Sequential Treatment with Reduced Intensity Allogeneic Stem Cell Transplantation and Imatinib for Chronic Myelogenous Leukemia (CML.

Chronic myelogenous leukemia is uniquely sensitive to the graft-vs-malignancy effects. Donor lymphocyte infusion (DLI) can induce a high rate of durable remissions in patients relapsing after BMT. Imatinib mesylate may also induce remission in patients with recurrent disease post BMT. This suggests a strategy of sequential therapy using a reduced intensity allogeneic transplant to achieve initial cytoreduction with post transplant imatinib and DLI for recurrent disease as an approach to reduce the risks associated with allogeneic transplantation. We also assessed whether the addition of imatinib to the preparative regimen could be done without increased toxicity to take advantage of the synergistic effects of imatinib with cytotoxic chemotherapy. Patients received a reduced intensity regimen of imatinib (800 mg/d), busulfan ( 8 mg/m2 IV), fludarabine (160 mg/m2), Thymoglobulin (5 mg/kg) and allogeneic stem cell transplantation. Patients receive tacrolimus and mini-methotrexate for GVHD prophylaxis. Those who had molecular evidence of disease at 3 months receive imatinib and those with residual disease 3 months later receive DLI.

14 patients with Ph+ CML have been entered and have follow-up greater than 100 days. 8 had a matched sibling, 5 an unrelated donor and 1 a one antigen mismatched related donor. 4 received marrow and 10 blood progenitor cell transplants. All had received prior imatinib and all except 2 had failed to achieve a major cytogenetic response. 7 were in first chronic or accelerated phase and 7 were in > 2nd chronic phase after prior accelerated phase or blast crisis. All had hematologic control while receiving imatinib-based therapy. Median age was 48 (range 23–70) years.

All patients achieved engraftment and none have died from treatment related causes. 3 developed grade 1–2 acute GVHD and 4 have developed chronic GVHD. 13 patients achieved cytogenetic complete remission, one patient failed to respond and was taken off study. 3 had cytogenetic progression with one having fatal recurrence of lymphoid blast crisis. 9 patients who were pcr positive for bcr-abl rearrangement at 3 months received imatinib; 7 have had ongoing disease reduction by quantitative pcr, 1 currently has no response and 1 patient had progressive disease and was taken off study. None have received DLI. 13 patients remain alive with 11 in cytogenetic remission.

In summary, addition of imatinib to the preparative regimen was not associated with increased toxicity. This strategy allows for allogeneic transplantation using a reduced intensity regimen with capture of persistent or recurrent disease by post transplant imatinib and/or DLI. The low rate of severe morbidity and treatment related mortality makes this approach attractive for CML patients failing to have an optimal initial response to imatinib based therapy.