Received: 13 September 2018 | Revised: 24 November 2018 | Accepted: 14 December 2018 DOI: 10.1111/ajt.15240 ORIGINAL ARTICLE Solid organ transplantation after hematopoietic stem cell transplantation in childhood: A multicentric retrospective survey Maura Faraci1 | Alice Bertaina2,3 | Arnaud Dalissier4 | Marianne Ifversen5 | Ansgar Schulz6 | Andrew Gennery7 | Birgit Burkhardt8 | Isabel Badell Serra9 | Cristina Diaz‐de‐Heredia10 | Edoardo Lanino1 | Arjan C. Lankester11 | Bernd Gruhn12 | Susanne Matthes‐Martin13 | Joern S. Kühl14 | Stefania Varotto15 | Catherine Paillard16 | Audrey Guilmatre17 | Ana Sastre18 | Manuel Abecasis19 | Birgit Garwer20 | Petr Sedlacek21 | Jaap J. Boelens22,23 | Eric Beohou4 | Peter Bader24 | On behalf of the EBMT Pediatric Disease Working Party 1 Hematopoietic Stem Cell Transplantation Unit, Hematology‐Oncology, Istituto G Gaslini, Genova, Italy 2 Dipartimento di Onco‐Ematologia Pediatrica, IRCSS Ospedale Pediatrico Bambino Gesù, Rome, Italy 3 Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, School of Medicine, Stanford University, Stanford, California 4 European Society for Blood and Marrow Transplantation Pediatric Disease Working Party, Paris, France 5 Department for Children and Adolescents, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark 6 Department of Pediatrics, University Medical Center, Ulm, Germany 7 Institute of Cellular Medicine, Pediatric Immunology Department, Newcastle University, Great North Children's Hospital, Newcastle‐upon‐Tyne, UK 8 Pediatric Hematology and Oncology, University Hospital Münster, Muenster, Germany 9 Pediatric Hematopoietic Transplant Unit, Sant Pau Hospital, Barcelona, Spain 10 Department of Pediatric Oncology and Hematology, Hospital Universitario Vall d'Hebron, Barcelona, Spain 11 Department of Pediatrics Stem Cell Transplantation Program, Leiden University Medical Center, Leiden, The Netherlands 12 Department of Pediatrics, Jena University Hospital, Jena, Germany 13 St Anna Children′s Hospital, Medical University of Vienna, Vienna, Austria 14 Department Pediatric Hematology, Oncology, Hemostaseology, Universitätsklinikum Leipzig, Leipzig, Germany 15 Clinic of Pediatric Hemato‐Oncology, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy 16 Hematology, Oncology and Stem Cell Transplantation, Department of Pediatrics, Hôpital Hautepierre, Strasbourg, France 17 Service of Pediatric Hematology‐Oncology, Hôpital Armand Trousseau, Paris, France 18 Unidad de Hematología y Oncología Pediátrica, Hospital Universitario La Paz, Madrid, Spain 19 Instute Portugues Oncologia Lisboa, Lisboa, Portugal 20 University Hospital Eppendorf, Hamburg, Germany 21 University Hospital Motol, Prague, Czech Republic 22 Pediatric Blood and Marrow Transplantation Program, Laboratory for Translational Immunology Tumor‐immunology, University Medical Center, Utrecht, The Netherlands 23 Stem Cell Transplant and Cellular Therapies Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York 24 Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, University Hospital Frankfurt, Frankfurt am Main, Germany Abbreviations: a‐GvHD, acute‐Graft vs Host disease; allo‐HSCT, allogeneic hematopoietic stem cell transplantation; auto‐HSCT, autologous hematopoietic stem cell transplantation; BO, bronchiolitis obliterans; c‐GvHD, chronic‐Graft vs Host disease; EBMT, European Society for Blood and Marrow Transplantation; HTx, heart transplantation; IS, immunosuppressive; KTx, kidney transplantation; LTX, liver transplantation; LuTx, lung transplantation; OS, overall survival; PID, primary immunodeficiency; SCD, sickle cell disease; SOT, solid organ transplanta- tion; TBI, total body irradiation. 1798 | © 2018 The American Society of Transplantation amjtransplant.com Am J Transplant. 2019;19:1798–1805. and the American Society of Transplant Surgeons 16006143, 2019, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ajt.15240 by Readcube (Labtiva Inc.), Wiley Online Library on [11/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License FARACI et al. | 1799 Correspondence Maura Faraci We report data obtained from a retrospective multicenter pediatric survey on behalf Email: maurafaraci@gaslini.org of the European Society for Blood and Marrow Transplantation (EBMT). Information on solid organ transplantation (SOT) performed in pediatric recipients of either au- tologous or allogeneic hematopoietic stem cell transplantation (HSCT) between 1984 and 2016 was collected in 20 pediatric EBMT Centers (25.6%). Overall, we evaluated data on 44 SOTs following HSCT including 20 liver (LTx), 12 lung (LuTx), 6 heart (HTx), and 6 kidney (KTx) transplantations. The indication for SOT was organ failure related to intractable graft‐vs‐host disease in 16 children (36.3%), acute or chronic HSCT‐re- lated toxicity in 18 (40.9%), and organ dysfunction related to the underlying disease in 10 (22.8%). The median follow‐up was 10.9 years (95% confidence interval: 1.7‐29.5). The overall survival rate at 1 and 5 years after SOT was 85.7% and 80.4%, respectively: it was 74% and 63.2% after LTx, 83.2% after HTx, and 100% equally after LuTx and KTx. This multicenter survey confirms that SOT represents a promising option in children with severe organ failure occurring after HSCT. Additional studies are needed to further establish the effectiveness of SOT after HSCT and to better understand the mechanism underlying this encouraging success. KEYWORDS bone marrow/hematopoietic stem cell transplantation, clinical research/practice, graft‐vs‐host disease (GVHD), heart failure/injury, kidney failure/injury, liver disease, lung (allograft) function/dysfunction, organ transplantation in general, pediatrics 1 | I NTRO D U C TI O N The use of SOT after HSCT has been recently described by the Leukemia Working Party group of the European Society for Blood Solid organ transplantation (SOT) represents a therapeutic oppor- and Marrow Transplantation (EBMT) in a retrospective survey in- tunity for pediatric and adult patients affected by severe/intracta- cluding both children and adults.10 However, little is known about ble chronic or acute organ failure. Since the first report of a kidney the use of SOT after HSCT in pediatric patients. Indeed, it has only 1 transplant performed in 2 identical twins in 1956, the number of been discussed in single case reports11-16 and in a multicenter study SOTs in children has increased over time. More appropriate choice of children who underwent exclusively lung transplantation after of donor, as well as improved surgical procedures and supportive HSCT.17 care, dramatically reduced SOT mortality.2 Table 1 shows the most The present study represents the first multicenter survey on pe- frequent indications for SOT in children that differ according to diatric patients receiving SOT after HSCT. The main aim is to analyze organ dysfunction.3-6 Considering the spectrum of severe acute and indications and outcome of SOTs performed after HSCT, as well as chronic complications that may occur after hematopoietic stem cell patient‐ and disease‐related variables affecting the outcome. transplantation (HSCT), HSCT‐related potential SOT indications in- clude the following: (1) severe acute or chronic Graft‐vs‐Host disease (GvHD); (2) acute and chronic toxicity related to chemo‐radiotherapy 2 | M ATE R I A L A N D M E TH O DS and immunosuppressive therapies administered before, during, and after HSCT; and (3) organ dysfunction related to the underlying dis- Patients’ eligibility criteria for this retrospective survey included a ease. In particular, the most frequent determinants of organ failure previous allogeneic (allo‐HSCT) or autologous HSCT (auto‐HSCT) in requiring SOT after HSCT are the following: acute or chronic GvHD a pediatric EBMT center between 1984 and 2016 and age <18 years involving liver or lung (vanishing bile duct syndrome and bronchiolitis at the time of HSCT. Data were collected through a questionnaire obliterans [BO], severe veno‐occlusive disease, acute or chronic ne- that was sent to all EBMT pediatric centers, and included demo- phrotoxicity due to total body irradiation [TBI] or chemotherapy [ie, graphic data, type of primary diagnosis, date and type of HSCT, con- carboplatin or ifosfamide], severe restrictive pulmonary insufficiency ditioning regimens, occurrence of acute and chronic GvHD, grade secondary to TBI or chemotherapy [ie, busulfan], severe hypertrophic of GvHD, date of SOT, type of SOT, indication for SOT, presence cardiomyopathy due to high doses of anthracycline [>360 mg m ] or 2 of GvHD at the time of SOT, type of donor SOT (living or deceased cyclophosphamide [>240 mg kg] and/or TBI). 7-9 donor), immunosuppressive (IS) therapy, major complications after 16006143, 2019, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ajt.15240 by Readcube (Labtiva Inc.), Wiley Online Library on [11/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 1800 | FARACI et al. TA B L E 1 Indications for SOT in Kidney Heart Lung pediatric age Liver transplantation transplantation transplantation transplantation Extrahepatic and intrahe- Renal aplasia/ Congenital heart Cystic fibrosis patic cholestasis hypoplasia/ disease dysplasia Metabolic disorders Obstructive Coronary artery Interstitial lung uropathy disease disease Acute liver failure Focal renal Dilated left Pulmonary glomeruloscle- ventricular hypertension rosis cardiomyopathy Primary liver malignancies Chronic Restrictive Bronchiolitis glomerulone- cardiomyopathy obliterans phritis Cardiac tumor SOT, solid organ transplantation. SOT, and outcome. Two hundred forty‐nine EBMT centers were con- number represents 0.062% of the total HSCT number reported in the tacted: 78 centers (31%) filled in the questionnaire and 20 of them same time period to the EBMT registry from the centers participat- (25.6%) reported data of at least 1 child who received SOT after ing in this survey (allo‐HSCT n = 44 764 and auto‐HSCT n = 26 007; HSCT. 73% for malignant and 27% for nonmalignant diseases). Thirty‐five Overall, SOT was performed in patients affected by severe organ SOTs were performed after allo‐HSCT (0.078%) and 9 after auto‐ failure that occurred after HSCT as a consequence of: (1) acute and HSCT (0.034%). Twenty patients received liver transplantation (LTx) chronic GvHD (a‐GvHD and c‐GvHD); (2) acute and late toxicity re- (45%), 12 lung transplantation (LuTx) (27%), 6 heart transplantation lated to chemotherapy and/or radiotherapy and/or immunosuppres- (HTx) (14%), and 6 kidney transplantation (KTx) (14%). sive drugs; (3) organ dysfunction related to the underlying disease The median age at HSCT of these 44 patients was 7.2 years (range (ie, congenital kidney or liver abnormalities, organ insufficiency re- 1.8‐15.8 years), whereas it was 12.1 years (range 5.9‐22.7 years) lated to surgical procedure). at time of SOT (see also Table 2 for patient's characteristics). First, we stratified the patients based on age at the time of SOT: within children aged (1) 1‐4 years, 7 children received LTx (100%); 2.1 | Statistical analyses (2) 4‐12 years, 8 received LTx (53.3%), 4 received LuTx (26.7%), and 3 Standard demographic and baseline characteristics were summa- underwent KTx (20%); (3) 12‐18 years, 6 received LuTx (46.8%), 5 LTx rized using the number of available data, median and range (mini- (38.5%), and 2 HTx (15.4%); and (4) >18 years, 2 received HTx (50%), mum, maximum) for continuous data, and using the number and 2 KTx (25%), and 2 LuTx (25%). percentage of patients for categorical and ordinal data. P values on The median time elapsing between HSCT and SOT was 5.2 years demographic and baseline characteristic data were calculated using (range 4.08‐8.4 years), specifically 0.83 years for KTx, 1.8 years for Fisher exact test or χ2 test or Mann‐Whitney test, as appropriate. LTx, 5.9 years for LuTx, and 12.4 years for HTx. Overall survival (OS) was defined as the time elapsing between Second, we analyzed our cohort by the underlying disease re- the SOT and the date of death due to any cause. Univariate Cox pro- quiring HSCT. Twenty‐six patients (59%) received HSCT for a malig- portional hazards (PH) models were developed in order to determine nant disease: it was an acute leukemia in 14 (31.8%), a solid tumor in potential risk factors. Results of Cox‐PH models were summarized 7 (15.9%), a lymphoma in 3 (6.8%), and a myelodysplastic syndrome using hazard ratio and 95% confidence interval (CI). A P value <.05 in 2 (4.5%) patients, respectively. Eighteen children (40.9%) received was considered statistically significant, and all P values were based HSCT due to nonmalignant disorders: 14 had a primary immunode- upon 2‐tailed tests. Statistical analysis was performed using R ver- ficiency (PID, 31.8%), 3 a bone marrow failure syndrome (6.8%), and sion 3.2.3 (2015‐12‐10). 1 a sickle cell disease (SCD, 2.2%). The majority of children (65%) received a myeloablative conditioning regimen including TBI or bu- sulfan. Acute GvHD was reported in 48.5% of patients who received 3 | R E S U LT S allogeneic HSCT; it was grade III‐IV in 59% of these. Acute GvHD was the most frequent indication for SOT in LuTx recipients followed 3.1 | Patient and transplant characteristics of SOT by recipients of LTx and KTx (35% and 33%, respectively). Chronic‐ recipients GvHD was responsible for SOT in 37% of patients; the highest inci- A total of 44 SOTs following HSCT in childhood has been reported dence (83%) was observed in patients who subsequently received by 20 EBMT pediatric centers (25.6%) between 1986 and 2014. This a LuTx. 16006143, 2019, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ajt.15240 by Readcube (Labtiva Inc.), Wiley Online Library on [11/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License FARACI et al. | 1801 TA B L E 2 Characteristics of 44 patients who underwent SOT following HSCT Liver transplant Lung transplant Heart transplant Kidney transplant Total transplant N = 20 (45%) N = 12 (27%) N = 6 (14%) N = 6 (14%) N = 44 Age (y) at HSCT, median 4.7 (0.6‐15.9) 7.8 (0.9‐17.2) 7.4. (1.6‐13.3) 8.2 (4.1‐17.1) 7.2 (1.8‐15.9) (range) Age (y) at SOT, median 6.5 (1.0‐16.3) 13.7 (4.2‐20.4) 19.8 (13.1‐31.3) 9.0 (5.2‐22.7) 12.1 (5.9‐22.7) (range) Underlying disease Malignant 12 (60%) 7 (58.3%) 6 (100%) 4 (66.7%) 29 (66%) Nonmalignant 8 (40%) 5 (41.7%) 0 2 (33.3%) 15 (34%) Type of HSCT Allogeneic 16 (80%) 12 (100%) 2 (33.3%) 5 (83.3%) 35 (78%) Autologous 4 (20%) 4 (66.7%) 1 (16.7%) 9 (22%) Type of donor Related donor 7 (35%) 7 (58.3%) 2 (33.4%) 4 (66.6%) 20 (45%) Unrelated donor 9 (45%) 5 (41.7%) 0 1 (16.7%) 15 (43%) Unknown 4 (20%) 4 (66.6%) 1 (16.7%) 9 (12%) TBI Yes 4 (20%) 3 (25%) 5 (83.3%) 3 (60%) 15 (35%) No 16 (80%) 9 (75%) 1 (16.7%) 2 (40%) 28 (64%) Bus Yes 5 (25%) 7 (58.3) 1 (16.6%) 1 (16.6%) 14 (32%) No 15 (75%) 5 (41.7%) 5 (83.4%) 5 (83.4%) 30 (68%) a‐GVHD Absent 8 (50%) 4 (33.3%) 2 (100%) 3 (60%) 17 (48.5%) Grade I‐II 1 (6.3%) 5 (41.7%) 1 (20%) 7 (20%) Grade III‐IV 7 (43.7%) 2 (16.6%) 1 (20%) 10 (28.5%) Unknown 0 1 (8.3%) 1 (3%) c‐GVHD Yes 3 (18.7%) 10 (83.3%) 13 (37%) No 13 (81.3% 2 (16.7%) 2 (100%) 5 (100%) 22 (63%) a‐GvHD, acute Graft vs Host disease; Bus, busulfan; c‐GvHD, chronic‐Graft vs Host disease; HSCT, hematopoietic stem cell transplantation; SOT, solid organ transplantation; TBI, total body irradiation. TA B L E 3 Indications for SOT Indication of SOT 12 LuTx, n (%) 6 KTx, n (%) 6 HTx, n (%) 20 LTx, n (%) 44 Overall, n (%) Acute or chronic GvHD 10 (83) 0 0 6 (30) 16 (36.3) Acute or chronic toxicity 2 (16.6) 3 (50) 6 (100) 7 (35) 18 (40.9) Organ dysfunction 0 3 (50) 0 7 (35) 10 (22.8) GvHD, Graft vs Host disease; HTx, heart transplantation; KTx, kidney transplantation; LTx, liver transplantation; LuTx, lung transplantation; SOT, solid organ transplantation. of the 6 patients reported (100%), 3/6 KTx (50%), 7/20 LTx (35%), 3.2 | Indications for SOT and 2/12 LuTx (16.6%). Organ dysfunction related to the underly- Severe a‐GvHD (10%) and c‐GvHD (90%) were the primary indica- ing disease was the indication for SOT in 7 patients who received tions to perform LuTx in 10 out of 12 patients (83.3%) and in 6 out LTx (35%) (3 hepatoblastoma, 1 lymphoma, 1 bone marrow failure of 20 patients who received LTx (30% a‐GvHD and 50% c‐GvHD). syndrome, and 2 primary immunodeficiency) and in 3 who received No patients received HTx or KTx due to GvHD. Acute and long‐ KTx (50%, 1 Fanconi anemia, 1 Wiskott‐Aldrich syndrome, and 1 term HSCT therapy‐related toxicity was responsible for HTx in all SCD). Overall, the indications for SOT are summarized in Table 3. 16006143, 2019, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ajt.15240 by Readcube (Labtiva Inc.), Wiley Online Library on [11/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 1802 | FARACI et al. TA B L E 4 SOT characteristics Liver Lung Heart Kidney Total n = 20 (45%) n = 12 (27%) n = 6 (14%) n = 6 (14%) n = 44 Donor of HSCT = Donor of SOT 1 1 0 2 4 SOT source: from deceased donor 12 (60%) 1 (8%) 4 (60%) 3 (50%) 30 (68%) From living donor 6 (30%) 11 (92%) 0 3 (50%) 10 (23%) Unknown 2 (10%) 0 2 (40%) 0 4 (19%) Major complications after SOT No complications 9 (45%) 3 (25%) 3 (50.0%) 4 (66.6%) 18 (41%) Infections 0 5 (42%) 0 1 (16.6%) 6 (15%) Graft rejection 3 (15%) 2 (16.6%) 1 (16.6%) 1 (16.6%) 7 (16%) Organ failure 4 (20%) 1 (8.3%) 2 (33.3%) 0 7 (16%) Other (surgical complications) 4 (20%) 1 (8.3%) 0 0 5 (12%) IS in connection to SOT? No 0 1 0 1 2 Yes 18 11 5 5 39 Unknown 2 0 1 0 3 IS still ongoing at last follow‐up No 0 1 0 3 4 Yes 18 11 5 3 37 Unknown 2 0 1 0 3 Survival at last follow‐up Alive 13 (65%) 10 (83%) 4 (66.6%) 6 (100%) 33 (75%) Dead 7 (35%) 2 (17%) 2 (33.4%) 0 11 (25%) Age (y) at last follow‐up, median (range) 14.6 (4.0‐24.7) 17.2 (11.4‐31.3) 30.0 (21.3‐37.0) 25.1 (6.5‐44.1) Age (y) at time of death, median (range) 7.3 (1.1‐16.1) 21.5 (21.4‐1.7) 23.0 (13.1‐32.8) – HSCT, hematopoietic stem cell transplantation; IS, immunosuppression; SOT, solid organ transplantation. 3.3 | Characteristics of SOTs 3.4 | Survival after SOT The characteristics of SOTs are illustrated in Table 4. The median At the last follow‐up, patients who received KTx were all alive follow‐up of the 44 patients who received SOT was 10.9 years (100%), while patients who received LuTx, HTx, and LTx were alive in (1.7‐29.5 years; 95% CI: 1.7‐29.5). The median age at last follow‐up 83%, 66.7%, and 65% of cases, respectively. was 14.65 years (range 4.09‐24.77 years) for LTx, 17.27 years (range The OS for all patients at 1 and 5 years after SOT was 85.7% (95% 11.46‐31.36 years) for LuTx, 30.6 years (range 21.39‐37.07 years) CI, 75.8%‐97%) and 80.4% (95% CI, 69%‐93.6%), respectively. The OS for HTx, and 25.17 years (range 6.58‐44.16 years) for KTx. at 1 and 5 years after KTx and LuTx was 100% (95% CI, 100%‐100); The majority of patients (90%) received SOT from a donor dif- it was 74.7% after HTx (95% CI; 57.7%‐96.6%), and 63.2% after LTx ferent from the HSCT donor, except in 4 cases (1 LTx, 1 LuTx, and 2 (95% CI, 44.7%‐89.3%). Two patients died 5.36 years and 10.08 years KTx). Major complications following SOT were reported in 56.8% after LuTx due infection and underlying disease (PID). of patients and included organ failure in 7 (16%), infections in 6 The causes of death were original disease related (n = 7), hemor- (15%), graft failure in 7 (15.9%; in 3 associated with infections), rhages (n = 1), infection (n = 1), GvHD (n = 1), and other transplant‐re- and other complications including surgical complications in 5 pa- lated cause (n = 1). In univariate analysis, different indications for SOT, tients (11%). Rejection occurred after LTx in 3 children (15%), after such as a‐GvHD and c‐GvHD, toxicity, organ failure, organ dysfunction LuTx in 2 (16.6%), after HTx in 1 (16.6%), and after KTx in another related to underlying disease, and type of SOT donor (living or deceased 1 (16.6). Post HSCT, pharmacological IS was administered at the donor) did not impact on OS at 1 and 5 years (Table 5). Moreover, the time of SOT in 39 patients (88.6%), while 2 patients (LuTx and KTx) univariate Cox analysis of factors related to HSCT such as the stem cells did not receive any IS at the time of SOT (1 of them received SOT source, the type of the donor (autologous or allogeneic), the condition- from the same HSCT donor). In 3 cases, this information was not ing regimen, and age at HSCT did not have an impact on OS after SOT available. (Table 6). 16006143, 2019, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ajt.15240 by Readcube (Labtiva Inc.), Wiley Online Library on [11/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License FARACI et al. | 1803 TA B L E 5 Risk factors impacting on OS OS at 1 y, % OS at 5 y, % at 1 and 5 years in patients who Risk factors (95% CI) (95% CI) P value underwent SOT Reason for SOT GvHD 92.3 (78.9‐100) 84.6 (67.1‐100) .46 Underlying disease 87.5 (67.3‐100) 75 (50.3‐100) Organ failure 68.6 (44.5‐100) 68.6 (44.5‐100) pre‐HSCT Source of SOT From deceased 96.6 (90.1‐100) 92.7 (83.4‐100) .070 donor From living 78.8 (56.4‐100) 67.5 (43‐100) CI, confidence interval; GvHD, graft vs host disease; OS, overall survival; y, years; SOT, solid organ transplantation. questionnaire‐based survey, we were able to analyze data coming TA B L E 6 Univariate analysis with Cox analysis of survival of patients who underwent SOT 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 Variables HR 95% CI for HR P children who received SOT could have been underestimated, and Diagnosis: nonmalignant vs 0.17 (0.02, 1.34) .09 also some specific information regarding complications that oc- malignant curred after SOT can be missed, since only the HSCT center was Age of patients at HSCT (y) 0.99 (0.88, 1.11) .85 contacted for this survey. Furthermore, SOTs performed in chil- Age of patients at HSCT dren in adult centers might have been missed. Notwithstanding <4 y (ref) — — — these possible biases, the incidence of SOT (0.062%) in this pedi- <4‐11 y 1.11 (0.28, 4.38) .88 atric survey is similar to the incidence of SOT (0.067%) reported in >2 y 0.47 (0.05, 4.50) .51 the recent EBMT published survey combining adult and pediatric Age of patient at SOT 0.97 (0.89, 1.06) .55 data.10 In our cohort, the most frequent indications for SOT were acute Age of patient at SOT or chronic HSCT‐related toxicity (40.9%), followed by a‐GvHD and <4 y (ref) — — — c‐GvHD (36.3%), and organ dysfunction related to the underlying <4‐11 y 0.93 (0.18, 4.79) .93 disease (22.8%). <12‐17 y 0.81 (0.13, 4.92) .82 The indications for SOT collected in this survey were similar >18 y 0.33 (0.03, 3.66) .37 to those reported in the previous EBMT survey.10 In particular, Sex: female vs male 1.39 (0.37, 5.27) .63 GvHD and acute and chronic toxicity represented the most fre- Type of HSCT: auto‐HSCT 2.07 (0.60, 7.20) .25 quent indications for SOT as shown by the current study.10 Lungs vs allo‐HSCT and liver represent the organs more frequently transplanted in Interval between HSCT and 0.94 (0.80, 1.11) .49 the presence of intractable acute or chronic GvHD (83.3% and SOT (y) 30%, respectively), and the majority of patients were already Conditioning regimen under IS therapies at time of SOT. While the indication for LuTx TBI based (ref) — — — was represented by BO/c‐GvHD (83.3%), an isolated and very Bu based 0.64 (0.11, 3.60) .61 often IS‐resistant complication that leads to irreversible respi- Nonmyeloablative regimen 1.56 (0.37, 6.61) .54 ratory failure, acute or chronic GvHD represented more rare in- Stem cell sources: PBSC vs 2.78 (0.49, 15.66) .25 dications for LTx (30% and 50%, respectively). Of interest, the BM frequency of complications after LTx was lower than that re- Donor: AD vs RD 1.77 (0.39, 7.95) .46 ported after LuTx (55% vs 75%); by contrast, LTx recipients appear AD, alternative donor; Bu, busulfan; BM, bone marrow; CI, confidence to be at increased risk of severe and irreversible complications, interval; HR, hazard ratio; HSCT, hematopoietic stem cell transplanta- with a mortality rate more than double when compared to LuTx tion; PBSC, peripheral blood stem cells; RD, related donor; SOT, solid recipients (35% vs 17%). Moreover, the median interval between organ transplantation; TBI, total body irradiation; y, years. 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 4 | D I S CU S S I O N immunocompromised recipients and thus at increased risk of complications. The main difference between our survey and the The purpose of this study was to retrospectively collect data on one already published is represented by the more frequent use the outcome of pediatric patients receiving SOT after a previous of SOT due to organ dysfunction related to underlying disease in either auto‐ or allo‐HSCT. After reviewing data obtained through a the pediatric cohort (22.8 vs 4.4%). This result could be explained 16006143, 2019, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ajt.15240 by Readcube (Labtiva Inc.), Wiley Online Library on [11/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 1804 | FARACI et al. by the highest number of patients transplanted for nonmalignant eligibility for a post‐HSCT SOT and for establishing an appropriate diseases in the pediatric group in comparison to the adult one. follow‐up. Our study shows that OS of all children at 5 years was 80.4% In conclusion, our study shows that SOT after either auto‐ or (95% CI, 69%‐93.6%), similar to the OS of 78% (95% CI, 64%‐92%) allo‐HSCT is a feasible therapeutic option in pediatric patients. A reported in the recent EBMT survey, which included both chil- close collaboration with the SOT team will improve the definition of 10 dren and adults. A review of the literature on pediatric patients the eligibility criteria and the appropriate timing for SOT in pediatric who received SOT without a previous HSCT showed that OS at HSCT recipients. 5 years is 97% for KTx, 4 80% for HTx 5 and LTx, 3 and from 49% 18 to 61%19 for LuTx. In the present study, in comparison with pub- D I S C LO S U R E lished 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 The authors of this manuscript have no conflicts of interest to dis- that received LTx (63.2% vs 80%), while it was similar for HTx‐ close as described by the American Journal of Transplantation. 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 ORCID compared to those included in the large cohort study reported by Maura Faraci https://orcid.org/0000-0001-5715-501X 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% REFERENCES at 5 years to 44% at 10 years, whereas in our population, OS after 1. Merrill JP, Murray JE, Harrison JH, et al. Successful homotrans- LuTx started to decrease after 10 years, suggesting a potential plantation of the human kidney between identical twins. JAMA. role of HSCT as a tool of immune tolerance for SOT. 21 1956;160:277. The complications that occurred after SOT included failure of 2. Kim JJ, Marks SD. 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