Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2015, 159(3):372-377 | DOI: 10.5507/bp.2015.022

Bone marrow suppression and associated consequences in patients after heart transplantation: A 6-year retrospective review

Michal Pazdernik, Ivan Malek, Eva Koudelkova, Jan Sochman, Josef Kautzner
Department of Cardiology, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic

Aims: To evaluate the incidence of bone marrow suppression and consequences of MMF dose adjustment in patients within the first year after heart transplantation.

Methods: Group I (n=47) was treated with a regimen currently used in patients after heart transplantation (mycophenolatemofetil - MMF, valganciclovir - VGC and trimethoprim/sulfamethoxazole - TMP-SMX). Group II (n=47) received only MMF of potentially myelotoxic medications. The myelotoxic effect and need for dose modification were assessed. The incidence of rejections and infectious episodes associated with MMF adjustment were analyzed during the first 12 months in Group I.

Results: There was a significantly greater proportion of patients with leukopenia (leukocyte count < 4 x 10^9/L) at 3 months after orthotopic heart transplantation in Group I compared with Group II (19.1% vs 2.1%; P = 0.02). The difference in lymphopenia (lymphocyte count < 0.8 x 10^9/L) at 3 months follow-up was highly significant (38.3 % vs 6.4 %; P = 0.0002). MMF was modified due to bone marrow suppression or severe infection in 63.8% patients in Group I and in only 8.5% of patients in Group II (P < 0.001). Reducing or stopping MMF was not associated with increased rejections. In Group I, at least 1 episode of higher degree cellular or humoral rejection occurred in 35% of patients with the standard MMF dosage compared with only 26% in patients with modified MMF (P = 0.0534).

Conclusions: Addition of VGC+TMP-SMX to current immunosuppressive medication regimen in patients after heart transplantation is associated with significant lymphocytopenia and leukopenia. Importantly, modification of immunosuppressive prophylaxis (reducing or stopping MMF) leads to normalization of blood count without increased incidence of rejections.

Keywords: heart transplant, medication regimen, myelotoxicity, rejections

Received: December 2, 2014; Accepted: April 22, 2015; Prepublished online: May 14, 2015; Published: September 30, 2015  Show citation

ACS AIP APA ASA Harvard Chicago Chicago Notes IEEE ISO690 MLA NLM Turabian Vancouver
Pazdernik, M., Malek, I., Koudelkova, E., Sochman, J., & Kautzner, J. (2015). Bone marrow suppression and associated consequences in patients after heart transplantation: A 6-year retrospective review. Biomedical papers, 159(3), 372-377. doi: 10.5507/bp.2015.022
Share...
Download citation
  • BibTeX (.bib)
  • Bookends (.ris)
  • EasyBib (.ris)
  • EndNote (.enw)
  • EndNote 8 (.xml)
  • ISI WoS (.isi)
  • Medlars (.medlars)
  • Mendeley (.ris)
  • MODS (.xml)
  • Papers (.ris)
  • RefWorks (.txt)
  • RefManager (.ris)
  • RIS (.ris)
  • MS Word (.xml)
  • Zotero (.ris)
    • Open full article

    References

    1. Delgado JF, Sánchez V, de la Calzada CS. Acute rejection after heart transplantation. Expert Opin Pharmacother 2006;7(9):1139-49. Go to original source... Go to PubMed...
    2. Gurguí M, Muñoz P. [Infection in heart transplantation]. Enferm Infecc Microbiol Clin 2007;25(9):587-597; quiz 598. Go to original source... Go to PubMed...
    3. Montoya JG, Giraldo LF, Efron B, Stinson EB, Gamberg P, Hunt S, Giannetti N, Miller J, Remington JS. Infectious complications among 620 consecutive heart transplant patients at Stanford University Medical Center. Clin Infect Dis 2001;33(5):629-40. Go to original source... Go to PubMed...
    4. Costanzo MR, Dipchand A, Starling R, Anderson A, Chan M, Desai S, Fedson S, Fisher P, Gonzales-Stawinski G, Martinelli L, McGiffin D, Smith J, Taylor D, Meiser B, Webber S, Baran D, Carboni M, Dengler T, Feldman D, Frigerio M, Kfoury A, Kim D, Kobashigawa J, Shullo M, Stehlik J, Teuteberg J, Uber P, Zuckermann A, Hunt S, Burch M, Bhat G, Canter C, Chinnock R, Crespo-Leiro M, Delgado R, Dobbels F, Grady K, Kao W, Lamour J, Parry G, Patel J, Pini D, Towbin J, Wolfel G, Delgado D, Eisen H, Goldberg L, Hosenpud J, Johnson M, Keogh A, Lewis C, O'Connell J, Rogers J, Ross H, Russell S, Vanhaecke J. The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. J Heart Lung Transplant 2010;29(8):914-56. Go to original source... Go to PubMed...
    5. Roth D, Colona J, Burke GW, Ciancio G, Esquenazi V, Miller J. Primary immunosuppression with tacrolimus and mycophenolate mofetil for renal allograft recipients. Transplantation 1998;65(2):248-52. Go to original source... Go to PubMed...
    6. Blosser CD, Bloom RD. Posttransplant anemia in solid organ recipients. Transplant Rev (Orlando) 2010;24(2):89-98. Go to original source... Go to PubMed...
    7. Kobashigawa J, Miller L, Renlund D, Mentzer R, Alderman E, Bourge R, Costanzo M, Eisen H, Dureau G, Ratkovec R, Hummel M, Ipe D, Johnson J, Keogh A, Mamelok R, Mancini D, Smart F, Valantine H, The Mycophenolate Mofetil Investigators. A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients. Transplantation 1998;66(4):507-15. Go to original source... Go to PubMed...
    8. Eisen H, Kobashigawa J, Keogh A, Bourge R, Renlund D, Mentzer R, Alderman E, Valantine H, Dureau G, Mancini D, Mamelok R, Gordon R, Wang W, Mehra M, Constanzo MR, Hummel M, Johnson J; Mycophenolate Mofetil Cardiac Study Investigators. Three year results of a randomized, double blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients. J Heart Lung Transplant 2005;24(5):517-25. Go to original source... Go to PubMed...
    9. Squifflet JP, Backman L, Claesson K, Dietl KH, Ekberg H, Forsythe JL, Kunzendorf U, Heemann U, Land W, Morales JM, Mühlbacher F, Talbot D, Taube D, Tyden G, van Hooff J, Schleibner S, Vanrenterghem Y, European Tacrolimus-MMF Renal Study Group. Dose optimization of mycophenolate mofetil when administered with a low dose of tacrolimus in cadaveric renal transplant recipients. Transplantation 2001;72(1):63-9. Go to original source... Go to PubMed...
    10. Mourad M, Malaise J, Chaib Eddour D, De Meyer M, König J, Schepers R, Squifflet JP, Wallemacq P.Correlation of mycophenolic acid pharmacokinetic parameters with side effects in kidney transplant patients treated with mycophenolate mofetil. Clin Chem 2001;47(1):88-94. Go to original source...
    11. Pelletier RP, Akin EB, Bumgardner GL, Rajab A, Elkhammas EA, Henry ML, Ferguson RM. Mycophenolate mofetil dose reduction influences clinical outcome following kidney transplantation. Am J Transplant 2003;2(Suppl 3):467.
    12. Sundar KM, Sires M. Sepsis induced immunosuppression: Implications for secondary infections and complications. Indian J Crit Care Med 2013;17(3):162-9. Go to original source... Go to PubMed...
    13. Muenzer JT, Davis CG, Chang K, Schmidt RE, Dunne WM, Coopersmith CM, Hotchkiss RS. Characterization and modulation of the immunosuppressive phase of sepsis. Infect Immun 2010;78(4):1582-92. Go to original source... Go to PubMed...
    14. Sánchez-Lázaro IJ, Almenar L, Blanes M, Martínez-Dolz L, Portolés M, Roselló E, Rivera M, Salvador A. Timing, etiology, and location of first infection in first year after heart transplantation. Transplant Proc 2010;42(8):3017-19. Go to original source... Go to PubMed...
    15. Kotton CN, Kumar D, Caliendo AM, Åsberg A, Chou S, Snydman DR, Allen U, Humar A; Transplantation Society International CMV Consensus Group. International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation 2010;89(7):779-95. Go to original source... Go to PubMed...
    16. Brum S, Nolasco F, Sousa J, Ferreira A, Possante M, Pinto JR, Barroso E, Santos JR. Leucopenia in kidney transplant patients with the association of valganciclovir and mycophenolate mofetil. Transplant Proc 2008;40(3):752-4. Go to original source... Go to PubMed...
    17. Chen I, Chang H, Hsu C, Lai ST, Hsieh YC, Shih CC. Correlation between body mass index and leucopenia after administration of valganciclovir for cytomegalovirus infection in Chinese cardiac recipients. Circ J 2007; 71(6):968-72. Go to original source... Go to PubMed...
    18. Knoll GA, MacDonald I, Khan A, Van Walraven C. Mycophenolate mofetil dose reduction and the risk of acute rejection after renal transplantation. J Am Soc Nephrol 2003;14(9):2381-6. Go to original source... Go to PubMed...
    19. Bunnapradist S, Lentine KL, Burroughs TE, Pinsky BW, Hardinger KL, Brennan DC, Schnitzler MA. Mycophenolate mofetil dose reductions and discontinuations after gastrointestinal complications are associated with renal transplant graft failure. Transplantation 2006;82(1):102-7. Go to original source... Go to PubMed...
    20. Kahu J, Kyllönen L, Salmela K. Impact of mycophenolate mofetil intolerance on early results of kidney transplantation. Transplant Proc 2005;37(8):3276-9. Go to original source... Go to PubMed...
    21. Segovia J, Gerosa G, Almenar L, Livi U, Viganò M, Arizón JM, Yonan N, Di Salvo TG, Renlund DG, Kobashigawa JA; ERL 2401 Study Group. Impact of dose reductions on efficacy outcome in heart transplant patients receiving enteric-coated mycophenolate sodium or mycophenolate mofetil at 12 months post-transplantation. Clin Transplant 2008;22(6):809-14. Go to original source... Go to PubMed...
    22. Galiwango PJ, Delgado DH, Yan R, Kozuszko S, Smith R, Rao V, Ross HJ. Mycophenolate mofetil dose reduction for gastrointestinal intolerance is associated with increased rates of rejection in heart transplant patients. J Heart Lung Transplant 2008;27(1):72-7. Go to original source... Go to PubMed...
    23. Khosroshahi HT, Shoja MM, Peyrovifar A, Hashemi SR, Amjadi M. Mycophenolate Mofetil Dose Reduction in Renal Transplant Recipients: A 5-Year Follow-up Study. Transplant Proc 2009;41(7):2797-9. Go to original source... Go to PubMed...
    24. Baran DA, Zucker MJ, Arroyo LH, Camacho M, Goldschmidt ME, Nicholls SJ, Prevost-Fernandez J, Carr C, Adams L, Pardi S, Hou V, Binetti M, McCahill J, Chichetti J, Viloria V, Sanagustin MG, Ebuenga-Smith J, Mele L, Martin A, Blicharz D, Wolski K, Olesnicky L, Qian F, Gass AL, Cohen M. A prospective, randomized trial of single-drug versus dual-drug immunosuppression in heart transplantation: the tacrolimus in combination, tacrolimus alone compared (TICTAC) trial. Circ Heart Fail 2011;4(2):129-37. Go to original source... Go to PubMed...
    25. Teuteberg JJ, Shullo MA, Zomak R, Toyoda Y, McNamara DM, Bermudez C, Kormos RL, McCurry KR. Alemtuzumab induction prior to cardiac transplantation with lower intensity maintenance immunosuppression: one-year outcomes. Am J Transplant 2010;10(2):382-8. Go to original source... Go to PubMed...
    26. Emery V. Facing the facts: the indirect effects of cytomegalovirus. Transplantation 2007;84(6S):S7-S10. Go to original source... Go to PubMed...
    27. Grattan MT, Moreno-Cabral CE, Starnes VA, Oyer PE, Stinson EB, Shumway NE. Cytomegalovirus infection is associated with cardiac allograft rejection and atherosclerosis. JAMA 1989;261(24):3561-6. Go to original source... Go to PubMed...
    28. Vymetalova J, Kubanek M, Gazdic T, Vrbska J, Malek I, Kautzner J. Comparison of universal prophylaxis and preemptive treatment with valganciclovir in management of cytomegalovirus infection in heart transplant recipients. Cor Vasa 2012;54(1):e16-e21. Go to original source...
    29. Molina Perez E, Fernández Castroagudín J, Seijo Ríos S, Mera Calviño J, Tomé Martínez de Rituerto S, Otero Antón E, Bustamante Montalvo M, Varo Perez E. Valganciclovir-induced leukopenia in liver transplant recipients: influence of concomitant use of mycophenolate mofetil. Transplant Proc 2009;41(3):1047-9. Go to original source... Go to PubMed...
    30. Rerolle JP, Szelag JC, Le Meur Y. Unexpected rate of severe leucopenia with the association of mycophenolate mofetil and valganciclovir in kidney transplant recipients. Nephrol Dial Transplant 2007;22(2):671-2. Go to original source... Go to PubMed...
    31. Reischig T, Prucha M, Sedlackova L, Lysak D, Jindra P, Bouda M, Matejovic M. Valganciclovir prophylaxis against cytomegalovirus impairs lymfocyte proliferation and activation in renal transplant recipients. Antivir Ther 2011;16(8):1227-35. Go to original source... Go to PubMed...

    Return to the content