REGULAR ARTICLE Outcomes of subsequent neoplasms after umbilical cord blood transplantation in Europe Hanadi Rafii,1,2 Annalisa Ruggeri,1,3 Chantal Kenzey,1,2 Jaime Sanz,4 Régis Peffault De La Tour,5 Albert Esquirol,6 Gérard Michel,7 Patrice Chevallier,8 Marie-Thérèse Rubio,9 Jan J. Cornelissen,10 Mauricette Michallet,11 Fernanda Volt,1,2 Monica M. Rivera-Franco,1,2 Graziana Maria Scigliuolo,1,2 Barbara Cappelli,1,2 Vanderson Rocha,1,12 and Eliane Gluckman1,2 ˇ 1 Eurocord, Hopital Saint Louis, Assistance Publique–Hopitaux de Paris, Institut de Recherche de Saint-Louis (IRSL) EA3518, Université de Paris-Cité, Paris, France; 2 Monacord, Centre Scientifique de Monaco, Monaco, Monaco; 3 Haematology and Bone Marrow Transplant Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; 4 Department of ˇ Hematology, Hospital Universitario La Fe, Valencia, Spain; 5 Bone Marrow Transplant Unit, Saint Louis Hospital, Assistance Publique–Hopitaux de Paris, Paris, France; 6 Hematology Department, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau and Jose Carreras Leukemia Research Institutes, Universitat Autonoma of Barcelona, Barcelona, Spain; 7 Department of Hematology, Hopital pédiatrique de la Timone, Marseille, France; 8 Department of Hematology, Hospital Hotel Dieu, Nantes, France; 9 Department of Hematology, CHRU Nancy, Nancy, France; 10 Department of Hematology, Erasmus MC-Daniel den Hoed Cancer Centre, Rotterdam, The Netherlands; 11 Department of Hematology and Oncology, Centre Leon Berard, Lyon, France; and 12 Department of Hematology, Clinics Hospital, São Paulo Medical School, São Paulo, Brazil Subsequent neoplasms (SNs) compromise long-term survivors after hematopoietic cell Key Points transplantation. We performed a retrospective analysis of SNs in 10 358 recipients • Subsequent of umbilical cord blood transplantation (UCBT) from 1988 to 2018. SNs developed in neoplasms observed in 233 patients and 84 were of pediatric age. Indications for UCBT were malignant recipients of umbilical hematological diseases in 199 patients (85%). Three groups of SNs were observed. cord blood Posttransplant lymphoproliferative disorders (PTLD) were reported in 145 patients in a transplantation are median of 4 months after UCBT. Of these, 9 patients died from relapse, 83 from PTLD, and 24 rare, although associated with poor from transplant-related causes. At last follow-up, 29 were alive; 5-year overall survival (OS) survival. after PTLD diagnosis was 21%. Acute leukemia/myelodysplasia (AL/MDS) was diagnosed in 23 patients in a median of 28 months after UCBT and included 3 donor-cell AL. Four of 23 • Determining risk patients died from relapse of primary disease, 8 from progression of SNs, and 4 from TRM. factors and lifelong Seven patients remain alive; the 5-year OS after AL/MDS diagnosis was 36%. Solid tumors screening for early detection of (ST) were reported in 65 patients in a median of 54 months after UCBT. Most common tumor subsequent neoplasms sites were lung, thyroid, bone, and soft tissue. A total of 33 patients died (26 owing to ST, 6 to are mandatory to relapse of primary disease, and 1 cause missing). At last follow-up, 32 of 65 patients were improve survival. alive; the 5-year OS after the diagnosis of ST was 51%. In conclusion, despite their poor outcomes, SNs that occur after UCBT are extremely rare. Identification of risk factors and early detection may help to improve OS. Introduction Long-term survivors after hematopoietic cell transplantation (HCT) are at higher risk for developing subsequent neoplasms (SNs), with a twofold to fivefold increased risk compared with their age-matched controls.1 The cumulative incidence (CI) of SNs continues to increase with longer follow-up Submitted 25 April 2022; accepted 14 October 2022; prepublished online © 2023 by The American Society of Hematology. Licensed under Creative Commons on Blood Advances First Edition 9 November 2022. https://doi.org/10.1182/ Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), bloodadvances.2022007941. permitting only noncommercial, nonderivative use with attribution. All other rights Data are available on request from the corresponding author, Hanadi Rafii (hanadi.rafii- reserved. elayoubi@aphp.fr). 1976 23 MAY 2023 • VOLUME 7, NUMBER 10 after transplantation with no apparent plateau, and it is estimated to and pathology reports were reviewed to confirm the diagnosis of be 1% to 6% and 2% to 15% at 10 and 15 years after HCT, SN and exclude relapse. respectively.1 These malignant posttransplant complications are the All patients or their legal guardians provided informed consent result of the interactions of a large panel of transplant-related factors according to the Declaration of Helsinki to use transplantation (conditioning regimen, T-cell depletion, antithymocyte globulin [ATG] data for research purposes. The Institutional Review Board of administration, graft-versus-host disease [GVHD] immunosuppres- EBMT/Eurocord approved this study. sion [IS], infections, among others), patient-related factors (recipient age, gender, genetic predisposition, lifestyle aspects), and disease- End points related factors (disease type, disease stage, pretransplant treatment).2,3 The primary end point was OS, calculated from the date of diag- nosis of the SNs until death or last follow-up for survivors. Sec- Malignant complications in posttransplant patients can be stratified ondary end points included the description of the subtypes of SNs into 3 groups: posttransplant lymphoproliferative disorders (PTLD), occurring after UCBT and their associated risk factors and the acute leukemia/myelodysplasia (AL/MDS, recipient cell–derived, or evaluation of all causes of death. donor cell–derived), and solid tumors (ST). Statistical analysis The time of occurrence after HCT varies according to the type of SNs: PTLD peaks in the first year after transplant, AL/MDS occurs, Median values and ranges (or interquartile ranges [IQR]) were used usually, between 1 and 4 years after transplant, and ST starts to for numerical variables and frequencies and percentages for cate- develop around 5 years after transplant, increasing in incidence gorical variables. Time to diagnosis of SNs was calculated as the time with longer survival.1,4 interval between UCBT and the occurrence of SNs. The probabilities of OS from the diagnosis of SNs were determined using Kaplan-Meier Reported incidences of SNs after HCT are based largely on estimates and the log-rank test for bivariate comparisons. For patients registry data and show no difference according to donor type or who developed more than 1 SN after HCT, the outcome was degree of HLA matching. The prognosis is poor as SN-related assessed considering the first diagnosis. SPSS and R software death is observed, respectively, in 25% and 15% of adult packages were used for the statistical analyses. recipients of allogeneic and autologous transplants who survived at least 5 years after the procedure.5 However, published studies assessing the incidence of SNs after umbilical cord Results blood transplantation (UCBT) and characterizing their outcomes Patients, disease, and transplant characteristics are scarce.6-10 Between October 1988 (date of the first UCBT) and December The objective of the present study is to provide a general overview 2018, 10 358 eligible patients received their first UCBT in 311 and highlight the outcomes of SNs in UCB recipients transplanted EBMT-affiliated centers. Among these recipients, 233 (123 males and in European Group for Blood and Marrow Transplantation (EBMT) 110 females) developed SNs (2.2%). The median age at UCBT was affiliated centers over the last 3 decades. The findings of this study 31 years (range, 0.3-69), and 84 (36%) were pediatric patients. Pri- will help to better characterize the impact of SNs on overall survival mary diagnoses were 83% malignant (n = 199) and 15% (n = 34) (OS) after UCBT. nonmalignant hematological diseases. Myeloablative (MAC) regimens were administered in 54% (n = 126), and ATG in 67% (n = 157) of the UCBT recipients. Fifty-one percent (n = 118) of the patients Patients and methods received total body irradiation (TBI) as part of their conditioning with Study design and definitions either low doses (≤8 Gy; 70/118) or high doses (>8 Gy; 48/118) regimen. Graft sources included single (n = 154), single-expanded We performed a retrospective analysis of SNs in a cohort of (n = 2), and double (n=77) UCB. All patients received unrelated 10 358 UCBT recipients reported to Eurocord/EBMT registries UCB grafts. The median cell dose at cryopreservation was 4.7 × from 6 October 1988 to 31 December 2018. Eligible graft sources 107/kg (IQR, 3.6-6.3) of total nucleated cells and 1.9 × 105/kg (IQR, were single, double, and expanded UCB units. We excluded 1.3-3.1) of CD34+ cells. Graft-recipient pairs had 0 to 1/6 HLA transplants with UCB coinfused with adult-donor grafts. We also mismatch in 47%, and they had 2/6 and 3/6 HLA mismatches in 39% excluded patients with primary diagnosis of nonmalignant disease and 3% of the cases, respectively. UCBTs analyzed in this study were known to increase the risk of developing malignancies (Fanconi performed in 101 transplant centers. Patients, primary disease, and anemia and Blackfan-Diamond anemia). graft characteristics are summarized in Tables 1 and 2. HLA disparity was calculated based on the number of mismatches between the patient and the UCB for single UCBT, considering SNs characteristics the HLA antigen level for HLA-A and HLA-B and the allele level Three main subgroups of SNs were identified (Table 3): post- for HLA-DRB1, and based on the UCB with the worst match with transplant lymphoproliferative disorders (PTLD, n = 145, 62%), the recipient for double UCBT (dUCBT). Conditioning regimen AL/MDS (n = 23, 10%), and STs (n = 65 patients, 28%, who intensity was defined according to the current EBMT criteria.11 The developed 72 STs). diagnosis and grading of acute12 and chronic13 GVHD were per- formed by transplant centers using standard published criteria. Posttransplant lymphoproliferative disorders Data were based on transplant center reports. Centers were A total of 145 patients (56 children and 89 adults) developed contacted to complete missing data when needed. Cytogenetic PTLD in a median of 3.7 months (range, 0.8-67; IQR, 2-7) 23 MAY 2023 • VOLUME 7, NUMBER 10 SUBSEQUENT NEOPLASMS AFTER CORD BLOOD TRANSPLANTS 1977 Table 1. Patient and disease characteristics Table 2. Graft characteristics Number of patients, N (%) 233 (100%) Number of patients, N 233 Median age at diagnosis of primary disease, y (range) 28 (0.1-68) Median transplant year (range) 2009 (1992-2020) Median age at UCBT, y (range) 31 (0.3-69) Transplant period, n (%) Children (<18 y), n (%) 84 (36) 1988-2000 15 (6%) Adults (≥18 y), n (%) 149 (64) 2001-2005 32 (14%) Median age at diagnosis of SN, y (range) 32.4 (1-73) 2006-2010 110 (47%) Median age at last follow-up, y (range) 36.2 (1.6-75.4) 2011-2015 68 (29%) Males, n (%) 123 (53) ≥2016 8 (3%) Positive recipient CMV serology, n (%) 120 (52) Graft type, n (%) Type of primary disease, n (%) Unrelated UCB 233 (100%) Nonmalignant 34 (15) Graft source, n (%) Malignant 199 (83) Single UCB unmanipulated 147 (63%) Primary diagnosis, n (%) Single UCB expanded 2 (1%) Acute leukemia 121 (52) Double UCB 77 (33%) MDS/MPD 32 (14) Intrabone injection of 1 of the UCB 7 (3%) Lymphoproliferative disorders 45 (19) HLA mismatch, n (%) Histiocytic disorder 3 (1) 0-1/6 109 (47%) ST 1 (<1) 2/6 90 (39%) BM failure syndrome 13 (6) 3/6 7 (3%) Hemoglobinopathy 3 (1) Missing 27 (11%) Primary immune deficiency 7 (3) Cell dose, median (IQR) Inborn error of metabolism 8 (4) Median TNC at cryopreservation (×107/kg) 4.7 (3.6-6.3) Previous HCT, n (%) 52 (22) Median CD34+ cell at cryopreservation (×105/kg) 1.9 (1.3-3.1) MAC, n (%) 126 (54%) TNC, total nucleated cells. ATG, n (%) 157 (67) TBI, n (%) 118 (51) CMV, cytomegalovirus; MDS/MPD, myelodysplastic/myeloproliferative disease. causes of death were PTLD (n = 73), relapse of primary disease (n = 9), nonrelapse mortality (n = 20 [9 GVHD, 9 infections, 1 idiopathic pneumonia, 1 hemorrhage]), and 1 cause unknown. A total of 15 patients developed PTLD 1 year after UCBT; 9 of the after UCBT. Fifteen of the PTLD cases occurred after 1 year 15 had received ATG before transplant, and 8 of the15 had after transplant, including 1 late-onset Hodgkin lymphoma (HL). received heavy and prolonged IS therapy for aGVHD (n = 4) and/or The median age at UCBT was 26 (0.3-68) years (Table 3) cGVHD (n = 6). PTLD was not treated with rituximab in 4 of Primary disease was hematological malignancy in 116 patients 15 patients (2 who developed PTLD before year 2000, 1 who died (80%). Eighty-one patients (56%) had received a minimum of before initiation of rituximab and 1 HL); only 2 of 15 patients sur- 2 lines of therapy before UCBT and 34 (23%) had undergone a vived regardless of PTLD treatment with rituximab ± chemotherapy. previous autologous or/and allogeneic transplant (1 patient The causes of death were PTLD (n = 10), infection (n = 2), and had previous auto + alloHCT). Eighty-five patients (59%) gastrointestinal (GI) bleeding (n = 1). had received MAC regimens, 65 patients (45%) TBI (36 patients with doses ≤8 Gy, 29 patients with doses 10-14 Gy), and At last follow-up, 29 of 145 patients with PTLD were alive; the 117 patients (81%) had received ATG or alemtuzumab. One to probability of 5-year survival after the diagnosis of PTLD was 3 alkylating agents had been administered as part of the con- 21% ± 3%. (Figure 1) ditioning regimens in 135 patients (93%) and fludarabine in One case of late-onset HL, diagnosed 3 years after dUCBT, was 99 patients (68%). Fifty-eight (40%) of the graft-recipient pairs reported in our cohort in a male patient with primary acute myeloid had 2/6 HLA mismatches (Table 4). Before PTLD diagnosis, 39 leukemia (AML) in second complete remission. The patient had and 48 patients had developed acute GVHD (aGVHD) and positive pretransplant Epstein-Barr virus (EBV) serology. Condi- chronic GVHD (cGVHD) (23 extensive), respectively. tioning regimen included fludarabine, cyclophosphamide, and low- PTLD occurred within the first year post-UCBT in 130 recipients. dose (2 Gy) TBI with no ATG administration. Prolonged IS was From those, 105 had received ATG and 56 had received used because of the development of chronic GVHD. HL was prolonged IS to treat their aGVHD II-IV (n = 31) and/or cGVHD treated with appropriate chemotherapy. The patient was in com- (n = 40); 14 of the 130 did not receive rituximab to treat the PTLD plete remission of both the leukemia and the lymphoma when he (6 were diagnosed before year the 2000 and 8 died before ritux- died from a nonhematological cause (GI bleeding), 3.5 years after imab administration). A total of 103 of the 130 patients died; the the diagnosis of the SNs. 1978 RAFII et al 23 MAY 2023 • VOLUME 7, NUMBER 10 Table 3. Subtypes of SNs PTLD AL/MDS ST* Patients with SNs, n (%) 145 100% 23 100% 65* 100% Transplant period 1988-2000 8 6 1 5 6 9 2001-2005 19 13 8 35 5 8 2006-2010 66 45 9 39 35 54 2011-2015 46 32 4 17 18 28 ≥2016 6 4 1 4 1 1 Median age at UCBT, y (range) 26 (0.3-68) 23 (1-62) 50 (0.5-67) Age <18 56 39 10 43 18 28 Age ≥18 89 61 13 57 47 72 Median interval (UCBT-SN), mo (IQR) 3.7 (2-7) 28 (16-54) 54 (30-83) Nonmalignant diseases 29 20 2 9 3 5 Malignant diseases 116 80 21 91 62 95 MAC 85 59 12 52 29 45 TBI 65 45 10 43 43 66 ATG 114 79 12 52 31 48 Alemtuzumab 3 2 3 13 1 2 Recipient EBV-seropositivity 82 57 12 52 34 52 Collected TNC at cryopreservation (×107/kg), 4.5 3.5-6.0 5.0 3.4-7.3 5.1 4.3-6.4 median (IQR) HLA disparity, n (%) 0/6 MM 18 12 1 4 8 12 1/6 MM 55 38 7 30 20 31 2/6 MM 55 38 9 39 26 40 3/6 MM 3 2 3 13 1 2 Missing 14 10 3 13 10 15 Survivors, n 29 7 32 Median follow-up for survivors after UCBT, mo 96 7-225 72 29-161 125 55-292 Median follow-up for survivors after SN, mo 92 5-223 35 16-110 58 14-179 MM, mismatch; TNC, total nucleated cell. *Seven patients developed 2 STs, which corresponded to a total of 72 ST reported. Acute leukemia/myelodysplasia and cGVHD were observed in 6 and 3 recipients, respectively. Twelve subsequent allogeneic transplants were performed in AL/MDS was observed in 23 patients within a median of 12 UCBT recipients to treat AL/MDS (n = 7), graft failure (n = 1), 28 months (range, 8-103; IQR, 16-54) after UCBT, including or relapse (n = 4). Sixteen patients died; the causes of death were 12 with AML, 3 with donor-cell AML, 3 with acute lymphoblastic relapse of primary disease (n = 4), progression of the SN (n = 8), leukemia (ALL), and 5 with MDS (Tables 3 and 5). The median GVHD (n = 2), and infections (n = 2). At last follow-up, only recipient age at UCBT was 23 years (range, 1-62). Twenty-one 7 patients were alive (6 after a second allogeneic HCT). The 5-year patients (91%) had been transplanted for malignant diseases survival probability after the diagnosis of AL/MDS was 36% ± (ALL [n = 9], AML [n = 3], myeloproliferative diseases [n = 3], and 10%. (Figure 1) lymphoma [n = 6]), 1 patient for bone marrow (BM) failure and 1 patient for thalassemia. Fifteen patients had received a minimum Donor-cell myeloid leukemia was observed in 3 patients (primary of 2 treatment lines before UCBT, and 5 had received previous diagnosis: ALL [n = 2] and chronic myeloid leukemia [CML, n=1]) autologous or/and allogeneic HCT. (Tables 3 and 4) Twelve in a median of 20 months (range, 17-22) post-UCBT. Two patients patients had received MAC regimens, 10 patients had received TBI had received MAC regimens, and all 3 had received fludarabine. (7 patients with doses ≤8 Gy, 3 patients with doses >8 Gy), and ATG had been administered in 1, alemtuzumab in 1, and colony- 15 patients ATG or alemtuzumab. Alkylating agents had been stimulating factors in 2 of the 3 patients who developed donor- administered to all the patients as part of the conditioning regimen, cell AML. The donor origin of the leukemia was confirmed by and fludarabine was used in 15 patients. The UCB unit had ≥2/6 recipient/donor sex mismatch (n = 2) or molecular (n = 1) studies. HLA mismatches with the recipients in 12 patients. Acute GVHD A new allogeneic HCT (mismatched unrelated donor transplant) 23 MAY 2023 • VOLUME 7, NUMBER 10 SUBSEQUENT NEOPLASMS AFTER CORD BLOOD TRANSPLANTS 1979 Table 4. Risk factors for SNs skin (n = 7 basal cell carcinoma and n = 5 nonbasal cell carci- PTLD AL/MDS STs noma), oral cavity (n = 6), and breast (n = 5), in addition to other (N = 145) (N = 23) (N = 65) less common cancer sites (n = 14) (Table 5). Forty-eight (74%) n % n % n % patients had been heavily treated with at least 2 treatment lines ATG 114 79 12 52 31 48 before UCBT, including previous autologous or/and allogeneic transplants in 13 patients (20%) (Tables 3 and 4). Twenty-nine Alemtuzumab 3 1 3 13 1 2 patients (45%) had received MAC regimens, 43 patients (66%) ≥2/6 HLA mismatches 58 40 12 52 27 42 had received TBI (27 patients with doses ≤ 8 Gy, 16 patients with aGVHD II-IV 38 26 6 26 24 37 doses > 8 Gy), and 32 patients (49%) ATG or alemtuzumab. cGVHD 48 33 3 13 26 40 Alkylating agents had been administered to 62 patients (95%) and TBI 65 45 10 43 43 66 fludarabine to 50 patients (77%). Recipients and graft pairs had ≥2/6 HLA mismatches in 42% of cases. Acute GVHD had 2-8 Gys 36 7 27 developed in 37% (n = 24) and cGVHD in 40% (n = 26) of the 10-14 Gys 29 3 16 Previous autoHCT 25 17 4 17 12 18 Table 5. Types of SNs Previous alloHCT 10 7 1 4 1 2 PTLD N = 145 New alloHCT after UCBT 16 4 12 52 2 3 Early PTLD 130 Previous therapy lines ≥ 2 81 56 15 65 48 74 Late PTLD 15 Conditioning regimen AL/MDS N = 23 RIC 60 41 11 48 36 55 ALL 3 No alkylating agent 10 7 0 0 3 4 AML 12 One alkylating agent 72 50 14 61 44 68 Donor-derived AML 3 Two alkylating agents 59 41 8 35 18 28 MDS 5 Three alkylating agents 4 2 1 4 0 0 STs N = 72* Fludarabine 99 68 15 65 50 77 Lung 10 Thyroid 8 Bone sarcoma 1 was performed in 1 patient. All 3 patients died in a median of 1.25 months (range, 0.5-8.4) owing to the progression of the Soft tissue sarcoma 6 donor-cell AML. Oral cavity 3 Upper GI 2 Solid tumors Colorectal 3 Sixty-five patients developed 72 ST (7 patients with 2 ST) in a Skin (BCC) 4 median of 4.5 years (range, 4 months-14 years; IQR, 2.5-7 years) Skin (non-BCC) 4 after transplantation (Table 3). The median age was 50 years Breast 3 (range, 0.5-67) at UCBT. The most frequent tumors were lung (n = 11), bone and soft tissue (n = 8), thyroid (n = 9), GI (n = 7), Cervix 2 Kidney 2 Bladder 2 CNS 1 100 Neuroendocrine 1 Pancreas 1 80 Probability of survival (%) Parotide 1 Prostate 1 60 5y–OS after ST = 51±6% Other ST 3 Breast + skin (BCC) 1+1 40 Breast + skin (non-BCC) 1+1 5y–OS after AL/MDS = 36±10% Lung + skin (BCC) 1+1 20 5y–OS after PTLD = 21±3% Thyroid + bone sarcoma 1+1 P < .001 CNS+ colorectal 1+1 0 0 5 10 15 Upper GI + CNS 1+1 Years after subsequent neoplasm Neuroendocrine + skin (BCC) 1+1 BCC, basal cell carcinoma; CNS, central nervous system. Figure 1. Survival after diagnosis of SN: 5-year OS after diagnosis of PTLD *Seven patients developed 2 STs, which corresponded to a total of 72 ST reported. (21% ± 3%), AL/MDS (36% ± 10%), and STs (51% ± 6%). 1980 RAFII et al 23 MAY 2023 • VOLUME 7, NUMBER 10 recipients. Two patients had received a new allogeneic transplant onset (>2.5 years) with a relatively good prognosis if treated with before the development of ST because of graft failure (n = 1) or appropriate chemotherapy, which is in agreement with the case relapse (n=1) of primary disease. The median length of follow-up observed in our study.20-22 since UCBT was 7.6 years (range, 1-24) for the patients who PTLD is frequently attributed to EBV–induced B-cell proliferation of developed STs and 10 years (4.5-24) for those who survived with a donor cells in the immune-compromised host.18,19,23 UCB grafts ST. A total of 33 (51%) patients died with an ST diagnosis; 26 are characterized by EBV serological negativity, which may explain deaths were consequent to ST, 6 to relapse of primary disease, and the higher susceptibility to posttransplant EBV reactivation/infec- 1 cause of death was missing. Overall, half of the ST cases (n = 32; tion in UCBT recipients in the absence of anti-EBV immunity pro- 49%) were alive at the last follow-up. The 5-year probability of sur- vided by the donor.6,8 Although EBV serology was not available in vival after the diagnosis of ST was 51% ± 6%. (Figure 1), with a 34% of the recipients, 82 out of the 145 patients (57%) who median follow-up for survivors of 4.8 years (range,1-15) after diag- developed PTLD had positive EBV serology and were at risk of nosis of ST. posttransplant EBV reactivation. The median length of follow-up since UCBT was 26 months (1-292) In the literature, the incidence of PTLD after unrelated UCBT is in our cohort of 233 patients. Overall, 68 patients (29%) were alive 2.6% to 3.3% after MAC and 7% to 12.9% after reduced intensity at last follow-up, with a median follow-up for survivors since UCBT of conditioning (RIC) transplants,6,21 but higher rates (17%-21%) 104 (6.8-292) months (96 months for PTLD, 72 months for have been reported in UCBT with multiple risk factors, such as the AL/MDS, and 125 months for ST). There was no difference in association of ATG + RIC,6,7,24-27 and/or the use of dUCBT.24 median length of follow-up of survivors after UCBT based on TBI In our cohort, the incidence of PTLD was as low as 1.4% (145/ exposure (107 months for TBI vs 103 months for no TBI), cGVHD 10 358) despite the increased use of RIC over the last decade. (107 months for cGVH vs 103 months for no cGVH), or ATG This low incidence compares favorably with the incidence reported administration (106 months for ATG vs 103 months for no ATG). after matched and mismatched sibling donors (1.16%-2.86%) or matched unrelated (3.97%) and mismatched unrelated donor HCT Discussion (11.24%).28,29 Because of improved outcomes after UCBT over the last few PTLD occurring after UCBT, Ballen et al8 reported 68% mortality in decades and longer survival, late complications, including SNs, a small cohort of UCBT and a German group reported 82% have been reported in UCB recipients with associated late post- mortality in the patients who developed PTLD.17 In our patients, we transplant mortality. There is a paucity of studies addressing the also observed poor response to rituximab therapy when adminis- risk of SNs after UCBT, and data related to SNs in long-term tered and frequent relapse/progression even when chemotherapy survivors after this procedure are scarce. Few observational was given. The mortality rate after diagnosis of PTLD was 80% studies6-8,14,15 reported the occurrence of SNs after UCBT but the (116/145); PTLD was the main cause of death in most (72%) sample sizes were too narrow to allow risk comparison with patients, and many PTLD diagnoses were made in the perimortem transplants using adult donor grafts. period. In this large cohort of 10 358 patients who received UCBT in EBMT Overall, PTLD had a low occurrence rate in UCBT recipients but centers, 233 developed SNs; no major differences within tumor resulted in increased mortality, with a 5-year survival rate of 21%. types were observed compared with those reported after transplants This poor survival coincides with the results of Uhlin et al,30 who using other graft sources.7,8,16,17 PTLD was mainly diagnosed dur- reported a 3-year survival rate of 20% in patients developing PTLD ing the first year, AL/MDS after 1 to 2 years, and ST occurred later in after allogeneic HCT, despite initial successful treatment with rit- the course of follow-up. Risk factors included previous exposure uximab. However, new available and up-and-coming strategies to alkylating agents, TBI (both low-doses ≤8 Gy and high-doses (EBV-specific cytotoxic T lymphocytes,31 genetically engineered >8 Gy), ATG, and multiple lines of previous therapy (including cytotoxic T lymphocytes,32 etc) might transform the therapeutic HCT). The prolonged IS in the context of acute and chronic GVHD approach to PTLD in the near future with promising results and was also a critical risk factor. (Table 4) Outcomes were poor for all favorable toxicity profiles. 3 SNs subtypes with an overall mortality rate of 71% (165/233). SN AL/MDS occurring after allogeneic HCT is usually of myeloid origin was the primary cause of death in 71% of the patients who died with in 90% of cases. It represents a serious complication of cytotoxic a SN diagnosis. Similar results were published by the EBMT,7 the therapy and a leading cause of nonrelapse posttransplant mortality. CIBMTR,16 and in other smaller series.8,17 It occurs in heavily pretreated patients, it is more frequently PTLD was the most commonly reported SN in our study and was described in the autologous setting,27,33,34 and is rather related to observed mainly in the first year after UCBT, likely owing to pretransplant factors than the transplant itself.35 The incidence rate abnormal lymphoid proliferation of B cells in the absence of of AL/MDS was 0.22% in our study, consistent with data reported effective T cells or other immune regulation of B cells. The inci- after adult HCT using BM or peripheral blood (PB) grafts dence of PTLD substantially declined 2 years after UCBT, and no (<0.25%). AL/MDS developed between 1.5 and 4 years post- cases were reported after the third posttransplant year. Late PTLD UCBT, in a median of 2 years. Potential risk factors were previ- represents a distinct entity associated with GVHD,18,19 and was ous exposure to alkylating agents, fludarabine, radiotherapy, and reported in 15 patients after the first transplant year, in the context previous autologous (n = 4) or allogeneic (n = 1) HCT in line with of prolonged IS. One case of HL was observed 3 years after published series.36,37 The prognosis was poor, with a death rate of dUCBT in the context of prolonged, extensive GVHD. HL has been 69% (16/23), and a better chance to survive if a second allogeneic described as a type of PTLD characterized by late posttransplant HCT was performed. Among the 7 patients who were alive at the 23 MAY 2023 • VOLUME 7, NUMBER 10 SUBSEQUENT NEOPLASMS AFTER CORD BLOOD TRANSPLANTS 1981 last follow-up in our study, 6 had received a new allogeneic HCT ST was the primary cause of death in 78% (26/33) of the patients after the diagnosis of AL/MDS. who died with an ST diagnosis in our study. Similar death rates attributed to ST were reported in the EBMT62,63 and the Donor-cell–derived AL/MDS is a rare entity.38,39 In the context of CIBMTR55,56 registries. In a recent EBMT cohort, Tichelli et al63 our registry data, we observed an incidence of 0.03% (3/10358). reported a 5-year OS after ST of 47%; ST was the primary This incidence was lower than that reported in other UCBT series8; cause of death in 74.8% of patients. In the CIBMTR55 cohort, ST it was also lower than the incidence (<0.25%) after adult donor was the reported cause of death in 63% of patients who died with HCT.9,40-45 A previous EBMT survey estimated the incidence to be an ST diagnosis. Finally, ST was the cause of late mortality in 86% 0.12% after HCT.46 However, the true incidence of donor-cell in a large cohort of Japanese HCT recipients.57 leukemia after UCB or adult donor transplantation is unknown and probably underreported because chimerism or cytogenetic The 5-year OS after ST was 51% in our cohort, with 34% patients studies are not routinely performed after HCT to search for donor surviving less than 1 year after the ST diagnosis. However, half of origin to distinguish donor-cell AL/MDS from relapsed AML.8,47-49 the patients with an ST diagnosis survived, highlighting the In our cohort, all 3 patients with donor-cell leukemia died in a importance of strategies to promote lifelong surveillance of UCBT median of 1.2 months (range, 0.5-8.4) after diagnosis because of recipients.64 progression, despite salvage treatment with a new allogeneic HCT We acknowledge that our study has several limitations, mainly in 2 patients. Data were not available about the occurrence of because of its retrospective nature and registry-based data leukemia in the UCB donors. The pathogenesis of secondary reporting. In patients who developed PTLD, many data related to donor-cell leukemia remains unclear. The role of conditioning reg- pretransplant treatment regimens and exposures, the EBV sero- imens is less important as donor cells are not exposed to chemo- logical status of many recipients, the centers’ strategy for EBV therapy. The possible presence of preleukemic clones in up to 5% screening (as recommended by current best practice), the EBV of UCB units have been postulated,50 as well as the use of colony- viral load at PTLD diagnosis, and rituximab administration were stimulating factors that might foster preleukemic mutations, as missing. described in patients with aplastic anemia.51-53 Finally, an underreported incidence of ST in this population might be ST was observed in 65 patients who survived >2 years after UCBT. speculated owing to a possible loss of contact between long-term In our population of 10 358 UCBT recipients, 18 patients, 43 survivors and the transplant centers, considering the long time patients, and 58 patients developed ST at 5, 10, and 15 years after period between UCBT and the time that might take for the devel- transplant, respectively, which corresponded to an incidence rate opment of a ST. We lacked detailed information specific to the ST, of subsequent STs of 0.17% at 5 years, 0.42% at 10 years, and namely their stage and treatment. We also exclusively included in the 0.56% at 15 years, with increasing cumulative rates as per longer study the patients who reported having developed SNs, therefore, follow-up. Nevertheless, the incidence of STs after UCBT in our making it impossible to assess risk or perform comparisons using study was relatively low compared with that reported after BM or advanced statistical (univariate and multivariate) analyses to identify PB grafts in other registry-based studies.52-54 The CIBMTR variables that contribute to the development of SN. reported a large cohort55 of allogeneic sibling BM recipients transplanted between 1964 and 1994, mostly after TBI-based Similarly, the incidences for the SNs reported in our cohort might MAC regimen (>70%). The CI of subsequent ST was 2.2% at be underestimated because of the assumption that recipients of 10 years and 6.7% at 15 years after transplantation. Later, Majhail UCBT with missing information did not develop SNs. et al56 analyzed the impact of non-TBI based MAC regimen after In conclusion, early- or late-onset SNs are extremely rare compli- allogeneic HCT for AML/CML. The incidence of STs was 1.2% for cations occurring after UCBT with very poor outcome and high AML and 2.4% for CML at 10 years. More recently, Atsuta et al57 mortality. Particular attention should be paid to subsequent STs reported 269 ST in 17 545 HCT recipients, with a CI of 1.7% at 10 because of their increasing rates with longer survival and their years. In addition to registry data, most published studies58,59 associated late mortality, highlighting the importance of life-long reported incidences of subsequent STs ranging from 2.2% to screening for prevention and early detection of solid malig- 6.4% at 10 years after allogeneic BM or PB HCT. Ringden et al60 nancies to improve OS after UCBT.64 assessed the risk of subsequent STs in recipients of non- myeloablative and RIC HCT and reported a CI of 3.35% in 10 years. Two studies55,61 reported CI of 3.3% and 3.8% at 20 years Acknowledgments after HCT. The authors thank all the principal investigators and the partici- Although our study was not designed to evaluate risk factors, the pating centers who provided the data: Jaime Sanz, Hospital Uni- ST sites observed were similar to those reported in other graft versitario La Fe, Spain; Regis Peffault De La Tour, Hopital St Louis, sources, with high numbers of lung, sarcoma (bone + soft tissue), Paris, France; Gérard Michel, La Timone Children’s Hospital, oral, thyroid, and upper GI cancers. Marseille, France; Albert Esquirol, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Spain; Patrice Chevallier, Hotel Dieu, CHU The use of alkylating agents and TBI (to 96% and 66% of the Nantes France; Marie-Therese Rubio, CHRU Nancy, France; patients who developed ST in our study population, respectively) Mauricette Michallet, Centre Leon Berard, Lyon, France; Jan J. has been associated with the development of ST, especially sar- Cornelissen, Erasmus MC-Daniel den Hoed Cancer Centre, The coma.54 The exposure to TBI doses >8 Gy were associated with Netherlands; Petr Sedlacek, University Hospital Motol, Czech thyroid cancers, osteosarcomas, and central nervous system Republic; Henrik Sengeloev, National University Hospital Rig- tumors. shospitalet, Denmark; Xavier Leleu, Hopital La Miletrie, France; 1982 RAFII et al 23 MAY 2023 • VOLUME 7, NUMBER 10 Jose L Diez-Martin, Hospital Universitario Gregorio Maranon, Medical Center of Israel, Israel; Arnon Nagler, Chaim Sheba Madrid, Spain; Rachel Protheroe, Bristol Royal Hospital for Chil- Medical Center, Israel; Franco Locatelli, IRRCS Ospedale Pedia- dren, United Kingdom; Johan Maertens, University Hospital Gas- trico Bambino Gesù, Italy; Marco Zecca, IRCCS Policlinico San thuisberg, Belgium; Didier Blaise, Centre de Recherche en Matteo, Italy; Luigi Rigacci, Ospedale S. Camillo-Forlanini, Italy; Cancérologie de Marseille, France; Eric Deconinck, Hopital Jean Attilio Olivieri, Azienda Ospedali Riuniti di Ancona, Italy; Fulvio Minjoz, France; Noel Milpied, CHU Bordeaux, France; Ibrahim Porta, Universitá degli Studi di Brescia, Spedali Civili, Italy; Renato Yakoub-Agha, Hopital Claude Huriez, France; Pierre-Simon Rohr- ˇ Fanin, University Hospital, Italy; Nicola Mordini, Az. Ospedaliera S. lich, Hopital de L`Archet I, France; Roberto Foá, University ‘La Croce e Carle, Italy; Simona Sica, Universita Cattolica S. Cuore, Sapienza,’ Italy; Per Ljungman, Huddinge University Hospital, Italy; Giuseppe Basso, Clinica di Oncoematologia Pediatrica, Italy; Sweden; N.H. Russell, Nottingham City Hospital, United Kingdom; Emanuele Angelucci, Ospedale San Martino, Italy; Abdelghani Franca Fagioli, Regina Margherita Children’s Hospital In Turin, Italy; Tbakhi, King Hussein Cancer Centre, Jordan; Jolanta Gozdzik, Victoria Potter, King’s College Hospital NHS Foundation Trust, University Children`s Hospital in Krakow, Poland; Alexei Maschan, United Kingdom; Alessandro Rambaldi, Ospedale Bergamo, Russian`s Children`s Hospital, Russia; Antonio Perez Martinez, France; Nathalie Fegueux, CHU Lapeyronie Montpellier, France; Hospital Universitario La Paz, Hospital Infantil, Spain; Arancha Charlotte Jubert, Groupe Hospitalier Pellegrin-Enfants, CHU Bermúdez Rodríguez, Hospital U. Marqués de Valdecilla, Spain; Bordeaux, France; Giuseppe Bandini, Bologna University, Fernandez Navarro, Hospital Infantil La Fe, Spain; Maria Jesús S.Orsola-Malpighi Hospital, Italy; Thierry Lamy, Hopital Pontch- Pascual, Hospital Regional de Málaga, Spain; Manuel Jurado aillou, CHU Rennes, France; Joan Hendrik Veelken, Leiden Uni- Chacón, Hospital Universitario Virgen a de las Nieves, Spain; versity Hospital, The Netherlands; Eefke Petersen, University Carlos Solano, Hospital Clínico Universitario, Spain; Montserrat Medical Centre, The Netherlands; Dolores Caballero, Hospital Rovira, Hospital Clinic, Spain; Jan-Erik Johansson, Sahlgrenska Gregorio Marañón, Spain; Rafael Duarte, Hospital Universitario University Hospital, Sweden; Urs Schanz, University Hospital, Puerta de Hierro, Spain; Jose Antonio Pérez-Simó, Hospital Uni- Switzerland; Ellen Meijer, VU University Medical Center, The versitario Virgen del Rocío, Spain; John Snowden, Sheffield Netherlands; R.F. Wynn, Department of Paediatric Haematology, Teaching Hospitals NHS Trust (Adult) BMT Programme, United United Kingdom; Charles Craddock, Queen Elizabeth Hospital, Kingdom; Jean Yves Cahn, Hopital A. Michallon, Grenoble, France; United Kingdom; Brenda E. Gibson, Royal Hospital for Sick Chil- Alberto Bosi, Ospedale di Careggi, Italy; Cristina Diaz de Heredia, dren, United Kingdom; Keith M.O. Wilson, University of Wales, Vall d`Hebron, Pediatrico, Spain; Michael Potter, Royal Marsden College of Medicine, United Kingdom; Matthew Collin, Royal Vic- Hospital, United Kingdom; Peter J. Shaw, The Children’s Hospital toria Infirmary, United Kingdom; and Maria Anjum Khan, Yorkshire at Westmead, Australia; Tracey O`Brien, Sydney Children`s Hos- Blood & Marrow Transplant Programme, United Kingdom. pital, Australia; Olga Aleinikova, Belorussian Centre for Paediatric Oncology / Hematology, Belarus; L.A. Noens, University Hospital Gent, Belgium; Xavier Poiré, Cliniques Universitaires St Luc Authorship Belgium; Philippe Lewalle, Institut Jules Bordet, Belgium; Henrique ˇ Contribution: E.G., H.R., A.R., and V.R. designed the study; Bittencourt, St Justine, Canada; Jean-Hugues Dalle, Hopital Robert ˇ H.R., C.K., and F.V. prepared and analyzed data, H.R., F.V., and Debre, France; Sebastien Maury, Hopital Henri Mondor, France; ˇ E.G. wrote the manuscript; H.R. and A.R. performed the statistical Bénédicte Bruno, Hopital Jeane de Flandre, France; Schneider ˇ analysis; J.S., R.P.D.L.T., A.E., G.M., P.C., M.-T.R., J.J.C., and M.M. Pascale, Hopital Charles Nicolle, CHU Rouen, France; Bruno ˇ provided cases for the study; A.E., C.K., F.V., M.M.R.-F., B.C., and Lioure, Hopital de Hautepierre, France; Mathilde Hunault-Berger, G.M.S. helped with data and manuscript preparation; and all CHRU Angers, France; Jacques-Olivier Bay, Service authors edited and approved the final version of the manuscript. D`Hématologie Clinique Adulte et Pédiatrie, France; Véronique ˇ Leblond, Hopital de La Pitie Salpetrière, France; Gandhi Damaj, ˇ Conflict-of-interest disclosure: The authors declare no Centre Hospitalier Universitaire, France; Benedicte Neven, Hopital ˇ competing financial interests. Necker, France; Gérard Michel, Hopital Timone-Enfants, France; ORCID profiles: H.R., 0000-0003-3344-0611; A.R., 0000- Ernst Holler, University Regensburg, Germany; Arndt Borkhardt, 0002-7261-2765; A.E., 0000-0002-6062-5980; V.R., 0000-0003- Universitaetsklinikum Zentrum für Kinderheilkunde, Düsseldorf, 0094-619X; E.G., 0000-0001-7893-2199. 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