Prevention of graft-versus-host disease in high risk patients by depletionof CD4(+) and reduction of CD8(+) lymphocytes in the marrow graft

From March 1994 to September 1997, 30 patients with hematological malignanc ies (12 ANLL, 10 CML, four ALL and four multiple myeloma) received HLA-iden tical allogeneic bone marrow transplants with the marrow graft selectively depleted of CD4(+) lymphocytes and the CD8(+) cell content adjusted to 1 x 10(6)/kg, Total depletion of CD4(+) and partial depletion of CD8(+) lymphoc ytes was carried out by an immunomagnetical method. All patients were consi dered as having high risk for developing GVHD by at least one of the follow ing criteria: patient age >35 years; donor age >35 years; donor multiparity or marrow from an unrelated donor. Twenty-four cases received marrow from an identical sibling and six from an unrelated donor. In order to assess th e role of methotrexate (MTX) in addition to cyclosporin A (CsA) after trans plant, patients were randomly assigned to received either CsA alone (n = 15 ) or CsA plus a short course of MTX (n = 15). No case of primary graft fail ure was observed, but two patients developed late graft failure. Six patien ts presented grade II acute GVHD and no case of severe III-IV GVHD was seen . The actuarial probability of developing grade II-IV acute GVHD was 25.9 /- 9.6% for the entire population, Patients receiving post-transplant CsA MTX had significantly less probability of acute GVHD than those receiving CsA exclusively (6.7 +/- 6.4% vs 50.5 +/- 17.8 %, P = 0.03) and the schedul e of post-transplant immunosuppression was the only factor associated with the incidence of acute GVHD in a multivariate analysis. The actuarial incid ence of chronic GVHD for the entire population was 31.8 +/- 12.5, and there was no significant difference between both groups with additional prophyla xis, Four patients with CML and three with ANLL relapsed: the actuarial pro bability of remaining in complete remission for all patients was 53.6 +/- 1 7.3%. For patients with acute leukemia, the probability of remaining in com plete remission did not differ significantly between those transplanted in first complete remission and those receiving a transplant in more advanced phases of the disease (87.5 +/- 11.6% vs 72.9 +/- 16.5%; P = 0.44). The inc idence of mixed chimerism assessed by PCR was 34%, Nineteen patients are al ive between 2 and 43 months post-transplant, the probability of overall sur vival being 57.8 +/- 10.4%, Our data indicate that this method of selective T cell depletion is very effective in preventing acute GVHD in high risk p atients, particularly when used in combination with post-transplant CsA + M TX.