Nonmyeloablative Allogeneic Transplantation in the Imatinib Era: Three Chances To Achieve Molecular Remission in CML.

Abstract Background: Allogeneic stem cell transplantation is an established, potentially curative therapy for patients(pts) with CML. Its use has declined related to the favorable results of tyrosine kinase inhibitors (TKI) and related to concerns regarding toxicities and GVHD. Minimal residual disease is detectable in most pts treated with TKIs and some have overt progression of their leukemia. The efficacy of allotransplantation in CML is largely derived from the immune graft-vs-leukemia effect mediated by alloreactive donor T cells. Nonmyeloablative conditioning has reduced the toxicity of allotransplantation, and post transplant treatment with imatinib and donor lymphocyte infusions can produce durable molecular complete remissions in substantial fractions of patients who have persistent or recurrent disease. Methods: We conducted a prospective clinical trial designed to induce molecular CR (mCR) in pts with CML with residual disease despite imatinib treatment. Pts received a reduced intensity preparative regimen involving imatinib 800 mg daily, fludarabine 40 mg/m2 x 4 days, busulfan 130 mg/m2 x 2 days, and Thymoglobulin 2.5 mg/kg daily x 3 days followed by allogeneic stem cell transplant from an HLA-identical or one antigen mismatched related or unrelated donor. The regimen was designed to achieve engraftment with a low rate of GVHD and treatment related mortality. Pts with residual disease after 3 mo by quantitative PCR analysis for bcr-abl received imatinib and those who did not achieve mCR within 3 mo received escalating doses of donor lymphocyte infusion (DLI). Results: 33 pts were entered, median age 41 (range 22–69) yrs. All were previously treated with imatinib, 11 were in cytogenetic CR (CyCR), 32 had detectable disease by PCR. 16 pts had early disease (in chronic phase or with isolated clonal evolution) and 17 had advanced disease (with prior accelerated phase or in second chronic phase after blast crisis). Median follow up time is 2.4 (range 0.3 – 4.2) yrs. The regimen was well tolerated. One pt required a second transplant for rejection. 7 pts (21%) developed reversible grade 2–3 acute GVHD. None died within 100 days post transplant and only one patient died later from causes other than relapse. At 3 months, all 16 early pts and 12 of the 17 advanced pts achieved CyCR and 4 early and 2 advanced pts had mCR respectively. 18 pts with residual or recurrent molecular residual disease after 3 mo and received treatment with imatinib; mCR was achieved in 7 of 9 early pts and 2 of 9 with advanced CML. 8 pts subsequently received DLI; one early pt achieved mCR another pt is too early to evaluate (TE). Of 6 advanced pts receiving DLI, 2 have a mCR, and one is TE. 25 patients are alive, including 15 of 16 pts with early disease (94%), all currently in CyCR, 9 in mCR. Of the 17 pts with advanced disease, 10 are alive (58%), 8 in CyCR and 5 in mCR. 6 advanced pts succumbed to recurrent blast crisis. Conclusion: Sequential therapy including nonmyeloablative allotransplantation, post transplant imatinib, and DLI deserves further study as a well tolerated approach to induce durable mCR in imatinib treated CML patients. Best results occurred in patients transplanted before overt transformation of their leukemia.