Allogeneic Hematopoietic Stem Cell Transplantation for Peripheral T Cell Lymphomas; Evidence of Graft-Versus-T Cell Lymphoma Effect

Field: Medicine (Health Sciences)

T cell non-Hodgkin lymphomas (TNHL) are an uncommon and heterogeneous group of lymphoid malignancies characterized by a poor prognosis. They usually present with advanced-stage disease and high International Prognostic Index (IPI) score [1Feyler S. Prince H.M. Pearce R. et al.The role of high-dose therapy and stem cell rescue in the management of T-cell malignant lymphomas: a BSBMT and ABMTRR study.Bone Marrow Transplant. 2007; 40: 443-450Crossref PubMed Scopus (44) Google Scholar]. Patients with TNHL treated with conventional-dose chemotherapy alone in general have inferior overall survival (OS) and event-free survival compared to those with diffuse large B cell lymphoma [2Gisselbrecht 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).Blood. 1998; 92: 76-82PubMed Google Scholar]. High-dose therapy and autologous hematopoietic stem cell transplantation (HSCT) in relapsed or refractory patients have produced 3-yr OS and progression free survival (PFS) rates of 35%-58% and 28%-50% respectively [1Feyler S. Prince H.M. Pearce R. et al.The role of high-dose therapy and stem cell rescue in the management of T-cell malignant lymphomas: a BSBMT and ABMTRR study.Bone Marrow Transplant. 2007; 40: 443-450Crossref PubMed Scopus (44) Google Scholar, 3Vose J.M. Peterson C. Bierman P.J. et al.Comparison of high-dose therapy and autologous bone marrow transplantation for T-cell and B-cell non-Hodgkin's lymphomas.Blood. 1990; 76: 424-431PubMed Google Scholar, 4Rodriguez J. Munsell M. Yazji S. et al.Impact of high-dose chemotherapy on peripheral T-cell lymphomas.J Clin Oncol. 2001; 19: 3766-3770Crossref PubMed Scopus (136) Google Scholar, 5Blystad A.K. Enblad G. Kvaløy S. et al.High-dose therapy with autologous stem cell transplantation in patients with peripheral T cell lymphomas.Bone Marrow Transplant. 2001; 27: 711-716Crossref PubMed Scopus (120) Google Scholar]. These modalities are however not curative for majority of patients with TNHL. Experience with allogeneic HSCT in TNHL is limited, whereas the evidence for graft-versus-T cell lymphoma effect is scant [6Kahl C. Leithäuser M. Wolff D. et al.Treatment of peripheral T-cell lymphomas (PTCL) with high-dose chemotherapy and autologous or allogeneic hematopoietic transplantation.Ann Hematol. 2002; 81: 646-650Crossref PubMed Scopus (30) Google Scholar, 7Feyler S. Prince H.M. Pearce R. et al.The role of high-dose therapy and stem cell rescue in the management of T-cell malignant lymphomas: a BSBMT and ABMTRR study.Bone Marrow Transplant. 2007; 40: 443-450Crossref PubMed Scopus (86) Google Scholar]. Between May 1997 to February 2007, 14 patients with peripheral T cell lymphoma (PTCL), diagnosed according to World Health Organization lymphoma classification [8Harris N.L. Jaffe E.S. Diebold J. et al.World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997.J Clin Oncol. 1999; 17: 3835-3849Crossref PubMed Scopus (2487) Google Scholar], underwent allogeneic HSCT at our institution. Patients with ALK1 positive anaplastic large cell lymphoma (ALCL) were excluded from this analysis. Baseline and treatment characteristics of the patients are shown in Table 1. There were 11 male and 3 female patients with a median age of 43 ys (range 30-52). Histology included PTCL unspecified (n = 5), angioimmunoblastic T-cell lymphoma (n = 4), ALCL (n = 2), extranodal NK/T-cell lymphoma, nasal type (n = 2), and panniculitis like T-cell lymphoma (n = 1). Eight patients (57%) had chemosensitive disease, whereas 6 had high or intermediate/high age-adjusted IPI score. Eleven (78%) had advanced stage (III-IV) disease at transplantation. The median number of prior chemotherapy regimens was 3 (range 1-4). Median time from diagnosis to allogeneic HSCT was 12 mos. Donors included matched siblings (n = 9) or unrelated donors (n = 5) (MUD). Eight and 6 patients received myeloablative (MA) and reduced intensity conditioning (RIC) respectively. Antithymocyte globulin (ATG) was administered as part of conditioning regimen in 3 RIC patients.Table 1Baseline and treatment characteristics of patientsAllogeneic-HSCT N = 14 (%)Sex Male FemaleMedian age, yrs (range)43 (30-52)Histology PTCL-NOS5 (36) Angioimmunoblastic T cell lymphoma4 (28) Anaplastic large cell lymphoma2 (14) Extranodal NK/T cell lymphoma, nasal type2 (14) Panniculitis like T cell lymphoma1 (7)Stage at diagnosis I3 (21) II- III3 (21) IV8 (57)Bone marrow involvement Yes7 (50) No7 (50)aaIPI Score Low1 (7) Low/intermediate7 (50) High/intermediate3 (21) High3 (21)Median number of prior therapies (range)3 (1-4)Prior autologous transplantation Yes2 (14) No12 (86)Donor type HLA-identical sibling donor9 (64) Matched unrelated donor5 (36)Stem cell source Bone marrow2 (14) Peripheral blood12 (86)GVHD prophylaxis Cyclosporine/MTX9 (64) Tacrolimus/MTX5 (36)Conditioning regimen Myeloablative (Bu/Cy)8 (57) Reduced intensity conditioning (Flu/Bu)6 (43)Disease status at transplantation CR21 (7) CR32 (14) PR13 (21) PR22 (14) Refractory disease6 (43)aaIPI indicates age adjusted International Prognostic Index; Bu/Cy, busulfan/cyclophosphamide; CR, complete remission; Flu/Bu, fludarabine/busulfan; GVHD, graft-versus-host disease; HSCT, hematopoietic stem cell transplantation; MTX, methotrexate; PTCL-NOD, peripheral T cell lymphoma-not otherwise specified; PR, partial remission. Open table in a new tab aaIPI indicates age adjusted International Prognostic Index; Bu/Cy, busulfan/cyclophosphamide; CR, complete remission; Flu/Bu, fludarabine/busulfan; GVHD, graft-versus-host disease; HSCT, hematopoietic stem cell transplantation; MTX, methotrexate; PTCL-NOD, peripheral T cell lymphoma-not otherwise specified; PR, partial remission. Median number of CD34+ cells infused was 5.11 × 106 cells/Kg. Median time to neutrophil and platelet engraftment was 15 and 24 d respectively. Rates of grade II-IV and III-IV acute graft-versus-host disease (aGVHD) were 50% (n = 7) and 21% (n = 3) respectively. Seven patients developed chronic GVHD (cGVHD). Median follow-up is 34 m (range 10-127mos). Among 12 patients evaluable for response assessment, 8 achieved complete remission (CR) and 4 patients had partial remission (PR) after allografting. Two and 4 patients with refractory disease (RD) and PR before allografting respectively, were in CR immediately following allogeneic HSCT, whereas 3 patients with RD achieved PR following allogeneic HSCT. Day +100 and overall non-relapse mortality (NRM) rates were 28% and 57%, respectively. Cause of death included sepsis (n = 2), invasive fungal infections in patients with GVHD (n = 2), GVHD (n = 2), disease progression (n = 1), sudden cardiac death (n = 1), and post-transplant lymphoproliferative disorder (n = 1). Cumulative incidence of relapse at 3 yrs adjusted for competing risks (non-relapse mortality) was 69%. Kaplan-Meier estimates of 3-yr OS and PFS were 35% and 31%, respectively (Figure 1). On univariate analysis RIC was associated with improved OS (P = .03), but not PFS (P = .12). No impact of age, LDH, stage, performance status, age adjusted IPI score, marrow involvement, chemosensitivity, prior treatment, and donor type (matched sibling vs. MUD) on OS and PFS was seen (P > 0.05). However, on multivariate logistic regression analysis, no significant improvement in OS with RIC was found (P = .99). Interestingly, 1 patient in PR after MA transplantation converted to CR on tapering immunosuppression. Immunosuppression was tapered in a second (RIC) patient at time of disease progression, which resulted in prolonged CR. Only 3 patients experienced disease relapse. Disease relapse was heralded in 2 patients with loss of full donor chimerism. Notably, no patient surviving beyond one year after transplantation developed any evidence of disease progression. Conventional dose chemotherapy and autologous HSCT do not appear to be curative for the majority of patients with TNHL [1Feyler S. Prince H.M. Pearce R. et al.The role of high-dose therapy and stem cell rescue in the management of T-cell malignant lymphomas: a BSBMT and ABMTRR study.Bone Marrow Transplant. 2007; 40: 443-450Crossref PubMed Scopus (44) Google Scholar, 2Gisselbrecht 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).Blood. 1998; 92: 76-82PubMed Google Scholar, 4Rodriguez J. Munsell M. Yazji S. et al.Impact of high-dose chemotherapy on peripheral T-cell lymphomas.J Clin Oncol. 2001; 19: 3766-3770Crossref PubMed Scopus (136) Google Scholar]. The experience with allogeneic HSCT in TNHL is limited with spare evidence of graft-versus-T cell lymphoma effect after allografting. Rodriguez et al [4Rodriguez J. Munsell M. Yazji S. et al.Impact of high-dose chemotherapy on peripheral T-cell lymphomas.J Clin Oncol. 2001; 19: 3766-3770Crossref PubMed Scopus (136) Google Scholar] reported 3-yr OS and PFS of 29% and 14% respectively in 7 patients who received allogeneic HSCT. Kahl et al. [6Kahl C. Leithäuser M. Wolff D. et al.Treatment of peripheral T-cell lymphomas (PTCL) with high-dose chemotherapy and autologous or allogeneic hematopoietic transplantation.Ann Hematol. 2002; 81: 646-650Crossref PubMed Scopus (30) Google Scholar] reported 1-y survival probability of 40% following allografting in 5 patients. No objective evidence of graft-versus-lymphoma effect was noted in these small patient series. Recently, Australasian Bone Marrow Transplant Recipient Registry and the British Society of Bone Marrow Transplantation database revealed 3-y OS and PFS of 39% and 33%, respectively in 18 patients with allografting [7Feyler S. Prince H.M. Pearce R. et al.The role of high-dose therapy and stem cell rescue in the management of T-cell malignant lymphomas: a BSBMT and ABMTRR study.Bone Marrow Transplant. 2007; 40: 443-450Crossref PubMed Scopus (86) Google Scholar]. This study showed no evidence of graft-versus-lymphoma effect in PTCL patients. Moreover, relapse rates following allografting were similar to those seen following autologous HSCT. Unlike these studies, the temporal association of loss of full donor chimerism and disease relapse, as well as clear evidence of disease remission with tapering of immunosuppressive medications in our patients suggests that allogeneic HSCT is associated with a relevant graft-versus-T cell lymphoma effect in TNHL. Five patients in our study with chemo-refractory disease at the time of transplantation showed either a CR or PR following allografting, again supporting immune recognition of TNHL. No disease relapse in patients surviving beyond 1 y in our series hints at the curative potential of this modality. In fact Corradini et al [9Corradini P. Dodero A. Zallio F. et al.Graft-versus-lymphoma effect in relapsed peripheral T-cell non-Hodgkin's lymphomas after reduced-intensity conditioning followed by allogeneic transplantation of hematopoietic cells.J Clin Oncol. 2004; 22: 2172-2176Crossref PubMed Scopus (258) Google Scholar] reported impressive 3-yr OS and PFS rates of 81% and 64% in TNHL patients undergoing RIC HSCT. Notably donor lymphocyte infusions (DLI) given to 4 patients at the time of disease progression produced disease response in 2 patients. The sustained response to withdrawing immunosuppression in our series precluded the use of DLI. However, these observations suggest that immune competent cells in the allograft can exert tumor-specific immune responses in TNHL. In conclusion, our limited and preliminary results demonstrate that allogeneic HSCT is associated with clinical evidence of graft-versus-lymphoma effect in TNHL. Larger, prospective studies employing RIC earlier in the disease course are warranted.