Intravenous pulse administration of cyclophosphamide is an effective and safe treatment for sensitized cardiac allograft recipients.
BACKGROUND
The proportion of cardiac transplant recipients with preexisting sensitization to HLA alloantigens has been increasing. Sensitization prolongs duration to obtaining a donor and predicts poorer long-term allograft survival because of increased risk of cellular rejections. We investigated the effect of cyclophosphamide pulse therapy in sensitized cardiac allograft recipients.


RESULTS
Pretransplant and posttransplant outcomes were compared between 88 cardiac allograft recipients at risk for sensitization and 26 sensitized recipients treated with intravenous cyclophosphamide pulse therapy together with intravenous immune globulin before transplant and as part of a cyclosporine-based triple immunosuppressive regimen after transplant. Preformed IgG anti-HLA antibodies predicted longer duration to transplantation, earlier cellular rejection, and 2.7-fold higher cumulative rejection frequency (P=0.002). Before transplant, cyclophosphamide reduced waiting time and mortality to levels in nonsensitized patients. After transplant, cyclophosphamide prevented induction of IgG anti-HLA class II antibodies and interleukin-2 receptor--positive T-cell outgrowth from biopsy sites (both P<0.01), prolonged the rejection-free interval (P=0.009), and reduced cumulative rejections to levels in nonsensitized patients (P=0.003). By multivariable analysis, the risk of rejection was 3.7-fold higher in patients treated with mycophenolate mofetil than patients treated with cyclophosphamide (P=0.019). There were no differences in infectious or other significant complications.


CONCLUSIONS
Immunosuppression incorporating intravenous cyclophosphamide before and after transplantation is safe and highly effective in sensitized cardiac transplant recipients. When used after transplantation as part of triple immunosuppression, cyclophosphamide is superior to mycophenolate mofetil in reducing rejection. The mechanism may involve prevention of diversification of the recipient immune response to donor HLA class II molecules.
Itescu
Silviu
S
College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA. si5@columbia.edu
Burke
Elizabeth
E
Lietz
Katherine
K
John
Ranjit
R
Mancini
Donna
D
Michler
Robert
R
Rose
Eric
E
Oz
Mehmet
M
Edwards
Niloo
N
D000328:Adult; D001379:Azathioprine / Q000627:therapeutic use; D001706:Biopsy; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007262:Infusions, Intravenous; D007519:Isoantigens / Q000276:immunology; D008297:Male; D015080:Mesna / Q000008:administration & dosage; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome
D000949:Histocompatibility Antigens Class II; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D007519:Isoantigens; D003520:Cyclophosphamide; D009173:Mycophenolic Acid; D001379:Azathioprine; D015080:Mesna