Arif T

Barnett S

Brown S

Burke GAA

Carruthers V

Graham C

Johnson K

Ramanujachar R

Rees R

Slater O

Veal GJ

\ua9 2022 The Authors. Pediatric Blood &amp; Cancer published by Wiley Periodicals LLC. Infantile myofibroma is a rare, benign tumour of infancy typically managed surgically. In a minority of cases, more aggressive disease is seen and chemotherapy with vinblastine and methotrexate may be used, although evidence for this is limited. Chemotherapy dosing in infants is challenging, and vinblastine disposition in infants is unknown. We describe the use of vinblastine therapeutic drug monitoring in four cases of infantile myofibroma. Marked inter- and intrapatient variability was observed, highlighting the poorly understood pharmacokinetics of vinblastine in children, the challenges inherent in treating neonates, and the role of adaptive dosing in optimising drug exposure in challenging situations

Newcastle University E-Prints

Received: 15 February 2022 Revised: 14March 2022 Accepted: 15March 2022DOI: 10.1002/pbc.29722 PediatricBlood &Cancer The American Society ofPediatric Hematology/OncologyONCO LOGY: B R I E F R E PORTClinical utility of vinblastine therapeutic drugmonitoring forthe treatment of infantile myofibroma patients: A case seriesVickyanne Carruthers1,2 Shelby Barnett1 Rebecca Rees1 TasnimArif2Olga Slater3 Ramya Ramanujachar4 Katie Johnson4 Sarah Brown4Catherine Graham5 G.A. Amos Burke6 Gareth J. Veal11Newcastle University Centre for Cancer,Newcastle University, Newcastle upon Tyne,UK2Great North Children’s Hospital, Newcastleupon Tyne, UK3Great Ormond Street Hospital, London, UK4Southampton General Hospital,Southampton, UK5Clinical School, University of Cambridge,Cambridge, UK6Cambridge University Hospitals NHSFoundation Trust, Addenbrooke’s Hospital,Cambridge, UKCorrespondenceGareth J. Veal, Newcastle University Centrefor Cancer, Medical School, NewcastleUniversity, Paul O’Gorman Building, Newcastleupon TyneNE2 4HH, UK.Email: G.J.Veal@ncl.ac.ukAbstractInfantilemyofibroma is a rare, benign tumourof infancy typicallymanaged surgically. Inaminority of cases,more aggressive disease is seen and chemotherapywith vinblastineand methotrexate may be used, although evidence for this is limited. Chemotherapydosing in infants is challenging, and vinblastine disposition in infants is unknown. Wedescribe the use of vinblastine therapeutic drug monitoring in four cases of infantilemyofibroma. Marked inter- and intrapatient variability was observed, highlighting thepoorly understood pharmacokinetics of vinblastine in children, the challenges inher-ent in treating neonates, and the role of adaptive dosing in optimising drug exposure inchallenging situations.KEYWORDSinfantile myofibroma, neonate, pharmacokinetics, therapeutic drugmonitoring, vinblastine1 INTRODUCTIONInfantile myofibroma (IM) is the commonest fibrous tumour of child-hood, typically occurring in the first 2 years of life.1,2 It is a benign lesionand spontaneous regression occurs frequently.2,3 Where the lesion isamenable to surgical resection, the prognosis is excellent, even withincomplete resection.3,4 However, in multifocal lesions, those with vis-ceral involvement, or inoperable solitary lesions, together comprising15%–20% of cases, morbidity and mortality have been described.1,2,5Chemotherapeuticmanagement of such cases is not standardised,withvarying approaches described in case studies, including vinblastineand methotrexate, vincristine, dactinomycin and cyclophosphamide,Abbreviations: AUC, Area under the plasma concentration-time curve; CL, Clearance; IM,Infantile myofibroma; TDM, Therapeutic drugmonitoring; MRI, Magnetic resonance imaging.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, providedthe original work is properly cited.© 2022 The Authors. Pediatric Blood & Cancer published byWiley Periodicals LLCand tyrosine kinase inhibitors.2,4–7 Vinblastine and methotrexate areused widely in other fibrous tumours, with minimal long-term toxicityreported.8,9While vincristine pharmacokinetics are relativelywell characterisedin children, including neonates,10 vinblastine is less well understood.14Vinblastine exhibits high inter- and intrapatient pharmacokinetic vari-ability in adult populations but there is currently no published data ondrug disposition in children.11,12 Dosing of all chemotherapeutics inneonates is challenging, due to marked physiological changes impact-ing drug clearance, which can lead to variable drug exposures.13–15Empiric dose reductions are therefore commonly advised, with-out strong clinical pharmacologic data to support dosing decisionsmade.13–15We investigated the potential for therapeutic drug monitoring(TDM) to guide treatment in this challenging clinical situation, whilePediatr Blood Cancer. 2022;e29722. wileyonlinelibrary.com/journal/pbc 1 of 5https://doi.org/10.1002/pbc.297222 of 5 CARRUTHERS ET AL.generating novel data on vinblastine pharmacokinetics, in four infantsreceiving vinblastine for IM at different clinical centres.2 METHODS2.1 PatientsFour infants are reported with an average age at first dose of vinblas-tine of 3.6 weeks (range 3–5.5). All had normal renal and liver functionfor age. Concomitant medications had no reported interactions witheither vinblastine or methotrexate in any case.2.1.1 Case 1In the first days of life, a term infant was found to have dissemi-nated IM, including subcutaneous, pulmonary and abdominal deposits(Figure 1A). The abdominal disease caused small bowel obstructionand gut failure requiring parenteral nutrition. Weekly vinblastine(initial dose3mg/m2)was commencedwithmethotrexatewithhelddueto fluid collections in the gut.2.1.2 Case 2A term infant was found to have disseminated IM with nodules involv-ing the stomach, small bowel, bilateral ovaries, mesenteric lymphnodes, lungs, pleura, cerebellum, cardiac muscle, renal parenchyma,bones and multifocal intramuscular soft tissue masses in the thorax,abdomen, pelvis and thighs (Figure 1B). Chemotherapy was initiatedwith vinblastine (initial dose 0.1mg/kg) andmethotrexate (0.5mg/kg).2.1.3 Case 3A large tumourof the left upper armwas identifiedantenatally andcon-firmed to be IM following premature birth of a child at 36+2 weeks.Nonmutilating surgery was not possible due to replacement of thesoft tissues of the entire upper arm and extension to the chest wall(Figure 1C). The infant was clinically unstable due to arteriovenousshunting through the tumour and therefore chemotherapy with vin-blastine (initial dose0.1mg/kg) andmethotrexate (0.7mg/kg)was com-menced.2.1.4 Case 4An infant was diagnosed with multicentric IM at 3 days of age, withsubcutaneous, intramuscular, bony, liver and lung disease (Figure 1Dand E). They were treated with vinblastine (initial dose 3 mg/m2) andmethotrexate (15mg/m2).2.2 Sample analysisSamples for pharmacokinetic analysis were collected at 0.5, 2 and6 h post-bolus administration of vinblastine. Plasma was separatedfrom whole blood samples by centrifugation (1200 g, 4◦C, 10 min),and samples were stored at –20◦C prior to analysis. Quantificationof vinblastine levels in plasma samples was carried out using a vali-dated liquid chromatography-mass spectrometry (LC/MS) assay, with alower limit of quantification (LLOQ) of 0.5 ng/ml. A non-compartmentalpharmacokinetic analysis of the data was performed using WinNon-lin version 8.1 (Certara, Princeton, NJ, USA) to determine the maxi-mum vinblastine plasma concentration (Cmax), area under the plasmaconcentration-time curve (AUC) and clearance (CL). Inter- and intra-patient variability was assessed using the coefficient of variation(CV%). Methotrexate levels were not measured at the discretion oftreating clinicians.3 RESULTSTable 1 shows the pharmacokinetic parameters observed for the fourcase subjects, with summary vinblastine plasma concentration–timedata provided in Figure S1. Intra-patient variability was high for allparameters, ranging between 7% and 84% (CV), with Cmax showing thegreatest intra-patient variability. Inter-patient variability was difficultto assess due to changes in dose between cycles. However, an eightfoldrange in vinblastine CLwas observed between patients acrossmultiplecycles (2.3–18.7 L/h). This is reflected in the wide range of AUC valuesobserved (19.4–232.6 µg/L⋅h). No clear relationship between toxicityand exposure was observed. Case subject 1 experienced hyperbiliru-binaemia at concentrations of 57.4–128.7 µg/L⋅h, exposures well tol-erated by other patients. Consequently, their dose was decreased by50%, resulting in a decrease in exposure (19.4–25.2 µg/L⋅h), howeverthepatient continued toexperienceexcessive toxicity. This infant expe-rienced good partial response in pulmonary and subcutaneous lesionswith stable abdominal disease.Case subject 2 had a dose increase due to good tolerability andobtained a partial response, with drug exposures toward the high endof the range observed across all patients. Case subject 3 had a doseincrease based on low drug exposure, with the increase well tolerated.They completed eight cycles of therapy with stable disease before reg-istering for a clinical trial. Case subject 4 required dose reductions ofboth vinblastine and methotrexate throughout 18 treatment cycles,despite experiencing exposures lower than those tolerated by others(47.1–59.7 µg/L⋅h). They had good clinical and radiological responses.Treatment is ongoing in three cases.4 DISCUSSIONMarked intra- and inter-patient variabilities in vinblastine clearanceandexposureobserved in this series highlight the challenges in treatingCARRUTHERS ET AL. 3 of 5F IGURE 1 MRI images demonstrating extent of disease in each case. (A) Extensive pulmonary disease in case 1, abdominal disease notappreciable byMRI. (B) Renal, retroperitoneal nodal, and intramuscular disease deposits in case 2, following surgical resection of ovariandisease. (C) Large unifocal myofibroma in case 3. (D and E) Extensive subcutaneous disease with pulmonary and liver nodules in case 4neonates with drugs whose pharmacokinetics are not well estab-lished. Infant physiology changes significantly during the first weeksof life, with marked variability in drug exposure previously reported inneonates treated with several chemotherapeutics.13–16 It is likely thatvariability in vinblastine pharmacokinetics observed in adults is ampli-fied in infants due to these physiological changes. While limited pub-lished data exist concerning the metabolism of vinblastine in patients,with desacetylvinblastine the only metabolite identified,12 the isoen-zyme cytochrome P450 3A4 (CYP3A4) has been shown to contributeto its metabolism in human liver microsomes.17 In addition, vinblastineis known to be transported by P-glycoprotein, encoded by ABCB1.18It is therefore possible that changes in the ontogeny of these enzymesaffecting expression and activity may impact on drug disposition in thefirst weeks of life.19,20 However, more detailed and expansive clinical4 of 5 CARRUTHERS ET AL.TABLE 1 Vinblastine pharmacokinetic parameters observed in four case subjectsCaseParameterDosePK cyclesmonitoredAge(weeks) Cmax (µg/L) CL (L/h) AUC0-inf (µg/L⋅h) Vz (L)1 1.5mg/m2 2 9–12 7.8–9.5 (14) 16.5–18.7 (9) 19.4–25.2 (18) 43.3–49.5 (9)3mg/m2 3 3–5 12–51.2 (84) 4.9–11 (38) 57.4–128.7 (47) 10.2–41.5 (57)2 0.1mg/kg 6 3–11 28.8–53 (20) 2.3–5.2 (32) 69–174.3 (26) 6.9–15.2 (38)0.15–0.2mg/kg 3 12–32 17.2–60 (61) 7.5–16.2 (45) 70.2–232.6 (62) 21.7–55.9 (52)3 0.1mg/kg 1 3 6.48 11.1 26.1 36.90.2mg/kg 7 4–10 20.9–53.3 (53) 3–9 (43) 70.8–212.7 (55) 11.1–28.5 (35)4 2.5mg/m2 2 8–27 13.9–23.4 (36) 15.9–17.9 (7) 47.1–59.7 (17) 32.6–51.1 (31)Note: Numbers in parenthesis represent the coefficient of variation (CV%).Abbreviations: AUC0-inf, area under the plasma concentration-time curve; Cmax, maximum plasma concentration; CL, clearance, PK, pharmacokinetic; Vz,volume of distribution.pharmacology studies are required to better understand the pharma-cokinetics of vinblastine in infants and children.With an improved knowledge of the clinical pharmacology of vin-blastine, TDMapproaches canpotentially havea role inoptimisingdrugexposure for rare conditions without established treatment guide-lines. In this series, vinblastine starting doses varied from 0.1 mg/kgto 3 mg/m2, reflecting the lack of a standardised treatment protocol.Toxicity developed in both patients treated at 3mg/m2, improvingwithreduced doses, although there was no association with drug exposure.Utilisation of a TDM approach to treatment for the patient exhibitinga low vinblastine exposure, incorporating a dose increase to 0.2mg/kg,was clinically well tolerated.The current case series highlights the challenges of diagnosing andtreating IM. Indeed, in this respect the diagnosis of IM in case 3 wassubsequently modified based on advanced molecular results. The casehas been included here based on similar phenotypic features and a clin-ical decision-making process based on the diagnosis of IM.5 CONCLUSIONSChemotherapy dosing in infants and neonates is challenging, particu-larly for drugs such as vinblastine, where no age-specific pharmacoki-netic data exist. Adaptive dosing can potentially have a role to play inoptimising drug exposure in rare conditions without established treat-ment guidelines, even in the absence of a defined therapeutic window,but relationships between exposure and clinical response and/or tox-icity need to be determined. Marked intra- and inter-patient variabili-ties in vinblastine exposurewere observed in the current study, provid-ing novel clinical pharmacology data in a rare patient population. Moreexpansive, prospective clinical pharmacology studies are required tobetter understand the disposition of this drug in infants and children.Such an approach will help to support the development of evidence-based vinblastine dosing guidelines in this challenging population.ACKNOWLEDGEMENTSThe authors thank the clinical centres and the patient’s families forallowing presentation of these cases for publication. This work wassupported in part by Cancer Research UK, the Experimental CancerMedicine Centre Network, the Little Princess Trust and the Sir BobbyRobson Foundation.CONFLICT OF INTERESTThe authors declare that there is no conflict of interest.ORCIDGareth J. Veal https://orcid.org/0000-0002-1897-8678REFERENCES1. Zhao G, Zhu M, Qin C, Liu X, Zhao X. Infantile myofibromato-sis: 32 patients and review of literature. J Pediatr Hematol Oncol.2020;42:495-498.2. Sparber-Sauer M, Vokuhl C, Seitz G, et al. Infantile myofibromatosis:excellent prognosis but also rare fatal progressive disease. Treatmentresults of five CooperativeWeichteilsarkomStudiengruppe (CWS) tri-als and one registry. Pediatr Blood Cancer. 2021;69:e29403.3. Mahajan P,Hicks J, ChintagumpalaM, Venkatramani R.Myofibroma ininfancy and childhood. J Pediatr Hematol Oncol. 2017;39:e136-e139.4. Levine E, Fréneaux P, Schleiermacher G, et al. Risk-adapted ther-apy for infantile myofibromatosis in children. Pediatr Blood Cancer.2012;59(1):115-120.5. Bidadi B, Watson A, Weigel B, Oliveira A, Kirkham J, Arndt C. Treat-ment of generalized infantilemyofibromatosiswith sorafenib and ima-tinib: a case report. Pediatr Blood Cancer. 2020;67(6):e28288.6. Weaver MS, Navid F, Huppmann A, Meany H, Angiolillo A. Vincristineand dactinomycin in infantile myofibromatosis with a review of treat-ment options. J Pediatr Hematol Oncol. 2015;37:237-241.7. Proust S, Benchimol G, Fraitag S, et al. Major response to ima-tinib and chemotherapy in a newborn patient prenatally diagnosedwith generalized infantile myofibromatosis. Pediatr Blood Cancer.2021;68(1):e28576.8. Skapek SX, Ferguson WS, Granowetter L, et al. Vinblastine andmethotrexate for desmoid fibromatosis in children: results of a Pedi-atric Oncology Group phase II trial. J Clin Oncol. 2007;25(5):501-506.CARRUTHERS ET AL. 5 of 59. Nishida Y, Hamada S, Urakawa H, et al. Desmoid with biweeklymethotrexate and vinblastine shows similar effects to weekly admin-istration: a phase II clinical trial. Cancer Sci. 2020;111(11):4187-4194.10. Barnett S, Hellmann F, Parke E, et al. Vincristine dosing, drug exposureand therapeutic drugmonitoring inneonate and infant cancerpatients.Eur J Cancer. 2022;164:127-136.11. Ratain MJ, Vogelzang NJ, Sinkule JA, Chicago P. Interpatient andintrapatient variability in vinblastine pharmacokinetics.Clin PharmacolTher. 1987;41:61-67.12. Owellen R, Hartke C, Hains F. Pharmacokinetics and metabolism ofvinblastine in humans. Cancer Res. 1977;37:2597-2602.13. Nijstad AL, Barnett S, Lalmohamed A, et al. Clinical pharmacologyof cytotoxic drugs in neonates and infants: providing evidence-baseddosing guidance. Eur J Cancer. 2022;164:137-154.14. Adamson PC. It’s not easy being small. Pediatr Blood Cancer.2010;54:341-343.15. Veal GJ, Boddy AV. Chemotherapy in newborns and preterm babies.Semin Fetal Neonatal Med. 2012;17(4):243-248.16. Veal GJ, Errington J, Hayden J, et al. Carboplatin therapeutic monitor-ing in pretermand full-termneonates.Eur J Cancer. 2015;51(14):2022-2030.17. Zhou-Pan XR, Sérée E, Zhou XJ, et al. Involvement of human livercytochrome P4503A in vinblastine metabolism: drug interactions.Cancer Res. 1993;53:5121-5126.18. Horio M, Gottesman MM, Pastan I. ATP-dependent transport of vin-blastine in vesicles from human multidrug-resistant cells. Proc NatlAcad Sci USA. 1988;85:3580-3584.19. de Wildt SN, Kearns GL, Leeder JS, van den Anker JN. CytochromeP450 3A: ontogeny and drug disposition. Clin Pharmacokinetic.1999;37(6):485-505.20. BrouwerKLR,AleksunesLM,BrandysB, et al.Humanontogenyofdrugtransporters: review and recommendations of the pediatric trans-porter working group. Clin Pharmacol Ther. 2015;98(3):266-287.SUPPORTING INFORMATIONAdditional supporting information may be found in the online versionof the article at the publisher’s website.How to cite this article: Carruthers V, Barnett S, Rees R, et al.Clinical utility of vinblastine therapeutic drugmonitoring forthe treatment of infantile myofibroma patients: A case series.Pediatr Blood Cancer. 2022;e29722.https://doi.org/10.1002/pbc.29722

English

Clinical utility of vinblastine therapeutic drug monitoring for the treatment of infantile myofibroma patients: A case series

Clinical utility of vinblastine therapeutic drug monitoring for the treatment of infantile myofibroma patients: A case series

Abstract

Similar works

Full text

Available Versions

Newcastle University E-Prints