The effect of graft-versus-host disease on reconstitution of the immune system following marrow transplantation for aplastic anemia or leukemia.
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Biomedical subjects
Publications and source records attributed to R Storb.
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Leucocyte group 5 has two dominant alleles (5a and 5b) which segregate independently of the major histocompatibility complex. The group-5 system was studied in a Caucasian population of controls and patients with acute lymphoblastic leukaemia. The 5a gene frequency was 0-09 in 72 controls and 0-38 in 39 patients with acute lymphoblastic leukaemia (p less than 0-001). 15 patients with acute myelogenous leukaemia and 12 patients with aplastic anaemia had 5a and 5b frequencies similar to those seen in the control population. It is concluded that 5a or a closely linked gene is involved in susceptibility to acute lymphoblastic leukaemia.
Seventy-three consecutive patients with severe aplastic anemia were treated by marrow grafts from normal, HLA-identical siblings, and 68 lived long enough to demonstrate engraftment. In 21 patients the garft was rejected, and 19 of these patients died. This analysis, using a binary logistic regression model, was aimed at identifying factors that predicted marrow-graft rejection. Of the 24 factors entered into the analysis, only two strongly correlated with graft rejection: a positive relative response index in mixed leukocyte culture indicating sensitization of patient against donor (P less than 0.01); and a low number of marrow cells ( less than 3 X 10(8) cells per kilogram) used for transplantation (P less than 0.01). These findings suggest that more powerful immunosuppressive conditioning regimens should be used in patients who are sensitized, and that the greatest possible amount of donor marrow, perhaps supplemented by stem cells derived from the peripheral blood, should be obtained.
Aplastic anemia is a rare but usually fatal complication of gold salt therapy for rheumatoid arthritis. This report describes 3 patients who developed aplastic anemia while receiving gold salts, and a fourth patient who developed aplastic anemia after receiving gold and then cytotoxic agents. These patients failed to respond to conventional therapy for aplastic anemia and subsequently received bone marrow transplants from HLA-matched siblings. Engraftment occurred in all 4 patients. One patient is alive 2 years after transplantation, and 3 patients died of complications following transplantation.
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A satisfactory and reproducible technique of cryopreservation of canine lymphocytes for use in mixed leukocyte culture (MLC) and cell-mediated lympholysis tests has been developed. Dimethyl sulfoxide was used as the cryopreservation agent. Cells were frozen to -50 C at a controlled rate (-1 C/min) and stored at -169 C. The best preservation was obtained with a concentration of 10 x 10(6) lymphocytes/ml in Waymouth's MB-752/1 medium supplemented with 30% dog serum (MB-30). Before use in MLC or cell-mediated lympholysis tests, lymphocytes were rapidly thawed at 40 C and then rapidly diluted with MB-30 at room temperature. For best responses in MLC, one fresh component (either stimulating or stimulated cells or serum) was needed. The magnitudes of responses of frozen lymphocytes to phytohemagglutinin or in MLC were similar to those seen with fresh cells, but peak responses occurred usually 24 hr after those seen with fresh cells.
Marrow transplants were carried out between unrelated donor-recipient pairs of dogs that were homozygous and identical for DLA-A, B, C, and D, i.e., mutually nonreactive in mixed leukocyte culture. Recipients were conditioned for transplantation by 1,200 R of total body irradiation and then treated with intermittent methotrexate for 102 days in order to prevent or delay graft-versus-host disease (GVHD). Of 13 dogs that received transplants, 4 are surviving with good grafts and no GVHD for more than 12 to 20 minutes. Nine died, 6 with GVHD between days 26 and 141, 1 with wasting on day 65, 1 with interstitial pneumonia on day 83, and 1 with graft rejection on day 23. In comparison, the survival of 17 DLA-identical littermates treated in the same manner was significantly better with 16 surviving without GVHD (P less than 0.01), while the survival of 54 DLA-nonidentical littermates was significantly worse with only two surviving without GVHD (P less than 0.025). These results are incompatible with the concept that solely the loci detected by mixed leukocyte culture and serotyping are responsible for GVHD. One or more additional loci appear to be involved. Knowledg e of this locus (loci) is important if marrow grafting between unrelated individuals is to be successful. However, results also indicate that an unrelated "compatible" marrow graft is more likely to succeed than a graft from an incompatible littermate.
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73 consecutive patients with severe aplastic anemia were treated by marrow transplantation from hematologically normal HLA identical siblings. 68 patients lived long enough to document marrow engraftment. 21 rejected the graft and 19 of these died. 47 sustained engraftment and 18 of these died. In 16 patients, death was associated with graft versus host disease. 29 patients with sustained engraftment are alive with complete hematologic restoration between 8 mo and 5 yr. This analysis, by using a proportional hazards regression model, was directed at identifying factors that predicted survival (and absence of graft versus host disease). Of the 24 factors entered into the analysis only two strongly correlated with survival: (a) sex match of donor and recipient (P less than 0.01), and (b) absence of refractoriness to random donor platelets at the time of transplantation (P less than 0.05). Refractoriness adversely influenced the survival of the sex mismatched patients, These data suggest that X and Y-associated transplantation antigen systems are important determinants of the outcome of marrow grafts between HLA identical siblings for the treatment of aplastic anemia. The machanism by which refractoriness to random donor platelets influences survival is currently unclear.
One hundred patients, 54 with acute myelogenous leukemia (AML) and 46 with acute lymphoblastic leukemia (ALL), considered to be in the end stages of their disease, after combination chemotherapy were treated by marrow transplantation. All patients were given a marrow graft from an HLA-identical sibling after receiving 1000-rad total body irradiation (TBI). One group of 43 patients was given cyclophosphamide (CY), 60 mg/kg on each of 2 days, 5 and 4 days before TBI. In a second group of 31 patients, additional chemotherapy was given before CY and TBI. In a third group of 19 patients, BCNU was given before CY and TBI. A fourth group of 7 patients received other chemotherapy regimens before TBI. Six patients died 3-17 days after marrow infusion without evidence of engraftment. Ninety-four patients were engrafted and only one patient rejected the graft. Thirteen patients are alive with a marrow graft, on no maintenance antileukemic therapy, and without recurrent leukemia 1-4 1/2 yr after transplantation. Three have chronic graft-versus-host disease (GVHD). Four patients are alive 1 1/2 - 3 1/2 yr after grafting but have had a relapse of their leukemia. Of 93 evaluable patients, 19 did not develop GVHD and 24 developed very mild GVHD. Fifty patients developed moderate to severe GVHD, and 40 of these were treated with antithymocyte globulin. Interstitial pneumonia occurred in 54 patients and was the primary cause of death in 34. Interstitial pneumonia often occurred in association with GVHD and the most common etiologic agent was cytomegalovirus. A total of 31 patients have had a relapse of leukemia. There was no definite correlation between relapse of leukemia and the presence or absence of GVHD. The relapse rate appeared to be relatively constant over the first 2 yr and was extremely low after that time. Neither survival nor leukemic relapse appeared to be influenced by the type of leukemia nor by the preparative chemotherapy regimen given before TBI. Patients in fair clinical condition at the time of transplantation showed significantly longer survival times than patients in poor condition (p = 0.001). This observation, coupled with the observation that some patients may be cured of their disease, indicates that marrow transplantation should now be undertaken earlier in the management of patients with acute leukemia who have an HLA-matched sibling marrow donor.
Clinical results of marrow transplantation in the treatment of aplastic anemia and acute leukemia are reviewed. The principal problem areas in this field at this time are discussed.