Clinical and Translational Oncology

, Volume 20, Issue 5, pp 584–590 | Cite as

Outcome of childhood leukaemia survivors and necrosis of the femoral head treated with autologous mesenchymal stem cells

  • T. de Rojas
  • S. Martínez-Álvarez
  • S. Lerma-Lara
  • M. Á. Díaz
  • L. Madero
  • M. Ramírez
Research Article
  • 218 Downloads

Abstract

Purpose

Corticoid-induced osteonecrosis (ON) of femoral head can lead to severe hip joint impairment and hip replacement, with negative impact in young survivors of acute lymphoblastic leukaemia (ALL) with long life expectancy. We aim to improve quality of life in these patients with a novel approach.

Methods/patients

Based on the regenerative capacities of mesenchymal stem cells (MSCs), we performed locally implanted autologous cell therapy in two adolescents suffering of bilateral femoral ON. This required a simple, minimally invasive surgical procedure.

Results

Both patients experienced significant pain relief and restoration of gait kinematic values. Radiographic evaluation showed cessation of hip collapse. No toxicities/complications were observed after a 4-year follow-up.

Conclusions

Our preliminary results suggest that autologous MSCs can be considered as a novel treatment for children and young adults with ON after overcoming ALL. It may avoid hip replacement and improve quality of life of leukaemia survivors.

Keywords

Osteonecrosis Necrosis of the femoral head Acute lymphoblastic leukaemia Children Mesenchymal stem cells Cell therapy 

Notes

Acknowledgements

This work was supported by a grant from the Madrid Regional Government (P2010/BMD-2420, CellCAM) to MR.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments and comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Kuhlen M, Moldovan A, Krull K, Meisel R, Borkhardt A. Osteonecrosis in paediatric patients with acute lymphoblastic leukaemia treated on Co-ALL-07-03 trial: a single centre analysis. Klin Padiatr. 2014. doi: 10.1055/s-0033-1358723.Google Scholar
  2. 2.
    Girard P, Auquier P, Barlogis V, Contet A, Poiree M, Demeocq F, et al. Symptomatic osteonecrosis in childhood leukaemia survivors: prevalence, risk factors and impact of quality of life in adulthood. Haematologica. 2013;98:1089–97.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Hyakuna N, Shimomura Y, Watanabe A, Taga T, Kikuta A, Matsushita T, et al. Assessment of corticosteroid-induced osteonecrosis in children undergoing chemotherapy for acute lymphoblastic leukemia: a report from the Japanese Childhood Cancer and Leukemia Study Group. J Pediatr Hematol Oncol. 2014;36:22–9.CrossRefPubMedGoogle Scholar
  4. 4.
    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.CrossRefGoogle Scholar
  5. 5.
    Kawedia JD, Kaste SC, Pei D, Panetta JC, Cai X, Cheng C, et al. Pharmacokinetic, pharmacodynamic, and pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic leukemia. Blood. 2011;117:2340–7.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Karol SE, Mattano LA, Yang W, Maloney KW, Smith C, Liu CC, et al. Genetic risk factors for the development of osteonecrosis in children under age 10 treated for acute lymphoblastic leukemia. Blood. 2016;127:558–64.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Karol SE, Yang W, Van Driest SL, Chang TY, Kaste S, Bowton E, et al. Genetics of glucocorticoid-associated osteonecrosis in children with acute lymphoblastic leukemia. Blood. 2015;126:1770–6.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Mostoufi-Moab S, Halton J. Bone morbidity in childhood leukemia: epidemiology, mechanisms, diagnosis, and treatment. Curr Osteoporos Rep. 2014;12:300–12.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    te Winkel ML, Pieters R, Wind EJD, Gert Bessems JHJM, van den Heuvel-Eibrink MM. Management and treatment of osteonecrosis in children and adolescents with acute lymphoblastic leukemia. Haematologica. 2014;99:430–6.CrossRefGoogle Scholar
  10. 10.
    Hernigou P, Flouzat-Lachaniette CH, Delambre J, Poignard A, Allain J, Chevallier N, et al. Osteonecrosis repair with bone marrow cell therapies: state of the clinical art. Bone. 2015;70:102–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Daltro GC, Fortuna V, de Souza ES, Salles MM, Carreira AC, Meyer R, et al. Efficacy of autologous stem cell-based therapy for osteonecrosis of the femoral head in sickle cell disease: a five-year follow-up study. Stem Cell Res Ther. 2015;6:110.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Müller I, Vaegler M, Holzwarth C, Tzaribatchev N, Pfister SM, Schütt B, et al. Secretion of angiogenic proteins by human multipotent mesenchymal stromal cells and their clinical potential in the treatment of avascular osteonecrosis. Leukemia. 2008;22:2054–61.CrossRefPubMedGoogle Scholar
  13. 13.
    Tzaribachev N, Vaegler M, Schaefer J, Reize P, Rudert M, Handgretinger R, et al. Mesenchymal stromal cells: a novel treatment option for steroid-induced avascular osteonecrosis. Isr Med Assoc J. 2008;10:232–4.PubMedGoogle Scholar
  14. 14.
    Müller I, Kordowich S, Holzwarth C, Isensee G, Lang P, Neunhoeffer F, et al. Application of multipotent mesenchymal stromal cells in pediatric patients following allogeneic stem cell transplantation. Blood Cells Mol Dis. 2008;40:25–32.CrossRefPubMedGoogle Scholar
  15. 15.
    Chen YP, Chen WC, Wang KC, Chen CH. Effectiveness of synovial fluid mesenchymal stem cells embedded in alginate beads for treatment of steroid-induced avascular necrosis of the femoral head. J Orthop Sci. 2014;19:657–66.CrossRefPubMedGoogle Scholar
  16. 16.
    Wang C, Wang Y, Meng H-Y, Yuan X-L, Xu X-L, Wang A-Y, et al. Application of bone marrow mesenchymal stem cells to the treatment of osteonecrosis of the femoral head. Int J Clin Exp Med. 2015;8:3127–35.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Martinez-Laperche C, Gomez-Garcia AM, Lassaletta A, Moscardo C, Vivanco JL, Molina J, et al. Detection of occult cerebrospinal fluid involvement during maintenance therapy identifies a group of children with acute lymphoblastic leukemia at high risk for relapse. Am J Hematol. 2013;88:359–64.CrossRefPubMedGoogle Scholar
  18. 18.
    Salazar J, Altés A, del Río E, Estella J, Rives S, Tasso M, et al. Methotrexate consolidation treatment according to pharmacogenetics of MTHFR ameliorates event-free survival in childhood acute lymphoblastic leukaemia. Pharmacogenomics J. 2012;12:379–85.CrossRefPubMedGoogle Scholar
  19. 19.
    Assi A, Ghanem I, Lavaste F, Skalli W. Gait analysis in children and uncertainty assessment for Davis protocol and Gillette Gait Index. Gait Posture. 2009;30:22–6.CrossRefPubMedGoogle Scholar
  20. 20.
    Hernigou P, Beaujean F, Lambotte JC. Decrease in the mesenchymal stem-cell pool in the proximal femur in corticosteroid-induced osteonecrosis. J Bone Jt Surg [Br]. 1999;81:349–55.CrossRefGoogle Scholar
  21. 21.
    Suh KT, Kim SW, Roh HL, Youn MS, Jung JS. Decreased osteogenic differentiation of mesenchymal stem cells in alcohol-induced osteonecrosis. Clin Orthop Relat Res. 2005;431:220–5.CrossRefGoogle Scholar
  22. 22.
    Hernigou P, Beaujean F. Treatment of osteonecrosis with autologous bone marrow grafting. Clin Orthop Relat Res. 2002;405:14–23.CrossRefGoogle Scholar
  23. 23.
    Chen G, Park C-K, Xie R-G, Ji R-R. Intrathecal bone marrow stromal cells inhibit neuropathic pain via TGF-β secretion. J Clin Investig. 2015;125:3226–40.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Von Bahr L, Batsis I, Moll G, Hägg M, Szakos A, Sundberg B, et al. Analysis of tissues following mesenchymal stromal cell therapy in humans indicates limited long-term engraftment and no ectopic tissue formation. Stem Cells. 2012;30:1575–8.CrossRefGoogle Scholar
  25. 25.
    Chen C, Qu Z, Yin X, Shang C, AoQ GuY, et al. Efficacy of umbilical cord-derived mesenchymal stem cell-based therapy for osteonecrosis of the femoral heda: a three-year follow-up study. Mol Med Rep. 2016;14:4209–15.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Gianakos AL, Moya-Angeler J, Duggal S, Zambrana L, Fields KG, Mintz DN, et al. The efficacy of bisphosphonates with core decompression and mesenchymal stem cells compared with bisphosphonates alone in the treatment of osteonecrosis of the hip: a retrospective study. HSSJ. 2016;12:137–44.CrossRefGoogle Scholar
  27. 27.
    Villa JC, Husain S, van der List JP, Gianakos A, Lane JM. Treatment of pre-collapse stages of osteonecrosis of the femoral head: a systematic review of randomized control trials. HSSJ. 2016;12:261–71.CrossRefGoogle Scholar
  28. 28.
    Tomaru Y, Yoshioka T, Sugaya H, Aoto K, Wada H, Akaogi H, et al. Hip preserving surgery with concentrated autologous bone marrow aspirate transplantation for the treatment of asymptomatic osteonecrosis of the femoral head: retrospective review of clinical and radiological outcomes at 6 years postoperatively. BMC Musculoskeletal Disord. 2017;18:292.CrossRefGoogle Scholar
  29. 29.
    Samy AM. Management of osteonecrosis of the femoral head: a novel technique. Indian J Orthop. 2016;50:359–65.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Gadji V, De Maertelaer V, Hauzeur JP. Autologous bone marrow cell implantation in the treatment of non-traumatic osteonecrosis of the femoral head: five year follow-up of a prospective controlled study. Bone. 2011;46(5):1005–9.Google Scholar
  31. 31.
    Sen RK, Tripathy SK, Aggarwal S, Marwaha N, Sharma RR, Khandelwal N. Early results of core decompression and autologous bone marrow mononuclear cells instillation in femoral head osteonecrosis: a randomized control study. J Artrhoplasty. 2012;27(5):679–86.CrossRefGoogle Scholar
  32. 32.
    Liu Y, Liu S, Su X. Core decompression and implantation of bone marrow mononuclear cells with porous hydroxiapatite composite filler for the treatment of osteonecrosis of the femoral head. Arch Orthop Trauma Surg. 2013;133(1):125–33.CrossRefPubMedGoogle Scholar
  33. 33.
    Ma Y, Wang T, Liao J, Gu H, Lin X, Jiang Q, et al. Efficacy of autologous bone marrow buffy coat grafting combined with core decompression in patients with avascular necrosis of the femoral head: a prospective, double blinded, randomized, controlled study. Stem Cell Res Ther. 2014;5(5):115.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2017

Authors and Affiliations

  1. 1.Paediatric Oncology Hematology and Stem Cell TransplantUniversity Hospital Niño JesúsMadridSpain
  2. 2.Orthopedics and Traumatology DepartmentUniversity Hospital Niño JesúsMadridSpain
  3. 3.Gait Analysis LaboratoryUniversity Hospital Niño JesúsMadridSpain
  4. 4.Research Institute La PrincesaMadridSpain

Personalised recommendations