THE OUTCOME OF MATCHED UNRELATED DONOR BONE-MARROW TRANSPLANTATION INPATIENTS WITH HEMATOLOGIC MALIGNANCIES USING MOLECULAR TYPING FOR DONOR SELECTION AND GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS REGIMEN OF CYCLOSPORINE, METHOTREXATE, AND PREDNISONE

Graft-versus-host disease (GVHD) is a major obstacle to successful bon e marrow transplantation (BMT) from matched unrelated donor (MUD). Cur rently available HLA-A, -B, and -DR serologic testing may not be sensi tive enough to detect clinically relevant donor/recipient (D/R) nonide ntity. Better HLA matching of D/R pairs using molecular typing for cla ss II antigens in combination with intensive GVHD prophylaxis may pote ntially reduce the incidence of GVHD and lead to an improved outcome o f MUD transplantation. Between July 1991 and August 1993, thirty conse cutive patients with hematologic malignancies underwent MUD transplant ation from donors who were identical for HLA -A, -B, and -DR by serolo gic typing. Twenty-five D/R pairs were matched for DRB and DQB by mole cular typing (restriction fragment-length polymorphism and sequence-sp ecific oligonucleotide probe hybridization analyses), whereas five wer e allele mismatched at either DRB or DQB. All patients also received G VHD prophylaxis with the combination of cyclosporine (CSA), methotrexa te (MTX), and prednisone (PSE). The median age was 35 years (range, 15 to 50). The diagnoses were: chronic myelogenous leukemia (CML) in chr onic phase (CP) (16), CML in more than CP (3), acute leukemia in more than first complete remission (CR) (8), acute leukemia in first CR (1) , and advanced high-grade lymphoma (2). The preparative regimen consis ted of 1,320 cGy fractionated total body irradiation (FTBI) and 60 mg/ kg cyclophosphamide (CY) daily for 2 days in 17 good-risk patients (CM L/CP and acute leukemia first CR); and 1,320 cGy FTBI in combination w ith 60 mg/kg etoposide and 20 to 60 mg/kg CY in 13 patients with advan ced leukemia and lymphoma. All patients received CSA, PSE, and MTX on days 1, 3, 6 for GVHD prophylaxis, and 10 patients also received day 11 MTX. All patients engrafted except one who died early of regimen-re lated toxicity. The incidence of grade III or IV acute GVHD was 24% (9 5% confidence interval [CI], 10% to 44%) and that of extensive chronic GVHD was 65% (95% CI, 43% to 84%). At a median follow-up of 13.6 mont hs, 57% of the patients are alive in remission with a median Karnofsky performance status of 90%. The cumulative probability of 2-year disea se-free survival for all patients was 53% (95% CI, 33% to 71%); for go od-risk patients, 71% (95% CI, 46% to 87%) and for the poor-risk group , 34% (95% CI, 13% to 64%). Stepwise logistic regression analysis show ed that status at BMT was the only significant prognostic variable ass ociated with severe acute GVHD, whereas donor age greater than 30 pred icted for extensive chronic GVHD. These results suggest that the utili zation of both serologic and molecular typing for D/R matching with an intensive GVHD regimen may reduce the incidence of acute GVHD and may potentially improve the outcome of unrelated donor BMT. Further contr olled clinical trials are warranted to confirm our results. (C) 1995 b y The American Society of Hematology.