PROLONGED ADMINISTRATION OF INTERFERON-ALPHA IN PATIENTS WITH CHRONIC-PHASE PHILADELPHIA-CHROMOSOME-POSITIVE CHRONIC MYELOGENOUS LEUKEMIA BEFORE ALLOGENEIC BONE-MARROW TRANSPLANTATION MAY ADVERSELY AFFECT TRANSPLANT OUTCOME

To assess the influence of pretransplant cytoreductive therapy with special reference to interferon-alpha (IFN-alpha) treatment on major endpoints of allogeneic bone marrow transplantation (BMT), we studied 133 consecutive patients with Philadelphia chromosome (Ph(1))-positive chronic myelogenous leukemia (CML) in first chronic phase who received marrow grafts from HLA-identical family (n = 103) or alternative donors (n = 30) at a referral-based transplant center. Fifty of these patients (38%) were previously exposed to IFN-a for a median duration of 14 months (range, 1 to 61 months), whereas 83 patients (62%) exclusively received hydroxyurea and/or busulfan therapy between 1 and 129 months (median, 15 months) pretransplant. Using the categorized treatment duration with each pretransplant cytoreductive agent as a measure for individual patient exposure to each agent, prolonged(>12 months) IFN-alpha administration was identified as the sole significant pretransplant therapy-related predictor of transplant outcome by proportional hazards regression analysis. The adjusted risk ratio (RR) of transplant-related mortality (TRM) was 2.5-fold higher (95% confidence limits [95% CL], 1.4 to 4.5; P <.004) compared with other pretransplant therapy and this was mainly attributable to a 3.1-fold higher RR (95% CL., 1.4 to 6.4; P <.005) of fatal posttransplant infections after prolonged IFN-alpha treatment pretransplant. Marrow graft failure developed exclusively among 7 of 30 patients (23%) with donors other than HLA-identical family members and was further restricted to patients who had been previously exposed to IFN-alpha. The probability of graft failure was 49% +/- 28% in 17 patients pretreated with IFN-alpha compared with 0% for the other 13 patients with mismatched family or unrelated donors (P <.008). In addition, a significant delay in neutrophil and platelet count reconstitution was observed among patients with donors other than HLA-identical family members after pretransplant IFN-alpha exposure. No influence of pretransplant cytoreductive therapy on either acute and chronic graft-versus-host disease or leukemic relapse was detected in this study. As a consequence of its adverse effect on TRM, prolonged pretransplant IFN-alpha treatment was independently associated with a 2.5 fold lower likelihood (95% CL, 1.4 to 4.5; P <.003) of 5-year overall survival and with a 2.3-fold lower likelihood (95% CL, 1.3 to 4.2; P <.004) of 5-year disease-free survival postransplant after adjustment for other significant prognostic factors in multivariate analysis. In conclusion, the present study strongly suggests that prolonged pretransplant IFN-alpha administration in patients with chronic-phase Ph(1)-positive CML may be associated with an increased risk of fatal transplant-related complications and an inferior outcome after allogeneic BMT. Future analyses on transplant results in chronic-phase CML patients should carefully evaluate the impact of treatment duration or, if applicable, of the cumulative doses of IFN-alpha and other cytoreductive agents administered pretransplant. (C) 1995 by The American Society of Hematology.