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We report the results of the first prospective randomized multicenter study of immunosuppressive treatment in patients with previously untreated nonsevere aplastic anemia (AA) as defined by a neutrophil count of at least 0.5 × 109/L and transfusion dependence. Patients were randomized to receive cyclosporin (CSA) alone or the combination of horse antithymocyte globulin ([ATG] Lymphoglobuline; Merieux, Lyon, France) and CSA. The endpoint of the study was the hematologic response at 6 months. One hundred fifteen patients were randomized and assessable with a median follow-up period of 36 months; 61 received CSA and 54 ATG and CSA. In the CSA group, the percentage of complete and partial responders was 23% and 23%, respectively, for an overall response rate of 46%. A significantly higher overall response rate of 74% was found in the ATG and CSA group, with 57% complete and 17% partial responders (P = .02). Compared with CSA alone, the combination of ATG and CSA resulted in a significantly higher median hemoglobin level and platelet count at 6 months. Fewer patients required a second course of treatment before 6 months due to a nonresponse. In the CSA group, 15 of 61 (25%) patients required a course of ATG before 6 months because of disease progression, compared with only 3 of 54 (6%) in the ATG and CSA group. The survival probabilities for the two groups were comparable, 93% (CSA group) and 91% (ATG and CSA group), but at 180 days, the prevalence of patients surviving free of transfusions, which excluded patients requiring second treatment because of nonresponse, death, disease progression, or relapse, was 67% in the CSA group and 90% in the ATG and CSA group (P = .001). We conclude that the combination of ATG and CSA is superior to CSA alone in terms of the hematologic response, the quality of response, and early mortality, and a second course of immunosuppression is less frequently required.

Purpose : To determine whether in vitro radiosensitivity parameters are predictive of treatment outcome. Methods and Materials : Biopsies were obtained from patients with head and neck cancers (57) and cervical carcinomas (20) and in vitro radiosensitivity parameters were obtained using the CAM plate assay. Results : In most cases (75%) patients were treated with radiation alone. The median follow up was 461 days. When the whole group of head and neck cancers and cervical carcinomas was considered, patients with a SFZ value below 0.36 had a higher 2-year local control rate (93% versus 68%) and a higher 2-year survival rate (71% vs. 62%) than those with SFZ values above that threshold, but differences were not significant. These trends persisted when head and neck cancers were considered alone with a higher local control rate (86% vs. 67%) and a higher survival rate (75% vs. 52.5%) obtained for patients with a SFZ value below 0.36. When the alpha value was evaluated for the whole group of patients a significantly higher local control rate (80.5% vs. 40.5%) and overall survival rate (71% versus 37.5%) at 2 years were obtained for patients with alpha values above 0.07 Gy−1 When only the group of head and neck cancers was considered, local control rate was significantly higher (79% vs. 33%) but overall survival rate (65.5% vs. 33%) was not significantly higher for alpha values above 0.07 Gy−1. Conclusion : These results are encouraging but need to be confirmed with a larger number of patients with a longer follow-up.

Summary. Chimaerism was studied early (2 weeks to 3 months) during haematopoietic reconstitution after bone marrow transplantation in 18 severe aplastic anaemia patients (acquired SAA: 14 patients; Fanconi anaemia: four patients). Fourteen patients received marrow from an identical sibling donor, one from the phenoidentical father and three from a matched unrelated donor. Peripheral blood cell DNA was first analysed by Southern blotting with a multilocus minisatellite probe (33.6.3) or a Y chromosome specific probe (pHY2.1). For all 14 patients grafted with a genotypically identical sibling donor, the post-graft DNA profile strictly matched the respective donor profile (minisatellite probe) or disclosed the Y chromosome specific band in the case of female patients grafted with a male donor. In contrast, for the one patient grafted in a mismatched situation and for two out of three patients grafted with a matched unrelated donor, the results indicated autologous bone marrow recovery. This difference between patients grafted with an identical sibling donor and those grafted in other situations is statistically significant (P < 0.01). The 15 patients with circulating cells of donor origin were then studied by polymerase chain reaction amplification of the DNA samples. The three male patients with a female donor were studied by amplification of a Y chromosome specific sequence (DYZ1), allowing the detection of one male cell in 104 female cells. In all three cases, residual male nucleated celts were detected. The analysis was performed by amplification of the 33.6.3 minisatellite sequence for the 12 remaining patients. No residual recipient cells were detected within the sensitivity limit of the method which is 1% in that case. This suggests that detection of residual host cells depends on the sensitivity of the technique used.

Non infectious pulmonary complications which frequently occur in the late follow-up of haemopoietic stem cell transplant (HSCT) recipients account for an increase in mortality and morbidity. Different histological entities have been described among which bronchiolitis obliterans is the most common.Because of the absence of prospective epidemiological studies and the difficulties in obtaining surgical lung biopsies from these frail patients little is known about these conditions. Although their pathogenesis is poorly understood they probably result from a chronic pulmonary graft versus host disease (GVHD). The introduction of or increase in systemic immunosuppressive treatment, usually indicated for controlling extra-thoracic manifestations of GVHD, may lead to the resolution of an organising pneumonia but is usually ineffective in the treatment of bronchiolitis obliterans.Current prospective cohort studies together with randomised prospective studies evaluating more targeted treatments should help determine the frequency, the risk factors and the precise characteristics of the different entities of late non-infectious pulmonary diseases following HSCT and should also improve their management. Furthermore, the recent demonstration of lung abnormalities in animal models of chronic GVHD, similar to those observed in humans, should allow a better understanding of the pathogenesis.The prevalence of these diseases is increasing throughout the world. More precise analysis, the identification of risk factors and study of the pathophysiological mechanisms involved should allow better understanding and management than at present.

Toxoplasmosis is a rare but severe complication of bone marrow transplantation. Here, we report three patients in whom toxoplasmic pneumonitis developed, leading to fatal acute respiratory distress syndrome (ARDS). All patients had positive pretransplantation tests for Toxoplasma gondii and were therefore at risk to develop toxoplasmosis reactivation. They all recovered from aplasia, but soon after they died from brutal and severe ARDS. The possible role of an immunopathologic response to T gondii in the lungs in triggering ARDS is discussed.Early screening of parasitemia using highly sensitive polymerase chain reaction methods in seropositive patients with unexplained fever may be needed.

A study of long term survival of 1487 patients given an allogeneic bone marrow transplant for acute myelogenous leukaemia and 729 patients given a transplant for severe aplastic anaemia was conducted by the International Bone Marrow Transplant Registry. One aim of this study is to determine if the mortality rates of these patients return after some period of time to the same mortality rate as in the general population. To examine this question a model for the relative mortality of a bone marrow transplant patient relative to a matched individual in the general population is presented. This model allows for different relative mortality rates depending on the risk factors the patient may have. We discuss an estimation procedure for this model and construct a test that the mortality rate in the transplanted population is the same as in the reference population over a given time interval.

Secondary malignancies (lymphomas, leukemias, and solid tumors) occurring after bone marrow transplantation are now more frequently reported, as the patients surviving the early phase of the graft and remaining free of their original disease are more numerous. Besides early Epstein-Barr virus-associated B-cell lymphoproliferative diseases, which are the most common type and most often of donor origin, few late-occurring lymphomas have been described that might represent a distinct entity. We report here a case of Hodgkin's disease developing 8 years after allogeneic bone marrow transplantation for chronic myelogeneous leukemia. Only two Hodgkin's diseases after allogeneic bone marrow transplantation have been reported in the literature so far. The case we report is of interest because of its donor origin and its association with Epstein-Barr virus infection.

Purpose: To evaluate the incidence of lung complications and leukemia recurrences after two different doses to the lungs during total body irradiation. Methods and Materials: Seventy-nine patients with acute leukemia (AML or ALL) in first complete remission or chronic myeloid leukemia in the chronic phase, five patients with high grade lymphoma, and one with chronic lymphocytic leukemia were entered in the study. They were given a single dose of total body irradiation (10 Gy over 4 h) with two different doses to the lungs (6 Gy or 8 Gy) prior to bone marrow transplantation. The median dose rate was 0.04 Gy/min. The median follow-up for both groups of patients was 24 months. Results: The actuarial 5-year overall survival rate was similar in both groups, 59% and 43% for patients given 8 Gy and 6 Gy to the lungs, respectively. The lung complication rate was similar in the two groups (28% vs. 22% for the 8 Gy and 6 Gy group, respectively). The actuarial leukemia recurrence rate was significantly higher in the group of patients given 6 Gy to the lungs (25%) vs. 0% in the 8 Gy group. Interestingly, all recurrences occurred in the group of patients who were given 6 Gy to the lungs, who had acute leukemia, and no chronic graft vs. host disease (GVHD). Conclusions: Although the number of patients was not very large and the follow-up relatively short, these findings suggest that a lower dose to the lungs could lead to an increased incidence of leukemia recurrences due to a lower dose to the thoracic wall or to a lower incidence of chronic GVHD

We used polymerase chain reaction amplification of minisatellite sequences (33.6.3, MS51, YNZ22) and of a Y chromosome-specific sequence (DYZ1) to document prospectively chimerism in 23 leukemia patients grafted with non T-cell depleted marrows from HLA-identical sibling donors. Twenty-two patients had a complete hematopoietic chimerism (within the sensitivity limit of the method used: 1%) early (about 1 month) after transplantation and one had detectable residual host cells (partial chimerism). These cells were still present after 8 months, and this patient relapsed 16 months after transplantation. Two patients with early complete chimerism relapsed 16 and 17 months after transplantation. Seven patients died from toxicity or infections and 13 are in clinical remission with a follow-up of 16 to 48 months. Nine male patients grafted with the marrow from a female donor were also studied by amplification of the DYZ1 marker (0.01% sensitivity). In all nine cases, residual male nucleated cells were detected early and up to 1 year after transplantation. These results suggest that the detection of persistent residual recipient cells above a 1% level might be predictive of relapse but that the detection of such cells in a 0.01-1% range is probably unrelated to relapse and does not seem to influence the outcome of the transplantation procedure.

We are concerned about the inappropriate use of haemopoietic growth factors in patients with severe aplastic anaemia (SAA). The treatment of choice for this disorder is bone-marrow transplantation from an HLA-identical sibling donor if the patient is younger than 45 years, but it must be done soon after onset before the patient becomes sensitised by multiple red-cell and platelet transfusions. Other patients should receive immunosuppressive therapy with antithymocyte globulin alone or with cyclosporin or oxymetholone. Haemopoietic growth factors may have a role in stimulation of granulopoiesis after immunosuppressive therapy, but there is no evidence that they can correct the underlying stem-cell defect in SAA, and therefore no justification for their use alone in newly diagnosed SAA. Such treatment is harmful because it delays bone-marrow transplantation, or immunosuppressive therapy in older patients and those without suitable donors, thus reducing the chances of a successful outcome.

The purpose of this retrospective study was to evaluate the efficacy of low-dose limited field radiation therapy (LDLRT) in low-grade non-Hodgkin's lymphoma (NHL) patients, in order to outline its possible role. The rationale of the analysis was as follows: (1) there is no clear dose-response relationship for radiation therapy (RT) in localized low-grade non-Hodgkin's lymphomas (LGNHL); (2) long-term disease-free survival can be achieved in advanced LGNHL with low-dose (1.5-2 Gy) fractionated total body irradiation; (3) moreover, some of our previous LGNHL patients stopped their conventional planned RT course for convenience after 5 to 7.5 Gy and remained free from local progression in irradiated volumes for a long period of time. Patient selection criteria were the following: (1) patients with low-grade NHL (LGNHL); (2) patients who received no other form of therapy concomitantly with LDLRT until evaluation of the response; (3) patients who received a planned dose of 4 Gy in two fractions and over 3 days in a limited field. Out of 37 patients, 27 patients were fully evaluable. Twenty-two patients had stage III or IV disease. The median logevity of the disease was 73 months. Twenty-five patients had previously received chemotherapy (18 with anthracyclines). Nineteen patients had received one LDLRT course only. Eight patients responding to the first LDLRT had received at least one subsequent LDLRT course. After the first LDLRT course, an objective response in irradiated sites was observed in 24 of the 27 patients (89 per cent). Ten and 14 patients respectively demonstrated a complete response (CR) (37 per cent) and partial response (PR) (52 per cent). Freedom from progression in irradiated volumes for evaluable patients ranged from 4 to 35 months. Among the eight patients who received at least two LDLRT courses, a total of 20 different areas were irradiated, and 15 areas (75 per cent) showed a CR. Toxicity due to LDLRT was minimal. In conclusion, low-dose limited-field RT resulted in a high proportion of responses in LGNHL. The mechanisms explaining this radioresponsiveness are poorly understood. However, the efficacy of LDLRT could have several clinical applications in the general management of patients with advanced LGNHL.

Serum alpha-amylase was measured before and 24 h after either total body (31 patients) or localized irradiation including the salivary glands (40 patients) or the pancreatic area (22 patients). A significant increase in amylasemia was observed for doses to the parotid glands larger than 0.5 Gy. A sigmoid function of dose was fitted to the data and predicted a maximum amylasemia level for doses larger than 4 Gy and smaller than 10 Gy. The raw data from other published series were adequately described by the same model. However, the confidence limits of the parameters remained wide, because of a considerable interindividual variability. Post-irradiation hyperamylasemia appears to provide a good criterion for triage of accidentally irradiated patients: 24 h after a dose larger than 2 Gy to the parotid glands, 91% of the patients had an amylasemia level higher than 2.5-fold the upper normal value (sensitivity). Conversely, 96% had their serum amylasemia lower than 2.5-fold the upper normal value when dose was smaller than 2 Gy (specificity). However, a retrospective estimation of the absorbed dose (dosimetry) is not likely to be very precise because of the large interindividual variability.

Cancer may be serious late effect of marrow transplantation. Radiation, chemotherapy, immunosuppression and the original disease for which transplantation was performed may predispose to the development of cancer. 116 of 9732 patients reported to the IBMTR (International Bone Marrow Transplant Registry) have developed a new malignancy. Late effects were evaluated by the EBMT-EULEP (European Bone Marrow Transplant-European Late Effect Project) Late Effect Study Group in 147 patients surviving 6 years and 79 patients surviving more than 10 years. New malignancies developed in 11 of these patients. Lymphomas and leukemia comprised 73 cases reported to the IBMTR and one case reported to the EBMT-EULEP study. Tumors of the skin, oropharynx, vulva vagina and cervix prevailed in 41 patients with solid tumors. The distribution of malignancies is similar to that observed in organ transplant patients not given radiation or chemotherapy and suggests immunosuppression as a major contributory factor. In dogs the incidence of malignancies was studied after either chemotherapy or total body radiation in various regimens and marrow transplantation. Both chemotherapy and radiation shortened tumor-free survival in comparison to untreated dogs. Higher doses, larger fractions and shorter treatment schedules enhanced earlier tumor development. Soft tissue sarcomas and thyroid carcinoma were most frequent in treated, mammary carcinoma in untreated dogs. In treated dogs deaths from cancer were observed starting at the age of 5 years as compared to untreated dogs at the age of 9 years. The data from animal experiments indicate that the incidence of solid tumors in marrow transplant patients may still rise in the coming decades.

Since 1980, 107 consecutive patients (pts) underwent bone marrow transplantation (BMT) for nonconstitutional severe aplastic anemia (SAA) at our institution. All received conditioning with Cytoxan (150 mg/kg) and thoraco-abdominal irradiation (6 Gy) from an HLA-identical sibling donor. Mean age was 19 years (5 to 46 years). Forty-nine pts had less than 0.2 x 10(9)/L PMN and 53 failed to respond to previous immunosuppressive therapy before BMT. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate (22 pts), cyclosporine (52 pts), or both (33 pts). With a median follow-up of 45 months (12 to 120 months), overall actuarial survival was 68% (confidence interval 95%:9.7). Of 16 factors tested, five were shown to adversely influence survival by multivariate analysis: grade greater than or equal to 2 acute GVHD (relative risk [RR]: 5.5), prior immunosuppressive therapy (RR: 3.5), female as donor (RR: 2.4), nonidiopathic SAA (RR: 2), and more than 0.2 x 10(9)/L PMN AA (RR: 2). Because acute GVHD was the most potent factor for survival, we analysed risk factors for acute GVHD. By multivariate analysis, 2 of 14 factors tested were independent: male as recipient (RR: 3) and previous alloimmunization of the donor (RR: 4.3). On long-term follow-up, chronic GVHD was observed in 49 pts of 89 surviving more than 100 days (55%). Multivariate analysis showed that infection before transplant (RR: 1.3) and previous history of acute GVHD (RR: 1.8) were associated with an increased risk of chronic GVHD.

One hundred eighty patients with chronic myelogenous leukemia, who received an unmanipulated marrow graft from an Human Leucocyte Antigen identical sibling donor, were reported to our group (G.E.G.M.O.) by 21 transplant teams. All were grafted after a total body irradiation-cytoxan conditioning regimen. Of these 180 patients, 126 were non-randomly assigned to single dose total body irradiation (STBI group) and, 54 to fractionated total body irradiation (FTBI group). With a median follow-up of 40 months, there is no statistically significant difference in the 5-year survival rate between the two groups (51% for the whole population). In a first step we demonstrate by multivariate analysis that total body irradiation fractionation can dramatically decrease the incidence of interstitial pneumonitis. However, a multivariate analysis of potent risk factors for relapse post-transplant strongly suggests that TBI fractionation is also linked to an increased relapse rate. So, a sparing effect of fractionation for lung tissue could be offset by a less effective leukemic stem cell kill. Those results from a retrospective, non-randomized, multi-institutional study clearly need additional clinical data, ideally from a randomized study.

Primary CNS lymphoma is a rare entity. In the last few years, increasing numbers of reports have focused on the clinical, radiological and biological aspects of this tumor. The problem of the therapy of this particular localisation of lymphoma remains mostly unsolved. Radiotherapy still remains the standard approach. However, recent trials combining chemo and radiotherapy have shed promising light on a dark prognosis. These aspects are reviewed based on recent reports in the literature.

Allogeneic bone marrow transplantation is widely used for the treatment of leukemias. Relapse is one of the main complications. Various types of conditioning have been used. Most teams use a combination of cyclophosphamide and different modalities of total body irradiation. In some regimens, high dose alkylating drugs like Busulfan are substituted for radiation. None of these regimens has modified significantly the long term disease free survival, indicating the need for prospective randomized trials.

Early hematotoxicity following 4 to 8 courses of polychemotherapy has been analysed in 78 patients (mean age 32.5 years) treated for advanced stage Hodgkin's disease (53 stages III, 25 stages IV). Toxicity occurred in a third of the patients, and led to interrupt the treatment in one case out of 7, definitively in half of them. The thrombocyte lineage appeared the most sensitive to irradiation. Toxicity was proportional to the target volume (42% of upper and infra-diaphragmatic field versus 11.5% of one sided irradiation, P = 0.01). Toxicity was more frequent after infra-diaphragmatic irradiation (32% of para-aortic field, 43.75% of inversed Y field) than after mantle field (12.3%, P = 0.01). Tolerance to extended field irradiations seemed better in young patients. Sex, stage, type of chemotherapy did not influence toxicity in our series. Abnormalities of the blood count before irradiation was predictive of toxicity. While expecting development of megakaryocytic growth factors of autologous bone marrow transplantation, we suggest: 1) to achieve total lymphoïd irradiation in three periods (mantle field then lombo-aortic field-/+ spleen, then iliac and inguinal fields); 2) to wait, if possible, until normalization of the hemogram before starting the irradiation.

PURPOSE: Fractionated total-body irradiation (HTBI) is considered to induce less toxicity to normal tissues and probably has the same efficacy as single-dose total-body irradiation (STBI) in patients with acute myeloid leukemia. We decided to determine whether this concept can be applied to a large number of patients with various hematologic malignancies using two dissimilar fractionation schedules. PATIENTS AND METHODS: Between December 1986 and October 1994, 160 patients with various hematologic malignancies were randomized to receive either a 10-Gy dose of STBI or 14.85-Gy dose of HTBI. RESULTS: One hundred forty-seven patients were assessable. The 8-year overall survival rate and cause-specific survival rate in the STBI group was 38% and 63.5%, respectively. Overall survival rate and cause-specific survival rate in the HTBI group was 45% and 77%, respectively. The incidence of interstitial pneumonitis was similar in both groups. However, the incidence of veno-occlusive disease (VOD) of the liver was significantly higher in the STBI group. In the multivariate analysis with overall survival as the end point, the female sex was an independent favorable prognostic factor. On the other hand, when cause-specific survival was considered as the end point, the multivariate analysis demonstrated that sex and TBI were independent prognostic factors. CONCLUSION: The efficacy of HTBI is probably higher than that of STBI. Both regimens induce similar toxicity with the exception of VOD of the liver, the incidence of which is significantly more pronounced in the STBI group.

Blood lymphocyte subsets after the first fraction in patients given hyperfractionated total body irradiation for bone marrow transplantation

Chronic graft-versus-host disease (GVHD) is a very heterogeneous entity with variable clinical expression. The pathophysiology involves autoimmune disorders and features of fibrosis. Four patients transplanted for severe aplastic anaemia conditioned with cyclophosphamide and thoraco-abdominal irradiation developed skin scleroderma specifically localized in the irradiation fields. This syndrome was remarkable for its late onset and the absence of factors known to trigger chronic GVHD. It is postulated that irradiation used in this protocol may induce keratinocyte damage and trigger chronic GVHD.

Treatment with GM-CSF or G-CSF is becoming widely used in patients with chronic neutropenia, or who are aplastic following chemotherapy or autologous or allogeneic bone marrow transplantation. Recently, some authors have described a phenomenon analogous to cyclic agranulocytosis following treatment with G-CSF in a patient with chronic neutropenia. We wish to describe the same phenomenon in a patient with chronic granulocytic leukemia who received GM-CSF (Sandoz) after T cell depletion in order to accelerate hematological reconstitution.