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We investigated 23 patients for their chimerism status who underwent allogeneic transplantation using peripheral blood progenitor cells (PBPCT) for chronic myelogenous leukemia (CML) (n = 14), acute myelogenous leukemia (AML) (n = 5), acute lymphoblastic leukemia (n = 1), myelodysplasia (MDS) (n = 1), and Hodgkin's disease (HD) (n = 2). These data were compared with those of patients after allogeneic BMT after matching them for disease and disease stage, sex of donor and recipient, GVHD prophylaxis, conditioning therapy and degree of HLA disparity. Patients were studied monthly up to 16 months post-transplant. In 11 of 23 (48%) patients who were transplanted with PBPCs and in 18 of 23 (78%) patients after BMT a mixed chimerism was detected at 1 month post-transplant. After 3 months, six of 21 (29%) evaluable patients after PBPCT remained mixed chimeric as opposed to 12 of 21 (57%) patients after BMT. We also assessed minimal residual disease using detection of the chimeric BCR/ABL transcripts by PCR of CML patients in this study. In four of 14 (29%) patients who underwent PBPCT, the BCR/ABL chimeric transcript was detected, while after BMT eight of 14 (57%) CML patients remained BCR/ABL positive. In two of these BMT patients, a cytogenetic relapse developed subsequently, and one other patient suffered a hematological relapse, whereas one of the CML patients relapsed after PBPCT. The present data may indicate that after PBPCT the incidence of leukemic relapse is similar or even lower than after BMT.

We investigated the persistence of host-type hematopoiesis as defined by mixed chimerism (MC) in 28 male patients with chronic myelogenous leukemia (CML) who underwent opposite sex, non-T cell-depleted bone marrow transplantation (BMT) by amplification of Y-chromosome specific sequences, and correlated these results with the detection of minimal residual disease (MRD) by BCR/ABL mRNA amplification. Patients were studied at two time periods (> 3 months and > 24 months post-BMT). All but two patients were conditioned with total body irradiation (TBI) and cyclophosphamide (CY). One patient received busulfan (Bu), thiothepa (Thio) and CY, another patient CY and Bu. Detection of MRD occurred exclusively among patients with a MC (significance P < 0.04). Six of 18 patients with MC had detectable MRD, four of these consecutively developed cytogenetic and hematological relapse. Of 28 patients studied more than 3 months post-transplant, 18 (64%) had mixed chimerism and 10 (36%) had exclusively donor-derived blood cells. Nineteen patients were followed for their chimeric status between 24 months and 136 months post-BMT. Four patients converted from MC to complete chimerism and 10 patients (53%) remained mixed chimeric. The high incidence of MC in patients who underwent BMT without T cell depletion was measured by using a PCR assay with a sensitivity of 0.001%. As previously described by other investigators patients with complete chimerism developed more acute GVHD grade I-II (seven of 10 patients (70%) than patients with MC (nine of 18 patients (50%), not significant). This study also suggests that chimeric status might depend upon the regimen to prevent GVHD. One of four patients who received weekly methotrexate as GVHD prophylaxis developed MC, whereas in 11 of 18 patients receiving short course methotrexate and cyclosporine MC was detectable. All of six patients, prophylactically treated with a murine monoclonal antibody directed to the human alpha/beta T cell receptor in combination with cyclosporine, were mixed chimeras.

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 (Ph1)-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-alpha 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.(ABSTRACT TRUNCATED AT 400 WORDS)