Graft versus host inhibition: fetal liver and thymus cells to minimize secondary disease.

Long-lived radiation chimeras were produced in mice diflering at the major histocompatibility locus. Survival occurred in lethally irradiated recipients inoculated with allogeneic fetal liver and allogeneic fetal thymus cells in combination. The survival rate was equal or superior to that of mice with transplanted syngeneic fetal, neonatal, or adult hematopoietic cells.

Graft versus leukemia: quantification of adoptive immunotherapy in murine leukemia.

Quantification of the antileukemic reactivity of transplanted immunocompetent cells from various allogeneic donors was achieved against a long-passage lymphocytic leukemia of AKR mice. Adoptive immunotherapy was the exclusive antileukemic treatment. Cells from DBA/2 donors exhibited maximal antileukemic effect, inactivating up to an estimated 10(7) leukemia cells. The cellular events were interpreted by using a theoretical cytokinetic construct.

Low-dose chemotherapy as a prelude to intensive treatment of spontaneous leukemia-lymphoma in AKR mice.

Groups of AKR mice bearing spontaneous leukemia-lymphoma were treated with five different combinations of chemotherapy or chemoradiotherapy. Each treatment combination was given in two sequences--high dose first and low dose last, or low dose first and high dose last--administered over 6-7 days. When the initial treatment was a high dose of chemotherapy, radiotherapy, or chemoradiotherapy, mortality in the first 24 hours exceeded 40%, and at least 70% of the mice in each group were dead within 2 weeks. When low-dose chemotherapy was given first, mortality in the first 24 hours was minimal but, most significantly, no deaths occurred in the 24 hours after subsequent high-dose treatment. In the most successful group (100 mg cyclophosphamide/kg on day 0, and 250 mg cyclophosphamide/kg and 400 R total-body X-irradiation on day 7), the median survival time increased significantly as compared with the median survival time among mice given the same regimen in reverse sequence (p less than 0.001) or among untreated control mice (p less than 0.01). With this regimen, survival 60 days after the last treatment was 47%. No mouse survived 30 days when the sequence of treatments was reversed. From these results, we conclude that chemotherapeutic and chemoradiotherapeutic regimens for AKR spontaneous leukemia-lymphoma should be designed so that low, minimally lethal doses precede higher doses.

Graft versus leukemia. VI. Adoptive immunotherapy in combination with chemoradiotherapy for spontaneous leukemia-lymphoma in AKR mice.

A three-step treatment plan incorporating adoptive immunotherapy and chemoradiotherapy was used to treat AKR (H-2k) mice bearing spontaneous leukemia-lymphoma (SLL). 1) Leukemic mice were treated with chemoradiotherapy for immunosuppression and leukemia cytoreduction. 2) To introduce a graft-versus-leukemia reaction against residual malignant cells, the immunosuppressed AKR mice were given immunocompetent cells from H-2 mismatched DBA/2 (H-2d) donors. 3) To "rescue" the AKR hosts from incipient graft-versus-host disease, the mismatched DBA/2 cells were killed with combination chemotherapy, and cells from allogeneic H-2 matched RF (H-2k) donors were administered to restore hematopoiesis. Leukemic AKR mice thus treated had significant prolongation of their median survival time and a higher 60-day survival rate post treatment than did untreated controls, chemoradiotherapy controls, or control mice that received chemoradiotherapy plus cells from syngeneic donors. Therefore, adoptive immunotherapy may be useful as an adjunct to conventional therapy for treatment of SLL in AKR mice.

Bone marrow transplants from HLA-identical siblings in advanced Hodgkin's disease.

PURPOSE: To determine the outcome of HLA-identical sibling bone marrow transplants in advanced Hodgkin's disease. PATIENTS AND METHODS: We reviewed the data on 100 consecutive patients with Hodgkin's disease who received HLA-identical sibling bone marrow transplants between April 1, 1982 and August 12, 1992, reported to the International Bone Marrow Transplant Registry (IBMTR). The median interval from diagnosis to transplant was 2.5 years (range, < 1 to 14). All had advanced disease. Eighty-nine of 100 patients were not in remission at the time of transplant. Fifty had pretransplant Karnofsky scores less than 90% and 27 had active infection in the week before transplant. Patients received a variety of conditioning regimens; 45 received total-body radiation. RESULTS: The 100-day probability of acute graft-versus-host disease (GVHD) was 35% (95% confidence interval [CI], 26% to 46%); the 3-year probability of chronic GVHD was 45% (95% CI, 31% to 59%). The 3-year probability of relapse was 65% (95% CI, 50% to 78%). The 3-year probability of survival was 21% (95% CI, 14% to 30%). The 3-year disease-free survival rate was 15% (95% CI, 9% to 24%). CONCLUSION: HLA-identical sibling bone marrow transplants have a limited role in advanced Hodgkin's disease.

Progress in allogeneic bone marrow transplantation for acute lymphoblastic leukemia in the 1980's: a report from the IBMTR. The International Bone Marrow Transplant Registry.

Among patients with ALL and irrespective of disease state at transplant, highly significant improvements in treatment-related mortality, relapse and leukemia-free survival were observed during the 1980's. Although these results are encouraging, further reductions in treatment-related toxicity and posttransplant relapse are needed to achieve additional advances in the 1990's.

Chemotherapy versus transplants for acute myelogenous leukemia in second remission.

The best therapy for persons with acute myelogenous leukemia (AML) in 2nd remission is unknown. Bone marrow transplants from an HLA-identical sibling are reported to be better than chemotherapy but this is controversial. The objective of the study was to compare 3-year leukemia-free survival (LFS) in comparable subjects receiving chemotherapy or a transplant. 485 persons with AML in 2nd remission were studied. The chemotherapy cohort included 244 persons treated on trials of the British Medical Research Council, Eastern Cooperative Oncology Group and MD Anderson Hospital. The transplant cohort included 257 persons transplanted worldwide and reported to the international Bone Marrow Transplant Registry (16 were also chemotherapy subjects.) Subjects were selected for comparable age and year of treatment. Preliminary analyses identified two factors correlated with LFS: age < or = or > 30 years and 1st remission duration < or = or > 1 year; subsequent analyses were partitioned accordingly. Three-year probabilities of treatment-related mortality with chemotherapy and transplants were 7% (95% confidence interval, 3-15%) vs 56% (49-63%). Three-year leukemia relapse probabilities were 81% (74-86%) vs 41% (33-49%). Three-year probabilities of LFS were 17% (12-23%) vs 26 (20-32%). Cohort analysis showed significantly higher LFS with transplants vs chemotherapy in persons < or = 30 years and 1st remissions > 1 year (41% (29-53%) vs 17% (7-32%); P = 0.017) and those in > 30 years with 1st remissions < or = 1 year (18% (9-29%) vs 7% (2-16%); P = 0.046). Others had comparable LFS with both treatments. These data indicate better LFS with HLA-identical sibling transplants than chemotherapy in some persons with AML in 2nd remission.

The first official meeting of the International Society for Experimental Hematology.

In 1972, 85 scientists from 10 countries came to Milwaukee to participate in the first official meeting of the International Society for Experimental Hematology. We summarize here some of the events leading up to the meeting, fondly recollect the enthusiastic spirit of the meeting and reprint the program, which is not all that different in content from the program of the 21st meeting.

Major complications of marrow harvesting for transplantation.

Complications to bone marrow donors were analyzed for 2027 transplants reported to the International Bone Marrow Transplant Registry and for 1263 transplants performed in Seattle. Thus, a total of 3290 donor risk episodes were available for study. The incidence of major, i.e., life-threatening complications in the combined series was 0.27%. Neither death nor permanent residua occurred in any of the donors.

Mitigation of graft-versus-host disease in mice by treatment of donors with bacterial endotoxin.

Treatment of DBA/2 (H-2d) mice with bacterial endotoxin prior to transplantation of their spleen and lymph node cells into immunosuppressed AKR (H-2k) mice prevented acute mortality from graft-versus-host (GVH) disease. AKR mice that received immunocompetent cells from untreated DBA/2 mice had a median survival time (MST) of 13 days. In contrast, AKR mice that received immunocompetent cells from endotoxin-treated DBA/2 donors had an MST of 54 days. Endotoxin treatment of AKR recipients was not essential for preventing mortality from acute GVH disease. Chimerism was proved by demonstrating that the lymphoid cells of long-term surviving AKR mice had the characteristics of DBA/2 lymphoid cells as measured by their response in mixed leukocyte culture (MLC) tests. Spleen cells from endotoxin-treated DBA/2 mice were able to stimulate, and to be stimulated by, AKR spleen cells in MLC assays. Furthermore, spleen cells from endotoxin-treated DBA/2 mice did not suppress the responses of DBA/2 or AKR spleen cells in 'three-party' MLC tests.

Graft versus leukemia. VIII. Selective reduction in antihost reactivity without loss of antileukemic reactivity by treatment of donor mice with lipopolysaccharide.

Spleen and lymph node cells from DBA/2 (H-2d) donor mice treated with multiple injections of bacterial lipopolysaccharide (LPS) were tested in vivo for reactivity against normal tissues of host AKR (H-2k) mice against an AKR long-passage, acute lymphoblastic leukemia (BW5147). LPS treatment of donor mice resulted in a reduction in graft-versus-host (GVH) reactivity without loss of graft-versus-leukemia (GVL) reactivity. Immunocompetent cells from LPS treated DBA/2 donors were effective when used for adoptive immunotherapy (in combination with chemoradiotherapy) of BW5147 leukemia. GVH associated mortality decreased as the dose of spleen cells from LPS treated histoincompatible donors was increased as much as four times the number necessary to eliminate leukemia. The mechanism by which LPS reduced GVH reactivity without eliminating GVL reactivity is unclear; however, it does not appear to be the result of a dilution in the number of GVH reactive cells by nonlymphoid elements in the donor spleen nor of the adjuvant effects of LPS on resistance to bacterial infections.

Increasing utilization of bone marrow transplantation. II. Results of the 1985-1987 survey.

The International Bone Marrow Transplant REgistry conducts periodic surveys to determine activity in the field of allogeneic and syngeneic bone marrow transplantation. Data were reported to the IBMTR by 258 institutions in 41 countries regarding their patients who received bone marrow transplants during the period 1985-1987. To the best of our knowledge, the data represent essentially all bone marrow transplants (exclusive of autologous transplants) performed in the past 3 years. A total of 10,887 patients received bone marrow transplants; 73% were for leukemia, 11% for other malignant diseases, 9% for severe aplastic anemia and related disorders, 3% for immune deficiency diseases, 2% for thalassemia major, and 2% for genetic, metabolic, and several other rare diseases. 161 (62%) of the 258 institutions performed fewer than one transplant per month. More than 50% of the patients were transplanted in 37 institutions. 46% of the world's bone marrow transplants were performed in North America, 42% in Western Europe, 5% in Asia, 3% in Australia and New Zealand, 2% in the Mideast and Africa, 1% in South and Central America, and 1% in Eastern Europe and the USSR. The data reflect continued growth in utilization of allogeneic and syngeneic bone marrow transplantation and quantify the annual increases in the number of patients receiving transplants.

Transplantation of hematopoietic and lymphoid cells in mice.

CBA mice were exposed to a supralethal dose of whole body X-irradiation and recieved transplants of graded, small doses of bone marrow, fetal liver, or fetal liver plus fetal thymus cells obtained from H-2 matched C58 or H-2 mismatched A donors. Survival at 20 days was used to evaluate the ability of the transplants to restore hematopoiesis following the acute radiation injury. In the higher dose ranges of 6 X 10(7) and 1.2 X 10(8) cells/kg body weight, the fetal cells were as effective as adult bone marrow in both the matched and mismatched strain combinations. Survival at 100 days was used to evaluate the severity of chronic graft-versus-host disease produced by each of the transplants. In the higher dose ranges, cells from fetal donors promoted higher long-term survival rates than did comparable doses of bone marrow cells in both the matched and mismatched strain combinations. In some experimental groups, the addition of fetal thymus cells to fetal liver cells resulted in higher short-term and long-term survival rates than did fetal liver alone, but this was inconsistent and generally fell short of statistical significance. The most important finding was that cells from mismatched unrelated fetal donors (using a cell dose per kilogram body weight comparable to the number of fetal liver and thymus cells which would be obtainable from one human fetus at 14 weeks of embryonation) promoted higher long-term survival rates than did bone marrow transplants from matched unrelated donors.

Migration patterns and functional activity of cloned cytotoxic T lymphocytes in syngeneic and allogeneic mice.

The quantitative distribution of cytolytic T lymphocytes (CTL) generated in mixed leukocyte culture (MLC) and an interleukin-2 (IL-2)-dependent, CTL clone (WRL-A3) was investigated in various tissues of irradiated syngeneic and allogeneic mice. In addition, the ability of the WRL-A3 CTL clone to remain viable and retain antigen specificity following in vivo passage was evaluated. Injection i.v. of 51Cr-labeled cultured CTL resulted in: (1) extensive deposition of cells in the lungs with significantly more lymphocytes being recovered in allogeneic as compared with syngeneic lung tissue; (2) minimal accumulation in spleen with more in syngeneic than in allogeneic tissue; and (3) no localization in blood, femurs, thymus, or lymph nodes. The migration rate of cultured CTL exiting the lung during the first 4 hr was markedly faster in syngeneic than in allogeneic recipients and was directly associated with the distribution of these cells in other tissues at 24 hr. The WRL-A3 CTL clone recovered from irradiated syngeneic and allogeneic lung tissue at 1, 3, 6, 8, and 13 days after i.v. injection remained viable, even though no exogenous IL-2 was administered to the recipient mice. The recovered cells proliferated when recultured with IL-2, and retained their antigen specificity for Qed-1b target cells after in vivo passage. These findings indicate that restricted and undesirable tissue distribution, rather than impaired viability or loss of antigenic specificity, is the major obstacle to successful use of cultured CTL for adoptive immunotherapy of disseminated cancer.

Graft-versus-leukemia following bone marrow transplantation.

Considerable data in animals suggest an anti-leukemia reaction associated with transplantation of allogeneic bone marrow cells. In some instances, this graft-versus leukemia (GVL) reaction may be distinct from graft-versus-host-disease (GVHD). Data in humans also support the concept of a GVL effect associated with bone marrow transplantation. These observations include an increased risk of leukemia relapse in identical twin transplants and in recipients of T cell-depleted allogeneic transplants, and a decreased risk-of leukemia relapse in individuals who develop acute or chronic GVHD. These findings are among the most convincing evidence that the immune system plays a role against cancer in man.

Progress report from the International Bone Marrow Transplant Registry.

The International Bone Marrow Transplant Registry receives and analyses detailed information contributed by more than 200 transplant teams worldwide. This collaborative research program has grown rapidly; there are now more than 15,000 cases in the database. This progress report summarizes the current status of bone marrow transplantation, the results of recent investigations and studies planned for the coming year.

Temporal relationships between the major complications of bone marrow transplantation for leukemia.

Data from 3113 patients receiving HLA-identical sibling bone marrow transplants for leukemia were analysed to determine the time course of the major causes of treatment failure. The median interval from transplant to onset of acute graft-versus-host disease (GVHD) was 17 days, interstitial pneumonitis 63 days, and chronic GVHD 111 days. The median interval from transplant to relapse was 3.3 months for patients transplanted in relapse of acute leukemia or blast phase of chronic myelogenous leukemia (CML), 6.4 months when transplants were performed in second or subsequent remission of acute leukemia or accelerated phase of CML, and 7.8 months for patients transplanted during first remission of acute leukemia or while in the first chronic phase of CML. Shorter intervals from transplant to onset of interstitial pneumonitis or chronic GVHD were associated with a significantly lower probability of 2-year survival. The temporal relationships between these complications are displayed graphically and demonstrate the overlapping and competing causes of death following allogeneic bone marrow transplantation.

1993 progress report from the International Bone Marrow Transplant Registry. Advisory Committee of the International Bone Marrow Transplant Registry.

The International Bone Marrow Transplant Registry is an organization devoted to scientific research in BMT. More than 230 transplant teams worldwide contribute detailed information about recipients of allogeneic and syngeneic BMT for study. Results of analyses are published in medical journals and presented at national and international scientific meetings (more than 60 publications and more than 500 presentations in the past 4 years). This collaborative research program has grown rapidly with more than 2000 cases reported annually. This report summarizes results of several recent investigations and reviews the state of BMT in leukemia and aplastic anemia.

Therapy decisions in leukemia.

Complex factors determine how physicians select between alternative therapies. We conducted a survey of 352 leukemia experts to determine consensus regarding optimal treatment for leukemia and to identify factors correlated with therapy decisions. The study evaluated both general treatment policies and recommendations for specific clinical situations. Responses of chemotherapy, allotransplant and autotransplant experts were compared. Although responses of these groups were similar for general treatment policies, recommendations for specific cases differed substantially. Interestingly, responses of the three groups to some clinical situations also differed from conclusions of several published studies examining these issues. These data suggest that experts may discount published results in favor of personal experiences, perceptions of the best treatment strategy (based on published data or not) or available resources.

Bone marrow transplantation for Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is a rare disorder usually diagnosed in the first year of life. Although most cases respond to corticosteroids, > 20% are, or become, steroid-resistant. We report 10 children with DBA who received a bone marrow transplant from an HLA-identical sibling (n = 8), maternal (n = 1) or unrelated (n = 1) donor and reported to the International Bone Marrow Transplant Registry. Among eight recipients of HLA-identical sibling transplants, six are alive 5-87 months after transplant with no evidence of DBA and with Karnofsky performance scores of 90-100%. The two recipients of non-HLA-identical sibling transplants died < 2 weeks after transplant. The actuarial 2-year probability of survival for the eight sibling transplants was 72 (37-92)% (95% confidence interval).