Immunologic Effects of Sirolimus in Patients With Vascular Anomalies

Nozawa, Akifumi; Ozeki, Michio; Yasue, Shiho; Endo, Saori; Kawamoto, Norio; Ohnishi, Hiroyuki; Fumino, Shigehisa; Furukawa, Taiji; Tajiri, Tatsuro; Maekawa, Takanobu; Fujino, Akihiro; Souzaki, Ryota; Fukao, Toshiyuki

doi:10.1097/mph.0000000000001650

Cited by 6 publications

(8 citation statements)

References 34 publications

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“…6,17 However, sirolimus mediates immunosuppressive effects through multiple immune cell types and processes, 21 and lead to life-threatening infection when after a long-term use with higher levels of sirolimus, especially for young children or with other concomitant medications such as corticosteroids. 15,22 Nevertheless, the immunosuppression effects of sirolimus in patients with VAs have not been widely studied. Some researcher suggested lower initial doses and target level for neonates and young infants, and there had similar efficacy but improved tolerability compared with standard recommended dose.…”

Section: Discussionmentioning

confidence: 99%

“…It was previously reported that younger patients may have more favorable responses to sirolimus than older patients 6,17 . However, sirolimus mediates immunosuppressive effects through multiple immune cell types and processes, 21 and lead to life-threatening infection when after a long-term use with higher levels of sirolimus, especially for young children or with other concomitant medications such as corticoste-roids 15,22 . Nevertheless, the immunosuppression effects of sirolimus in patients with VAs have not been widely studied.…”

Section: Discussionmentioning

confidence: 99%

“…This intermittent administration regimen, on the 1 hand, could exert effects of sirolimus in 1 course, on the other hand, could help to restore the immunity after 1 month interval, and avoid supra-therapeutic levels. Nozawa et al 22 investigated the immunologic effects of sirolimus treatment in 18 patients with VAs, they found that the immunologic parameters appeared to be affected minimally by sirolimus treatment for 6 months. In this series, all the patients had basically normal immunologic parameters during follow-up, did not have severe infection or septicemia, did not contracted PCP without concurrent PCP prophylaxis therapy.…”

Section: Discussionmentioning

confidence: 99%

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Intermittent Administration Regimen of Sirolimus for Refractory Cervicofacial Lymphatic Malformation

Gao

Chen²,

Sun³

et al. 2021

Journal of Craniofacial Surgery

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Background: The cervicofacial lymphatic malformations (LMs) often have poor outcomes due to their microcystic component and diffuse infiltration. Mostly, traditional treatments are inadequate for these refractory cases. Recent researches have shown that sirolimus is effective in the treatment of complicated LMs, however, there is still no standard strategy. Objective: To evaluate the efficacy and safety of intermittent oral sirolimus in treating refractory cervicofacial LMs as a second-line treatment. Methods: Fifteen pediatric patients of refractory cervicofacial LMs were retrospectively analyzed in this study. All the cases had received traditional therapy before, but could not completely control the symptoms and eliminate lesions. As a remedy, sirolimus was then proceeded with an intermittent administration regimen, that is 3 continuous months as a course and started the next course after 1 month interval. The clinical characteristics, imaging data of patients, the changes in the signs and symptoms observed, and associated adverse effects were collected and analyzed. Results: The patients initiated sirolimus therapy at the average age of 2.3 years (range 28 days-8 years 9 months). At the end point of the study, 2 patients remained on sirolimus in continuous courses of treatment. Of 13 patients who withdrawn therapy, 4 had restarted due to recurrence of symptoms and re-expansion of LMs. All patients demonstrated reduction in residual LMs and complete disappearance of symptoms during treatment, and 2 patients with complete resolution on imaging. Toxicity was tolerant in this series. There was no patient develop opportunistic or systemic bacterial infection. Conclusions: Sirolimus is commended as a second-line treatment to treat intractable cervicofacial LMs after failure of traditional therapy. The intermittent administration regimen is efficacious to completely control symptoms and partially reduce residual lesions with good tolerance and limited side effects.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Intermittent Administration Regimen of Sirolimus for Refractory Cervicofacial Lymphatic Malformation

Gao

Chen²,

Sun³

et al. 2021

Journal of Craniofacial Surgery

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“…One of the most concerning side effects of sirolimus is immunosuppression. The degree of immunosuppression caused by sirolimus in the treatment of VAs is unclear, and formal testing in one series showed negligible immunosuppression due to sirolimus 12 . However, many VAs, particularly “leaky” lymphatic anomalies such as KLA and central conducting lymphatic anomalies (CCLA) are associated with protein loss, lymphopenia, and hypogammaglobinemia.…”

Section: Therapeutic Treatment Options For Vascular Anomaliesmentioning

confidence: 99%

“…The degree of immunosuppression caused by sirolimus in the treatment of VAs is unclear, and formal testing in one series showed negligible immunosuppression due to sirolimus. 12 However, many VAs, particularly "leaky" lymphatic anomalies such as KLA and central conducting lymphatic anomalies (CCLA) are associated with protein loss, lymphopenia, and hypogammaglobinemia. Furthermore, infants with VAs on sirolimus who already have immature immune systems are presumed to be at higher risk.…”

Section: Sirolimusmentioning

confidence: 99%

How we approach the use of sirolimus and new agents: Medical therapy to treat vascular anomalies

Shimano

Eng

Adams

2022

Pediatric Blood & Cancer

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Vascular anomalies (VAs) are a heterogeneous group of primarily congenital tumors and malformations. The International Society for the Study of Vascular Anomalies (ISSVA) has developed a standard classification of these disorders, creating a uniform approach to their diagnosis. Recent discoveries evaluating the genetic causes of VAs have revealed that they are due to mutations in cancer pathways, including the PI3K/AKT/mTOR and RAS/MAPK/MEK pathways. These discoveries have led to improved phenotype-genotype correlation and have expanded medical therapy for this group of unique disorders.

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Infectious complications of vascular anomalies treated with sirolimus: A systematic review

Kalbfell,

Cohen‐Cutler,

Grisham

et al. 2023

Pediatric Blood & Cancer

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Background and objectivesInitially developed as immunosuppressive agents, mammalian target of rapamycin (mTOR) inhibitors are currently used widely in the management of vascular malformations and tumors. The incidence of infectious complications in the vascular anomalies (VA) population is not well defined. The goal of this systematic review was to better define the types and severity of reported infectious complications in patients with VAs treated with mTOR inhibition.MethodsThis was a systematic review conducted following PRISMA guidelines evaluating all research articles focused on infectious complications in patients with VAs treated with sirolimus or everolimus. Thirty articles including 1182 total patients and 316 infections (in 291 unique patients) were ultimately included.ResultsThe majority of infections were viral upper respiratory (n = 137, 54%), followed by pneumonia (n = 53, 20%), and cutaneous infections (n = 20, 8%). There were six total infection‐related fatalities, which all occurred in patients younger than 2 years. Two cases of Pneumocystis jirovecii pneumonia (PJP) were reported. These were infants with kaposiform hemangioendothelioma (KHE) who were also treated with steroids and did not receive PJP prophylaxis. Almost one‐third (n = 96, 32%) of infectious complications were graded 3–4 according to Common Terminology Criteria for Adverse Events (CTCAE) criteria. Details of patient age, subtype of VA, and timing of infection were lacking from many reports.ConclusionsMost infectious complications reported in patients with VA on mTOR inhibitors were viral respiratory infections and non‐severe. Bacteremia, infectious fatalities, and PJP are exceedingly rare. Future studies are needed to clarify the spectrum of infectious risks in VA patients and to provide guidance for infection prevention.

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Immunologic Effects of Sirolimus in Patients With Vascular Anomalies

Cited by 6 publications

References 34 publications

Intermittent Administration Regimen of Sirolimus for Refractory Cervicofacial Lymphatic Malformation

Intermittent Administration Regimen of Sirolimus for Refractory Cervicofacial Lymphatic Malformation

How we approach the use of sirolimus and new agents: Medical therapy to treat vascular anomalies

Infectious complications of vascular anomalies treated with sirolimus: A systematic review

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