Autologous marrow transplantation for malignant lymphoma: a report of 101 cases from Seattle.

Between October 1979 and January 1988, 101 patients with malignant lymphoma who failed initial induction treatment or relapsed received high-dose combination chemotherapy or chemoradiotherapy followed by infusion of autologous bone marrow. Twenty-eight of the 101 patients survive, 18 of whom are disease-free for a median of 26 (range, 12 to 66) months. The 5-year actuarial probabilities of survival, event-free survival (EFS), and relapse from transplantation were 20%, 11%, and 84%, respectively. Multivariate analysis showed that the likelihood of EFS was decreased among patients transplanted with a Karnofsky score of less than 80%. Recurrent lymphoma after transplant was the most important cause of treatment failure with 36 of 62 relapses occurring within 100 days from marrow infusion. Early, but not late relapse, was more frequent in patients transplanted for advanced lymphoma, and both early and late relapses were increased among patients with impaired pretransplant clinical performance or high-grade histology of lymphoma. Ten patients who relapsed post-transplant are alive, seven in remission. Further improvement of these results will require earlier transplantation, improved preparative regimens, or early posttransplant therapy.

Studies on conversion of yellow marrow to red marrow by using ectopic bone marrow implants.

Previous work has suggested that an increase in temperature in conjunction with hemopoietic stimuli can convert yellow marrow to red marrow. Ectopic implantation of yellow marrow in rabbits was used to confirm this suggestion and to determine whether sustained stimulation is needed to maintain hemopoiesis. Tibial marrow (temperature 28.5 degrees C) was implanted in the subcutaneous tissue of the abdomen (temperature 33 degrees C). Phenylhydrazine-induced hemolysis was used as a hemopoietic stimulus. Implants of yellow marrow in control animals, not subjected to modulation of hemopoiesis, led to the formation of fatty marrow nodules. These nodules became hemopoietically active when the hemopoietic stimulus was applied to the animals, either concomitantly with implantation or even two months after implantation. The stimulus was required continuously to maintain the hemopoietic activity of the nodules. These findings confirm that increased temperature acts synergistically with hemopoietic stimuli to induce hemopoiesis in yellow marrow. This supports the concept that, while the total volume of hemopoietic tissue is determined by the body's demands, its distribution may be determined by such factors as local temperature.

Impact of RLA matching and cyclosporine on long-term survival in transplanted rabbits.

In order to measure the impact on long-term survival of rabbit leukocyte antigen (RLA) matching and the administration of cyclosporine (CSP) in allogeneic marrow transplantation of irradiated adult rabbits, four groups of five rabbits each were studied. Group 1 consisted of RLA-mismatched animals that did not receive CSP following transplant. All five animals died of infectious complications or graft-versus-host disease (GVHD) (median survival 12 days, range 6-20 days). Group 2 consisted of animals that were similarly mismatched but treated with CSP as postgrafting immunosuppression. All animals also died of GVHD or infection but the median survival was extended to 18 days, range 12-27 days. Group 3 consisted of RLA-matched animals that did not receive CSP. Median survival was 65 days, range 27-121 days, and two are still alive at 120 and 121 days after transplant. Three of five animals died of GVHD. The only group of animals to consistently achieve long-term survival was group 4; these animals were RLA matched and were treated with CSP. Five of five animals survived with a median survival of 564 days following transplant, range 220-806 days. All five became complete hematopoietic chimeras as determined by cytogenetic analysis of bone marrow lymphocytes. Thus, long-term survival after allogeneic bone marrow transplantation in the irradiated adult rabbit was achieved and was dependent upon the use of RLA-matched donors and the administration of cyclosporine as GVHD prophylaxis.

Allogeneic bone marrow transplantation in irradiated adult rabbits.

In an effort to produce stable, long-term, complete hematopoietic chimerism in unrelated RLA-matched adult rabbits, the maximum dose of total-body irradiation (TBI) tolerated both with and without autologous marrow support was defined, and it was then determined whether the maximum tolerated dose was sufficiently immunosuppressive and myeloablative to allow engraftment of allogeneic marrow. Forty rabbits received TBI at 4.8 cGy/min at doses from 525-925 cGy. All rabbits receiving 525, 625, 725 and 825 cGy survived without marrow transplantation. At 875 cGy 50% of animals died and at 925 cGy all animals died within 96 hr of TBI. Survival was not changed with autologous marrow support, with all animals receiving 825 cGy surviving, while 50% survived at 875 cGy, and none at 925 cGy. Two RLA-matched, sex and immunoglobulin allotype-mismatched pairs were transplanted following 825 cGy and were given posttransplant cyclosporine. Both recipients survived beyond 200 days posttransplant, with cytogenetic and immunoglobulin allotype evidence of complete, or nearly complete, hematopoietic engraftment. Thus, stable, long-term complete chimerism can be achieved in adult RLA-matched unrelated rabbits prepared by TBI, and this animal model can be used for bone marrow transplantation studies.

Busulfan and cyclophosphamide as a preparative regimen for bone marrow transplantation in patients with prior chest radiotherapy.

In a previous study, we reported that patients with hematologic malignancies who had received prior chest radiotherapy had a 32% risk of developing fatal interstitial pneumonia (IP) when prepared for bone marrow transplantation (BMT) with a regimen containing total body irradiation (TBI). To determine if avoidance of TBI would lessen the incidence of fatal IP, 37 patients who had received prior chest radiotherapy in excess of 2000 cGy were prepared with busulfan (BU, 4 mg/kg x 4 days) and cyclophosphamide (CY, 60 mg/kg x 2 days) followed by autologous (n = 15) or allogeneic (n = 22) BMT. Thirty-five of these patients had recurrent or refractory hematologic malignancies and most were heavily pretreated. Results were compared with the group of similar patients (n = 25) previously treated at our institution with a CY/TBI conditioning regimen. Among those treated with BU/CY, two patients (5%) developed fatal interstitial pneumonia, 12 (32%) died of other transplant related toxicities and 13 (35%) died of relapse. Seven (19%) patients remain alive and well. Among those treated with CY/TBI, eight (32%) died of pneumonia, six (24%) died of relapse, nine (36%) died of other causes and two (8%) remain alive and well. The 5% incidence of fatal interstitial pneumonitis in the chemotherapy conditioned group was significantly less than the 32% incidence in the previously treated CY/TBI group (p = 0.005). However, long-term survival and relapse probabilities were not significantly better than seen previously with CY/TBI, although a trend towards improved survival was observed in the BU/CY group. Avoidance of TBI appeared to lower the incidence of fatal pneumonitis in patients with prior chest radiotherapy.

High-dose cytosine arabinoside, total body irradiation and marrow transplantation for advanced malignant lymphoma.

Twenty-four patients with advanced malignant lymphoma including Hodgkin's disease (HD, n = 1), intermediate grade non-Hodgkin's lymphoma (IGL, n = 12) and high-grade non-Hodgkin's lymphoma (HGL, n = 11) were prepared for syngeneic (n = 2), allogeneic (n = 11) or autologous (n = 11) marrow transplantation with cytosine arabinoside, 3 g/m2 every 12h for 12 doses (HDAC) and total body irradiation, 200 cGy daily for 6 days (TBI) to determine toxicity and efficacy. Eight patients (33%) died from early regimen related toxicity and all eight had a Karnofsky performance score less than or equal to 80 at the start of treatment. The actuarial probability of disease-free survival was 17% with a 65% probability of relapse at 4 years after transplantation. Four patients are surviving 2-4 years post-transplant, three transplanted for IGL and one for HD. None of the patients transplanted for HGL survived. The result of this phase II study suggests that HDAC followed by TBI and marrow infusion offers no apparent advantage over cyclophosphamide + TBI for patients with relapsed advanced malignant lymphoma. Earlier transplantation currently is the only demonstrated method of achieving better results.

Aplastic anemia and immune-mediated thrombocytopenia: concurrent complications encountered in the third trimester of pregnancy.

BACKGROUND: Aplastic anemia has been described rarely in pregnancy. The etiology is uncertain, and the treatment of choice, bone marrow transplant, is contraindicated in pregnancy. Thus, the occurrence of this complication during gestation presents a management challenge. Concurrent immune-mediated thrombocytopenia further complicates an already complex situation. CASE: Our patient with aplastic anemia and immune-mediated thrombocytopenia was diagnosed during the third trimester of pregnancy and treated with prednisone/high-dose intravenous (i.v.) immunoglobulin (Ig) and multiple transfusions of packed red blood cells and platelets. Fetal surveillance included twice-weekly non-stress tests coupled with sequential sonographic pregnancy evaluation. A successful term vaginal delivery was achieved with good maternal and perinatal outcomes. CONCLUSION: Selective transfusion of blood products, therapy with prednisone, high-dose i.v. Ig, and intensive fetal surveillance resulted in a successful maternal and perinatal outcome for a pregnancy complicated with aplastic anemia and immune-mediated thrombocytopenia.

Bone marrow transplantation: a new treatment approach for Mississippians.

Bone marrow transplantation makes it possible to treat patients with malignancies using doses of systemic chemotherapy and/or radiotherapy that otherwise would result in fatal hematologic toxicity. This approach has found its widest application in the treatment of hematologic malignancies, but it is also being used for aplastic anemia, severe immunodeficiency diseases, and selected solid tumors. The University of Mississippi will soon (October, 1991) be able to offer this treatment approach to Mississippians; therefore the indications, the general technique, and results of transplantation for a variety of diseases are reviewed herein.

Fatty involution of bone marrow in rabbits.

The developmental pattern of red and yellow bone marrow was studied in rabbits of different ages from newborn to 6 months of age. At birth no adipose cells were seen in any of the marrow cavities. Most bones were still developing and marrow cavities were relatively limited. Nonetheless a distinct difference in the cellularity of marrow in the trunk versus limb bones was noted, the latter being significantly less cellular. Adipose cells began to develop at 2 weeks of age and proceeded so that the adult pattern of red and yellow marrow was fully established by 4 months. The development of adipose cells occurred in both trunk and limb bones; the magnitude of the process, however, was considerably greater in the limb bones. Adipocyte precursors may be present in the marrow at birth with a differential distribution in the areas of prospective red and yellow marrow. Thus, fatty involution of marrow appears to be a programmed developmental event.

Treatment of acute myelogenous leukemia in patients over 50 years of age with V-TAD: a Southwest Oncology Group study.

Acute myelogenous leukemia (AML) in the elderly continues to have a poor prognosis and new treatment approaches are needed. This Phase II trial was undertaken to evaluate the complete remission rate and toxicity of a chemotherapeutic regimen including etoposide and 6-thioguanine, combined with reduced doses of cytosine arabinoside and daunorubicin (V-TAD) in individuals greater than 50 years of age with AML. Thirty-five patients, ranging in age from 51 to 80 years (median, 66 years), were registered onto the study. Twenty-nine patients were entered at the first dose level (daunomycin 20 mg/m2 days 1 and 2, ara-C 75 mg/m2 days 1-5, 6-thioguanine 75 mg/m2 every 12 hr days 1-5, and etoposide 50 mg/m2 days 1, 2, and 3) and six patients underwent therapy at the second dose level (ara-C 75 mg/m2 days 1-7 with the remainder of the regimen unchanged). After achieving a complete remission, patients underwent two to three consolidation cycles of chemotherapy. Thirty-one patients were evaluable for response. Thirteen patients (ten of twenty-five at the first dose level and three of six at the second dose level) achieved a complete remission (42%). Median remission duration was 6 months (range 1-21 months). The current regimen, while tolerated, did not result in improved survival compared with prior treatment regimens because of a high incidence of resistant and recurrent leukemia.