Influence of nephrotoxic drugs on the late renal toxicity associated with bone marrow transplant conditioning regimens

The total body irradiation that is given as part of bone marrow transplant conditioning regimens is a factor in the renal toxicity that is observed after bone marrow transplant, but it may not be the only factor. We hypothesize that nephrotoxic drugs used in prior chemotherapy can precipitate renal radiation damage. Studies were designed to determine if nephrotoxic antineoplastic drugs could shorten the latent period for the development of radiation nephritis. Rats were given bilateral renal irradiation using a radiation schedule that produced moderate nephritis. Cisplatinum, BCNU, or mitomycin were given before, during, or after irradiation at doses that produced only mild nephrotoxicity. All cisplatinum-radiation sequences resulted in decreased renal function, with radiation prior to cisplatinum producing the greatest dysfunction. BCNU increased renal dysfunction equally in all schedules, but mitomycin had only minimal effects. Most drug schedules, including those with mitomycin, produced earlier development of morbidity after fractionated renal irradiation. In a second set of studies, rats were given single doses of the same nephrotoxic drugs, followed 3 months later by total body irradiation plus bone marrow transplant. The drugs had no effect on the marrow ablation dose, but BCNU and cisplatinum decreased gastrointestinal tolerance. Four months after total body irradiation, rats which received drugs alone or total body irradiation alone have essentially normal renal function, but rats which received cisplatinum plus total body irradiation or BCNU plus total body irradiation show a dose-dependent decrease in renal function. These studies show that radiation nephritis can be precipitated by low doses of nephrotoxic drugs, and may help to explain the incidence of early radiation nephritis in bone marrow transplant patients conditioned with total body irradiation.     

Effect of total-body irradiation with bone marrow transplantation on toxicity of cisplatin

In defined-flora, barrier-maintained rats (WAG/RijMCW males), radiation nephritis is the principal late toxicity seen after high-dose-rate, total-body irradiation (TBI) when hematologic toxicity is prevented by bone marrow transplantation. Pneumonitis develops only if rats are exposed to a conventional environment during and after bone marrow transplantation. Low-dose-rate TBI gives similar toxicity at doses twice as large. Rats surviving for 9 months after TBI show decreased tolerance for cisplatin. This decreased tolerance is related to dose and dose rate and is seen for radiation doses that show little or no renal toxicity. Evidence suggests that the decrease in renal tolerance is due to decreased renal platinum clearance in the irradiated kidneys.     

Renal toxicity after total body irradiation

PURPOSE: To evaluate the incidence of renal dysfunction after total body irradiation (TBI). METHODS AND MATERIALS: Between 1990 and 1997, 64 patients (median age 50 years) received TBI as part of the conditioning regimen before bone marrow transplantation (BMT). Five patients with abnormal renal function at the beginning of treatment or with incomplete data were excluded. All patients received a total of 12 Gy (6 fractions twice daily for 3 consecutive days) prescribed to the peak lung dose (corrected for lung transmission) at a dose rate of 7.5 cGy/min. Renal shielding was not used. Renal dysfunction was assessed on the basis of the serum creatinine levels measured at the start and end of TBI and at 6, 12, 18, and 24 months after completion of BMT. Cox proportional hazard analysis was used to evaluate the various factors known to affect renal function. RESULTS: Only 4 patients had elevated serum creatinine levels at 12 months and subsequently only 2 of the 33 surviving patients had persistent elevated renal serum creatinine levels 24 months after BMT. A fifth patient developed proteinuria and mildly elevated serum creatinine levels at 2.5 years. In 2 patients, the elevation coincided with disease relapse and normalized once remission was achieved. In the third patient, the elevation in serum creatinine levels coincided with relapse of multiple myeloma and the presence of Bence-Jones proteinuria. The fourth patient was the only patient who developed chronic renal failure secondary to radiation nephritis at 2 years. The etiology of the fifth patient's rise in creatinine was unknown, but may have been secondary to radiation nephritis. On univariate analysis, but not on multivariate analysis, a significant correlation was found between TBI-related renal dysfunction and hypertension before and after BMT. CONCLUSION: A dose of 12 Gy at 2 Gy/fraction resulted in only 1 case of radiation nephritis in the 59 patients studied 24 months after the completion of TBI and BMT.     

Radiobiological considerations in magna-field irradiation

Radiobiological considerations are described for total body irradiation (TBI) as given to patients undergoing bone marrow transplantation (BMT). Although much progress has been made in the use of BMT for refractory leukemias, many patients still die from interstitial pneumonia and relapse. Fractionated TBI has been introduced in order to improve leukemic cell kill, while increasing the degree of normal tissue tolerance. Traditionally, bone marrow stem cells, leukemic cells and immunocytes have been considered as having a limited ability to repair radiation damage while cells of lung tissue and intestinal epithelial cells have a greater capacity. During fractionated radiation therapy or continuous low-dose rate exposure, repair of sublethal damage between fractions allows greater recovery in the cells of lung tissue compared to those in the bone marrow. Clinically, the potential benefit of six fractions over one fraction or low dose-rate TBI has yet to be proved, although there is suggestive evidence for a reduced incidence of interstitial pneumonitis. However, other extraneous factors such as doses to the lung, differences in conditioning regimens, effect of increased delay in BMT for patients receiving fractionated TBI, and the immeasurable differences between institutions make definite conclusions impossible. Despite this, a consensus for dose fractionation has developed and most centers are moving away from the use of large single dose TBI.     

Bone Marrow Stromal Damage after Chemo/Radiotherapy: Occurrence, Consequences and Possibilities of Treatment

High dose chemotherapy (CT) followed by bone marrow transplant (BMT) is increasingly used for the treatment of both hematological and solid neoplasms, but an understanding of its late consequences on the marrow microenvironment is still only at its beginning. It is in fact known that marrow stroma is damaged by high-dose cytotoxic therapy and by radiation exposure. However little is known on the extent of this damage and on the self-repair ability of the stroma. The damage of the stromal microenvironment affects the long-term stem cell engraftment and the maintenance of hemopoietic functions. Furthermore, marrow stroma also represents a progenitor compartment for endosteal osteoblasts, and therefore its damage implies alterations of bone metabolism. Indeed, osteoporosis has recently been recognized as a consequence, of BMT, but only a few studies have been performed to establish the functional status of the stromal compartment after treatment with cytotoxic drugs with or without total body irradiation (TBI) and its role in post-BMT sequelae.     

Late renal dysfunction in adult survivors of bone marrow transplantation

Until recently long-term renal toxicity has not been considered a major late complication of bone marrow transplantation (BMT). Late renal dysfunction has been described in a pediatric population status post-BMT which was attributable to the radiation in the preparatory regimen. A thorough review of adults with this type of late renal dysfunction has not previously been described. Fourteen of 103 evaluable adult patients undergoing allogeneic (96) or autologous (7) bone marrow transplantation, predominantly for leukemia and lymphomas, at the Medical College of Wisconsin (Milwaukee, WI) have had a syndrome of renal insufficiency characterized by increased serum creatinine, decreased glomerular filtration rate, anemia, and hypertension. This syndrome developed at a median of 9 months (range, 4.5 to 26 months) posttransplantation in the absence of specific identifiable causes. The cumulative probability of having this renal dysfunction is 20% at 1 year. Renal biopsies performed on seven of these cases showed the endothelium widely separated from the basement membrane, extreme thickening of the glomerular basement membrane, and microthrombi. Previous chemotherapy, antibiotics, and antifungals as well as cyclosporin may add to and possibly potentiate a primary chemoradiation marrow transplant renal injury, but this clinical syndrome is most analogous to clinical and experimental models of radiation nephritis. This late marrow transplant-associated nephritis should be recognized as a potentially limiting factor in the use of some intensive chemoradiation conditioning regimens used for BMT. Some selective attenuation of the radiation to the kidneys may decrease the incidence of this renal dysfunction.     

Late onset of renal dysfunction in survivors of bone marrow transplantation

Between 1980 and 1986, 44 children with acute lymphoblastic leukemia (ALL) or Stage IV neuroblastoma (NB) underwent allogeneic or autologous bone marrow transplantation (BMT). Twenty-nine of these patients were alive and in remission 3 months post BMT and were evaluable for this analysis of whom eleven have developed renal dysfunction. Six of 17 (35%) evaluable ALL patients developed renal dysfunction (3.5 to 6 months post BMT). This group was transplanted for CALLA positive ALL and received an autologous transplant. Preparation included tenopiside (VM 26) cytosine arabinoside, and cyclophosphamide 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). Five of 7 (71%) evaluable patients who received a BMT for NB have developed late renal problems (4-7 months after BMT). The preparation for NB patients included VM 26, cis-platinum, melphalan, cyclophosphamide, and fractionated TBI (1200-1296 cGy). All seven NB patients had received cis-platinum as induction treatment prior to transplantation. All patients presented with anemia, hematuria, and elevations of BUN and creatinine. Two patients underwent renal biopsies which were consistent with radiation nephropathy or hemolytic uremic syndrome. In conclusion, a high incidence of renal dysfunction has occurred 3 to 7 months after BMT for children with NB and ALL. The clinical and laboratory features are consistent with either acute radiation nephropathy or hemolytic-uremic syndrome. These patients were prepared for BMT with multiple chemotherapeutic agents as well as TBI. The relatively young age of these patients and conditioning with intensive multi-agent chemotherapy may decrease the tolerance of the kidney to radiation injury.     

Impact of drug therapy, radiation dose, and dose rate on renal toxicity following bone marrow transplantation

PURPOSE: To demonstrate a radiation dose response and to determine the dosimetric and chemotherapeutic factors that influence the incidence of late renal toxicity following total body irradiation (TBI). METHODS AND MATERIALS: A comprehensive retrospective review was performed of articles reporting late renal toxicity, along with renal dose, fractionation, dose rate, chemotherapy regimens, and potential nephrotoxic agents. In the final analysis, 12 articles (n = 1,108 patients), consisting of 24 distinct TBI/chemotherapy conditioning regimens were included. Regimens were divided into three subgroups: adults (age > or =18 years), children (age <18 years), and mixed population (both adults and children). Multivariate logistic regression was performed to identify dosimetric and chemotherapeutic factors significantly associated with late renal complications. RESULTS: Individual analysis was performed on each population subgroup. For the purely adult population, the only significant variable was total dose. For the mixed population, the significant variables included total dose, dose rate, and the use of fludarabine. For the pediatric population, only the use of cyclosporin or teniposide was significant; no dose response was noted. A logistic model was generated with the exclusion of the pediatric population because of its lack of dose response. This model yielded the following significant variables: total dose, dose rate, and number of fractions. CONCLUSION: A dose response for renal damage after TBI was identified. Fractionation and low dose rates are factors to consider when delivering TBI to patients undergoing bone marrow transplantation. Drug therapy also has a major impact on kidney function and can modify the dose-response function.     

Amifostine (WR2721) for dose escalation in marrow-ablative treatment of leukaemia

The in vivo effect of the radiochemoprotectant Amifostine on the therapeutic efficacy of marrow ablative treatment with cyclophosphamide (CP) and total body irradiation (TBI) followed by bone marrow transplantation (BMT) was studied in normal rats as well as in the Brown Norway rat acute myelocytic leukaemia (BNML) model. In normal rats, when the dose of TBI was escalated and the CP dose was kept constant, pretreatment with Amifostine yielded a positive dose modification factor of 1.26. No significant improvement was found after Amifostine pretreatment when the TBI dose was kept constant and CP dose escalated. When leukaemic rats received CP as the only antileukaemia treatment, Amifostine pretreatment did not lead to a reduction in the antileukaemic efficacy of CP, although protection against treatment-related mortality was observed. In the CP only groups, 9 out of 40 animals died of treatment-related toxicity, compared with none of the 40 animals in the Amifostine pretreatment groups. When applying the maximum tolerated treatment of CP and TBI in various combinations to leukaemic rats, 25 out of 36 rats died from treatment-related toxicity, whilst pretreatment with Amifostine reduced this to 11 out of 36, (P=0.002). Of those animals which survived the CP+TBI conditioning treatment, 10 out of 25 in the Amifostine pretreatment group were cured, versus 8/11 in the CP+TBI only control group (P=0.146). In conclusion, incorporation of Amifostine as a radiochemoprotectant in a marrow-ablative conditioning regimen allows the use of escalated doses of chemoradiotherapy without reducing the antileukaemic efficacy.     

Total Body Irradiation for Hematopoietic Stem Cell Transplantation: What Can We Agree on?

Total body irradiation (TBI), used as part of the conditioning regimen prior to allogeneic and autologous hematopoietic cell transplantation, is the delivery of a relatively homogeneous dose of radiation to the entire body. TBI has a dual role, being cytotoxic and immunosuppressive. This allows it to eliminate disease and create “space” in the marrow while also impairing the immune system from rejecting the foreign donor cells being transplanted. Advantages that TBI may have over chemotherapy alone are that it may achieve greater tumour cytotoxicity and better tissue penetration than chemotherapy as its delivery is independent of vascular supply and physiologic barriers such as renal and hepatic function. Therefore, the so-called “sanctuary” sites such as the central nervous system (CNS), testes, and orbits or other sites with limited blood supply are not off-limits to radiation. Nevertheless, TBI is hampered by challenging logistics of administration, coordination between hematology and radiation oncology departments, increased rates of acute treatment-related morbidity and mortality along with late toxicity to other tissues. Newer technologies and a better understanding of the biology and physics of TBI has allowed the field to develop novel delivery systems which may help to deliver radiation more safely while maintaining its efficacy. However, continued research and collaboration are needed to determine the best approaches for the use of TBI in the future.     

Phase I study of escalating doses of low-dose-rate,locoregional irradiation preceding Cytoxan-TBI for patients with chemotherapy-resistant non-Hodgkin's or Hodgkin's lymphoma

PURPOSE: In patients in whom bone marrow transplantation (BMT) fails, recurrence often occurs at sites known to have contained disease before initiating BMT. The purpose of this study was to find the maximal tolerable dose of locoregional irradiation (LRT) between 1000 and 2000 cGy that could be integrated with our Cytoxan-total body irradiation (TBI) BMT conditioning regimen in the treatment of lymphoma. METHODS AND MATERIALS: Patients had Hodgkin's or non-Hodgkin's lymphoma in chemotherapy-refractory relapse. All patients received LRT to a maximum of three sets of fields encompassing either all current or all previously known sites of disease. Cytoxan-TBI consisted of cyclophosphamide 50 mg/kg daily for 4 days followed by TBI of 1200 cGy given in four fractions. RESULTS: Twenty-one patients were enrolled. Radiation Therapy Oncology Group Grade 3 in-field acute toxicity was observed in 1 patient at each dose level up to 1500 cGy and in 3 of 6 patients receiving 2000 cGy. Clinically evident late toxicities were limited to hypothyroidism and one second malignancy occurring outside the LRT fields. CONCLUSION: Low-dose-rate, LRT with concurrent Cytoxan-TBI before BMT has acceptable rates of in-field toxicity for doses up to 1500 cGy in five fractions. This regimen safely permits the use of a total combined radiation dose of up to 2700 cGy during 2 weeks, with encouraging in-field response rates in treatment-refractory patients.     

Cyclophosphamide 24 hours before or after total body irradiation: effects on lung and bone marrow

Preparative regimens for bone marrow transplantation (BMT) use a sequence of drugs, such as cyclophosphamide, in combination with radiation. However, the optimum sequencing of the two agents that will maximize tumor cell kill and minimize normal tissue damage is unknown and controversial. The studies presented here were done in order to determine the effect of cyclophosphamide on bone marrow and lung damage in mice when given 24 h before or after total body irradiation (TBI). A range of single doses of TBI was given before or after a single sublethal dose of 180 mg/kg of cyclophosphamide. The bone marrow of all mice intended for lung damage assessment was reconstituted with 5 x 10(6) syngeneic bone marrow cells. Lung damage was assessed by breathing rate and lethality; bone marrow damage by lethality at 30 days. LD50 values for pneumonitis were obtained between 30 and 84 days after cyclophosphamide and radiation and between 80 and 180 days after radiation alone. Dose modifying factors were obtained as the ratio of LD50s for mice given only TBI compared to those for mice given cyclophosphamide and TBI. Cyclophosphamide enhanced radiation pneumonitis when given before or after TBI, giving DMFs of 1.4 and 1.2 (1.1-1.4, 95% c.l.) respectively. The effect of cyclophosphamide on radiation pneumonitis was drug dose-dependent. The LD50 for death from bone marrow damage was reduced when cyclophosphamide was given either before or after TBI but the effect was greater, i.e. the LD50 was lower when cyclophosphamide was given after TBI. These data show that cyclophosphamide given 24 h after TBI causes less lung damage but more bone marrow damage in this mouse model.     

Modification of radiation-induced damage to bone marrow stem cells by dose rate, dose fractionation, and prior exposure to cytoxan as judged by the survival of CFUs: application to bone marrow transplantation (BMT)

The relative importance of the effects of dose rate, dose fractionation, and prior exposure to Cytoxan on the recovery of cells in the bone marrow, following conditioning for BMT, remains controversial. Traditionally, bone marrow stem cells and leukemic cells have been considered as having a limited ability to repair radiation-induced damage following total body irradiation (TBI) compared to cells of the lung (the dose-limiting tissue for TBI). We examined the survival response of the bone marrow stem cells of mice (CFUs) at three TBI dose rates (0.47, 0.25 and 0.08 Gy/min). The radiation response of CFUs (compilation Do = 0.75 Gy) was independent of dose rate. One TBI dose fractionation was chosen: two fractions per day, separated by 6 hours, for 3 days. The radiation survival curve of CFUs showed a compilation Do of 1.09 Gy, compared to 0.75 Gy for the one-fraction case. The recovery of CFUs following 2 days of Cytoxan demonstrated an "overshoot," whereas recovery of CFUs was incomplete, even by day 23, following the initiation of the complete conditioning regimen of Cytoxan plus TBI. These data demonstrate no significant effect of dose rate, at least in the range 0.08 to 0.48 Gy/min, on the survival of CFUs following either single or six fractionated TBI doses. However, the statistically significant difference in the Do of CFUs in going from one to six fractions has direct application to bone marrow transplantation techniques. Moreover, Cytoxan, at least at 200 mg/kg for 2 days, prior to TBI, appears to have only a marginal modifying effect on the eventual recovery of CFUs.     

Total body irradiation in bone marrow transplantation: the influence of fractionation and delay of marrow infusion

Bone marrow transplantation (BMT) after total body irradiation (TBI) and cyclophosphamide is being employed increasingly in the therapy of end stage leukemia. Interstitial pneumonitis (IP) represents a major acute toxicity after allogeneic transplantation. A more rapid reconstitution of lymphoid organs and bone marrow post transplant may result in increased immune competence and hence fewer opportunistic pulmonary infections and IP. By delaying the infusion of marrow to 72 hr after TBI (1250 rod at 7.5 rad/min) instead of the customary 24 hr, we can demonstrate an increase in initial repopulation of thymus, spleen and marrow, with syngeneic transplants in Lewis rats.Interstitial pneumonitis may also be caused, in part, by the pulmonary toxicity of large single exposures of TBI. Clinical and laboratory data suggest that fractionated TBI may be less toxic to the lung. When fractionated TBI (625 rad × 2, 7.5 rad/min) is compared to single dose TBI (1250 rad, 7.5 rad/min), an increased initial repopulation of lymphoid organs is observed when fractionated therapy is employed. Delay in marrow infusion and fractionation of TBI exposure may have clinical advantages in patients who receive BMT.     

Effect of dose-rate on total body irradiation: lethality and pathologic findings

The effect of low dose-rate total body irradation (TBI) on hemopoietic and nonhemopoietic lethality has been studied in BALB/c mice using dose-rates ranging from 25 to 1 cGy/min. Deaths were scored at 10 days, 30 days, and one year after irradiation, and dose-response curves were constructed to determine the dose-rate dependence of deaths from the gastrointestinal syndrome, hemopoietic syndrome, and late lethal syndrome(s), respectively. A plot of the LD50S for each of these lethal syndromes versus dose-rate showed the dose-rate dependence for late lethality to be somewhat greater than that for gut death, but both of these endpoints were markedly more dose-rate dependent than was hemopoietic lethality, particularly at dose rates less than 5 cGy/min. To determine which late responding normal tissues might be critical for low dose-rate TBI, complete necropsies were performed on all mice dying later than 60 days after irradiation and on all mice surviving at one year; all tissues were examined histologically. Morphologic evidence of radiation injury was present in only three tissues, lung (fibrosis and scarring) kidney (tubule depletion), and liver (presence of mitoses). Subjectively, the lung changes were most severe up to 9 months while kidney changes became more prominent after this time, suggesting that late death after low dose-rate TBI may not be entirely attributable to lung injury. However, regardless of which late responding normal tissue is dose-limiting, it is clear that low dose-rate TBI preferentially spares these tissues compared with hemopoietic stem cells.     

Late tissue-specific toxicity of total body irradiation and busulfan in a murine bone marrow transplant model

Total body irradiation (TBI) and busulfan were compared for late effects in a murine model of bone marrow transplantation (BMT). Male C57BL/6 mice were given fractionated TBI or busulfan given in 4 equal daily doses followed by infusion of 10(7) syngeneic bone marrow cells. Total doses of 16.4 Gy TBI and 3.4 mg busulfan were chosen for their equivalence in inducing near complete engraftment of allogeneic marrow from donor mice of the LP strain. The two treatment groups had a late wave of mortality starting at about 80 weeks after transplantation. Specific tissue damage was manifested in bone marrow stem cells, splenic T-cell precursors, hair greying and cataract formation for both TBI and busulfan but to varying degrees. Severe nephrotoxicity and anemia were observed only after TBI. Although both busulfan and TBI kill early marrow stem cells and are effective preparative agents in bone marrow transplantation, their effects on other stem cell and organ systems are not similar. In addition, many of the injuries seen are late to occur. The delayed expression of injury deserves careful long-term evaluation of BMT recipients before the therapeutic potential of effective preparative regimens can be fully appreciated.     

Development of secondary skull sarcoma after treatment for childhood acute myeloid leukemia

Secondary cancer is a serious late complication in childhood leukemia survivors. Here, we report a case of secondary skull sarcoma developing after treatment for childhood acute myeloid leukemia, including bone marrow transplantation (BMT). This patient had breast cancer 1 year before treatment for the skull sarcoma. The patient underwent macroscopic total removal of the skull tumor with bone margin with postoperative radiation therapy and did not develop tumor recurrence for 25 months. Our patient's experience suggests that survivors of childhood leukemia are at risk of developing skull sarcoma and that multi‐agent chemotherapy, including anthracycline, TBI used as conditioning for BMT, and development of GVHD, are possible risk factors. Considering the possibility of multiple secondary malignancies in such patients, careful long‐term follow up is mandatory.     

Renal insufficiency in patients with hematologic malignancies undergoing total body irradiation and bone marrow transplantation: a prospective assessment

PURPOSE: Patients with malignant hematologic disorders undergoing bone marrow transplantation (BMT) may develop renal insufficiency. A study was undertaken to assess prospectively the subclinical renal function changes with radioisotopic methods in patients undergoing BMT for hematologic malignancies. METHODS AND MATERIALS: We studied 71 patients with normal renal function undergoing BMT for various hematologic malignancies, mostly leukemias. Conditioning included chemotherapy and 12 Gy (45 patients) or 13.5 Gy (26 patients) fractionated total-body irradiation (TBI). In 21 patients receiving 12 Gy TBI, the kidney dose was limited to 10 Gy using partial transmission blocks fabricated after renal opacification with nonionic, hypo-osmolar contrast medium. The glomerular filtration rate (GFR) and effective renal plasmatic flow (ERPF) were determined radioisotopically before conditioning and at 4, 12, and 18 months, using (51)Cr ethylene-diamine-tetra-acetic acid and (131)I ortho-iodo-hippurate, respectively. Renal insufficiency was defined as a decrease of >/=30% in GFR or ERPF compared with the baseline values. The potential influence of patient- and treatment-related variables on renal dysfunction was assessed. RESULTS: At 4 (early) and 12-18 (late) months, a >/=30% GFR drop was observed in 54% and 49% of patients and a >/=30% ERPF drop in 44% and 34% of patients, respectively. After stepwise logistic analysis, a GFR reduction at 4 months correlated significantly with age (<40 years old, worse), TBI using kidney blocks (partial kidney shielding to 10 Gy was associated with a higher rate of renal dysfunction at 4 months compared with the full TBI dose), and days of aminoglycoside/vancomycin use. An ERPF drop at 4 months was independently related with the days of amphotericin use and days of prostaglandin E(1) use (prophylaxis against hepatic venoocclusive disease). A GFR and ERPF reduction at 12-18 months correlated with days of amphotericin use and days of prostaglandin E(1) use, respectively. CONCLUSION: Early post-BMT renal dysfunction is associated with the administration of potentially nephrotoxic drugs. An inverse correlation with the prescribed TBI dose was observed; patients whose kidneys received 10 Gy through the use of partial shielding blocks had significantly greater renal dysfunction at 4 months. The administration of potentially nephrotoxic contrast agents used in radiotherapy treatment planning may be responsible for the latter observation. Prostaglandin E(1) use correlated with a significant reduction in ERPF at both 4 and 12-18 months.     

Monoclonal Antibody-Purged Bone Marrow Transplantation Therapy for Multiple Myeloma

This report describes the clinical characteristics, treatment associated toxicity, and follow-up of fifty-eight patients with plasma cell-dyscrasias treated with high dose chemotherapy and total body irradiation (TBI) at a single institution. Following TBI, 36 patients received anti-B cell monoclonal antibody (MoAb)-treated autologous bone marrow, 21 patients received anti-CD6 cell MoAb-treated allogeneic bone marrow to deplete T cells, and one patient received unpurged bone marrow from a syngeneic donor. Evaluation after high dose chemotherapy and bone marrow transplantation (BMT) demonstrated 26 complete responses (CR), 26 partial responses (PR), 2 non-responders, 1 not yet evaluated, and three toxic deaths. Fourteen of 36 patients who underwent autologous BMT are alive free from progression at 18 (range 5 to 68) months post transplant (post-BMT); of these, 11 remain in continuous complete response at 16 (range 5 to 68) months post-BMT. Seven of 21 patients who underwent allogeneic BMT are alive free from progression at 30 (range 4 to 44) months post-BMT; of these, three patients remain in continuous complete response at 43 (range 33 to 45) months post-BMT. These data suggest that high dose chemotherapy with TBI followed by MoAb purged BM can be performed with acceptable toxicity and high tumor response rates.     

Radiobiological and Clinical Bases for Total Body Irradiation in the Leukemias and Lymphomas

In spite of the recent introduction of conditioning regimens consisting of chemotherapy alone, therapeutic total body irradiation (TBI) remains a powerful antileukemic and immunosuppressive tool in preparative regimens for bone marrow transplantation. However, the question of the "best" TBI schedule has not been answered. Available radiobiological and clinical data show that (1) the role of fractionation (or dose rate) on leukemia cell killing may vary with the leukemia type. Acute myeloid leukemia cells have been found to be insensitive or only slightly sensitive to fractionation, whereas chronic myeloid leukemia cells appear to be sensitive. Data are still controversial for acute lymphocytic leukemia and the non-Hodgkin's lymphomas; (2) the immunosuppressive effect of TBI is very fractionation sensitive; and (3) most normal tissues at risk are also highly sensitive to fractionation and dose rate. These data permit some cautious adaptations of the TBI schemes to the type of leukemia, use of T-cell-depleted donor marrow, and potential normal tissue toxicity. However, we still lack data concerning the precise intrinsic and fractionation radiosensitivity of the leukemia/lymphoma of a given patient. Recent improvements in leukemia-cell cultures allowing the generation of dose survival curves and the study of in vitro radiation-induced apoptosis (mainly for lymphomas) may soon provide radiation oncologists with the data to allow further refinement and individualization of TBI schedules.