Sequential Treatment After Allogeneic Stem Cell Transplantation for Chronic Myelogenous Leukemia.

Abstract 3129 Background Tyrosine kinase inhibitors (TKI) have revolutionized treatment of chronic myeloid leukemia (CML), nonetheless as seen in follow-up of the IRIS study, almost 30% of patients discontinued imatinib due to inadequate response or intolerance. Allogeneic stem cell transplant (ASCT) remains the only effective treatment to produce durable complete remissions in CML; curative effect is largely derived from immune graft-versus-leukemia (GVL) effect mediated by alloreactive donor T cells reacting against residual host malignant cells. We evaluated sequential therapy after a nonmyeloablative preparative regimen, designed to reduce risks of toxicity, graft-versus-host disease (GVHD) and treatment related mortality. Patients with residual CML 3 months post ASCT received imatinib and those without a complete molecular remission after an additional 3 months received donor lymphocyte infusions (DLI). Objective: To increase frequency of achievement of complete molecular response (CMolR) following reduced intensity ASCT. Eligibility: CML in chronic phase (CP) with failure to respond/intolerance to one or more TKIs. Patients received a reduced intensity preparative regimen involving fludarabine 40 mg/m2 × 4 days, busulfan 130 mg/m2 × 2 days, and antithymocyte globulin (Thymoglobulin) 2.5 mg/kg daily × 3 days followed by ASCT from an HLA identical or one antigen mismatched related or unrelated donor. GVHD prophylaxis was tacrolimus and methotrexate (5 mg/m2 on SCT days 1, 3, 6 and 11). Patients who had engraftment but residual disease by quantitative PCR for bcr-abl rearrangement at 3 months post ASCT received imatinib treatment with dose titrated to hematologic toxicity. Those with residual disease 6 months post ASCT and no active GVHD received DLI. Patients were treated between 4/2003 - 6/2008; median follow up was 74 months (4–99). Outcome of interest was progression free survival (PFS) and overall survival (OS), estimated using Kaplan-Meier estimate, and survival comparisons between groups was by log rank test. Results Patient characteristics summarized in [Table 1][1]; response analysis in [Table 2][2]. 41 patients were entered on study, all were previously treated with a TKI; at time of ASCT, 10 were in first chronic phase (CP1), 8 had isolated clonal evolution (CE) and 23 had a history of advanced CML (>CP1, or accelerated phase). One patient died within 100 days post HSCT and 3 had graft failure; one required a second transplant; 2 had autologous recovery with CMolR and are both alive. At 3 months, all patients in CP1 or with CE (18/44%) obtained complete cytogenetic response (CCgR); 15(36%) of 23 advanced patients achieved CCgR. CMolR was attained by 8 patients, 4 in CP1. No one with minimal residual disease achieved a CMolR without intervention. 22 patients received treatment with TKIs post ASCT; and of those 9 later received DLI. CMolR was achieved in 12 of 22 patients who had molecular progression post ASCT. 26 patients are alive at last follow up and 15 deaths were due to, relapsed leukemia (9), GVHD (3), and infection (3), respectively. Conclusion In conclusion, sequential therapy including reduced intensity HSCT, post transplant treatment with TKI, and donor lymphocyte infusion was associated with a low rate of treatment related mortality. This approach is capable of prolonged cytogenetic and molecular complete remissions and survival. Disease status at time of transplant was the most important prognostic factor. This is an effective option for patients in chronic phase who have failed to respond optimally to TKI based treatment. | | N (%) | | N (%) | |:----------------------- | ---------- | ------------------------ | ----------- | | Age at TP, med (range) | 42 (14–69) | Median f/up in alive, mo | 74 (4–99) | | Age ≥50 yr | 10 (76) | % OS | 60% (42–74) | | ≤50 | 31 (24) | % PFS | 56% (38–70) | | Donor Type | | | | | MRD | 21/51% | Disease status | | | MUD | 19/46% | CP1 | 10/24% | | Ag MM rel | 1/2% | CP2 | 14/34% | | TKI prior to transplant | N (%) | ≥CP3 | 5/12% | | Imatinib | 33/80% | AP1 | 3/7% | | Dasatinib | 6/15% | AP2 | 1/2% | | Nilotinib | 1/2% | CE | 8/20% | | Bafetinib | 1/2% | | | Table 1 - Patient Characteristics | n= 41 | Response to prep regimen at 3 mo | Molecular CR to imatinib (n=22) | Molecular CR to DLI (n=9) | Alive/CCgR/CMolR | Relapse/Dead | |:---------------:| -------------------------------- | ------------------------------- | ------------------------- | ---------------- | ------------ | | CP1 n=10 | CCgR = 10 (100%) | 1 of 4 | 1 of 2 | 10/10/5 | 0/0 | | | CMolR = 4 (40%) | | | | | | CP2/CE/AP1 n=25 | CCgR = 21 (84%) | 4 of 17 | 5 of 7 | 17/16/11 | 8/10 | | | CMolR= 3 (12%) | | | | | | AP2/≥CP3 n=6 | CCgR = 2 (33%) | 1 of 1 | none | 1/1/1 | 5/5 | | | CMolR = 1 (17%) | | | | | | Disease status | | OS | p | PFS | p | | | | N=15 died | | N=17 | | | CP1 | 10 | | 0.02 | | 0.01 | | CP2/AP1/CE | 25 | 9 | | 12 | | | ≥CP3/AP2 | 6 | 5 | | 5 | | Table 2 - Responses After Sequential Therapy Protocol ![Figure][3] Disclosures: No relevant conflicts of interest to declare. [1]: #T1 [2]: #T2 [3]: pending:yes