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Transplant Toxicities

Incidence and severity of crucial late effects after allogeneic HSCT for malignancy under the age of 3 years: TBI is what really matters


Younger children are considered to be more vulnerable to late effects (LE), which prompted us to study LE in patients after haematopoietic stem cell transplantation (HSCT) for a haematological malignancy before the age of 3. In this multicentre EBMT study, cumulative incidence (CI) and severity of endocrine LE, central nervous system complications and secondary malignancies at 5, 10, 15 and 20 years of follow-up were assessed. Risk factors (RF) like gender, diagnosis, age at and year of HSCT, TBI- or chemo-conditioning and GVHD were analysed. CI of any LE was 0.30, 0.52, 0.66 and 0.72 at 5, 10, 15 and 20 years after HSCT, respectively. In 25% of the patients, LE were severe at a median follow-up of 10.4 years. In multivariate analysis, only TBI was a RF for having any LE and for thyroid dysfunction and growth disturbance. Female gender was a RF for delayed pubertal development. Some more insight could be gained by descriptive analysis regarding the role of TBI and GVHD on the severity of LE. Although only five selected LE have been studied and median follow-up is relatively short, the incidence and severity of these LE are considerable but not different from what has been found in older children and TBI is the main RF.


In children with high risk haematological malignancies, allogeneic haematopoietic stem cell transplantation (HSCT) may be the only curative treatment or may improve survival rates as compared with further chemotherapy alone. Owing to the advances in transplant procedures and supportive care, better survival rates after HSCT have been achieved. However, this cure comes at a price, because it has been shown that late effects (LE) of oncological treatment are more frequent and more severe after HSCT as compared with chemotherapy only.1, 2, 3, 4, 5, 6, 7

Prepubertal children are a unique patient cohort in whom data regarding LE after HSCT in adults are not directly applicable.8 It has been shown that young age is a risk factor (RF) for several LE.1, 2, 3, 4, 5, 6, 7 To our knowledge, only three studies on LE after HSCT in very young children (less than 3 years old), with small patient numbers, have been published to date and the results of these studies suggest that LE in these patients are common and often related to irradiation.9, 10, 11, 12 The adverse effect of radiotherapy on the youngest children has been recognised for several years. In the past, however, some of these children did receive radiotherapy, for example, cranial radiotherapy and/or TBI during HSCT. As the number of patients in these studies in very young children was small, results are contradictory regarding an increased cumulative incidence (CI) and severity of LE in this age group as compared with older children who have undergone HSCT.

In decision-making on the most effective treatment to cure the disease in young children, the risk of LE has to be considered. For paediatric long-term survivors, quality of life is considerably affected by the presence of LE. It is thus important to assess the incidence and severity of and RFs for LE in these patients. This is especially true for the most common LE after HSCT which concern endocrine complications2, 3, 13 and life-threatening LE, for example, secondary malignancy.14, 15, 16, 17 In terms of neurocognitive function, there are only few data on mostly small patient cohorts regarding the outcome beyond 5 years post HSCT,18, 19, 20, 21, 22 although the very young age group may be more susceptible for neurological problems.2, 23

This prompted us to perform a multicentre study within the EBMT community to study the CI and severity of a selection of LE in patients transplanted for a haematological malignancy under the age of 3 years.

Subjects and methods

This is a multicentre cross-sectional joint study of the Paediatric Diseases Working Party and the Complications and Quality of Life Working Party of the EBMT and was approved by both scientific committees. Data processing was carried out in accordance with the standards for patient confidentiality and good clinical practice.

Patients transplanted for a haematological malignancy before age 3 and alive at least 5 years after HSCT were identified from the EBMT registry. Haematological malignancies are defined as: ALL, AML, CML, juvenile myelomonocytic leukaemia/myeloproliferative disorder, myelodysplastic syndrome and lymphoma.

Paediatric HSCT centres within the EBMT were sent a predesigned questionnaire for each eligible patient treated in this centre concerning the presence and severity of a selection of LE. In case of missing or incomplete data, a data manager contacted the centres and completed the data.

We selected five specific LE for this analysis: endocrine LE were chosen because of their well-known high prevalence in HSCT survivors.4, 13, 24 Central nervous system (CNS) complications are of special interest because long-term follow-up (FU) data are scarce18, 21, 22 and secondary malignancies because of their life-threatening consequences were also selected for this study. The questionnaire asked for thyroid dysfunction, growth retardation and/or growth hormone deficiency, gonadal dysfunction/delayed puberty, and for CNS complications, including cognitive impairment, concentration impairment/attention-deficit–hyperactivity disorder, leukoencephalopathy, epilepsy and cerebrovascular angiopathy, and for secondary malignancies. Given that most of our patients were still underage at their last FU and in children fertility testing is rarely performed, we decided to assess gonadal function by pubertal development. As gonadal dysfunction defined for this study as delayed or absent pubertal development can only be assessed in children who have reached pubertal age, we decided to assess the CI of delayed puberty at 15 and 20 years of FU in patients who were at least 15 years old at last FU. The CI of other LE was assessed at 5, 10, 15 and 20 years of FU except for CNS LE, as date of onset was often missing.

The severity of the reported LE was graded according to the CTCAE (Common Terminology Criteria for Adverse Events v4.0 (CTCAE), (

The following potential RFs for LE were analysed: gender, diagnosis (acute leukaemia or lymphoma vs myelodysplastic syndrome or juvenile myelomonocytic leukaemia), age at HSCT, year of transplant, conditioning regimen with TBI/total lymphoid irradiation (TLI) or without irradiation (chemotherapy only), acute and chronic GVHD (aGVHD and cGVHD).

Statistical analysis

The CI of having one or more LE and the CI of each of the five selected LE were assessed. Some data regarding presence and/or date of diagnosis of the LE were missing and/or not evaluated. To account for the fact that missing data is not random, we performed separate analyses. In the first analysis, it is assumed that for not evaluated LE, there is no evidence that this LE is present and hence it is assumed that this LE is not present. A second complete case analysis evaluated only patients with complete data on the LE of interest. A third analysis used a case–control approach, comparing the frequency of RFs in patients with and without LE. All three analyses yielded very similar results and only the data using the first approach are shown.

Starting from year 5 post transplant, the CI of LE is estimated according to Prentice et al.25 Death without LE is considered as a competing event. Grays test is used to investigate the impact of RFs on the CI.26 The proportional cause-specific hazard model was used for the multivariate analysis of these RFs.


From the EBMT registry, 840 patients were identified who were transplanted for a haematological malignancy before the age of 3 and who survived at least 5 years after HSCT. Questionnaires were sent to the transplant centres for each eligible patient and 297 (35%) questionnaires from 40 centres were completed and returned. The clinical characteristics of the patients are summarised in Table 1. FU was longer, TBI was applied more often and ALL was more common in the study group. Also, study patients were transplanted in the more recent era. Sixteen children underwent a second transplant and two patients a third.

Table 1 Clinical characteristics of study patients and of eligible patients not included in this study

CumuIative incidence and severity of LE

The CI of any LE was 0.30±0.03, 0.52±0.03, 0.66±0.04 and 0.72±0.05 at 5, 10, 15 and 20 years after HSCT, respectively, and only three patients experienced a competing event, that is, death not caused by LE (Figure 1). The CI of each type of LE is shown in Figure 2, and also illustrates an increase with longer FU.

Figure 1

Cumulative incidence of LE.

Figure 2

Cumulative incidence of (a) thyroid dysfunction, (b) growth retardation, (c) delayed pubertal development and (d) secondary malignancy.

In 130 of 163 patients with a LE, severity was graded (according to the CTCAE): 63 (48%) patients had only mild (grade 1) LE and at least one moderate (grade 2) LE was found in 35 (27%) of the patients with LE. Severe (grade 3) and disabling or life-threatening (grade 4) LE were found in 18 (14%) and 13 (10%) patients, respectively. One patient died because of a LE (secondary malignancy). Hence, severe LE (grade 3/4/5) were found in 25% (32/130) of the patients.

With respect to details of the reported LE, the majority (92.5%) of patients with thyroid dysfunction showed hypothyroidism. Only a small number (19%) of patients with growth retardation received growth hormone therapy. CNS complications were diagnosed in 58 patients (Table 2). Of note, the exact time of onset of these CNS complications was difficult to evaluate and accordingly no CI curves are shown. Four patients with CNS sequelae had an underlying disease associated with cognitive impairment, for example, Noonan syndrome. Nineteen of 58 (33%) patients with CNS sequelae received TBI and only 1 patient also received cranial irradiation. The incidence of grade 3/4 CNS sequelae was 20% in the chemo-conditioned vs 47% in the TBI-conditioned patients (data not shown). Thirteen patients developed a secondary malignancy after a median FU of 10.3 years (range: 0.94–22.8 years): 4 thyroid carcinoma, 3 basal cell skin carcinoma, 1 melanoma, 2 brain tumours (1 glioma and 1 oligodendroglioma), 1 osteosarcoma, 1 secondary ALL and 1 secondary AML. Only one patient died because of a secondary malignancy (brain tumour).

Table 2 CNS complications in 58 patients

Risk factors for LE

In univariate analysis of RFs for any LE and for each of the three endocrine LE (Table 3), female gender was a RF for delayed pubertal development (CI at 15 and 20 years: 0.09 and 0.16 in males and 0.32 and 0.36 in females, respectively; P<0.001). Age 2–3 years at HSCT vs 0–1 and 1–2 years was a RF for both thyroid dysfunction and growth disturbance (P=0.036 and P=0.003, respectively). Age >2 year as compared with 0–1 and 1–2 years was significantly associated with TBI conditioning (results not shown, P=0.001).

Table 3 Univariate analysis of risk factors for LE

TBI conditioning is not only a significant RF for any LE (P<0.001), but also for more severe LE (in TBI/non-TBI 39%/17% had grade 2–5 LE and 22%/7% grade 3–5 LE, P=0.0002 and P=0.002, respectively). Moreover, TBI is a RF for the specific LE thyroid dysfunction (P<0.001) and growth retardation (P<0.001). Diagnosis of underlying malignant diseases and year of HSCT were not a RF. The incidence of LE at 15 years was higher in grade 3/4 aGVHD patients (especially for thyroid dysfunction with 0.74 vs 0.39 in patients without aGVHD), but not statistically significant. Of note, analysis of grade 3/4 aGVHD and extensive cGVHD as RF was hampered by low patient numbers, but a trend existed for cGVHD as a RF for growth disturbance (P=0.053). In general, the incidence of acute and chronic GVHD was similar both in the TBI- and in the chemo-conditioned group (56 and 20% vs 61 and 16%).

The influence of GVHD was further analysed: in patients after chemo-conditioning, the incidence of any LE was only 23%, after TBI 37%, after GVHD 25%, but in patients with GVHD and TBI, it was 53% at 5 years, although these differences narrowed over time and this is also true for both thyroid and growth LE (Figure 3). In addition, we grouped patients with most severe GVHD (aGVHD 3/4 (n=28) and extensive cGVHD (n=20)) and 90% of these patients developed any LE at 10, 15 and 20 years of FU. In addition, we evaluated the burden of LE: the incidence of severe LE (grade 3/4/5) was similar in chemo-conditioning with and without GVHD (25%), 29% in the TBI group but 71% in the TBI group with any GVHD (data not shown).

Figure 3

Cumulative incidence of (a) any LE, (b) thyroid dysfunction, (c) growth retardation and (d) delayed pubertal development and the influence of TBI and GVHD.

In multivariate analysis, only a TBI-containing conditioning regimen was a RF for LE (Table 4), whereas gender, age at HSCT, diagnosis (comparing patients having had chemotherapy prior to HSCT with those who had not) and GVHD were not. RFs were also assessed for each endocrine LE in multivariate analysis and again TBI conditioning was a RF for thyroid dysfunction and growth retardation (hazard ratio 3.09 and 3.89, respectively, P<0.001 for both). For delayed pubertal development, female gender was shown to be a RF (hazard ratio 3.4, P=0.002). No significant RFs could be found for CNS complications. RF analysis for secondary malignancy was hampered by the low number.

Table 4 Multivariate analysis of risk factors for LE


After a median FU of 10.4 years after HSCT for a haematological malignancy under the age of 3 years, and although only data on five selected LE were studied, 55% of survivors have at least one LE and the CI increased with time up to 72% at 20 years. In 25% of the patients with LE, these conditions are severe (CTC grade 3/4/5). The CI of LE in HSCT survivors, including patients transplanted during childhood, has been reported by the American Bone Marrow Transplantation Survivor Study as 59% at 10 years.1, 6, 7 Severe LE were reported in 35% and 41% at 10 and 15 years of FU, respectively.1, 6, 7 A broad range of LE was assessed, but by patient self-report.1, 6, 7 In a single-centre study in 162 childhood HSCT survivors, a CI of LE, assessed by a paediatric oncologist, of 93% was found at a median FU of 7.2 years, with severe LE in 25%.3

Endocrine LE have been shown to be the most common LE in HSCT survivors, especially after TBI at a young age. In previous paediatric studies, with a median FU of at least 10 years, the CI of thyroid dysfunction varied between 12 and 48%.3, 4, 5, 27, 28, 29, 30, 31 The prevalence of thyroid dysfunction in our study of 30% and the increase in CI with time is in accordance with previous reports on all paediatric age groups. Growth retardation occurred in 27% of our patients and showed a sharp increase after 5 years FU, presumably because growth disturbance is most notable during puberty. In previous reports, the prevalence varied between 20 and 85% depending on the conditioning regimen, median age at HSCT and the definition of growth disturbance.3, 13, 32, 33, 34, 35, 36 Although gonadal insufficiency and infertility has been studied extensively in paediatric HSCT survivors, only a few studies have looked specifically at delayed pubertal development. Three studies have investigated LE in survivors of infant leukaemia and of HSCT for haematological malignancy before age 3 and have found hypothyroidism in 29–36% and growth hormone deficiency in 43–92%.10, 11, 12 As in these studies, the majority of children had not reached pubertal age at last FU, no conclusions could be drawn regarding gonadal function. In conclusion, our study suggests that with comparable FU time the CI of endocrine LE is not different from that found in childhood HSCT survivors from all age groups.

Regarding neuropsychological outcome after paediatric HSCT, most studies showed a relatively good neurocognitive outcome, but younger age at transplant and TBI are RFs for neurocognitive deficits.18, 19, 20, 21, 22, 37, 38, 39, 40, 41 In our study, a considerable number of survivors with LE (n= 58/163, 36%) had CNS LE and this is comparable with the study by Smedler et al.22 and one study reported that 11 of 13 (85%) patients transplanted before age 3 with TBI had neuropsychological abnormalities.11 In the study by Leung et al.,10 two of seven infant leukaemia patients with cranial irradiation (CRT/TBI) and HSCT developed a seizure disorder. To our knowledge, no other data on the occurrence of concentration impairment/attention-deficit–hyperactivity disorder, leukoencephalopathy, epilepsy and cerebrovascular complications in HSCT survivor populations have been published. Only 13 patients (4%) developed a secondary malignancy. In previous studies, the CI of secondary malignancies increased from 2.5–6% 10 years after HSCT to 7–13% 15 years after HSCT and shows no plateau with longer FU.14, 15, 16, 17, 42, 43, 44 Also, young age and radiotherapy were shown to be the most important RFs.14, 16, 42 The type of malignancy in our patients is in agreement with other studies.14, 15, 16, 17, 42, 43, 44 One may speculate that the low incidence in our study is influenced by the fact that secondary malignancies are often not diagnosed in paediatric HSCT centres.

Our data clearly show that TBI is the main RF for any LE, hypothyroidism and growth disturbance and this is consistent with many previous studies.3, 5, 13, 15, 16, 17, 27, 45, 46, 47, 48, 49, 50, 51 Age 2–3 years at HSCT was a RF for both thyroid dysfunction and growth disturbance, and the significant correlation with a higher proportion of TBI within this age group further highlights the harmful impact of TBI. The incidence of severe CNS LE was higher in the TBI-conditioned as compared with the chemo-conditioned patients (47 vs 21%). Although we expected TBI also to be a RF for the incidence of CNS sequelae and secondary malignancies, we could not confirm this, probably because of the low patient numbers. A considerable number of our study patients received TBI/TLI (n=74, 25%); however, in more recent years, irradiation has been widely omitted from both the leukaemia and HSCT protocols in children under the age of 2–3 years. Female gender was found to be a RF for delayed pubertal development, as previously described in childhood cancer and HSCT survivors.13, 52, 53, 54 This is explained by the higher likelihood of males having preserved androgen production as compared with preservation of female oestrogen production.13, 24, 52, 53, 54, 55, 56

Previous reports depict GVHD and its treatment as RFs for many LE.5, 6, 7, 15, 44 Surprisingly, we are not able to confirm these data either for acute or chronic GVHD. Analysis was, however, hampered by the low number of patients with GVHD.

Our study is limited by the fact that data on LE were available for only 35% of the eligible patients. Survivors with LE are probably more likely to be in FU and thus we may have overestimated the prevalence of LE. This assumption is also suggested by a higher percentage of TBI conditioning in the study group as compared with the whole cohort of eligible patients. On the other hand, only five major LE were assessed and the median FU of 10 years is relatively short by which the true burden of LE will be underestimated. Although selection of five major LE makes it impossible to assess the actual burden of LE, it seemed not feasible in a multicentre study with quite different approaches to HSCT aftercare within Europe to assess this. Nevertheless, CI and severity of the studied five LE are considerable. Underestimation of true CI may be especially true for some CNS complications with the need of specific diagnostic tools. Mild cognitive impairment might go undetected if no neuropsychological testing is performed, as was the case in the majority of our patients. Also, leukoencephalopathy and cerebral vascular abnormalities might go undetected if asymptomatic.

Our study is the largest to date on LE after HSCT before the age of 3 years and data accrual was carried out by dedicated paediatric transplant centres. Detailed information on the selected LE and their severities was thus obtained and clearly TBI is the main RF. The additive RF of GVHD could not be proven in our data set so far, but a possible association with the burden of LE exists. Our study underlines the importance of international initiatives like the survivorship passport within the European HSCT community, which summarizes previous treatments and FU recommendations for each survivor (


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We thank the data managers and paediatricians from all 40 EBMT centres who participated in this study and provided the patient data on LE.

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Correspondence to D Bresters.

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The authors declare no conflict of interest.

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A study on behalf of the EBMT Working Parties Paediatric Diseases and Complications and Quality of life.

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Bresters, D., Lawitschka, A., Cugno, C. et al. Incidence and severity of crucial late effects after allogeneic HSCT for malignancy under the age of 3 years: TBI is what really matters. Bone Marrow Transplant 51, 1482–1489 (2016).

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