DISTINCT PATTERNS OF MINIMAL RESIDUAL DISEASE-ASSOCIATED WITH GRAFT-VERSUS-HOST DISEASE AFTER ALLOGENEIC BONE-MARROW TRANSPLANTATION FOR CHRONIC MYELOGENOUS LEUKEMIA

Purpose: Allogeneic bone marrow transplantation (BMT) has been shown t o provide effective therapy for chronic myelogenous leukemia (CML), bu t previous reports have also demonstrated the persistence of bcr-abl-p ositive cells for months to years after BMT in the majority of patient s. To evaluate the biologic significance of persistent bcr-abl-positiv e cells, we examined the relationship between clinical parameters know n to affect the risk of relapse and the ability to detect bcr-abl-posi tive cells post-BMT. Patients and Methods: We analyzed 480 samples fro m 92 patients at two transplant centers for the presence of bcr-abl-po sitive cells by polymerase chain reaction (PCR). two different BMT pre parative regimens and protocols for prevention of graft-versus-host di sease (GVHD) were used. One center used cyclophosphamide plus total-bo dy irradiation (CY/TBI) and T-cell-depleted marrow; the second center used busulfan plus cyclophosphamide (Bu/CY) and untreated marrow with cyclosporine and methotrexate (Csp/MTX) os GVHD prophylaxis. Results: We first determined the percent of patients at each center with greate r than or equal to one PCR-positive (PCR(+)) result at defined interva ls post-BMT. Between 0 and 6 months post-BMT, the majority of patients (80% to 83%) in both populations had PCR-detectable bcr-abl-positive cells. Between 6 and 24 months post-BMT, 80% to 83% of patients who re ceived T-cell-depleted marrow remained PCR(+), as compared with 26% to 30% of patients who received unmodified marrow. After 24 months post- BMT, the percentage of PCR(+) patients was not significantly different in the two populations. This pattern of detection of bcr-abl-positive cells post-BMT followed the development of chronic GVHD in patients w ho received unmodified marrow. All patients were also divided into thr ee groups based on post-BMT PCR results os follows: (1) persistent PCR (+) (n = 29), (2) intermittent PCR-negative ([PCR(-)] n = 40), and (3) persistent PCR(-) (n = 23). These three groups were found to have a l ow, intermediate, and high probability of maintaining remission and di sease-free survival, respectively (P = .0001). Intermittent or persist ent PCR(-) results, which reflect levels of minimal residual disease l ess than or equal to the limit of detection by PCR, were clearly assoc iated with both acute (P = .004) and chronic (P = .000005) GVHD. Never theless, 44% of patients without GVHD also had intermittent or persist ent PCR(-) assays. Conclusion: The persistence of PCR-detectable bcr-a bl-positive cells early post-BMT in more than 80% of patients suggests that neither BMT preparative regimen effectively eradicates CML cells in most patients. Subsequently, acute and/or chronic GVHD are associa ted with a decreased ability to detect residual bcr-abl-positive cells , which suggests that immunologic mechanisms mediated by donor cells a re important for inducing longterm remissions after BMT. The demonstra tion that 44% of patients without GVHD had either low or undetectable levels of residual leukemia suggests the presence of mechanisms capabl e of suppression or eradication of CML independent of GVHD. (C) 1995 b y American Society of Clinical Oncology.