Solid organ transplantation after hematopoietic stem cell transplantation in childhood: A multicentric retrospective survey

1 INTRODUCTION

Solid organ transplantation (SOT) represents a therapeutic opportunity for pediatric and adult patients affected by severe/intractable chronic or acute organ failure. Since the first report of a kidney transplant performed in 2 identical twins in 1956,1 the number of SOTs in children has increased over time. More appropriate choice of donor, as well as improved surgical procedures and supportive care, dramatically reduced SOT mortality.2 Table 1 shows the most frequent indications for SOT in children that differ according to organ dysfunction.3-6 Considering the spectrum of severe acute and chronic complications that may occur after hematopoietic stem cell transplantation (HSCT), HSCT-related potential SOT indications include the following: (1) severe acute or chronic Graft-vs-Host disease (GvHD); (2) acute and chronic toxicity related to chemo-radiotherapy and immunosuppressive therapies administered before, during, and after HSCT; and (3) organ dysfunction related to the underlying disease. In particular, the most frequent determinants of organ failure requiring SOT after HSCT are the following: acute or chronic GvHD involving liver or lung (vanishing bile duct syndrome and bronchiolitis obliterans [BO], severe veno-occlusive disease, acute or chronic nephrotoxicity due to total body irradiation [TBI] or chemotherapy [ie, carboplatin or ifosfamide], severe restrictive pulmonary insufficiency secondary to TBI or chemotherapy [ie, busulfan], severe hypertrophic cardiomyopathy due to high doses of anthracycline [>360 mg m²] or cyclophosphamide [>240 mg kg] and/or TBI).7-9

The use of SOT after HSCT has been recently described by the Leukemia Working Party group of the European Society for Blood and Marrow Transplantation (EBMT) in a retrospective survey including both children and adults.10 However, little is known about the use of SOT after HSCT in pediatric patients. Indeed, it has only been discussed in single case reports11-16 and in a multicenter study of children who underwent exclusively lung transplantation after HSCT.17

The present study represents the first multicenter survey on pediatric patients receiving SOT after HSCT. The main aim is to analyze indications and outcome of SOTs performed after HSCT, as well as patient- and disease-related variables affecting the outcome.

2 MATERIAL AND METHODS

Patients’ eligibility criteria for this retrospective survey included a previous allogeneic (allo-HSCT) or autologous HSCT (auto-HSCT) in a pediatric EBMT center between 1984 and 2016 and age <18 years at the time of HSCT. Data were collected through a questionnaire that was sent to all EBMT pediatric centers, and included demographic data, type of primary diagnosis, date and type of HSCT, conditioning regimens, occurrence of acute and chronic GvHD, grade of GvHD, date of SOT, type of SOT, indication for SOT, presence of GvHD at the time of SOT, type of donor SOT (living or deceased donor), immunosuppressive (IS) therapy, major complications after SOT, and outcome. Two hundred forty-nine EBMT centers were contacted: 78 centers (31%) filled in the questionnaire and 20 of them (25.6%) reported data of at least 1 child who received SOT after HSCT.

Overall, SOT was performed in patients affected by severe organ failure that occurred after HSCT as a consequence of: (1) acute and chronic GvHD (a-GvHD and c-GvHD); (2) acute and late toxicity related to chemotherapy and/or radiotherapy and/or immunosuppressive drugs; (3) organ dysfunction related to the underlying disease (ie, congenital kidney or liver abnormalities, organ insufficiency related to surgical procedure).

3 RESULTS

4 DISCUSSION

The purpose of this study was to retrospectively collect data on the outcome of pediatric patients receiving SOT after a previous either auto- or allo-HSCT. After reviewing data obtained through a questionnaire-based survey, we were able to analyze data coming from 20 pediatric EBMT Centers, for a total of 44 SOTs performed after HSCT. As expected by the limit of a survey, the number of children who received SOT could have been underestimated, and also some specific information regarding complications that occurred after SOT can be missed, since only the HSCT center was contacted for this survey. Furthermore, SOTs performed in children in adult centers might have been missed. Notwithstanding these possible biases, the incidence of SOT (0.062%) in this pediatric survey is similar to the incidence of SOT (0.067%) reported in the recent EBMT published survey combining adult and pediatric data.10

In our cohort, the most frequent indications for SOT were acute or chronic HSCT-related toxicity (40.9%), followed by a-GvHD and c-GvHD (36.3%), and organ dysfunction related to the underlying disease (22.8%).

The indications for SOT collected in this survey were similar to those reported in the previous EBMT survey.10 In particular, GvHD and acute and chronic toxicity represented the most frequent indications for SOT as shown by the current study.10 Lungs and liver represent the organs more frequently transplanted in the presence of intractable acute or chronic GvHD (83.3% and 30%, respectively), and the majority of patients were already under IS therapies at time of SOT. While the indication for LuTx was represented by BO/c-GvHD (83.3%), an isolated and very often IS-resistant complication that leads to irreversible respiratory failure, acute or chronic GvHD represented more rare indications for LTx (30% and 50%, respectively). Of interest, the frequency of complications after LTx was lower than that reported after LuTx (55% vs 75%); by contrast, LTx recipients appear to be at increased risk of severe and irreversible complications, with a mortality rate more than double when compared to LuTx recipients (35% vs 17%). Moreover, the median interval between HSCT and LTx was shorter than the time between HSCT and LuTx (1.8 vs 12.9 years), suggesting that LTx was performed in more immunocompromised recipients and thus at increased risk of complications. The main difference between our survey and the one already published is represented by the more frequent use of SOT due to organ dysfunction related to underlying disease in the pediatric cohort (22.8 vs 4.4%). This result could be explained by the highest number of patients transplanted for nonmalignant diseases in the pediatric group in comparison to the adult one. Our study shows that OS of all children at 5 years was 80.4% (95% CI, 69%-93.6%), similar to the OS of 78% (95% CI, 64%-92%) reported in the recent EBMT survey, which included both children and adults.10 A review of the literature on pediatric patients who received SOT without a previous HSCT showed that OS at 5 years is 97% for KTx,4 80% for HTx5 and LTx,3 and from 49% 18 to 61%19 for LuTx. In the present study, in comparison with published data, the 5-year OS is higher in the group of children who underwent LuTx (100% vs 49% or 61%), and lower in the group that received LTx (63.2% vs 80%), while it was similar for HTx- and KTx-recipients. The surprisingly favorable outcome of the relatively small number of patients who underwent LuTx might be explained by the strict selection of candidates in our series as compared to those included in the large cohort study reported by the Society for Heart and Lung Transplantation (n = 2171 since 1988).20 Moreover, it has been reported2 that the OS of patients who received LuTx for any cause decreased over time from 54.8% at 5 years to 44% at 10 years, whereas in our population, OS after LuTx started to decrease after 10 years, suggesting a potential role of HSCT as a tool of immune tolerance for SOT.21

The complications that occurred after SOT included failure of the transplanted organ (16%), graft rejection (16%), infections (15%), and surgical complications (12%). While graft rejection, organ failure, and surgical complications occurred more frequently after LTx, infections were more frequent after LuTx and they were mostly responsive to therapies.

In this study, none of the evaluated variables (stem cells source, type of the donor, conditioning regimen, age at HSCT) related to HSCT had statistically significant impact on the patients’ outcome. The dismal outcome observed in patients who received peripheral blood stem cells as stem cell source (hazard ratio = 2.78) as well as from an alternative donor (hazard ratio  = 1.77) could be related to the higher risk of developing c-GvHD, which is typical of these kinds of HSCT. In addition, the SOT rejection incidence in our cohort was similar (15.9%) to that reported in the EBMT survey (13.3%)10 and similar to the incidence of rejection reported after SOT performed for other causes.

Our data confirm that SOT is a valuable and potentially lifesaving treatment for patients who develop otherwise intractable end-stage organ failure after HSCT. When compared to children undergoing SOT for other indications, the OS of SOT recipients after HSCT performed in pediatric-age patients appears to be similar. For this reason, the decision to perform SOT after HSCT should involve patients, family, and the entire multidisciplinary team. The option of SOT should be limited to selected cases in which the failure of a single organ resistant to other treatment (as in the case of GvHD) or a consequence of a severe organ toxicity or pre-existing before the HSCT has been demonstrated. Social and psychological aspects should also deserve a specific evaluation.2 Nevertheless, the success of this approach lay only in the presence of strict cooperation between the SOT and HSCT teams, to determine the eligibility for a post-HSCT SOT and for establishing an appropriate follow-up.

In conclusion, our study shows that SOT after either auto- or allo-HSCT is a feasible therapeutic option in pediatric patients. A close collaboration with the SOT team will improve the definition of the eligibility criteria and the appropriate timing for SOT in pediatric HSCT recipients.

DISCLOSURE

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.