Tacrolimus for prevention of graft-versus-host disease after mismatched unrelated donor cord blood transplantation

Abstract

Summary:Ten children with hematologic malignancies or a storage disease underwent transplantation using cord blood cells from an unrelated donor mismatched for 1 (n ‫؍‬ 7) or 2 (n ‫؍‬ 3) HLA antigens. The median total nucleated cell dose was 4.0 (range, 2.2-7.1) ؋ 10 7 /kg. GVHD prophylaxis consisted of tacrolimus doseadjusted to maintain a whole blood level of 5-15 ng/ml with or without methotrexate 5 mg/m 2 i.v. on days 1, 3, 6 and 11. Corticosteroids were not administered prophylactically. Median follow-up is 12 months (range, 5-28 months). One patient had autologous recovery and subsequently relapsed 153 days post transplant. For the remainder of the patients, the median time to an ANC Ͼ0.5 ؋ 10 9 /l was 21 days (range, 19-38 days), and the median time to platelets Ͼ20 ؋ 10 9 /l was 39 days (range, 21-97 days). The actuarial risk of grade 2 GVHD was 77% (95% CI, 49-100%), and no patient had grades 3-4 GVHD. Two patients developed chronic GVHD. The survival rate is 90% (95% CI, 81-100%). The combination of tacrolimus and minidose methotrexate is active for the prevention of severe but not moderate acute GVHD after mismatched unrelated donor cord blood transplantation. Keywords: cord blood transplantation; graft-versus-host disease prophylaxis; tacrolimus; unrelated donor Indications for allogeneic transplantation in the pediatric population have increased greatly over the past decade, and now include metabolic storage diseases and hemoglobinopathies in addition to immunodeficiency disorders, marrow failure states and hematologic malignancies. The pool of potential donors has also recently expanded with the introduction of unrelated donor cord blood transplantation (CBT). 1-5 An unexpected advantage of CBT was the lower risk of acute graft-versus-host disease (GVHD) in comparison to marrow or mobilized peripheral blood stem cell transplantation. 6 This is thought to result from the relative immaturity of the T cells in cord blood. and cytokine profile, do not express IL-2 receptors, and have a V␤ chain diversity consistent with lack of prior antigenic stimulation. 7,8 However, the incidence of acute GVHD with CBT from HLA-mismatched unrelated donors remained substantial (38-73%), and the associated treatment-related mortality has limited long-term outcome. [1][2][3][4][5][6] Tacrolimus is an immunosuppressive macrolide lactone that inhibits the effects of calcineurin in the earliest steps of T cell activation, a mechanism of action similar to that of cyclosporine, but the potency of tacrolimus in vitro is more than 100 times that of cyclosporine. 9 This suggested that tacrolimus might be more effective than cyclosporine as GVHD prophylaxis in high-risk settings. We 10,11 and others 12,13 have reported that the combination of tacrolimus and methotrexate (MTX) is active in preventing acute GVHD after alternative donor marrow transplantation (unrelated donor marrow or mismatched related donor marrow transplantation) in adults, and the superiority of tacrolimus over cyclosporine as GVHD prophylaxis was recently de...

Tacrolimus (FK506) and methotrexate as prophylaxis for acute graft-versus-host disease in pediatric allogeneic stem cell transplantation

“…Only one report has been limited to pediatric patients, involving 10 recipients of mismatched unrelated cord blood. 25 The major adverse effects previously reported with tacrolimus have included nephrotoxicity, neurotoxicity, hyperglycemia, and hypertension. [29][30][31][32] Other commonly reported side-effects include microangiopathic hemolytic anemias, 33 hyperkalemia, 34 hypomagnesemia, 35 and hypercholesterolemia.…”

“…11,12,[14][15][16][17][18][19][20][21][22]25 Six reports were studies in related donor transplantation, and six were studies in unrelated donor transplantation. Only one report has been limited to pediatric patients, involving 10 recipients of mismatched unrelated cord blood.…”

“…[11][12][13][14][15][16][17][18][19][20][21][22][23] However, clinical experience using tacrolimus in pediatric marrow transplant trials remains limited. 24,25 Based on clinical observations in the adult population, our center subsequently examined the use of tacrolimus for the prevention of graft-versus-host disease in recipients of pediatric stem cell allografts.…”

Short-term methotrexate could reduce early immune reactions and improve outcomes in umbilical cord blood transplantation for adults

“…In contrast, tacrolimus exerts stronger suppression of acute GVHD than cyclosporine according to several randomized clinical studies. [28][29][30] The reason for this contrast is unknown, as studies of CBT using tacrolimus for acute GVHD prophylaxis are highly limited, 27,31 but unique manifestations of immune reactions in CBT might be involved.…”

Phase II study of unrelated cord blood transplantation for adults with high-risk hematologic malignancies

“…Interestingly, the combination of tacrolimus and mini-methotrexate has been used without excessive toxicity in the pediatric setting. 16 Fludarabine and melphalan was the preparative regimen in four cases. One patient engrafted, whereas three patients did not.…”