The risk of dying from a transplant-related complication or recurrence of primary disease is high within the first two years after transplantation. Thereafter, the risk is substantially lower such that the survival curves reach a plateau. However, the risk for late mortality exists for several years after transplantation and is linked to several factors including pre-transplant treatment, transplant conditioning regimen, chronic GVHD, infections and autoimmunity.2–11
We describe late mortality in a large group of patients with SCID, non-SCID PIDD and IEM who survived longer than two years after transplantation with normal T-cell function (SCID) and >95% donor chimerism (non-SCID PIDD and IEM). There are important differences in the characteristics of patients in the current analysis and those included in published reports.2–8
In this analysis: 1) patients had to live longer than two years after transplantation with sustained immunologic recovery or donor chimerism; 2) the majority of SCID patients received chemotherapy for transplant conditioning and a third received allografts from unrelated donors; and 3) over half of all patients with non-SCID PIDD and IEM received allografts from unrelated donors.
We found that most patients in the current analysis are long-term survivors with 7-year survival rates of 93%, 96% and 90% after transplantation for SCID, non-SCID PIDD and IEM, respectively. Overall, 7% of surviving patients died of transplant-related complications more than two-years after the procedure confirming that the risk of late mortality after transplantation is not negligible. High relative mortality in transplant recipients compared to an age, sex and nationality matched general population was observed in all patients as long as 6 years after transplantation. Excess mortality was seen only for IEM beyond six years. The observed excess mortality risk among patients with IEM may reflect failure of the transplantation procedure to prevent progression of end organ damage or fully correct organ dysfunction that may have occurred as a consequence of the disease process prior to transplantation or soon thereafter.4
Active chronic GVHD led to higher mortality in all disease groups. Others have also identified active chronic GVHD as a significant contributor to long-term morbidity and mortality after transplantation for malignant diseases, aplastic anemia, SCID and Wiskott Aldrich syndrome.3,6,7,9,10,11,17
In our analysis late mortality risks were not associated with donor source for transplantation for SCID and non-SCID PIDD. This differs from that reported by others.2
However, donor source was associated with late mortality for patients with IEM; mortality risks were higher after mismatched related and unrelated donor transplants compared to HLA-matched sibling transplants. Transplant strategies including donor selection (donor-recipient HLA matching at the allele-level at HLA-A, -B, -C, DRB1) and improvements in supportive care in recent years have resulted in fewer early deaths from transplant-related complications and may result in comparable improvement in late outcomes after alternative donor transplantations in the current era. Another hypothesis being the current analysis is limited to those who survived for two years or longer after transplantation and for diseases such as SCID and non-SCID PIDD, donor type may not be associated with survival beyond two years from transplantation.
Consistent with other reports, the most frequently reported causes of death were chronic GVHD, infection without chronic GVHD and organ failure.3,7,9,–11
Deaths occurring in patients with chronic GVHD may occur as a direct complication of GVHD such as bronchiolitis obliterans or as a consequence of the immunodeficiency associated with chronic GVHD which in turn increases susceptibility to infections and death.17,18
Though not the focus of this analysis and not feasible when utilizing data collected by a registry, information on the burden of morbidity in patients with chronic GVHD is not available.19
Death from infection in the absence of chronic GVHD was also frequent. Approximately, 75% of late infections were bacterial and indicate long-lasting immunodeficiency after transplantation.20
Organ failure was common and occurred more frequently after transplantation for IEM and SCID. Cardiac and pulmonary failures were the most frequently cited causes of organ failure. Death from organ failure may be related to the transplantation procedure and organ toxicity from radiation or chemotherapeutic agents used for transplant conditioning or the underlying disease. Patients with immunodeficiency are subject to frequent broncho-pulmonary infections prior to transplantation and patients with IEM may have cardio-pulmonary end organ dysfunction at time of transplantation. Ninety percent of IEM patients in this analysis received myeloablative conditioning regimens and it remains to be seen whether recent strategies aimed at lowering transplant-related complications such as substitution of treosulfan for busulfan,21
results in lower risks of fatal organ toxicity in long-term survivors. Organ failure can also be autoimmune mediated and autoimmunity without chronic graft-versus-host disease in long-term survivors with SCID and non-SCID PIDD is documented.3,6,7
Malignancy excluding EBV-PTLD accounted for 5% of late deaths; malignancy occurred only in patients with non-SCID PIDD. Increase in risk of malignancy compared to the general population matched for age, sex and nationality was confined to melanoma, brain stem glioma and acute myeloid leukemia. The study population is relatively small and the cancers noted to occur in excess limited by one or two events. Solid cancer after allogeneic transplantation is well documented and its incidence increases with longer follow-up.22–24
Post-transplant malignancy can be explained by the altered immune system/function after transplantation, very young age at transplantation, irradiation-containing transplant conditioning regimen and transplantation of T-cell depleted allografts all of which are known risk factors.22–24
Transplantation strategies have evolved and in recent years aggressive measures are instituted with respect to defining a suitably matched related or unrelated donor, graft-versus-host disease prevention, and, surveillance and treatment of infections. So, several of the late complications that resulted in death in this report may no longer be as relevant for patients receiving transplantation now. Only 25% of surviving patients in the current analysis have over 10 years of follow-up and complications occurring beyond this period are under reported. Curtis and colleagues22
have reported a sharp increase in new solid malignancies at 15 years after bone marrow transplantation for hematological malignancies and Baker and colleagues,25
an increase in diabetes, hypertension and cardiovascular events after transplantation in very long-term survivors.
Though the probability of long-term survival after transplantation for SCID, non-SCID PIDD and IEM is high, the risk of mortality is substantially higher than that expected for a normal general population for several years after transplantation. Allogeneic transplantation is unlikely to reverse end organ damage that occurred prior to transplantation and for some of the IEM diseases, progressive end organ damage continues despite adequate engraftment. Further, this treatment procedure may not fully correct the immunologic or metabolic defect resulting in continued interplay between inflammatory process and poorly regulated cellular repair. Consequently late mortality could be attributed to the primary disease as well as transplantation procedure. We recommend life-long surveillance to prevent and treat life-threatening late complications and better define the long-term risks of transplantation for SCID, non-SCID PIDD and IEM. Surveillance should include assessments for chronic GVHD, pulmonary function, cardiovascular risk including echocardiogram, lipid profile, diabetes, obesity and renal function tests in addition to the other recommended tests.26
Others have reported that survivors experience considerable difficulty in holding jobs and obtaining health insurance10
and this will likely hinder life-long surveillance of survivors of transplantation in countries without national health insurance.