Haematopoietic stem cell transplantation (HSCT) is a consolidation treatment for high-risk acute lymphoblastic leukaemia (ALL). This treatment requires previous conditioning, whose purpose is to create room in the bone marrow of the recipient for the donor haematopoietic stem cells, achieve a sufficient level of immunosuppression to keep the immune system of the patient from rejecting the graft and eliminate as much residual disease as possible.1 Traditionally, myeloablative regimens were recommended in malignant blood tumours due to their strong antitumour effect. However, their toxicity is their main limitation in paediatric care.

Total body irradiation (TBI) is a treatment included in some myeloablative conditioning regimens, with delivery of radiation to the whole body at a dose of about 12 Gy.2 Conditioning with TBI is the standard of care for HSCT since more than 70 years ago, with clinical outcomes that have yet to be surpassed by chemotherapy-based conditioning regimens. The results of the FORUM study, an international, multicentre phase III trial comparing TBI and chemotherapy, were published in 2021, showing an increased 2-year overall survival and decreased relapse risk with TBI.3

However, the FORUM study did not assess long-term outcomes of TBI in the paediatric population. Total body irradiation is a treatment associated with multiple adverse events in the medium and long term, especially in paediatric patients.4–6 Its adverse effects increase with decreasing patient age, and TBI is not recommended in children aged less than 4 years.7,8

In recent years, variables known as patient-reported outcome measures (PROMs) and patient-reported experience measures (PREMs) have been analysed to help measure the impact of a given intervention from the perspective of the patient,9 and their study is particularly important in patients with a high risk of morbidity, such as HSCT recipients.10

The aim of our study was to make a retrospective analysis of survival in patients with ALL treated with HSCT, comparing those who had undergone TBI as part of their conditioning regimen and those who had not. A secondary objective was to describe the cumulative morbidity of patients who underwent TBI as part of their conditioning regimen, taking into account PREMs to obtain more comprehensive information about the adverse effects associated with TBI based on the personal experience of the patients.

We conducted a retrospective study analysing the HSCT performed for treatment of ALL in the department of paediatric haematology and oncology of a tertiary care hospital between 1996 and 2009. During this time, 69 HSCTs were performed in 57 patients. We recorded clinical data, grouping patients based on whether they had received TBI as part of the conditioning regimen and those who only received chemotherapy (Table 1). We collected clinical data from the health records and expressed quantitative variables as mean and standard deviation.

We used the Kaplan-Meier method for the survival analysis. The outcomes we analysed were the overall survival (OS), the event-free survival (EFS), with event defined as relapse or death, the relapse probability (RP) and transplant-related mortality (TRM). We compared these outcomes using the log-rank test.

In the second part of the study, we identified a total of 27 survivors of HSCT performed for treatment of ALL that had been followed up for a minimum of 10 years, of who 21 agreed to be interviewed. Of this total, 18 patients (86%) received TBI as part of the conditioning regimen and 3 patients (14%) did not undergo TBI. Due to the small number of patients in the no TBI group (Appendix A, supplemental material 1), it was not possible to compare the two groups, so we decided to conduct a descriptive analysis of the adverse events in the TBI group.

A single researcher conducted all of the telephone interviews, administering a questionnaire developed in house consisting of close-ended questions that is shown in Fig. 1. This questionnaire assessed for the most frequent adverse events experienced after HSCT: (a) pulmonary toxicity,11 (b) metabolic syndrome,12 (c) hypothyroidism and thyroid cancer,13 (d) development of cataracts,13 (e) tinnitus and hearing loss,14 (f) neurocognitive deficits,15,16 (g) pubertal and gonadal development17 and (h) secondary malignancies.18 To complete the interview, we added 2 open-ended questions to allow patients to describe any other relevant adverse effects not covered before and to report their perceived current quality of life on a scale from 0-100.

Figure 1.

Items included in the telephone interview with survivors grouped based on the main adverse effects of total body irradiation (TBI).

(0.78MB).

The study was approved by the Clinical Research Ethics Committee of the hospital on May 28, 2022.

Although we did not find significant differences in the 2-year OS between the TBI and no TBI groups, the EFS and RP were better in patients who underwent TBI for conditioning. These findings were similar to those of the prospective FORUM study.3 This suggests that TBI has a protective effect against relapse.

In our study, there was a higher proportion of autologous HSCT in the TBI group compared to the no TBI group, in which the proportion of allogeneic HSCT was greater. Autologous HSCT does not produce graft versus tumour effects that may be present in allogeneic HSCT, in spite of which the survival outcomes were better in the group conditioned with TBI. This suggests that TBI has a significant effect against leukaemia, but it is also important to remember that autologous HSCT has not been recommended for treatment of paediatric ALL for a decade.

To make a comprehensive assessment of TBI, we sought to describe the adverse events in patients who had received it as part of their conditioning regimen, including the personal perspective of the patient applying the recently established performance measures, PROMs and PREMs.9

The development of secondary malignancies is a known adverse event of HSCT, and there are studies demonstrating an increased risk of secondary malignancy when TBI is used for conditioning.6 In our series of patients treated with TBI, 39% developed secondary malignancies, most of them involving the thyroid or skin, an incidence much higher compared to the previous literature, in which the reported incidence is approximately 3% to 5%.19

According to the existing evidence, one of the main adverse effects of TBI is pulmonary toxicity, with the main adverse events including pulmonary fibrosis, decreased lung function as measured by spirometry and an increased frequency of respiratory infections.11 In our patients, we found that 44% reported poorer exercise tolerance compared to their peers and 11% a diagnosis of asthma. In addition, all had a mild to moderate level of recurrent respiratory infections, with 11 patients (61%) reporting fewer than 3 episodes a year and 7 (39%) 3 to 6 episodes a year.

Thirty-three percent of patients in the TBI group reported concentration problems, in agreement with the previous literature, in which impaired concentration is described as one of the major neurocognitive adverse events of radiation therapy, found in 50% of patients.16

Cataracts developed in 22% of patients treated with TBI at a mean age of 14 years and a latency time of approximately 2 to 2.5 years after performance of the HSCT, which was consistent with the previous literature, in which an incidence of 28% is reported following TBI.20

Up to 50% of patients who underwent TBI received a diagnosis of hypercholesterolaemia, at a mean age of 17 to 18 years, and most achieved adequate control with lifestyle and dietary measures. Diabetes and metabolic syndrome are both common adverse events in patients managed with radiation therapy, and can develop even in patients with a normal body mass index.21

When it comes to adverse effects in the area of sexual development, they are most frequent in female patients, and most of those affected (89%) develop premature ovarian failure, require lifelong hormone replacement therapy and are unable to conceive. A previous study found that female patients treated with TBI are 30% less likely to be able to have children.17 Male patients are less affected, and in our interview, many reported premature balding.

However, when asked about quality of life, most interviewed patients (83%) reported a moderate to very good quality of life, in agreement with previous evidence in which only 12% rated it as poor.19 However, we must highlight that patients also reported mental health problems in the early years after the disease, especially features of anxiety and depression, in many cases requiring professional help.22

Despite these adverse events, most of the patients in our study reported a good quality of life, with scores above 80 or 90 points, which was consistent with the previous literature, in which 57% of the patients rated their quality of life as good or excellent and only 12% as poor.23

Although the use of TBI as part of the conditioning regimen for HSCT in childhood ALL is still recommended,24 TBI has significant associated toxicities in the medium and long term. However, current chemotherapy-only conditioning regimens are clearly inferior, so randomised controlled trials should be conducted to explore the possibility of combining them with other post-transplantation strategies to intensify the anti-leukaemia effect without increasing toxicity, for instance, through the use of drugs such as tyrosine kinase inhibitors or immunotherapy with adoptive cell transfer.

Another alternative that is currently being considered is reducing the dose of TBI to 8 Gy, an approach already supported by evidence in adults with ALL but it has yet to be confirmed in the paediatric population.25

Patients who received TBI for conditioning had a greater EFS and a lower RP compared to patients who underwent chemotherapy for conditioning. This suggests that TBI has a protective effect against relapse, in agreement with the findings of the FORUM study.

Another of the goals of our study was to assess the potential adverse events associated with TBI, taking into account the subjective perspective of patients through PREMs. We found that a high proportion of the survivors experienced respiratory complications in the form of recurrent respiratory infections and dyspnoea, metabolic syndrome with obesity, HTN, diabetes and dyslipidaemia, thyroiditis and thyroid cancer, cataracts and myopia, hearing problems, difficulty concentrating and school failure, premature ovarian failure in female patients and secondary malignancies (especially thyroid and skin cancers).

Strategies for followup, monitoring and intervention in the medium and long term need to be established for these patients on account of the high morbidity that they experience throughout the lifespan. To this end, it is important to take into account the experience of the patient and directly involve the patient in the assessment of the outcomes of treatment and the impact in their quality of life of the adverse events resulting from HSCT.

The authors have no conflicts of interest to declare.