Current Hematologic Malignancy Reports

, Volume 11, Issue 2, pp 71–79 | Cite as

Long-Term Side Effects of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia

  • Lauren Caldemeyer
  • Michael Dugan
  • John Edwards
  • Luke Akard
Chronic Myeloid Leukemias (J Pinilla-Ibarz, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Chronic Myeloid Leukemias

Abstract

Most patients with chronic myeloid leukemia have deep and durable responses when treated with BCR-ABL1 tyrosine kinase inhibitors (TKIs). Imatinib (the first approved TKI), nilotinib, and dasatinib are used in newly diagnosed, relapsed or intolerant patients, while bosutinib and ponatinib are used only in relapsed or intolerant patients. Previously the drug of choice was related to the likelihood of response and, to a small extent, patient comorbidities. The long-term toxicities, particularly cardiopulmonary side effects, are now impacting treatment choice, making patient comorbidities of significant concern. About 10 % of patients do not tolerate their initial BCR-ABL1 TKI and an increasing number are developing long-term side effects, particularly with the second generation drugs. Side effects of the five drugs reviewed here highlight the differences between cardiovascular, pulmonary, gastrointestinal, and endocrine toxicities, as well as possible second malignancies. There is increasing evidence that patients whose disease is controlled by TKI’s will have greater impact on their quality of life from comorbidities or drug adverse events than from the disease itself. Research into management of long-term toxicities is needed.

Keywords

CML BCR-ABL1 TKI Imatinib Dasatinib Nilotinib 

Notes

Compliance with Ethical Standards

Conflict of Interest

Lauren Caldemeyer, Michael Dugan, and John Edwards report no potential conflicts of interest.

Luke Akard: Speakers Bureau: Ariad, BMS, Novartis, Teva. Research funding: Ariad, BMS, Novartis, Pfizer, Teva.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Gambacorti-Passerini C, Antolini L, Mahon FX, et al. Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib. J Natl Cancer Inst. 2011;103:553–61.CrossRefPubMedGoogle Scholar
  2. 2.
    The WJYJ, Capable ABL. What is its biological function? Mol Cell Biol. 2014;34:1188–97.CrossRefGoogle Scholar
  3. 3.
    Hantschel O. Structure, regulation, signaling, and targeting of Abl kinases in cancer. Genes Cancer. 2012;3:436–46.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Bartram CR, de Klein A, Hagemeijer A, et al. Translocation of c-abl1 oncogene correlates with the presence of a Philadelphia chromosome in chronic myelocytic leukaemia. Nature. 1983;306:277–80.CrossRefPubMedGoogle Scholar
  5. 5.
    Groffen J, Stephenson JR, Heisterkamp N, et al. Philadelphia chromosomal breakpoints are clustered within a limited region, BCR, on chromosome 22. Cell. 1984;36:93–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Deininger MW, Manley P. What do kinase inhibition profiles tell us about tyrosine kinase inhibitors used for the treatment of CML? Leuk Res. 2012;36:253–61.CrossRefPubMedGoogle Scholar
  7. 7.•
    Rea D. Management of adverse events associated with tyrosine kinase inhibitors in chronic myeloid leukemia. Ann Hematol. 2015;94 Suppl 2:S149–58. Most recent discussion of clinical management of TKI side effects.CrossRefPubMedGoogle Scholar
  8. 8.
    Druker BJ, Guilhot F, O’Brien SG, et al. Five-year follow-up for patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408–17.CrossRefPubMedGoogle Scholar
  9. 9.•
    Brummendorf TH, Cortes JE, de Souza AC, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukaemia: results from the 24-month follow-up of the BELA trial. Br J Haematol. 2014;168:69–81. Randomized trial comparing the outcome and side effects of imatinib to bosutinib.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.•
    Jabbour E, Kantarjian HM, Saglio G, et al. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2014;123:494–500. Randomized trial comparing the outcome and side effects of imatinib to dasatinib.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.•
    Larson RA, Hochhaus A, Hughes TP, et al. Nilotinib vs. imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia. 2012;26:2197–203. Randomized trial comparing the outcome of imatinib to nilotinib.CrossRefPubMedGoogle Scholar
  12. 12.
    Uitdehaag JC, de Roos JA, van Doornmalen AM, et al. Comparison of the cancer gene targeting and biochemical selectivities of all targeted kinase inhibitors approved for clinical use. PLoS ONE. 2014;9:e921–46.CrossRefGoogle Scholar
  13. 13.
    Cheng H, Force T. Molecular mechanisms of cardiovascular toxicity of targeted cancer therapeutics. Circ Res. 2010;106:21–34.CrossRefPubMedGoogle Scholar
  14. 14.
    Hochhaus A, O’Brien SG, Guilhot F, et al. Six-year follow-up of patients receiving imatinib for the first line treatment of chronic myeloid leukemia. Leukemia. 2009;23:1054–61.CrossRefPubMedGoogle Scholar
  15. 15.
    O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic phase chronic myeloid leukemia. N Engl J Med. 2003;348:994–1004.CrossRefPubMedGoogle Scholar
  16. 16.
    Efficace F, Baccarani M, Breccia M, et al. Health-related quality of life in chronic myeloid leukemia patients receiving long-term therapy with imatinib compared with the general population. Blood. 2011;118:4554–60.CrossRefPubMedGoogle Scholar
  17. 17.
    Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260–70.CrossRefPubMedGoogle Scholar
  18. 18.
    Hughes TP, Lipton JH, Spector N, et al. Deep molecular responses achieved in patients with CML-CP who are switched to nilotinib after long-term imatinib. Blood. 2014;124:729–36.CrossRefPubMedGoogle Scholar
  19. 19.
    Kantarjian HM, Giles FJ, Bhalla KN, et al. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow up results. Blood. 2011;117:1141–5.CrossRefPubMedGoogle Scholar
  20. 20.
    Cortes JE, Kim DW, Kantarjian HM, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol. 2012;30:3486–92.CrossRefPubMedGoogle Scholar
  21. 21.
    Lipton JH, Chuah C, Guerci-Bresler A, et al. EPIC: A phase 3 trial of ponatinib compared with imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CP-CML). Blood. Abstract 2014;124:519.Google Scholar
  22. 22.•
    Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369:1783–96. First report on the efficacy and side effects of ponatinib.CrossRefPubMedGoogle Scholar
  23. 23.
    Shah NP, Guilhot F, Cortes JE, et al. Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study. Blood. 2014;123:2317–24.CrossRefPubMedGoogle Scholar
  24. 24.
    Giles FJ, le Coutre PD, Pinilla-Ibarz J, et al. Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study. Leukemia. 2013;27:107–12.CrossRefPubMedGoogle Scholar
  25. 25.
    Kantarjian HM, Cortes JE, Kim DW, et al. Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. Blood. 2014;123:1309–18.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783.CrossRefPubMedGoogle Scholar
  27. 27.
    Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Kerkela R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nature. 2006;12:908–16.Google Scholar
  29. 29.
    Atallah E, Durand JB, Kantarjian H, et al. Congestive heart failure is a rare event in patients receiving imatinib therapy. Blood. 2007; 110.Google Scholar
  30. 30.
    Orphanos GS, Ioannidis GN, Ardavanis AG. Cardiotoxicity induced by tyrosine kinase inhibitors. Acta Oncol. 2009;48:964–70.CrossRefPubMedGoogle Scholar
  31. 31.
    Groarke JD, Cheng S, Moslehi J. Cancer-drug discovery and cardiovascular surveillance. N Engl J Med. 2013;369:1779–81.CrossRefPubMedGoogle Scholar
  32. 32.
    Force T, Krause DS, Van Etten RA. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nature. 2007;7:332–44.Google Scholar
  33. 33.
    Bronte G, Bronte E, Novo G, et al. Conquests and perspectives of cardio-oncology in the field of tumor angiogenesis-targeting tyrosine kinase inhibitor-based therapy. Expert Opin Drug Saf. 2015;14:253–67.CrossRefPubMedGoogle Scholar
  34. 34.•
    Kalmanti L, Saussele S, Lauseker M, et al. Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV. Leukemia. 2015;29:1123–32. Long-term study showing the side effects of imatinib and nilotinib.CrossRefPubMedGoogle Scholar
  35. 35.
    Castagnetti F, Gugliotta G, Breccia M. Long-term outcome of chronic myeloid leukemia patients treated frontline with imatinib. Leukemia. 2015;29:1823–31.CrossRefPubMedGoogle Scholar
  36. 36.
    Sprycel (dasatinib) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company. 2006.Google Scholar
  37. 37.
    Iclusig (ponatinib) [package insert]. Cambridge, MA: ARIAD Pharmaceuticals, Inc.;2012.Google Scholar
  38. 38.•
    Cortes JE, Saglio G, Baccarani M, et al. Final study results of the phase 3 dasatinib vs. imatinib in newly diagnosed chronic myeloid leukemia (CML-CP) trial (DASISION). Blood. Abstract. 2014;124(21):152. Long-term toxicities of imatinib and dasatinib show differences. Google Scholar
  39. 39.•
    Larson RA, Kim DW, Issaragrilsil S, et al. Efficacy and safety of nilotinib (NIL) vs imatinib (IM) in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): long-term follow-up of ENESTnd. Blood. Abstract. 2014;124:4541. Long-term side effects comparing imatinib and nilotinib show differences. Google Scholar
  40. 40.
    Tasigna (nilotinib) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation. 2007.Google Scholar
  41. 41.
    Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006;354:2542–51.CrossRefPubMedGoogle Scholar
  42. 42.
    Kantarjian HM, Giles F, Gattermann N, et al. Nilotinib, a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive CML-CP following imatinib resistance and intolerance. Blood. 2007;110(10):3540–6.CrossRefPubMedGoogle Scholar
  43. 43.
    Dahlen T, Edgren G, Hoglund M, et al. Increased risk of cardiovascular events associated with TKI treatment in chronic phase chronic myeloid leukemia: data from Swedish population-based registries. Blood. Abstract 2014;124:3134Google Scholar
  44. 44.
    Breccia M, Loglisci G, Salaroli A, et al. Nilotinib-mediated increase in fasting glucose level is reversible, does not convert to type 2 diabetes, and is likely correlated with increase body mass index. Leuk Res. 2012; e66-e67.Google Scholar
  45. 45.
    Rea D, Mirault T, Cluzeau T, et al. Early onset hypercholesterolemia induced by the 2nd-generation tyrosine kinase inhibitor nilotinib in patients with chronic phase-chronic myeloid leukemia. Haematolgica. 2014;99:1197–203.CrossRefGoogle Scholar
  46. 46.
    Giles FJ, Mauro MJ, Hong F, et al. Rates of peripheral arterial occlusive disease in patients with chronic myeloid leukemia in the chronic phase treated with imatinib, nilotinib, or non-tyrosine kinase therapy: a retrospective cohort analysis. Leukemia. 2013;27:1310–15.CrossRefPubMedGoogle Scholar
  47. 47.
    Aichberger KJ, Herndhofer S, Schernthaner GH, et al. Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML. Am J Hematol. 2011;86:533–9.CrossRefPubMedGoogle Scholar
  48. 48.
    Le Coutre P, Rea D, Abruzzese E, et al. Severe peripheral arterial disease during nilotinib therapy. J Natl Cancer Inst. 2011;103:1347–8.CrossRefPubMedGoogle Scholar
  49. 49.
    Quintas-Cardama A, Kantarjian H, Cortes J, et al. Nilotinib-associated vascular events. Clin Lymphoma Myeloma Leuk. 2012;12:337–40.CrossRefPubMedGoogle Scholar
  50. 50.
    Levato L, Cantaffa R, Kroop MD, et al. Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in chronic myeloid leukemia: a single institution study. Eur J Haematol. 2013;90:531–2.CrossRefPubMedGoogle Scholar
  51. 51.
    Gugliotta G, Castagnetti F, Breccia M, et al. Long-term outcome of a phase 2 trial with nilotinib 400 mg twice daily in first-line treatment of chronic myeloid leukemia. Haematologica. 2015;100:1146–50.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Kim TD, Rea D, Schwarz M, et al. Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients treated with nilotinib or imatinib. Leukemia. 2013;27:1316–21.CrossRefPubMedGoogle Scholar
  53. 53.
    Breccia M, Molica M, Zacheo I, et al. Application of systematic coronary risk evaluation chart to identify chronic myeloid leukemia patients at risk of cardiovascular diseases during nilotinib treatment. Ann Hematol. 2015;94:393–7.CrossRefPubMedGoogle Scholar
  54. 54.
    Tefferi A. Nilotinib treatment-associated accelerated atherosclerosis: when is the risk justified? Leukemia. 2013;27:1939–40.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Jain P, Kantarjian H, Jabbour E, et al. Ponatinib as first-line treatment for patients with chronic myeloid leukemia in chronic phase: a phase 2 study. Lancet. 2015;2:e376–83.CrossRefPubMedGoogle Scholar
  56. 56.
    Hochhaus A. Optimizing tolerability of TKI therapy in CML. Blood. 2014;123:1284.CrossRefPubMedGoogle Scholar
  57. 57.••
    Valent P, Hadzijusufovic E, Schernthaner GH, et al. Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors. Blood. 2015;125:901–6. Review of cardiovascular toxicities of TKIs with discussion of how these toxicities were initially overlooked.CrossRefPubMedGoogle Scholar
  58. 58.••
    Moslehi JJ, Deininger M. Tyrosine Kinase Inhibitor-Associated Cardiovascular Toxicity in Chronic Myeloid Leukemia. J Clin Oncol. 2015;33. Important review of the published data on cardiovascular toxicities. Google Scholar
  59. 59.••
    Saussele S, Krauss MP, Hehlmann R, et al. Impact of comorbidities on overall survival in patients with chronic myeloid leukemia: results of the randomized CML Study IV. Blood. 2015;126:42–9. Co-morbidities in responsive patients appear to have major impact upon survival in CML.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Ohnishi K, Sakai F, Kudoh S, et al. Twenty-seven cases of drug-induced interstitial lung disease associated with imatinib mesylate. Leukemia. 2006;20:1162–4.CrossRefPubMedGoogle Scholar
  61. 61.
    Peerzada MM, Spiro TP, Daw HA. Pulmonary toxicities of tyrosine kinase inhibitors. Clin Adv Hematol Oncol. 2011;9:824–36.PubMedGoogle Scholar
  62. 62.
    Go SI, Lee WS, Kang JH, et al. Nilotinib-induced interstitial lung disease. Int J Hematol. 2013;98:361–5.CrossRefPubMedGoogle Scholar
  63. 63.
    Shah NP, Wallis N, Farber HW, et al. Clinical features of pulmonary arterial hypertension in patients receiving dasatinib. Am J Hematol. 2015;90:1060–4.CrossRefPubMedGoogle Scholar
  64. 64.
    Tatarczuch M, Burbury K, Creati L, et al. Dasatinib therapy can result in significant pulmonary toxicity. Am J Hematol. 2015; Accepted Article.Google Scholar
  65. 65.
    Quintas-Cardama A, Kantarjian H, Ravendi F, et al. Bleeding diathesis in patients with chronic myelogenous leukemia receiving dasatinib therapy. Cancer. 2009;115:2482–90.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Quintas-Cardama A, Han X, Kantarjian H, et al. Tyrosine kinase inhibitor-induced platelet dysfunction in patients with chronic myeloid leukemia. Blood. 2009;114:261–3.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Patodi N, Sagar N, Rudzki Z, et al. Haematologic colitis caused By dasatinib. Case Rep Hematol. 2012;2012:ID 417106.Google Scholar
  68. 68.
    Apperley JF. Chronic myeloid leukaemia. Lancet. 2015;385:1447–59.CrossRefPubMedGoogle Scholar
  69. 69.
    Shah RR, Morganroth J, Shah DR. Hepatotoxicity of tyrosine kinase inhibitors: clinical and regulatory perspectives. Drug Saf. 2013;36:491–503.CrossRefPubMedGoogle Scholar
  70. 70.
    Bosulif (bosutinib) [package insert]. New York, NY: Pfizer Laboratories Div. Pfizer Inc.; 2012.Google Scholar
  71. 71.
    Gleevec (imatinib mesylate) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2001.Google Scholar
  72. 72.
    Marcolino MS, Boersma E, Clementino NCD, et al. Imatinib treatment duration is related to decreased estimated glomerular filtration rate in chronic myeloid leukemia patients. Ann Oncol. 2011;22:2073–9.CrossRefPubMedGoogle Scholar
  73. 73.
    Yilmaz M, Lahoti A, O’Brien S, et al. Estimated glomerular filtration rate changes in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. Cancer. 2015;121:3894–904.CrossRefPubMedGoogle Scholar
  74. 74.
    Salie R, Silver RT. Uncommon or delayed adverse events associated with imatinib treatment for chronic myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2010;10:331–5.CrossRefPubMedGoogle Scholar
  75. 75.
    Berman E, Nicolaides M, Maki RG, et al. Altered bone and mineral metabolism in patients receiving imatinib mesylate. N Engl J Med. 2006;354:2006–13.CrossRefPubMedGoogle Scholar
  76. 76.
    Aleman JO, Farooki A. Girotra M Effects of tyrosine kinase inhibition on bone metabolism: untargeted consequences of targeted therapies. Endocr Relat Cancer. 2014;21:R247–59.CrossRefPubMedGoogle Scholar
  77. 77.
    Farmer S, Horvath-Puho E, Vestergaard H, et al. Chronic myeloproliferative neoplasms and risk of osteoporotic fractures; a nationwide population-based cohort study. Brit J Haematol. 2013;163:603–10.CrossRefGoogle Scholar
  78. 78.
    Millot F, Guilhot J, Baruchel A, et al. Growth deceleration in children treated with imatinib for chronic myeloid leukemia. Eur J Cancer. 2014;50:3206–11.CrossRefPubMedGoogle Scholar
  79. 79.
    Narayanan KR, Bansal D, Walia R, et al. Growth failure in children with chronic myeloid leukemia receiving imatinib is due to disruption of GH/IGF-1 axis. Pediatr Blood Cancer. 2013;60:1148–53.CrossRefPubMedGoogle Scholar
  80. 80.
    Giona F, Mariani S, Gnessi L, et al. Bone mineral metabolism, growth rate and pubertal development in children with chronic myeloid leukemia treated with imatinib during puberty. Haematolgica. 2013;98:e25–7.CrossRefGoogle Scholar
  81. 81.
    Gambacorti-Passerini C, Tornaghi L, Cavagnini F, et al. Gynaecomastia in men with chronic myeloid leukemia after imatinib. Lancet. 2003;361:1954–6.CrossRefPubMedGoogle Scholar
  82. 82.
    Pilot PR, Sablinska K, Owen S, et al. Epidemiologic analysis of second primary malignancies in more than 9,500 patients treated with imatinib. Leukemia. 2006;20:148.CrossRefPubMedGoogle Scholar
  83. 83.
    Verma D, Kantarjian H, Strom S, et al. Malignancies occurring during therapy with tyrosine kinase inhibitors for chronic myeloid leukemia and other hematologic malignancies. Blood. 2011;118:4353–8.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Togasaki-Yoshimoto E, Shono K, Onoda M, et al. The occurrence of second neoplasms after treatment with tyrosine kinase inhibitors for chronic myeloid leukemia. Leuk Lymphoma. 2014;55:453–6.CrossRefPubMedGoogle Scholar
  85. 85.•
    Gunnarsson N, Stenke L, Hoglund M, et al. Second malignancies following treatment of chronic myeloid leukaemia in the tyrosine kinase inhibitor era. Br J Haematol. 2015;169:683–8. Long-term concern is reopened regarding second malignancies from this retrospective population-based study.CrossRefPubMedGoogle Scholar
  86. 86.
    Helbig G, Bober G, Seweryn M, et al. Occurrence of secondary malignancies in chronic myeloid leukemia during therapy with imatinib mesylate-single institution experience. Mediterr J Hematol Infect Dis. 2015;7:e2015003.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Duman BB, Paydas S, Disel U, et al. Secondary malignancy after imatinib therapy: eight cases and review of the literature. Leuk Lymphoma. 2012;53:1706–8.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Lauren Caldemeyer
    • 1
  • Michael Dugan
    • 1
  • John Edwards
    • 1
  • Luke Akard
    • 1
  1. 1.Indiana Blood and Marrow TransplantationFranciscan AllianceIndianapolisUSA

Personalised recommendations