Bone marrow transplantation from partially HLA‐matched related donors in adults with leukaemia: The Experience at the University Hospital of Essen, Germany

Summary:With the increasing frequency of haploidentical transplantation, it is becoming more important to establish the degree of HLA mismatch that can be accepted. We retrospectively analyzed clinical data of 50 adult Japanese patients with high-risk hematologic malignancies who underwent allogeneic peripheral blood stem cell transplantation (PBSCT) from two-or three-loci-mismatched related donors with HLA class I and II gene disparities in the graft-versus-host direction. They were treated at 20 transplant centers between 1996 and 2002. In all, 18 patients received unmanipulated PBSC, while 32 received purified CD34 þ blood cells. Conventional (n ¼ 31) or reduced-intensity (n ¼ 19) conditioning regimens were used. Of the 39 patients (78%) who survived for X28 days after transplant, 37 (95%) achieved neutrophil engraftment, while graft failure and rejection occurred in two of 39 (5%) and three of 37 (8%) patients, respectively. Stepwise Cox regression analysis revealed a significantly lower incidence of grades II-IV acute GVHD in patients receiving purified CD34 þ cells (hazard ratio 0.32; 95% CI 0.12-0.84; P ¼ 0.022). By 1 year post transplant, 28 patients (56%) had died of transplantrelated problems, including infectious complications (30%). Although the number of patients is small, our data suggest that transplant-related problems, particularly infectious complications, are major obstacles to the success of this therapy.

Section: Discussionmentioning

confidence: 99%

Allogeneic peripheral blood stem cell transplantation from two- or three-loci-mismatched related donors in adult Japanese patients with high-risk hematologic malignancies

Yamasaki

Ohno

Taniguchi

et al. 2003

“…The incidence of grades 2-4 acute GVHD is 40-70% in 1-antigen mismatched marrow transplant recipients. [1][2][3][4][5] Factors that appear to alter the risk of GVHD include use of the combination of cyclosporine (CsA) and methotrexate (MTX) rather than MTX alone, 3 T cell depletion, 4,6,7 and recipient age. 3 Tacrolimus is an immunosuppressive fungal metabolite with pharmacokinetics and pharmacodynamics similar to those of CsA.…”

mentioning

confidence: 99%

Tacrolimus and minidose methotrexate for prevention of acute graft-versus-host disease after HLA-mismatched marrow or blood stem cell transplantation

Przepiorka

Khouri

Ippoliti

et al. 1999

100

111

Summary:Thirty adults with leukemia or lymphoma transplanted with marrow or blood stem cells from 1-antigen mismatched related donors received tacrolimus and minidose methotrexate to prevent acute graft-versus-host disease (GVHD). The group had a median age of 42 years (range 18-56 years). Twenty-seven patients had advanced disease, and 13 were resistant to conventional therapy. Tacrolimus was administered at 0.03 mg/kg/day i.v. by continuous infusion from day ؊2, converted to oral at four times the i.v. dose following engraftment, and continued to day 180 post-transplant. Methotrexate 5 mg/m 2 was given i.v. on days 1, 3, 6 and 11. Mild nephrotoxicity was common before day 100; 69% of patients had a doubling of creatinine, 56% had a peak creatinine greater than 2 mg/dl, and two patients were dialyzed. Other toxicities prior to day 100 thought to be related to tacrolimus included hypertension (45%), hyperkalemia (17%), hyperglycemia (14%), seizures (13%), headache (3%) and hemolytic uremic syndrome (3%). Grades 2-4 GVHD occurred in 59% (95% CI, 38-70%), and grades 3-4 GVHD in 17% (95% CI, 1-32%). Overall survival at 1 year was 29% (95% CI, 12-45%). We conclude that tacrolimus and minidose methotrexate is active post-transplant immunosuppression for patients with 1-antigen mismatched donors. Keywords: tacrolimus; graft-versus-host disease; mismatched marrow transplantation Family members partially-matched at the major histocompatibility complex (MHC) have served as donors for marrow transplant candidates lacking an HLA-identical sibling. 1,2 The risks of graft-versus-host disease (GVHD), graft rejection, and mortality for these patients increase with increasing degrees of histoincompatibility with the donor, but the outcomes have generally been considered acceptable for patient-donor pairs with up to a single major mis- match in the MHC. The incidence of grades 2-4 acute GVHD is 40-70% in 1-antigen mismatched marrow transplant recipients. [1][2][3][4][5] Factors that appear to alter the risk of GVHD include use of the combination of cyclosporine (CsA) and methotrexate (MTX) rather than MTX alone, 3 T cell depletion, 4,6,7 and recipient age. 3 Tacrolimus is an immunosuppressive fungal metabolite with pharmacokinetics and pharmacodynamics similar to those of CsA. 8,9 In randomized trials, the combination of tacrolimus and standard-dose MTX was superior to CsA and MTX for prevention of acute GVHD in HLA-identical marrow transplant recipients and unrelated donor marrow transplant recipients. 10,11 In an effort to reduce the risk of severe treatment-related mucositis, we previously evaluated a lower dose of MTX in combination with tacrolimus as GVHD prophylaxis for HLA-matched unrelated donor marrow transplant recipients; the incidence of grades 2-4 GVHD was 34%. 12 Using the same regimen, Geller et al 13 reported that 40% of unrelated donor marrow transplant recipients developed GVHD. Further, in a nonrandomized multicenter study of tacrolimus for unrelated donor marrow transplant recipients, the resulting incidence ...

“…All patients in this study received short-course MTX and CyA for GVHD prophylaxis and all but one patient had TBI-based conditioning. 33 In contrast, several smaller studies have shown an adverse outcome with single antigen-mismatched transplants. 34,35 These studies, however, had single HLA-mismatched groups that were too small to be appropriate for subgroup analysis.…”

Section: Discussionmentioning

confidence: 93%

“…Most of the patients reported by Anasetti et al 32 received MTX and prednisone for GVHD prophylaxis and all had total body irradiation (TBI)-based conditioning regimens. On the other hand, Ottinger et al 33 found equivalent overall SV in the 37 recipients of one-antigen HLA-mismatched transplant when a matched pair analysis was performed. Interestingly, no difference in GVHD was noted between the two groups, although the overall incidence of GVHD was low.…”

Section: Discussionmentioning

confidence: 99%

Significance of one human leukocyte antigen mismatch on outcome of nonmyeloablative allogeneic stem cell transplantation from related donors using the Mexican schedule

Ruíz‐Argüelles

López-Martı́nez

Manzano

et al. 2005

Summary:Using the Mexican approach to conduct nonablative stem cell transplantation (NST), we have prospectively performed 58 allografts in individuals with various malignant and nonmalignant hematological diseases using sibling donors, either HLA identical (6/6) or compatible, with one mismatch (5/6). When comparing allografts obtained from HLA identical (n ¼ 40) or compatible (n ¼ 18) siblings, respectively, the overall median survival was found to be 33 vs 8 months (Po0.01), the 52-month survival was 47 vs 38% (P40.2), the prevalence of acute graft-versus-host disease (GVHD) 57 vs 38%, that of chronic GVHD 25 vs 11% and the relapse rate 45 vs 55%. The two patients who failed to engraft were both 5/6 matches. Probably stemming from the low number of patients, and despite a trend toward worse results in patients allografted from HLA compatible (5/6) siblings, most differences in outcome were not significant. It seems that NST can be offered to individuals with either an HLA identical or a compatible sibling donor.