors in micro LM or from our stringent selection criteria that required studies to specifically state that the patients included were diagnosed with a micro LM treated with sirolimus, which may have resulted in some studies being omitted from the search results. Finally, there was considerable heterogeneity in study conditions, processes, and outcome assessments, an expected source of variability that clouds the interpretation of retrospective, systematic reviews.

Conclusion

Data from the current retrospective review suggest a potentially important role for sirolimus as an effective and safe treatment option in the management of micro LMs. Due to the retrospective nature of this review and the heterogeneity of the studies included, the current findings, although intriguing, can only be considered heuristic. Yet findings such as these are sufficiently compelling to provide an impetus for future prospective, controlled studies.