Tumor Burden and Intraosseous Metabolic Activity as Predictors of Bone Marrow Failure during Radioisotope Therapy in Metastasized Prostate Cancer Patients.

RATIONALE: Radium-223-Dichloride (Ra-223) is an alpha-emitter, used to treat bone metastases. Patients with high metastatic burden and/or with increased trabecular bone uptake could present a higher incidence of hematologic toxicity. We hypothesized that these two factors are predictors of bone marrow failure. MATERIAL AND METHODS: A computer algorithm discriminated between trabecular bone (BVol) and tumor metastases (MVol) within pretherapeutic whole-body skeletal SPECT/CT (N = 47). The program calculated the metastatic invasion percent (INV%) as the MVol/(MVol + BVol) ratio and extracted the BVol mean counts. BVol counts were correlated to % drop of hemoglobin (Hb), leukocytes (WBC), and platelets (PLT) after 3/6 Ra-223 cycles. Patient-specific and computational-derived parameters were tested as predictors of hematologic toxicity with MANOVA. RESULTS: BVol counts correlated with drop of Hb (R = 0,65, p < 0.01) and PLT (R = 0,45, p < 0.01). Appendicular BVol counts showed a better correlation (p < 0.05, p < 0.01, and p < 0.001 for Hb, WBC, and PLT, resp.). INV% directly correlated with BVol counts (R = 0.68, p < 0.001). At MANOVA, grade III/IV toxicity was predicted by INV% (p < 0.01), by long-bone invasion (p < 0.005), and by BVol counts (p < 0.05). CONCLUSIONS: In patients with significant bone tumor burden, degree of bone invasion and trabecular bone uptake are predictors of subsequent bone marrow failure.

Total body irradiation (TBI) in pediatric patients. A single-center experience after 30 years of low-dose rate irradiation.

PURPOSE: To retrospectively analyze patient characteristics, treatment, and treatment outcome of pediatric patients with hematologic diseases treated with total body irradiation (TBI) between 1978 and 2006. PATIENTS AND METHODS: 32 pediatric patients were referred to the Department of Radiation-Oncology at the University of Zurich for TBI. Records of regular follow-up of 28 patients were available for review. Patient characteristics as well as treatment outcome regarding local control and overall survival were assessed. A total of 18 patients suffered from acute lymphoblastic leukemia (ALL), 5 from acute and 2 from chronic myelogenous leukemia, 1 from non-Hodgkin lymphoma, and 2 from anaplastic anemia. The cohort consisted of 15 patients referred after first remission and 13 patients with relapsed leukemia. Mean follow-up was 34 months (2-196 months) with 15 patients alive at the time of last follow-up. Eight patients died of recurrent disease, 1 of graft vs. host reaction, 2 of sepsis, and 2 patients died of a secondary malignancy. RESULTS: The 5-year overall survival rate (OS) was 60%. Overall survival was significantly inferior in patients treated after relapse compared to those treated for newly diagnosed leukemia (24% versus 74%; p=0.004). At the time of last follow-up, 11 patients survived for more than 36 months following TBI. Late effects (RTOG ≥ 3) were pneumonitis in 1 patient, chronic bronchitis in 1 patient, cardiomyopathy in 2 patients, severe cataractogenesis in 1 patient (48 months after TBI with 10 Gy in a single dose) and secondary malignancies in 2 patients (36 and 190 months after TBI). Growth disturbances were observed in all patients treated prepubertally. In 2 patients with identical twins treated at ages 2 and 7, a loss of 8% in final height of the treated twin was observed. CONCLUSION: As severe late sequelae after TBI, we observed 2 secondary malignancies in 11 patients who survived in excess of 36 months. However, long-term morbidity is moderate following treatment with the fractionated TBI at the low-dose rate that was generally used here. Conditioning for bone marrow transplantation without radiation is an attractive option, but is not sufficiently effective to completely replace TBI for the most common pediatric indications.

[Transplantation of the bone marrow from a HLA-compatible unrelated donor after immunoablative conditioning in children with acquired aplastic anemia unresponsive to combined immunosuppressive therapy: preliminary results].

AIM: To analyze the efficiency of transplantation of the bone marrow from a HLA-compatible unrelated donor and continued immunosuppressive therapy (IST) in children with aplastic anemia (AA) unresponsive to 2 courses of IST. SUBJECTS AND METHODS: The study enrolled 14 children aged 2-16 years (median 9 years). A control group comprised 26 patients in whom IST was continued. The median interval between the diagnosis of AA and transplantation was 26 months (9-156 months). The conditioning regimen consisted of thoracoabdominal irradiation in a dose of 2 Gy, fludarabin (Flu) 100-150 mg/m2, cyclophosphamide (Cy) 100-200 mg/kg, antithymocyte globulin (ATG) in 11 patients and Flu, Cy, and ATG in 3. A graft-versus-host reaction was prevented with mycophenolate mefetil in all the patients, tacrolimus in 11, and cyclosporin A in 3. Donors were compatible for high-resolution typing of 10/10 and 9/10 alleles in 8 and 6 patients, respectively; the source of a transplant was bone marrow in 13 patients and granulocyte colony-stimulating factor-mobilized peripheral blood precursors in one case. RESULTS: Thirteen patients achieved primary engraftment after single transplantation; one patient did after repeat transplantation. Grades I to II graft-versus-host reaction (GVHR) developed in 9 patients; postengraftment life-threatening infections in 3, extensive chronic GVHR in 2, circumscribed GVHR in 7. All fourteen hemopoietic cell transplant recipients followed for a median 17.5 months (range 1-71 months) were survivors. CONCLUSION: The likelihood of good survival after unrelated transplantations in AA is much higher than that after continued IST: 100% versus 15 +/- 11%.

[Experimental study of low dose irradiation for treatment of immuno-mediated aplastic anemia in mice].

As the lymphocytes of immuno-mediated aplastic anemia (IMAA) are in active state, and the hematopoietic stem cells are in silence, this study was aimed to design a new strategy to treat IMAA. To utilize the difference of radiosensitivity between active lymphocytes and silent hematopoietic stem cells, the animals suffered from IMAA were treated with a single low dose of irradiation, killing the active lymphocytes to release its suppression to hematopoietic stem cells without injuring the hematopoietic stem cells. Therefore, the hematopoiesis can be restored. Experiments were completed in IMAA mouse model. At day 4 after making IMAA, the model mice were giren total body irradiation of 150 cGy, the non-treated model mice and normal mice irradiated with 150 cGy were used as control. The survive time and survive rate of mice, blood picture, the account of nucleated cell of bone marrow, and pathological changes of bone marrow and lymphoid tissues of each group mice were observed. The results were as follows: (1) Survive rate of IMAA mice in non-treated group was 12.5%, the average survive time was 27.4 +/- 13.4 days. 100% of IMAA mice in irradiation-treated group survived over 60 days. The mice of irradiation control group all survived. (2) The account of WBC of IMAA mice in non-treated group dramatically decreased until to die, and in the irradiation-treated group it was gradually increased since the 10th day after treatment and close to normal level at the 28th day. (3) The RBC hematocrit of IMAA mice in non-treated group progressively decreased at day 14, and IMAA mice of irradiation-treated group gradually recovered closely to normal level after slightly fall at day 14, similar to the mice of irradiation control group. (4) The account of nucleated cells of bone marrow in non-treated IMAA mice dramatically decreased, and in the IMAA mice of the irradiation-treated group it was rapidly increased following transient fall, and restored to normal. (5) Pathological observations showed that the bone marrow and spleen of non-treated IMAA mice demonstrated typical aplastic anemia pattern, including bone marrow failure, marked splenatrophy, but the bone marrow and lymphoid tissues in the IMAA mice of irradiation-treated group were recovered to normal at day 28 after treatment. It is concluded that the low dose of irradiation displayed a significant therapeutic effect to IMAA mice, their hematopoisis could be completely restored to normal. The mechanism of therapeutic effect may contribute to low dose of irradiation killing the immunocompetent lymphocytes, therefore, suppressing hematopoiesis. The experiment results not only set up a new strategy for IMAA treatment, but also provided a clue to study the mechanism of IMAA.

Radiotherapy-based conditioning is effective immunosuppression for patients undergoing transplantation with T-cell depleted stem cell grafts for severe aplasia.

BACKGROUND: We studied the outcome of individuals with aplastic anemia conditioned with a radiation-containing regimen followed by an infusion of stem cell grafts that had been depleted of lymphocytes with CAMPATH-1H (antiCD52; humanised). METHODS: The conditioning regime consisted of fractionated (f) TBI 8 Gy followed by f total nodal irradiation (TNI) 6 Gy. In addition, patients received CY 60 mg/kg on 2 consecutive days. Cytokine-mobilized peripheral blood grafts from HLA-identical siblings were T-cell depleted with CAMPATH-1H 'in the bag'. CsA was commenced on day -1 and continued until day +90. RESULTS: Seventeen heavily transfused patients with aplastic anemia, median age 18 years (range 14-56 years), were studied. The median time from diagnosis to transplantation was 172 days (range 34-443 days). The median CD34(+) cell number infused was 3.47 x 10(6)/kg (range 1.03-18.4 x 10(6)/kg). All patients engrafted. Recovery was fast and patients reached 0.5 x 10(9)/L polymorphs by median day 11 (range 9-17 days). Toxicity from the conditioning included grade 4 hematologic toxicity in all patients. Another major toxicity was gastrointestinal mucosal damage, which exceeded grade 2 in two instances. One patient developed thrombotic thrombocytopenic purpura, which responded to substitution of CsA with tacrolimus and plasmapheresis. Another patient, who had normal blood counts, died of infection on day 241. Chimerism studies at 6 months post-transplantation confirmed the donor origin of hematopoiesis in all seven patients tested. None of the patients developed acute or chronic GvHD. There was no delayed graft failure and 94% of patients had survived disease free at a median of 1303.5 days (range 216-2615 days) from graft infusion. DISCUSSION: In this cohort of multiply transfused patients, the radiation-containing schedules described in this study led to universal engraftment with limited toxicity despite T-cell depletion. No patient developed GvHD or late graft failure. Lower doses of radiation-containing conditioning should be explored further.

Nutritional status and growth after bone marrow transplantation (BMT) during childhood: EBMT Late-Effects Working Party retrospective data. European Group for Blood and Marrow Transplantation.

The European Group for Blood and Marrow Transplantation (EBMT) Late-Effects Working Party collected data on patients who survived more than 5 years after BMT. Height at transplant and at the latest follow-up examination were evaluated in 79/258 subjects who were below the age of 15 at BMT. A significant decrease in height-standard deviation score (SDS) was observed in leukemic children conditioned with total body irradiation (TBI) and in those who received both cranial irradiation and TBI. The majority of these patients, however, received single-dose TBI (28/41). A significant decrease in height-SDS was also seen in children who received thoraco-abdominal irradiation suggesting that the deleterious effect of irradiation on growth after BMT is not entirely due to injury to cranial neuroendocrine structures, but also probably due to damage to bone epiphyses, thyroid and gonads. A non-significant decrease in height was observed in children transplanted using chemotherapy alone. Nutritional status, expressed as body-mass index (BMI), was found unchanged in the adult group (n = 158). A significant increase in BMI was observed in the younger patients (n = 88), which parallels the normal increase in BMI observed during childhood. This suggests that on long-term analysis, a good nutritional status is maintained in patients undergoing BMT at any age.

Total body irradiation: a neuropsychological risk factor in pediatric bone marrow transplant recipients.

Bone marrow transplantation (BMT) involves conditioning with cyclophosphamide and, for leukemic patients, total body irradiation (TBI). Based on the concern that this may lead to later neuropsychologic impairment in children, a longitudinal study was conducted. Thirty pediatric bone marrow transplant recipients, treated for leukemia or severe aplastic anemia (SAA), and their sibling donors, were given a neuropsychological examination in 1986 and 1988. A third follow-up study of patients treated before 12 years of age was undertaken in 1990-91. We present longitudinal data on patients treated with BMT when 3-11 (n = 15) and 12-17 (n = 11) years old. No neuropsychological deficits were found in the older group, or among non-irradiated SAA patients. In the first follow-up, children treated with BMT, including TBI at 3-11 years of age, performed less well than donors on tasks involving perceptual and fine-motor speed. In the second follow-up, this group of patients also demonstrated a slight deficit in non-verbal problem solving. An additional relative decline in verbal reasoning was noted in the third follow-up, 5.5-10 years after treatment. Alertness to signs of developmental difficulties in children treated with BMT, including TBI, is recommended.

Successful pregnancy following allogeneic bone marrow transplantation after conditioning by thoraco-abdominal irradiation.

A 26-year-old woman delivered a normal child 5 years after bone marrow transplantation for severe aplastic anemia. The conditioning regimen comprised high dose cyclophosphamide and thoraco-abdominal irradiation (6 Gy). This and two previous cases demonstrate that normal pregnancy can follow total body or thoracoabdominal irradiation.

The development of cataract in children as a late side-effect of bone marrow transplantation.

Children with hematological malignancies (n = 33), severe aplastic anemia (SAA, n = 7) and other non-malignant diseases (n = 4) were followed for cataract development after bone marrow transplantation (BMT). The children with hematological malignancies were subjected to total body irradiation (TBI), 10 Gy, in one session with no shielding of the eyes as part of their conditioning regimen before BMT. The children with SAA or other non-malignant diseases received either no irradiation before BMT or a reduced dose, 8 Gy, with shielding of their eyes. After 3 years all patients who had undergone BMT for hematological malignancies had developed lens opacification. No patients in the other groups, without leukemia, showed any sign of cataract development. There was no relationship between steroid treatment for graft-versus-host disease and cataract development. No relation to age of onset of treatment or to the sex of the patient and cataract formation was seen. It seems evident from the present study that TBI given in one session was the main cause of cataract development after BMT.

[Bone marrow transplantation for girls with aplastic anemia utilizing modified field of total lymphoid irradiation and cyclophosphamide: with emphasis on the field of pelvic cavity].

A preparative regimen for allogeneic bone marrow transplantation, consisting of total lymphoid irradiation (TLI) with 750 cGy and cyclophosphamide (CY), was used in five girls with aplastic anemia. All patients received bone marrow from HLA matched/mixed lymphocyte culture negative siblings. In our regimen the "inverted Y" field to irradiate the pelvic nodes was modified, which did not include the whole pelvic cavity in an attempt to protect the ovaries from irradiation. Although some of the pelvic nodes was supported not to be irradiated in order to protect the ovaries, engraftment occurred in all five patients including four who had been transfused prior to transplantation. All five are alive from 47 days to 1378 days (median 285 days) after transplantation without transplantation-associated complications. The calculated dose to the ovaries was sixteen percent of the entire dose of the regimen. Both of the two evaluable patients that had received transplantation just before or during the puberty are developing normal sex maturity including menstruation. This study suggests that our preparative regimen is effective not only for engraftment of the donor marrow but also for protecting the ovaries from irradiation.

Plasma vitamin E and beta-carotene concentrations during radiochemotherapy preceding bone marrow transplantation.

Blood from 19 patients was examined for the essential antioxidants alpha-tocopherol and beta-carotene before, during, and after bone marrow transplantation (BMT). Marrow ablation and immunosuppression for BMT conditioning was achieved by treatment with high-dose chemotherapy, mostly combined with total body irradiation. All patients required total parenteral nutrition beginning 1 wk before BMT. After conditioning therapy the concentration of absolute and lipid-standardized alpha-tocopherol and beta-carotene in plasma decreased significantly, presumably as a result of an enhanced breakdown of these antioxidants. The loss of these lipid-soluble antioxidants has to be considered as a possible cause for early posttransplant organ toxicity.

TBI technique and clinical results of leukemia patients at the University of Tübingen.

Since 1976, more than 180 patients suffering from leukemia or aplastic anemia have been treated with BMT and TBI. The improvement of TBI-technique starting from single fraction irradiation without any shielding to different types of fractionation schemes with lung, head and neck shielding and an electron boost to the thoracal wall is shown. A more detailed description of the actual TBI-technique is given; this has been applied to 64 patients to-date. Some clinical results are summarised into four subgroups. Life table analyses are shown for single fraction irradiation as well as for fractionated irradiation separated for high and for low risk patient groups.

Transient engraftment of syngeneic bone marrow after conditioning with high-dose cyclophosphamide and thoracoabdominal irradiation in a patient with aplastic anemia.

We describe the clinical course of a 16 year old girl with aplastic anemia who was treated by syngeneic bone marrow transplantation. Engraftment was not obtained by simple infusion of bone marrow without immunosuppression. The patient received a high-dose cyclophosphamide and thoracoabdominal irradiation, followed by second marrow transplantation from the same donor. Incomplete but significant hematologic recovery was observed; however, marrow failure recurred 5 months after transplantation. Since donor and recipient pairs were genotypically identical, graft failure could not be attributed to immunological reactivity of recipient cells to donor non-HLA antigens. This case report implies that graft failure in some cases of aplastic anemia might be mediated by inhibitory cells resistant to cyclophosphamide and irradiation.

Growth in children following irradiation for bone marrow transplantation.

Longitudinal height data from 46 pediatric bone marrow transplant (BMT) patients, including 18 with aplastic anemia (AA), 19 with acute nonlymphoblastic leukemia (ANLL), and 9 with acute lymphoblastic leukemia (ALL), were analyzed to assess growth posttransplantation. Patients were prepared for BMT with high-dose cyclophosphamide followed by 7.5 Gy single-dose irradiation; AA patients received total lymphoid irradiation (TLI), and leukemia patients received total body irradiation (TBI). AA patients demonstrated reduced height posttransplant as reflected in a negative mean standard deviation score. The observed reduction was statistically significant only at 3 years following transplant. In contrast, leukemia patients showed a significant loss in relative height that was first visible at 1 year post-BMT and continued until at least 4 years post-BMT. Mean growth velocities in the leukemia patients were significantly below median for the 3 years following transplant. With a median follow-up of 4 years, antithymocyte globulin plus steroids in combination with methotrexate as graft vs. host prophylaxis was associated with less severe growth suppression than methotrexate alone, while there were no significant associations between growth during the first 2 years following transplant and prepubertal status at transplant (as defined by age), graft vs. host disease, thyroid or gonadal function, or previous therapies received by the leukemia patients. Children undergoing marrow transplantation, particularly those receiving TBI, are at significant risk of subsequent growth suppression.

Total lymphoid irradiation as an immunosuppressive agent for transplantation and the treatment of 'autoimmune' disease: a review.

Total lymphoid irradiation (TLI) is a powerful immunosuppressive agent. This immunosuppression has the potential for clinical application in certain selected situations. In this review, the immunological changes produced by TLI and its potential applications in organ transplantation and the treatment of certain 'autoimmune' diseases are discussed.