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Originally published as JCO Early Release 10.1200/JCO.2007.14.1366 on April 7 2008 © 2008 American Society of Clinical Oncology. Graft-Versus-Lymphoma Effect for Aggressive T-Cell Lymphomas in Adults: A Study by the Société Française de Greffe de Moëlle et de Thérapie Cellulaire
From the Hematology Department; Service de la recherche bio-médicale, Centre Hospitalier Universitaire, Hôtel-Dieu, Nantes; Hematology Department, Centre Hospitalier Universitaire Haut-Lévêque, Pessac; Hematology Department, Hôpital Necker-Enfants malades; Service de greffe de moelle osseuse, Hôpital Saint-Louis; Hematology Department, Hôpital de la Pitié-Salpetrière; Hematology Department, Hôpital Hôtel-Dieu; Hematology Department, Institut Curie, AP-HP, Paris; Unité de transplantation et de thérapie cellulaire, Institut Paoli-calmette, Marseille; Hematology Department, Medical University, Angers; Hematology Department, Centre Hospitalier Universitaire, Grenoble; Hematology Department, Hôpital Henri Mondor, AP-HP, Creteil; Hematology Department, Medical University, Nice; Hematology Department, Medical University, Lille; Hematology Department, Medical University, Toulouse; Hematology Department, Medical University, Clermont-Ferrand; Hematology Department, Institut Gustave-Roussy, Villejuif; and the Unité de Greffe de Moelle Osseuse, Centre Hospitalier Universitaire, Lyon, France Corresponding author: Steven Le Gouill, MD, PhD, Hematology Department, University Hospital, Hôtel-Dieu, Nantes, France; e-mail: steven.legouill{at}chu-nantes.fr
Purpose Aggressive T-cell lymphomas (ATCLs) represent 10% to 15% of non-Hodgkin's lymphomas (NHLs) in adults. ATCLs show a worse prognosis than B-cell lymphomas. Patients and Methods On behalf of the Société Française de Greffe de Moëlle et de Thérapie Cellulaire, we conducted a retrospective analysis including 77 ATCL patients who underwent allogeneic stem-cell transplantation (alloSCT).
Results The different diagnosis included anaplastic large-cell lymphoma (ALCL; n = 27), peripheral T-cell lymphoma not otherwise specified (PTCL-NOS; n = 27), angioimmunoblastic T-cell lymphoma (AITL; n = 11), hepatosplenic Conclusion We conclude that alloSCT is a potentially efficient therapy for NK/T lymphomas and is worth further investigation through prospective clinical trials.
Mature peripheral aggressive T-cell lymphomas (ATCLs) include several entities. The WHO classification identifies ATCLs according to histopathologic characteristics and sites of involvement (nodal, extranodal, leukemic, or cutaneous).1 They represent 10% to 15% of non-Hodgkin's lymphoma (NHL) in adults. Anaplastic large-cell lymphoma (ALCL), peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), and angioimmunoblastic T-cell lymphoma (AITL) are the most frequent histologic subtypes. Hepatosplenic  / lymphoma (HSL), T-cell granular lymphocytic leukemia (GLL), nasal natural killer (NK)/T-cell lymphoma (nasal-NK/L) or non-nasal NK/T-cell lymphoma (non-nasal-NK/L), enteropathy-type T-cell, and subcutaneous-like T-cell lymphomas are less frequent. Nasal-NK/L associated with the Epstein-Barr virus and acute T-cell leukemia/lymphoma (ATLL) associated with human T-lymphotropic virus (HTLV) -1 is more frequent in Japan and other Asian nations than in North America and Europe.2 ATCLs have a more aggressive clinical initial presentation than diffuse large B-Cell lymphoma (DLBCL). Stage IV disease including more than one extranodal localization, elevated lactate dehydrogenase (HDL) level, "B" symptoms and hemophagocytosis are frequently observed at diagnosis. Although relevant, the International Prognostic Index (IPI) proved to be less accurate for ATCLs than for DLBCL. Other prognostic indexes have been suggested.3-6 Excluding ALK-positive ALCLs, it is established that T-cell lymphomas have a worse prognosis than DLBCL. Gisselbrecht et al7 reported the experience of the Groupe d'Etude des Lymphomes de l'Adulte (GELA) showing that the 5-year overall survival (OS) and the event-free survival (EFS) rates only reach 41% and 33%, respectively. However, OS and EFS may differ from one ATCL entity to another. Indeed, the median 5-year OS may vary from 60% to 90% in ALK-positive ALCLs to 10% to 45% in ALK-negative ALCLs; 10% to 30% in AICLs and 15% to 35% for PTCL-NOS.8,9 There still is no standardized approach for front-line treatment. Several chemotherapy regimens (with or without monoclonal antibodies), including autologous stem-cell support (autoSCT) or not, have been suggested as part of the frontline therapy. However, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) can still be considered a standard.7,10-13 Because conventional therapies failed to maintain a continued complete remission (CR), allogeneic stem-cell transplantation (alloSCT) may seem a potentially curative therapy. There is evidence of a graft-versus-lymphoma effect indeed, but treatment-related mortality (TRM) stands out as a major limitation. Evidence from alloSCT for ATCL in adults is still limited. Recently, Corradini et al14 reported reduced-intensity conditioning (RIC) alloSCT to be feasible and less toxic than myeloablative alloSCT. The 3-year OS and TRM rates were 81% and 6%, respectively. However, this study was restricted to a series of 17 selected relapsed/refractory patients. Until now, the effectiveness of alloSCT for ATCL patients has been investigated only in small series. We here make a retrospective analysis on 77 ATCL patients having received alloSCT, using data from the Société Française de Greffe de Moëlle-Thérapie Cellulaire (SFGM-TC) register.
Study Design, Inclusion Criteria, Clinical Evaluation, and Data Collection This study is a retrospective analysis using the register of the SFGM-TC. All ATCL patients who underwent alloSCT were included. Patients were treated in 20 French centers between September 1988 and September 2006. Clinical history and presentation, biologic characteristics, histologic subtypes, disease status at time of alloSCT, and transplant procedures were reported by local investigators from each center participating. Before inclusion on the study, each local histopathologist and clinical investigator was requested to confirm the clinical and biologic parameters and the histopathologic subtype for each patient. Lymphoblastic lymphomas and patients younger than 15 years at the time of transplantation were excluded. A minimum follow-up of 90 days was required. Acute and chronic graft-versus-host disease (GVHD) was graded according to the international procedure: grades 0, I, II, III or IV or absent, limited or extensive; respectively.15 CR was defined as the disappearance of all clinical, biologic, and radiologic disorders related to lymphoma. Partial response (PR) was defined as more than 50% reduction of the tumor burden. Progressive disease (PD) was defined as more than 25% increase of the tumor mass. Other cases were defined as stable disease (SD). This study has been approved by a local investigation committee.
Statistical Analysis
The factors assessed in the univariate analysis for potential prognostic significance included the histopathologic subtype, the IPI score at diagnosis (0/1 v > 1 and 0/1/2 v > 2), the number of therapy lines before alloSCT ( Variables found to be statistically significant at the P < .05 level were included in the multivariate analysis. For multivariate analysis, P < .05 was considered significant. Assumption of proportional hazards was tested for all factors. Interaction with histopathologic subtypes was tested. The statistical analysis was performed using SAS software version 9.1 (SAS Institute, Cary, NC).
Patient Characteristics Patient characteristics according to histopathologic subtypes are summarized in Table 1. Ninety-six patients were initially selected. Nineteen cases were excluded from the analysis because of an unconfirmed diagnosis (n = 13) or insufficient data (n = 6). The final analysis was restricted to the 77 remaining cases.
The median age at diagnosis was 36 years (range, 12 to 61 years). There was a majority of male patients (66%). The main histopathologic subtypes were ALCL in 27 cases (35%), PTCL-NOS in 27 cases (35%), and AITL in 11 cases (14%). Other histologic subtypes were HSL in three cases, T-GLL in one case, nasal-NK/L in three cases, non-nasal-NK/L in two cases, enteropathy-type T-cell in one case, and HTLV-1 lymphoma in two cases. At the time of diagnosis, 64 patients (data missing in six cases) had a stage III or IV disease. Forty-one patients had elevated LDH in the serum (data missing in 19 cases). Only 17 patients did not show evidence of extra-nodal localization. More than one extranodal localization was observed in 25 cases (35%; data missing in six cases). The IPI score was at least 1 in 47 cases and more than 2 in 33 cases (data missing in 19 cases). The ALK status for ALCL patients was known in 14 cases and found positive in eight cases. All patients received at least one line of therapy before alloSCT. Prior therapies included autoSCT in 25% cases. The median number of prior therapies was two (range, one to five). Forty-five patients reached CR with conventional therapy, but 59% subsequently experienced relapse before alloSCT. We first compared patient characteristics (age at diagnosis, sex, stage, IPI score > 1, number of therapies before alloSCT, autoSCT before alloSCT, and CR before alloSCT) according to histopathologic subtype. The ALCL patients were younger than the other entities at diagnosis: 28 years for ALCL versus 47 years for AITL, 41 years for PTCL-NOS and 35 years in the other cases (P = .0006).
Transplant Conditioning and Post-AlloSCT Response
Fifty-seven patients (74%) received myeloablative conditioning regimens (based on total-body irradiation in 66%), whereas twenty-six percent underwent a so-called RIC regimen. The source of stem cells was BM in 52 cases and PB in 24 cases. One patient underwent an allogeneic double human cord blood transplantation. Donors were related and HLA identical in 60 cases, HLA identical and unrelated in 10 cases, and unrelated HLA mismatched in seven cases. GVHD prophylaxis was cyclosporine/methotrexate in 65% of the cases. At transplantation, ALCL patients were younger than AITL patients (P = .003) and PTCL-NOS patients (P = .004). The source of stem cells was BM more frequently in ALCL than in PTCL (P = .002). The cytomegalovirus (CMV) status of the donor was different in PTCL-NOS and AITL versus other histologic subtypes (P = .046 and .029, respectively). However, these parameters had no significant impact on OS, EFS, or TRM.
Survival and EFS The 5-year OS and EFS rates were 57% (95% CI, 45% to 68%) and 53% (95% CI, 41% to 64%), respectively (Fig 1A). According to the histopathologic subtypes, the 5-year OS and EFS rates were 80% (95% CI, 39% to 94%) and 80% (95% CI, 39% to 94%) for AITL patients, 63% (95% CI, 41% to 79%) and 58% (95% CI, 35% to 75%) for PTCL patients, 55% (95% CI, 35% to 72%), and 48% (95% CI, 28% to 65%) for ALCL patients, respectively (Fig 1B). The 5-year OS for other histopathologic subtypes (n = 12) was 33% (95% CI, 8% to 58%), and four of these patients are still alive in CR (HSL in two cases; T-GLL in one case and nasal-NK/L in one case). All patients who could not achieve CR after alloSCT died within 10 months as a result of disease progression.
Interestingly, two patients received donor lymphocyte infusions (DLIs) and both reached a second CR. They were in continuous CR more than 2 years post-DLI. One patient underwent a second alloSCT and relapsed.
GVHD, Toxicity, and TRM
Univariate and Multivariate Analysis for OS, EFS, and TRM Univariate and multivariate analyses for OS, EFS, and TRM Are summarized in Table 3. The univariate analysis showed no statistical difference for OS, EFS, and TRM according to histopathologic subtypes and IPI score. Three parameters had an impact on both OS and EFS: the number of chemotherapy lines before alloSCT (  2 v > 2), the disease status at transplantation (chemosensitive v chemoresistant disease; Fig 3), and the occurrence of grade 3 to 4 aGVHD. Improved OS and EFS rates were observed in patients who received two or fewer lines of chemotherapy before alloSCT: 73% (95% CI, 57% to 84%) versus 39% (95% CI, 20% to 57%) for OS (P = .003) and 71% (95% CI, 55% to 82%) versus 28% (95% CI, 11% to 47%) for EFS (P = .0009), respectively. The OS and EFS rates were significantly higher for CR/PR versus SD/PD/relapse: 69% (95% CI, 54% to 80%) versus 29% (95% CI, 11% to 50%) for OS (P = .0003) and 64% (95% CI, 49% to 76%) versus 27% (95% CI, 10% to 46%) for EFS (P = .0002), respectively. Patients with a severe grade 3 to 4 aGVHD had a worse OS and EFS than other patients: 25% (95% CI, 8% to 47%) versus 66% (95% CI, 52% to 77%) for OS (P = .0001), and 25% (95% CI, 8% to 47%) versus 61% (95% CI, 47% to 73%) for EFS (P = .004), respectively.
The 5-year OS was best with a male donor and a female patient:50% (95% CI, 37% to 63%) versus 86% (95% CI, 55% to 96%; P = .03). The 5-year OS was better with an HLA-matched donor: 61% (95% CI, 48% to 71%) versus 19% (95% CI, 1% to 56%; P = .025). For patients without an HLA-matched donor, deaths occurred within 100 days after transplantation in 75% of the cases, and 50% of the patients experienced aGVHD grade 3 to 4. On the contrary, the age at the time of alloSCT, the time between diagnosis and alloSCT, the event of autoSCT prior alloSCT, the source of stem cells and the CMV serostatus had no impact on the 5-year OS. For ALCL patients, the ALK status had no impact (data not shown). The 5-years TRM incidence was higher in patients receiving more than two lines of chemotherapy before alloSCT (23% (95% CI, 13% to 39%) versus 51% (95% CI, 33% to 72%; P = .012). The 5-years TRM incidence was also higher for patients with a grade 3 to 4 aGVHD 63% (95% CI, 38% to 87%) versus 27% (95% CI, 17% to 40%; P = .012), for patients with a chemo-resistant disease at the time of alloSCT (28% (95% CI, 17% to 43%) versus 47% (95% CI, 28% to 70%; P = .037) and for patients receiving a graft from an HLA-mismatched donor 29% (95% CI, 20% to 42%) versus 81% (95% CI, 44% to 99%; P = .006). There was a trend of increased TRM for patients whose delay between diagnosis and alloSCT more than 12 months (P = .082), patients with a positive CMV serostatus (P = .082) and patients with an unrelated donor (P = .071). With multivariate analysis, both grade 3 to 4 aGVHD and chemoresistant disease at time of alloSCT had a negative prognostic value for OS. The only parameter affecting EFS was the disease status (P = .003). Five-year TRM was higher for patients with a HLA-mismatched donor (related or unrelated; P = .039). There was a trend for a higher TRM for patients with grade 3 to 4 aGVHD (P = .089).
We showed that nearly 60% of the patients reached disease-free survival after alloSCT, with a plateau likely to be reached 18 months after alloSCT. Only five of the 59 patients in CR after alloSCT experienced a relapse. We did not observe a better OS or EFS for patients with a aGVHD grade1/2 than for patients without aGVHD (P = .5). However, two patients received DLI at time of relapse and both reached a second durable CR. We noted that the 5-year OS rate for chemoresistant patients also was encouraging (29%). These patients could not be cured with conventional approaches and benefited from alloSCT. All together, this suggests that a graft-versus-ATCL effect may play a major role in the curative potential of alloSCT. This observation is in line with results reported by other groups.14,16 We observed a trend of longer OS and EFS for ALCL, AITL, or PTCL patients than for the so-called "other histopathologic subtypes." As opposed to patients treated with chemotherapy alone, the histopathologic subtypes did not significantly influence OS, EFS, or TRM in patients receiving alloSCT.17-19 We noted that the largest histopathologic subgroup, which contained 27 PTCL-NOS patients, had a 5-year OS rate of 63%, which triggers the interest for an allogeneic approach of this disease. Because the group of so-called "other" ATCL was heterogeneous, it is difficult to state the role of alloSCT. Of the three reported HSL patients, two reached CR and did not relapse. HSL is known to have a dismal outcome with conventional therapy.20 Our results suggest that alloSCT is probably the only curative therapy for these patients. The two patients with HTLV-1 lymphomas died because of TRM. However, other clinical studies have demonstrated the effectiveness of allo-SCT in HTLV-1 lymphomas.21,22 Few other studies addressed the role of allo-SCT in ATCL T/NK NHL.14,16,23,24 However, these studies underlined the high rate of TRM (except in Corradini's report).14 The obstacles for alloSCT are similar with ATCL than with other hematologic malignancies: the identification of an HLA-identical donor and the high risk for TRM. The Italian study showed that RIC alloSCT could reduce the TRM rate dramatically, down to 6%. In univariate analysis, our analysis also showed a trend for a longer EFS and less TRM in RIC alloSCT (P = .108 and .107, respectively). The other major issue is determining when alloSCT should be performed. At the time of relapse, ATCLs frequently show a rapid dismal clinical course with chemoresistant diseases excluding alloSCT. In our series, we show that better OS and EFS rates were obtained for patients receiving two or fewer lines of therapy before alloSCT. There also was a trend for a better TRM rate when time from diagnosis to alloSCT was less than 12 months (P = .082). All together, these results may suggest that alloSCT should be done at an early stage in the chemosensitive disease course. Novel agents triggering therapeutic targets have shown some efficiency, but the preliminary studies included only a limited number of patients.25-28 In contrast, our report—and reports by others—provides solid results showing that alloSCT probably is the only curative treatment for a majority of ATCL, including relapsed ALK-positive ALCL. However, greater efforts are required to reduce TRM incidence. There is some evidence that RIC might help reduce TRM incidence. Thus, a reduction of the tumor burden by conventional chemotherapy followed by RIC alloSCT might be a good approach upfront.
The author(s) indicated no potential conflicts of interest.
Conception and design: Steven Le Gouill Collection and assembly of data: Steven Le Gouill, Noel Milpied, Agnes Buzyn, Régis Peffault De Latour, Jean-Paul Vernant, Mohamad Mohty, Marie-Pierre Moles, Krimo Bouabdallah, Claude-Eric Bulabois, Jehan Dupuis, Bernard Rio, Nicole Gratecos, Ibrahim Yakoub-Agha, Michel Attal, Olivier Tournilhac, Didier Decaudin, Jean-Henry Bourhis, Didier Blaise, Mauricette Michallet Data analysis and interpretation: Steven Le Gouill, Noel Milpied, Agnès Buzyn, Mohamad Mohty, Bernard Rio, Christelle Volteau Manuscript writing: Steven Le Gouill, Noel Milpied, Agnes Buzyn, Régis Peffault De Latour, Mohamad Mohty Final approval of manuscript: Steven Le Gouill, Noel Milpied, Agnes Buzyn, Régis Peffault De Latour, Didier Blaise, Mauricette Michallet
The following coauthors also contributed to the work: Jean-Luc Harousseau, Hematology Department, Nantes; Nathalie Contentin, Hematology Department, Rouen; Francis Witz, Hematology Department, University Hospital Nancy, Nancy; and Gaelle Guillerm, Institut d'Hématologie et de Cancérologie, University Hospital Brest, France.
published online ahead of print at www.jco.org on April 7, 2008 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
40 years), the duration from diagnosis and alloSCT (< 12 v 
