Melanie Weiss

Malignant Neoplasms in Long-Term Survivors of Bone Marrow Transplantation

Bone marrow transplantation offers a chance for cure to patients with leukemia, lymphoma, and severe aplastic anemia (1-3). However, long-term survival may be impaired by the development of secondary neoplasms (4). Secondary malignant diseases are known complications of the radiation and chemotherapy used to treat primary cancers (5-7). An increased risk for malignant neoplasms has also been reported in patients who receive organ transplants (8, 9) and those treated with immunosuppression for aplastic anemia (10). Patients who receive marrow transplants are at increased risk for malignant neoplasms because of several risk factors: ionizing radiation and chemotherapy used for pretransplantation conditioning and treatment of the primary malignant disease, immune deficiency due to delayed and incomplete recovery of the immune system, immune stimulation and immunosuppression by the graft-versus-host reaction, and immunosuppressive therapy for graft-versus-host disease. Most reports on malignant neoplasm after marrow transplantation have included patients early after transplantation and have had short follow-up (1, 4, 11-15). A recent multicenter study of more than 19 000 patients (16) included patients early after transplantation and evaluated solid cancers only. The aim of this study was to assess the risk for malignant neoplasm in long-term survivors of marrow transplantation and to identify risk factors for new malignant disease. Methods Marrow transplantation programs were started in Europe in the early 1970s in several university hospitals. The indication for marrow transplantation changed with time: Before 1976, the main indication was severe aplastic anemia, whereas after 1980, the main indication was leukemia. The European Cooperative Group for Blood and Marrow Transplantation (EBMT) was founded in 1977. A central registry of all cooperating centers was instituted at the University of Leiden; this registry includes basic information on disease-related and transplant-related variables, including the form of radiation, radiation dose, dose rate, fractionation, and treatment times. Patients We studied 1036 patients who underwent transplantation in 45 European centers cooperating in the EBMT. We limited our study to patients surviving more than 5 years for two reasons. First, mortality due to transplant-related complications other than malignant neoplasm and recurrence of the original disease are high in the first years after transplantation. These causes of death may interfere in a nonrandom manner with the development of malignant neoplasms. In addition, most major complications other than malignant neoplasm occur within that time, and their influence on the development of new malignant disease can be studied independently. Data Collection The EBMT registry provided basic data on patients who underwent transplantation before 1986 and on the transplantation centers, including age and sex of the patient and his or her donor; diagnosis and status of the disease at the time of transplantation; histocompatibility with the donor in the transplantation categories of monozygotic twin, HLA-identical family member, HLA-mismatched family member, and autologous; conditioning treatment, including radiation, radiation source, radiation field, radiation dose, dose rate, fractionation schedule, number of days with radiation, and the form of chemotherapy; methods of prevention of graft-versus-host disease; and the occurrence of acute graft-versus-host disease, graded on a 0 to 4 scale, and chronic graft-versus-host disease, graded on a 0 to 2 scale. Additional information on occurrence of a secondary neoplasm, date of tumor detection, International Classification of Diseases code, histology report on the tumor, recurrence and treatment of the original disease, agents used for the treatment of graft-versus-host disease, the date of last follow-up, clinical performance status at the time of last follow-up, and cause of morbidity or death was requested. The transplantation centers were asked to check the registry data and to provide the additional information. Furthermore, they were asked to report all consecutive patients undergoing transplantation who survived more than 5 years. Copies of the original histology reports were provided for 62% of all tumors. Radiation as preparative treatment was classified as single-dose or fractionated total-body radiation and partial-body radiation, including total lymphoid and thoracoabdominal radiation. The radiation source, dose, acute dose rate, number of fractions, number of days with radiation, and dose to the lungs were scored as radiation variables. Statistical Analysis Kaplan-Meier survival analysis was performed to estimate the risk for malignant neoplasm with time after transplantation (8, 17). The date of onset of a pathologically confirmed malignant neoplasm was the date on which the clinical diagnosis was first suspected. The risk for neoplasms in the observation group was compared with that in the general population; patients were matched for age and sex. Data were provided by the Danish Cancer Registry and the Cancer Registry of the Saarland/Germany (18) on the annual incidence of malignant cancer at all body sites, including the skin. These registries are representative of the European population. The expected number of cases (E) in the cohort was calculated by using age, sex, and length of follow-up, and the incidence rates were compared with the incidence in the transplant cohort (O). Significance was assessed under the null hypothesis that O is equal to E in a Poisson distribution. A standardized ratio (O/E) was also calculated. Analysis of potential risk factors was performed with the time to diagnosis of malignant neoplasm in a log-rank test for univariate analysis. Multivariate regression analysis was performed with the Cox model for proportional hazards. Analyses were performed by using the NCSS statistical package (Dr. J.L. Hintze, Kaysville, Utah). Results Survival The median duration of observation was 128 months; the longest observation was 265 months (Figure 1). 90 patients died more than 5 years after transplantation. Causes of death were recurrence of the original disease in 44 patients, chronic graft-versus-host disease with or without pulmonary complications in 22 patients, secondary malignant neoplasm in 10 patients, AIDS in 5 patients, pulmonary complications and infections in 3 patients, and accidents in 3 patients. The cause of death was not known for 3 patients. Secondary malignant neoplasms in patients who died were brain tumors in 3 patients; squamous-cell carcinoma of the oral cavity, larynx, esophagus, and anus in 5 patients; and secondary leukemia and neurofibrosarcoma in 1 patient each. The risk for death from all causes ( SE) was 7.9% 0.9% at 10 years and 12% 1.4% at 15 years after transplantation. Figure 1. Cumulative probability of developing a malignant neoplasm as a function of time after bone marrow transplantation. n Tumors New malignant disease was diagnosed in 53 patients. The most frequent tumors were carcinomas of the skin; basal-cell and squamous-cell carcinomas; tumors of the oral cavity; carcinomas of the uterus, including carcinoma in situ of the cervix; breast cancer; thyroid gland cancer; and brain tumors (Table 1). The actuarial risk for a malignant neoplasm was 3.5% 0.6% at 10 years and 11.5% 2.3% at 15 years (Figure 1). The overall incidence of malignant tumors is about fivefold greater than that in an age- and sex-matched population (Figure 2). This increase was more than 10-fold for cancer of the oral cavity, esophagus, or thyroid gland (Figure 3). Table 1. Malignant Neoplasms in Patients Who Survived 5 Years after Transplantation Figure 2. Cumulative number of malignant neoplasms after bone marrow transplantation as a function of age. Figure 3. Standardized incidence ratios of malignant neoplasms after bone marrow transplantation. circles Risk Factor Analysis The median age of donors and patients was 21 years (range, 1 to 51.9 years). Older age of the recipient at the time of transplantation was a risk factor for malignant neoplasm in female patients only (Table 2). Older age of the donor was also a risk factor for neoplasms in the recipient if the donor was female. Neoplasms were detected earlier in these recipients. The increased incidence of malignant neoplasms in recipients of allogeneic transplants compared with recipients of autologous and syngeneic transplants did not reach statistical significance. Only patients with extensive, chronic graft-versus-host disease had a significantly increased risk. Treatment of graft-versus-host disease with cyclosporine, azathioprine, and thalidomide significantly increased the risk for malignant neoplasms (Table 2). Variables with P values less than 0.2 in a log-rank test comparing time until tumor development were entered into a multivariate analysis using the Cox proportional-hazards model. Only patient age remained significant after adjustment for histocompatibility group and development of graft-versus-host disease (Table 3). Treatment of graft-versus-host disease with cyclosporine, thalidomide, or methotrexate was a significant risk factor (Table 3). Table 2. Malignant Neoplasm after Bone Marrow Transplantation: Univariate Analysis Table 3. Malignant Neoplasms after Bone Marrow Transplantation: Multivariate Analysis in Cox Proportional Hazards Model In the subgroup analysis, the effect of age on carcinogenesis was limited to female patients (Table 2), in part because of carcinomas of the breast and the uterus. However, the effect of age in female patients was still significant after malignant disease of the genital organs and breast was excluded from analysis (P=0.04). Neoplasms of the skin are frequent in patients who receive solid organ transplants (8). We also analyzed the risk factors in patients with tumors in organs other than skin. In these patients, chronic graft-versus-h

Health and Functional Status of Long-Term Survivors of Bone Marrow Transplantation

Bone marrow transplantation is used to treat patients who have life-threatening hematologic diseases [1, 2]. Many patients survive the acute complications of transplantation and remain free of their original disease for more than 5 years. However, information on the health and activity of surviving patients is sparse. Most studies of quality of life after bone marrow transplantation have involved a small number of patients and short observation times after transplantation [3-6, 7-11]. The assessment of late illness and death and the identification of the causes of and the risk factors for impaired health and reduced functional status may help to improve treatment strategies. Using data from centers that are collaborating in the European Group for Blood and Marrow Transplantation (EBMT), we conducted a retrospective, descriptive study on late death, health, and social reintegration of patients who had received allogeneic and syngeneic bone marrow transplants for hematologic disorders before 31 December 1985 and who had survived for at least 5 years. We evaluated variables associated with late illness and death and reduced participation in school or work. The patients primary disease, age, and sex and the availability of a donor were predetermined variables. However, evaluation of the variables related to the treatment strategy, such as the selection of the optimal time in the course of the disease for transplantation, the choice of the conditioning treatment (that is, with or without radiation), and the regimen used for prophylaxis of graft-versus-host disease, is of particular interest. Methods All European transplantation centers cooperating in the EBMT were asked to provide information on patients who had transplantation before 31 December 1985 and had survived for at least 5 years after receiving the graft. Data on 798 consecutive transplant recipients were reported from 43 centers in 13 European countries. The mean percentage (SD) of long-term survivors was 39.2% 8.8%. Selective reporting was excluded by scoring unique patient numbers that were previously reported to the EBMT registry in Leiden, the Netherlands. The data were validated at meetings of the EBMT Late Effects Working Party and through personal contact with the responsible persons at the centers. Clinical performance was assessed according to the latest Karnofsky score, and social activity was evaluated according to the patients ability to attend work or school full-time or part-time. Karnofsky scores were assigned in increments of 10%. Scores of 90% and 100% are compatible with normal activity; a score of 80% reflects special efforts to carry on normal activity; and scores of 70% or less reflect varying need for assistance with normal activity. For patients who died more than 5 years after transplantation, the causes of illness and death were reported. We considered the following factors as potential risk factors for impaired clinical and social performance and late death and entered them into a bivariate analysis: age and sex of the patient and donor; histocompatibility of the donor; primary disease and status at the time of transplantation; conditioning regimen, including details on radiation; method of prophylaxis of graft-versus-host disease; occurrence of acute and chronic graft-versus-host disease; development of secondary cancer; and recurrence of original disease. Patient Data Patient characteristics are summarized in Table 1. Patients younger than 18 years of age were classified as children (321 patients), and patients 18 years of age or older were classified as adults (477 patients). Most patients (n = 652) had transplantation for the treatment of leukemia. Early phases of disease were defined as first remission of acute leukemia or the chronic phase of chronic myelogenous leukemia; intermediate phases were acute leukemia in second remission or chronic myelogenous leukemia in the accelerated phase; and advanced phases were later remissions of or active acute leukemia and blastic transformation of chronic myelogenous leukemia. Donors were HLA-identical siblings for 775 patients, HLA-mismatched family members for 7 patients, and syngeneic twins for 16 patients. Table 1. Characteristics of Treated Patients* A total of 645 patients (80%) received total-body radiation; 434 patients were treated with single-dose total-body irradiation, and 211 patients received fractionated total-body irradiation. Thirty-four patients were conditioned by total lymphoid or thoracoabdominal radiation, and 89 patients were conditioned by chemotherapy only. For total lymphoid irradiation, the radiation field involved an inverted Y for the lower half of the body and a mantle field with shielding of the oropharynx. When thoracoabdominal irradiation was given to the trunk, the head and the limbs remained outside the field. Chemotherapy most frequently consisted of cyclophosphamide, either alone (50 mg/kg of body weight per day for 4 days) or in combination with radiation (60 mg/kg per day for 2 days or 50 mg/kg per day for 4 days). Other chemotherapy consisted of combination regimens, including cytosine-arabinoside (38 patients), melphalan (16 patients), busulfan (8 patients), daunomycin (13 patients), and the nitrosoureas bischlorethylnitrosourea or cyclohexylchlorethylnitrosourea (11 patients). In 30 patients, the type of conditioning procedure was not reported. The most frequently used methods of prophylaxis of graft-versus-host disease were methotrexate given after transplantation, cyclosporine, or the combination of cyclosporine and methotrexate. Eighty-three patients received prophylaxis with T-cell-depleted bone marrow or antithymocyte globulin. Data on the occurrence of graft-versus-host disease were reported for 655 recipients of allogeneic bone marrow. Acute graft-versus-host disease of grade II or higher developed in 23% of patients. Limited chronic graft-versus-host disease was seen in 182 patients (28%), and extended chronic graft-versus-host disease was seen in 92 patients (14%). Graft-versus-host disease had not developed in 381 patients (58%). Statistical Analysis Age and sex of the patients and donors, diagnosis and stage of the disease at the time of transplantation, conditioning regimen, method of prophylaxis of graft-versus-host disease, occurrence of acute and chronic graft-versus-host disease, development of secondary cancer, and recurrence of the original disease were assessed for their influence on late death, impaired clinical performance (Karnofsky score 80%), and return to social activity (full-time attendance at work or school). In a bivariate analysis, we used the Fisher exact test to compare proportions. Mortality was evaluated by comparing duration of survival using the log-rank test. A P value of 0.05 or less was considered statistically significant. Analyses were done using the Number Cruncher Statistical Systems (NCSS) statistical package (Dr. J.L. Hintze, Kaysville, Utah). Results Survival and Late Mortality The median duration of observation was 8.4 years (range, 5 to 19 years). Figure 1 shows the number of patients as a function of time since treatment; the cumulative overall mortality of the observed patients; and the expected mortality of a similar, unselected group of patients. Fifty-five patients died more than 5 years after bone marrow transplantation, and 743 patients are alive and evaluable for clinical performance and social activity. For 5-year survivors, the actuarial risk for death is 8% (95% CI, 6% to 11%) at 10 years (216 patients at risk) and 14% (CI, 8.1% to 19.9%) at 15 years (16 patients at risk). Figure 1. Mortality more than 5 years after bone marrow transplantation. The causes of death occurring more than 5 years after bone marrow transplantation are listed in Table 2. Leukemic relapse was the most common single cause of death and most frequently occurred in patients with chronic myelogenous leukemia (14%) and lymphoma (25%); it was also seen in 4% of patients with acute myelogenous leukemia and 4% of patients with acute lymphoblastic leukemia. Chronic graft-versus-host disease with and without infection and chronic lung disease were the second most frequent causes of death. Secondary cancer and transfusion-associated acquired immunodeficiency syndrome (AIDS) also contributed to mortality. Table 2. Causes of Death Occurring More Than 5 Years after Transplantation* The most important risk factor for survival after more than 5 years is recurrence of leukemia and lymphoma. Other statistically significant factors in the bivariate analysis were the development of secondary cancer, chronic graft-versus-host disease, stage of disease at the time of transplantation, and the use of radiation for conditioning treatment (Table 3). After patients with recurrent disease were excluded, extended chronic graft-versus-host disease, the development of secondary cancer, female sex of the donor, male sex of the patient, and the use of methotrexate were statistically significantly associated with late mortality (Table 3). Table 3. Risk Factors for Death More Than 5 Years after Allogeneic Bone Marrow Transplantation* Clinical Performance Information on Karnofsky scores was available for 647 patients. Patients with a Karnofsky score of 80% or less are considered to be unable to perform normally without special effort. Factors associated with clinical performance reduced to less than 100% were reported for 125 patients. After 15 patients who were living with recurrent disease were excluded, the major cause of illness was chronic graft-versus-host disease (Table 4). Pulmonary changes consisted of obliterative bronchiolitis, lung fibrosis, and recurrent infections, which were probably the sequelae of chronic graft-versus-host disease. Similarly, aseptic osteonecrosis and osteoporosis were associated with chronic graft-versus-host disease and its treatment with corticosteroids. Table 4. Causes of Reduced Performance Status in Pati

The Outcome of Local Radiation Injuries: 14 Years of Follow-up after the Chernobyl Accident

Abstract Gottlöber, P., Steinert, M., Weiss, M., Bebeshko, V., Belyi, D., Nadejina, N., Stefani, F. H., Wagemaker, G., Fliedner, T. M. and Peter, R. U. The Outcome of Local Radiation Injuries: 14 Years of Follow-up after the Chernobyl Accident. The Chernobyl nuclear power plant accident on April 26, 1986 was the largest in the history of the peaceful use of nuclear energy. Of the 237 individuals initially suspected to have been significantly exposed to radiation during or in the immediate aftermath of the accident, the diagnosis of acute radiation sickness (ARS) could be confirmed in 134 cases on the basis of clinical symptoms. Of these, 54 patients suffered from cutaneous radiation syndrome (CRS) to varying degrees. Among the 28 patients who died from the immediate consequences of accidental radiation exposure, acute hemopoietic syndrome due to bone marrow failure was the primary cause of death only in a minority. In 16 of these 28 deaths, the primary cause was attributed to CRS. This report describes the characteristic cutaneous sequelae as well as associated clinical symptoms and diseases of 15 survivors of the Chernobyl accident with severe localized exposure who were systematically followed up by our groups between 1991 and 2000. All patients presented with CRS of varying severity, showing xerosis, cutaneous telangiectasias and subungual splinter hemorrhages, hemangiomas and lymphangiomas, epidermal atrophy, disseminated keratoses, extensive dermal and subcutaneous fibrosis with partial ulcerations, and pigmentary changes including radiation lentigo. Surprisingly, no cutaneous malignancies have been detected so far in those areas that received large radiation exposures and that developed keratoses; however, two patients first presented in 1999 with basal cell carcinomas on the nape of the neck and the right lower eyelid, areas that received lower exposures. During the follow-up period, two patients were lost due to death from myelodysplastic syndrome in 1995 and acute myelogenous leukemia in 1998, respectively. Other radiation-induced diseases such as dry eye syndrome (3/15), radiation cataract (5/15), xerostomia (4/15) and increased FSH levels (7/15) indicating impaired fertility were also documented. This study, which analyzes 14 years in the clinical course of a cohort of patients with a unique exposure pattern, corroborates the requirement for long-term, if not life-long, follow-up not only in atomic bomb survivors, but also after predominantly local radiation exposure.

Nutritional status and growth after bone marrow transplantation (BMT) during childhood : EBMT Late-Effects Working Party retrospective data

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.

Thyroid examination in highly radiation-exposed workers after the Chernobyl accident

CONTEXT Radioactive contamination from the Chernobyl nuclear accident that happened on the morning of 26th April 1986 had a major impact on thyroid health in the Belarus region. OBJECTIVE Observational study of a cohort of 99 adults, most strongly exposed to ionizing radioactivity. DESIGN, SETTING AND PATIENTS Observational study performed between 1998 and 2000. The cohort comprised 99 workers (92 male) of the Chernobyl nuclear power plant. Examination including physical examination, ultrasonography of the thyroid gland and measurement of serum free thyroxin (fT(4)), free triiodothyronine (fT(3)) and TSH. Anti-thyroperoxidase (anti-TPO), antithyroglobulin (anti-Tg) antibodies and thyroid stimulating immunoglobulin were also determined. MAIN OUTCOME MEASURES The impact of exposure to high-dose radiation, including radioactive iodine, on the thyroid gland was examined. RESULTS Levels of fT(4) in all probands were within the normal World Health Organization-defined range. Elevated levels of fT(3) were found in two workers (2%), high titres of anti-TPO and anti-Tg antibodies were present in four subjects (4%). Mild hypothyroidism was present in one patient. Enlargement of the thyroid gland was observed in 17 workers (17%). There was no evidence of clinically overt thyroid cancer. CONCLUSIONS The Chernobyl accident showed surprisingly little impact on the thyroid in a cohort of workers strongly exposed to radiation. Our data suggest an age-dependent heterogeneity in response to the short-lived radioiodine isotopes and favours long-term follow-up analysis.

Project RATEMA-one year's experience

The RATEMA project is an international cooperation between the University of Ulm in Germany and the Urals Research Centre for Radiation Medicine in Chelyabinsk, Russia. For one year we conducted weekly conferences between the two sites, based on a satellite link with a 384 kbit/s connection. During the videoconferences the physicians on both sides—experts in radiation medicine—discussed the health status of Russian patients who had been chronically exposed to ionizing radiation in the South Urals region. The German partners presented patients with comparable haematological and oncological diseases. The project has shown the advantages and difficulties of working in an international and interdisciplinary environment. The experience gained has been very valuable for planning new projects with similar tasks. The results and the contents of the RATEMA database are the basis for education and research for physicians involved in the management of radiation victims.