ALLOGENEIC BONE-MARROW TRANSPLANTATION WITH MATCHED UNRELATED DONORS FOR PATIENTS WITH HEMATOLOGIC MALIGNANCIES USING A PREPARATIVE REGIMENOF HIGH-DOSE CYCLOPHOSPHAMIDE AND FRACTIONATED TOTAL-BODY IRRADIATION

Allogeneic bone marrow transplantation (BMT) from an HLA-identical sib ling donor is effective therapy for patients with bone marrow failure states and those with hematologic malignancies. However, only a minori ty of them will have an HLA-identical sibling donor; unrelated donors, matched or partially mismatched, have been used successfully for pati ents lacking a related donor. Even though results with allogeneic tran splants using unrelated donors are encouraging, the incidence of compl ications including graft-versus-host disease (GVHD) and graft rejectio n or late graft failure is increased compared to identical sibling tra nsplants. The combination of cyclophosphamide and total body irradiati on (TBI) has been used as an effective preparative regimen for allogen eic transplants, however, the total dosage and dosing schedule of both the cyclophosphamide and TBI has varied significantly among studies. To decrease the rate of graft rejection and late graft failure with vo lunteer donors, we evaluated a preparative regimen of high-dose cyclop hosphamide (200 mg/kg over 4 consecutive days, days -8, -7, -6, -5) fo llowed by fractionated TBI (1400 cGy administered in eight fractions o ver 4 days, days -4, -3, -2, -1). GVHD prophylaxis included FK506 and methotrexate. From July 1993 to January 1996, 43 adult patients, media n age 38 years (range 18-58 years), were treated with this preparative regimen. Seventeen patients had low-risk disease and 26 had high-risk disease. Thirty-one donor/recipient pairs were matched for HLA-A, -B, and -DR by serology and molecular typing, Seven additional pairs were minor mismatched at the HLA-A or HLA-B loci. Four other donor/recipie nt pairs were HLA-A,-B, and -DR identical by serology but allele misma tched at either DRB1 or DQB. Forty patients were evaluable for myeloid engraftment. Engraftment occurred in all 40 patients at a median of 1 9 days. There were no cases of graft rejection or late graft failure. Nephrotoxicity was the primary adverse event with 26 patients (60%) ex periencing a doubling of their creatinine. Hepatic veno-occlusive dise ase occurred in seven patients, six of whom had high-risk disease. All patients who had relapsed or refractory disease prior to BMT achieved a complete remission following BMT. Six patients transplanted for hig h-risk disease relapsed a median of 377 days post-BMT. None of the pat ients with low-risk disease have relapsed following transplant; the Ka plan-Meier survival for those patients with low-risk disease is 62% an d 37% for those patients transplanted with high-risk disease (P = 0.01 29). The median Karnofsky performance status is 100% (range 70-100%). Therefore, a preparative regimen of high-dose cyclo-phosphamide and fr actionated TBI is an acceptable regimen for patients receiving an allo graft from unrelated donors.