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Adolescent and young adult (AYA) versus pediatric patients with acute leukemia have a significantly increased risk of acute GVHD following unrelated donor (URD) stem cell transplantation (SCT): the Children’s Oncology Group experience

Abstract

Adolescent and young adult (AYA) patients with acute leukemia (AL) have inferior outcomes in comparison to younger patients, and are more likely to develop acute and chronic GVHD than younger children following HLA matched sibling donor stem cell transplant (SCT). We compared the incidence of grade II–IV acute GVHD, chronic GVHD, and survival in AYA (age 13–21 years) to younger children (age 2–12 years) who received an unrelated donor SCT for acute leukemia on Children’s Oncology Group trials between 2004–2017. One hundred and eighty-eight children and young adults ages 2–21 years underwent URD SCT. Sixty-three percent were aged 2–12 and 37% were age 13–21. Older age was a risk factor for grade II–IV acute GVHD in multivariate analysis with a hazard ratio (HR) of 1.95 [95% confidence interval (CI) 1.23–3.10], but not for chronic GVHD, HR 1.25 [95% CI 0.57–2.71]. Younger patients relapsed more often (34.5 ± 4.4% vs. 22.8 ± 4.0%, p = 0.032), but their Event-Free Survival (42.6 ± 4.7% vs. 51.8 ± 6.1%, p = 0.18) and Overall Survival at 5 years (48.5 ± 4.9% vs. 51.5 ± 6.4%, p = 0.56) were not different than AYA patients. AYA patients who receive an URD SCT for acute leukemia are significantly more likely to develop grade II–IV acute GVHD, though survival is similar.

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Fig. 1: Cumulative incidence of acute GVHD (grade II–IV) by age (13–21 years vs.2–12 years), among URD recipients.
Fig. 2: Cumulative incidence of chronic GVHD (limited and extensive) by age, among URD recipients.
Fig. 3: Cumulative incidence of chronic GVHD (limited and extensive) by cancer remission status, among URD recipients.
Fig. 4: Event-free Survival of URD recipients by age.
Fig. 5: Cumulative incidence of relapse by age, among URD recipients.

References

  1. Bleyer A, Barr R, Hayes-Lattin B, Thomas D, Ellis C, Anderson B. The distinctive biology of cancer in adolescents and young adults. Nat Rev Cancer. 2008;8:288–98. https://doi.org/10.1038/nrc2349. e-pub ahead of print 2008/03/21.

    CAS  Article  PubMed  Google Scholar 

  2. McNeer JL, Bleyer A. Acute lymphoblastic leukemia and lymphoblastic lymphoma in adolescents and young adults. Pediatr Blood Cancer. 2018;65:e26989 https://doi.org/10.1002/pbc.26989. e-pub ahead of print 2018/02/09.

    Article  PubMed  Google Scholar 

  3. Creutzig U, Kutny MA, Barr R, Schlenk RF, Ribeiro RC. Acute myelogenous leukemia in adolescents and young adults. Pediatr Blood Cancer. 2018;65:e27089 https://doi.org/10.1002/pbc.27089.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Curran E, Stock W. How I treat acute lymphoblastic leukemia in older adolescents and young adults. Blood. 2015;125:3702–10. https://doi.org/10.1182/blood-2014-11-551481. e-pub ahead of print 2015/03/26.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. Hochberg J, Khaled S, Forman SJ, Cairo MS. Criteria for and outcomes of allogeneic haematopoietic stem cell transplant in children, adolescents and young adults with acute lymphoblastic leukaemia in first complete remission. Br J Haematol. 2013;161:27–42. https://doi.org/10.1111/bjh.12239. e-pub ahead of print 2013/02/07.

    CAS  Article  PubMed  Google Scholar 

  6. Eisner MD, August CS. Impact of donor and recipient characteristics on the development of acute and chronic graft-versus-host disease following pediatric bone marrow transplantation. Bone Marrow Transpl. 1995;15:663–8.

    CAS  Google Scholar 

  7. Zecca M, Prete A, Rondelli R, Lanino E, Balduzzi A, Messina C, et al. Chronic graft-versus-host disease in children: incidence, risk factors, and impact on outcome. Blood. 2002;100:1192–1200. https://doi.org/10.1182/blood-2001-11-0059.

    CAS  Article  PubMed  Google Scholar 

  8. Qayed M, Wang T, Hemmer MT, Spellman S, Arora M, Couriel D. et al. Influence of age on acute and chronic GVHD in children undergoing HLA-identical sibling bone marrow transplantation for acute leukemia: implications for prophylaxis. Biol Blood Marrow Transpl. 2018;24:521–8. https://doi.org/10.1016/j.bbmt.2017.11.004.

    Article  Google Scholar 

  9. Chaudhury SS, Morison JK, Gibson BE, Keeshan K. Insights into cell ontogeny, age, and acute myeloid leukemia. Exp Hematol. 2015;43:745–55. https://doi.org/10.1016/j.exphem.2015.05.008.

    CAS  Article  PubMed  Google Scholar 

  10. Bleyer A, Budd T, Montello M. Adolescents and young adults with cancer: the scope of the problem and criticality of clinical trials. Cancer. 2006;107:1645–55. https://doi.org/10.1002/cncr.22102.

    Article  PubMed  Google Scholar 

  11. Smith AW, Keegan T, Hamilton A, Lynch C, Wu XC, Schwartz SM, et al. Understanding care and outcomes in adolescents and young adult with Cancer: A review of the AYA HOPE study. Pediatr Blood Cancer. 2019;66:e27486 https://doi.org/10.1002/pbc.27486.

    Article  PubMed  Google Scholar 

  12. Pulsipher MA, Langholz B, Wall DA, Schultz KR, Bunin N, Carroll WL, et al. The addition of sirolimus to tacrolimus/methotrexate GVHD prophylaxis in children with ALL: a phase 3 Children’s Oncology Group/pediatric blood and marrow transplant consortium trial. Blood. 2014;123:2017–25. https://doi.org/10.1182/blood-2013-10-534297.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Gamis AS, Alonzo TA, Meshinchi S, Sung L, Gerbing RB, Raimondi SC, et al. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group trial AAML0531. J Clin Oncol. 2014;32:3021–32. https://doi.org/10.1200/jco.2014.55.3628.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Aplenc R, Meshinchi S, Sung L, Alonzo T, Choi J, Fisher B, et al. Bortezomib with standard chemotherapy for children with acute myeloid leukemia does not improve treatment outcomes: a report from the Children’s Oncology Group. Haematologica. 2020;105:1879–86. https://doi.org/10.3324/haematol.2019.220962.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496–509.

    Article  Google Scholar 

  16. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant 1995;15:825–8.

    CAS  PubMed  Google Scholar 

  17. Flowers ME, Kansu E, Sullivan KM. Pathophysiology and treatment of graft-versus-host disease. Hematol Oncol Clin North Am. 1999;13:1091–112. https://doi.org/10.1016/s0889-8588(05)70111-8.

    CAS  Article  PubMed  Google Scholar 

  18. Kalbfleisch JD, Prentice RL. The statistical analysis of failure time data. 2nd ed. New York: John Wiley & Sons; 2002.

  19. Kleinbaum DG KLL, Nizam A., Rosenberg, E.S. Applied regression analysis and other multivariable methods. 5th ed. Cengage Learning: Boston, MA; 2013.

  20. StataCorp. Stata statistical software: release 15. In: College Station. TX: StataCorp LLC.; 2017.

  21. Pulsipher MA, Langholz B, Wall DA, Schultz KR, Bunin N, Carroll W, et al. Risk factors and timing of relapse after allogeneic transplantation in pediatric ALL: for whom and when should interventions be tested? Bone Marrow Transpl. 2015;50:1173–9. https://doi.org/10.1038/bmt.2015.103.

    CAS  Article  Google Scholar 

  22. Yeshurun M, Weisdorf D, Rowe JM, Tallman MS, Zhang MJ, Wang HL, et al. The impact of the graft-versus-leukemia effect on survival in acute lymphoblastic leukemia. Blood Adv. 2019;3:670–80. https://doi.org/10.1182/bloodadvances.2018027003.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Woolfrey AE, Anasetti C, Storer B, Doney K, Milner LA, Sievers EL, et al. Factors associated with outcome after unrelated marrow transplantation for treatment of acute lymphoblastic leukemia in children. Blood. 2002;99:2002–8. https://doi.org/10.1182/blood.v99.6.2002.

    CAS  Article  PubMed  Google Scholar 

  24. Bitan M, Ahn KW, Millard HR, Pulsipher MA, Abdel-Azim H, Auletta JJ, et al. Personalized prognostic risk score for long-term survival for children with acute leukemia after allogeneic transplantation. Biol Blood Marrow Transpl. 2017;23:1523–30. https://doi.org/10.1016/j.bbmt.2017.05.011.

    Article  Google Scholar 

  25. Bunin N, Carston M, Wall D, Adams R, Casper J, Kamani N, et al. Unrelated marrow transplantation for children with acute lymphoblastic leukemia in second remission. Blood. 2002;99:3151–7. https://doi.org/10.1182/blood.v99.9.3151.

    CAS  Article  PubMed  Google Scholar 

  26. Yang F, Lu D, Hu Y, Huang X, Huang H, Chen J, et al. Risk factors for graft-versus-host disease after transplantation of hematopoietic stem cells from unrelated donors in the china marrow donor program. Ann Transpl. 2017;22:384–401. https://doi.org/10.12659/aot.902805.

    CAS  Article  Google Scholar 

  27. Tan J, Wang Y, Yu SJ, Ma YY, Lei HY, Liu QF. Prognostic factors on graft-versus-host disease-free and relapse-free survival after allogeneic hematopoietic stem cell transplantation for adults with acute leukemia. Leuk Res. 2017;59:1–7. https://doi.org/10.1016/j.leukres.2017.05.011.

    Article  PubMed  Google Scholar 

  28. Remberger M, Kumlien G, Aschan J, Barkholt L, Hentschke P, Ljungman P, et al. Risk factors for moderate-to-severe chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2002;8:674–82. https://doi.org/10.1053/bbmt.2002.v8.abbmt080674.

    Article  PubMed  Google Scholar 

  29. Gassas A, Ishaqi MK, Afzal S, Finkelstein-Shechter T, Dupuis A, Doyle J. A comparison of the outcomes of children with acute myelogenous leukemia in either first or second complete remission (CR1 vs.CR2) following allogeneic hematopoietic stem cell transplantation at a single transplant center. Bone Marrow Transplant. 2008;41:941–5. https://doi.org/10.1038/bmt.2008.16.

    CAS  Article  PubMed  Google Scholar 

  30. Davies SM, Wang D, Wang T, Arora M, Ringden O, Anasetti C, et al. Recent decrease in acute graft-versus-host disease in children with leukemia receiving unrelated donor bone marrow transplants. Biol Blood Marrow Transplant. 2009;15:360–6. https://doi.org/10.1016/j.bbmt.2008.12.495.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the patients and families who participated in the Children’s Oncology Group stem cell transplant trials, as well as the physician investigators who collaborated with the authors. We also appreciate the collaborative efforts of the Cellular Therapy and Adolescent and Young Adult Children’s Oncology Group committees.

Funding

N01 HC-45220/HHSN268200425220C. COG Chair’s grant U10CA098543. U10CA180899. CA98413-08. U10CA180886. R01CA1116660. 2U01HL069254. St. Baldrick’s Foundation

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JRA, LJ, MSC designed the study; YW, LJ collected the data; all authors analyzed and interpreted the results; JRA, LJ, MSC wrote the initial manuscript; all authors edited the manuscript.

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Correspondence to Jeffrey R. Andolina or Mitchell S. Cairo.

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Competing interests

JL: Ironwood None Personal Fees, Incyte None Consultancy and Research Funding, Kamada None Research Funding, Biogen None non-financial support, Bluebird Bio Consultant Consultancy, Novartis Consultant Consultancy, Viracor Inventor Royalty. MAP: Miltenyi N/A Research Support and Educational honoraria, Adaptive N/A Research Suppor and Educational honoraria, Novartis Advisory Board, Study Steering Committee, Educational honoraria. Mesoblast, Advisory board. MSC: Jazz Advisory Board and Speaker Bureau, Amgen Speaker Bureau, Sanofi Speaker Bureau, Nektar Advisory Board, Servier Speaker Bureau. JA, LJ, YW, DF, AG, RA, and LH have nothing to disclose, financial or otherwise.

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Andolina, J.R., Wang, YC., Ji, L. et al. Adolescent and young adult (AYA) versus pediatric patients with acute leukemia have a significantly increased risk of acute GVHD following unrelated donor (URD) stem cell transplantation (SCT): the Children’s Oncology Group experience. Bone Marrow Transplant 57, 445–452 (2022). https://doi.org/10.1038/s41409-021-01558-6

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