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Originally published as JCO Early Release 10.1200/JCO.2007.11.6053 on October 1 2007 © 2007 American Society of Clinical Oncology. Donor Lymphocyte Infusion in the Treatment of First Hematological Relapse After Allogeneic Stem-Cell Transplantation in Adults With Acute Myeloid Leukemia: A Retrospective Risk Factors Analysis and Comparison With Other Strategies by the EBMT Acute Leukemia Working Party
From the Department of Medicine II, Klinikum Augsburg, Ludwig Maximilians University of Munich; Jos Address reprint requests to Christoph Schmid, MD, Department of Medicine II, SCT Unit, Klinikum Augsburg, Ludwig-Maximilians-Universität München, PO Box 101920, 86009 Augsburg, Germany; e-mail: christoph.schmid{at}2med.zk.augsburg-med.de
Purpose To evaluate the role of donor lymphocyte infusion (DLI) in the treatment of relapsed acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT). Patients and Methods We retrospectively analyzed the data of 399 patients with AML in first hematological relapse after HSCT whose treatment did (n = 171) or did not (n = 228) include DLI. After correction for imbalances and established risk factors, the two groups were compared with respect to overall survival. Further, a detailed analysis of risk factors for survival among DLI recipients was performed. Results Median follow-up was 27 and 40 months, respectively. Estimated survival at 2 years (± standard deviation) was 21% ± 3% for patients receiving DLI and 9% ± 2% for patients not receiving DLI. After adjustment for differences between the groups, better outcome was associated with age younger than 37 years (P = .008), relapse occurring more than 5 months after HSCT (P < .0001), and use of DLI (P = .04). Among DLI recipients, a lower tumor burden at relapse (< 35% of bone marrow blasts; P = .006), female sex (P = .02), favorable cytogenetics (P = .004), and remission at time of DLI (P < .0001) were predictive for survival in a multivariate analysis. Two-year survival was 56% ± 10%, if DLI was performed in remission or with favorable karyotype, and 15% ± 3% if DLI was given in aplasia or with active disease. Conclusion Although further evidence for a graft-versus-leukemia effect by DLI is provided, our results confirm, that the clinical benefit is limited to a minority of patients. Strategies to reduce tumor burden before DLI, as well as alternative treatment options should be investigated in adults with relapsed AML after HSCT.
Donor lymphocyte infusion (DLI) for treatment of leukemic relapse after allogeneic hematopoietic stem-cell transplantation (HSCT) was introduced in the early 1990s.1-3 Being extremely effective in chronic myeloid leukemia, the procedure was less successful in acute myeloid leukemia (AML), although remissions were observed in selected cases.4-6 Therefore, the use of DLI for AML relapse post-transplant has been questioned in general. Since randomized trials will not be available in the near future, a retrospective comparison among patients treated with or without DLI was performed to evaluate the role of DLI in this setting. In addition, a detailed analysis of risk factors for survival among DLI recipients was performed to define patients who will or will not benefit from the procedure.
Data Collection Centers for allogeneic HSCT within the European Group for Blood and Marrow Transplantation were asked to report on their experience in the treatment of AML relapse after allogeneic HSCT. Forty-one participating centers received a questionnaire, designed to assess pretransplant, transplant, and relapse characteristics, as well as details on the management and outcome of relapse. Centers were asked to report on all sequentially treated patients. Physician review of submitted data and personal contact to centers ensured the data quality. Collected data included age, sex, relationship and HLA compatibility of patients and donors, French-American-British (FAB) subtype, cytogenetics, conditioning, disease status at transplantation, stem cells source (bone marrow [BM] or peripheral blood stem cells [PBSC]), graft-versus-host disease (GVHD) prophylaxis, disease response, and GVHD after transplantation. Relapse-related information included duration of post-transplant remission, percentage of BM blasts at time of relapse, and treatment. In patients undergoing DLI, details on the type of transfused cells (unstimulated donor lymphocyte or BM/PBSC-containing lymphocytes), disease status at transfusion, cell doses, and transfusion schedule were requested.
Criteria of Eligibility
Definitions For evaluation of response, remission was defined by the absence of signs of leukemia without ongoing antileukemic therapy. Complete reconstitution of hematopoiesis, as used for the definition of complete remission (CR), was not required because factors other than leukemia and radiochemotherapy might contribute to leukocytopenia and thrombocytopenia (eg, GVHD or virus). GVHD was classified as described.8
Statistical Analysis The second analysis was performed on DLI recipients only, in order to identify patient subgroups who did or did not benefit from DLI. The same variables as in the first analysis were considered. OS after DLI was the primary end point. For both analyses, probabilities of OS were calculated using the Kaplan-Meier estimate.9 The log-rank test was used for univariate comparisons. In the first analysis, all factors differing in distribution between the two groups with a P < .10, and factors found to influence outcomes in univariate analysis were included into a Cox proportional hazard model using time-dependant variables.10 All factors associated with a P < .10 by univariate testing were included into the second model. Further, a stepwise backward procedure was used for both analyses with a cutoff significance level of .05 for deleting factors. All tests were two sided. The type-I error was fixed at .05 for determination of factors associated with time-to-event outcomes. Finally, patients were classified into prognostic groups on the basis of a score derived from the proportional hazard model, after introduction of significant interactions between all remaining prognostic factors as shown by the likelihood ratio test. Statistical analysis was performed using SPSS software version 14.0 (SPSS Inc, Chicago, IL).
Patient Characteristics A total of 399 patients who received transplantation between 1990 and 2003 were included (Table 1). 11,12 In 171 patients, the treatment included DLI, whereas 228 patients received other types of treatment. Among other characteristics, the two groups were well matched in terms of FAB subtype, cytogenetic subgroups,11 donor type, median duration of post-transplant remission, and leukemia burden at time of relapse. However, DLI recipients were older (P = .07), had a later median year of transplant (P < .0001), had received more PBSC for transplantation (P = .007), had received transplantation in more advanced stages (P < .0001), had received more reduced conditioning (P < .001),12 and had developed less cGVHD before relapse (P = .0003).
Comparison of Using or Not Using DLI To determine the general role of DLI within the managment of AML relapse after HSCT, we compared the outcome of the two cohorts, whose treatment did or did not include DLI, using a Cox proportional hazard model. Among the patients not receiving DLI, information on the chemotherapy administered for management of relapse was available in 72%, 33 patients had received a second transplantation, as compared with 13 from the DLI group, who received a second transplantation after failing to respond to DLI. A univariate analysis of survival showed a significant advantage for DLI recipients, who achieved a 2-year OS from relapse of 21% ± 3%, as compared with 9% ± 2% in the no DLI group (P < .0001; Fig 1). In contrast, a second transplantation was not associated with better outcome (P = .77). In the multivariate model, three variables were found to be predictive for survival: an interval from transplantation to relapse more than 5 months (P < .0001; relative risk [RR], 0.49; 95% CI, 0.4 to 0.61); age above the median of 37 years (P = .008; RR, 1.33; 95% CI, 1.08 to 1.64); and the use of DLI (P = .04; RR, 0.8; 95% CI, 0.64 to 0.99).
Patients Receiving DLI The characteristics of 171 DLI recipients are presented in Table 2. Median time from transplantation to relapse was 5.5 months (range,1 to 55 months), and median time from relapse to DLI was 27 days (range,1 to 623 days). At time of relapse, patients showed a median of 35% blasts in BM and 5% in PB. Chemotherapy was given before DLI in 75% of patients. Nevertheless, only 12% of patients received donor cells in remission, and 21% in aplasia, whereas 67% had active leukemia when the cells were transfused.
DLI consisted of unstimulated leukapheresis products in 60% of patients; 40% of patients received hematopoietic stem cells in addition to lymphocytes, either as BM or mobilized PBSC. Among recipients of unstimulated lymphocytes, the median total number of mononuclear cells transfused was 2.8 x 108/kg. One single infusion was given to 61% of informative patients, 39% received between two and 11 infusions. A dose escalating schedule was reported in 28 patients.
Response, GVHD and Survival After DLI The center reported that between June 2005 and February 2006, 30 patients were alive with a median follow-up of 26 months (range, 5 to 98 months). Median OS from DLI was 5 months, and 2-year OS was 20% ± 3%. Persisting or relapsed leukemia was the cause of death in 120 patients (71%), whereas death from infections (n = 6) or GVHD (n = 13) occurred less frequently. In a univariate analysis of risk factors for survival (Table 3), younger age, female sex, favorable cytogenetics, reduced conditioning for transplantation, a longer interval from transplantation to relapse, a lower tumor burden at relapse, and remission at time of DLI were associated with superior outcome. The outcome of patients who received transfusion in aplasia were identical to those receiving donor cells with active disease. Among other factors, no significant impact could be detected for donor type, sex match of donor and recipient, conditioning, presence of GVHD at relapse, the interval from relapse to DLI, and the type of DLI (containing stem cells or not). Concerning the numbers of transfused donor cells, only mononuclear cells counts could be compared, which is of limited value given the different types of cells transfused. Due to missing data, CD3-positive cell counts could only be analyzed in a 51 informative recipients of unstimulated DLI. No difference in OS was found between patients receiving more or less cells than the median (data not shown). However, because of the low numbers, the role of cell counts could not be finally assessed. Two or more transfusions seemed to be superior to one single DLI, but this finding must be interpreted with caution, since the opportunity to give more than one DLI might reflect a less aggressive disease.
Multivariate analysis identified a lower blast count (< 35%) in BM at time of relapse (P = .006), female sex (P = .02), favorable cytogenetics (P = .004), and a status of remission at time of DLI (P < .0001) as the most significant prognostic factors (Table 4). The time from transplantation to relapse was closely linked to the stage at DLI, and was therefore eliminated from the model. The role of chemotherapy could not be evaluated as an independent variable because both the use of a cytotoxic agent by itself and the intensity of the applied regimen were influenced by the leukemia load at time of relapse and were linked to the disease stage at DLI.
Based on the multivariate model, three prognostic groups could be defined, allowing the calculation of the survival to be expected after a DLI-containing treatment. Patients who received DLI in remission and/or had a favorable karyotype had a 2-year OS of 56%. A second group with a 2-year OS of 21% included female patients not in remission at time of DLI, but with a lower tumor burden at time of relapse, whereas 2-year OS was only 9% among the remaining patients. Of note, no overlap of the 95% CI of 2-year OS was observed among the three groups (Fig 2).
The influence of GVHD on survival after DLI was evaluated as a time-dependant variable. Due to excess mortality, aGVHD grade II to IV was associated with inferior survival (P = .003; RR, 0.54; 95% CI, 0.36 to 0.81), whereas cGvHD was associated with a better outcome among survivors of more than 100 days after DLI (P = .004; RR, 2.29; 95% CI, 1.3 to 4).
AML relapse after allogeneic HSCT has a poor prognosis. Treatment options include supportive care, chemotherapy,13,14 second HSCT using the same or an alternative donor,15-20 and infusion of lymphocytes and/or other immunocompetent effector cells from the original donor (DLI).4-6 So far, no standard approach to this difficult clinical problem could be established. This analysis was performed to more precisely define the role of DLI in this setting. As suggested by others,7 simultaneous transfusions of donor lymphocytes and hematopoietic stem cells given as PBSC and (in few cases) BM were defined as DLI, if no prophylactic immunsuppression was given, since both strategies are characterized by an unhindered graft-versus-leukemia reaction from the day of transfusion. In contrast, patients receiving stem cell–containing products followed by prophylactic immunosuppression were included into the no DLI group because a pure graft-versus-leukemia effect could not be studied in these patients. In the analysis, the results of stem cell containing and pure DLI were identical (Table 3). To improve the homogenicity of the study population, the analysis was restricted to patients in first hematological relapse after allogeneic HSCT. An extensive survey among EBMT centers, including repeated questionnaires and personal contacts with treating physicians, produced a population with sufficient patient numbers and data quality for reliable analysis. When the outcome of DLI recipients was compared with those patients who had been treated without DLI, the use of DLI, among other established risk factors, was a significant factor for survival in a multivariate analysis. These data confirm an allogeneic graft-versus-leukemia effect even against a highly proliferative disorder as AML. This is further supported by the 35 patients who achieved a remission after receiving DLI in an active disease stage, and by the better results of DLI recipients who developed cGvHD. First clinical evidence for a graft-versus-leukemia effect in AML had come from trials comparing different postremission strategies in newly diagnosed AML, which reported on lower relapse rates and improved progression-free survival after allogeneic as compared with autologous HSCT.21,22 A large retrospective analysis by the International Bone Marrow Transplant Registry described a higher risk of relapse in patients receiving a T-cell depleted transplantation, and among patients without GVHD after HSCT.23 In earlier studies on DLI, responses were observed in patients who had received donor lymphocytes without prior chemotherapy, or after chemotherapy had failed.4,6 Hence, there is now a bulk of evidence justifying in principle the use of DLI-based strategies in the treatment of post-transplant relapse in AML. However, our data also confirm the results from earlier studies, in that the efficacy of DLI on AML relapse after allogeneic HSCT is limited to a small subgroup of patients.4-6 Therefore, for the clinician who is in charge of treating those patients, it will be important to identify in advance, which patient will or will not benefit from the procedure. According to our results, mainly patients with favorable cytogenetics, those achieving a hematological remission before DLI, or patients with a lower tumor burden at time of relapse will benefit from this procedure. Among the DLI recipients of our cohort, female patients seemed to achieve better results. Because prospective trials are very difficult to perform in the field of AML relapse after HSCT, clinicians will have to base their treatment decisions to a certain extent on retrospective data such as ours. Therefore, based on our observations, we would propose the following strategy for the use of DLI within the management of AML relapse after allogeneic HSCT: because of the inferior results after DLI given with active disease, chemotherapy or other cytoreductive treatment modalities (eg, gemtuzumab and ozogamicin24,25) should first be administered. Patients who achieve a remission should immediately go for a DLI, since their chance to be alive at 2 years is more than 50%. According to our data, female patients with a lower leukemia burden at time of relapse have a 21% chance of 2-year OS, even without achieving a remission before DLI. The relevance of this observation is unclear; therefore, a decision for DLI should be made on an individual basis in these patients. In all other patients, DLI certainly remains an option. However, since survival after DLI given with persistent leukemia was only 9%, repeated attempts of prior remission induction, or the use of alternative strategies should be seriously considered. As an exception, patients with favorable cytogenetics might benefit from DLI even with active disease, although this observation was based on 12 patients only. Obviously, although our results are based on the largest cohort studied so far in this field, the validation of the identified risk factors and the proposed strategy in a prospective study is warranted. As long as such data are not available, the proposal might be helpful to recommend or not a DLI-based treatment strategy in a given patient. In conclusion, the results of our analysis confirm a role for an allogeneic graft-versus-leukemia effect in AML, but also point out the limited efficacy of DLI in the treatment of AML relapse after allogeneic HSCT. Various modifications of DLI have been investigated. These included the systematical use of mobilized donor PBSC concentrates instead of lymphocytes,7,26,27 or the systemic application of cytokines for additional immunostimulation28-30 to increase graft-versus-leukemia efficacy. In vitro studies have suggested the possibility to create specific antileukemic cytotoxicity by stimulation of donor lymphocytes using AML-derived dendritic cells.31 Recently, Porter and colleagues32 reported encouraging results from a phase I trial using conventional DLI, followed by an additional infusion of ex vivo activated donor T cells. A second allogeneic transplantation using a reduced conditioning regimen represents another graft-versus-leukemia–based option.18,33 In our study, the role of a second transplantation could not be evaluated separately due to small numbers. As with second transplantations,18,20 tumor load at time of relapse and DLI was crucial for success in our analysis. Therefore, the use of donor lymphocytes as maintenance therapy after HSCT for patients in remission or in a minimal residual disease situation (prophylactic DLI) might be a better way to exploit the graft-versus-leukemia efficacy. This strategy has already been used in a variety of promising clinical studies, mostly in the context of reduced conditioning regimen.34-36 However, prophylactic DLI was associated with a considerable risk of GVHD, and its exact role remains to be defined. Further experimental and clinical research is required to overcome the obviously high capacity of leukemic blasts to escape from an allogeneic immune reaction in patients relapsing after allogeneic HSCT for AML.
The author(s) indicated no potential conflicts of interest.
Conception and design: Christoph Schmid, Myriam Labopin, Hans-Jochem Kolb, Vanderson Rocha Administrative support: Christoph Schmid, Emanuelle Polge, Norbert-Claude Gorin, Vanderson Rocha Provision of study materials or patients: Christoph Schmid, Arnon Nagler, Martin Bornhauser, Jurgen Finke, Athanasios Fassas, Liisa Volin, Gunhan Gurman, Johan Maertens, Pierre Bordigoni, Ernst Holler, Gerhard Ehninger, Norbert-Claude Gorin, Hans-Jochem Kolb Collection and assembly of data: Christoph Schmid, Myriam Labopin, Emanuelle Polge Data analysis and interpretation: Christoph Schmid, Myriam Labopin, Norbert-Claude Gorin, Vanderson Rocha Manuscript writing: Christoph Schmid, Arnon Nagler, Martin Bornhauser, Liisa Volin, Ernst Holler, Vanderson Rocha Final approval of manuscript: Christoph Schmid, Myriam Labopin, Arnon Nagler, Martin Bornhauser, Jurgen Finke, Athanasios Fassas, Liisa Volin, Gunhan Gurman, Johan Maertens, Pierre Bordigoni, Ernst Holler, Gerhard Ehninger, Emanuelle Polge, Norbert-Claude Gorin, Hans-Jochem Kolb, Vanderson Rocha
List of contributors. CIC 234: Ferrant, Augustin Brussels (St Luc); CIC 307: Leone, Giuseppe Rome (Univ S Cuore); CIC 785: Schubert, Joerg Homburg (Univ Saarland); CIC 212: Ringden Olle, Huddinge (Univ H); CIC 601: Liu Yin, John, Manchester (Royal Infirmary); CIC 766: Napoli (Federico II); CIC 788: Olivieri, Attilio, Ancona (Torrette; Umberto I); CIC 295 Eder, Matthias; Hannover (Medical Univ); CIC 630: Schots, Rik, Brussels (Univ H); CIC: 731 Wahlin, Anders, Umea (Univ H); CIC: 218 Potter, Mike London (Royal Marsden); CIC: 232 Iori, Anna Paola, Rome (Emat, "La Sapienza"); CIC 248: Di Bartolomeo, Paolo; Pescara (Osp Civile); CIC 257: McCann, Shaun Dublin (St James), CIC 300: Abecasis, Manuel, Lisboa (Inst Oncologia); CIC 389: Niederwieser, Dietger, Leipzig (Univ, Hemat/Oncol); CIC 614 Zander, Axel R, Hamburg (Univ H); CIC 642: Carrera Fernández, Dolores Oviedo (H Covadonga); CIC: 680 Kienast J, Münster (University); CIC 717: Russell Nigel H, Nottingham (City H); CIC 718: Koza, Vladimir, Pilsen (Charles Univ H); CIC 759: Duarte Palomino, Rafael Barcelona (H Univ Bellvitge); CIC: 214 Esteve, Jordi, Barcelona (H Clinic); CIC 255: Littlewood Tim, Oxford (Radcliffe H); CIC: 284 Milligan, DW Birmingham (Heartlands H); CIC 311: Schwerdtfeger, Rainer, Wiesbaden (Kl Diagnostik); CIC: 506 Selleslag, Dominik, Brugge (AZ Sint-Jan); CIC 641: Wachowiak, Jacek; Poznan (Univ Med Sci); CIC: 727Caballero, Dolores Salamanca (H Clinico); CIC: 780 Liakopoulou, Effie Manchester (Christie).
Following European Group for Blood and Marrow Transplantation publication rules, coauthorship was offered to centers contributing the highest number of patients. Nevertheless, the authors highly appreciate the contribution by many physicians and data managers throughout the European Group for Blood and Marrow Transplantation who made this analysis possible. Centers and representatives are named in the online only appendix.
published online ahead of print at www.jco.org on October 1, 2007. Presented in part at the meeting of the American Society of Hematology, San Diego, CA, December 4-7, 2004, and at the European Group for Blood and Marrow Transplantation, Prague, Czech Republic, March 20-23, 2005. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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; Carrears Unit for Hematopoietic Transplantation, Department of Medicine III, Ludwig Maximilians University of Munich; Department of Hematology and Oncology, University of Dresden; Department of Medicine-Hematology, Oncology, University of Freiburg; Department of Hematology and Oncology, University Regensburg, Germany; Acute Leukemia Working Party-European Group of Blood and Marrow Transplantation; Hôpital Saint-Antoine AP-HP et Université Pierre et Marie Curie; Bone Marrow Transplant Unit, Hôpital Saint Louis, Université de Paris 7, Paris; Unité de transplantation médullaire, Hôpital d'enfants de Brabois-Médecine Infantile II, Vandoeuvre Les Nancy, France; Chaim Sheba Medical Center, Tel-Aviv University, Tel-Hashomer, Israel; George Papanicolaou General Hospital, Thessaloniki, Greece; Department of Medicine, Helsinki University Central Hospital, HUS Helsinki, Finland; Adult Stem Cell Transplantation Unit, Ankara University, Faculty of Medicine, Ankara, Turkey; and the Department of Hematology, University Hospital Gasthuisberg, Leuven, Belgium
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ABSTRACT
INTRODUCTION
16 years; allogeneic HSCT for AML in 1990 or after; first hematological relapse after HSCT; and survival from post-transplant relapse of 
2 test for categoric and the Mann-Whitney test for continuous variables. Variables considered were: recipient age at time of transplantation, sex, disease characteristics (FAB, white blood count at diagnosis, cytogenetics), donor characteristics (type, age, sex, HLA compatibility), transplant characteristics (year of transplant, disease status at transplant, conditioning, source of stem cells, acute GVHD [aGVHD] and/or chronic GVHD [cGVHD] before DLI), and relapse characteristics (interval from transplant to relapse, blasts in BM or PB at relapse, chemotherapy, DLI, and second transplant after relapse). For continuous variables, the median was used as cutoff point. DLI and second transplants were studied as time-dependant variables. 
