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Originally published as JCO Early Release 10.1200/JCO.2008.12.6219 on December 10 2007 © 2008 American Society of Clinical Oncology. High-Dose Therapy and Autologous Stem-Cell Transplantation in Angioimmunoblastic Lymphoma: Complete Remission at Transplantation Is the Major Determinant of Outcome—Lymphoma Working Party of the European Group for Blood and Marrow Transplantation
From the University College London; European Bone Marrow Transplantation Group, London; and Leicester Royal Infirmary, Leicester, United Kingdom; Hospital Clínico Servicio de Hematología, Salamanca; and Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; University Hospital, Dept. of Hematology; and University Hospital, Department of Medicine, Uppsala, Sweden; University of Freiburg, Department of Medicine -Hematology, Oncology, Freiburg; Medical Klinik, Wurzburg; University of Münster, Department of Hematology/Oncology, Münster; Klinikum Grosshadern, Munich; Heinrich Heine Universität, Düsseldorf; and Klinikum Oldenburg, Abt Onkologie/Hämatologie, Oldenburg, Germany Corresponding author: Charalampia Kyriakou, MD, University College London, 4 Sentis Court, 8 Carew Rd, Northwood, Middlesex, United Kingdom HA6 3NG; e-mail: c.kyriakou{at}btinternet.com
Purpose Patients with angioimmunoblastic T-cell lymphoma (AITL) have poor prognoses with current conventional chemotherapy. The aim of this study was to evaluate the effect of high-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) on patients with AITL. Patients and Methods We report a retrospective, multicenter study of 146 patients with AITL who received ASCT. The source of the stem cells was peripheral blood in 143 patients. The conditioning regimen varied, and 74% of the patients received carmustine and 1,3-bis(2-chloroethyl)-1-nitrosourea; etoposide; ara-C; and melphalan chemotherapy. Results After a median follow-up of 31 months (range, 3 to 174 months), 95 patients (65%) remained alive, and 51 patients (35%) died. Forty-two patients died as a result of disease progression, and nine died as a result of regimen-related toxicity. The cumulative incidence of nonrelapse mortality was 5% and 7% at 12 and 24 months, respectively. The actuarial overall survival (OS) was 67% at 24 months and 59% at 48 months. The cumulative incidence of relapse was estimated at 40% and 51% at 24 and 48 months, respectively. Disease status at transplantation was the major factor that impacted outcome. Patients who received a transplant during first complete remission (CR) had significantly superior progression-free survival and OS. The estimated PFS rates for patients who received their transplants in CR were 70% and 56% at 24 and 48 months, respectively; 42% and 30% for patients with chemotherapy-sensitive disease at those time points, respectively; and 23% at both time points for patients with chemotherapy-refractory disease. Conclusion This study shows that HDT and ASCT offers the possibility of long-term disease-free survival to patients with AITL. Early transplantation is necessary to achieve optimal results.
Angioimmunoblastic T-cell lymphoma (AITL) is a rare subtype of lymphoma that represents 1% to 2% of non-Hodgkin's lymphoma (NHL).1,2 Although initially classified as a low-grade lymphoma, it is now evident that AILT usually follows an aggressive course, with short disease-free and overall survival (OS).3 By using current therapeutic approaches, less than 50% of patients with AITL achieve a complete remission (CR), and the estimated median survival is 18 months.4 Published data about treatment outcomes are quite limited because of the rarity of the disease. Single-agent steroids, cytotoxic drugs, or combination chemotherapeutic regimens, such as cyclophosphamide, doxorubicin, vincristine, prednisone5; vincristine, doxorubicin, and prednisolone6,7; and cyclophosphamide, vincristine, prednisolone, bleomycin, doxorubicin, procarbazine, ifosfamide, methotrexate, and etoposide,8 have all failed to increase the response and survival rate of patients with AITL to more than 30%. Low-dose methotrexate together with steroids,9,10 fludarabine or 2-chlorodeoxyadenosine,11-13 interferon-alfa (IFN-alpha),14-18 cyslosporine,19-21 or thalidomide22,23 have been reported to have efficacy in AITL, but no consensus exists to determine if any of these agents improve outcomes more than conventional treatment. Published information on the role of high-dose therapy (HDT) with autologous stem-cell transplantation (ASCT) for AITL is limited to a single study by Schetelig et al.24 on 29 patients. In this article, we summarize the results from the largest cohort so far reported, which consisted of 146 patients with AITL who underwent HDT with ASCT (HDT-ASCT) of hematopoietic stem cells reported to the European Group for Bone and Marrow Transplantation (EBMT).
Patient Selection and Investigation Patients with a confirmed diagnosis of AITL, as defined by WHO classification, who received a first ASCT and were reported to the EBMT Lymphoma Registry until December 2004, were analyzed. All EBMT centers were invited to contribute data to the current study. Data from participating centers were derived from both the EBMT database and additionally from questionnaires distributed to each center to obtain missing data. Minimum data required for the inclusion of a patient in the study were age, date of diagnosis, disease status at transplantation, source of stem cells, date of transplantation, conditioning regimen, Karnofsky performance status, and outcome after ASCT with a minimum follow-up of 3 months. Additional data studied were disease stage at diagnosis, lactate dehydrogenase (LDH) levels, size of largest mass, "B" symptoms, conventional chemotherapy treatment details, and response. Histologic diagnoses that had been made by a national lymphoma pathology group were accepted without further review. If the material was not available and a detailed report from an expert hematopathologist was not available, the case was excluded from further study. From the initial cohort of 183 patients with AITL undergoing a first ASCT from January 1992 to December 2004, 146 patients from 100 EBMT centers were included in the final study.
Response Criteria
Statistical Analysis
Patient and Disease Characteristics One hundred EBMT centers contributed data on 146 patients with AITL who received HDT followed by ASCT between 1992 and 2004. Baseline patient data and disease characteristics are listed in Table 1. Seventy-three percent of the patients initially presented with an advanced disease stage (IV); 81% had B symptoms; and 68% had elevated LDH levels. Twenty-five patients (22%) received one, whereas 86 patients (78%) required two or more, treatment lines before HDT. The majority of patients (83%) received anthracyclin-containing regimens as first-line therapy. Cyclophosphamide, etoposide, DHAP (dexamethasone, ara-C, cisplatin), Dexa-BEAM (dexamethasone; carmustine and 1,3-bis(2-chloroethyl)-1-nitrosourea [BCNU]; etoposide; ara-C; melphalan), IVE, (ifosfamide, etoposide, epirubicin) ICE (ifosfamide, carboplatin, etoposide), or ESHAP (etoposide, ara-C, cisplatin, methylprednisolone) in combination with granulocyte colony-stimulating factor were used for mobilization of stem cells before harvest, according to center preference.
The median age at transplantation was 53 years (range, 19 to 72 years), and the median time from diagnosis was 9 months (range, 2 to 80 months). At the time of transplantation, 49 patients (33.6%) were in first CR, 21(14.4%) were in second CR, 52 (35.6%) were in PR, 4 (2.7%) were in chemotherapy-sensitive relapse, and 20 (13.7%) underwent transplantation with chemotherapy-refractory disease (of which seven were considered primary refractory and 13 were considered relapse/progression). Overall, 126 patients (86%) had chemotherapy-sensitive disease, whereas 20 (14%) had refractory disease at transplantation. Karnofsky performance status was greater than 80% in all but seven patients who underwent transplantation with a poor performance status (score, 60 to 80). One hundred and thirty-one patients (90%) received HDT without total-body irradiation (TBI), whereas 15 (10%) had a combination of chemotherapy with TBI. Conditioning regimens varied depending on the center preference; 74% of the patients received BEAM (BCNU, etoposide, ara-C, and melphalan) chemotherapy. Other regimens used were TBI/cyclophosphamide ± etoposide (n = 15), CBV (cyclophosphamide, BCNU, and etoposide; n = 3), BEAC (BCNU, etoposide, ara-C, cyclophosphamide; n = 8), BECYM (BCNU, etoposide, cyclophosphamide, melphalan; n = 4), BuEAM (busulfan, etoposide, ara-C, melphalan; n = 3), ME (melphalan, etoposide; n = 2), and CET (carboplatin, etoposide, thiotepa; n = 3). The stem cells were obtained from peripheral blood in 143 patients and from bone marrow in three patients. Patients who received transplantation in first CR were those with an advanced disease stage at diagnosis (stage IV, 72%) or with high-risk features (B symptoms, 87%; elevated LDH, 64%; or required two or more lines of treatment to achieve a CR, 50%).
Disease Response to Transplantation and Outcome
After a median follow-up of 31 months (range, 3 to 174 months) for the surviving patients, ninety-five patients (65%) were alive. The estimated OS rates at 24 and 48 months were 67% and 59%, respectively (Fig 1A). Seventy patients (48%) were alive and remained progression-free, and estimated PFS rates at 24 and 48 months were 53% and 42%, respectively (Fig 1B). Sixty-seven patients (46%) had relapsed or progressed, and the median time from transplantation to relapse was 7 months (range, 1 to 63 months). Fifty-one patients (35%) died, and 42 of these deaths (29% of total patients) were from disease progression. The cumulative incidence of relapse was 40% and 51% at 24 and 48 months, respectively. Nine patients died without disease relapse or progression, which lead to a cumulative incidence of NRM of 5% and 7% at 12 and 24 months after ASCT, respectively. There were two early deaths on days 2 and 5 post-transplantation, and these were not assessable for engraftment. Engraftment was successful in all but two patients who, although they had received adequate doses of CD34+ cells, failed to engraft and died as a result of infectious complications. One patient died as a result of esophageal cancer 34 months after transplantation.
Prognostic Factors for NRM, RR, PFS, and OS To ascertain which factors may significantly affect outcome, both univariate and multivariate Cox regression analyses were performed (Table 3). NRM was significantly influenced by age and disease status at ASCT. Patients older than 60 years (P = .02) and those who underwent transplantation with chemotherapy-refractory disease (P = .003) showed significantly greater transplant-related complications. Patients who underwent transplantation with a poor performance status showed a trend towards greater NRM (P = .1).
According to multivariate analysis, disease status at the time of transplantation remained the most significant factor that influenced outcome. Chemotherapy-refractory disease at the time of transplantation was associated with a greater relapse rate compared with patients who received transplantation while in CR (P = .01). Similarly, chemotherapy-sensitive disease at the time of transplantation was associated with a greater relapse rate compared with patients who received transplantation while in CR (P = .01). Relapse rates at 24 and 48 months were 29% and 42%, respectively, for patients in CR, were 52% and 64%, respectively, for those with chemotherapy-sensitive disease, and were 48% and 60%, respectively, for the chemotherapy-refractory patients. Patients who received two or more treatment lines before HDT had significantly greater relapse rates (P = .03) compared with the ones entering the transplant procedure after completing only one previous therapy. Patients who presented with advanced disease at diagnosis showed a trend towards greater relapse (P = .08) compared with patients who had early-stage disease. Patients who received TBI-based conditioning regimens had a lower relapse rate after HDT-ASCT (P = .04). The characteristics of this group of patients were comparable to the remaining patients in the study (CR1, n = 7; CR2, n = 1; PR, n = 6; PD, n = 1). Disease status at transplantation was the major factor that predicted PFS. Patients with CR had a significantly longer time to progression compared with those who had chemotherapy-refractory disease (P < .001) or chemotherapy-sensitive disease (P < .001). The estimated PFS rates for patients who received their transplantation while in CR were 70% and 56% at 24 and 48 months, respectively; the rates were 42% and 30%, respectively, for patients with chemotherapy-sensitive and were 23% and 23%, respectively, for patients with chemotherapy-refractory disease (Fig 2A). Requiring two or more treatment lines before ASCT significantly worsened the PFS (P = .04). TBI in the conditioning regimen was associated with a trend to improved PFS (P = .07).
OS was superior in patients who underwent ASCT in CR compared with those who had chemotherapy-sensitive (P = .006) and with those who had chemotherapy-refractory disease (P < .0001; Fig 2B). The estimated OS rates at 24 and 48 months were 81% and 78%, respectively, for the patients in CR compared with 60% and 47%, respectively, for patients with chemotherapy-sensitive disease and 38% and 25%, respectively, for the chemotherapy-refractory patients. Patients who had elevated LDH levels at diagnosis, who had poor performance status at transplantation, and who received two or more treatment lines before transplantation had worse OS.
AITL primarily affects the elderly, mostly presents as advanced disease, and is characterized by aggressive behavior and a poor outcome. The best approach for treating patients with AITL is still unknown. Various treatment strategies, which range from the watch-and-wait method to combinations of chemotherapeutic agents, have been tested and have proved to be largely unsuccessful in curing the disease. The large Group d’ Edutes des Lymphoma de l’Adulte study on T-cell lymphomas reported a 42% CR rate for patients with AITL and an OS at 5 years of 31%.3 Other studies on T-cell lymphomas have consistently reported poor outcomes for patients with AITL.2,3,29,30 The possible benefit of HDT-ASCT for patients with AITL was initially suggested from case reports, in which prolonged PFS post-HDT was observed.5,8,31-34 A retrospective analysis of 64 patients with AITL showed good initial overall response (81%) to conventional chemotherapy.35 However, this was transient, and early relapse or progression led to an OS less than 30% at 4 years. The application of HDT in 22 patients in the same study resulted in significantly longer time to progression compared with the patients treated with conventional chemotherapy only. Another study that reported on a relatively high number of patients with HDT-ASCT (29 patients) demonstrated an encouraging response rate of 76%, including PFS and OS rates at 5 years of 37% and 44%, respectively.24 This study reports the outcome of HDT-ASCT for the largest cohort of patients with AITL assessed to date. We report a high (77%) response rate to a well-tolerated procedure. At 2 and 4 years after transplantation, OS was 67% and 59%, respectively, and the PFS rate was 53% and 42%, respectively. This outcome may be better than that reported for conventional chemotherapy. Within a median follow-up of 31 months, 48% of the patients were alive and free of progression. Disease status at the time of HDT represented the major predictive factor for important outcome parameters. Patients who received ASCT in CR had significantly lower relapse rates, which led to longer times to progression and better OS. In a subanalysis of the patients who received HDT in first CR (n = 49), 34 patients (69%) were alive and in CR. Fifteen patients (31%) relapsed, and 10 of these patients died as a result of disease progression. Patients who required two or more therapy lines to achieve a CR before ASCT (n = 16) had a trend toward shorter times to progression compared with those who had received only one therapy line. This had no impact on the OS of this subgroup of patients. Most of the patients who received a transplantation fell into the high-intermediate and high-risk categories based on the International Prognostic Index at presentation. Therefore International Prognostic Index score could not define the high-risk group as predictive for response to treatment or survival. Interestingly, 15 patients with comparable patient and disease characteristics to other patients in the group received TBI-based conditioning (CR1 n = 7, CR2 n = 1, PR n = 6, PD, n = 1). Patients conditioned with TBI had a lower relapse rate and a trend toward a greater PFS. The worst outcome was observed in patients with chemotherapy-refractory disease who underwent transplantation, the majority of whom failed to respond to HDT. Even in the small number of patients who were rescued by HDT-ASCT, a response was not maintained. Although the number of patients with chemotherapy-refractory disease who underwent transplantation was low, this observation raises the question as to whether HDT-ASCT should be offered to this poor-risk subgroup of patients with AITL. The NRM is greater than that reported for high-grade B-cell lymphoma and may be attributed to chemotherapy-refractory disease, extensive pretreatment, poor performance status at SCT, and advanced age of the patients (seven of these nine affected patients were older than 62 years). None of the patients who received ASCT in CR1 died as a result of procedure-related complications. Bacterial infection leading to multiorgan failure was the cause of death in eight patients; one patient experienced engraft failure and succumbed to fungal infection. Our observations also demonstrate that there may be a role for TBI-based conditioning in AITL. Fifteen patients received TBI-based conditioning. These patients had comparable characteristics with those of the non-TBI group and had significantly lower relapse rates. The data suggest that new treatment approaches that incorporate TBI, perhaps a combination of radiotherapy with radiosensitizing chemotherapy, should be evaluated. To answer this question, a randomized trial would be necessary. This study again showed that patients with chemotherapy-sensitive disease at the time of transplantation have a better outcome than chemotherapy-refractory ones; the best outcome was seen in patients who could receive transplantation in CR. This observation would suggest the use of HDT-ASCT early, as soon as maximum response is achieved.36-38 The majority of patients with AITL are older than 50 years at presentation. In this study, 62% of the patients were older than 50 years at the time of transplantation, and 25% were older than 60 years. Overall, NRM was still low (5% and 7% at 12 and 24 months, respectively) and did not call for an age restriction for ASCT. In contrast, patients older than 60 years generally are not deemed good candidates for allogeneic transplantation; however, with reduced-intensity conditioning regimens, the age limit has increased. Data for allogeneic transplantation in younger patients with AITL38were encouraging, but patient numbers were low and no patients in first CR were included. At this time, therefore, it remains to be settled if allogeneic transplantation would offer any benefit over autologous transplantation in younger patients with AITL. We conclude that HDT-ASCT plays an important role in the management of AITL and should be considered early in the course of the disease, as a soon as maximum response to conventional chemotherapy has been achieved. To shed light on the best treatment strategy for younger patients with T-cell lymphoma, including AITL, the EBMT together with the German High-Grade Lymphoma Study Group, is about to launch a prospective, randomized study that will compare the efficacy of HDT-ASCT with allogeneic transplantation after reduced-intensity conditioning in patients who respond to conventional chemotherapy. Other new therapies using gemcitabine as single agent,39 506U78 compound a deoxyguanosine analog,40 denileukin difitox,41 or alemtuzumab as single agent42 or in combination with fludarabine, cyclophosphamide and doxorubicin43 also are being explored currently. AITL is a rare disease; therefore, prospective, multicenter clinical trials remain critically important for determining the most effective regimens that will continue to improve cure rates in this aggressive disease.
The author(s) indicated no potential conflicts of interest.
Conception and design: Charalampia Kyriakou, Anthony Goldstone, Norbert Schmitz Provision of study materials or patients: Anthony Goldstone, Dolores Cabalero, Bernd Metzner, Guido Kobbe, Hans-Jochem Kolb, Joachim Kienast, Peter Reimer, Jurgen Finke, Gunnar Oberg, Ann Hunter, Niklas Theorin Collection and assembly of data: Charalampia Kyriakou, Guido Kobbe Data analysis and interpretation: Charalampia Kyriakou, Carmen Canals, Anna Sureda, Norbert Schmitz Manuscript writing: Charalampia Kyriakou, Anthony Goldstone, Anna Sureda, Norbert Schmitz Final approval of manuscript: Charalampia Kyriakou, Carmen Canals, Anthony Goldstone, Dolores Cabalero, Bernd Metzner, Guido Kobbe, Hans-Jochem Kolb, Joachim Kienast, Peter Reimer, Jurgen Finke, Gunnar Oberg, Ann Hunter, Niklas Theorin, Anna Sureda, Norbert Schmitz
We thank G. Taghipour, registry manager for the Lymphoma Working Party, who collected the data.
published online ahead of print at www.jco.org on December 10, 2007. C.K., A.S., and N.S. shared primary responsibility for drafting the manuscript. C.C. performed the statistical analyses; all authors contributed data and discussed the final manuscript. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
50% response to treatment; refractory disease (RD), if the response was 50%; and progressive disease (PD), if there was 
