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Lymphoma

Symptomatic osteonecrosis as a treatment complication in Hodgkin lymphoma: an analysis of the German Hodgkin Study Group (GHSG)

Abstract

The majority of patients with Hodgkin Lymphoma (HL) can be cured with stage and risk adapted treatment today. Therefore, current research focuses on reducing long-term sequelae of treatment. Osteonecrosis (ON) is a severe long-term complication of HL treatment which has so far not been systematically evaluated. Hence, we investigated incidence, risk factors and timing of symptomatic ON in HL patients. Further endpoints included localization, intervention and outcome of ON. We included all qualified HL patients of the randomized German Hodgkin Study Group trials HD10-15 and HD18, recruited between 05/1998 and 07/2014 and aged from 16 to 60 years. Among 11 330 patients, 66 developed symptomatic ON after first-line treatment, 83.3% within three years. The incidence of symptomatic ON was 0.2% in early-stage HL and 1.0% in advanced-stage HL. Logistic regression revealed the total cumulative corticosteroid dose to be a strong risk factor interacting with younger age. Male sex additionally increased the risk of symptomatic ON. The prognostic value of the corresponding logistic regression model was rather high (AUC = 0.78). Other tested potential risk factors including obesity, IPS and radiotherapy did not further increase the risk of ON. Further development of current treatment protocols should aim to reduce the cumulative corticosteroid dose.

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References

  1. Skoetz N, Trelle S, Rancea M, Haverkamp H, Diehl V, Engert A, et al. Effect of initial treatment strategy on survival of patients with advanced-stage Hodgkin’s lymphoma: a systematic review and network meta-analysis. Lancet Oncol. 2013;14:943–52.

    Article  Google Scholar 

  2. Borchmann S, von Tresckow B, Engert A. Current developments in the treatment of early-stage classical Hodgkin lymphoma. Curr Opin Oncol. 2016;28:377–83.

    Article  CAS  Google Scholar 

  3. Behringer K, Mueller H, Goergen H, Thielen I, Eibl AD, Stumpf V, et al. Gonadal function and fertility in survivors after Hodgkin lymphoma treatment within the German Hodgkin study group HD13 to HD15 Trials. J Clin Oncol. 2013;31:231–9.

    Article  CAS  Google Scholar 

  4. Eichenauer DA, Thielen I, Haverkamp H, Franklin J, Behringer K, Halbsguth T, et al. Therapy-related acute myeloid leukemia and myelodysplastic syndromes in patients with hodgkin lymphoma: a report from the German Hodgkin Study Group. Blood. 2014;123:1658–64.

    Article  CAS  Google Scholar 

  5. Schaapveld M, Aleman BMP, van Eggermond AM, Janus CPM, Krol ADG, van der Maazen RWM, et al. Second cancer risk up to 40 years after treatment for Hodgkin’s lymphoma. N Engl J Med. 2015;373:2499–511.

    Article  CAS  Google Scholar 

  6. Behringer K, Goergen H, Müller H, Thielen I, Brillant C, Kreissl S, et al. Cancer-related fatigue in patients with and survivors of Hodgkin lymphoma: the impact on treatment outcome and social reintegration. J Clin Oncol. 2016;34:4329–37.

    Article  Google Scholar 

  7. Kreissl S, Mueller H, Goergen H, Mayer A, Brillant C, Behringer K, et al. Cancer-related fatigue in patients with and survivors of Hodgkin’s lymphoma: a longitudinal study of the German Hodgkin Study Group. Lancet Oncol. 2016;17:1453–62.

    Article  Google Scholar 

  8. te Winkel ML, Pieters R, Hop WCJ, de Groot-Kruseman HA, Lequin MH, van der Sluis IM, et al. Prospective study on incidence, risk factors, and long-term outcome of osteonecrosis in pediatric acute lymphoblastic leukemia. J Clin Oncol. 2011;29:4143–50.

    Article  Google Scholar 

  9. Prosnitz LR, Lawson JP, Friedlaender GE, Farber LR, Pezzimenti JF. Avascular necrosis of bone in Hodgkin’s disease patients treated with combined modality therapy. Cancer. 1981;47:2793–7.

    Article  CAS  Google Scholar 

  10. Ellis J, MacLeod U, Sammon D, Lindsay E, Erskine JG. Osteonecrosis following treatment for Hodgkin’s disease. Clin Lab Haematol. 1994;16:3–8.

    Article  CAS  Google Scholar 

  11. Enrici RM, Anselmo AP, Donato V, Santoro M, Tombolini V. Avascular osteonecrosis in patients treated for Hodgkin’s disease. Eur J Haematol. 1998;61:204–9.

    Article  CAS  Google Scholar 

  12. Fosså A, Fiskvik IH, Kolstad A, Lauritzsen GF, Aurlien E, Blystad AK, et al. Two escalated followed by six standard BEACOPP in advanced-stage high-risk classical Hodgkin lymphoma: high cure rates but increased risk of aseptic osteonecrosis. Ann Oncol. 2012;23:1254–9.

    Article  Google Scholar 

  13. Renedo RJG, Sousa MM, Pérez SF, Zabalbeascoa JR, Carro LP. Avascular necrosis of the femoral head in patients with Hodgkin’s disease. Hip Int. 2010;20:473–81.

    Article  Google Scholar 

  14. Engert A, Plütschow A, Eich HT, Lohri A, Dörken B, Borchmann P, et al. Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med. 2010;363:640–52.

    Article  CAS  Google Scholar 

  15. Eich HT, Diehl V, Görgen H, Pabst T, Markova J, Debus J, et al. Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin’s lymphoma: final analysis of the German Hodgkin Study Group HD11 trial. J Clin Oncol. 2010;28:4199–206.

    Article  Google Scholar 

  16. Borchmann P, Haverkamp H, Diehl V, Cerny T, Markova J, Ho AD, et al. Eight cycles of escalated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage Hodgkin’s lymphoma: final analysis of the HD12 trial of the German Hodgkin Study Group. J Clin Oncol. 2011;29:4234–42.

    Article  CAS  Google Scholar 

  17. Behringer K, Goergen H, Hitz F, Zijlstra JM, Greil R, Markova J, et al. Omission of dacarbazine or bleomycin, or both, from the ABVD regimen in treatment of early-stage favourable Hodgkin’s lymphoma (GHSG HD13): an open-label, randomised, non-inferiority trial. Lancet. 2015;385:1418–27.

    Article  CAS  Google Scholar 

  18. von Tresckow B, Plutschow A, Fuchs M, Klimm B, Markova J, Lohri A, et al. Dose-intensification in early unfavorable Hodgkin’s lymphoma: final analysis of the German Hodgkin Study Group HD14 Trial. J Clin Oncol. 2012;30:907–13.

    Article  Google Scholar 

  19. Borchmann P, Goergen H, Kobe C, Lohri A, Greil R, Eichenauer DA, et al. PET-guided treatment in patients with advanced-stage Hodgkin’s lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group. Lancet. 2017. https://doi.org/10.1016/S0140-6736(17)32134-7.

    Article  Google Scholar 

  20. Engert A, Haverkamp H, Kobe C, Markova J, Renner C, Ho A, et al. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet. 2012;379:1791–9.

    Article  CAS  Google Scholar 

  21. NCI, NIH, DHHS, National Cancer Institute. Common terminology criteria for adverse events v4.0. NIH publication; 2009.

  22. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649–55.

    Article  CAS  Google Scholar 

  23. Cooper C, Steinbuch M, Stevenson R, Miday R, Watts NB. The epidemiology of osteonecrosis: findings from the GPRD and THIN databases in the UK. Osteoporos Int. 2010;21:569–77.

    Article  CAS  Google Scholar 

  24. Mattano LAJ, Sather HN, Trigg ME, Nachman JB. Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children’s Cancer Group. J Clin Oncol. 2000;18:3262–72.

    Article  Google Scholar 

  25. Sharma S, Yang S, Rochester R, Britton L, Leung WH, Yang J, et al. Prevalence of osteonecrosis and associated risk factors in children before allogeneic BMT. Bone Marrow Transplant. 2011;46:813–9.

    Article  CAS  Google Scholar 

  26. Kaste SC, Karimova EJ, Neel MD. Osteonecrosis in children after therapy for malignancy. Am J Roentgenol. 2011;196:1011–8.

    Article  Google Scholar 

  27. Mont MA, Baumgarten KM, Rifai A, Bluemke DA, Jones LC, Hungerford DS. Atraumatic osteonecrosis of the knee. J Bone Jt Surg Am. 2000;82:1279–90.

    Article  CAS  Google Scholar 

  28. Moya-Angeler J, Gianakos AL, Villa JC, Ni A, Lane JM. Current concepts on osteonecrosis of the femoral head. World J Orthop. 2015;6:590–601.

    Article  Google Scholar 

  29. Mont MA, Carbone JJ, Fairbank AC. Core decompression versus nonoperative management for osteonecrosis of the hip. Clin Orthop Relat Res. 1996:169–78.

    Article  Google Scholar 

  30. Chan KL, Mok CC. Glucocorticoid-induced avascular bone necrosis: diagnosis and management. Open Orthop J. 2012;6:449–57.

    Article  CAS  Google Scholar 

  31. Niinimäki RA, Harila-Saari AH, Jartti AE, Seuri RM, Riikonen PV, Pääkkö EL, et al. High body mass index increases the risk for osteonecrosis in children with acute lymphoblastic leukemia. J Clin Oncol. 2007;25:1498–504.

    Article  Google Scholar 

  32. Pritchett JW. Statin therapy decreases the risk of osteonecrosis in patients receiving steroids. Clin Orthop Relat Res. 2001:173–8.

    Article  Google Scholar 

  33. Jäger M, Zilkens C, Bittersohl B, Matheney T, Kozina G, Blondin D, et al. Efficiency of iloprost treatment for osseous malperfusion. Int Orthop. 2011;35:761–5.

    Article  Google Scholar 

  34. Lai K.-A, Shen W.-J, Yang C.-Y, Shao C.-J, Hsu J.-T, Lin R.-M. The use of alendronate to prevent early collapse of the femoral head in patients with nontraumatic osteonecrosis. A randomized clinical study. J Bone Jt Surg Am. 2005;87:2155–9.

    Article  Google Scholar 

  35. Kaste SC, Pei D, Cheng C, Neel MD, Bowman WP, Ribeiro RC, et al. Utility of early screening magnetic resonance imaging for extensive hip osteonecrosis in pediatric patients treated with glucocorticoids. J Clin Oncol. 2015;33:610–5.

    Article  Google Scholar 

  36. Connors JM, Jurczak W, Straus DJ, Ansell SM, Kim WS, Gallamini A, et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med. 2018;378:331–44.

    Article  CAS  Google Scholar 

  37. Borchmann P, Eichenauer DA, Pluetschow A, Haverkamp H, Kreissl S, Fuchs M, et al. Targeted Beacopp variants in patients with newly diagnosed advanced stage classical Hodgkin lymphoma: final analysis of a randomized phase II study. Blood. 2015;126:580.

    Google Scholar 

Download references

Acknowledgements

This study was presented in part at the 21st annual congress of the European Hematology Association (EHA) in Copenhagen, Denmark in June 2016 and at the 10th International Symposium on Hodgkin Lymphoma (ISHL) in October 2016 in Cologne, Germany. This study was supported by grants of the Deutsche Krebshilfe e.V. (German Cancer Aid) for the HD10-HD15 and HD18 trials.

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Correspondence to Andreas Engert.

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Borchmann, S., Müller, H., Haverkamp, H. et al. Symptomatic osteonecrosis as a treatment complication in Hodgkin lymphoma: an analysis of the German Hodgkin Study Group (GHSG). Leukemia 33, 439–446 (2019). https://doi.org/10.1038/s41375-018-0240-8

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