Supportive Care in Cancer

, Volume 27, Issue 3, pp 839–848 | Cite as

Retrospective study of the digestive tract mucositis derived from myeloablative and non-myeloablative/reduced-intensity conditionings with busulfan in hematopoietic cell transplantation patient

  • Fernanda P. EduardoEmail author
  • Leticia Mello Bezinelli
  • Marcella Gobbi
  • Flavia C. P. Rosin
  • Danielle L. C. Carvalho
  • Mariana Henriques Ferreira
  • Cinthya Correa da Silva
  • Nelson Hamerschlak
  • Luciana Corrêa
Original Article


Busulfan is a major component of chemotherapy conditioning in hematopoietic cell transplantation (HCT). This alkylating agent is highly toxic at myeloablative doses, exposing HCT patients to risks of mortality. Non-myeloablative (NMA) and reduced-intensity conditioning (RIC) using busulfan have shown impaired toxicity. However, the toxicity of NMA/RIC in the digestive tract is poorly described. This study aimed to characterize the mucositis in the oral cavity (OM), oropharynx/esophagus, and gastrointestinal tract derived from conditionings with myeloablative and non-myeloablative doses of busulfan. We retrospectively retrieved clinical data of HCT patients (n = 100) who underwent myeloablative conditioning (MAC) or NMA/RIC with busulfan. Frequency and time duration of mucositis in the oral cavity and oropharynx/esophagus, diarrhea, and prescription of total parenteral nutrition (TPN) and opioids were also collected. OM severity (p = 0.009) and time duration of mucositis in oropharynx/esophagus (p = 0.022) were frequently higher in MAC than NMA/RIC. A myeloablative dose of busulfan was a risk factor for OM grade ≥ 2 (OR = 4.8, p = 0.002) and for mucositis in oropharynx/esophagus ≥ 5 days (OR = 2.64, p = 0.035). A longer duration of mucositis in the oropharynx/esophagus was also associated with an increase in the prescription of opioids (OR = 7.10, p < 0.001).Overall survival (OS) in MAC was significantly higher than that in NMA/RIC (p = 0.017). No variables related to mucositis interfere significantly in OS. In conclusion, myelosuppression in busulfan-based regimens are predisposed to a high risk for severe OM and to prolonged mucositis in the oropharynx/esophagus.


Oral mucositis Gastrointestinal mucositis Hematopoietic cell transplantation Busulfan 


Funding information

We thank the São Paulo Research Foundation (FAPESP, Proc. no. 2016/03650–4) and AmigoH for their financial support.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Palmer J, McCune JS, Perales MA, Marks D, Bubalo J, Mohty M, Wingard JR, Paci A, Hassan M, Bredeson C, Pidala J, Shah N, Shaughnessy P, Majhail N, Schriber J, Savani BN, Carpenter PA (2016) Personalizing busulfan-based conditioning: considerations from the American Society for Blood and Marrow Transplantation Practice Guidelines Committee. Biol Blood Marrow Transplant 22(11):1915–1925CrossRefGoogle Scholar
  2. 2.
    Ben-Barouch S, Cohen O, Vidal L, Avivi I, Ram R (2016) Busulfan fludarabine vs busulfan cyclophosphamide as a preparative regimen before allogeneic hematopoietic cell transplantation: systematic review and meta-analysis. Bone Marrow Transplant 51(2):232–240CrossRefGoogle Scholar
  3. 3.
    Lee KH, Lee JH, Lee JH, Kim DY, Park HS, Choi EJ, Ko SH, Seol M, Lee YS, Kang YA, Jeon M, Baek S, Kang YL, Kim SH, Yun SC, Kim H, Jo JC, Choi Y, Joo YD, Lim SN (2017) Reduced-intensity conditioning with busulfan, fludarabine, and antithymocyte globulin for hematopoietic cell transplantation from unrelated or Haploidentical family donors in patients with acute myeloid leukemia in remission. Biol Blood Marrow Transplant 23(9):1555–1566CrossRefGoogle Scholar
  4. 4.
    Magenau JM, Braun T, Reddy P, Parkin B, Pawarode A, Mineishi S, Choi S, Levine J, Li Y, Yanik G, Kitko C, Churay T, Frame D, Riwes MM, Harris A, Bixby D, Couriel DR, Goldstein SC (2015) Allogeneic transplantation with myeloablative FluBu4 conditioning improves survival compared to reduced intensity FluBu2 conditioning for acute myeloid leukemia in remission. Ann Hematol 94(6):1033–1041CrossRefGoogle Scholar
  5. 5.
    Kröger N, Iacobelli S, Franke GN, Platzbecker U, Uddin R, Hübel K, Scheid C, Weber T, Robin M, Stelljes M, Afanasyev B, Heim D, Deliliers GL, Onida F, Dreger P, Pini M, Guidi S, Volin L, Günther A, Bethge W, Poiré X, Kobbe G, van Os M, Brand R, de Witte T (2017) Dose-reduced versus standard conditioning followed by allogeneic stem-cell transplantation for patients with myelodysplastic syndrome: a prospective randomized phase III study of the EBMT (RICMAC trial). J Clin Oncol 35(19):2157–2164CrossRefGoogle Scholar
  6. 6.
    Wanquet A, Crocchiolo R, Furst S, Granata A, Faucher C, Devillier R, Harbi S, Lemarie C, Calmels B, Vey N, Weiller PJ, Chabannon C, Castagna L, Blaise D, El-Cheikh J (2016) The efficacy and safety of a new reduced-toxicity conditioning with 4 days of once-daily 100 mg/m(2) intravenous busulfan associated with fludarabine and antithymocyte globulins prior to allogeneic stem cell transplantation in patients with high-risk myelodysplastic syndrome or acute leukemia. Leuk Lymphoma 57(10):2315–2320CrossRefGoogle Scholar
  7. 7.
    Le Bourgeois A, Lestang E, Guillaume T, Delaunay J, Ayari S, Blin N, Clavert A, Tessoulin B, Dubruille V, Mahe B, Roland V, Gastinne T, Le Gouill S, Moreau P, Mohty M, Planche L, Chevallier P (2013) Prognostic impact of immune status and hematopoietic recovery before and after fludarabine, IV busulfan, and antithymocyte globulins (FB2 regimen) reduced-intensity conditioning regimen (RIC) allogeneic stem cell transplantation (allo-SCT). Eur J Haematol 90(3):177–186CrossRefGoogle Scholar
  8. 8.
    Scott BL, Pasquini MC, Logan BR, Wu J, Devine SM, Porter DL, Maziarz RT, Warlick ED, Fernandez HF, Alyea EP, Hamadani M, Bashey A, Giralt S, Geller NL, Leifer E, Le-Rademacher J, Mendizabal AM, Horowitz MM, Deeg HJ, Horwitz ME (2017) Myeloablative versus reduced-intensity hematopoietic cell transplantation for acute myeloid leukemia and myelodysplastic syndromes. J Clin Oncol 35(11):1154–1161CrossRefPubMedCentralGoogle Scholar
  9. 9.
    de Paula Eduardo F, Bezinelli LM, da Graça Lopes RM, Nascimento Sobrinho JJ et al (2015) Efficacy of cryotherapy associated with laser therapy for decreasing severity of melphalan-induced oral mucositis during hematological stem-cell transplantation: a prospective clinical study. Hematol Oncol 33:152–158CrossRefGoogle Scholar
  10. 10.
    Bezinelli LM, de Paula Eduardo F, da Graça Lopes RM, Biazevic MG, de Paula Eduardo C et al (2014) Cost-effectiveness of the introduction of specialized oral care with laser therapy in hematopoietic stem cell transplantation. Hematol Oncol 32:31–39CrossRefGoogle Scholar
  11. 11.
    Sonis ST, Oster G, Fuchs H, Bellm L, Bradford WZ, Edelsberg J, Hayden V, Eilers J, Epstein JB, LeVeque FG, Miller C, Peterson DE, Schubert MM, Spijkervet FK, Horowitz M (2001) Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation. J Clin Oncol 19(8):2201–2205CrossRefGoogle Scholar
  12. 12.
    Vera-Llonch M, Oster G, Ford CM, Lu J, Sonis S (2007) Oral mucositis and outcomes of autologous hematopoietic stem-cell transplantation following high-dose melphalan conditioning for multiple myeloma. J Support Oncol 5(5):231–235Google Scholar
  13. 13.
    Chaudhry HM, Bruce AJ, Wolf RC, Litzow MR, Hogan WJ, Patnaik MS, Kremers WK, Phillips GL, Hashmi SK (2016) The incidence and severity of oral mucositis among allogeneic hematopoietic stem cell transplantation patients: a systematic review. Biol Blood Marrow Transplant 22(4):605–616CrossRefGoogle Scholar
  14. 14.
    Kashiwazaki H, Matsushita T, Sugita J, Shigematsu A, Kasashi K, Yamazaki Y, Kanehira T, Kondo T, Endo T, Tanaka J, Hashino S, Nishio M, Imamura M, Kitagawa Y, Inoue N (2012) A comparison of oral mucositis in allogeneic hematopoietic stem cell transplantation between conventional and reduced-intensity regimens. Support Care Cancer 20(5):933–939CrossRefGoogle Scholar
  15. 15.
    Legert KG, Remberger M, Ringdén O, Heimdahl A, Dahllöf G (2014) Reduced intensity conditioning and oral care measures prevent oral mucositis and reduces days of hospitalization in allogeneic stem cell transplantation recipients. Support Care Cancer 22(8):2133–2140CrossRefGoogle Scholar
  16. 16.
    Takahashi K, Soga Y, Murayama Y, Udagawa M, Nishimoto H, Sugiura Y, Maeda Y, Tanimoto M, Takashiba S (2010) Oral mucositis in patients receiving reduced-intensity regimens for allogeneic hematopoietic cell transplantation: comparison with conventional regimen. Support Care Cancer 18(1):115–119CrossRefGoogle Scholar
  17. 17.
    Chen YB, Coughlin E, Kennedy KF, Alyea EP, Armand P, Attar EC, Ballen KK, Cutler C, Dey BR, Koreth J, McAfee SL, Spitzer TR, Antin JH, Soiffer RJ, Ho VT (2013) Busulfan dose intensity and outcomes in reduced-intensity allogeneic peripheral blood stem cell transplantation for myelodysplastic syndrome or acute myeloid leukemia. Biol Blood Marrow Transplant 19(6):981–987CrossRefGoogle Scholar
  18. 18.
    Gayoso J, Balsalobre P, Pascual MJ, Castilla-Llorente C, López-Corral L, Kwon M, Serrano D, Piñana JL, Herrera P, Ferrá C, Pascual C, Heras I, Montesinos P, Zabalza A, Bento L, Figuera A, Buño I, Díez-Martín JL (2016) Busulfan-based reduced intensity conditioning regimens for haploidentical transplantation in relapsed/refractory Hodgkin lymphoma: Spanish multicenter experience. Bone Marrow Transplant 51(10):1307–1312CrossRefGoogle Scholar
  19. 19.
    Ringdén O, Erkers T, Aschan J, Garming-Legert K, Le Blanc K, Hägglund H, Omazic B, Svenberg P, Dahllöf G, Mattsson J, Ljungman P, Remberger M (2013) A prospective randomized toxicity study to compare reduced-intensity and myeloablative conditioning in patients with myeloid leukaemia undergoing allogeneic haematopoietic stem cell transplantation. J Intern Med 274(2):153–162CrossRefGoogle Scholar
  20. 20.
    Yu ZP, Ding JH, Chen BA, Li YF, Ding BH, Qian J (2013) An anti-human thymocyte globulin-based reduced-intensity conditioning regimen is associated with a higher quality of life and lower organ toxicity without affecting lymphocyte reconstitution. PLoS One 8(9):e73755CrossRefPubMedCentralGoogle Scholar
  21. 21.
    Bezinelli LM, Eduardo FP, de Carvalho DLC, Dos Santos Ferreira CE, de Almeida EV, Sanches LR, Esteves I, Campregher PV, Hamerschlak N, Corrêa L (2017) Therapeutic salivary monitoring of IV busulfan in patients undergoing hematopoietic stem cell transplantation: a pilot study. Bone Marrow Transplant 52(10):1384–1389CrossRefGoogle Scholar
  22. 22.
    Sibai H, Falcone U, Deotare U, Michelis FV, Uhm J, Gupta V, Kuruvilla J, Lipton JH, Seftel MD, Messner HA, Kim DDH (2016) Myeloablative versus reduced-intensity conditioning in patients with myeloid malignancies: a propensity score-matched analysis. Biol Blood Marrow Transplant 22(12):2270–2275CrossRefGoogle Scholar
  23. 23.
    Chiesa R, Cappelli B, Crocchiolo R, Frugnoli I, Biral E, Noè A, Evangelio C, Fossati M, Roccia T, Biffi A, Finizio V, Aiuti A, Broglia M, Bartoli A, Ciceri F, Roncarolo MG, Marktel S (2010) Unpredictability of intravenous busulfan pharmacokinetics in children undergoing hematopoietic stem cell transplantation for advanced beta thalassemia: limited toxicity with a dose-adjustment policy. Biol Blood Marrow Transplant 16(5):622–628CrossRefGoogle Scholar
  24. 24.
    Lombardi LR, Kanakry CG, Zahurak M, Durakovic N, Bolaños-Meade J, Kasamon YL, Gladstone DE, Matsui W, Borrello I, Huff CA, Swinnen LJ, Brodsky RA, Ambinder RF, Fuchs EJ, Rosner GL, Jones RJ, Luznik L (2016) Therapeutic drug monitoring for either oral or intravenous busulfan when combined with pre- and post-transplantation cyclophosphamide. Leuk Lymphoma 57(3):666–675CrossRefGoogle Scholar
  25. 25.
    Devillier R, Fürst S, El-Cheikh J, Castagna L, Harbi S, Granata A, Crocchiolo R, Oudin C, Mohty B, Bouabdallah R, Chabannon C, Stoppa AM, Charbonnier A, Broussais-Guillaumot F, Calmels B, Lemarie C, Rey J, Vey N, Blaise D (2014) Antithymocyte globulin in reduced-intensity conditioning regimen allows a high disease-free survival exempt of long-term chronic graft-versus-host disease. Biol Blood Marrow Transplant 20(3):370–374CrossRefGoogle Scholar
  26. 26.
    Cutler C, Li S, Kim HT, Laglenne P, Szeto KC, Hoffmeister L, Harrison MJ, Ho V, Alyea E, Lee SJ, Soiffer R, Sonis S, Antin JH (2005) Mucositis after allogeneic hematopoietic stem cell transplantation: a cohort study of methotrexate- and non-methotrexate-containing graft-versus-host disease prophylaxis regimens. Biol Blood Marrow Transplant 11(5):383–388CrossRefGoogle Scholar
  27. 27.
    Zhao M, Liang L, Ji L, Chen D, Zhang Y, Zhu Y, Ongaro A (2016) MTHFR gene polymorphisms and methotrexate toxicity in adult patients with hematological malignancies: a meta-analysis. Pharmacogenomics 17(9):1005–1017CrossRefGoogle Scholar
  28. 28.
    Alamo J, Shahjahan M, Lazarus HM, de Lima M, Giralt SA (2005) Comorbidity indices in hematopoietic stem cell transplantation: a new report card. Bone Marrow Transplant 36(6):475–479CrossRefGoogle Scholar
  29. 29.
    Diaconescu R, Flowers CR, Storer B, Sorror ML, Maris MB, Maloney DG, Sandmaier BM, Storb R (2004) Morbidity and mortality with nonmyeloablative compared with myeloablative conditioning before hematopoietic cell transplantation from HLA-matched related donors. Blood 104(5):1550–1558CrossRefGoogle Scholar
  30. 30.
    Sorror ML, Maris MB, Storer B, Sandmaier BM, Diaconescu R, Flowers C, Maloney DG, Storb R (2004) Comparing morbidity and mortality of HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative and myeloablative conditioning: influence of pretransplantation comorbidities. Blood 104(4):961–968CrossRefGoogle Scholar
  31. 31.
    R Development Core Team (2008) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria ISBN 3-900051-07-0Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Fernanda P. Eduardo
    • 1
    Email author
  • Leticia Mello Bezinelli
    • 1
  • Marcella Gobbi
    • 1
  • Flavia C. P. Rosin
    • 1
  • Danielle L. C. Carvalho
    • 1
    • 2
  • Mariana Henriques Ferreira
    • 1
    • 2
  • Cinthya Correa da Silva
    • 1
  • Nelson Hamerschlak
    • 1
  • Luciana Corrêa
    • 2
  1. 1.Hematology/Oncology of Hospital Israelita Albert Einstein_HIAESão PauloBrazil
  2. 2.General Pathology Department, School of DentistryUniversity of São PauloSao PauloBrazil

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