Long-term results of adjuvant donor lymphocyte transfusion in AML after allogeneic stem cell transplantation

Abstract

Adjuvant transfusion of donor lymphocytes (aDLT) may reduce the risk of relapse after allogeneic stem cell transplantation in high-risk AML. We performed a retrospective analysis on the safety and efficacy of aDLT in a cohort of 46 patients. To be eligible for aDLT, patients had to be in CR for at least 120 days from transplantation, off immunosuppression for ⩾ 30 days and free of GvHD. Thirty-four patients with similar disease characteristics and fulfilling the same selection criteria served as controls. Median follow-up among aDLT recipients was 7.2 years. Ten patients (22%) relapsed inspite of aDLT, as compared with 53% in the control group. Induction of GvHD was the main complication. However, non-relapse mortality was low with patients dying from infection (n = 2), severe chronic GvHD (n = 1) and secondary malignancy (n = 2). At the time of analysis, 31/46 aDLT recipients were alive in CR at a median of 5.7 years after first aDLT. Overall survival at 7 years after transplant was 67% as compared with 31% in the control group (P o 0.001). In conclusion, aDLT is safe, when given in escalating doses to a well predefined group of patients. Long-term survival can be achieved. INTRODUCTIONDespite advances in allogeneic transplantation (allogeneic stem cell transplantation; alloSCT), high-risk AML remains a disease with poor outcome, lacking optimal therapeutic strategy. In particular, patients with refractory disease or early relapse still have a poor prognosis. High-risk disease can further be defined by delayed response to chemotherapy, unfavorable karyotype or molecular genetics 1 and by a history of preceding neoplasia and/or chemotherapy.In the era of reduced intensity conditioning (RIC), high rates and a poor outcome of relapse after alloSCT (2 years overall survival (OS) 20%) 2,3 are the main causes for treatment failure in high-risk AML. Thus, effective strategies for preventing post-transplant relapse are urgently needed. As donor lymphocyte transfusion (DLT) enhances the graft-versus-leukemia (GVL) effect, it offers an attractive therapeutic option to decrease relapse-related mortality rates. The GVL potential of donor T-lymphocytes has been described in several preclinical 4,5 and clinical studies. [6][7][8] In particular, their use in the management of post-transplant relapses of chronic myeloid leukemia has been a story of success. However, despite of its desirable GVL effects, DLT may also increase the incidence and severity of GvHD. Thus, DLT protocols have to be optimized to minimize the risk of severe GvHD and maximize the benefit of the GVL effect.The establishment of RIC provided a basis for the employment of DLT in the post-transplantation period of AML therapy. There are several clinical studies supporting the positive role of DLT in the prophylaxis 9 and treatment of post-transplant relapse in AML. 2,10 Despite these encouraging data, the efficacy and the toxicity of DLT in the management of AML is still poorly assessed,

Prophylactic donor lymphocyte infusion in patients with high-risk acute myeloid leukemia: ready for prime time?

“…Fifteen patients (out of 56 consecutive patients registered) received prophylactic DLI a median of 162 days after allo-HCT. As observed in the Jedlickova et al 20 study, the relapse incidence was very low after prophylactic DLI (none of the 15 patients). However, in contrast to what was observed by Jedlickova et al, 20 4 of 15 patients died of steroid-refractory GvHD.…”

“…As observed in the Jedlickova et al 20 study, the relapse incidence was very low after prophylactic DLI (none of the 15 patients). However, in contrast to what was observed by Jedlickova et al, 20 4 of 15 patients died of steroid-refractory GvHD. Reasons for this apparent discrepancy are unclear.…”

“…One possible explanation might be that the low doses of alemtuzumab given in the Liga et al 19 study impaired the recovery of regulatory T cells. Another possible explanation might be that DLI were given as soon as 2 weeks after cyclosporine discontinuation in the Liga et al 19 study, versus at least 30 days, in the study by Jedlickova et al 20 Although the data reported by Jedlickova et al 20 are impressive, prospective randomized studies are needed to confirm the benefit of prophylactic DLIs in patients transplanted for high-risk AML, and also to compare strategies of prophylactic versus preemptive DLI.…”

“…There are some limitations in the study by Jedlickova et al 20 including the diversity of disease status at transplantation, the retrospective design of the study and some differences between DLI and control patients (including the type of conditioning regimen and GvHD prophylaxis). However, the study is informative for several aspects.…”

“…These approaches include decreasing the level of post-grafting immunosuppression, 13 preemptive (i.e., administered in patients with post-transplant evidence of minimal residual disease or low / decreasing donor chimerism levels) or prophylactic administration of diseasespecific medications such as demethylating agents 14 or FLT3 inhibitors, 15 or preemptive 16,17 or prophylactic DLI. 18,19 In this issue of Bone Marrow Transplantation, Jedlickova et al 20 report the results of a retrospective analysis assessing the safety and efficacy of prophylactic DLI in a cohort of 46 high-risk AML patients given grafts following a sequential treatment consisting of chemotherapy (FLAMSA) followed by RIC allo-HCT. Post-grafting immunosuppression included cyclosporine tapered from day +60 to +90 and mycophenolate mofetil discontinued by day +45.…”