Factors associated with graft rejection after HLA-identical marrow transplantation for aplastic anaemia.

One hundred and seventy-five consecutive patients with severe aplastic anaemia were given high-dose cyclophosphamide followed by marrow grafts from healthy, HLA-identical family members, and 168 lived long enough to show engraftment. In 38 patients the graft was rejected and 29 of these died. This analysis, using a binary logistic regression model, was aimed at identifying factors that predicted marrow graft rejection. Five factors correlated with graft rejection: (1) previous blood transfusion; (2) a positive relative response in mixed leucocyte culture indicating sensitization of patient against donor; (3) a low number of marrow cells used for transplantation; (4) marrow grafts from male donors; and (5) lack of infusion of viable donor buffy coat cells in addition to the marrow for transfused patients. The findings confirm the importance of transplanting early before transfusion and indicate that the greatest possible amount of donor marrow (supplemented by stem cells/lymphoid cells derived from the peripheral blood) should be obtained.

Marrow transplantation for patients with acute lymphoblastic leukemia: a long-term follow-up.

Twenty-two patients with acute lymphoblastic leukemia in second or subsequent remission and 26 with acute lymphoblastic leukemia in relapse were given cyclophosphamide (60 mg/kg on each of 2 days), total body irradiation (920 rad), and marrow transplants from HLA-identical siblings. With a minimum follow-up of more than 5 yr, an actuarial analysis shows a survival and apparent cure of 27% of the patients transplanted in remission and 15% of the patients transplanted in relapse.

Marrow transplantation with or without donor buffy coat cells for 65 transfused aplastic anemia patients.

Sixty-five multiply transfused patients with severe aplastic anemia were given cyclophosphamide followed by grafts anemia were given cyclophosphamide followed by grafts from HLA-identical siblings. The effect of the administration of viable donor buffy coat cells following the marrow inoculum was evaluated with regard to graft rejection and survival. Results in 43 patients so treated are presented along with those in 22 concurrent patients given marrow alone. Most patients given buffy coat had positive in vitro tests of sensitization indicating a high risk for graft rejection, while all but one of the patients given marrow alone had negative tests. Thirty of the 43 (70%) patients given marrow and buffy coat are alive between 10 and 61 mo (median 36) after grafting; 4 died after graft rejection and 6 with acute or chronic graft-versus-host disease (GVHD). Eleven of the 22 (50%) patients given marrow alone are alive between 29 and 65 mo (median 52); 7 died after graft rejection and 3 with GVHD. The addition of buffy coat cell infusions to the marrow inoculum reduced the risk of rejection and increased survival in the currently reported transfused patients when compared to patients grafted before 1976. However, there was an increased risk of chronic GVHD. Recipients of marrow from female donors survived slightly better (73%) than recipients of male marrow (58%).

Marrow transplantation in thirty "untransfused" patients with severe aplastic anemia.

Thirty patients with severe aplastic anemia had no transfusions of blood products until just before marrow transplantation from HLA-identical family members. They were conditioned for grafting with cyclophosphamide, 50 mg/kg body weight on each of 4 successive days. All 30 had prompt initial marrow engraftment, which was sustained in 27. Twenty-five of the 30 are alive between 9 to 84 (median, 19.5) months. The actuarial projection of survival for 2 to 6 years is 75%. Twenty of the 25 surviving patients have no problems. Five have chronic graft-versus-host disease, resolving in two and active in three. Five patients died with infection or hemorrhage, four of whom had graft-versus-host disease. These data show that early transplantation should be carried out before transfusions are given for any patient with severe aplastic anemia who has an HLA-identical family member. If sensitization to minor transplantation antigens contained in blood products is avoided, the incidence of marrow-graft rejection will decrease, and survival will improve.

One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation.

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.

Aplastic anemia treated by allogeneic bone marrow transplantation: a report on 49 new cases from Seattle.

Forty-nine patients with severe aplastic anemia, 33 due to unknown cause, 11 drug or chemical related, 2 associated with hepatitis, 1 with paroxysmal nocturnal hemoglobinuria, and 2 possibly associated with Fanconi syndrome did not show recovery after 0.5-96 (median 2) mo of conventional therapy. Twenty-two were infected and 21 were refractory to random platelet transfusions at the time of admission. All were given marrow grafts from HLA-identical siblings. Forty-five were conditioned for grafting by cyclophosphamide (CY), 50 mg/kg on each of 4 successive days, and four by 1000 rad total body irradiation. All were given intermittent methotrexate therapy within the first 100 days of grafting to modify graft-versus-host disease (GVHD). Three patients died from infection too early to evaluate (days 1-8). Forty-six had marrow engraftment. Of these, 20 are surviving with good peripheral blood counts between 186 and 999 days, and 18 have returned to normal activities. Chronic GCHD is a problem in five. Twelve patients died of infection following rejection of the marrow graft. Twelve patients died with bacterial or fungal infections or interstitial pneumonia and active GVHD or soon following resolution of GVHD. Two patients died with marrow engraftment and no GVHD, one with an interstitial, and the other with a bacterial pneumonia. Thirty-six patients who had received random donor blood transfusions were randomly assigned to receive either CY or procarbazine-antithymocyte globulin-CY as conditioning regimens to test whether the incidence of graft rejection could be decreased. There was no difference in the incidence of graft rejection between the two regimens. In 13 patients with rejection, second transplants were attempted either with the original marrow donor (9 patients) or another HLA-identical sibling (4 patients). Three of these transplants were not evaluable, seven were unsuccessful and three were successful with only one of the three surviving for more than 468 days. In conclusion, the long-term survival of 41% of the patients in the present study is similar to that achieved in our first 24 patients, and confirms the importance of marrow transplantation for the treatment of severe aplastic anemia. Marrow graft rejection, GVHD, and infections continue to be the major causes of failure.