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Improved detection of sinusoidal obstructive syndrome using pediatric–AYA diagnostic criteria and severity grading

Bone Marrow Transplantation volume 56, pages 175–184 (2021)Cite this article

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Abstract

New diagnostic criteria and severity grading for sinusoidal obstructive syndrome (SOS) among pediatric and adolescent young adult (AYA) patients have been recently endorsed by international consensus. The extent to which these have been adopted in the US remains unclear. We sought to assess the potential impact via retrospective application of these criteria among patients treated at a large academic center in the United States. This is a single center retrospective study of pediatric–AYA patients who underwent hematopoietic cell transplantation (HCT) between July 2009 and 2019. The incidence of SOS was assessed using historic Baltimore and Seattle diagnostic criteria and compared with more recent guidelines (pEBMT) as proposed by the Paediatric Diseases Working Party of the European Society for Blood and Marrow Transplantation. Among 226 patients, application of the pEBMT diagnostic criteria was associated with a higher incidence (15.9%) and earlier time to diagnosis of SOS (by 2.5–3 days) compared with the modified Seattle (12.3%), and Baltimore (6.6%) criteria, respectively. The pEBMT criteria were sensitive and highly specific. Refractory thrombocytopenia was present in 75% of patients at diagnosis. Approximately 61% of patients with SOS were anicteric at diagnosis, though the majority (94.4%) developed hyperbilirubinemia as SOS progressed over a median time of 4 (1–57) days. Application of pEBMT criteria may have resulted in earlier indication for definitive treatment by 3 days. Timely diagnosis and administration of definitive treatment of SOS has been associated with improved outcomes. Prospective studies may better characterize the risk factors and natural course of SOS using pEBMT criteria.

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Fig. 1: Identification of patients with sinusoidal obstructive syndrome.
Fig. 2: Patient outcome based on severity grade of SOS.
Fig. 3: 100-Day survival (Fig. 3a) and overall survival (Fig. 3b) of patients with and without SOS post-HCT.

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References

  1. 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 haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial. Lancet. 2012;379:1301–9.

    Article  CAS  Google Scholar 

  2. Barker CC, Butzner JD, Anderson RA, Brant R, Sauve RS. Incidence, survival and risk factors for the development of veno-occlusive disease in pediatric hematopoietic stem cell transplant recipients. Bone Marrow Transpl. 2003;32:79–87.

    Article  CAS  Google Scholar 

  3. Cesaro S, Pillon M, Talenti E, Toffolutti T, Calore E, Tridello G, et al. A prospective survey on incidence, risk factors and therapy of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation. Haematologica. 2005;90:1396–404.

    Google Scholar 

  4. Corbacioglu S, Honig M, Lahr G, Stohr S, Berry G, Friedrich W, et al. Stem cell transplantation in children with infantile osteopetrosis is associated with a high incidence of VOD, which could be prevented with defibrotide. Bone Marrow Transpl. 2006;38:547–53.

    Article  CAS  Google Scholar 

  5. Richardson PG, Elias AD, Krishnan A, Wheeler C, Nath R, Hoppensteadt D, et al. Treatment of severe veno-occlusive disease with defibrotide: compassionate use results in response without significant toxicity in a high-risk population. Blood. 1998;92:737–44.

    CAS  PubMed  Google Scholar 

  6. Corbacioglu S, Greil J, Peters C, Wulffraat N, Laws HJ, Dilloo D, et al. Defibrotide in the treatment of children with veno-occlusive disease (VOD): a retrospective multicentre study demonstrates therapeutic efficacy upon early intervention. Bone Marrow Transpl. 2004;33:189–95.

    Article  CAS  Google Scholar 

  7. Richardson PG, Smith AR, Triplett BM, Kernan NA, Grupp SA, Antin JH, et al. Earlier defibrotide initiation post-diagnosis of veno-occlusive disease/sinusoidal obstruction syndrome improves Day +100 survival following haematopoietic stem cell transplantation. Br J Haematol. 2017;178:112–8.

    Article  CAS  Google Scholar 

  8. Corbacioglu S, Carreras E, Ansari M, Balduzzi A, Cesaro S, Dalle JH, et al. Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in pediatric patients: a new classification from the European society for blood and marrow transplantation. Bone Marrow Transpl. 2018;53:138–45.

    Article  CAS  Google Scholar 

  9. Jones RJ, Lee KS, Beschorner WE, Vogel VG, Grochow LB, Braine HG, et al. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation. 1987;44:778–83.

    Article  CAS  Google Scholar 

  10. McDonald GB, Sharma P, Matthews DE, Shulman HM, Thomas ED. Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology. 1984;4:116–22.

    Article  CAS  Google Scholar 

  11. Mahadeo KM, Bajwa R, Abdel-Azim H, Lehmann LE, Duncan C, Zantek N, et al. Diagnosis, grading, and treatment recommendations for children, adolescents, and young adults with sinusoidal obstructive syndrome: an international expert position statement. Lancet Haematol. 2020;7:e61–72.

    Article  Google Scholar 

  12. Ovchinsky N, Frazier W, Auletta JJ, Dvorak CC, Ardura M, Song E, et al. Consensus Report by the Pediatric Acute Lung Injury and Sepsis Investigators and Pediatric Blood and Marrow Transplantation Consortium Joint Working Committees on Supportive Care Guidelines for Management of Veno-Occlusive Disease in Children and Adolescents, Part 3: focus on cardiorespiratory dysfunction, infections, liver dysfunction, and delirium. Biol Blood Marrow Transpl. 2018;24:207–18.

    Article  Google Scholar 

  13. McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M, et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med. 1993;118:255–67.

    Article  CAS  Google Scholar 

  14. Rio B, Andreu G, Nicod A, Arrago JP, Dutrillaux F, Samama M, et al. Thrombocytopenia in venocclusive disease after bone marrow transplantation or chemotherapy. Blood. 1986;67:1773–6.

    Article  CAS  Google Scholar 

  15. Bearman SI. The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood. 1995;85:3005–20.

    Article  CAS  Google Scholar 

  16. Embaby MM, Rangarajan HG, Abu-Arja R, Auletta JJ, Stanek J, Pai V, et al. Refractory thrombocytopenia is a valid early diagnostic criteria for hepatic veno-occlusive disease in children. Biol Blood Marrow Transpl. 2020;26:546–52.

    Article  CAS  Google Scholar 

  17. Coppell JA, Richardson PG, Soiffer R, Martin PL, Kernan NA, Chen A, et al. Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome. Biol Blood Marrow Transpl. 2010;16:157–68.

    Article  Google Scholar 

  18. Kammersgaard MB, Kielsen K, Heilmann C, Ifversen M, Muller K. Assessment of the proposed EBMT pediatric criteria for diagnosis and severity grading of sinusoidal obstruction syndrome. Bone Marrow Transpl. 2019;54:1406–18.

    Article  Google Scholar 

  19. Bajwa RPS, Mahadeo KM, Taragin BH, Dvorak CC, McArthur J, Jeyapalan A, et al. Consensus Report by Pediatric Acute Lung Injury and Sepsis Investigators and Pediatric Blood and Marrow Transplantation Consortium Joint Working Committees: Supportive Care Guidelines for Management of Veno-Occlusive Disease in Children and Adolescents, Part 1: focus on investigations, prophylaxis, and specific treatment. Biol Blood Marrow Transpl. 2017;23:1817–25.

    Article  Google Scholar 

  20. Richardson PG, Riches ML, Kernan NA, Brochstein JA, Mineishi S, Termuhlen AM, et al. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood. 2016;127:1656–65.

    Article  CAS  Google Scholar 

  21. Lewis DR, Seibel NL, Smith AW, Stedman MR. Adolescent and young adult cancer survival. J Natl Cancer Inst Monogr. 2014;2014:228–35.

    Article  Google Scholar 

  22. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc: Ser B (Methodol). 1995;57:289–300.

    Google Scholar 

  23. R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria 2017. https://www.R-project.org/.

  24. Skeens MA, McArthur J, Cheifetz IM, Duncan C, Randolph AG, Stanek J, et al. High variability in the reported management of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation. Biol Blood Marrow Transpl. 2016;22:1823–8.

    Article  Google Scholar 

  25. Szmit Z, Gorczynska E, Mielcarek-Siedziuk M, Ussowicz M, Owoc-Lempach J, Kalwak K. Veno-occlusive disease in children and adolescents after hematopoietic stem cell transplantation: did the modified Seattle criteria fit the characteristics of pediatric population? Adv Clin Exp Med. 2020;29:339–44.

    Article  Google Scholar 

  26. Naples JC, Skeens MA, Auletta J, Rangarajan H, Abu-Arja R, Horwitz E, et al. Anicteric veno-occlusive disease after hematopoietic stem cell transplantation in children. Bone Marrow Transpl. 2016;51:135–7.

    Article  CAS  Google Scholar 

  27. Faraci M, Bertaina A, Luksch R, Calore E, Lanino E, Saglio F, et al. Sinusoidal obstruction syndrome/veno-occlusive disease after autologous or allogeneic hematopoietic stem cell transplantation in children: a retrospective study of the Italian Hematology-Oncology Association-Hematopoietic Stem Cell Transplantation Group. Biol Blood Marrow Transpl. 2019;25:313–20.

    Article  Google Scholar 

  28. Veal GJ, Nguyen L, Paci A, Riggi M, Amiel M, Valteau-Couanet D, et al. Busulfan pharmacokinetics following intravenous and oral dosing regimens in children receiving high-dose myeloablative chemotherapy for high-risk neuroblastoma as part of the HR-NBL-1/SIOPEN trial. Eur J Cancer. 2012;48:3063–72.

    Article  CAS  Google Scholar 

  29. Ladenstein R, Potschger U, Pearson ADJ, Brock P, Luksch R, Castel V, et al. Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial. Lancet Oncol. 2017;18:500–14.

    Article  CAS  Google Scholar 

  30. Bhojwani D, Sposto R, Shah NN, Rodriguez V, Yuan C, Stetler-Stevenson M, et al. Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. Leukemia. 2019;33:884–92.

    Article  CAS  Google Scholar 

  31. Wadleigh M, Richardson PG, Zahrieh D, Lee SJ, Cutler C, Ho V, et al. Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation. Blood. 2003;102:1578–82.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank our patients and their caregivers, the nursing unit staff for their clinical care, and Ms Latarsha Williams and Marisol Gonzalez for administrative support.

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Author notes

  1. These authors contributed equally: K. M. Mahadeo, F. P. Tambaro

Authors and Affiliations

  1. Department of Pediatrics, Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA

    D. Ragoonanan, S. J. Khazal, A. Payne, M. Kohorst, A. Harden, P. Tewari, D. Petropoulos, B. Shoberu, K. M. Mahadeo & F. P. Tambaro

  2. Department of Biostatistics, Division of Basic Sciences, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA

    J. Wang

  3. Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, 77030, USA

    P. Kebriaei

  4. UOC SIT-TMO AORN Santobono-Pausilipon, Napoli, Italy

    F. P. Tambaro

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Contributions

KMM conceptualized the paper. DR, AP, MK, AH, and BS participated in data collection. JW and DR completed statistical analysis. DR, KMM, and FPT wrote the manuscript. KMM, PT, DP, PK, and SJK treated patients. All authors reviewed and/or edited the manuscript and made meaningful contributions before submission.

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Correspondence to D. Ragoonanan.

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Conflict of interest

PK has research support from Amgen and ZIOP harm; has served on advisory boards for Pfizer, Kite and Novartis and reports consulting fees from Jazz Pharmaceuticals FPT reports personal fees from Jazz Pharmaceuticals outside the submitted work.

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Ragoonanan, D., Khazal, S.J., Wang, J. et al. Improved detection of sinusoidal obstructive syndrome using pediatric–AYA diagnostic criteria and severity grading. Bone Marrow Transplant 56, 175–184 (2021). https://doi.org/10.1038/s41409-020-00998-w

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