R Storb

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.

Graft rejection has been a problem after marrow grafts for patients with aplastic anemia who were conditioned with cyclophosphamide (CY). Rejection lessened when patients were given the marrow donor's peripheral blood buffy-coat cells in addition to the marrow, but this result was achieved at the price of more chronic graft-versus-host disease (GVHD). Results with second transplants suggested that CY alternating with antithymocyte globulin (ATG) was more immunosuppressive than CY alone. Therefore, the current study explored CY and ATG without buffy-coat cell transfusions in 39 patients with aplastic anemia given marrow transplants from HLA-identical family members (siblings in 38 cases, father in 1 case). We hoped both to minimize the risks of graft rejection and of chronic GVHD and to improve survival. Patients were 2 to 52 years of age (median, 24.5); 87% had received previous transfusions, and 41% had therapy with immunosuppressive agents before transplant. They were administered four daily doses of CY (total, 200 mg/kg) alternating with three doses of ATG (total, 90 mg/kg) followed by an HLA-identical marrow graft. Methotrexate and cyclosporine were administered to prevent GVHD. Two patients rejected their grafts (5%), and both were successfully retransplanted. Acute (grade 2 or 3) GVHD occurred in 15% and chronic GVHD in 34% of patients. The actuarial survival rate at 3 years was 92%, which compares favorably to the 72% survival rate in 39 historical patients who were matched with current patients for age and risk factors for rejection and GVHD. CY/ATG is a well-tolerated and effective conditioning program for marrow grafting in aplastic anemia that, when combined with GVHD prevention by methotrexate/cyclosporine, results in excellent survival.

This clinicopathologic study of patients with chronic graft-versus-host disease (GVHD) after allogeneic marrow transplantation emphasizes the most prominent feature of the syndrome, the cutaneous aspects, and describes the ophthalmic-oral sicca syndrome with sialoadenitis and the neurologic findings. Chronic cutaneous GVHD affected 19 of 92 recipients surviving 150 days or more. In 6 patients chronic GVHD presented as a continuation of acute GVHD; in 8 it occurred after the resolution of acute GVHD; and in 5 it arose without preceding acute GVHD, ie, de novo late onset. Two cutaneous types were distinguished. The generalized type affected 16 patients and ran a progressive course resulting in late complications of poikiloderma, diffuse dermal and subcutaneous fibrosis, and contractures. Microscopically, it resembled generalized morphea and lupus erythermatosus hypertrophicus et profundus. The local type affected 3 patients with a more variable picture of poikiloderma, dermal sclerosis, and contractures. Microscopically, it resembled lupus of erythematosus profundus and scleroderma. Guidelines for defining and subclassifying chronic cutaneous GVHD are proposed.

This report describes a study of humoral and cellular immune reactivities in 56 patients who have survived for 1 yr to more than 6 yr after marrow transplantation from an HLA-identical sibling for the treatment of aplastic anemia or hematologic malignancy. All were conditioned for the transplant by high doses of cyclophosphamide and/or total body irradiation. Immunologic studies on the marrow donors served to establish the normal range for the tests used. The influence of an episode of graft-versus-host disease (GVHD) on the subsequent immunologic recovery was emphasized. Thirty-two patients had GVHD, which resolved in 19 and evolved into a chronic form in 13. Tests used included serial determinations of serum immunoglobulins, complement (C3 and C4), lymphocyte counts, T and B cells, lymphocyte responses to allogeneic cells and to mitogens, isohemagglutinin titers, clearance of bacteriophage ϕX174 (phage) from the blood, primary and secondary antibody responses to phage and to keyhole limpet hemocyanin (KLH), and tests of skin reactivity to recall and neoantigens, dinitrochlorobenzene, and KLH. Concluded from the study were the following: (1) All patients, regardless of whether they had GVHD or not, had pronounced impairment of all immunologic parameters during the first 4 mo after grafting. (2) The speed of immunologic recovery thereafter was faster in patients without GVHD than in those with GVHD. The deficient immune responsiveness in patients with GVHD lasted approximately 2 yr and thereafter tended to persist only in patients with chronic GVHD. A peculiar and unexplained finding in patients with GVHD was significantly higher than normal IgG levels. As a clinical correlate of the prolonged and intense immune deficiency, patients with GVHD showed a tendency toward more frequent and severe infections than those without GVHD. (3) Given enough time, most patients regained near-normal immune reactivity. This occurred much earlier and more frequently in patients without GVHD than in those with GVHD. Patients who regained near-normal immune reactivity did not have unusually frequent infections.