Near-Complete Response to Low-Dose Ceritinib in Recurrent Infantile Inflammatory Myofibroblastic Tumour

Near-complete response to low-dose ceritinib in recurrent infantile inflammatory myofibroblastic tumour

Abhenil Mittal1, Aarushi Gupta2, Sameer Rastogi1, Adarsh Barwad3 and Swati Sharma2

1Department of Medical Oncology, Dr Bhim Rao Ambedkar (BRA) Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India 2Department of Radiodiagnosis, ABVIMS and Dr RML Hospital, New Delhi 110001, India 3Department of Pathology, All India Institute of Medical Sciences, New Delhi 110029, India

Abstract

Background: Infantile inflammatory myofibroblastic tumour (IMT) is rare and the majority are driven by anaplastic lymphoma kinase (ALK) rearrangements. Previous literature on the use of ALK inhibitors in paediatric IMTs is extremely limited with no published literature on the use in infants. Crizotinib and ceritinib are two ALK inhibitors which are available and have been used in IMTs; however, ceritinib is much more affordable in the low- and middle-income country (LMIC) setting than crizotinib.

Case: An 11-month-old child, who had undergone surgery for mesenteric IMT at the age of 3 months, had an unresectable recurrence with soft tissue deposits in the subdia- Case Report phragmatic location abutting the spleen and paravesical location. As surgery would have entailed splenectomy and partial cystectomy, she was treated with low-dose ceritinib (300 mg/m2/day) with which she had a near-complete response without any toxicity.

Discussion and conclusion: This is the first report of the use of ceritinib at a lower dose for infantile IMT having immense practical applications for the low- and middle-income setting.

Keywords: ceritinib, infant, inflammatory myofibroblastic tumour, low dose

Correspondence to: Sameer Rastogi Email: [email protected] ecancer 2021, 15:1215 Introduction https://doi.org/10.3332/ecancer.2021.1215 Published: 01/04/2021 Inflammatory myofibroblastic tumours (IMTs) are considered to be potentially malignant Received: 10/11/2020 tumours with a propensity for local recurrence and rarely metastasis [1, 2]. With increas- Publication costs for this article were supported by ing expertise in diagnosis, they have been described in almost all anatomical locations ecancer (UK Charity number 1176307). and in all age groups [3, 4]. Presentation in infancy is rare with description limited to small Copyright: © the authors; licensee case series and case reports [3, 5–9]. Histologically, IMTs are characterised by a variably ecancermedicalscience. This is an Open Access cellular spindle cell proliferation in a myxoid to collagenous stromal background with the article distributed under the terms of the predominance of inflammatory cells. Histology rarely correlates with prognosis, except Creative Commons Attribution License (http:// creativecommons.org/licenses/by/3.0), which for the rare aggressive epithelioid variant [3, 10]. Immunohistochemistry (IHC) is non- permits unrestricted use, distribution, and specific [3, 10]. The need for an experienced sarcoma pathologist for correct diagnosis reproduction in any medium, provided the original cannot be overemphasised. work is properly cited.

ecancer 2021, 15:1215; www.ecancer.org; DOI: https://doi.org/10.3332/ecancer.2021.1215 1 experience with ALK inhibitors was limited to NSCLC andadultIMTs. monthsand 73%of patients the were progression-free at1 year [13].However, efficacy inthepaediatric population was not established as byCREATE the trial, in of50% which patients the with ALK-positive IMTs responded to crizotinib with amedianduration of response of 9 Efficacy of crizotinib in ALK-positive IMTs was reported by Butrynski et al dren). Majority of fusion-negative IMTs (90%) were adultsindicating a highprevalence of driver fusionsinpaediatric IMTs. arrangement series ofcase of 62cases IMT, 35patients(56%) were positive for 6patientsALK, (10%) were positive for ROS1 and1patient hadRET gene ing ROS1, RET (rearrange duringtransfection)(neurorophic andNTRK tropomyosin receptor kinase) gene [8,10,18].In fusions arecent not found inother tumours [17,18]. With advances inmolecular pathology, additionalabnormalitieshave beencharacterised inIMTs, includ- in IMT,been described binding protein(RAN RANBP2–ALK including (cysteinyl andCARS–ALK 2–ALK) t-RNA synthetase–ALK), which are protein-likearefusions 4–ALK) commonly most cell seeninnon-small lungcancer (NSCLC), aset of uniquetranslocations involving ALK has to constitutive activation of receptor tyrosine kinaseandtumourigenesis [16]. Although (echinoderm EML4–ALK microtubule-associated adult patients have showed that upto 50% of the patients harbour rearrangements in the geneALK detected by either FISH or IHC, leading a near-complete response to low-dose ceritinib. easily availablemore andmuch affordable. Here, we reportthe first ever caseof aninfant girlchild with recurrent ALK-positive IMT who had a favourable response [10,14].However, crizotinibis expensive inIndia andisunaffordable for mostpatients, whereas generic ceritinib is inhibitorsALK inpaediatricpatients islimited. Only four infants have beentreated with inhibitorsALK sofar (all crizotinib), with three having of tumour cells by dualprobe break-apartfluorescence insitu IMTs. Crizotinibis now standard the of careunresectable inadult ALK-positive IMTs (defined asthepresence of rearrangementALK in>15% genekinase (ALK) lymphoma seeninaround 50%of thecasesof IMTs, precision oncology hascome to theforefront of themanagement of Surgery remains thetreatment of choice for thelocaliseddisease[11,12]. With thediscovery of targetable alterations intheanaplastic ecancer 2021, 15:1215; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1215 Prior to thediscovery of the geneALK rearrangements by Griffin Discussion splenectomycystectomy, andpartial she was started onceritinib 150mgonce aday (300mg/m in rightparavesical andleftsubdiaphragmatic regions (Figure 1eandf nosis of infantile IMT was suggested. She developed abdominalpain6months after surgery andimaging(CECT) showed recurrent disease (100%) on D5F3 Ventana platform andcytoplasmicpositivity for smooth muscle actin (SMA) and desmin (Figure 2cand mitosis was seen(4–5/10per high-power field)(Figure 2aandb cells showed mild-to-moderate pleomorphism finelywith dispersed chromatin andmoderate-to-abundant oeosinophiliccytoplasm. Variable and haphazard pattern abundantwith admixture of inflammatory cells richinplasmacells, lymphocytes andfew oeosinophils. The tumour and resectionanastomosisof the involvedbowel. small Histopathology showed aspindlecell tumour with cells arranged inafascicular findings were suggestive of amesentericlikelymass, malignant.She underwentexploratory laparotomy with gross total excision of themass men andinthemidlineshowing mildheterogeneous post-contrast enhancement ondelayed images (at 5minutes) (Figure 1a andb a large ill-definedhomogenous hypodense lesion of size 8.4×11.411.3cm(APxTRAxSag), predominantly ontheright sideof theabdo- in bowelor habit constitutionalsymptoms. Contrast-enhanced computed tomography (CECT) scanofabdomen andpelvisshowed chest, A 3-month-oldfemale an uncomplicatedwith presented childbirth with agradually progressive abdominaldistension anywithout change Results scan at 6 months of startingceritinib showed complete response to therapy with notoxicity. response the disappearancewith of theparavesical lesionand95%reduction of thesubdiaphragmatic lesion(Figure 1gandh prior toceritinib, starting at 2 weeks oftreatment starting andthenmonthly. Response assessment after 2months showed anear-complete counts, liver andrenaltests function for thefirst month, followed by monthly liver functiontesting. An electrocardiogram (ECG) was obtained capsule),the after discussion multidisciplinarythe with tumour board. The child was monitored for toxicity with two weekly complete blood [19]. Outof these,ROS1gene rearrangements were particularly more common inchildren (5/6ROS1-positive cases were chil- hybridisation or (FISH) stainingby IHC)[13].However, literature ontheuseof ). Tumour cells showed nuclear diffuse immunoreactivity for ALK-1 protein et al [15] in1999,thebiology of IMTs was anenigma.Since then,studiesin ). As resection would have required debilitating surgery intheform of [20]. Concrete evidence of theefficacy of crizotinib was provided 2 ) with food (the child was ableto swallow d). Hence, a diag- ). A follow-up). A ). These 2

Case Report ecancer 2021, 15:1215; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1215 with myofibroblastic differentiation. (d): Immunostain for SMA showing cytoplasmic reactivity in cells with myofibroblastic differentiation. and few oeosinophils(H&E200×).(c): Immunostain for ALK-1 onD5F3 Ventana platform showing diffusenuclear reactivity in100% ofthetumour cells nuclear pleomorphism,finely dispersed chromatin andmoderate-to-abundant cytoplasm. The inflammatory cells arerichinplasma cells withlymphocytes and admixed inflammatory cells. (b): High-power picture showing spindle cell population exhibiting myofibroblastic differentiation with mild-to-moderate Figure 2.(a): Low-power photomicrograph of the tumour showing cells arranged infascicles anda haphazard pattern withanoedematous background CECT abdomenaxialimages showing complete resolution of aright paravesical lesionandnear-complete resolution of the left subdiaphragmatic lesion. enhancing lesionintheright paravesical region indenting theright lateral wall of urinary bladder withloss of fat plane.(g, h): Two months post-Ceritinib abutting thesuperior surface of thespleen withindentation and loss of fatplane. f): (e, CECT abdomenaxial + coronal images showing a heterogeneously infiltration. (c,d): CECT abdomen at recurrence axial+ coronal images showing a heterogeneously enhancinglesioninthe left subdiaphragmatic region contrast enhancement displacingsmallbowel loopsto theleft sideandascending colon posteriorly andabutting inferior surface of liver with no obvious Figure 1.(a, b): Pre-operative CECT abdomenaxial+ coronal images showing alarge hypodense mesenteric lesion withmildheterogeneous post- 3

Case Report to crizotinib which needsto beexplored further inlarger studies,especially setting. inanLMIC Based onpreviousdata published inNSCLC andour experience, we believe that low-dose ceritinib isanexcellent cost-effective alternative therapystarting andanear-complete response in2months notoxicity,with thusshowing promising efficacy of alower doseof ceritinib. approach, we were abletodown cut costthe by to Rs. one-fifth 8000/month ($110).She hadimprovement insymptoms within 2 weeks of costthe of therapy wouldhave beenaroundRs. 40,000($550)per month, which would have beenunaffordable for our patient. With this ceritinib taken with low fat(150 mg/day) meal –similar todose ofadult the 450mg/day. Had we usedcrizotinib at itsrecommended dose, atricIMTs. Based onthisevidence andprevious data of lower doseceritinib inNSCLC [25,26], we treated our patient 300mg/mwith developed acute liver failure related to ceritinib [24]. This provided preliminary evidence of the efficacy of a lower dose of ceritinib in paedi- 14 children metastatic/unresectablewith IMT was found The first relatively large study to reportthe efficacy of crizotinib inpaediatric IMTs was in2017, published which a36%response rate in mention whether ceritinib was given with food or empty stomach and although both patients responded, theone treated 450mg/mwith cal Oncology (ASCO) 2015,inchildren more than1 year of age, therecommended tolerated maximum dose was 510mg/m ofdose) adult [22].In aphaseIstudy of ceritinibin 22 ALK-positive paediatric tumours (six IMTs) presented at American Society of- Clini None. Acknowledgments andfunding None. Conflicts of interest Taken from parents. Consent FISH, Fluorescence insitu IMT, Inflammatory myofibroblastictumour; ALK, kinase;IHC,Immunohistochemistry;Anaplasticlymphoma SMA,Smooth muscleactin; Abbreviations dose andhasimmensepractical implications, especially for LMICs. unwanted toxicity andcost. This isthefirst caseto describecomplete response to ceritinib ininfantile IMTs at a lower thanrecommended efficacy of inhibitorsALK predominantlyRecommended inadults. dosesinchildren seem higher thanrequired for optimal response with Withadvancements in molecular pathology, precisiononcology isthefuture to managingthis very rare tumour. Published data describethe Conclusion ecancer 2021, 15:1215; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1215 responsesto ceritinib inadolescentIMTs intheir twothey cases; usedlower dosesof 300mg/m all grade vomiting, 54%elevated alaninetransaminase and 40%decreased appetite) [23].Brivio andZwaan [24]demonstrated excellent However, themedianage inthisstudy was 10 years (no infants were recruited) andtoxicities were significant (86%allgrade diarrhoea,81%

hybridisation; NSCLC, Non-small cell lungcancer;Low- LMIC, andmiddle-income country [21]. The recommended phaseIIdose of crizotinib was 280mg/m 2 and450mg/m 2 . The manuscript didnot 2 without food. without 2 (double that 2 /day /day 4 2

Case Report ecancer 2021, 15:1215; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1215 15. 14. 13. 12. 11. 10. References

3. 9. 8. 7. 4. 2. 1. 6. 5. A clinicopathologicimmunohistochemicalstudy and of 84cases CoffinCM, Watterson J, andPriest JR, 59(12) 2776–2780PMID: GriffinCA, Hawkins and DvorakAL, C,et (1999)Recurrent al involvement of inflammatoryin 2p23 myofibroblastic tumors org/10.1016/S2213-2600(18)30116-4 trial 2 phase non-randomised prospective, single-drug, multicentre, a CREATE): 90101 tumours with and without anaplastic lymphoma kinase gene alterations (European Organisation for Research and Treatment of Cancer SchöffskiP, Sufliarsky J, andGelderblom H,et al(2018)Crizotinibpatientsin advanced,with inoperable inflammatory myofibroblastic and review of theliterature Fetal Pediatr Pathol Caporalini C,Moscardiand S, Tamburini A, et al(2018)In India 33(1)82–84 https://doi.org/10.4103/0970-2113.173058 PMID: Maturu BalVN, A, andSingh(2016) Inflammatory N myofibroblastic tumor of thelunginpregnancy carcinoid mimicking tumor PMCID: report and systematic review of the literature Ray A, Suri JC, and Bhattacharya D, et al (2014) characterization of 12cases Lopez-Nunez O, John I, and Panasiti RN,et al (2020) org/10.1016/j.humpath.2017.06.013 PMID: lesions pulmonaryinfantile of diagnosis differentialreview the ofand cases infantile 2 ofreport TanakaKohashi M, and Kushitani K, K, tumours. Histopathology69 72–83 https://doi.org/10.1111/his.12910 Yamamoto H, Yoshida A, and TaguchiK, pathogenic link? Saabin ST,in Hornick cells and FletcherJL, plasma CD, etal (2011)IgG4 study immunohistochemical comparative a tumor: Cook DehnerJR, LP, andCollins MH, 199508000-00001 PMID: matory pseudotumor Meis and EnzingerJM (1991) Inflammatory FM fibrosarcomaof themesentery andretroperitoneum. A tumor closely simulating inflam- S0096-5588(20)32030-4 BrunnH. (1939)Two interesting benign lung tumors of contradictory histopathology logicaland immunohistochemicalcomparison Hill KA,Gonzalez-Crussi F,(2001) Calcifying andChouPM nant tumors Am J Surg Pathol Gonzalez-CrussiF, deMelloand Sotelo-Avila DE, C(1983)Omental mesenteric myxoid hamartomas. Infantile lesions simulating malig - 00003 3999683 Mod Pathol Am J Surg Pathol 10383129 7611533 24606–612https://doi.org/10.1038/modpathol.2010.226 PMID:21297584 Mod Pathol 7567–578https://doi.org/10.1097/00000478-198309000-00007 etal (2017)In 151146–1156https://doi.org/10.1097/00000478-199112000-00005 Anaplastic lymphoma kinase (ALK) expression in the inflammatorymyofibroblasticthe in expression (ALK) kinase lymphoma et al (2011)Anaplastic etal (1995)Extrapulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor). PMID: 33(4)576–590https://doi.org/10.1038/s41379-019-0406-6 ALK, ROS1 and NTRK3 gene rearrangements in in in rearrangements gene NTRK3 and ROS1 et al(2016)ALK, 28705706 Lung India

Mod Pathol 37117–125https://doi.org/10.1080/15513815.2017.1385667 PMID:29336647 29669701 Bronchoscopic resection of endobronchial inflammatory myofibroblastic acase tumor:

flammatory myo Am J Surg Pathol Infantileinflammatory myofibroblastic tumors: clinicopathological andmolecular 31(2) 172–175https://doi.org/10.4103/0970-2113.129866 PMID:

ammatory myoflammatory 14 784–790https://doi.org/10.1038/modpathol.3880390 PMID: brous pseudotumorfibrousin versus

Am J Surg Pathol fibroblastic tumors of the lung carrying a chimeric A2M-ALK gene: 25 1364–1371https://doi.org/10.1097/00000478-200111000- 26933315 PMCID: ammatory myoflammatory broblastic tumor of the tongue. Report of a pediatric case pediatric a ofReport tongue. the oftumor fibroblastic 19(8) 859–872https://doi.org/10.1097/00000478- J ThoracSurg 9119–131https://doi.org/10.1016/ LancetRespir Med 4748673 flammatorymyo broblastic tumor: in tumor: fibroblastic PMID:6625050 Hum Pathol ammatory myo flammatory broblastic tumor: a histo- a tumor: fibroblastic 6(6) 431–441https://doi. PMID:1746682 66 177–182 ammatory marker ormarker flammatory fibroblastic https://doi. 11504838 24778486 Cancer Res Lung 5

Case Report ecancer 2021, 15:1215; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2021.1215 Geoerger 23. 22. 21. 20. 16. 19. 18. 17. 25. 24. 26. org/10.1016/S1470-2045(13)70095-0 orlarge-cell anaplastic a Children’s lymphoma: Oncology Group phase1consortium study tumours solid refractory with patients paediatric forMoss´e crizotinibYP, of and MS, Lim activityVoss and SD, et al(2013)Safety myofibroblasticchildren'sa tumor: oncology groupstudy Mossé YP, Voss SD,MS, andLim 363(18) 1727–1733https://doi.org/10.1056/NEJMoa1007056 PMID:20979472PMCID:3014292 Butrynski JE, D'Adamo DR,and Hornick JL, et al (2010) matory myofibroblastic tumor inflam- in rearrangements2p23 involvingchromosomalCoffin and CM, Patel expression p80 A, andPerkinsand S,et al(2001)ALK1 genetic alteration in ALK (ALK+): safety, pharmacokinetic (PK), and efficacy results efficacy and (PK), pharmacokinetic safety, (ALK+): ALK in alteration genetic PMID: PAS.0000000000000404 PMID: rearrangement RET novel rare and fusions gene ROS1 and ALK frequent AntonescuCR, Suurmeijer AJ, andZhang L,et al(2015)Molecular characterization of inflammatory myofibroblastictumors with tumor Ma Z,Hill DA, andCollins et MH, (2003) alFusion of toALK the Ran-binding protein gene 2(RANBP2) ininflammatory myofibroblastic matory myofibroblastic tumor Debelenko LV, Arthur DC,andPack SD, et al(2003)Identification of inprimary fusion CARS-ALK andmetastatic lesionsof aninflam- Shaw AT, DW,Kim and Mehra R, et al(2014) side effects Pediatr Blood Cancer 66(5)e27645https://doi.org/10.1002/pbc.27645 PMID:30697903 Brivioand Zwaan E in twoinhibition (2019) ALK CM emblematic casesof pediatric inflammatory myofibroblastic tumor:efficacy and jco.2015.33.15_suppl.10005 cancer (NSCLC) lung cell non-small metastatic(ALK)-rearranged kinase lymphoma anaplastic patientswith in state fasted in Fatmg 750 Mealversus DW,Cho BC,Kim andBearz A, https://doi.org/10.1056/NEJMoa1311107 PMID: Genes Chromosomes Cancer 37(1)98–105https://doi.org/10.1002/gcc.10177 PMID:12661011 28787259 PMCID:

β, Schulte JThoracOncol 12(9)1357–1367https://doi.org/10.1016/j.jtho.2017.07.005 PMID: J, and 5617123 Zwaan Mod Pathol Lab Invest etal (2017) etal (2017)Targeting ALK with crizotinib in pediatric anaplastic large cell lymphoma and inflammatory 25723109 PMCID: CM, etal (2015)Phase I study of ceritinib inpediatric patients (Pts) with malignanciesharboringa 83(9)1255–1265https://doi.org/10.1097/01.LAB.0000088856.49388.EA 14569–576https://doi.org/10.1038/modpathol.3880352 PMID: ASCEND-8: a randomized phase 1 studyrandomized1 a phase ASCEND-8: of ortakenmg ceritinib,mg, 450 600 low-a with Ceritinib in ALK-rearranged non-small-cell lungcancer PMCID: 4079055 24670165 PMCID: 4465992 Crizotinib in ALK-rearranged inflammatory myofibroblastic tumorNEngl J Med

J ClinOncol 35(28) 3215–3221https://doi.org/10.1200/JCO.2017.73.4830 Am J Surg Pathol J ClinOncol 39(7) 957–967https://doi.org/10.1097/ Lancet Oncol 33 10005https://doi.org/10.1200/ 28729021 N Engl J Med 11406658 14 472–480https://doi. 370(13) 1189–1197 PMID:13679433 6

Case Report