Introduction

Late complications, particularly in patients who received transplantation in childhood, have become a major concern since long-term survivors are increasing following allogeneic hematopoietic stem cell transplantation (HSCT). Total body irradiation (TBI) and chronic graft-versus-host disease (cGVHD) are well known risk factors of long-term complications.¹ However, few data are available which analyse risk factors of various complications and psycho-social aspects in the same cohort of children following HSCT for hematologic malignancies. Herein we analyzed complications and their risk factors as well as psychosocial outcomes of 112 children with hematologic malignancies who survived at least 1 year, without relapse, after HSCT.

Patients and methods

The inclusion criteria of this retrospective study were:

1. children younger than 16 years,
2. who received allogeneic HSCT for hematologic malignancies between 1985 and 2000 at St Louis Hospital to allow meaningful analyses on long-term outcomes, and
3. who survived at least 1 year from transplantation without relapse.

Only complications occurring after 1 year from transplant were analyzed. One hundred and twelve patients met these eligibility criteria.

Patients

The median age at transplant was 8.3. years (0.73–15). Most frequently, children had acute leukemia (70 had acute lymphoblastic leukemia and 31 acute myeloblastic leukemia), 6 had chronic myeloid leukemia, 6 myelodysplasia and 2 non-Hodgkin's lymphoma. At transplant, 44% of patients had advanced stage of disease, and 59 patients were in first complete remission (52%). Eighty-seven (78%) patients received an irradiation-based conditioning regimen (single dose; n=52). Most patients received stem cells from an HLA identical sibling (82%, n=92) and marrow was the major source of stem cells (92%, n=103). Graft-versus-host disease (GVHD) prophylaxis consisted in the majority of patients of cyclosporine A associated to methotrexate. Twenty-nine patients had a history of previous acute GVHD (II and III) and 40 patients (36%) developed chronic GVHD within 1 year of transplantation. Other patient, disease and transplant characteristics are summarized in Table 1.

Table 1 - Patients, donor and transplant characteristics of 112 children with hematological malignancies surviving 1 year after HSCT.

Full table

Statistical analysis

Landmark analysis was used for all statistical analyses, with a starting point at 1 year after the HSCT. Long-term complications such as dental, liver and cardiac abnormalities, growth retardation, ovarian and spermatogenesis dysfunction and secondary malignancies were also studied, but not analyzed for associated prognostic factors due to the low number of events. In fact, only the following end points were studied for prognostic factors: first episode of infections, cataract, pulmonary and osteoarticular complications, hypothyroidism, relapse and death. The predictive effect of each of the following variables was assessed: diagnosis (ALL versus AML) and stage of the disease (CR1 vs more advanced disease), recipient and donor sex, sex matching, serotherapy, recipient and donor CMV serology, patient age, year of HSCT, type of donor, use of TBI, fractionated versus single-dose TBI (sTBI) and chronic GVHD.

For the assessment of prognostic factors, except chronic GVHD by univariate analyses, the methodology used a competing risks setting, death and relapse being treated as competing events. Since chronic GVHD was expected to be an important risk factor for long-term complications, it was therefore included as a time-dependent variable in a Cox proportional hazards model either in univariate or multivariate analyses.

Finally, in order to adjust for chronic GVHD, all multivariable analyses were performed using Cox proportional hazards model.

A stepwise backward procedure was used to construct a set of independent predictors of each end point. All predictors achieving a P-value below 0.10 were considered and sequentially removed if the P-value, in the multiple models, was above 0.05. All tests were two sided, with type I error rate fixed at 0.05. Statistical analyses were performed with SPSS 11.5 and Splus6 (Math Soft, Inc., Seattle, WA, USA) software packages.

Results

Outcomes

Twenty-three patients died; nine from relapse, nine from chronic GVHD, three from secondary malignancies and two from infection. At 10 years overall survival after 1-year post transplant was 75%5 (Figure 1). Cumulative incidence at 10 years of non-relapse mortality and relapse incidence was 18%4 and 14%3, respectively. No risk factor was statistically significant for both outcomes. Eighteen patients (16%) developed limited cGVHD and 22 (19.6%) extensive cGvHD and the cumulative incidence at 10 years was 36%4.

Figure 1.

Overall survival rate, cumulative incidence of non-relapse mortality and of relapse in 112 children with malignancies surviving 1-year after HSCT. HSCT=hematopoietic stem cell transplantation.

Full figure and legend (10K)

Long-term complications

Table 2 lists the number of events and 10-year cumulative incidence of complications. The number of complications per patient increased with time. In fact, patients who experienced only one of those complications (21%) have an observational time of 73 months (5–198); however, for those experiencing four complications (16% of the cohort) the observational time is longer (104 months (48–180). Table 3 lists the most important risk factors associated with main long-term complications in a multivariate analysis.

Table 2 - Cumulative incidence of outcomes and first long-term complications of 112 children with hematological malignancies surviving 1 year after HSCT.

Full table

Table 3 - Multivariate analysis of main long-term complications.

Full table

Infections

The 10-year cumulative incidence of first episode of infections was 31%4 (Figure 2). Ten patients had bacterial infections, 18 viral infection, mostly Varicella zoster virus reactivation (n=10). Two patients developed fungus infection: one pulmonary aspergillosis and one oesophageal candidosis. In a multivariate analysis, positive CMV serology before HSCT (P=0.01, relative risk (RR)=2.8) and patient age (>8.3 years) (P=0.004, RR=3.18) were factors significantly associated with infections. There was a trend of higher risk of infection in patients who developed cGVHD (P=0.07, RR=1.98).

Figure 2.

10-year cumulative incidence of first episode of infections in 112 children with malignancies surviving 1-year after HSCT. HSCT=hematopoietic stem cell transplantation.

Full figure and legend (6K)

Lung complications

The 10 years cumulative incidence of pulmonary complications was 20%4 (n=21). Results of pulmonary function testing showed that 14 patients had more restrictive defect and 7 patients more obstructive ventilatory defects (Figure 3). The median time of onset was 917 days (23–3663) for restrictive syndrome and 775 days (173–1587) for obstructive syndrome. Obliterans bronchiolitis was diagnosed in three patients (2.7%). Multivariate analysis showed that pulmonary complications were associated with presence of cGVHD (P=0.02, RR=3.24), recipient's positive CMV serology (P=0.007, RR=4.05) and use of sTBI in conditioning regimen (P=0.004, RR=5.12).

Figure 3.

Cumulative incidence of non-infectious pulmonary complications in 112 children with malignancies surviving 1-year after HSCT. HSCT=hematopoietic stem cell transplantation.

Full figure and legend (7K)

Ocular complications

Cataract was the major cause of ocular complications. At 10 years cumulative incidence of cataract was 44%4; it was 4%4 in patients without TBI in their preparative regimen, 30%9 in patients given fractionated TBI (fTBI) and 62%7 in those patients given sTBI. Among 49 patients who developed cataract, 24 needed surgery. The median time of cataract onset was 908 days (262–4078). In a multivariate analysis, presence of cataract was associated with patient age (>8.3 years; P=0.009, RR=2.3) and use of sTBI in the conditioning regimen (P=0.0006, RR=12.3) or fTBI (P=0.003, RR=13).

Endocrinological complications

Thyroid dysfunction

Hypothyroidism was diagnosed in 39 patients. The median time of diagnosis was 516 days (19–1837). Treatment has been initiated for 38 patients. Only patients who received TBI-based regimen developed hypothyroidism. At 10 years cumulative incidence of hypothyroidism was 36%4. In univariate analysis, use of TBI was the most important factor (P<0.0001); moreover, in multivariate analysis sTBI was a major risk factor for developing hypothyroidism (P=0.0005, RR=7.4).

Growth retardation

Growth retardation defined using a comparison with the Sempe and Pedron curves (1979) was observed in 81 patients among 105 (75.7%). In fact, median final height for males who were 18 years old or more at last follow-up was 1.63 m (1.46–1.82) vs 1.75 m (1.55–1.92) and for females who were 16 years old or more 1.51 m (1.42–1.66) vs 1.65 m (1.45–1.80). Twenty-nine patients of 84 had growth hormone (GH) deficiency. The median time of diagnosis was 2.8 years (0.13–9.5). Among them, 25 patients received treatment by GH. The median time of treatment was 4 years.

Ovarian and spermatogenesis dysfunction

Among 99 patients aging more than 10 years old, 56 patients achieved puberty. For patients achieving puberty, median age for males was of 15.2 years (12.5–22) and for females 13.8 years (11.7–16). Four patients at age of 18 years did not achieve puberty. Forty-one patients had gonadal failure (24 males and 17 females), and 12 men and 15 women received substitutive treatment. None patient had children after transplantation.

Osteoarticular complications

Twenty patients had osteoarticular problems after 1 year. They were avascular necrosis in 13 patients, osteoporosis in 3 and scoliosis in 5. Four patients underwent surgery. The 10 years cumulative incidence was 29%10 (Figure 4). Twelve patients developed bone complications before 1 year (132–329 days) and among them four developed avascular necrosis and were not considered in this analysis. In multivariate analysis the only factor associated with higher incidence of osteoarticular complications occurring after 1-year post-HSCT was TBI (P=0.04, RR=4.5) independent of single- or fractionated-dose TBI.

Figure 4.

Cumulative incidence of osteoarticular complications in 112 children with malignancies surviving 1-year after HSCT. HSCT=hematopoietic stem cell transplantation.

Full figure and legend (7K)

Cardiovascular complications

The probability to develop cardiovascular complications at 10 years was 11%3. Eleven out of 48 patients had abnormal echocardiography. Eight patients had high blood pressure and two patients had cerebrovascular injuries. Among patients who had cardiac complications, all received TBI.

Secondary malignancies

Eight patients (7.1%) developed secondary malignancies. The cumulative incidence at 10 years of secondary malignancies was 7%3. Median time of occurrence after the first year of transplant was 5.2 years (1.3–11.2). One patient developed two tumors. Three patients had brain or central nervous system localization (glioma, glioblastoma and cerebellum primitive neuroectodermal tumor), one tongue localization (epithelioma), two melanomas, one abdominal tumor, one uterine carcinoma and one testicular tumor. All but one 1 patient (abdominal tumor) had received a TBI-based regimen.

Psychosocial aspects

Intellectual function and social issues

At 5 years, 85.5% of patients had Lansky score between 90 and 100 and 4% between 60 and 70. At time of last follow-up, 36 patients achieved normal scholarship and 69 had scholar difficulties. Eleven patients achieved superior level studies and 20 patients out of 40 patients who had more than 18 years had employment. Only three patients got married (two men and one woman).

Psychological problems

Fifty-two patients (49.5%) had psychological disturbance: 13 patients had sign of depression; 11 patients had sleep disturbance; 15 patients had history of anorexia and 1 developed hyperphagia. Psychological problems were associated with the presence of long-term complications. In fact, 54% of patients with 1 or more long-term complications had psychological problems as compared to 26% of patients having psychological problems and without long-term complications (P=0.012).

Discussion

This retrospective study reported only complications occurring 1 year after HSCT for hematological malignancies in children. Three points were underlined by this study:

1. the confirmation of the importance of TBI as risk factor of long-term complications,
2. that these complications increased with time even with a very long follow-up and importantly,
3. that the frequency of psychosocial disorders and their association with long-term complications.

We have found that TBI and particularly sTBI was the most important risk factor for cataract, osteoarticular complications, hypothyroidism and lung impairment (if single dose). Moreover TBI, when used in single dose, was a major risk factor for cataract, pulmonary complications and hypothyroidism. Another worrying complication related to TBI was the occurrence of secondary malignancies as reported in other studies.^{2, 3, 4} In our study, eight patients developed secondary malignancies and only one previously received a non-irradiation-based conditioning regimen. The incidence of 7% will probably increase with longer follow-up.

In several studies, cGVHD appeared to be a major factor of late effects⁵ particularly for pulmonary complications,⁶ osteonecrosis⁷ and infections.⁸ In our analysis, cGVHD was found as a risk factor only for pulmonary complications, although there was a trend for its association with increased risk of TRM, osteoarticular complications and infections.

We have also found that the number of complications increased with the time and aging of the patients and all these complications are associated with psychosocial disorders. Unfortunately, in our study we did not collect specific information on quality of life, but we can suggest that the long-term complication and psychosocial disorders will affect patient's quality of life and that of their relatives. Although most of the studies showed improvement of quality of life, anxiety and sleep disturbance remained a problem in long-term survivors.^{9, 10} Psychosocial disorders appeared to be very frequent. Half of the patients had psychological disturbances, mainly depression syndrome and sleep disturbance. Eating behavior disorders were reported in 14% of patients. Less than half of the patients achieved normal schooling. Patients with one or more long-term complications have higher risk of developing psychological problems. Few data have been published about long-term psychological problems in patients transplanted in childhood. Leung¹¹ reported academic difficulties in 14% of long-term survivors of childhood acute myeloblastic leukemia. Thompson¹² reported that 15–30% of children with chronic illness had significant behavioral problems. Baker et al.¹³ reported fatigue, troubles with eating, anxiety and depression in survivors at 1 year after bone marrow transplantation. Although this study was retrospective, behavioral problems also seemed to be frequent in our population and these problems are probably underestimated particularly anxiety and eating disorders.

This retrospective study confirmed the impact of TBI in conditioning regimen in the development of late effect. Incidence and numbers of complications increase with time, and careful attention on visual impairment, endocrinological dysfunction and secondary malignancies should be low particularly in patients who received TBI and even more if they received sTBI. This study also revealed that psychological problems persist and are probably underestimated in long-term survivors transplanted in childhood

These results underlined the importance of monitoring patients treated by stem cell transplantation all their lives. Results of very long-term late effects in children beyond 10 years after transplantation are scarce and we need more prospective studies. Furthermore, we need more studies on the evaluation of less toxic conditioning regimens to prevent late effects and improve quality of life for long-term survivors.

References

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