Radiotherapy and Oncology, Suppl. 1 (1990) 139-14’2 Elsevier
Renal insuffxiency after total body irradiation for pediatric bone marrow transplantation Nancy J. Tarbell’, Eva C. Guinan2, Lee Chin’, Peter Mauch’ and Howard J. Weinstein2 lDepartment
of Radiation Therapy, Joint Center for Radiation Therapy, Harvard Medical School, 2Division of Pediatric Oncology,
Dana Farber
Cancer Institute and The Children’s Hospital, Harvard Medical School, Boston, MA, U.S.A.
Keywords: Total body irradiation; Radiation nephrotoxicity
Summary Between 1980 and 1987,59 children with acute lymphoblastic leukemia (ALL) or stage IV neuroblastoma (NB) underwent allogeneic or autologous bone marrow transplantation (BMT). Thirty-nine of these patients were alive and in remission 6 months post BMT and were evaluable for this analysis. Sixteen have developed renal dysfunction. Eight were transplanted for relapsed ALL and received an autologous transplant. Preparation included tenopiside (VM 26), cytosine arabinoside, and cyclophospharnide followed by total body irradiation (TBI). One patient received 850 cGy in a single fraction, while all other patients received fractionated TBI (1200-1400 cGy in 6-8 fractions over 3-4 days). Eight of 11 evaluable patients who received a BMT for NB have developed late renal problems (4-7 months after BMT). The preparation for neuroblastoma patients included VM 26, cis-platinum, melphalan, cyclophosphamide and fractionated TBI (1200-1296 cGy). All 8 neuroblastoma patients had received cis-platinum as induction treatment prior to transplantation. All patients presented with anemia, hematuria and elevations of BUN and creatinine. Renal biopsies were consistent with radiation nephropathy. In conclusion, a high incidence of renal dysfunction has occurred after BMT in children with neuroblastoma and ALL. The clinical and laboratory features are consistent with either radiation nephropathy or hemolytic-uremic syndrome. The relatively young age of these patients and conditioning with intensive multi-agent chemotherapy may decrease the tolerance of the kidney to radiation injury.
Introduction Recent reports detail the acute and chronic toxicities associated with BMT, however, primary renal disease after BMT is rarely observed. There are only three previous cases reported in the literature. We describe here the relatively frequent occurrence of a syndrome consistent with acute radiation nephropathy in two groups of patients prepared with multi-agent chemotherapy and TBI prior to either autologous or allogeneic bone marrow reinfusion.
0167-8140/90/$03.50
0 1990 Elsevier Science Publishers B.V. (Biomedical Division)
140 Patients and Methods Fifteen children with stage IV neuroblastoma and 44 patients with CALLA (common acute lymphoblastic leukemia antigen) positive acute lymphoblastic leukemia (ALL) received bone marrow transplants between November 1980 and January 1988; late onset renal insufficiency was observed in several of these children and prompted a study of renal function in these patients. Patients who were alive and in remission for greater than three months post-transplant were considered evaluable for late effects of transplantation. The 44 patients with relapsed CALLA positive acute lymphoblastic leukemia (ALL) did not have HLA-identical sibling donors and were transplanted in second or subsequent remission with autologous marrow purged with monoclonal antibody [l]. All had received prior therapy with multiple chemotherapeutic agents and had been conditioned for transplantation with cyclophosphamide, cytosine arabinoside, tenopiside (V&l-26), and total body irradiation (TBI). The original TBI for the first five CALLA patients was given as 850 cGy in a single fraction at 5 cGy/min. A dedicated facility was built in 1983 and at that time a change was made from single fraction to fractionated TBI (1200 cGy in 6 fractions). With time the total dose for the autologous ALL protocol increased to 1300 cGy and then 1400 cGy with a change in the fractionation as well from 216 cGy in 6 fractions to 175 in 8 fractions. All patients were treated twice daily with a time interval of 4-6 h between fractions. All patients receiving fractionated TBI were treated at 10 cGy/min (range 9-l 1 cGy/min). The dose was prescribed at the midplane at the level of the umbilicus in all patients. The design and characteristics of the 4 MV total body irradiator include two 4 MV linear accelerators, one mounted in the ceiling, the other in a floor-pit. The distance between the two sources is 410 cm to produce a field size of 200 cm x 75 cm in the midplane. This field covers the patient, lying supine on a stretcher halfway between the sources. Special beam hardening and flattening filters were built to achieve acceptable dose profiles in the large field. Because of the wide beams, large rectangular parallel-plate ionisation chambers were built to serve as beam monitors. The dose rate at 205 cm distance from the sources is 10 cGy/min, each machine contributing half [2]. After BMT, all patients were followed routinely as outpatients. None of the patients were treated with cyclosporin. Of the 15 patients with neuroblastoma, 6 received HLA-identical marrow, one received paternal haploidentical marrow, and 8 received autologous marrow purged with monoclonal antibodies. All patients received prior therapy with multiple chemotherapeutic agents according to the MADDOC protocol (cyclophospharnide, cis-platinum, vincristine, doxorubicin, nitrogen mustard, and DTIC) [31. The pretransplant conditioning regimen included VM-26, cyclophosphamide, cisplatinum, melphalan, and TBI. The TBI dose for the neuroblastoma patients was 1200 cGy in 200 cGy fractions given twice daily at a dose rate of 10 cGy/min (one patient received 1296 cGy in six fractions). The patients who received allogeneic transplants were given methotrexate 10 mdm2 on days, 1,3,6 and 11 post-transplant for graft-versus-host disease prophylaxis.
Results Eleven of the 15 patients with neuroblastoma and 28 of the 44 patients with ALL were evaluable for late complications. Eight of 11 evaluable patients post-transplant for stage IV neuroblastoma and 8 out of 28 evaluable patients post-autologous transplant for relapsed ALL were found to have evidence for concurrent renal dysfunction and anemia presenting between 3 to 7 (median of 5) months post BMT. The 16 affected patients ranged in age from 3 to 15 years (median of 6). Three patients had renal biopsies performed after the onset of clinical renal dysfunction. Pathology showed striking mesangiolysis with
141 Table I. Total body irradiation (# FX)
Overall TX time (days)
Fraction size cGy (twice daily)
Dose rate cGy/min
# Renal prob/ # Survivors
All patients 850 1200 1300 1400
(1) (6) (6) (8)
1 3 3 4
200 216 175
5 10 10 10 Total
115 l/5 316 4112 9128
NB patients 1200 1300
(6) (6)
3 3
200 216
10 10
6110 l/l
Total dose ~GY
# FX = number of fractions.
intraglomerular capillary aneurysm formation, and mesangial hyperplasia. Some glomeruli showed ischemic atrophy and were surrounded by atrophic tubules and fibrotic interstitium. The blood vessel changes were limited to the small interlobular vessels and afferent arterioles. Mild intimal hyperplasia without fibrinoid necrosis was seen [4]. As of June 1988, these patients had been followed for a median of 25 months post-BMT (range, 6-75 months) and 11 of the 16 have not had a recurrence of their underlying malignancy. Of these 11, one patient had a complete return of blood-urea nitrogen (BUN) and creatinine to normal levels after four months. Seven patients had modest stable renal dysfunction. Three patients had significant renal dysfunction. The dose and schedule of TBI were analysed as shown in Table 1 for the transplant patients. The incidence of renal dysfunction appears similar for each dose and fractionation schedule. The number of patients in each TBI dose group are, however, too small to provide a meaningful statistical comparison.
Conclusion To summarise, we herein report 16 of 39 evaluable pediatric patients who developed anemia and renal insufficiency after bone marrow transplantation. It seems likely that one or more of the chemotherapeutic agents in the conditioning regimens altered the normal tolerance of the kidneys to TBI. Administration of chemotherapeutic agents to patients can result in renal toxicity as may treatment with radiation; it may be that additive effects of these agents result in the clinical syndrome described here. Investigators need to be alerted to possible unexpected toxicities of more intensive chemotherapeutic and radiotherapeutic conditioning regimens for BMT. Animal models of radiation nephropathy should study the possible effects of combination chemotherapy and TBI with respect to renal damage [5,6]. Improvements of the therapeutic ratio in TBI may have to consider the optimal fraction size, the total dose and the interfraction interval for many late reacting tissues, including the kidney.
References 1. Lutz, W. and Chin, L. Design characteristics of a 4 MV total body irradiation. In: Proceedings of the International Symposium on Dosimetry in Radiotherapy (in press).
142 2. Moulder, J.E., Fish, B.L. and Abrams, R.A. Renal toxicity following total body irradiation and syngeneic bone marrow transplantation. Transplantation, 43, 589-592, 1987. 3. Ritz, J., Bast Jr, R.C., Clavell, L.A., Hercend, T., Sallan, SE., Lipton, J.M., Feeney, M., Nathan, D.C. and Schlassman, SF. Autologous bone marrow transplantation in CALLA-positive acute lymphoblastic leukemia after in vitro treatment with J5 monoclonal antibody and complement. Lancet, 2, 60-63, 1982. 4. Rosen, E.M., Cassady, J.R., Frantz, C.N., Kmtschmar, C., Levey, R. and Sallan, S.E. Neuroblastoma: The Joint Center for Radiation Therapy/Dana-Farber Cancer Institute/Children’s Hospital Experience. J. Clin. Oncol., 2, 719-732, 1984. 5. Stewart, F.A., Somnson, J.A., Alpen, E.L., Williams, M.V. and DeneKamp, J. Radiation-induced renal damage: The effect of hyperfractionation. Radiat. Res., 98, 407-420, 1984. 6. Tarbell, NJ., Guinan, E.C., Niemeyer, C., Mauch, P., Salan, S.E. and Weinstein, H.J. Late onset of renal dysfunction in survivors of bone marrow transplantation. Int. J. Radiat. Oncol., 15, 99-104, 1988.
Renal insuffxiency after total body irradiation for pediatric bone marrow transplantation Nancy J. Tarbell’, Eva C. Guinan2, Lee Chin’, Peter Mauch’ and Howard J. Weinstein2 lDepartment
of Radiation Therapy, Joint Center for Radiation Therapy, Harvard Medical School, 2Division of Pediatric Oncology,
Dana Farber
Cancer Institute and The Children’s Hospital, Harvard Medical School, Boston, MA, U.S.A.
Keywords: Total body irradiation; Radiation nephrotoxicity
Summary Between 1980 and 1987,59 children with acute lymphoblastic leukemia (ALL) or stage IV neuroblastoma (NB) underwent allogeneic or autologous bone marrow transplantation (BMT). Thirty-nine of these patients were alive and in remission 6 months post BMT and were evaluable for this analysis. Sixteen have developed renal dysfunction. Eight were transplanted for relapsed ALL and received an autologous transplant. Preparation included tenopiside (VM 26), cytosine arabinoside, and cyclophospharnide followed by total body irradiation (TBI). One patient received 850 cGy in a single fraction, while all other patients received fractionated TBI (1200-1400 cGy in 6-8 fractions over 3-4 days). Eight of 11 evaluable patients who received a BMT for NB have developed late renal problems (4-7 months after BMT). The preparation for neuroblastoma patients included VM 26, cis-platinum, melphalan, cyclophosphamide and fractionated TBI (1200-1296 cGy). All 8 neuroblastoma patients had received cis-platinum as induction treatment prior to transplantation. All patients presented with anemia, hematuria and elevations of BUN and creatinine. Renal biopsies were consistent with radiation nephropathy. In conclusion, a high incidence of renal dysfunction has occurred after BMT in children with neuroblastoma and ALL. The clinical and laboratory features are consistent with either radiation nephropathy or hemolytic-uremic syndrome. The relatively young age of these patients and conditioning with intensive multi-agent chemotherapy may decrease the tolerance of the kidney to radiation injury.
Introduction Recent reports detail the acute and chronic toxicities associated with BMT, however, primary renal disease after BMT is rarely observed. There are only three previous cases reported in the literature. We describe here the relatively frequent occurrence of a syndrome consistent with acute radiation nephropathy in two groups of patients prepared with multi-agent chemotherapy and TBI prior to either autologous or allogeneic bone marrow reinfusion.
0167-8140/90/$03.50
0 1990 Elsevier Science Publishers B.V. (Biomedical Division)
140 Patients and Methods Fifteen children with stage IV neuroblastoma and 44 patients with CALLA (common acute lymphoblastic leukemia antigen) positive acute lymphoblastic leukemia (ALL) received bone marrow transplants between November 1980 and January 1988; late onset renal insufficiency was observed in several of these children and prompted a study of renal function in these patients. Patients who were alive and in remission for greater than three months post-transplant were considered evaluable for late effects of transplantation. The 44 patients with relapsed CALLA positive acute lymphoblastic leukemia (ALL) did not have HLA-identical sibling donors and were transplanted in second or subsequent remission with autologous marrow purged with monoclonal antibody [l]. All had received prior therapy with multiple chemotherapeutic agents and had been conditioned for transplantation with cyclophosphamide, cytosine arabinoside, tenopiside (V&l-26), and total body irradiation (TBI). The original TBI for the first five CALLA patients was given as 850 cGy in a single fraction at 5 cGy/min. A dedicated facility was built in 1983 and at that time a change was made from single fraction to fractionated TBI (1200 cGy in 6 fractions). With time the total dose for the autologous ALL protocol increased to 1300 cGy and then 1400 cGy with a change in the fractionation as well from 216 cGy in 6 fractions to 175 in 8 fractions. All patients were treated twice daily with a time interval of 4-6 h between fractions. All patients receiving fractionated TBI were treated at 10 cGy/min (range 9-l 1 cGy/min). The dose was prescribed at the midplane at the level of the umbilicus in all patients. The design and characteristics of the 4 MV total body irradiator include two 4 MV linear accelerators, one mounted in the ceiling, the other in a floor-pit. The distance between the two sources is 410 cm to produce a field size of 200 cm x 75 cm in the midplane. This field covers the patient, lying supine on a stretcher halfway between the sources. Special beam hardening and flattening filters were built to achieve acceptable dose profiles in the large field. Because of the wide beams, large rectangular parallel-plate ionisation chambers were built to serve as beam monitors. The dose rate at 205 cm distance from the sources is 10 cGy/min, each machine contributing half [2]. After BMT, all patients were followed routinely as outpatients. None of the patients were treated with cyclosporin. Of the 15 patients with neuroblastoma, 6 received HLA-identical marrow, one received paternal haploidentical marrow, and 8 received autologous marrow purged with monoclonal antibodies. All patients received prior therapy with multiple chemotherapeutic agents according to the MADDOC protocol (cyclophospharnide, cis-platinum, vincristine, doxorubicin, nitrogen mustard, and DTIC) [31. The pretransplant conditioning regimen included VM-26, cyclophosphamide, cisplatinum, melphalan, and TBI. The TBI dose for the neuroblastoma patients was 1200 cGy in 200 cGy fractions given twice daily at a dose rate of 10 cGy/min (one patient received 1296 cGy in six fractions). The patients who received allogeneic transplants were given methotrexate 10 mdm2 on days, 1,3,6 and 11 post-transplant for graft-versus-host disease prophylaxis.
Results Eleven of the 15 patients with neuroblastoma and 28 of the 44 patients with ALL were evaluable for late complications. Eight of 11 evaluable patients post-transplant for stage IV neuroblastoma and 8 out of 28 evaluable patients post-autologous transplant for relapsed ALL were found to have evidence for concurrent renal dysfunction and anemia presenting between 3 to 7 (median of 5) months post BMT. The 16 affected patients ranged in age from 3 to 15 years (median of 6). Three patients had renal biopsies performed after the onset of clinical renal dysfunction. Pathology showed striking mesangiolysis with
141 Table I. Total body irradiation (# FX)
Overall TX time (days)
Fraction size cGy (twice daily)
Dose rate cGy/min
# Renal prob/ # Survivors
All patients 850 1200 1300 1400
(1) (6) (6) (8)
1 3 3 4
200 216 175
5 10 10 10 Total
115 l/5 316 4112 9128
NB patients 1200 1300
(6) (6)
3 3
200 216
10 10
6110 l/l
Total dose ~GY
# FX = number of fractions.
intraglomerular capillary aneurysm formation, and mesangial hyperplasia. Some glomeruli showed ischemic atrophy and were surrounded by atrophic tubules and fibrotic interstitium. The blood vessel changes were limited to the small interlobular vessels and afferent arterioles. Mild intimal hyperplasia without fibrinoid necrosis was seen [4]. As of June 1988, these patients had been followed for a median of 25 months post-BMT (range, 6-75 months) and 11 of the 16 have not had a recurrence of their underlying malignancy. Of these 11, one patient had a complete return of blood-urea nitrogen (BUN) and creatinine to normal levels after four months. Seven patients had modest stable renal dysfunction. Three patients had significant renal dysfunction. The dose and schedule of TBI were analysed as shown in Table 1 for the transplant patients. The incidence of renal dysfunction appears similar for each dose and fractionation schedule. The number of patients in each TBI dose group are, however, too small to provide a meaningful statistical comparison.
Conclusion To summarise, we herein report 16 of 39 evaluable pediatric patients who developed anemia and renal insufficiency after bone marrow transplantation. It seems likely that one or more of the chemotherapeutic agents in the conditioning regimens altered the normal tolerance of the kidneys to TBI. Administration of chemotherapeutic agents to patients can result in renal toxicity as may treatment with radiation; it may be that additive effects of these agents result in the clinical syndrome described here. Investigators need to be alerted to possible unexpected toxicities of more intensive chemotherapeutic and radiotherapeutic conditioning regimens for BMT. Animal models of radiation nephropathy should study the possible effects of combination chemotherapy and TBI with respect to renal damage [5,6]. Improvements of the therapeutic ratio in TBI may have to consider the optimal fraction size, the total dose and the interfraction interval for many late reacting tissues, including the kidney.
References 1. Lutz, W. and Chin, L. Design characteristics of a 4 MV total body irradiation. In: Proceedings of the International Symposium on Dosimetry in Radiotherapy (in press).
142 2. Moulder, J.E., Fish, B.L. and Abrams, R.A. Renal toxicity following total body irradiation and syngeneic bone marrow transplantation. Transplantation, 43, 589-592, 1987. 3. Ritz, J., Bast Jr, R.C., Clavell, L.A., Hercend, T., Sallan, SE., Lipton, J.M., Feeney, M., Nathan, D.C. and Schlassman, SF. Autologous bone marrow transplantation in CALLA-positive acute lymphoblastic leukemia after in vitro treatment with J5 monoclonal antibody and complement. Lancet, 2, 60-63, 1982. 4. Rosen, E.M., Cassady, J.R., Frantz, C.N., Kmtschmar, C., Levey, R. and Sallan, S.E. Neuroblastoma: The Joint Center for Radiation Therapy/Dana-Farber Cancer Institute/Children’s Hospital Experience. J. Clin. Oncol., 2, 719-732, 1984. 5. Stewart, F.A., Somnson, J.A., Alpen, E.L., Williams, M.V. and DeneKamp, J. Radiation-induced renal damage: The effect of hyperfractionation. Radiat. Res., 98, 407-420, 1984. 6. Tarbell, NJ., Guinan, E.C., Niemeyer, C., Mauch, P., Salan, S.E. and Weinstein, H.J. Late onset of renal dysfunction in survivors of bone marrow transplantation. Int. J. Radiat. Oncol., 15, 99-104, 1988.
