Comparison of Allogeneic Stem Cell Transplant and Autologous Stem Cell Transplant in Refractory or Relapsed Peripheral T-Cell Lymphoma: A Systematic Review and Meta-analysis | Stem Cell Transplantation | JAMA Network Open | JAMA Network
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Figure 1.  Search Strategy
Search Strategy
Figure 2.  Three-Year Survival Outcomes in Patients with Refractory or Relapsed Peripheral T-Cell Lymphoma
Three-Year Survival Outcomes in Patients with Refractory or Relapsed Peripheral T-Cell Lymphoma

HSCT indicates hematopoietic stem cell transplant; OS, overall survival; PFS, progression-free survival.

Figure 3.  Five-Year Survival Outcomes in Patients with Refractory or Relapsed Peripheral T-Cell Lymphoma
Five-Year Survival Outcomes in Patients with Refractory or Relapsed Peripheral T-Cell Lymphoma

HSCT indicates hematopoietic stem cell transplant; OS, overall survival; PFS, progression-free survival.

Table 1.  Overview of the Literature on Allogeneic HSCT in R/R-PTCL
Overview of the Literature on Allogeneic HSCT in R/R-PTCL
Table 2.  Overview of the Literature on ASCT in R/R-PTCL
Overview of the Literature on ASCT in R/R-PTCL
1.
Salhotra  A, Nikolaenko  L, Chen  L,  et al.  Long term outcomes of patients with aggressive T-cell non-Hodgkin lymphoma undergoing allogeneic stem cell transplantation: retrospective results from single center.   Biol Blood Marrow Transplant. 2020;26(3):S249. doi:10.1016/j.bbmt.2019.12.499 Google ScholarCrossref
2.
Vose  J, Armitage  J, Weisenburger  D; International T-Cell Lymphoma Project.  International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes.   J Clin Oncol. 2008;26(25):4124-4130. doi:10.1200/JCO.2008.16.4558 PubMedGoogle ScholarCrossref
3.
Mak  V, Hamm  J, Chhanabhai  M,  et al.  Survival of patients with peripheral T-cell lymphoma after first relapse or progression: spectrum of disease and rare long-term survivors.   J Clin Oncol. 2013;31(16):1970-1976. doi:10.1200/JCO.2012.44.7524 PubMedGoogle ScholarCrossref
4.
Zinzani  PL, Bonthapally  V, Huebner  D, Lutes  R, Chi  A, Pileri  S.  Panoptic clinical review of the current and future treatment of relapsed/refractory T-cell lymphomas: peripheral T-cell lymphomas.   Crit Rev Oncol Hematol. 2016;99:214-227. doi:10.1016/j.critrevonc.2015.12.016 PubMedGoogle ScholarCrossref
5.
Domingo-Domènech  E, Boumendil  A, Climent  F,  et al; Lymphoma Working Party of the European Society for Blood and Marrow Transplantation.  Autologous hematopoietic stem cell transplantation for relapsed/refractory systemic anaplastic large cell lymphoma. a retrospective analysis of the lymphoma working party (LWP) of the EBMT.   Bone Marrow Transplant. 2020;55(4):796-803. doi:10.1038/s41409-019-0734-7 PubMedGoogle ScholarCrossref
6.
Marchi  E, O’Connor  OA.  The rapidly changing landscape in mature T-cell lymphoma (MTCL) biology and management.   CA Cancer J Clin. 2020;70(1):47-70. doi:10.3322/caac.21589 PubMedGoogle ScholarCrossref
7.
Allen  PB, Pro  B.  Therapy of peripheral T cell lymphoma: focus on nodal subtypes.   Curr Oncol Rep. 2020;22(5):44. doi:10.1007/s11912-020-00902-1 PubMedGoogle ScholarCrossref
8.
Mitsui  T, Fujita  N, Koga  Y,  et al.  The effect of graft-versus-host disease on outcomes after allogeneic stem cell transplantation for refractory lymphoblastic lymphoma in children and young adults.   Pediatr Blood Cancer. 2020;67(4):e28129. doi:10.1002/pbc.28129 PubMedGoogle Scholar
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World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053
10.
Slim  K, Nini  E, Forestier  D, Kwiatkowski  F, Panis  Y, Chipponi  J.  Methodological index for non-randomized studies (minors): development and validation of a new instrument.   ANZ J Surg. 2003;73(9):712-716. doi:10.1046/j.1445-2197.2003.02748.x PubMedGoogle ScholarCrossref
11.
Mamez  AC, Dupont  A, Blaise  D,  et al.  Allogeneic stem cell transplantation for peripheral T cell lymphomas: a retrospective study in 285 patients from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).   J Hematol Oncol. 2020;13(1):56. doi:10.1186/s13045-020-00892-4 PubMedGoogle ScholarCrossref
12.
McIlroy  G, Barmayehvar  B, Kamarajah  SK,  et al.  Improved outcomes with allogeneic compared with autologous stem cell transplantation in aggressive T-cell lymphoma.   Eur J Haematol. 2020;105(4):514-516. doi:10.1111/ejh.13465 PubMedGoogle ScholarCrossref
13.
Zhenyang  G.  Outcomes of myeloablative peripheral blood stem cell transplantation for non-complete remission patients with relapsed/refractory peripheral T cell lymphomas.   Ann Hematol. 2019;5(98):1237-1247. doi:10.1007/s00277-018-3559-3Google Scholar
14.
Wulf  G, Hasenkamp  J, Jung  W,  et al.  Allogeneic stem cell transplantation for patients with relapsed or refractory T-cell lymphoma: efficacy of lymphoma-directed conditioning against advanced disease.   Bone Marrow Transplant. 2019;54(6):877-884. doi:10.1038/s41409-018-0360-9 PubMedGoogle ScholarCrossref
15.
Wang  L, Li  NN, Wang  Z,  et al.  Evaluation of clinical outcomes of allogeneic hematopoietic stem cell transplantation for relapsed/refractory peripheral T-cell lymphoma with chemoresistance.  Article in Chinese.  Zhonghua Yi Xue Za Zhi. 2019;99(48):3786-3791.PubMedGoogle Scholar
16.
Huang  H, Jiang  Y, Wang  Q,  et al.  Outcome of allogeneic and autologous hematopoietic cell transplantation for high-risk peripheral T cell lymphomas: a retrospective analysis from a Chinese center.   Biol Blood Marrow Transplant. 2017;23(8):1393-1397. doi:10.1016/j.bbmt.2017.04.021 PubMedGoogle ScholarCrossref
17.
Corradini  P, Vitolo  U, Rambaldi  A,  et al.  Intensified chemo-immunotherapy with or without stem cell transplantation in newly diagnosed patients with peripheral T-cell lymphoma.   Leukemia. 2014;28(9):1885-1891. doi:10.1038/leu.2014.79 PubMedGoogle ScholarCrossref
18.
Smith  SM, Burns  LJ, van Besien  K,  et al.  Hematopoietic cell transplantation for systemic mature T-cell non-Hodgkin lymphoma.   J Clin Oncol. 2013;31(25):3100-3109. doi:10.1200/JCO.2012.46.0188 PubMedGoogle ScholarCrossref
19.
Czajczynska  A, Günther  A, Repp  R,  et al.  Allogeneic stem cell transplantation with BEAM and alemtuzumab conditioning immediately after remission induction has curative potential in advanced T-cell non-Hodgkin’s lymphoma.   Biol Blood Marrow Transplant. 2013;19(11):1632-1637. doi:10.1016/j.bbmt.2013.07.003 PubMedGoogle ScholarCrossref
20.
Dodero  A, Spina  F, Narni  F,  et al.  Allogeneic transplantation following a reduced-intensity conditioning regimen in relapsed/refractory peripheral T-cell lymphomas: long-term remissions and response to donor lymphocyte infusions support the role of a graft-versus-lymphoma effect.   Leukemia. 2012;26(3):520-526. doi:10.1038/leu.2011.240 PubMedGoogle ScholarCrossref
21.
Zain  J, Palmer  JM, Delioukina  M,  et al.  Allogeneic hematopoietic cell transplant for peripheral T-cell non-Hodgkin lymphoma results in long-term disease control.   Leuk Lymphoma. 2011;52(8):1463-1473. doi:10.3109/10428194.2011.574754 PubMedGoogle ScholarCrossref
22.
Jacobsen  ED, Kim  HT, Ho  VT,  et al.  A large single-center experience with allogeneic stem-cell transplantation for peripheral T-cell non-Hodgkin lymphoma and advanced mycosis fungoides/Sezary syndrome.   Ann Oncol. 2011;22(7):1608-1613. doi:10.1093/annonc/mdq698 PubMedGoogle ScholarCrossref
23.
Shustov  AR, Gooley  TA, Sandmaier  BM,  et al.  Allogeneic haematopoietic cell transplantation after nonmyeloablative conditioning in patients with T-cell and natural killer-cell lymphomas.   Br J Haematol. 2010;150(2):170-178. doi:10.1111/j.1365-2141.2010.08210.x PubMedGoogle Scholar
24.
Le Gouill  S, Milpied  N, Buzyn  A,  et al; Société Française de Greffe de Moëlle et de Thérapie Cellulaire.  Graft-versus-lymphoma effect for aggressive T-cell lymphomas in adults: a study by the Société Francaise de Greffe de Moëlle et de Thérapie Cellulaire.   J Clin Oncol. 2008;26(14):2264-2271. doi:10.1200/JCO.2007.14.1366 PubMedGoogle ScholarCrossref
25.
Wulf  GG, Hasenkamp  J, Jung  W, Chapuy  B, Truemper  L, Glass  B.  Reduced intensity conditioning and allogeneic stem cell transplantation after salvage therapy integrating alemtuzumab for patients with relapsed peripheral T-cell non-Hodgkin’s lymphoma.   Bone Marrow Transplant. 2005;36(3):271-273. doi:10.1038/sj.bmt.1705036 PubMedGoogle ScholarCrossref
26.
Corradini  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(11):2172-2176. doi:10.1200/JCO.2004.12.050 PubMedGoogle ScholarCrossref
27.
Yamasaki  S, Chihara  D, Kim  SW,  et al.  Risk factors and timing of autologous stem cell transplantation for patients with peripheral T-cell lymphoma.   Int J Hematol. 2019;109(2):175-186. doi:10.1007/s12185-018-2560-x PubMedGoogle ScholarCrossref
28.
Roerden  M, Walz  JS, Müller  MR,  et al.  The role of autologous stem cell transplantation in peripheral T cell lymphoma: a long-term follow-up single-center experience.   J Cancer Res Clin Oncol. 2019;145(10):2595-2604. doi:10.1007/s00432-019-02999-9 PubMedGoogle ScholarCrossref
29.
Wang  QL, Huang  HW, Jin  ZM,  et al.  Comparison of allogeneic or autologous hematopoietic stem cell transplant for high-risk peripheral T cell lymphomas.  Article in Chinese.  Zhonghua Xue Ye Xue Za Zhi. 2016;37(11):952-956.PubMedGoogle Scholar
30.
d’Amore  F, Relander  T, Lauritzsen  GF,  et al.  Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01.   J Clin Oncol. 2012;30(25):3093-3099. doi:10.1200/JCO.2011.40.2719 PubMedGoogle ScholarCrossref
31.
Nickelsen  M, Ziepert  M, Zeynalova  S,  et al.  High-dose CHOP plus etoposide (MegaCHOEP) in T-cell lymphoma: a comparative analysis of patients treated within trials of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL).   Ann Oncol. 2009;20(12):1977-1984. doi:10.1093/annonc/mdp211 PubMedGoogle ScholarCrossref
32.
Reimer  P, Rüdiger  T, Geissinger  E,  et al.  Autologous stem-cell transplantation as first-line therapy in peripheral T-cell lymphomas: results of a prospective multicenter study.   J Clin Oncol. 2009;27(1):106-113. doi:10.1200/JCO.2008.17.4870 PubMedGoogle ScholarCrossref
33.
Chen  AI, McMillan  A, Negrin  RS, Horning  SJ, Laport  GG.  Long-term results of autologous hematopoietic cell transplantation for peripheral T cell lymphoma: the Stanford experience.   Biol Blood Marrow Transplant. 2008;14(7):741-747. doi:10.1016/j.bbmt.2008.04.004 PubMedGoogle ScholarCrossref
34.
Smith  SD, Bolwell  BJ, Rybicki  LA,  et al.  Autologous hematopoietic stem cell transplantation in peripheral T-cell lymphoma using a uniform high-dose regimen.   Bone Marrow Transplant. 2007;40(3):239-243. doi:10.1038/sj.bmt.1705712 PubMedGoogle ScholarCrossref
35.
Kim  MK, Kim  S, Lee  SS,  et al.  High-dose chemotherapy and autologous stem cell transplantation for peripheral T-cell lymphoma: complete response at transplant predicts survival.   Ann Hematol. 2007;86(6):435-442. doi:10.1007/s00277-007-0254-1 PubMedGoogle ScholarCrossref
36.
Kewalramani  T, Zelenetz  AD, Teruya-Feldstein  J,  et al.  Autologous transplantation for relapsed or primary refractory peripheral T-cell lymphoma.   Br J Haematol. 2006;134(2):202-207. doi:10.1111/j.1365-2141.2006.06164.x PubMedGoogle ScholarCrossref
37.
Kevin  WS.  Autologous stem cell transplant for relapsed and refractory peripheral T-cell lymphoma: variable outcome according to pathological subtype.   Br J Haematol. 2003;6(120):978-985. doi:10.1046/j.1365-2141.2003.04203.xGoogle Scholar
38.
Rodríguez  J, Caballero  MD, Gutiérrez  A,  et al.  High-dose chemotherapy and autologous stem cell transplantation in peripheral T-cell lymphoma: the GEL-TAMO experience.   Ann Oncol. 2003;14(12):1768-1775. doi:10.1093/annonc/mdg459 PubMedGoogle ScholarCrossref
39.
Blystad  AK, Enblad  G, Kvaløy  S,  et al.  High-dose therapy with autologous stem cell transplantation in patients with peripheral T cell lymphomas.   Bone Marrow Transplant. 01;27(7):711-716. doi:10.1038/sj.bmt.1702867 PubMedGoogle ScholarCrossref
40.
Schmitz  N, Truemper  LH, Bouabdallah  K,  et al.  A randomized phase 3 trial of auto vs. allo transplantation as part of first-line therapy in poor-risk peripheral T-NHL.   Blood. 2020;blood.2020008825. doi:10.1182/blood.2020008825 PubMedGoogle Scholar
41.
Kyriakou  C, Canals  C, Finke  J,  et al.  Allogeneic stem cell transplantation is able to induce long-term remissions in angioimmunoblastic T-cell lymphoma: a retrospective study from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation.   J Clin Oncol. 2009;27(24):3951-3958. doi:10.1200/JCO.2008.20.4628 PubMedGoogle ScholarCrossref
42.
Shmitz  N, Truemper  L, Ziepert  M,  et al. First-line therapy of T-cell lymphoma: allogeneic or autologous transplantation for consolidation—final results of the AATT study. J Clin Oncol. 2019;37(15 suppl):7503-7503. doi:10.1002/hon.64_2629
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Wei  J, Xu  J, Cao  Y, Zhou  J, Zhang  Y.  Allogeneic stem-cell transplantation for peripheral T-cell lymphoma: a systemic review and meta-analysis.   Acta Haematol. 2015;133(2):136-144. doi:10.1159/000358579 PubMedGoogle ScholarCrossref
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O’Connor  OA, Marchi  E, Volinn  W, Shi  J, Mehrling  T, Kim  WS.  Strategy for assessing new drug value in orphan diseases: an international case match control analysis of the PROPEL study.   J Natl Cancer Inst Cancer Spectr. 2018;2(4):pky038. doi:10.1093/jncics/pky038 PubMedGoogle Scholar
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    Original Investigation
    Hematology
    May 27, 2021

    Comparison of Allogeneic Stem Cell Transplant and Autologous Stem Cell Transplant in Refractory or Relapsed Peripheral T-Cell Lymphoma: A Systematic Review and Meta-analysis

    Author Affiliations
    • 1State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, People’s Republic of China
    • 2Shenzhen PKU-HKUST Medical Center, Shenzhen, People’s Republic of China
    • 3Binjiang College of Nanjing University of Information Science & Technology, Jiangsu, People’s Republic of China
    • 4Department of Hematology, The First Affiliated Hospital of Gannan Medical University, Jiangxi, People’s Republic of China
    JAMA Netw Open. 2021;4(5):e219807. doi:10.1001/jamanetworkopen.2021.9807
    Key Points

    Question  Is allogeneic hematopoietic stem cell transplant (HSCT) or autologous HSCT more effective and safer for patients with refractory or relapsed peripheral T-cell lymphoma?

    Findings  In this systematic review and meta-analysis of 30 trials with 1765 patients, for patients undergoing allogeneic HSCT, the 3-year overall survival was 50%, the 3-year progression-free survival was 42%, and the 3-year transplant-related mortality was 32%. For patients undergoing autologous HSCT, the 3-year overall survival was 55%, the 3-year progression-free survival was 41%, and the 3-year transplant-related mortality was 7%.

    Meaning  These findings suggest that allogeneic HSCT may have better effectiveness but be less safe than autologous HSCT for patients with refractory or relapsed peripheral T-cell lymphoma.

    Abstract

    Importance  Hematopoietic stem cell transplant (HSCT) is an advisable option for refractory or relapsed peripheral T-cell lymphoma (R/R-PTCL), but whether allogeneic HSCT or autologous HSCT is more beneficial is unknown.

    Objective  To compare the effectiveness and safety of allogeneic HSCT vs autologous HSCT in patients with R/R-PTCL.

    Data Sources  A systematic search of the PubMed, Embase, the Cochrane Central Register of Controlled Trials, Wanfang, and China National Knowledge Infrastructure databases with the search items refractory or relapsed peripheral T-cell lymphoma, ASCT/autologous stem-cell transplantation, allo-HSCT/allogeneic stem-cell transplantation, therapeutic effect, and treatment was conducted for articles published from January 12, 2001, to October 1, 2020.

    Study Selection  After duplicate and irrelevant publications were discarded, 329 were ineligible according to the inclusion (clinical trials or retrospective studies with >10 samples) and exclusion criteria (articles without overall survival [OS], progression-free survival [PFS], and transplantation-related mortality [TRM]). Thirty trials were included in the meta-analysis. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.

    Data Extraction and Synthesis  Data on study design, individual characteristics, and outcomes were extracted. All statistics were pooled by applying a random-effects model.

    Main Outcomes and Measures  The prespecified main outcomes were OS, PFS, and TRM.

    Results  Of 6548 articles, data extracted from the 30 studies (including 880 patients who underwent allogeneic HSCT and 885 who underwent autologous HSCT) were included in this meta-analysis. In the allogeneic HSCT group, a 3-year OS of 50% (95% CI, 41%-60%) and PFS of 42% (95% CI, 35%-51%), a 5-year OS of 54% (95% CI, 47%-62%) and PFS of 48% (95% CI, 40%-56%), and a 3-year TRM of 32% (95% CI, 27%-37%) were observed. In the autologous HSCT group, a 3-year OS of 55% (95% CI, 48%-64%) and PFS of 41% (95% CI, 33%-51%), a 5-year OS of 53% (95% CI, 44%-64%) and PFS of 40% (95% CI, 24%-58%), and a 3-year TRM of 7% (95% CI, 2%-23%) were observed.

    Conclusions and Relevance  In this systematic review and meta-analysis, OS and PFS were similar in the allogeneic HSCT and autologous HSCT groups; however, allogeneic HSCT was associated with specific survival benefits among patients with R/R-PTCL.

    Introduction

    Peripheral T-cell lymphomas (PTCLs), a rare and heterogeneous group of non-Hodgkin lymphomas, have a dismal prognosis.1 The main subtypes are PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma, anaplastic large-cell lymphoma, and natural killer/T-cell lymphoma and are typically treated with conventional regimens for aggressive B-cell lymphomas, resulting in poor clinical outcomes.2 Furthermore, frequent relapses and initially refractory diseases are not uncommon in PTCL, making it more challenging. A study3 reported poor survival outcomes for 153 patients with refractory or relapsed PTCL (R/R-PTCL) receiving chemotherapy without hematopoietic transplantation, with a median overall survival (OS) of 13.7 months and progression-free survival (PFS) of 5 months. So far, because of the multitudinous morphologic features of the subtypes and the lack of randomized clinical trials, treatment of this disease remains a challenge, especially for R/R-PTCL.4

    Given the extremely poor results of current treatments, many researchers have pursued exploratory strategies. Although molecular targeted drugs, such as brentuximab vedotin, provide objective hope for CD30+ PTCL, hematopoietic stem cell transplant (HSCT) continues to be a reasonable option. Currently, the concept of high-dose chemotherapy followed by autologous HSCT during first remission in patients with PTCL has been widely accepted by clinical practitioners.5-7 However, the roles of autologous HSCT and allogeneic HSCT in R/R-PTCL remain far more controversial. Although HSCT has certain beneficial effects, adverse events (AEs) will negatively influence survival as well.8 Therefore, this meta-analysis was performed to compare the efficacy and safety of autologous HSCT vs allogeneic HSCT in R/R-PTCL.

    Methods
    Search Strategy and Study Selection

    Our search strategy is shown in in Figure 1. We searched the Cochrane Central Register of Controlled Trials, Embase, PubMed, Wanfang, and China National Knowledge Infrastructure databases with the search terms refractory or relapsed peripheral T-cell lymphoma/refractory or relapsed lymphoma, peripheral T-cell/refractory or relapsed T-cell lymphoma, peripheral R/R-PTCL, ASCT/autologous stem-cell transplantation, allo-HSCT/allogeneic stem-cell transplantation, therapeutic effect/effectiveness/efficacy, and treatment. All records from January 12, 2001, to October 1, 2020, were included. We quantitatively controlled for the factors listed above as well as others we deemed relevant. No language restrictions were applied on retrieval. The protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO). The study was performed in accordance with the Declaration of Helsinki,9 with prior approval of the institutional review board and the ethics committee of each hospital. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.

    Inclusion Criteria

    All studies were independently evaluated by 2 authors (D.Y. and X.H.). Subsequently, we inspected and discussed the outcomes to reach an agreement. We selected studies based on the following criteria: (1) clinical trials (including randomized clinical trials and nonrandomized clinical trials) and retrospective analytic studies with more than 10 samples; (2) patients with R/R-PTCL (no sex or age restrictions); (3) patients treated with autologous HSCT or allogeneic HSCT; and (4) providing outcome measurements, such as complete response (CR), partial response (PR), OS, PFS, and transplantation-related mortality (TRM). Prospective studies are clinical trials that were all registered online. Retrospective studies include a review of medical records from registry centers.

    Data Extraction

    We extracted the following information: (1) basic research information, including the study type, journal, author, areas, year of publication, and number of cases; (2) main characteristics, including age, histologic findings, prior chemotherapy, and complications; and (3) main outcome measurements, including CR, PR, overall response rate, OS, PFS (including event-free survival [EFS] and disease-free survival [DFS]), duration of response, TRM, nonrelapse mortality (NRM), and graft-vs-host disease (GVHD). Two researchers (D.Y. and X.H.) extracted the data independently.

    Statistical Analysis

    We performed a meta-analysis for each outcome using the meta package in R software, version 3.6 (R Foundation for Statistical Computing). Because most of the eligible studies we enrolled in were single-arm tests, we calculated single ratios and integrated ratios with 95% CIs. Furthermore, meta-analysis requires that the distribution type of a single rate should be a normal distribution. If not, it must be transformed to follow or be close to a normal distribution to improve the reliability of the combined results. Therefore, we transformed the data we extracted via R software by 5 methods, which were without conversion, logarithmic conversion, logit conversion, arcsine conversion, and Freeman-Tukey double arcsine conversion. After comparing the P values of the Shapiro-Wilk test calculated over the data transformed by each method, we chose the most suitable one to determine the integrated results. Considering there were inevitable limitations in the study, such as the diverse populations, we choose the random-effects model as our default regardless of the Cochran Q test results.

    Quality Assessment and Bias Risk

    We evaluated the quality of all evidence using the Methodological Index for Non-Randomized Studies (MINORS) scale (eFigure 1 in the Supplement) and plotted a heat map using OriginPro software, version 2020b (OriginLab Corp). According to the MINORS scale, 8 methodologic items were estimated for noncomparative studies, and 4 other criteria were estimated for comparative studies. The items are scored 0 (not reported), 1 (reported but inadequate), or 2 (reported and adequate); 16 and 24 are the global ideal scores for nonrandomized and randomized studies, respectively.10 We evaluated publication bias by assessing the symmetry of the funnel plot and by performing the Begg test and the Egger test, and we conducted sensitivity analysis as well with R software, version 3.6.

    Results

    A total of 6548 studies describing autologous HSCT or allogeneic HSCT for R/R-PTCL were included, including 10 other relevant references identified from additional sources. As shown, 1216 duplicates were discarded, and 5332 remaining articles underwent title and abstract screening to remove irrelevant records. A total of 359 full-text studies were available for us to assess after excluding 4983 unrelated articles. A total of 329 publications did not fulfill the inclusion and exclusion criteria; therefore, our final analysis included 30 trials (7 prospective and 23 retrospective) (Figure 1). However, only 2 trials were comparative studies that evaluated the efficiency and safety of autologous HSCT vs allogeneic HSCT treatment for R/R-PTCL. Therefore, the autologous HSCT group and allogeneic HSCT groups have 16 publications each. Our study included 1765 patients in total; 885 patients underwent autologous HSCT treatment, and 880 patients underwent allogeneic HSCT treatment.

    We used a bubble chart (eFigure 2A and B in the Supplement) to show the numbers of patients over the years. Basically, the patient number of the allogeneic HSCT group showed wavelike increases with each passing year. For the autologous HSCT group, there was no apparent association between the patient number and the years. We provide an overview of the literature in Table 1 and Table 2, including basic characteristics. In the autologous HSCT group, the age ranged from 4 to 73 years, and the follow-up time ranged from 1 to 278 months. For the allogeneic HSCT group, the age ranged from 16 to 74 years, and the follow-up time ranged from 0.3 to 195 months. All patients enrolled were no older than 75 years when they received HSCT.

    We used the MINORS scale to assess study quality, and the results are shown in eFigure 3 in the Supplement. The final scores for each study ranged from 11 to 14. Overall, the studies included in the meta-analysis were of relatively good reliability. Four funnel plots (eFigure 4 in the Supplement) were used to estimate all articles’ publication bias. We drew 4 plots for 4 groups, into which all studies were divided based on the survival outcomes concerning OS and PFS at 3 or 5 years. Two small studies with extreme distributions exist, making them asymmetrical. However, we still selected those studies. On the one hand, funnel plots are usually used for comparative studies to identify bias, whereas studies included in our article are mostly single-arm trials; however, those studies that yielded asymmetry could be selected. On the other hand, because HSCT is an exploratory approach for patients with R/R-PTCL and the studies in this field are few, we included all studies, which might have affected the results. We conducted a sensitivity analysis for the 2 comparative studies, which reported opposite findings, and the results are shown in the eFigure 5 in the Supplement.

    The outcomes can be classified into 2 categories: survival measurements and AEs. Survival measurements included OS, PFS (including event-free survival and disease-free survival), AEs (including TRM and NRM), and GVHD incidence. Overall survival is the time from receiving transplantation to death from any cause, and PFS is the time from undergoing transplant to relapse or progressive disease or death from any cause. Patients who underwent autologous HSCT would not have a GVHD effect. We performed a subgroup analysis according to different transplant types and different observation times (Figure 2 and Figure 3). Therefore, a total of 6 subgroups were evaluated, including OS at 3 years and 5 years, PFS at 3 years and 5 years, and TRM at 3 years and 5 years.

    Association of Transplant Type With OS
    OS at 3 Years

    Sixteen trials5,13-16,18,19,22,23,26,27,30-32,35,39 with 1002 patients reported OS at 3 years. Nine trials13-16,18,19,22,23,26 with 388 patients were assessed for 3-year OS (I2 = 71%) in the allogeneic HSCT group, and the pooled 3-year OS was 50% (95% CI, 41%-60%) for all patients with R/R-PTCL treated with allogeneic HSCT. The autologous HSCT group included 9 studies5,16,18,27,30-32,35,39 with 614 patients, and the pooled 3-year OS was 55% (95% CI, 48%-64%). This finding indicates that patients who underwent autologous HSCT might have a relatively better OS than those who underwent allogeneic HSCT after 3 years of follow-up. However, on the basis of the pretransplant CR rate of allogeneic HSCT and autologous HSCT, 42.60% vs 63.37% (χ2 = 47.20, P < .001), which we calculated via SPSS software, version 25.0 (SPSS Inc), we found that the patients undergoing autologous HSCT were commonly sensitive to chemotherapy or experienced their first CR after induction therapy. Therefore, when we take the patient enrollment bias into consideration, allogeneic HSCT prolonged the 3-year OS overall, especially for those who did not acquire CR before transplantation.

    OS at 5 Years

    Eleven studies12,20,21,24,28-30,33,34,36,38 with 520 patients provided a 5-year OS for the 2 groups. Allogeneic HSCT had a combined 5-year OS of 54% (95% CI, 47%-62%) across 4 trials12,20,21,24 with 174 patients. Autologous HSCT had an integrated 5-year OS of 53% (95% CI, 44%-64%) across 7 trials28-30,33,34,36,38 with 346 patients. This result suggests that compared with autologous HSCT, the effectiveness of allogeneic HSCT was not different concerning the 5-year OS. Considering that autologous HSCT is a commonly accepted strategy for R/R-PTCL, whereas allogeneic HSCT occasionally serves as a salvage approach, allogeneic HSCT performed better for R/R-PTCL than autologous HSCT. The finding that survival for patients with R/R-PTCL receiving allogeneic HSCT at 3 years was lower than that at 5 years might be because the article sources are distinct, so OS could not be compared directly, and the patient baseline characteristics should be taken into consideration.

    DFS, EFS, and PFS

    Not all studies presented PFS, EFS, and DFS; therefore, we combined these variables and unified them as PFS to reveal the data more clearly. In the 11 trials13-16,18,20-24,26 that reported the PFS end point for the allogeneic HSCT group, the combined PFS was 42% (95% CI, 35%-51%) at 3 years (8 trials13-16,18,22,23,26) and 48% (95% CI, 40%-56%) at 5 years (3 trials20,21,24). In the 15 studies5,16,18,27-33,35,36,38,39 that reported the PFS end point for the autologous HSCT group, the combined PFS was 41% (95% CI, 33%-51%) at 3 years (9 trials5,16,18,27,30-32,35,39) and 40% (95% CI, 24%-58%) at 5 years (6 trials28-30,33,36,38). Confounding bias still existed in the 5-year outcome in the allogeneic HSCT group; therefore, we could compare the therapy efficiency based only on 3-year PFS, which was 42% (95% CI, 35%-51%) for the allogeneic HSCT group and 41% (95% CI, 33%-51%) for the autologous HSCT group, indicating they were approximately equivalent to each other in terms of the PFS at 3 years.

    TRM

    As with the PFS, EFS, and DFS, we performed statistical analysis of TRM by combining the data of TRM and NRM and labeled them together as TRM. Six trials reported a pooled 3-year TRM of 32% (95% CI, 27%-37%) in the allogeneic HSCT group, and 3 trials reported a pooled 3-year TRM of 7% (95% CI, 2%-23%) in the autologous HSCT group, suggesting higher TRM with allogeneic HSCT. The TRM at 5 years for R/R-PTCL patients was 24% (95% CI, 6%-95%) in the allogeneic HSCT group and 55% (95% CI, 32%-97%) in the autologous HSCT group.

    Discussion

    This systematic review and meta-analysis reviewed studies performed from 2001 to 2020 on transplant for R/R-PTCL, reporting outcomes of allogeneic HSCT and autologous HSCT for R/R-PTCL. Patients in the 2 groups had similar survival rates, whereas patients with R/R-PTCL who underwent autologous HSCT had fewer AEs than who underwent allogeneic HSCT, likely because GVHD counterbalances the accompanying graft-vs-lymphoma effect after allogeneic HSCT.40 However, considering the pretransplant status, most patients in the allogeneic HSCT group were insensitive to chemotherapy, and allogeneic HSCT served as a salvage therapy, which provided an additional survival advantage for patients with R/R-PTCL. These findings might be linked to the graft-vs-lymphoma effect.

    Peripheral T-cell lymphoma is rare, accounting for a small proportion of all non-Hodgkin lymphoma cases (6%-10%), with approximately 4800 to 8000 new cases per year in the US. Coupled with the diversified histologic findings (29 subtypes), personalized precision therapy is hard to establish. Especially in the R/R-PTCL setting, no ideal therapies have been developed, resulting in a dismal prognosis with high expenditure.6 The poor prognosis of patients with R/R-PTCL has always been concerning. Therefore, efficient treatment strategies should be explored for patients with R/R-PTCL. In the past 20 years, with the development of medical technology and the improvement of economic conditions, more patients, especially those in developing countries, have the opportunity to receive HSCT, which is the mainstay treatment for patients with PTCL. High-density chemotherapy combined with autologous HSCT has become a conventional treatment method for patients with PTCL at first CR. However, for R/R-PTCL, the preferred option between allogeneic HSCT and autologous HSCT is still controversial.

    Compared with allogeneic HSCT, more patients are eligible for autologous HSCT with less expenditure. Furthermore, no GVHD occurred in the autologous HSCT group. However, stem cells transplanted to patients may have a higher possibility of containing tumor cells, and no obvious graft-vs-lymphoma effect occurred in the autologous HSCT group, leading to an increased incidence of relapse compared with the allogeneic HSCT group. However, the outcome may be different for few specific histologic subtypes. The European Cooperative Group for Bone Marrow Transplantation demonstrated that favorable outcomes are seen in patients with angioimmunoblastic T-cell lymphoma angioimmunoblastic T-cell lymphoma undergoing allogeneic HSCT.41 In the current study, patients undergoing autologous HSCT had a 3-year OS of 55% and PFS of 41% and a 5-year OS of 53% and PFS of 40%, showing a similar OS for patients undergoing autologous HSCT compared with those undergoing allogeneic HSCT.

    Some studies16,18,42 compared OS between allogeneic HSCT and autologous HSCT in patients with PTCL. A large retrospective trial16 that included 67 patients found a 3-year OS of 53%, a 3-year PFS of 49%, and a 1-year NRM of 18% for patients undergoing allogeneic HSCT (n = 24) and a 3-year OS of 20%, a 3-year PFS of 20%, and a 1-year NRM of 7% for patients undergoing autologous HSCT (n = 43),16 indicating that favorable survival outcomes were observed in the allogeneic HSCT group. Nevertheless, Smith et al18 reported allogeneic HSCT outcomes in 126 patients with R/R-PTCL, with a 3-year OS of 46%, 3-year PFS of 37%, and 3-year NRM of 34%. In addition, 115 patients with R/R-PTCL undergoing autologous HSCT had a 3-year OS of 59%, 3-year PFS of 47%, and 3-year NRM of 6%.18 These 2 trials16,18 were included in the current study. To identify whether they would affect the conclusions, a sensitivity analysis was performed. After these 2 studies16,18 were omitted, similar results were found (eAppendix in the Supplement). Moreover, the AATT study42 with 103 patients reported no significant difference between allogeneic HSCT and autologous HSCT as first-line therapy, with a 3-year OS of 57% in allogeneic HSCT and 70% in autologous HSCT.42 Furthermore, a systematic review43 of allogeneic HSCT and autologous HSCT published in 2015 found no difference in OS. However, O’Connor et al44 noted that because of the different disease stages before transplantation between the 2 groups of patients, allogeneic HSCT provides extra survival advantages for patients with R/R-PTCL.6

    As demonstrated in this study, OS is not significantly different between different HSCT types; therefore, cutting-edge treatment strategies need to be explored. For example, using specific HSCT types for patients with PTCL with different risk stages is a recommended strategy. Autologous HSCT was used as the first-line therapy, and allogeneic HSCT was used when patients had R/R-PTCL. However, HSCT should not be recommended later than second-line therapy if patients who are ready for transplant have already undergone multiline treatment because the prognosis will be worse.11 Novel treatments, such as applying chimeric antigen receptor T or natural killer cells or developing multidrug combinations, can also be tried. Combinational medicine (particularly epigenetic drugs) was also suggested to improve the curative effect for patients with PTCL, especially for angioimmunoblastic T-cell lymphoma.45

    Researching the biological heterogeneity of T cells is of vital significance to reform the treatment strategies for PTCL, and multicenter randomized clinical trials should be conducted. Because of the paucity of patient numbers, case-matched control studies can be based on historical comparative trials,44 which is a reasonable analysis method for this orphan disease. In the future, developing targeted therapy and combining existing drugs as well as optimizing the transplant system are crucial goals.

    Limitations

    This study has limitations and biases, even though strict enrollment criteria were set. First, most of the eligible studies for inclusion were single-arm trials, so results could not be directly evaluated. Second, the data for some outcome measurements were too scarce to perform a subgroup analysis, resulting in heterogeneity. Third, there was wide variation in the included patients with R/R-PTCL, such as age, histologic findings, and treatment characteristics, which would have an impact. Although this study did not fulfill the above features completely, overall the bias risk of study quality was acceptable.

    Conclusions

    A historical retrospective conclusion about the ideal means to treat R/R-PTCL for 20 years was drawn from this meta-analysis. Patients with R/R-PTCL undergoing allogeneic HSCT and autologous HSCT had similar survival conditions, whereas GVHD and higher TRM occurred in the allogeneic HSCT group. However, because of the CR status before transplant, allogeneic HSCT was associated with a specific survival advantage over autologous HSCT. The findings of this study suggest that, overall, HSCT is an effective therapy for R/R-PTCL. Patients with R/R-PTCL with lower-risk stratification might prefer autologous HSCT, although allogeneic HSCT still serves as the cornerstone of salvage therapy in those with a higher-risk disease stage. In the future, multicenter collaboration should be performed to optimize treatment for patients with R/R-PTCL patients.46

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    Article Information

    Accepted for Publication: March 15, 2021.

    Published: May 27, 2021. doi:10.1001/jamanetworkopen.2021.9807

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Du J et al. JAMA Network Open.

    Corresponding Author: Zou-Fang Huang, MD, Department of Hematology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China 341000 (nfyyjsjj@126.com).

    Author Contributions: Drs Du and Yu contributed equally to this work. Drs Du and Yu had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Du, Yu, Zhu, Huang.

    Acquisition, analysis, or interpretation of data: Du, Yu, Han.

    Drafting of the manuscript: Du, Yu, Zhu.

    Critical revision of the manuscript for important intellectual content: Du, Yu, Han, Huang.

    Statistical analysis: Du, Yu, Han.

    Obtained funding: Du.

    Administrative, technical, or material support: Huang.

    Supervision: Du, Yu, Huang.

    Conflict of Interest Disclosures: None reported.

    Funding/Support: This study was funded by grant 3332018156 from the Central Subordinate University Basic Scientific Research Foundation of China (Dr Du).

    Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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