Carreras, Enric

Corbacioglu, Selim

Duarte, Rafael

Grupp, Stephan A.

Mahadeo, Kris

Pagliuca, Antonio

Richardson, Paul Gerard

Ruutu, Tapani

University of Regensburg Publication Server

EDITORIAL OPENPrevention of veno-occlusive disease/sinusoidal obstructionsyndrome: a never-ending story and no easy answer© The Author(s) 2023Bone Marrow Transplantation; https://doi.org/10.1038/s41409-023-02007-2The Harmony Trial (NCT02851407), a prospective randomized trialconducted among adults and children, reported that defibrotidewas not effective for the prevention of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) [1]. Importantly nosafety concerns were raised [2], but consecutively, in May 2022,the European Medicines Agency (EMA) recommended not to usedefibrotide for prophylaxis of VOD/SOS (https://www.ema.europa.eu/en/medicines/dhpc/defitelio-defibrotide-do-not-use-prophylaxis-veno-occlusive-disease-vod-after-post-hematopoietic).A decade ago, another prospective randomized trial, thePediatric Prevention Trial (NCT00272948), clearly demonstratedefficacy in the prevention of VOD/SOS [3]. Prospective randomizedtrials are considered the so-called “gold standard” of clinicalmedicine. What happened that such two prospective randomizedtrials yielded apparently contradictory results?The Pediatric Prevention Trial was conceptualized between2001 and 2005 and recruited 360 pediatric patients considered athigh risk for VOD/SOS between 2006 and 2009, being informed byprior and ongoing treatment studies at the time in whichdefibrotide had shown consistent efficacy in the setting ofestablished disease [4]. The sample size calculation generatedback in 2005 was based on the presumed incidence in high-riskpediatric patients of up to 30%. In order to reduce this incidenceby half, to 15%, the sample size calculation resulted in accrual of270 patients for both arms. In 2008, the interim analysis revealedthat the actual incidence of VOD/SOS in this high-risk populationbased on investigator assessment was only 20% according to themodified Seattle criteria. Consequently, the sample size wasadjusted as part of a planned interim analysis to 360 patients.Eventually the trial demonstrated efficacy in the competing riskanalysis of the intent-to-treat population reducing the incidencefrom 20 to 12% (p= 0.049; per protocol population: p= 0.022) [3].Whereas the Pediatric Prevention Trial focused exclusively onthe highest risk pediatric population, the Harmony Trial enrolledpediatric and adult patients and enrolled patients where high riskamong other criteria was defined as a myeloablative conditioning(MAC) with more than two (not further defined, see below)alkylators or TBI plus one or more alkylators. Current high-riskpopulations in adult disease—such as those exposed to sirolimus—were excluded, due to regulatory considerations on the part ofthe sponsor at the time. Almost half of the patients enrolled wereadults and half of the diagnoses were acute leukemias. Only 15%and 7% of the enrolled patients, respectively, were very high-riskpediatric patients with neuroblastoma and osteopetrosis.In 2010, a meta-analysis including 25,000 pediatric and adultpatients revealed an average VOD/SOS incidence of 13.7% [5]. Thereported incidence in children was around 20% [6, 7] which waslater confirmed in the Pediatric Prevention Trial with an overallincidence of 22.2% and an even higher incidence of 29.3%reported in infants [3].In 2018, a study including 13,000 patients defined the incidencein the highest risk population as ~18% with the most significantnon-linear relationship existing between age and risk of VOD/SOS[8], and a contemporaneous meta-analysis including more than27,000 patients confirmed a VOD/SOS incidence of 15% [9, 10]. Insummary, an average VOD/SOS incidence of ~15% can beconsidered realistic with a persistent and consistently higherincidence of VOD/SOS in children, particularly in infants ascompared to adults.The Harmony Trial had an adaptive design with a calculatedsample size of 400 patients based on a presumed incidence of28% in the best supportive care (BSC) group. This incidence in thecontrol arm was not even reached in the 10 years older trial inhigh-risk pediatric patients as described above. With a decadebetween the two trials with scientific advancements thatimproved the safety of hematopoietic stem cell transplantation(HSCT) significantly, the presumed incidence was not realistic. Oneexample, treosulfan, albeit an alkylator such as busulfan,demonstrates a reduced endothelial toxicity profile. This is mostevident in infantile malignant osteopetrosis (IMO) with a historicalincidence of VOD/SOS as high as 60% [3]. Shadur et al. [11]reported no VOD/SOS on 31 IMO patients using a treosulfan,fludarabine and thiotepa-based MAC regimen with an overallsurvival of 100%.In retrospect, these observations suggest that a powercalculation based on an overestimated incidence of VOD/SOS of28%, in an adult/pediatric study, resulting in an estimated samplesize of 400, was markedly insufficient to detect a significantreduction in a non-composite endpoint, i.e., the incidence of VOD/SOS.Moreover, this was not the primary endpoint ultimately chosenby the sponsor, as based on guidance from regulatory authorities.The primary endpoint of the Harmony Trial was required to beVOD/SOS-free survival by day 30 post-HSCT. There proved to beeven greater challenges with this composite endpoint than simplyan overestimate of the incidence. VOD/SOS is graded according toseverity and only the severe/very severe grades are associatedwith a mortality of up to 80% [5] whereas the mortality of mild/moderate cases is by comparison very low. VOD/SOS withmultiorgan failure (MOF; sometimes referred to as multiorgandysfunction) occurs in an estimated 30–40% of patients with VOD/SOS after HSCT [12]. Therefore, considering a population of 40%out of 15% that are at risk of treatment-related mortality due toVOD/SOS, the trial population at risk for this composite endpointwas further reduced to less than 7%. Szmit et al. analyzed theimpact of preemptive treatment with defibrotide by comparing ina single institution Seattle criteria with the pediatric EBMT criteria[13]. They not only found a significantly improved survival but alsoa shortened median hospitalization by 12 days correlating with aReceived: 29 March 2023 Revised: 12 April 2023 Accepted: 4 May 2023www.nature.com/bmt1234567890();,:reduced admission to the pediatric intensive care unit (PICU) (3.9%vs. 14.6%) (personal communication), clearly reflecting morbidityfrom VOD as a significant endpoint for treatment efficacy. Inconclusion, survival is a crude primary endpoint in defining thebenefit of an intervention in VOD/SOS by ignoring the substantialmorbidity related to this disease.In addition, and importantly, a statistically meaningful differ-ence in outcome for the endpoint of survival was diluted in bothtrials by the required and necessary equipoise of allowingdefibrotide use for the treatment of any emergent VOD/SOS inthe BSC group.In designing the study, there were also concerns about correctlyand reproducibly diagnosing VOD/SOS. To address this, theHarmony Trial implemented an independent Endpoint Adjudica-tion Committee (EPAC) to provide centralized assessment of theprimary endpoint (VOD/SOS-free survival by day 30 post-HSCT)which comprised 4 independent HSCT specialists. Unexpectedly,the EPAC assessment of VOD/SOS resulted in detection ofsignificantly more cases of VOD/SOS (25% for prophylaxis vs.21% for BSC) than that recorded by the investigators at thebedside (12% for prophylaxis vs. 16% for BSC) (Fig. 1). Disagree-ments between EPAC and investigators proved asymmetric: therewere many more cases of disagreement between EPAC andinvestigator in the direction of the EPAC calling VOD/SOS whenthe investigator did not, compared to the opposite scenario. Theprimary endpoint was based on EPAC assessment alone. Thissignificant discrepancy was not factored into the decision by thedata and safety monitoring committee (DSMC) to stop the trial forfutility at the time of interim analysis, which was based upon anapparent lack of efficacy in a limited sample size, a decisionworsened by its timing during the pandemic and legitimateconcerns regarding the pace of future enrollment. It is notpossible to know if a trial with a more realistic sample size;recruited over a longer period; using real world bedsideassessment of VOD/SOS, and designed to assess the impact ofdefibrotide prophylaxis based upon VOD/SOS incidence, mighthave reached a different conclusion, and above all, if it wasfocused on current higher risk patients, a conclusion that mightthen have matched the outcome of the previous PediatricPrevention Trial [3].Given the totality of evidence, and in particular when faced withpediatric patients at very high risk of VOD/SOS, we would point tothe results of the Pediatric Prevention Trial as providingjustification for use of prophylactic defibrotide in this smallerand highly selected group of patients for which there is exquisiteunmet medical need. Given the substantive methodologicalconcerns raised with the Harmony Trial, we still regard this asan open question, and would not use this latter result over othersto recommend against the use of defibrotide as prophylaxis forpatients at high risk. Therefore, before drawing any finalconclusions, we advocate the consideration of the entire bodyof clinical benefit seen to date, especially when there is such adiscrepancy in outcome in two prospective randomized trials andwould recommend further carefully designed studies in high-riskgroups. The consequences of not recommending any preventionof VOD/SOS are already devastating for a substantial number oftransplant patients, and especially for high-risk infants, beingamongst the most vulnerable populations undergoing HSCT, aswell as others.Selim Corbacioglu 1✉, Stephan A. Grupp 2,Paul Gerard Richardson 3, Rafael Duarte4, Antonio Pagliuca5,Tapani Ruutu6, Kris Mahadeo7 and Enric Carreras 81University of Regensburg, Regensburg, Germany. 2The Children’sHospital of Philadelphia, Philadelphia, PA, USA. 3Jerome LipperMultiple Myeloma Center, Dana-Farber Cancer Institute, HarvardMedical School, Boston, MA, USA. 4Department of Hematology,Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.5King’s College Hospital and Anthony Nolan Research Institute,London, UK. 6Comprehensive Cancer Center, Helsinki UniversityHospital, Helsinki, Finland. 7Duke University Children’s Hospital,Durham, NC, USA. 8Josep Carreras Foundation & Leukemia ResearchInstitute, (Hospital Clínic/Barcelona University Campus), Barcelona,Spain. ✉email: selim.corbacioglu@ukr.deREFERENCES1. Grupp SA, Corbacioglu S, Kang HJ, Teshima T, Khaw SL, Locatelli F, et al. Defi-brotide plus best standard of care compared with best standard of care alone forthe prevention of sinusoidal obstruction syndrome (HARMONY): a randomised,2520122816122125051015202530PPEstimationPPIncidenceBSCPPIncidenceDFHTEstimationHT INVIncidenceBSCHT INVIncidenceDFHT EPACIndicenceBSCHT EPACIndicenceDFVOD/SOS Incidence (%)VOD/SOS Estimates and incidencesFig. 1 VOD/SOS estimates and incidences in the Pediatric Prevention trial (PP) and the Harmony Trial (HT). PP Pediatric Prevention Trial,BSC best supportive care, HT Harmony trial, HT INV incidences of the Harmony trial according to the investigators, HT EPAC incidences of theHarmony trial according to the EPAC.Editorial2Bone Marrow Transplantationmulticentre, phase 3 trial. Lancet Haematol. 2023. https://doi.org/10.1016/s2352-3026(23)00011-x.2. Grupp S, Corbacioglu S, Jin Kang H, Teshima T, Zanette M, Lopez P, et al. A phase3, randomized, adaptive study of defibrotide versus best supportive care (BSC) forthe prevention of hepatic veno-occlusive disease/sinusoidal obstruction syn-drome (VOD/SOS) in patients undergoing hematopoietic cell transplantation(HCT): preliminary results. In: ASH. Atlanta, USA, 2021.3. Corbacioglu S, Cesaro S, Faraci M, Valteau-Couanet D, Gruhn B, Rovelli A, et al.Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric hae-mopoietic stem-cell transplantation: an open-label, phase 3, randomised con-trolled trial. Lancet. 2012;379:1301–9. https://doi.org/10.1016/S0140-6736(11)61938-7.4. Richardson P, Aggarwal S, Topaloglu O, Villa KF, Corbacioglu S. Systematic reviewof defibrotide studies in the treatment of veno-occlusive disease/sinusoidalobstruction syndrome (VOD/SOS). Bone Marrow Transplant. 2019;54:1951–62.https://doi.org/10.1038/s41409-019-0474-8.5. Coppell JA, Richardson PG, Soiffer R, Martin PL, Kernan NA, Chen A, et al. Hepaticveno-occlusive disease following stem cell transplantation: incidence, clinicalcourse, and outcome. Biol Blood Marrow Transplant. 2010;16:157–68. https://doi.org/10.1016/j.bbmt.2009.08.024.6. Barker CC, Butzner JD, Anderson RA, Brant R, Sauve RS. Incidence, survival andrisk factors for the development of veno-occlusive disease in pediatric hemato-poietic stem cell transplant recipients. Bone Marrow Transplant. 2003;32:79–87.7. Cesaro S, Pillon M, Talenti E, Toffolutti T, Calore E, Tridello G, et al. A prospectivesurvey on incidence, risk factors and therapy of hepatic veno-occlusive disease inchildren after hematopoietic stem cell transplantation. Haematologica.2005;90:1396–404.8. Strouse C, Zhang Y, Zhang MJ, DiGilio A, Pasquini M, Horowitz MM, et al. Riskscore for the development of veno-occlusive disease after allogeneic hemato-poietic cell transplant. Biol Blood Marrow Transplant. 2018;24:2072–80. https://doi.org/10.1016/j.bbmt.2018.06.013.9. Yoon JH, Min GJ, Park SS, Park S, Lee SE, Cho BS, et al. Incidence and risk factors ofhepatic veno-occlusive disease/sinusoidal obstruction syndrome after allogeneichematopoietic cell transplantation in adults with prophylactic ursodiol andintravenous heparin or prostaglandin E1. Bone Marrow Transplant.2021;56:1603–13. https://doi.org/10.1038/s41409-021-01215-y.10. Xia Y, Qin H, Yang J. Hepatic veno-occlusive disease development in thehematopoietic stem cell transplantation patients: incidence and associated riskfactors, a meta-analysis. Eur J Gastroenterol Hepatol. 2021;33:872–84. https://doi.org/10.1097/meg.0000000000001802.11. Shadur B, Zaidman I, NaserEddin A, Lokshin E, Hussein F, Oron HC, et al. Suc-cessful hematopoietic stem cell transplantation for osteopetrosis using reducedintensity conditioning. Pediatr Blood Cancer. 2018;65:e27010. https://doi.org/10.1002/pbc.27010.12. Carreras E, Diaz-Beya M, Rosinol L, Martinez C, Fernandez-Aviles F, Rovira M. Theincidence of veno-occlusive disease following allogeneic hematopoietic stem celltransplantation has diminished and the outcome improved over the last decade.Biol Blood Marrow Transplant. 2011;17:1713–20. https://doi.org/10.1016/j.bbmt.2011.06.006.13. Szmit Z, Gorczynska E, Król A, Ussowicz M, Mielcarek-Siedziuk M, Olejnik I, et al.Introduction of new pediatric EBMT criteria for VOD diagnosis: is it time-saving ormoney-wasting?: prospective evaluation of pediatric EBMT criteria for VOD. BoneMarrow Transplant. 2020. https://doi.org/10.1038/s41409-020-0918-1.AUTHOR CONTRIBUTIONSSC designed and drafted the manuscript. SAG, PGR, RD, AP, TR, KM and ECcontributed to the writing of the manuscript.FUNDINGOpen Access funding enabled and organized by Projekt DEAL.COMPETING INTERESTSAll authors have received honoraria and/or research support from JAZZ Pharmaceu-ticals whose product is discussed in this manuscript.ADDITIONAL INFORMATIONCorrespondence and requests for materials should be addressed to SelimCorbacioglu.Reprints and permission information is available at http://www.nature.com/reprintsPublisher’s note Springer Nature remains neutral with regard to jurisdictional claimsin published maps and institutional affiliations.Open Access This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in anymedium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made. The images or other third partymaterial in this article are included in the article’s Creative Commons license, unlessindicated otherwise in a credit line to the material. If material is not included in thearticle’s Creative Commons license and your intended use is not permitted by statutoryregulation or exceeds the permitted use, you will need to obtain permission directlyfrom the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.© The Author(s) 2023Editorial3Bone Marrow Transplantation

Prevention of veno-occlusive disease/sinusoidal obstruction syndrome: a never-ending story and no easy answer

https://epub.uni-regensburg.de/54305/1/s41409-023-02007-2.pdf

Prevention of veno-occlusive disease/sinusoidal obstruction syndrome: a never-ending story and no easy answer

Abstract

Similar works

Full text

Available Versions

University of Regensburg Publication Server