Total Body Irradiation Group Research Articles

Impact of Conditioning Regimen in Allogeneic Hematopoetic Stem Cell Tansplant for Children with AML beyond the First Complete Remission: Total Body Irradiation Versus Busulfan- a Pediatric Blood and Marrow Transplant Consortium (PBMTC) Study

Busulfan (Bu) based preparative regimen is the most commonly used regimen for children with AML in 1st complete remission (CR). However conditioning regimens for children with AML beyond the first clinical remission (≥ 2nd CR) often include total body irradiation (TBI), which may result in significant long term sequelae. There are limited data concerning outcome in children with AML beyond 1st CR and no data comparing conditioning regimens in this population. One hundred fifty-one patients ≤ 21 years with AML in ≥ CR2 were included in this study. These patients were treated at 47 pediatric transplant centers between 2000 and 2007 with complete data forms reported to the PBMTC database. The median follow up was 2.6 years (range 0.25–8.02). One hundred thirty-four (92%) were in CR2 with a median age 9.2 years (range 0.8–21.6). Ninety (60%) received TBI based regimens and 61 (40%) received Bu based regimens. A majority of those patients received TBI or Bu in combination with cyclophosphamide. Twenty-six (17%) received related donor transplants and 125 (83%) received stem cells from unrelated sources. Thirty nine percent of patients received cord blood transplants. AML was considered high risk in 4 (3%) patients, intermediate risk in 98 (82%) and low risk in 17 (14%). The median time between CR1 and relapse was 12 months (range 1–60) and from achieving 2nd CR to transplant was 1.5 months (range 0.23–10.4). There were no significant differences between patients receiving TBI and Bu conditioning regimens with respect to age, sex, disease risk, pretransplant performance score, duration of CR1, time from CR2 to transplant and stem cell or donor source. There were significantly more patients with history of extramedullary disease in the TBI group (36% vs. 18%, p=0.02). Transplant related mortality (TRM) was not significantly different between the TBI and Bu groups (22% vs. 16%, p=0.29). Infection was the most common cause of death accounting for 39 % of the overall TRM. The probability of relapse at 2 years was 26% and 27% in the TBI and Bu groups, respectively, and it was not significantly different (p=0.93). The probability of progression free survival (PFS) and overall survival (OS) at 2 years was 55% and 56 % respectively. There was no difference in PFS (p=0.29) or OS (p=0.11) between the 2 groups. A multivariable analysis was performed including patients age, donor relation (related versus unrelated), presence of extramedullary disease, donor sex, duration of CR1, time from CR2 to transplant, presence of HLA mismatch and use of TBI. Longer duration of CR1 was associated with improved OS (HR=0.93, 0.90 – 0.97, p<0.001) and PFS (HR=0.94, 0.91 – 0.97, p<0.001). Longer time from CR2 to transplant decreased OS (HR=1.28, 1.07 – 1.53, p=0.007) and PFS (HR=1.21, 1.02 – 1.44, p=0.033). Receiving a transplant from HLA mismatched donor decreased OS (HR=2.04, 1.07 – 3.86, p=0.030) and PFS (HR=2.04, 1.10 – 3.77, p=0.024). The use of TBI was not associated with improved PFS (HR=1.18, 0.66–2.11, p=0.58) or OS (HR=1.42, 0.77–2.65, p=0.27). Shorter duration of first complete remission, longer time from second remission to transplant and receiving HLA mismatched allogeneic transplant adversely affected PFS and OS. Our study provided no evidence of an advantage to using TBI in children with AML beyond first complete remission.

Limited Efficacy and Unacceptable Toxicity of Cyclophosphamide for the Induction of Mixed Chimerism and Renal Allograft Tolerance in Cynomolgus Monkeys

To induce mixed chimerism and renal allograft tolerance in cynomolgus monkeys, cyclophosphamide (CP) and total body irradiation (TBI) were compared as part of a nonmyeloablative conditioning regimen. CP induced dose-dependent neutropenia and lymphopenia, but hematopoietic recovery was more rapid than that observed in the TBI group. Absolute B cell counts after CP were significantly higher (P<0.01) than those in the TBI group. With CP, a total dose of 200 mg/kg with CD154 blockade regularly induced multilineage chimerism. Nevertheless, the recipients failed to achieve long-term survival because of rejection (3 of 5), posttransplantation B cell lymphoma (1 of 5), and toxicities of CP (1 of 5). As previously reported, 3 Gy of TBI with either splenectomy or CD154 blockade induced mixed chimerism and renal allograft tolerance, with significantly less morbidity and mortality than that produced by CP. Thus, TBI is more effective and less toxic than CP as part of a nonmyeloablative regimen for the induction of mixed chimerism and renal allograft tolerance in cynomolgus monkeys.

Total Body Irradiation (TBI) Based Versus Chemotherapy-Based Preparative Regimens Before Autologous Stem Cell Transplant for Non-Hodgkin's Lymphoma.

OBJECTIVES: The optimum high dose preparative regimen for non-Hodgkin lymphoma (NHL) patients undergoing autologous stem cell transplantation (ASCT) is unknown. We compared the radiation-based regimen of cyclophosphamide, etoposide and 12 Gy total body irradiation (CY/E/TBI) to carmustine, etoposide, cytarabine and melphalan (BEAM) in NHL patients who received ASCT. We investigated acute and long-term toxicities, disease free survival (DFS), overall survival (OS) of these two regimens.METHODS: A historical cohort study was performed at a provincial cancer centre. Cause specific survival was determined with the Kaplan-Meier method. Survival between groups was compared using the log-rank test.RESULTS: From Mar-1991 to Sep-2005, 79 patients received CY/E/TBI (n=32) or BEAM (n=47). Histology was indolent in 30 and aggressive in 49 patients. Cell source was bone marrow in six and 73 received peripheral blood progenitor cells. Prior to ASCT, ten patients were in complete remission, 47 had chemo-sensitive disease and 22 had chemo-resistant disease. There were only two cases of interstitial pneumonitis, with one in each preparative regimen group. There were six transplant related deaths; two in the BEAM group and four were in TBI group. The TBI based group has a higher mean mucosits score (p=0.03). Five year DFS was 47% and 51% in the TBI and BEAM groups, respectively (p=0.41). Five year OS was 50% and 64% for the TBI and BEAM based groups (p=0.07). Multivariate analyzes revealed that patients with more advanced disease and raised LDH at ASCT independently predicted inferior DFS. There was one case of acute myeloid leukemia and two of prostate cancer, all of whom were in the TBI group.CONCLUSIONS: In this study, a 12 Gy TBI-based regimen resulted in a similar DFS but a trend toward poorer OS and higher second malignancies than a BEAM-based regimen. However, there did not appear to be excess pulmonary acute toxicities in the TBI based group.

A prospective and randomized study of two conditioning regimens in treatment of severe systemic autoimmune diseases with autologous peripheral blood stem cell transplantation

To investigate the differences in immune reconstitution, hematopoietic reconstitution, efficacy, and complication between the two conditioning regimens with or without total body irradiation (TBI) in patients with refractory and severe autoimmune diseases (AID) who receiving autologous peripheral blood stem cell transplantation (APBSCT). Thirty-two AID patients, 5 males and 27 females, aged 29 (15 - 49), underwent APBSCT. The CD34(+) cells were mobilized with cytoxan (CTX) + granulocyte-colony stimulating factor (G-CSF) and selected by clinical magnetic activated cell sorting (CliniMACS). The conditioning regimen included CTX + antithymocyte globulin (ATG) in 11 patients and CTX + TBI in 21 patients. All the patients were followed up for more than 12 months. The median time of granulocyte recovery were 11 and 9 days in the CTX + TBI and CTX + ATG groups respectively (P = 0.003), the median time of platelet recovery were 13 and 8 days respectively (P = 0.001). In both groups, the lymphocyte subsets were recovered with the inverted CD4/CD8 ratio 12 months after transplantation. Relapse was seen in 3 cases of the CTX + TBI group (14.3%), and 2 cases of the CTX + ATG group (18.2%), and the rest of patients remained free of AID. During transplantation incidence of bacteria infection occurred in 5 of the 21 cases in the CTX + TBI group (23.8%) and in 2 of the 11 cases of the CTX + ATG group (18.2%) respectively; viral infection occurred in 1 of the 21 cases of the CTX + TBI group (4.8%) and in 2 of the 11 cases of the CTX + ATG group (18.2%) respectively. The number of radiated parotitis was 4 among the 21 patients of the CTX + TBI group (19%) and was 3 among the 12 patients of the CTX + ATG group (25%). Serum sickness reaction occurred in 3 of the 12 patients of the CTX + ATG group (25%). Bacterial and viral infections were cured soon after antibacterial or antiviral therapy, no fatal bleeding occurred due to thrombocytopenia in both groups. The conditioning regimen of TBI + CTX delays the hematopoietic reconstitution compared with the ATG + CTX regimen in treating AID. The regimen of CTX + TBI can be better tolerated, but there are no significant differences in efficacy and immune reconstitution among these two regimens.

Total Body Irradiation (TBI) Added to Fludarabine/Busulfan/Antithymocyte Gobulin (FLUBUP/ATG) Conditioning Increases Overall Survival and Relapse-Free Survival in Patients with Acute Myeloid Leukemia (AML) Receiving Allogeneic Stem Cell Transplants.

Myeloablative conditioning with FLUBUP (fludarabine 50mg/m2 i.v. days -6 to -2 and busulfan 3.2mg/kg i.v. once daily days -5 to -2) is convenient to administer and relatively well tolerated. The addition of ATG (Thymoglobulin 4.5mg/kg over 3 days) to cyclosporine and short course methotrexate appears to decrease the incidence and severity of graft-versus-host disease (GVHD) but may contribute to a still unacceptable relapse rate when this regimen is used in AML. We have added low dose TBI (200cGy x 2 day -1 or 0) to our standard FLUBUP/ATG conditioning regimen in all patients with AML in an effort to enhance cytotoxicity and reduce relapse rate. 135 patients (pts) received allogeneic stem cell transplants at our centre between 07/99 and 05/05. Ninety pts (66.7%), transplanted between 07/99 and 04/04 received FLUBUP/ATG while the remaining 45 (33.3%) received FLUBUP/ATG+TBI. Patient age was 16–65, median 42, in the FLUBUP/ATG group and 20–63, median 46, in the group with additional TBI. 71.1% of pts receiving TBI were in CR1 or CR2 compared to 62.2% of those not receiving TBI (p=ns). The remainder had more advanced disease. The distribution into standard cytogenetic risk groups between the two groups was also not statistically significant. More pts received peripheral blood stem cells in the TBI group (73.3% vs. 91.1%, p=0.02). In the TBI group 17 pts (37.8%) received a matched related donor transplant as opposed to 50 (55.6%) in the non-TBI group. The others were transplanted from mismatched related or volunteer unrelated donors. There was no difference between the groups with respect to neutrophil and platelet engraftment, rates of severe acute GVHD (6.6% Grade III-IV in the TBI group vs 7.8% for the non-TBI group) or chronic GVHD (51.1% in the TBI group vs 50.0 in the non TBI group). At one year non-relapse mortality was 12.2% vs.16.7% (p=ns) and relapse was 37.8% vs.13.3% (p=0.003) in the groups with and without TBI respectively. Overall survival (OS) at one year was 82% (95% CI 68%-91%) in the TBI group versus 61% (95% CI 50%-70%) in the non-TBI group (p=0.015). After adjusting for risk group, donor type and patient age the Cox proportional hazards ratio was 0.41 (0.19–0.90) in favour of the addition of TBI. Pts receiving FLUBUP/ATG+TBI were therefore 60% less likely to die within the first year than those receiving FLUBUP/ATG. When OS was assessed including all available observation time the statistical difference by log-rank test persisted, p=0.0237. Relapse-free survival was also improved by the addition of TBI (80% (65%-89% vs. 50% (39%-60%), p=0.001). After adjusting for risk group, donor type, patient age as well as cytogenetic risk group the Cox proportional hazards ratio was 0.23 (0.11–.0.50) in favour of additional TBI suggesting that pts receiving TBI were about 77% less likely to die or relapse within the first year compared to pts who did not receive TBI. The addition of TBI was well tolerated and helped overcome the risk of relapse associated with increased immunosuppression from ATG.

Impact of TBI on late effects in children treated by megatherapy for Stage IV neuroblastoma. A study of the French Society of Pediatric oncology

To determine the contribution of total body irradiation (TBI) to late sequelae in children treated with high-dose chemotherapy and autologous bone marrow transplantation for Stage IV neuroblastoma. We compared two populations that were similar with regard to age, stage, pre-autologous bone marrow transplantation chemotherapy (CT) regimen, period of treatment, and follow-up (12 years). The TBI group (n = 32) received TBI as part of the megatherapy procedure (1982-1993), whereas the CT group (n = 30) received conditioning without TBI (1985-1992). Analysis 12 years later focused on growth, weight and corpulence (body mass index) delay; hormonal deficiencies; liver, kidney, heart, ear, eye, and dental sequelae; school performance; and the incidence of secondary tumors. Impact of TBI was most marked in relation to growth and weight delay, although the mean delay was not severe, probably because of treatment with growth hormones. Other consequences of TBI were thyroid insufficiency, cataracts, and a high incidence of secondary tumors. Hearing loss and dental agenesis were more prominent in the group treated with CT alone. No differences were observed in school performance. The most frequent side effects of TBI were cataracts, thyroid insufficiency, and growth delay, but more worrying is the risk of secondary tumors. Because of the young mean age of patients and the toxicity of TBI regimens without any survival advantage, regimens without TBI are preferable in the management of Stage IV neuroblastoma.

The Influence of Adding Low-Dose (400cGy) Total Body Irradiation (TBI) on Outcomes of Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukaemia (AML) with Myeloablative Conditioning Incorporating Daily Intravenous Busulfan, Fludarabine and Low-Dose Antithymocyte Globulin.

Intravenous (IV) busulfan (BU) gives more predictable exposure than the oral form and is easier to administer once daily than the conventional four times daily schedule. Fludarabine is immunosuppressive, antileukaemic and perhaps better tolerated than cyclophosphamide. Antithymocyte globulin may reduce graft-versus-host disease (GVHD). We have investigated a conditioning regimen combining these agents in AML and are exploring the possibility that adding a low dose of total body irradiation (TBI) may enhance cytoreduction and decrease relapse rate without increasing toxicity. Of a total of 133 pts 86 (65%) had good-risk (GR) leukaemia in CR1 (n=64) or CR2 (n=22), 47(35%) had more advanced disease (HR). Of the 120 instances where cytogenetics were available 13 (11%) had good risk karyotypes while 84 (70%) of karyotpyes were standard risk and 23 (19%) high risk. Donors were matched siblings (MRD) for 66 (50%) and alternate donors (AD, 55 unrelated and 11 mismatched related) for 67 (50%). Cell source was blood in 64 MRD (98%) and 40 (60%) AD pts. Median pt age was 43 (range 16–65) years. All pts received fludarabine 50mg/m2 on days -6 to -2 and IV BU (Busulfex, ESP Pharma) at a “myeloablative” dose of 3.2 mg/kg daily days -5 to -2 inclusive. Additional TBI 200cGy x 2 was given to 43 pts (31 GR, 12 HR, 16 MRD, 27 AD). The distribution of cytogenetic changes was not significantly different in the TBI and no TBI groups (good risk 13% vs. 10%, standard risk 65% vs. 73% and high risk 23% vs. 14%). All pts received cyclosporine A, “short course” methotrexate with folinic acid and Thymoglobulin (Genzyme) 4.5 mg/kg in divided doses over 3 consecutive days pretransplant finishing D0. Follow-up of survivors is 4-71 months, median 30.5. Acute GVHD grade II-IV occurred in more recipients of SCT from AD (27±6% vs 11±4%, p = 0.02). Incidence of grade III-IV acute GVHD at 9±4% and 8±4% and chronic GVHD (at 2 years) at 59±7% and 62±10% was similar. Projected TRM at 3 years was 10±4% for MRD recipients vs 16±5% for the AD group (p = ns) and was 12±6% vs 15±4% with and without TBI respectively (p = ns). Relapse at 3 years was not significantly affected by donor (GR MRD 27±7% vs AD 21±7%, HR MRD 83±10% vs AD 68±15%) or by acute or chronic GVHD. There was less relapse after the TBI containing regimen in HR recipients (35±17% vs 81±8% at 3 years, p = 0.015), the difference for GR pts at 10±5% vs 31±7% respectively did not reach significance. Projected outcomes at 3 years for GR pts are OS 83±8% with TBI vs 66±6% without (p = ns), and DFS 83±8% with vs 60±7% without TBI respectively (p = 0.03). For HR disease projected OS was 61±15% with TBI and 28±8% without TBI (p = 0.06), DFS was 48±15% and 15±6% respectively (p = 0.06). For GR pts OS is estimated to be 71±8% and 68±8% and DFS 68±7% and 67±8% with MRD and AD respectively. Corresponding figures for HR disease are OS 29±10% 36±11% and DFS 13±8% and 26±13%. None of these differences are significant. This regimen appears relatively well tolerated and gives equivalent results for MRD and AD. Further study is needed to confirm that additional TBI does not add to TRM but may reduce relapse.

Normal spontaneous cortisol secretion in children after autologous bone marrow transplantation

To describe spontaneous cortisol secretion in children after autologous bone marrow transplantation (BMT) for acute leukaemia and lymphoma. Spontaneous cortisol secretion was analysed in 39 children before and after BMT. Thirteen patients were conditioned with chemotherapy only (group 1), and 26 patients also with total body irradiation (TBI). In the TBI group, 14 patients had received no additional irradiation (group 2), whereas 12 patients had received cranial irradiation (CRT) previously (group 3). Before BMT, in comparison with group 1, mean morning cortisol was significantly lower in group 2 (252 vs 415 mmol/l, p = 0.004), but not in group 3 (vs 312 mmol/l, p = 0.12). There was no change in group 1 six months after BMT (to 379 nmol/l), whereas morning cortisol increased significantly in group 2 and group 3 (to 386 and 343 nmol/l, respectively; p < 0.05). The change in mean morning cortisol correlated negatively with pretransplant morning cortisol (r = -0.63, p < 0.001). Neither TBI nor CRT were associated with changes in morning cortisol. Spontaneous cortisol secretion is maintained after BMT irrespective of whether cranial or total body irradiation has been given or not.

Treatment outcomes and patterns of failure following autologous stem cell transplant for relapsed/refractory Hodgkin’s disease

6671 Background: To evaluate all patients with relapsed or refractory HD who underwent autologous transplants with either chemotherapy or total body irradiation (TBI) based preparative regimens to determine their outcomes and analyze their pattern of failure. Methods: Retrospective chart review of 63 patients with relapsed/refractory HD who were treated with high dose therapy at Loyola University Medical Center over the past 7 years. Overall Survival (OS) and Progression-Free Survival (PFS) were analyzed with the Kaplan Meier method and the log rank test was used to test for differences. Patient, disease, and treatment factors were analyzed for their influence on relapse and survival. Results: 63 patients underwent transplant from February 1997 to February 2004. median age was 35 years, median follow-up was 27 months. The preparative regimens were TBI-based in 36 (57%) patients and chemotherapy-based in 27 (43%). Of the patients with chemo sensitive disease, only 3 of 27 (11%) who achieved complete remission (CR) prior to transplant failed compared to 4/12 (33%) who achieved a PR and 7 of 16 who had a minor response and 6/8 who had progressive disease (p <0.05). Of the 20 who relapsed after their transplant, 13 (65%) relapsed in the same site as their disease at relapse, 4 relapsed in the same and new sites of disease and 2 relapsed in new sites. The 5-year OS and PFS for the whole group of patients are 60% and 65%. The 5-year PFS for the TBI group is 69% vs. 57% for the non-TBI group (p=0.23). The 5-year OS for the patients who relapsed after autologous transplant was 25%, 5 of those who relapsed were salvaged with either an allogeneic transplant (4 patients) or radiotherapy (1 patient). 3 additional patients had therapy-related myelodysplastic syndrome or leukemia and two of them were salvaged with an allograft. Conclusions: The PFS at 5-years for TBI-based transplants appears to be better than non TBI regimens (69 vs 57%) although not statistically significant. Those transplanted in CR have the best outcome, thus attention to optimizing tumor cytoreduction prior to transplant should be a priority. A significant minority of patients who relapse after an autograft can be long-term survivors after an allograft. No significant financial relationships to disclose.

Neuropsychological resiliency after treatment for advanced stage neuroblastoma

The purpose of this study was to describe the neuropsychological functioning of survivors of advanced stage neuroblastoma. In all, 16 survivors, diagnosed at a median of 2.8 years, who had received intensive chemotherapy and surgical treatments, were identified; 11 had received myeloablative consolidation therapy, eight with total body irradiation (TBI). All patients were evaluated with a neuropsychological assessment battery at a median age of 8.8 years. Analyses included comparison of the performances of the TBI group vs the no-TBI group; determination of whether the proportion of individuals with impaired or superior performance on each measure exceeded normative expectations; and performance indexes reflecting patterns of performance. Results indicate no significant deleterious impact of TBI and/or presence or absence of myeloablative therapy on neurocognitive and neurobehavioral functioning. For this cohort, resilience to neuropsychological vulnerability was observed, which included the emergence of a profile of full-scale IQ, verbal IQ, and mathematical achievement well above average expectations. We concluded that the results document a lack of neuropsychological morbidity among this cohort of survivors of advanced stage neuroblastoma, regardless of the inclusion of TBI. Moreover, a striking pattern of excellent neurocognitive functioning with intact neurobehavioral functioning was observed.

Disturbed root development of permanent teeth after pediatric stem cell transplantation

Deficient dental root development has been reported after conventional pediatric anticancer therapy, but less information is available on stem cell transplantation (SCT) recipients. Root-crown (R/C) ratios of fully developed permanent teeth were assessed from panoramic radiographs of 52 SCT recipients, who were treated when they were age < 10 years. Using standard deviation scores (SDSs), the authors compared the R/C ratios to the corresponding tooth and gender-specific values in a healthy population. The percentage of affected R/C ratios per individual was examined in a subgroup of 39 (SG39) patients with advanced tooth development. The effects of total body irradiation (TBI) and SCT age on the R/C ratios were studied in TBI and high-dose chemotherapy (HDC = non-TBI) groups and in 3 age groups (< or = 3.0 years, 3.1-5.0 years, > or = 5.1 years). Per individual, 77% of the fully developed permanent teeth were affected in SG39. At the tooth level, in 77% of the 945 teeth studied (52 patients), the R/C ratios were outside +/-2 SDSs. More teeth were affected in the TBI (85%) than in the non-TBI (55%) group (P < 0.001). The teeth of the patients who were ages 3.1-5.0 years old at SCT presented with the most severe aberrations of the R/C ratio (mean SDS = -4.4) whereas the teeth of the youngest (age < or = 3.0 years) and the oldest (age > or = 5.1 years) patients were equally affected (mean SDSs = -3.1 and -3.0, respectively). Disturbances of dental root growth always followed pediatric SCT. HDC alone intensely harmed root growth but TBI further increased the adverse effects that were most extensive in the patients 3.1-5.0 years at SCT. These sequelae should be taken into account during the lifelong dental follow-up to minimize the clinical consequences of dental injuries.

Comparison of Conditioning Regimens with or without Total Body Irradiation in Bone Marrow Transplantation from an Alternative Donor.

An optimum conditioning regimen is indispensable in improving outcomes for patients with acquired aplastic anemia (AA) who receive bone marrow transplantation (BMT) from an alternative donor. Although high-dose total body irradiation (TBI) is effective in enhancing engraftment, intensive conditioning regimens are associated with increased regimen-related toxicity, which results in a decreased success rate. Currently, two different approaches are primarily used; a conditioning regimen including low-dose TBI and a fludarabin-based regimen without TBI. We attempt to clarify the efficacy and regimen-related toxicity of these two approaches. Ten patients (7 males, 3 females; median age 12y; range 9–17y) underwent an alternative donor transplant following a conditioning regimen with low-dose TBI (TBI group); patients received cyclophosphamide (50 mg/kg/d on days −5 to −2), antithymocyte globulin (Thymoglobulin, 2.5 mg/kg/d on days −5 to −2) and TBI (2.5 Gy x 2 on day −1). The donor was unrelated in 9 patients (3 were serologically HLA A or B antigen mismatched; 3 were serologically HLA DR antigen mismatched, 1 was both serologically and genotypically DR antigen mismatched; 1 was genotypically DRB1 mismatched; 1 was a genotypically complete match) and was a family member in 1 patient (serologically HLA A-mismatched father). Twelve patients (6 males, 6 females; median age, 11 y; range 2–20 y) received a conditioning regimen of fludarabine (25 mg/kg/d on days −5 to −2), cyclophosphamide (750 mg/m 2 /d on days −5 to −2), thymoglobulin (1.5 mg/kg/d on days −5 to −2) and thoracoabdominal irradiation (TAI, 3Gy x 1 on day −1) (TAI group). The donor was unrelated in 11 patients (8 were genotypically complete matches, and 3 were genotypically DRB1 antigen mismatched) and a family member in 1 patient (3 antigen-mismatched mother). The source of stem cells was unmanipulated bone marrow. Graft versus host disease (GVHD) prophylaxis consisted of tacrolimus (0.02 mg/kg from day −1) and short-term methotrexate. Rejection was seen in one patient in each group. The doses of infused nucleated marrow cells were less than 2.0 x 10 8 /kg in both patients, and both patients then received a second transplant and achieved full donor chimerism. Acute GVHD grade II-IV developed in 2/10 evaluable patients in the TBI group and in 3/12 patients in the TAI group. Chronic GVHD developed in 5/9 evaluable patients in TBI group and 3/10 evaluable patients in TAI group. Median follow up was 9 months (4–27 months) in the TBI group and 21 months (3–33 months) in the TAI group. Both conditioning regimens were well tolerated and effective even in HLA-mismatched unrelated donor transplantation. Long-term follow up is warranted in order to compare the late sequelae in both regimens.

Agenesis and microdontia of permanent teeth as late adverse effects after stem cell transplantation in young children

The objective of the current study was to examine the occurrence of tooth agenesis and microdontia in pediatric stem cell transplantation (SCT) recipients. The impact of total body irradiation (TBI) and age at SCT on agenesis and microdontia of permanent teeth was examined in 55 patients from panoramic radiographs. Assessment A1 (for tooth agenesis and microdontia) excluded the third molars, and assessment A2 (for tooth agenesis) included the third molars. Patients were grouped according to TBI status (the TBI group vs. the non-TBI group) and age at SCT (patients age < or = 3.0 years [Group Y], patients ages 3.1-5.0 years [Group M], and patients age > or = 5.1 years [Group O]). From 1 to 12 teeth were missing in 77%, 40%, and 0% of patients (assessment A1) in Groups Y, M, and O, respectively (Group Y vs. Group M, P=0.055; Group Y vs. Group O, P < 0.001; and Group M vs. Group O, P=0.002), increasing to 83%, 78%, and 43%, respectively, when the third molars were included (assessment A2; P values were not significant). Correspondingly, 75%, 60%, and 13%, respectively, of patients had 1-12 microdontic teeth (assessment A1: Group Y vs. Group M, P=0.306; Group Y vs. Group O, P <0.001; and Group M vs. Group O, P=0.003). Recipient age at the time of SCT was found to have a negative correlation with the number of missing teeth (P=0.001) and microdontic teeth (P=0.005). TBI appeared to have little effect on the prevalence of tooth agenesis (assessment A1: TBI group, 32%; non-TBI group, 29%; assessment A2: TBI group, 72%; non-TBI group, 46%; P values were not significant) or on the prevalence of microdontia (assessment A1: TBI, 41%; non-TBI, 50%; P value was not significant). A tendency toward an increased number of affected teeth was noticed in the group of patients who received TBI. Depending on their age at SCT, 50-100% of pediatric SCT recipients will later present with agenesis and/or microdontia of permanent teeth that may jeopardize occlusal development. Young age (< or = 5.0 years) at SCT was found to be a stronger risk factor than TBI, although TBI caused additive impairment.

Complications thyroïdiennes après greffes de cellules souches hématopoïétiques dans l’enfance

To evaluate the percentage and risk factors of thyroid dysfunction in 79 children who underwent bone marrow transplantation in a single centre. Patients and methods. – The mean age of the cohort was 6.8 and mean follow-up 5.5 years. The 79 patients were divided in two groups according to the pretransplant conditioning regimen: fractionated total body irradiation (TBI)( N =54), chemotherapy with Busulphan ( N =25). Thyroid function was evaluated by thyroid-stimulating hormone (TSH) and free thyroxine (fT4) tests. Overt hypothyroidism was defined by low fT4 blood levels and TSH > 4mU/l, and compensated hypothyroidism by normal fT4 index and TSH >4mU/L. Results. – The six-year probability of hypothyroidism was 36 ±6% for the whole group of 79 patients, 49 ±8% after TBI and 9 ±6% in the Busulphan group ( P <0.001). Neither gender, nor primary disease, nor presence of graft versus host disease were found to be statistically significant for occurrence of hypothyroidism in the TBI group. However, a younger age seemed to influence statistically the 6-year probability of hypothyroidism in the TBI group: 59 ±9% if age <7.7 years versus 34 ±13% if age >7.7 years ( P =0.02). Conclusion. – A careful follow-up of thyroid function is recommended even without TBI conditioning regimen. Young age as a potential risk factor of hypothyroidism has never been described and needs to be studied in a larger cohort.

Zinc Sulfate in the Prevention of Total-Body Irradiation-Induced Early Hematopoietic Toxicity: A Controlled Study in a Rat Model

Exposure to ionizing total-body radiation suppresses hematopoiesis, resulting in decreased production of blood cells. Many researchers have demonstrated the critical role of zinc (Zn) in diverse physiological processes, such as growth and development, maintenance and priming of the immune system, and tissue repair. The aim of the present study was to determine the effects of zinc sulfate (40 mg/kg and 80 mg/kg) on early hematopoietic toxicity, caused by total-body irradiation (TBI) of rats with a single dose of 8 Gy. Both in the Zn 40 and in the Zn 80 groups, there were significantly increased white blood cell (WBC) count, when compared with control group. The WBC count was higher in the control group than in the TBI group. This result was statistically significant (p<0.05). Both the TBI+Zn 40 and the TBI+Zn 80 groups had a significantly protected WBC count against TBI. No difference was detected in any final measurement of thrombocyte count and hemoglobin level with direct comparison among all groups, with the exception that the hemoglobin level in the Zn 80 group compared to the control group. Whereas hemoglobin level in the control group was at a median figure of 13.98 g/dL (13.30-14.80), it was at a median figure of 14.25 g/dL (14.10-15.50) in the Zn 80 group. It would be worthwhile studying the effect of oral zinc sulfate supplements in radiation-treated cancer patients, in the hope of reducing radiation-induced toxicity.

Tissue Trace Element Change after Total Body Irradiation

Purpose: In this study, we examined the changes of tissue contents of trace elements and iron after total body irradiation (TBI) and their possible impact on late toxicities. Material and Methods: 20 female Wistar rats were randomly assigned to two groups – either radiation (n = 10) or control (n = 10). Rats in the radiation group received TBI of 5 Gy in a single fraction. Rats were sacrificed and tissue samples of heart, lung and kidney were taken 8 weeks after radiation. Tissue levels of zinc, copper, magnesium, manganese and iron analysis were performed with an atomic absorption spectrophotometer and suprapure grade standard solutions. One kidney of each animal was taken for electron microscopic analysis. Blood samples were collected from all animals and the blood chemistry related to kidney function was studied. Results: The kidney levels of Fe and Cu significantly increased 8 weeks after irradiation (p < 0.05). The Cu/Zn ratio did not reach statistical significance in any tissue, however in kidney, there was a tendency to rise (p = 0.08). Myocardium and lung content of trace elements and iron did not show any significant change 8 weeks after irradiation. Electron microscopic analysis showed significant injury in glomerular endothelial cells, renal tubules and thickening of basement membrane. Blood chemistry showed a significant rise in serum creatinine (p = 0.008) and calcium (p = 0.01) in the TBI group. Serum creatinine levels were 0.73 and 0.84 mg/dl, and serum calcium levels were 10.1 and 11.3 mg/dl in control and TBI groups, respectively. Conclusion: A sublethal dose of TBI causes deposition of Cu and Fe within the kidney after TBI. Deposition of these elements may have some additional role on the toxicity caused by direct radiation on the kidney.

Effects of total body irradiation on the vascular endothelium.

Total body irradiation (TBI) is used as conditioning for stem cell transplantation. We studied its effects on the vascular endothelium in 55 consecutive patients undergoing stem cell transplantation with TBI (TBI group n=35) or without TBI (non-TBI group: n=20). Fifty patients underwent bone marrow transplantation and five underwent peripheral blood stem cell transplantation. The levels of thrombomodulin, plasminogen activator inhibitor-1, and cyclic GMP were measured before and after TBI. At both times, the thrombomodulin and plasminogen activator inhibitor-1 levels were within the normal range in all patients from the two groups, without any significant differences between the groups. The cyclic GMP level was increased after TBI in six of 35 patients. Five of these six patients died as a result of complications of transplantation, while one patient survived in whom the cyclic GMP level rapidly returned to normal. In contrast, the cyclic GMP level remained normal in all patients not receiving TBI. These results suggest that conditioning with TBI stimulates vascular endothelial cells, even if it does not cause immediate direct injury. Such stimulation may be related to vascular endothelial dysfunction, the development of which may be mediated by nitric oxide.

Long-term adverse effects on dentition in children with poor-risk neuroblastoma treated with high-dose chemotherapy and autologous stem cell transplantation with or without total body irradiation.

Chemo- and radiotherapy may have injurious effects on developing teeth. In this long-term follow-up study among poor-risk neuroblastoma (NBL) survivors our aims were: (1) to assess both the type and extent of the side-effects of the anticancer treatment on tooth development; and (2) to develop an index for expressing total damage to the permanent dentition. We studied the dental development from panoramic radiographs (PRG) of 18 long-term survivors treated under the age of 6 years with high-dose (HD) chemotherapy and autologous stem cell transplantation (ASCT) for poor-risk NBL. The myeloablative therapy was either HD chemotherapy and fractionated total body irradiation (TBI) of 10-12 Gy (TBI group, n = 10) or HD chemotherapy only (non-TBI group, n = 8). A defect index (DeI) was developed to describe the damage to the permanent dentition. The DeI was also tested in 18 healthy adolescents. All NBL patients had disturbances in dental development including short roots, arrested root development, microdontia and tooth aplasia. After TBI, 9/10 patients had very severe root defects, in contrast to none in the non-TBI group. All children in the TBI group had 2-12 (mean 6.6) missing permanent teeth, while 2/5 in the non-TBI group (3/8 excluded due to young age) had two and four missing permanent teeth, respectively. Microdontia was found at equal frequency in both groups. The mean value of the DeI was 70.0 (range 28-117) in the TBI group, 15.2 (range 4-34) in the non-TBI group (P<0.001, Mann-Whitney U test) and 1.8 (range 0-15) in healthy adolescents. Disturbances in dental development may compromise occlusal function in poor-risk NBL patients after ASCT, especially when TBI is included in the conditioning regimen. Long-term dental follow-up and rehabilitation is required.

Cataracts after autologous bone marrow transplantation in children

We recorded the incidence and degree of posterior subcapsular cataract (PSC) in 29 children who had undergone autologous (n = 28) or syngeneic (n = 1) bone marrow transplantation (BMT) due to haematologic or lymphoid malignancy. Conditioning prior to transplantation consisted either of a combination of chemotherapy and total body irradiation (TBI) (n = 21) or of chemotherapy only (n = 8). TBI was given in one fraction of 7.5 Gy. Nine patients had received previous cranial irradiation. The patients were followed for 4-10y (median 8 y) after transplantation. Of 29 patients, 22 developed PSC, all within 4 y after BMT. With the exception of one patient who developed unilateral PSC, all had received TBI. Conversely, 100% of those who received TBI developed PSC. In this group (+TBI), eight patients (38%) developed significant PSC, defined as best corrected visual acuity <0.8 in either eye. Six patients (10 eyes) have since needed surgical repair consisting of extracapsular cataract extraction and intraocular lens implantation. There was no clear relationship between previous cranial irradiation and cataract development, nor any other obvious baseline differences between those in the +TBI group who developed significant PSC and those who did not. Although effects of previous therapy cannot be ruled out, TBI appears to be the main cause of PSC in this group of patients. Twelve patients in the +TBI group had well-preserved visual acuity throughout the study, reflecting a slow progression of PSC. This compares favourably with previous reports of allogeneic BMT, possibly owing to less need for corticosteroids after autologous BMT. We conclude that the incidence of PSC was high after autologous BMT where the conditioning regimen included total body irradiation.

Cataracts after autologous bone marrow transplantation in children

We recorded the incidence and degree of posterior subcapsular cataract (PSC) in 29 children who had undergone autologous (n = 28) or syngeneic (n = 1) bone marrow transplantation (BMT) due to haematologic or lymphoid malignancy. Conditioning prior to transplantation consisted either of a combination of chemotherapy and total body irradiation (TBI) (n = 21) or of chemotherapy only (n = 8). TBI was given in one fraction of 7.5 Gy. Nine patients had received previous cranial irradiation. The patients were followed for 4-10 y (median 8y) after transplantation. Of 29 patients, 22 developed PSC, all within 4 y after BMT. With the exception of one patient who developed unilateral PSC, all had received TBI. Conversely, 100% of those who received TBI developed PSC. In this group (+TBI), eight patients (38%) developed significant PSC, defined as best corrected visual acuity < 0.8 in either eye. Six patients (10 eyes) have since needed surgical repair consisting of extracapsular cataract extraction and intraocular lens implantation. There was no clear relationship between previous cranial irradiation and cataract development, nor any other obvious baseline differences between those in the +TBI group who developed significant PSC and those who did not. Although effects of previous therapy cannot be ruled out, TBI appears to be the main cause of PSC in this group of patients. Twelve patients in the +TBI group had well-preserved visual acuity throughout the study, reflecting a slow progression of PSC. This compares favourably with previous reports of allogeneic BMT, possibly owing to less need for corticosteroids after autologous BMT. We conclude that the incidence of PSC was high after autologous BMT where the conditioning regimen included total body irradiation.