We report long-term outcomes of 329 childhood severe aplastic anemia (SAA) patients who underwent hematopoietic SCT (HSCT) from an HLA-matched sibling donor in the Japanese Hematopoietic Cell Transplantation Registry. OS and EFS at 10 years were as high as 89.7+/−1.7% and 85.5+/−2.0%, respectively. Five cases of late malignancies (LM) were identified (malignant peripheral nerve sheath tumor, thyroid carcinoma, colon carcinoma, MDS and hepatoblastoma). Cumulative incidence of LM was 0.8% at 10 years and 2.5% at 20 years, respectively, which was lower than that in previous reports. This low incidence is in keeping with the low occurrence of skin cancer in Japanese population and of acute GVHD in our study group. Radiation-containing conditioning was not significantly associated with the incidence of LM after HSCT probably because of absolute low patient number who developed LM in our series. In terms of LM development after HSCT, low-dose TBI in HSCT for SAA to avoid graft rejection, which is commonly used in Japan, might be tolerable in the Japanese population because of its low incidence.
Aplastic anemia is a hematopoietic disorder characterized by pancytopenia and BM hypoplasia. Therapeutic options for severe aplastic anemia (SAA) are immunosuppressive therapy and hematopoietic SCT (HSCT). In children, if an HLA-matched sibling donor (MSD) is available, HSCT is the first line of therapy for SAA. HSCT from MSD is an established standard therapy for SAA in children and high survival rates have already been reported. However, little is known about long-term outcomes of these children.
Late malignancies (LM) are serious complications for patients who undergo HSCT.3, 4 In SAA, LM are also reported in the patients with HSCT and its occurrence is related to radiation-containing conditioning regimen and GVHD grade in adults,5, 6 however, the incidence and prognostic factors of LM in children with SAA who undergo HSCT are totally unknown.
In this article, we report long-term outcomes of childhood SAA patients who underwent HSCT from MSD in the centers of the Japanese Hematopoietic Cell Transplantation Registry and describe the occurrence of LM.
Patients and methods
Between 1980 and 2004, 329 patients with SAA under the age of 15 years who underwent HSCT from MSD were registered to the Japanese Hematopoietic Cell Transplantation Registry. Congenital BM failure syndrome patients, such as Fanconi anemia, were excluded from this analysis. All treatments were performed with informed consent from patients’ parents or guardians according to the Declaration of Helsinki. Events were defined as treatment failure (rejection, secondary graft failure and relapse), death of all causes and LM. Survival curves were calculated by Kaplan–Meier method. Comparisons between survival curves were performed by log rank test. Multivariate analysis was performed using the Cox regression model. Statistical significance was defined as P <0.05.
The clinical characteristics of 329 SAA patients are summarized in Table 1. CY+anti-thymocyte globulin (ATG) or CY+TLI were mainly used for conditioning. Fludarabine (Flu)-based conditioning regimens were used in 27 patients (8.2%). CsA+MTX were mainly used for GVHD prophylaxis. Events were observed in 52 patients. The types of events were as follows; treatment failure in 29 patients, death of all causes in 18 patients (organ failure 7, infection 3, interstitial pneumonitis 2, bleeding 2, GVHD 2 and others 2) and LM in 5 patients. Out of 29 patients who suffered treatment failure, 16 patients were rescued by second HSCT; however, the other 13 patients died of complications after treatment failure. The effects of representative clinical factors, which could influence on outcome of HSCT for SAA, are shown in Table 2. Among these, transfusion number 20 or more before HSCT and acute GVHD grade II or more were poor prognostic factors for outcome (EFS) of these patients in univariate analysis. However, they did not reach statistical significance in multivariate analysis. Five patients who suffered LM are listed in Table 3. Crude incidence of LM was calculated as 1.5% (5 out of 329). All patients developed LM more than 50 months after HSCT. Three patients survived with further salvage therapy. However, two patients died of LM. Cumulative incidence of LM was 0.8% at 10 years and 2.5% at 20 years, respectively, which was much lower than those in previous reports.3, 4, 5, 6 As for conditioning regimen for SAA in patients with LM, four received radiation-containing regimen and one non-irradiation regimen. Comparisons of cumulative incidence of LM between radiation and non-radiation regimen did not reach statistical significance (2.5 vs 3.1% at 20 years, P= 0.718). One patient with LM after non-radiation regimen suffered transfusion-related hepatitis B virus infection-induced hepatic tumor, which was reported in detail elsewhere.7 Survival curves of all patients are shown in Figure 1. OS and EFS were as high as 89.7 +/−1.7% and 85.5 +/−2.0% at 10 years, respectively. Outcomes of the patients with Flu-based conditioning regimens are shown in Figure 2 and it did not differ from that with non-Flu-based regimens (5-year EFS: 84.9 with Flu vs 87.0% without). Among patients with radiation-containing regimen, we did not find any influence on patient outcomes according to different schedules and dosages of irradiation used.
In this article, we report long-term outcomes of childhood SAA patients who underwent allogeneic HSCT from MSD in Japan. OS and EFS at 10 years were as high as 89.7% and 85.5%, respectively, which were comparable to previous reports. Among several clinical factors, none was shown to be an independent prognostic factor for SAA patients after HSCT, although transfusion number 20 or more before HSCT and acute GVHD grade II or more were associated with poor prognosis of these patients in univariate analysis.
In our series, we identified five LM after HSCT for SAA. They were malignant peripheral nerve sheath tumor, thyroid carcinoma, colon carcinoma, MDS and hepatoblastoma. Cumulative incidence of LM was 0.8% at 10 years and 2.5% at 20 years, respectively. In the literature, there are two reports with large pediatric cohort concerning LM after HSCT for SAA.6, 8 Ades et al.6 reported long-term outcome of 133 patients, including both adult and pediatric patients after BMT for SAA, at the Hospital Saint Louis. They reported cumulative incidence of LM at 15 years as 10.9%. Burroughs et al.8 reported long-term outcome of children with SAA after HSCT at the Fred Hutchinson Cancer Research Hospital. Among 148 SAA patients in their series, they identified 12 patients (8%) who developed LM after HSCT. Cumulative incidence of LM in these patients was 5% at 25 years. Considering the data in these two reports, the patient number who developed LM (5 out of 329, 1.5%) and cumulative incidence of LM (2.5% at 20 years) in our series were lower than those in reports from western countries. In the latter report, 5 out of 12 LM were observed more than 25 years after HSCT, so that we need further careful follow-up for these patients because median follow-up period in our cohort is about 10 years. There are two possible reasons to explain such differences. One is the rarity of skin cancer in Japanese population due to constitutional skin color. The incidence of skin cancer in the Japanese population is estimated to be much lower than that in western populations.9, 10 Skin cancer has a relatively large proportion of LM after HSCT3, 4, 5 and actually skin cancers were included in the above two reports (5 out of 12 in Burroughs et al.8 and at least 2 out of 11 in Ades et al.6). In contrast, no skin cancer was observed in our series. The low incidence of skin cancer in the Japanese population seems to have contributed to the low incidence of LM after HSCT in our series. The other reason is the low incidence of GVHD in our series. The incidence of acute GVHD grade II or more was 12.1% in patients less than 12 years old and 15.6% in 12 years old or more in our series. Guardiola et al.11 reported the incidence of acute GVHD after HSCT from MSD for SAA to be 13% in patients less than 12 years old and 52% in 12 years old or more. In general, the Japanese population has a homogeneous genetic background and incidence and severity of GVHD is considered to be lower than that in western populations even in HSCT from MSD.12 Recently, Rizzo et al.13 reported there are, in respect of risk factors, two types of LM after HSCT. The squamous cell carcinoma of the skin and oral cavity are clearly related with GVHD, whereas the non-squamous cell carcinoma is not related with GVHD. Long-lasting inflammation of the skin or oral cavity caused by GVHD is considered to be cause of LM after HSCT and the low incidence of GVHD also seems to have contributed to the low incidence of LM after HSCT in our series. As for conditioning regimen, radiation-containing regimen was not significantly associated with LM after HSCT in our series, although radiation was reported to be associated with LM after HSCT.3, 4, 5 This is probably because of absolute low patient number who developed LM. Recently, Flu-based preconditioning regimen is widely used in HSCT for SAA from MSD or alternative donors.14, 15, 16 In such situations, low-dose TBI is usually combined with chemotherapeutic agents to avoid rejection in Japan. Adverse effects of radiation include not only LM but also endocrinological disorders, such as hypothyroidism or hypogonadism, or other organ dysfunctions. To reduce adverse effects, usage of radiation should be minimized, however, graft rejection is a serious complication of HSCT for SAA and low-dose TBI is an effective prophylactic tool for graft rejection. In terms of LM development after HSCT, usage of low-dose TBI might be tolerable in the Japanese population because of the low LM incidence, although long-term outcomes of childhood SAA patients after HSCT with Flu-based regimen has not yet been determined.
In conclusion, we reported long-term outcomes of childhood SAA patients who underwent HSCT from MSD in the Japanese Hematopoietic Cell Transplantation Registry with high OS and EFS. Only five cases of LM were identified in our series. The rarity of this event is in keeping with the low occurrence of skin cancer in Japanese population and with the low incidence of acute GVHD in our study group. In terms of LM development after HSCT, usage of low-dose TBI to avoid graft rejection might be tolerable in the Japanese population because of its low incidence.
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We thank all participating doctors and patients who were involved in the Japanese Hematopoietic Cell Transplantation Registry.
The authors declare no conflict of interest.
About this article
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