ORIGINAL ARTICLE Response to donor lymphocyte infusions for chronic myeloid leukemia is dose-dependent: the importance of escalating the cell dose to maximize therapeutic efficacy MP Simula 1 , S Marktel 1 , C Fozza, J Kaeda, RM Szydlo, E Nadal, M Bua, A Rahemtulla, E Kanfer, D Marin, E Olavarria, JM Goldman, JF Apperley and F Dazzi Department of Hematology, Imperial College at Hammersmith Hospital, London, UK Donor lymphocyte infusions (DLI) are an effective treatment for patients with chronic myeloid leukemia (CML) in relapse after allografting but the optimal cell dose has yet to be identified. To address this question, we investigated the factors affecting the dose required to achieve remission (effective cell dose, (ECD)) in 81 patients treated with an escalating dose regimen. The overall proportion of patients who achieved a molecular remission was 88%. The cumulative proportion of remitters increased significantly at each dose level. With a CD3 þ cell dose p10 7 /kg, 56% of patients in molecular/cytogenetic relapse obtained molecular remission, whereas only 20% of those in hematologic relapse did so. At the same cell dose, 58% of patients who received lymphocytes from volunteer unrelated donors achieved remission, as compared to 29% of those who received DLI from sibling donors. We conclude that the response to DLI is dose-dependent and that the ECD is influenced by the quantity and phase of CML at relapse and degree of donor/recipient histocompatibility. Leukemia (2007) 21, 943–948. doi:10.1038/sj.leu.2404641; published online 15 March 2007 Keywords: donor lymphocyte infusions; chronic myeloid leukemia; effective cell dose; escalating dose regimen; allogeneic stem cell transplantation Introduction The graft-versus-tumor effect exerted by donor lymphocytes is a major component of the therapeutic benefit that results from allogeneic stem cell transplantation (SCT). This conclusion was based originally on the observation that patients surviving acute graft-versus-host disease (GVHD) had a reduced rate of leukemia relapse 1 and on the later observation that patients transplanted with marrow cells subjected to T-cell depletion to prevent GVHD had an increased rate of leukemia relapse. 2 The success of lymphocyte infusions from the original stem cell donor (donor lymphocyte infusions, DLI) to treat leukemia relapse was first reported in 1990. 3 Subsequently, their overall efficacy and the durability of the responses obtained in chronic myeloid leukemia (CML) were confirmed by several transplant centers worldwide and DLI were used for different types of hematologic malignancy. 4–10 Among the various malignancies, CML is undoubtedly the most sensitive target for the DLI-induced graft-versus-leukemia (GVL) effect. Thus the use of DLI in this type of leukemia offers an opportunity to monitor a patient’s response attributable to the GVL effect with great precision. For CML, the best responses occur in patients diagnosed or treated in cytogenetic or molecular relapse as compared to those whose relapse was detected only at hematologic level. 11 Furthermore, among patients with hematologic relapse, complete remissions were more frequent in patients with chronic phase relapses than in those with CML recurring in accelerated phase or blastic transformation. 5,6,12 Other factors predictive of response include T-cell depletion at the time of transplant, 12 longer interval between transplant and diagnosis of relapse 6 and the presence of donor chimerism at time of DLI. 13 Although the relative importance of these factors varies in the different studies, there is general agreement that a minority of patients do not respond, but the reasons underlying this failure have not been elucidated. Although the failure of DLI in advanced phases could be attributed to the ‘rapid’ kinetic features of the leukemia population, as exemplified also in an acute leukemia, the resistance in chronic phase, observed in 29–45% of treated cases, 6,14 could be due in some patients to intrinsic insuperable resistance of leukemic cells to a general or specific GVL effect. However, the total dose of lymphocytes transfused in the various studies has been rather heterogeneous, so it remains possible that some patients who did not respond failed simply because they did not receive enough cells. Donor lymphocytes can be given as a single dose of somewhat arbitrary total numbers according to a bulk dose regimen (BDR) or in multiple doses of fixed or progressively escalating cell numbers. 15 The use of an escalating dose regimen (EDR), initially reported by the transplant group at the Memorial Sloan-Kettering in New York, 15 is based on the principle that the cell dose is increased progressively until remission is achieved. This approach should allow the therapeutic effect of each cell dose to be assessed. In this analysis, we have evaluated the effective cell dose (ECD) required to achieve molecular remission and the factors influencing ECD in patients undergoing DLI according to an EDR. The analysis was carried out retrospectively in a cohort of patients with CML in molecular, cytogenetic or hematologic (chronic or accelerated phase) relapse after allogeneic SCT. Our EDR was designed such that the intervals between successive doses were long enough to allow us to attribute a given clinical response to the immediately preceding dose. Patients and methods Patients Eighty-one patients were treated with escalating doses of donor lymphocytes following relapse of CML after standard condition- ing allogeneic SCT (Table 1). Patients were treated at the Hammersmith Hospital between February 1996 and November Received 4 December 2006; revised 30 January 2007; accepted 1 February 2007; published online 15 March 2007 Correspondence: Professor F Dazzi, Department of Hematology, Imperial College Faculty of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. E-mail: f.dazzi@imperial.ac.uk. 1 These authors contributed equally to this work. Leukemia (2007) 21, 943–948 & 2007 Nature Publishing Group All rights reserved 0887-6924/07 $30.00 www.nature.com/leu