Analysis of malignancies in patients after heart transplantation with subsequent immunosuppressive therapy

Abstract

ObjectiveThe aim of this study was to analyze the distribution of malignancies in patients after heart transplantation (HTX) and to evaluate the risk factors including immunosuppressive therapy with regard to the development of malignancies and survival. Special emphasis was placed on the effects of a mammalian target of rapamycin (mTOR) containing immunosuppressive regimen.MethodsA total of 381 patients (age ≥18 years) receiving HTX were included in the present analysis. All patients were followed-up at the University of Heidelberg Heart Center, Heidelberg, Germany. Data were retrieved from the Heidelberg Registry for Heart Transplantation being collected between 1989 and 2014. According to center standard, all patients received induction therapy with anti-thymocyte globulin guided by T-cell monitoring since 1994. The initial immunosuppressive regimen consisting of cyclosporine A (CsA) and azathioprine (AZA) was replaced by CsA and mycophenolate mofetil (MMF) in 2001 and by tacrolimus (TAC) and MMF in 2006. Additionally, mTOR inhibitors (everolimus/sirolimus) were applied since 2003.ResultsMean recipient age at HTX was 51.2±10.5 years and the mean follow-up period after HTX was 9.7±5.9 years. During follow-up, 130 patients developed a neoplasm (34.1% of total). Subgroup analysis revealed 58 patients with cutaneous malignancy only (15.2%), 56 patients with noncutaneous malignancy only (14.7%), and 16 patients with both cutaneous and noncutaneous malignancy (4.2%). Statistically significant risk factors associated with an increased risk of malignancy after HTX were older age (P<0.0001), male recipients (P=0.0008), dyslipidemia (P=0.0263), diabetes mellitus (P=0.0003), renal insufficiency (P=0.0247), and >1 treated rejection episode (TRE) in the first year after HTX (P=0.0091). Administration of CsA (P=0.0195), AZA (P=0.0008), or steroids (P=0.0018) for >1 year after HTX was associated with increased development of malignancy, whereas administration of MMF (P<0.0001) or mTOR inhibitors (P<0.0001) was associated with a lower risk for development of malignancy. Additionally, 5-year follow-up of cutaneous malignancy recurrence (P=0.0065) and noncutaneous malignancy mortality (P=0.0011) was significantly lower in patients receiving an mTOR inhibitor containing therapy after the development of a malignancy.ConclusionThis study highlights the complexity of risk factors including immunosuppression with regard to the development of malignancies after HTX. mTOR-inhibitor-based immunosuppression is associated with a better outcome after HTX, particularly in cases with noncutaneous malignancy.

Everolimus and Malignancy after Solid Organ Transplantation: A Clinical Update

“…An analysis of 381 patients transplanted at the University of Heidelberg in Germany during 1989 to 2014 investigated an association between development of neoplasms and inclusion of either everolimus or sirolimus in the initial immunosuppressive regimen [13]. During a mean follow-up of 9.7 years, 34.1% of patients developed a neoplasm, most frequently skin cancer (15.2% of patients).…”

“…As in other organ types, skin cancers are the most frequent type of neoplasms after heart transplantation [12] and use of mTOR inhibition appears to delay their recurrence [13]. Euvrard et al undertook an observational study of 10 patients with multiple recurrent skin tumors and/or fast-growing SCC [68].…”

Diabetes Is an Independent Risk Factor for Cancer after Heart and/or Lung Transplantation

“…De novo malignancies are a major source of morbidity and mortality in solid organ transplant recipients, and, probably due to the increased immunosuppressive therapy requirements, heart and/or lung transplant patients are at increased risk (e.g., four-fold compared to recipients of kidney transplantation) [ 12 , 13 , 14 , 15 ]. An analysis of more than 17,000 heart transplant patients from the International Society for Heart and Lung Transplantation Registry showed that more than 10% of adult heart recipients developed de novo malignancy between years 1 and 5 after transplantation [ 16 ].…”

Post-transplant Lymphoproliferative Disorder Following Cardiac Transplantation

“…In contrast, EBV positive PTLD cases tend to occur early posttransplant whereas EBV-negative PTLD cases have a continued increase in incidence in each year (30). The data on incidence of PTLD after HT are derived from single-center and multicenter reports with incidence rates that range from 0.7 to 6.8% (Table 1) (5,14,15,(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42). Kotton et al (25) analyzed PLTD rates based on EBV serology and type of organ transplant, the overall rates of PTLD in adult HT subgroup was 0.9% in all serology, 2.1% in EBV-negative serology and 0.6% in EBV-positive serology.…”