BACKGROUND AND OBJECTIVES: Complicated vascular anomalies accept bound ameliorative options and account cogent anguish and mortality. This Phase II balloon enrolled patients with complicated vascular anomalies to actuate the ability and assurance of assay with sirolimus for 12 courses; anniversary advance was authentic as 28 days.
METHODS: Assay consisted of a connected dosing agenda of articulate sirolimus starting at 0.8 mg/m2 per dosage alert daily, with pharmacokinetic-guided ambition serum canal levels of 10 to 15 ng/mL. The primary outcomes were admiration to sirolimus by the end of advance 6 (evaluated according to anatomic crime score, affection of life, and radiologic assessment) and the accident of toxicities and/or infection-related deaths.
RESULTS: Sixty-one patients were enrolled; 57 patients were evaluable for ability at the end of advance 6, and 53 were evaluable at the end of advance 12. No accommodating had a complete acknowledgment at the end of advance 6 or 12 as anticipated. At the end of advance 6, a absolute of 47 patients had a fractional response, 3 patients had abiding disease, and 7 patients had accelerating disease. Two patients were taken off of abstraction anesthetic accessory to assiduous adverse effects. Brand 3 and college toxicities attributable to sirolimus included blood/bone bottom toxicity in 27% of patients, gastrointestinal toxicity in 3%, and metaic/laboratory toxicity in 3%. No toxicity-related deaths occurred.
CONCLUSIONS: Sirolimus was alive and able-bodied acceptable in these abstraction patients with complicated vascular anomalies. Analytic activity was appear in the majority of the disorders.
Several case letters and attendant case alternation accept been appear on the use of sirolimus for the assay of vascular anomalies. Absolute acknowledgment with bound toxicity was obtained, but these letters accept no acclimation of acknowledgment or toxicity criteria.
This abstraction is the aboriginal -to-be balloon for accouchement and adolescent adults with complicated vascular anomalies. These patients accept bound medical options, and treatments accept been based on surgical and interventional procedures. Sirolimus was accurate able and safe.
Vascular anomalies are a spectrum of attenuate diseases classified into vascular tumors and malformations.1,2 An adapted allocation arrangement was adopted at the International Society for the Abstraction of Vascular Anomalies (ISSVA) in April 2014 .3 Generally, vascular tumors are proliferative, and malformations enlarge through amplification of a adorning aberration with no basal proliferation. Advance and/or amplification of vascular anomalies can account analytic problems such as disfigurement, abiding pain, alternate infections, coagulopathies (thrombotic and hemorrhagic), agency dysfunction, and death. Individuals generally acquaintance accelerating analytic affection with deepening affection of life. Bound assay options are available, and the ability of these options has not been accurate in -to-be analytic trials.4 Historically, therapies accept been mostly interventional and surgical for the absolution of symptoms. Ideal therapies for this assorted accommodating citizenry would ambition cellular pathways important in aberrant vascular admeasurement and growth.
The phosphatidylinositol 3-kinase (PI3K)/AKT signaling alleyway is analytical to corpuscle advance and adaptation and has been apparent to administer accustomed vascular development and angiogenesis.5 Sirolimus, a beastly ambition of rapamycin (mTOR), integrates signals from the PI3K/AKT alleyway to alike able corpuscle advance and admeasurement by acclimation ribosomal biogenesis and protein synthesis.6 Enhanced mTOR signaling increases announcement of the vascular endothelial advance factor, a key regulator of angiogenesis and lymphangiogenesis.7 Disorders that advance to inappropriate activation of the PI3K/AKT/mTOR alleyway accept been apparent to aftereffect in tissue overgrowth in affiliation with vascular anomalies.
Overexpression of AKT/protein kinase B, TIE2 receptor–activating mutations, and the accident of activity mutations in phosphatase and the tensin log deleted on chromosome 10 (PTEN) bump suppressor gene accept been associated with the development of vascular anomalies in animals and humans.8–11 Furthermore, tuberous sclerosis and lymphangioleiomyomatosis are acquired by inactivating mutations in the tuberous sclerosis circuitous bump suppressor proteins TSC1 and TSC2, arch to added activation of mTOR.12 Analytic trials of sirolimus in these diagnoses accept produced able results.12,13
Sirolimus was initially administered for compassionate use in a adolescent accommodating with a Kaposiform hemangioendothelioma (KHE) with Kasabach-Merritt aberancy (KMP) who had bootless to acknowledge to all accepted assay algorithms.14 Assay account was based on the tumor’s cogent aqueous basic and the activation of the PI3K/AKT/mTOR alleyway in angiogenesis and lymphangiogenesis, as able-bodied as its use in tumors, lymphangioleiomyomatosis, tuberous sclerosis, and neurofibromas.14 Back the alpha of the study, several case letters and attendant case alternation accept been published, with absolute results.15–24 This accommodating responded to sirolimus treatment, as did 5 added high-risk patients. The assay of actual mutations in the PI3K/mTOR alleyway (PIK3CA) and mutations, both actual and germline, in commutual pathways (TIE2, RASA1, and PTEN) accommodate acute affirmation for the analytical role of this alleyway in the acclimation of vascular advance and organization. These mutations accommodate the atomic account for mTOR inhibition in abounding of the disorders included in this study.25–28
The abstraction was advised by the board and accustomed by the Abstracts and Assurance Monitoring Board of the Cancer and Blood Ache Institute at Cincinnati Children’s Hospital Medical Center and the institutional assay boards at Cincinnati Children’s Hospital Medical Center and Boston Children’s Hospital. The protocol, including the statistical assay plan, is accessible in the Supplemental Information.
Inclusion belief included 1 of the 9 absolute vascular aberration diagnoses (initial enrolling diagnosis) (Table 1) and at atomic 1 of 6 predefined complications: coagulopathy, abiding pain, alternate cellulitis (defined as >3 episodes per year), ulceration, belly and/or cartilage involvement, and/or cardiac dysfunction. No patients were enrolled with multifocal lymphangioendotheliomatosis with thrombocytopenia/cutaneovisceral angiomatosis with thrombocytopenia) or capillary aqueous arterial venous malformations during the abstraction period. The majority of patients had undergone some anatomy of antecedent assay for their vascular aberration (Supplemental Table 10). Eligible patients were amid 0 and 31 years of age with able agency activity (liver, cartilage marrow, and renal), an able lipid panel, Karnofsky/Lansky achievement cachet ≥50, and no circumstantial use of cytochrome P450 3A4 agitator inducers or inhibitors. Patients could not accept circumstantial steroids (except for patients with KHE), chemotherapy, or radiation and 2 weeks charge accept delayed back ability above surgery. Patients were banned from accepting myelosuppressive chemotherapy aural 4 weeks of access into the study. Patients could not accept accustomed hematopoietic advance factors, antineoplastic agents, enzyme-inducing anticonvulsants, or cytochrome P450 3A4 inhibitors or inducers aural 7 to 14 canicule afore access to the study.
Exclusion belief included abiding steroid use, accepted HIV, abiding astringent or amoral medical disease, amoral infection, and antecedent use of an mTOR inhibitor. Dental braces or prostheses were banned abandoned if interfering with radiologic assay of the vascular anomaly. Patients who had crime of gastrointestinal activity or ache that may abatement the assimilation of sirolimus were excluded. Pregnant and feeding women were excluded, and macho and changeable capacity of changeable abeyant were adapted to use able contraceptive methods throughout the abstraction and for 3 months afterwards abstraction end. Patients with amoral infection and who were afraid or clumsy to accede with the agreement were afar from participation. All patients and/or guardians provided a accord as accustomed by the bounded institutional assay boards.
Sirolimus was administered orally on a connected dosing agenda at a starting dosage of 0.8 mg/m2 per dosage alert daily, with 1 advance agnate to 28 days. Application pharmacokinetically guided dosing, sirolimus levels were abstinent at adapted times, and canal levels were maintained amid 10 and 15 ng/mL. Planned assay continuance was 12 courses per patient. Assiduity of assay above 12 courses in patients with acknowledging or abiding ache was acceptable at the acumen of the alleviative institutions; abstracts apropos assay assiduity above 12 courses were collected. Dosage reductions or interruptions were acceptable for clinically cogent toxicities based on agreement outline. Patients with clinically cogent brand 3 or 4 toxicities changing by dosage acclimation were removed from the study. Afterwards achievement of the agreement treatment, patients are followed up for 5 years to appraise ache cachet (eg, advance of the vascular anomaly, complications) and therapy-related toxicity.
The primary aftereffect admeasurement was the ability of sirolimus by the end of advance (EOC) 6 authentic by complete or fractional acknowledgment (CR/PR) and the accident of toxicities and/or infection-related death. Adverse contest were adjourned according to the Accepted Terminology Belief for Adverse Contest (version 3.0). Laboratory testing to appraise assurance included hematologic, serum metaic, and urine actinic tests.
The optimal admeasurement of ache acknowledgment in patients with circuitous vascular anomalies has not been established. For this reason, assurance of the ability of sirolimus congenital 3 audible methods: radiologic evaluation, anatomic crime account (clinical altitude of disease), and health-related affection of activity (HRQOL). The best accepted radiologic appraisal was an MRI performed according to a connected protocol. Added entities accounted adapted by the abstraction radiologist included computed tomography scans and radiographs. HRQOL was adjourned by application the Pediatric Affection of Activity Inventory 4.0 (3–18 years) and Infant Scales (≤2 years) and the Anatomic Appraisal of Abiding Affliction arrangement (>18 years). The anatomic crime account was adopted from the measures of agency activity that accept been accurate in the altitude of adverse accident after-effects from medical therapies and procedures. This apparatus was piloted in the present abstraction for use in vascular anomalies. Baseline appraisal was performed afore administering of abstraction medication, and bookish acknowledgment was adjourned afterwards courses 3, 6, and 12. Acknowledgment was accustomed by change in at atomic 1 of these ambit (Table 2).
Evaluation of Ache Response
The primary outcomes were all-embracing admiration to sirolimus at EOC 6 authentic as CR/PR (compilation of radiologic evaluation, HRQOL, and anatomic assessment) and the accident of toxicities and/or infection-related deaths. Multinomial distributions were acclimated to appraisal the acknowledgment and the accident ante with their 95% aplomb intervals (CIs) for all-embracing acknowledgment at EOC 6 and 12. Frequencies and percentages were acclimated to accurate the breakdown of all-embracing responses according to ache stratification.
This abstraction comprised 2 stages to actuate if there is an able akin of ache admiration to sirolimus in accouchement and adolescent adults with vascular anomalies. The balloon was accounting to blame the use of sirolimus in this citizenry if the amount of CR/PR was ≤5%. Based on Simon’s optimal 2-stage design,29 an acting assay was conducted on the aboriginal 23 patients. Futility and abeyance of the abstraction were authentic as aught or abandoned 1 CR/PR. If the acknowledgment amount was at atomic 18%, the planned 60 patients would accommodate a 90% ability to appearance a cogent acknowledgment at a 0.05 level. The acting assay after-effects acceptable balloon continuation.
The abstraction was accessible to accretion from October 2009 through April 2013 and enrolled 61 patients. One accommodating was replaced afterwards after-effects of a biopsy appear an disqualified diagnosis. Fifty-seven patients completed 6 courses of assay and were evaluable for response; all 61 patients were evaluable for toxicity. Forty-six patients completed all 12 courses of agreement therapy. Fifteen patients did not complete assay due to accelerating ache (n = 8), drug-related toxicity (n = 2), physician accommodation to stop medication (n = 2), abnegation or abandonment of accord due to patient/family alternative (n = 2), and agreement contravention (n = 1). Ache stratification and accommodating demographic characteristics are abbreviated in Tables 1 and 3, respectively.
Forty-seven (83%) of 57 patients who completed 6 courses of assay had a PR at EOC 6, and 45 (85%) of 53 patients who completed 12 courses of assay had a PR at EOC 12. Three patients (5%) had abiding ache (SD) at EOC 6, and no accommodating had abiding ache at EOC 12. Seven patients (12%) had accelerating ache (PD) by EOC 6 and 8 (15%) by EOC 12 (Table 4). No patients accomplished a CR.
With advertence to the adapted ISSVA allocation system, several ache entities had 100% PR at EOC 6 and 12: ambiguous aqueous anomaly, KHE with KMP, capillary-lymphatic-venous aberancy (CLVM), PTEN/arterial venous malformation, and venous aqueous malformation. Gorham affection had 100% PR at the EOC 6. Abandoned 1 ache stratification had 100% accelerating disease: lymphangiectasia/abnormalities of the axial administering aqueous channels (Table 5).
Disease Acknowledgment at EOC 6 and 12
Overall, patients had cogent advance in affection of activity measurements. Thirty-two percent (95% CI: 17–47) had normalization (CR) at EOC 6 and 39% (95% CI: 23–55) at EOC 12. At EOC 6, 52% (95% CI: 36–68) had a PR, with 50% (95% CI: 34–67) accomplishing a PR at EOC 12. Sixteen percent (95% CI: 4–28) of patients had abiding ache at EOC 6 and 9% (95% CI: 0–19) at EOC 12. Abandoned 1 accommodating at EOC 12 had accelerating ache accompanying to affection of life. This accommodating had advance in anatomic crime and a abiding radiologic evaluation.
No patients had progression or CR. At EOC 6, 71% (95% CI: 56–85) had a PR, with 80% (95% CI: 67–94) at EOC 12. Twenty-nine percent (95% CI: 15–44) had abiding ache at EOC 6 and 20% (95% CI: 6–33) at EOC 12.
No patients had a CR at EOC 6 or 12. At EOC 6, abandoned 1 accommodating (2%) had accelerating ache (95% CI: 0–6), and no patients progressed at EOC 12. Thirty-five percent (95% CI: 20–51) had a PR at EOC 6, and 52% (95% CI: 36–69) had a PR at EOC 12. Abiding ache was begin in 63% (95% CI: 47–79) at EOC 6 and 48% (95% CI: 31–64) at EOC 12.
Toxicity abstracts are abbreviated in Tables 6, 7, and 8. The best accepted toxicities (grades 3 or 4) attributed to sirolimus included blood/bone bottom at 27%, metaic/laboratory at 3%, gastrointestinal at 3%, infection at 2%, aqueous at 2%, and pulmonary/upper respiratory at 2%. Dosage abridgement was abandoned adapted in 2 patients, 1 associated with accessible laryngospasm and the additional accompanying to hypertriglyceridemia. Two patients were taken off abstraction anesthetic accessory to toxicity. One accommodating was removed from the abstraction accessory to assiduous brand 2 abhorrence interfering with affection of activity and the additional for assiduous brand 3 lymphedema. No toxicity-related deaths occurred during the study. Patients are actuality followed up for abiding toxicities every 6 months for 5 years; none has occurred appropriately far.
Adverse Events: Summary of All Brand 2 and College AEs According to Category Attributable to Sirolimus
Summary of Adverse Events: Brand 3 and College Regardless of Attribution
Summary of AEs Brand 3 and College Attributable to Sirolimus
One accommodating with a CLVM who completed assay with PR died of accepted sepsis 1 year afterwards completion. The accommodating was accepting a low circadian dosage of sirolimus (recent akin <2 ng/mL). She had a delirious affliction for which no medical assay was accustomed admitting a history of alternate cellulitis and sepsis episodes.
To the best our knowledge, this abstraction is the abandoned completed -to-be analytic balloon for patients with these complicated vascular diagnoses, and it confirms the all-embracing ability of sirolimus in the assay of vascular anomalies. Vascular anomalies accept a capricious accustomed history and generally do not absolutely resolve, authoritative appraisal of acknowledgment difficult. Appraisal is added complicated by the allocation of abounding altered ache entities beneath the ample appellation “vascular anomaly,” with hardly altered and capricious phenotypes. In this -to-be study, best enrolled patients with vascular anomalies apparent benign all-embracing responses. One accommodating with a microcytic and macrocytic aqueous aberancy with airway accommodation had a arresting acknowledgment (Figs 1A and 1B).
Macrocystic and microcystic aqueous aberancy with airway compromise. A, Coronal short-tau inversion-recovery alluring resonance images of a adolescent boy with a ample focal macrocystic and microcystic aqueous malformation; images were acquired afore assay admission (left, at 6 weeks of age) and at the time of assay abeyance (right, 13 months later). The pretherapy angel shows a large, infiltrating, multicystic accumulation of the larboard scalp, face, neck, and . The accumulation was causing airway accommodation (not shown). With sirolimus assay alone, the accumulation decreased clearly in size. B, Analytic assay appear breach abatement in the admeasurement of the lesions, with decreased bump aggregate and compactness constant in “saggy” tissue with beneath accumulation effect.
Impressive ache aftereffect was apparent in patients with KHE and KMP, decidedly in their hematologic acknowledgment (Figs 2A and 2B). Previously, anguish and bloodshed for these patients were best frequently accessory to KMP.30 Currently, a randomized Phase II abstraction comparing vincristine assay (expert accord accepted of care) against sirolimus for the assay of high-risk patients with KHE/KMP is accruing subjects.31 An adaptive abstraction architecture will be acclimated because this abstraction is the aboriginal allegory for this citizenry (ClinicalTrials.gov identifier NCT02110069, adjourned by the US Food and Biologic Administering Office of Orphan Products Development 1R01FD004363 and Pfizer, Inc). Kaposiform lymphangiomatosis is a new commodity with cogent anguish and a bloodshed amount as aerial as 66%.32 Of the 6 patients with Kaposiform lymphangiomatosis who responded to therapy, all accept connected sirolimus assay above the 12 courses afterwards any ache progression. Figure 3 shows the awkward advance of 1 accommodating with ambiguous aqueous aberration according to after-effects of an MRI. Added ache entities had life-altering advance in agglomeration parameters, pain, affection of life, and bleeding/leaking issues. Table 9 displays the arresting abatement in cellulitis for a accommodating with CLVM. The aftereffect was so cogent that the majority of patients/families chose to abide sirolimus off-label at the end of the abstraction (42 of 53 patients).
KHE with KMP. A, Radiographic imaging of a accommodating with KHE and KMP. Coronal short-tau inversion-recovery alluring resonance images of a adolescent babe with a larboard bank KHE; images were acquired 18 canicule afore assay admission and at the time of abstraction conclusion. The pretherapy angel shows a ailing defined, aberrant accumulation of added arresting acuteness entering assorted tissue planes of the apparent and abysmal larboard crabbed wall. The posttherapy angel shows a apparent breach abatement in the admeasurement of the mass. B, KHE with KMP anatomic crime score/skin. Skin at prestudy and end of study. Physical assay at abstraction abeyance appear beneath purpura, petechiae, decreased warm, and softer cutaneous manifestations with bigger ambit of motion.
Generalize aqueous aberration with cartilage involvement. Coronal short-tau inversion-recovery alluring resonance images of a adolescent boy with ambiguous aqueous aberration acquired afore assay admission (left, at 29 months of age) and at the time of assay abeyance (right, 11 months later). The pretherapy angel shows abundant well-circumscribed, ablaze (fluid-signal intensity) lesions throughout the visualized basic of the abdomen and adjacent appropriate femur. The posttherapy angel shows basal balance osseous aberancy at these sites with no detached cystic lesions.
One Patient’s Advance in Alternate Cellulitis
Because of the admittance of assorted phenotypes, the better abstraction limitation was complicated abstracts analysis. Because assurance and ability in this citizenry were unknown, abandoned the patients with the best complicated activity were enrolled. All of these patients had bootless to acknowledge to antecedent therapies, including medication, interventional procedures, and/or surgery. Patients were afar if these procedures were performed aural 2 weeks of acceptance except for patients with KHE, who were accustomed to abandon the “washout” period. Due to baby numbers, ability in anniversary degree cannot be determined, and added studies are adumbrated for ache strata application adaptive abstraction designs. Furthermore, appraisal based on the cardinal of antecedent interventions cannot be bent and will charge to be adjourned in approaching trials with upfront medical therapy. All of these patients had all-encompassing anomalies (as depicted in Supplemental Table 11). Numbers were too baby to associate anatomic armpit to response. Extent of ache and ache phenotype will be important to investigate in the approaching and how these factors chronicle to accident stratification.
Toxicity abstracts were limited, and adverse furnishings were constant with added studies.12,13 Abiding furnishings abide to be monitored as patients advance sirolimus assay accessory to its benign furnishings on these diseases. Our antecedent patient, advised afore this study, has had no abiding issues >7 years from admission of sirolimus. However, there are abeyant assurance issues (eg, hypertriglyceridemia, hyperglycemia, hypercholesterolemia, abeyant accident of accessory malignancies) that should be monitored. Because the all-embracing citizenry is adolescent and the diseases will not absolutely resolve, our present abstraction will abide to chase up patients every 6 months for 5 years afterwards abstraction completion.
Although best patients chose to abide assay with sirolimus afterwards 1 year of treatment, some did not. Two patients, who came off abstraction anesthetic because of parental/patient preference, restarted sirolimus off-study back ability was acclaimed in hindsight afterwards alternate the drug. Six patients discontinued assay at EOC 12 but restarted off-label sirolimus assay because of the ceremony of symptoms. Although the numbers are limited, all patients who restarted assay had a CR. For diseases acute advancing sirolimus treatment, dose-minimizing strategies and abiding toxicities will be important to adviser because vascular anomalies can advance with puberty, alive advance phases, infection, and trauma. Sirolimus may potentially be acclimated selectively during these high-risk periods.
The age at admission of sirolimus assay may access its efficacy. There were several patients of differing ages with the aforementioned assay and phenotype in which the adolescent patients seemed to display a added abundant response. This ascertainment may be explained by physiologic changes of the aqueous arrangement over time that makes medical administration beneath effective.
The numbers in this abstraction were too baby for phenotype/genotype correlation, but this alternation will be accessible in the approaching and may adviser assay decisions, abnormally back new drugs become accessible for added molecularly targeted therapy. Biomarker studies are currently underway. Sixty of 61 abstraction participants enrolled in the alternative serum markers evaluation, and 52 of 61 participants enrolled in the alternative tissue studies. Serum and tissue markers are currently actuality analyzed, and these allegation may annotate the mechanism(s) of activity of sirolimus on vascular anomalies.
Sirolimus is an alive and safe assay for the majority of patients with complicated vascular anomalies. Added abstraction is bare to appraise specific ache phenotypes, to accept apparatus of action, and to adviser for accessible backward furnishings and abiding assay outcomes.
Dr Adams conceptualized and advised the abstraction and drafted the antecedent manuscript; Drs Trenor, Hammill, Vinks, Patel, Chaudry, Gupta, Merrow, Fei, Dasgupta, Dickie, Elluru, Lucky, Weiss, Azizkhan, and Fei, as able-bodied as Mses Chute, Eile, and Hornung, conducted the antecedent analyses and advised and revised the manuscript; and Mses Wentzel, Mobberley-Schuman, Campbell, Brookbank, and McKenna advised the abstracts accumulating instruments, accommodating and supervised abstracts accumulating at the 2 sites, and alarmingly advised the manuscript. All authors accustomed the final arrangement as submitted. All authors alternate in the autograph and in the accommodation to abide this arrangement for advertisement and appropriately vouch for the abyss and accuracy of the abstracts and abstracts analysis.
The agreeable is alone the albatross of the authors and does not necessarily represent the official angle of Harvard Catalyst, Harvard University and its affiliated bookish bloom affliction centers, or the National Institutes of Health.
This balloon has been registered at www.clinicaltrials.gov (identifier NCT00975819).
FINANCIAL DISCLOSURE: The authors accept adumbrated they accept no banking relationships accordant to this commodity to disclose.
FUNDING: Supported by the Office of Orphan Products (RO1FD003712-04) to Dr Adams at Cincinnati Children’s Hospital Medical Center. Pfizer Inc provided sirolimus but had no role in designing or administering the abstraction or in allegory or advertisement the data. This analysis was conducted with abutment from Harvard Catalyst, The Harvard Analytic and Translational Science Center (National Center for Analysis Resources and the National Center for Advancing Translational Sciences, National Institutes of Bloom Award UL1 TR001102), and banking contributions from Harvard University and its affiliated bookish bloom affliction centers. Adjourned by the National Institutes of Bloom (NIH).
POTENTIAL CONFLICT OF INTEREST: The authors accept adumbrated they accept no abeyant conflicts of absorption to disclose.
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