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Journal of Clinical Oncology, Vol 22, No 11 (June 1), 2004: pp. 2172-2176 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.12.050 Graft-Versus-Lymphoma Effect in Relapsed Peripheral T-Cell Non-Hodgkin's Lymphomas After Reduced-Intensity Conditioning Followed by Allogeneic Transplantation of Hematopoietic CellsFrom the Divisions of Hematology and Medical Oncology, Istituto Nazionale Tumori, University of Milano, and the Department of Hematology, H.S. Raffaele, Milan; the Department of Hematology, University of Torino, Torino; the Department of Hematology, Ospedale Regionale, Bolzano; the Department of Hematology, University of Modena, Modena; the Department of Hematology, University of Udine, Udine; the Department of Hematology, University of Verona, Verona; and the Department of Hematology, Ospedali Riuniti Bergamo, Bergamo, Italy Address reprint requests to Paolo Corradini, MD, Division of Hematology-Bone Marrow Transplantation, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via Venezian, 1, 20133 Milano, Italy; e-mail: paolo.corradini{at}unimi.it
PURPOSE: Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of malignancies characterized by a poor prognosis. We performed a pilot study to investigate the role of reduced-intensity conditioning (RIC) followed by allogeneic stem-cell transplantation in relapsed or refractory PTCLs. PATIENTS AND METHODS: We have conducted a phase II trial on 17 patients receiving salvage chemotherapy followed by RIC and allogeneic transplantation of hematopoietic cells. The RIC regimen consisted of thiotepa, fludarabine, and cyclophosphamide. The acute graft-versus-host disease prophylaxis consisted of cyslosporine and short course methotrexate. RESULTS: Patients had a median age of 41 years (range, 23 to 60 years). Two patients were primary chemorefractory, and 15 had relapsed disease; eight patients (47%) had a disease relapse after an autologous transplantation. After a median follow-up of 28 months from the day of study entry (range, 3 to 57 months), 14 of 17 patients were alive (12 in complete remission, one in partial remission, and one with stable disease), two died as a result of progressive disease, and one died as a result of sepsis concomitant to acute graft-versus-host disease. The estimated 3-year overall and progression-free survival rates were 81% (95% CI, 62% to 100%) and 64% (95% CI, 39% to 89%), respectively. The estimated probability of nonrelapse mortality at 2 years was 6% (95% CI, 1% to 17%). Donor lymphocyte infusions induced a response in two patients progressing after allografting. CONCLUSION: RIC followed by allogeneic stem-cell transplantation is feasible, has a low treatment-related mortality, and seems to be a promising salvage treatment for relapsed PTCL. These findings suggest that the existence of a graft-versus-T-cell lymphoma effect.
Peripheral T-cell lymphomas (PTCLs) are a rare and heterogeneous group of malignancies characterized by a poor prognosis. They usually present with advanced-stage disease and two or more adverse prognostic factors according to the International Prognostic Index, and in general, they have a significantly worse outcome compared with patients with aggressive B-cell lymphomas. Gisselbrecht et al1 reviewed the experience of the Groupe d'Etude des Lymphomes de l'Adulte (GELA) and found that PTCL patients receiving anthracycline-containing regimens have a five-year overall (OS) and event-free survival of 41% and 33% respectively.2 In addition, it has been recently shown that relapsed or refractory patients receiving a salvage treatment with high-dose chemotherapy and autologous transplantation have an OS and event-free survival of 48% and 37%, respectively.3 The role of allogeneic stem-cell transplantation (SCT) in the treatment of relapsed lymphomas is still under investigation, but it has been shown itself to be an effective salvage strategy for some patients.4,5 Although allogeneic transplantation with myeloablative conditioning is a potentially curative option, it is associated with an 40% to 50% treatment-related mortality (TRM), which is exceedingly high, and which then limits the widespread application of the procedure. In addition, the TRM is even higher in patients receiving allogeneic transplantation after a failed autograft.6 During the last 5 years, the use of reduced-intensity conditioning (RIC) has shown that the morbidity and mortality of allogeneic transplantation can be decreased in older and/or heavily pretreated patients.7–10 This approach might represent an attractive strategy for patients at high-risk of treatment-related toxicities such as relapsed lymphomas. In the present study, we report the results of a pilot study employing RIC followed by allogeneic SCT in PTCLs.
Eligibility Criteria and Patient Characteristics Seventeen consecutive patients undergoing allogeneic SCT were included in this prospective, phase II, multicenter study. The study design was approved by the ethics committee, and all patients gave written informed consent to participate. The eligible patients were adults younger than 65 years with a biopsy-proven diagnosis of specific variants or unspecified PTCL according to the Revised European-American Lymphoma classification.11 The patients with lymphoblastic lymphoma, anaplastic lymphoma kinase-positive lymphoma, or mycosis fungoides/Sezary syndrome were excluded. Patients who were primary chemorefractory, or who relapsed after first-line conventional chemotherapy or autologous transplantation were considered eligible to the RIC program if they had an HLA-identical donor or a one-antigen mismatched family donor, as determined by molecular typing of HLA A, B, C, DR, and DQ loci. The exclusion criteria were CNS involvement; positive HIV serology; or severe impairment of heart, liver, and pulmonary functions.
Patients had a median age of 41 years (range, 23 to 60 years). Thirteen (76%) of 17 patients had an advanced-stage disease at diagnosis (stage III/IV) and an International Prognostic Index score
Treatment Plan and Stem-Cell Harvesting Debulking chemotherapy before allogenic SCT consisted of 4 to 6 courses of cisplatin 100 mg/ms intravenous continuous infusion on day 1, followed by cytarabine 2 g/m2 every 12 hours on day 2, and dexamethasone 40 mg from days 1 to 4). The RIC regimen has been described in a previous study.10 Briefly, patients received thiotepa 10 mg/kg (day –6), cyclophosphamide 30 mg/kg (days –4 and –3), fludarabine 30 mg/m2 (days –4 and –3), and the transplantation of marrow or mobilized hematopoietic stem cells on day 0. Sibling donors received lenograstim 10 µg/kg subcutaneously from day 1 to day 5. Leukaphereses were performed on days 5 and/or 6, and in four cases, sibling donors underwent bone marrow harvest under general anesthesia.
Graft-Versus-Host Disease Prophylaxis and Supportive Care Patients were treated in laminar airflow rooms. All patients received prophylaxis with cotrimoxazole or pentamidine against Pneumocystis carinii infection. Acyclovir and fluconazole or itraconazole prophylaxis were routinely used. Red cell and platelet transfusions were given to maintain hemoglobin levels above 8 g/dL and platelet count above 10 x 109/L. Blood products were irradiated. Neutropenic patients received broad-spectrum intravenous antibiotics for the management of febrile neutropenia. Lenogastrim at 5 µg/kg per day was administered subcutaneously from day +7 until the neutrophil count was at least 1,000/µL for 3 consecutive days.
Response Criteria and Statistical Analysis
Engraftment and Chimerism All patients who underwent transplantation had a sustained engraftment as defined by neutrophil counts above 0.5 x 109/L and an untransfused platelet count above 20 x 109/L for at least 3 consecutive days. The median time to recover an absolute neutrophil count of 0.5 x 109/L was 14 days (range, 11 to 20 days), and the median time to achieve platelets above 20 x 109/L was 17 days (range, 9 to 50 days). All patients had chimerism studies performed on peripheral blood, using microsatellite polymerase chain reaction or fluorescent in situ hybridization for X and Y chromosomes. Chimerism studies performed on peripheral blood using microsatellite polymerase chain reaction were available for nine patients: eight were full-donor chimeras, and one was mixed chimeric at days +30 and +90 after allograft. The mixed chimera converted to full-donor at day +180.
Toxicity and Nonrelapse Mortality
Disease Response and Survival Analysis Two of 13 patients in CR after transplantation relapsed: one died of disease progression, and one had a PR after DLI. The outcome of the three pretransplantation PR patients progressing after allografting was as follows: one attained CR after DLI, one remained in stable disease after withdrawal of cyclosporine, and one died of disease progression. Overall, four patients received DLIs (three for progressive disease and one for recurrent infections), which were associated with a disease response in two patients, and the resolution of cytomegalovirus reactivation and improvement of immune reconstitution in a third patient (Table 2).
After a median follow-up of 28 months from the day of study entry (range, 3 to 57 days), 14 of 17 patients were alive: 12 in CR, one in PR, and one with stable disease. Two patients died as a result of disease progression, and one died as a result of sepsis concomitant to acute GVHD (Table 2). The estimated 3-year OS and PFS rates were 81% (95% CI, 62% to 100%) and 64% (95% CI, 39% to 89%), respectively (Fig 1).
Allogeneic transplantation can be a curative salvage treatment for relapsed lymphomas. Transplantation efficacy, however, is frequently hampered by its toxicity. Regimen-related toxicity and TRM remain the major obstacles to successfully perform allogeneic SCT. In the present report, we show the results of a pilot study combining RIC and allogeneic transplantation in patients with relapsed or primary refractory PTCLs. The encouraging results, in terms of OS, PFS, and the response to DLIs, suggest the existence of a graft-versus-T-cell lymphoma effect. In intermediate- and high-grade lymphomas, it has previously been demonstrated that myeloablative allogeneic SCT is associated with a lower relapse rate than autologous SCT.4,5 Very few studies, however, have addressed the role of allogeneic SCT in T-cell lymphomas. Dhedin et al performed a retrospective analysis on 73 patients receiving a myeloablative allografting for relapsed T-cell (n = 16) or B-cell aggressive lymphomas (n = 57), and reported 5-year OS and PFS rates of 41% and 40%, respectively. It is noteworthy that the 5-year OS rate was 76% for CR patients receiving allografting. The nonrelapse mortality, however, was quite relevant (44%).13 Rodriguez et al14 performed a myeloablative allogeneic SCT in seven PTCL patients and found that the treatment failure was mainly caused by the treatment toxicity; in fact, four patients died as a result of TRM in CR. Taken together, these studies have suggested a potential role for allogeneic SCT in the salvage treatment of aggressive lymphomas, but have also highlighted that the major concern is the unacceptably high TRM. It has been recently shown that nonmyeloablative or RIC regimens can be used to obtain the engraftment of allogeneic stem cells with a limited organ toxicity, and a rather low TRM. This strategy has been effective in producing clinical and molecular remissions in advanced hematological malignancies.7–10 The experience with RIC regimens in lymphomas is still limited, and in particular, it is unknown which histological subtypes may benefit more from the postulated graft-versus-lymphoma effect. A retrospective analysis by the European Group for Blood and Marrow Transplantation (EBMT), of 188 lymphoma patients, found that the 1-year OS and PFS rates in the subgroup of aggressive non-Hodgkin's lymphomas (both T- and B-cell histologies) were 52% and 32%, respectively.15 The authors observed a higher risk of disease progression in the high-grade, as compared with the low-grade subtypes, and also in the chemoresistant diseases. Furthermore, another recent study has shown that RIC regimens can be safely used to perform allografting in lymphoma patients already experiencing treatment failure with an autologous transplantation.16 Our study shows that nonrelapse mortality can be rather low in a cohort of high-risk patients. The outcome is encouraging since 14 of 17 patients are alive, with 12 of them in CR. In addition, two patients responded to DLI, and one attained stable disease after cyclosporine withdrawal, further suggesting the existence of an ongoing graft-versus-T-cell lymphoma effect. The differences, in terms of outcome, with the EBMT study may be in part explained by the following considerations: (1) they have evaluated the survival of both T- and B-cell histologies all together; (2) in our trial, only one patient received allografting in progressive disease, whereas in the EBMT study, 21% of the patients had a chemorefractory disease; (3) although there were a limited number of patients, our trial was prospective, not retrospective, and all patients received the same conditioning regimen; and (4) debulking chemotherapy was regularly used to induce a tumor response before transplantation. In conclusion, although on a limited number of patients, our study suggests that RIC followed by allogeneic SCT is feasible and effective to rescue relapsed PTCL, at least in those with a chemosensitive disease. Moreover, nonrelapse mortality seems to be lower than with myeloablative transplantations. Based on these findings, large prospective studies should be encouraged, and in addition, patients with an HLA-identical donor and poor prognostic features at diagnosis might be included in investigative trials of RIC followed by allografting.
The authors indicated no potential conflicts of interest.
Supported in part by grants from the Associazione Italiana Ricerca sul Cancro (AIRC); Compagnia di San Paolo, Programma Oncologia; and Fondazione Michelangelo. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Gisselbrecht C, Gaulard P, Lepage E, et al: Prognostic significance of T-cell phenotype in aggressive non-Hodgkin's lymphomas: Groupe d'Etudes des Lymphomes de l'Adulte (GELA). Blood92:76–82, 1998
2. Melnyk A, Rodriguez A, Pugh WC, et al: Evaluation of the Revised European-American Lymphoma classification confirms the clinical relevance of immunophenotype in 560 cases of aggressive non-Hodgkin's lymphoma. Blood89:4514–4520, 1997 3. Song KW, Mollee P, Keating A, et al: Autologous stem cell transplant for relapsed and refractory peripheral T-cell lymphoma: Variable outcome according to pathological subtype. Br J Haematol120:978–985, 2003[CrossRef][Medline]
4. Ratanatharathorn V, Uberti J, Karanes C, et al: Prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with non-Hodgkin's lymphoma. Blood84:1050–1055, 1994
5. Jones RJ, Ambinder RF, Piantadosi S, et al: Evidence of a graft-versus-lymphoma effect associated with allogeneic bone marrow transplantation. Blood77:649–653, 1991 6. Tsai T, Goodman S, Saez R, et al: Allogeneic bone marrow transplantation in patients who relapse after autologous transplantation. Bone Marrow Transplant20:859–863, 1997[CrossRef][Medline] 7. Khouri IF, Keating M, Korbling M, et al: Transplant-lite: Induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol16:2817–2824, 1998[Abstract]
8. Kottaridis PD, Milligan DW, Chopra R, et al: In vivo CAMPATH-1H prevents graft-versus-host disease following nonmyeloablative stem cell transplantation. Blood96:2419–2425, 2000
9. McSweeney PA, Niederwieser D, Shizuru JA, et al: Hematopoietic cell transplantation in older patients with hematologic malignancies: Replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood97:3390–3400, 2001
10. Corradini P, Tarella C, Olivieri A, et al: Reduced-intensity conditioning followed by allografting of hematopoietic cells can produce clinical and molecular remissions in patients with poor-risk hematologic malignancies. Blood99:75–82, 2002
11. Harris NL, Jaffe ES, Stein H, et al: A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood84:1361–1392, 1994
12. Cheson BD, Horning SJ, Coiffier B, et al: Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas: NCI Sponsored International Working Group. J Clin Oncol17:1244–1253, 1999 13. Dhedin N, Giraudier S, Gaulard P, et al: Allogeneic bone marrow transplantation in aggressive non-Hodgkin's lymphoma (excluding Burkitt and lymphoblastic lymphoma): A series of 73 patients from the SFGM database—Société Française de Greffe de Moelle. Br J Haematol107:154–161, 1999[CrossRef][Medline]
14. Rodriguez J, Munsell M, Yazji S, et al: Impact of high-dose chemotherapy on peripheral T-cell lymphomas. J Clin Oncol19:3766–3770, 2001
15. Robinson SP, Goldstone AH, Mackinnon S, et al: Chemoresistant or aggressive lymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor cell transplantation: An analysis from the Lymphoma Working Party of the European Group for Blood and Bone Marrow Transplantation. Blood100:4310–4316, 2002
16. Branson K, Chopra R, Kottaridis PD, et al: Role of nonmyeloablative allogeneic stem-cell transplantation after failure of autologous transplantation in patients with lymphoproliferative malignancies. J Clin Oncol20:4022–4031, 2002 Submitted December 9, 2003; accepted March 12, 2004. Related Correspondence
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2. Two patients were primary chemorefractory, and 15 had a relapsed disease. Eight patients (47%) had already experienced a treatment failure with front-line autologous transplantation (
