Marrow transplantation for acute nonlymphoblastic leukemia in first remission.
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Biomedical subjects
Publications and source records attributed to E D Thomas.
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To determine whether allogeneic bone-marrow transplantation is associated with a graft-versus-leukemia effect, we examined the relation between relapse of leukemia and graft-versus-host disease in 46 recipients of identical-twin (syngeneic) marrow, 117 recipients of HLA-identical-sibling (allogeneic) marrow with no or minimal graft-versus-host disease, and 79 recipients of allogeneic marrow with moderate to severe or chronic disease. The relative relapse rate was 2.5 times less in allogeneic-marrow recipients with graft-versus-host disease than in recipients without it (P less than 0.01). This apparent antileukemic effect was more marked in patients with lymphoblastic than nonlymphoblastic leukemia, and in those who received transplants during relapse rather than during remission, and was most evident during the first 130 days after transplantation. Survival of all patients was comparable since the lesser probability of recurrent leukemia in patients with graft-versus-host disease was offset by a greater probability of other causes of death.
Four patients (21, 41, 13 and 38 years of age) with a history of chronic granulocytic leukemia for 12, 10, 11, and 106 months, respectively, were treated with dimethyl busulfan, cyclophosphamide, 920 rads of total-body irradiation and intravenous marrow infusion from normal, genetically identical twins. Serial chromosome analyses were performed on marrow aspirates cultured without mitotic stimulants. No Ph1-positive cells were detected in the marrows from the normal twins, whereas just before therapy, all 100 metaphases examined from each patient were Ph1-positive. Chromosome analyses were performed three to five times per patient after transplantation, and not a single Ph1-positive cell was detected. The patients remain hematologically normal 22, 23, 26 and 31 months after transplantation. The results show that the Ph1-positive clone can be eradicated by vigorous therapy and that the marrow in chronic granulocytic leukemia can be repopulated by stem cells from normal twins.
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Evaluation of the diagnostic utility of the rectal biopsy in graft-versus-host disease (GVHD), using the crypt abscess as a major diagnostic criterion, was based on 52 patients who had received marrow allografts for leukemia or aplastic anemia. Thirty-six of these patients had acute GVHD by skin biopsy criteria. These 36 patients demonstrated a strong association of the rectal crypt abscess with severity of clinical GVHD. High stool volume also correlated strongly with the crypt abscess. Patients without clear evidence of GVHD usually had normal rectal histology. Serial studies showed a good correlation of rectal biopsy results with the clinical course of acute GVHD. Patients with chronic GVHD had rectal mucosal damage only during the acute phase. Rectal ileal and cecal disease accurately. The rectal biopsy is a useful adjunct to serial skin biopsies in the diagnosis of GVHD in man.
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The lymphocyte responses of 51 human marrow graft recipients were tested in vitro 18 to 45 days after marrow grafting by stimulation with lymphocytes from unrelated individuals or phytohemagglutinin (PHA). Fourteen of the 51 patients subsequently developed interstitial pneumonia (IP). The relative responses of the lymphocytes of patients who developed IP were significantly lower than those of individuals not developing IP (P less than 0.01 for allogeneic cells, P = 0.02 for PHA). These nonspecific in vitro tests of cell-mediated immunity are of value in identifying patients at risk of developing IP.
Thirty-three marrow transplant patients with Pneumocystis carinii pneumonia were studied to determine the usefulness of antibody and antigen detection in the diagnosis of pneumocystis infection. Antibody against P. carinii was present in one half of all patients tested, and changes in antibody titer were not helpful diagnostically. P. carinii antigen was detected by counterimmunoelectrophoresis in the serum of 22 of 28 patients tested. Fifteen of 28 patients had antigen detected before or within 72 h after diagnosis. However, antigen was also present in 35 of 52 marrow transplant patients with viral or idiopathic pneumonia, in 11 of 25 transplant patients with no pneumonia, and in 22 of 28 other patients with pulmonary infiltrates. Only 1 of 50 normal marrow donors had detectable antigenemia. Detection of this antigen does not appear to establish the diagnosis of P. carinii pneumonia in the absence of other clinical or histologic data. The data may suggest that subclinical infection with this agent is more common than was previously recognized.
A Corynebacterium species consistently resistant to all antibiotic therapy except vancomycin caused bacteremia in 32 of 284 (11%) marrow transplant patients. Twenty-one patients had colonization or infection before bacteremia. Twenty-six of the 32 patients were males, and males older than 16 years were infected significantly more often than females over 16, or than all patient under 16. A case-control study showed that infected patients had greater exposure to antibiotics; more often had failure of engraftment and persistent granulocytopenia; were in laminar air-flow rooms less often; and had greater inhospital mortality. Cultural surveillance showed that 17 of 42 marrow transplant patients were colonized with Corynebacterium species. Likelihood of colonization appeared related to age, sex, and duration of hospitalization. Prevalence of colonization in other populations was 1% in nonhospitalized healthy adults and 13% in adults in a general hospital. Corynebacterium species infections occur primarily in adult males with granulocytopenia, mucocutaneous defects, and receiving intensive antibiotic therapy.
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The epidermal ultrastructure of 11 allogeneic bone marrow recipients with chronic graft-versus-host disease (GVHD) was compared with that of 4 recipients without chronic GVHD. This electron microscope study revealed three patterns of epidermal injury typical of chronic GVHD. The first type was a nonacantholytic (nondissecting) injury with a prominent cellular infiltrate consisting primarily of lymphocytes accompanied by a few macrophages. The second type was an acantholytic (dissecting) injury with a prominent infiltrate, while the third was a nondissecting injury with a sparse infiltrate. Broad-zone contact was observed between lymphocytes and all epidermal cell types as well as between other lymphocytes and macrophages. Point contact was only observed between lymphocytes and epidermal cells. Lymphocytes appeared to detach desmosomes from adjacent keratinocytes by isolating them with cytoplasmic projections, a phenomenon not previously described. Typical damage to the epidermal cells in the basal and spinous layers consisted of either swelling of the organelles or condensation of the cytoplasm and nucleus. In the keratinocyte, the condensation reaction resulted in the formation of colloid bodies, some of which were phagocytized by macrophages. Besides the cytolytic events, a concurrent stimulatory reaction occurred in the epidermal cells. The number of melanosomes in melanocytes and of Langerhans cell granules and dense bodies in the Langerhans cells all increased. Extensive areas of replication and disruption of the basal lamina were subjacent to areas of necrosis in the basal layer.
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