ARTICLE - Non-Hodgkin Lymphoma Autologous stem-cell transplantation as consolidation of first-line chemotherapy in patients with peripheral T-cell lymphoma: a multicenter GELTAMO/FIL study Alejandro Martín García-Sancho,1 Monica Bellei,2 Miriam López-Parra,1 Giuseppe Gritti,3 María Cortés,4 Silvana Novelli,5 Carlos Panizo,6 Luigi Petrucci,7 Antonio Gutiérrez,8 Ivan Dlouhy9, Correspondence: A. M. García-Sancho Mariana Bastos-Oreiro,10 Juan M. Sancho,11 María J. Ramírez,12 José M. Moraleda,13 Estrella amartingar@usal.es Carrillo,14 Ana I. Jiménez-Ubieto,15 Isidro Jarque,16 Lorella Orsucci,17 Estefanía García-Torres,18 Received: July 21, 2021. Carlos Montalbán,19 Anna Dodero,20 Reyes Arranz,21 Natalia de las Heras,22 María J. Pascual,23 Accepted: January 28, 2022. Javier López-Jiménez,24 Michelle Spina,25 Alessandro Re,26 Sonia González de Villambrosia,27 Prepublished: March 24, 2022. Sabela Bobillo,28 Massimo Federico29 and Dolores Caballero1 on behalf of the Grupo Español de Linfomas y Trasplante Autólogo de Médula Ósea (GELTAMO) and Fondazione Italiana https://doi.org/10.3324/haematol.2021.279426 Linfomi (FIL) ©2022 Ferrata Storti Foundation Published under a CC BY-NC license 1 Department of Hematology, Hospital Universitario de Salamanca, IBSAL, CIBERONC, Salamanca, Spain; 2Fondazione Italiana Linfomi (FIL) Onlus, Modena, Italy; 3Hematology and Bone Marrow Transplant Unit, ASST Papa Giovanni XXIII, Bergamo, Italy; 4Department of Statistics, Hospital Universitario de Salamanca / IBSAL, Salamanca, Spain; 5Hematology Department, Hospital de la Santa Creu i Sant Pau, José Carreras Leukemia Research Institute and IIB Sant Pau, Barcelona, Spain; 6Department of Hematology, Clínica Universidad de Navarra, IdiSNA, Pamplona, Spain; 7Department of Translational and Precision Medicine, Sapienza University, Rome, Italy; 8Department of Hematology, Son Espases University Hospital, IdISBa, Palma de Mallorca, Spain; 9Department of Hematology, Hospital Clínic de Barcelona, Barcelona, Spain; 10Hematology Department, Hospital Gregorio Marañón / IISGM, Madrid, Spain; 11Hematology Department, ICO-IJC-Hospital Germans Trias i Pujol, Badalona, Spain; 12Hematology Department, Hospital de Especialidades de Jerez de la Frontera, Cádiz, Spain; 13Hematology Department, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; 14Hematology Department, Hospital Universitario Virgen del Rocío, Seville, Spain; 15Hematology Department, Hospital Universitario 12 de Octubre, Madrid, Spain; 16Hematology Department, CIBERONC, Instituto Carlos III, Hospital Universitario y Politécnico La Fe, Valencia, Spain; 17Hematology, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, Multidisciplinary Outpatient Oncology Clinic, Candiolo Cancer Institute, FPO-IRCCS, Candiolo (Torino), Italy; 18Hematology Department, Hospital Universitario Reina Sofía, Cordoba, Spain; 19Department of Translational Research, MD Anderson Cancer Center, Madrid, Spain; 20Division of Hematology and Bone Marrow Transplantation, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy; 21 Hematology Department, Hospital La Princesa, Madrid, Spain; 22Department of Hematology, Complejo Hospitalario de León, León, Spain; 23Hematology Department, Regional Hospital, Málaga, Spain; 24Hematology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain; 25Division of Medical Oncology and Immune-related Tumors, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy; 26Division of Hematology, ASST Spedali Civili di Brescia, Brescia, Italy; 27Hematology Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain; 28Department of Hematology, University Hospital Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain and 29Medical Oncology, CHIMOMO Department, University of Modena and Reggio Emilia, Modena, Italy. Abstract Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of rare lymphoid malignancies that mostly have poor prognoses with currently available treatments. Upfront consolidation with autologous stem cell transplantation (ASCT) is frequently carried out, but its efficacy has never been investigated in randomized trials. We designed a multicenter, international, retrospective study with the main objective of comparing progression-free survival and overall survival of patients with PTCL who underwent ASCT in complete remission (CR) after first-line chemotherapy with a control group who did not undergo ASCT. From the initial population of 286 registered patients, 174 patients with PTCL other than anaplastic large cell lymphoma, ALK-positive, deemed fit for ASCT at the time of diagnosis, and who were in CR or Haematologica | 107 November 2022 2675 ARTICLE - ASCT as consolidation of first-line treatment for PTCL A. M. García-Sancho et al. uncertain CR after induction therapy (CR1) were included in our analysis. one hundred and three patients underwent ASCT, whereas 71 did not, in most cases (n=53) because the physician decided against it. With a median follow-up of 65.5 months, progression-free survival was significantly better in the transplanted patients than in the non-transplanted group: 63% versus 48% at 5 years (P=0.042). Overall survival was significantly longer for ASCT patients in the subgroup with advanced stage at diagnosis (5-year overall survival: 70% vs. 50%, P=0.028). In the multivariate analysis, first-line ASCT was associated with significantly prolonged progression-free survival (HR=0.57, 95% CI: 0.35-0.93) and overall survival (HR=0.57, 95% CI: 0.33-0.99). In conclusion, our study supports the use of ASCT as a consolidation strategy for patients with PTCL in CR1. These results should be confirmed in a prospective randomized study. committees and regulatory authorities. Eligibility criteria Introduction were: (i) aged 18 to 65 years at diagnosis; (ii) histological Peripheral T-cell lymphomas (PTCL) are a heterogeneous diagnosis of PTCL between 2001 and 2011 from the fol- group of rare lymphoid malignancies. With the exception lowing subtypes:10 PTCL, not otherwise specified (NOS); of some primarily cutaneous and leukemic forms, PTCL angioimmunoblastic T-cell lymphoma; ALCL, ALK-positive; are aggressive in nature, with rapid disease progression ALCL, ALK-negative; extranodal NK/T-cell lymphoma, and poor response to treatment.1 Cyclophosphamide, dox- nasal type (non-localized cases); enteropathy-associated orubicin, vincristine and prednisone (CHOP), or variants of T-cell lymphoma; hepatosplenic T-cell lymphoma; primary it, has been the most commonly used regimen for treating cutaneous Ɣδ T-cell lymphoma; and primary cutaneous nodal PTCL.2 However, except for anaplastic lymphoma ki- CD8-positive aggressive epidermotropic cytotoxic T-cell nase (ALK)-positive anaplastic large cell lymphoma lymphoma; (iii) patients deemed fit for ASCT at the time (ALCL), prognosis when using this approach remains poor, of diagnosis; and (iv) documented partial response (PR), with 5-year overall survival (OS) rates of around 30% for or unconfirmed CR (CRu), or CR after anthracycline-based the remaining PTCL subtypes.3 first-line treatment. Patients who experienced progressive These poor outcomes have prompted many centers to in- disease within 3 months of the initiation of the last cycle clude autologous stem-cell transplantation (ASCT) as part of first-line chemotherapy were not considered to be re- of the first-line treatment of patients with PTCL. This sponders. strategy has been evaluated in prospective studies sug- Participating centers were required to identify eligible pa- gesting more favorable outcomes,4–8 but randomized trials tients from local databases. In each center, all records of are lacking. In addition, several large retrospective studies patients diagnosed in the designated period were re- have yielded conflicting results,1,9 so the precise role of viewed, and all eligible patients were registered. Data ASCT for PTCL remains largely unknown in front-line set- were retrospectively collected from the medical records tings. of all centers. The response to first-line treatment re- Given this background, we designed a large multicenter corded in the study was the response indicated in the and international retrospective study with the main ob- medical records according to the clinical judgment of the jective of analyzing the outcomes of patients with PTCL treating physician, provided that it was supported, at other than ALK-positive ALCL, who underwent ASCT in least, by the findings of an imaging study. complete remission (CR) after first-line chemotherapy, compared with a control group who did not undergo ASCT Study objectives and statistical analysis as part of their first-line treatment (Table 1). The primary objective was to assess survival in patients with PTCL different from ALCL, ALK-positive who under- went ASCT in CR/CRu after first-line therapy, and compare them with a control non-transplanted group. Secondary Methods objectives were to assess the influence on survival of Patients and study design other prognostic factors, and to assess survival in patients This is an international, multicenter, retrospective study undergoing ASCT in PR after first-line therapy. With re- designed by the Spanish and Italian lymphoma groups, spect to the cohort of patients with ALK-positive ALCL Grupo Español de Linfomas y Trasplante Autólogo de (n=41), only six patients underwent ASCT after first-line Médula Ósea (GELTAMO) and Fondazione Italiana Linfomi treatment, two in PR and four in CR. Given the very low (FIL), performed in accordance with the Declaration of number of transplanted patients in this cohort, no worth- Helsinki and approved in Spain by the national authorities while statistical analysis could be carried out. and the institutional ethics committee of Hospital Univer- A landmark analysis was performed in which time zero sitario de Salamanca, and in Italy by the relevant ethics was defined as the date of the response assessment after Haematologica | 107 November 2022 2676 ARTICLE - ASCT as consolidation of first-line treatment for PTCL A. M. García-Sancho et al. first-line treatment. The c2, Fisher exact or Mann-Whitney condition (n=9), patients’ refusal (n=7), pregnancy (n=1) test was used for statistical comparison of the ASCT and and early relapse (n=1). In these 18 cases, the decision not non-ASCT groups. Survival curves were constructed using to proceed to transplant was not taken at the beginning the Kaplan-Meier method and compared using the log- of first-line treatment but well into the treatment or at rank test. Progression-free survival (PFS) was calculated the end of it. The use of up-front ASCT did not change from the date of response assessment after first-line over time. From the overall series, 58 and 116 patients treatment until the date of relapse, progression, or death were diagnosed between 2001-2006 and 2007-2011, re- from any cause. OS was calculated from the date of re- spectively, and 34 (58.6%) and 69 (59.5%) patients from sponse assessment after first-line treatment to the date the two groups, respectively, underwent ASCT (P=0.913). of death or of last follow-up. Multivariate Cox analyses The patients’ characteristics are summarized in Table 1. were undertaken to investigate factors that could be The median age of patients in the non-transplanted group prognostic for survival. We tested all factors included in was older than that in the transplanted group (54 vs. 50 Table 2 in the multivariate regression model, eliminating years; P=0.037), and a higher proportion of the non-trans- non-significant terms by backward selection. Age was planted patients were older than 60 years compared with tested as a dichotomous variable (≤60 vs. >60 years, the transplanted patients. On the other hand, a signifi- based on the International Prognostic Index [IPI] and Prog- cantly higher proportion of patients in the transplant nostic Index for T-cell lymphoma [PIT] indices). Analyses group had adverse prognostic factors, such as advanced were performed using R version 4.0.3 (R Foundation for stage or increased lactate dehydrogenase (LDH) level. Ap- Statistical Computing, Vienna, Austria; https://www.R-pro- proximately 90% of patients in both groups had a nodal ject.org/), and IBM SPSS Statistics version 25 (IBM Cor- PTCL. The proportion of patients with angioimmunoblastic poration, Armonk, NY, USA). T-cell lymphoma was higher in the transplant group, whereas ALCL was a more frequent diagnosis in the non- ASCT group, although these differences were not statis- tically significant. Results The majority of patients in both groups received CHOP, Patients’ characteristics CHOEP or similar as an induction regimen, although a Figure 1 shows the study flowchart. From the initial popu- higher proportion of patients in the transplant group re- lation of 286 registered patients, the 174 patients who ceived a CHOP-like scheme that was alternated with other were in CR/CRu after induction therapy were included in regimens, as shown in Table 1. There were no significant the primary analysis. The other 112 patients were excluded differences in the time between the last cycle of first-line due to absence of CR/CRu after induction (60 patients; regimen and the evaluation of response between the PR, n=53; response to first-line not documented, n=7), transplanted and the non-transplanted groups (median of presence of ALK-positive ALCL histology (41 patients), re- 31.5 days [interquartile range, 22.0-53.0] vs. 33.5 days [in- lapse within 3 months of the initiation of the last cycle of terquartile range, 26.2-49.5, P=0.782]). Radiotherapy was first-line treatment (7 patients), or for not meeting other much more frequently administered in the non-transplant inclusion criteria (4 patients). One hundred and three pa- group; this was planned at diagnosis in most cases (16 out tients underwent ASCT, whereas 71 patients did not of 19) because the patients had limited-stage disease. undergo transplantation, in most cases because the phys- ician decided against it up-front (n=53). Other reasons Survival analysis why patients did not receive a transplant were patients’ With a median follow-up of 65.5 months (range, 4.1-176.7 Figure 1. Study flowchart. *Relapse within 3 months of the initiation of the last cycle of first-line treatment. **Relapse beyond 3 months of the initiation of the last cycle of first-line treatment. ALCL: anaplastic large cell lymphoma; ASCT: autologous stem-cell transplantation; CR: complete remission; CRu: unconfirmed complete remission. Haematologica | 107 November 2022 2677 ARTICLE - ASCT as consolidation of first-line treatment for PTCL A. M. García-Sancho et al. Table 1. Patients’ characteristics at diagnosis and first-line treatment. Characteristic Missing, N ASCT, N (%) Non-ASCT, N (%) P Total number of evaluable patients 103 71 Male sex 0 62 (60.2) 42 (59.2) 0.507 Age, years, median (range) 50 (18-65) 54 (19-65) 0.037 0 Older than 60 12 (11.7) 19 (26.8) 0.010 Histological diagnosis 0 41 (39.8) 26 (36.6) Peripheral T-cell lymphoma, NOS 31 (30.1) 17 (23.9) Angioimmunoblastic T-cell lymphoma 19 (18.4) 19 (26.8) Anaplastic large cell lymphoma, ALK-negative 5 (4.9) 4 (5.6) 0.336 Enteropathy-associated T-cell lymphoma 4 (3.9) 1 (1.4) Hepatosplenic T-cell lymphoma 2 (1.9) 4 (5.6) Extranodal NK/T-cell lymphoma, nasal type 1 (1.0) 0 Primary cutaneous ɣδ T-cell lymphoma ECOG performance status 2-4 3 20 (19.6) 7 (10.1) 0.071 Ann-Arbor stage III-IV 1 86 (84.3) 36 (50.7) <0.001 Lactate dehydrogenase increased 12 54 (55.1) 22 (34.4) 0.007 Bone marrow infiltration 2 33 (32.4) 15 (21.4) 0.080 International Prognostic Index 9 0-1 40 (40.8) 39 (58.2) 0.081 2-3 48 (49.0) 22 (32.8) 4-5 10 (10.2) 6 (9.0) Prognostic Index for T-cell Lymphoma 5 0-1 66 (64.7) 53 (79.1) 0.067 2 25 (24.5) 7 (10.4) 3-4 11 (10.8) 7 (10.4) First-line treatment 0 68 (66.0) 58 (81.7) CHOP or CHOP-like 11 (10.7) 5 (7.0) CHOEP or CHOEP-like 4 (3.9) 3 (4.2) 0.155 MACOP-B or VACOP-B 14a (13.6) 4b (5.6) CHOP-like alternating with others 6c (5.8) 1d (1.4) Others Radiotherapy as part of first-line treatment 0 3 (2.9) 19 (26.8) <0.001 a ESHAP (n=6), Hyper-CHiDAM (n=2), IFE (n=4), methotrexate-cytarabine (n=3); bESHAP (n=2), Hyper-CHiDAM (n=2); cESHAP (n=1), methotre- xate-L-asparaginase (n=1), ICE (n=1), IVE-MTX-dexamethasone (n=1), MACOP-HDMTX (n=1), MACOP-IVE-DHAP (n=1); dCOPP-EBV-CAD (n=1). ASCT: autologous stem-cell transplantation; NOS: not otherwise specified; ALK: anaplastic lymphoma kinase; NK: natural killer; ECOG: Easter Cooperative Oncology Group; CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisolone; CHOEP: cyclophosphamide, doxorubicin, etoposide; vincristine, and prednisolone; MACOP-B: methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin; VACOP-B: etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin; COPP-EBV-CAD: cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxorubicin, vincristine, procarbazine, vinblastine, and bleomycin; DHAP: dexamethasone, cytarabine, cisplatin; ESHAP: etoposide, solumedrol, cytarabine, and cisplatin; HDMTX: high-dose methotrexate; Hyper-CHiDAM: hyperfractionated cyclo- phosphamide, high-dose arabinosylcytosine, and high-dose methotrexate; ICE: ifosfamide, carboplatin, etoposide; IFE: ifosfamide, etoposide; IVE-MTX: ifosfamide, epirubicin, etoposide, and methotrexate. months), PFS was significantly higher in the transplant In the univariate analysis (Table 2), first-line transplanta- group (Figure 2), 63% (95% confidence interval [95% CI]: tion was the only factor significantly associated with PFS, 53.2-72.8) vs. 49% (95% CI: 37.2-60.8) at 5 years, with a whereas stage and number of extranodal sites were the median not reached (95% CI: not estimable) in the ASCT only factors associated with OS. Other variables that were group vs. 50.5 months (95% CI: 0-110.9) in the non-ASCT not associated (P>0.05) with PFS or OS were sex, age, his- group (P=0.042). The OS was also better in the transplant tology, performance status according to Easter Cooper- group, 74% (95% CI: 65.2-82.8) vs. 62% (95% CI: 50.0-73.9) ative Oncology Group (ECOG), LDH, bone marrow at 5 years, with a median not reached (95% CI: not esti- infiltration, B symptoms, IPI, PIT score, chemotherapy mable) in the ASCT group vs. 100.6 months (95% CI: 66.1- regimen, and radiotherapy (Table 2). 135.1) in the non-ASCT group, although the difference was We performed additional univariate analyses to assess the not statistically significant (P=0.124). impact of ASCT on OS by subgroups, as shown in Online Haematologica | 107 November 2022 2678 ARTICLE - ASCT as consolidation of first-line treatment for PTCL A. M. García-Sancho et al. Supplementary Table S1. We only detected statistically sig- calized stage at diagnosis, this was not the case among nificant differences in the subgroup of patients with ad- patients with advanced-stage disease, as shown in Figure vanced-stage disease. Although transplantation does not 3. In this group of patients, OS was significantly longer for seem to improve survival significantly in patients with lo- ASCT patients (median not reached [95% CI: not esti- Table 2. Univariate analysis of progression-free survival and overall survival. Characteristic N 5-year PFS, % P 5-year OS, % P Sex Male 104 56 0.427 69 0.510 Female 70 59 69 Histological diagnosis PTCL, NOS 67 58 67 AITL 48 49 0.220 65 0.199 ALCL, ALK-negative 38 68 81 Others 21 53 63 Age ≤60 years 143 59 0.303 68 0.778 >60 years 31 50 73 ECOG-PS 0-1 144 58 0.435 69 0.447 2-4 27 55 70 Lactate dehydrogenase Normal 86 59 0.478 72 0.227 Increased 76 55 66 Ann-Arbor stage I-II 51 62 0.191 80 0.034 III-IV 122 55 64 Extranodal sites 0-1 142 59 0.219 72 0.028 ≥2 32 49 57 Bone marrow infiltration Yes 48 53 0.270 62 0.190 No 124 59 72 B symptoms Yes 79 55 0.439 64 0.141 No 91 60 73 International Prognostic Index 0-1 79 59 72 0.058 0.089 2-3 70 59 70 4-5 16 36 53 Prognostic Index for T-cell Lymphoma 0-1 119 60 71 0.334 0.450 2 32 51 67 3-4 18 55 65 First-line treatment CHOP-like 126 54 0.606 70 0.505 Others 48 65 67 Radiotherapy Yes 22 45 0.229 63 0.522 No 152 59 70 First-line ASCT Yes 103 63 0.042 74 0.124 No 71 49 62 PFS: progression-free survival; OS: overall survival; PTCL, NOS: peripheral T-cell lymphoma, not otherwise specified; AITL: angioimmunoblastic T-cell lymphoma; ALCL: anaplastic large cell lymphoma; ALK: anaplastic lymphoma kinase; ECOG-PS: Eastern Cooperative Oncology Group Performance Status; CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisolone; ASCT: autologous stem-cell transplantation. Haematologica | 107 November 2022 2679 ARTICLE - ASCT as consolidation of first-line treatment for PTCL A. M. García-Sancho et al. mable], 5-year OS 70% [95% CI: 59.8–80.2]) than for non- agnosis maintained an independent influence on both PFS ASCT patients (median 71.0 months [95% CI: 40.3-101.7], (HR=0.55 [95% CI: 0.34-0.90] and 0.52 [95% CI: 0.29-0.93] 5-year OS 50% [95% CI: 32.0–68.0], P=0.028). for ASCT and stage, respectively) and OS (HR=0.53 [95% CI: 0.31-0.91] and 0.40 [95% CI=0.20-0.80] for ASCT and Multivariate analysis stage, respectively). To account for disease imbalances between groups, a In addition, we carried out a multivariate sensitivity analy- multivariate analysis using Cox regression was performed. sis including only patients with nodal PTCL (angioimmu- In 156 cases for which complete data were available, first- noblastic T-cell lymphoma, ALCL, ALK-negative and PTCL, line ASCT was associated with significantly prolonged PFS NOS). First-line ASCT and localized stage at diagnosis (HR=0.57, 95% CI: 0.35-0.93) and OS (HR=0.57, 95% CI: maintained their independent influence on both PFS 0.33-0.99) independently of the individual variables of the (HR=0.57 [95% CI: 0.34-0.96] and 0.45 [95% CI: 0.23-0.87] IPI and PIT scores, B-symptoms, sex, histological subtype, for ASCT and stage, respectively) and OS (HR=0.52 [95% and first-line regimen, as shown in Table 3. Localized CI: 0.29-0.93] and 0.31 [95% CI: 0.13-0.70] for ASCT and stage at diagnosis was also associated with better PFS stage, respectively). (HR=0.54, 95% CI: 0.31-0.96) and OS (HR=0.38, 95% CI: 0.19-0.78). We also tested IPI and PIT scores (excluding all Separate analysis of patients in partial response after individual variables other than disease stage) in the multi- first-line variate analysis. First-line ASCT and localized stage at di- As a secondary objective, we assessed survival in patients A B Figure 2. Kaplan–Meier estimation of survival in the transplanted and non-transplanted cohorts. (A) Progression-free survival; (B) overall survival. ASCT: autologous stem-cell transplantation Figure 3. Kaplan-Meier estimation of overall survival by stage at diagnosis in the transplanted and non-transplanted cohorts. ASCT: autologous stem-cell transplantation. Haematologica | 107 November 2022 2680 ARTICLE - ASCT as consolidation of first-line treatment for PTCL A. M. García-Sancho et al. undergoing ASCT in PR after first-line chemotherapy. Of OS (53% [95% CI: 24.4-82.4] vs. 52% [95% CI: 31.8-72.6] at 53 patients with a documented PR after first-line treat- 5 years [P=0.962] in the ASCT and non-ASCT groups, re- ment, 15 were excluded because they had disease pro- spectively). gression within 3 months of the initiation of the last cycle of first-line treatment. Fifteen patients underwent ASCT in PR after first-line treatment, whereas 23 patients did not undergo transplantation. Of these 23 patients, 17 re- Discussion ceived salvage chemotherapy while in PR and five received In the present study, we collected clinical data from pa- it after further progression. Eleven patients underwent tients with newly diagnosed PTCL from 44 institutions in transplantation (8 autologous and 3 allogeneic trans- Spain and Italy. The cohorts included in this analysis either plants) as part of the salvage therapy. underwent upfront ASCT or were observed after achieving There were no significant differences between ASCT and first CR/CRu (CR1). Although the clinical characteristics of non-ASCT groups with respect to patients’ characteristics the transplanted and non-transplanted patients differed, and first-line treatment, as shown in Online Supplemen- multivariate analysis identified ASCT as one of the main tary Table S2. With a median follow-up of 84.1 months variables influencing PFS (HR=0.57, 95% CI: 0.35-0.93) and (range, 26.3-138.7 months), there was a trend towards OS (HR=0.57, 95% CI: 0.33-0.99), suggesting a benefit of better PFS in the transplant group compared with the upfront ASCT in patients with PTCL in CR1. non-ASCT group (Online Supplementary Figure S1): 46% The current recommendation to consider ASCT in first re- (95% CI: 18.5-74.1) vs. 27% (95% CI: 7.7-45.3) at 5 years mission for most PTCL subtypes is largely based on the (P=0.081), respectively, with no significant differences in results from several phase II, single-arm studies.4-8 The Table 3. Multivariate Cox regression model (backward selection) for survival. PFS OS Characteristic (N=156) HR (95% CI) P HR (95% CI) P Included in the model First-line ASCT Yes vs. no 0.59 (0.36-0.96) 0.035 0.57 (0.33-0.99) 0.048 Stage I-II vs. III-IV 0.53 (0.29-0.96) 0.035 0.40 (0.19-0.81) 0.012 Removed from the model Sex Male vs. female 0.407 0.706 Histology 0.366 0.402 PTCL, NOS vs. AITL vs. ALCL, ALK-negative vs. others B symptoms Yes vs. no 0.986 0.528 Bone marrow infiltration No vs. yes 0.608 0.729 Age ≤60 vs. >60 years 0.997 0.281 ECOG-PS 0-1 vs. 2-4 0.617 0.779 Lactate dehydrogenase Normal vs. high 0.928 0.882 Extranodal sites 0-1 vs. ≥2 0.514 0.199 First-line chemotherapy CHOP-like vs. others 0.668 0.595 Radiotherapy Yes vs. no 0.188 0.135 PFS: progression-free survival; OS: overall survival; HR: hazard ratio; 95% CI: 95% confidence interval; ASCT: autologous stem-cell transplan- tation; PTCL, NOS: peripheral T-cell lymphoma, not otherwise specified; AITL: angioimmunoblastic T-cell lymphoma; ALCL: anaplastic large cell lymphoma; ALK: anaplastic lymphoma kinase; ECOG-PS, Eastern Cooperative Oncology Group Performance Status; CHOP, cyclophos- phamide, doxorubicin, vincristine, and prednisolone. Haematologica | 107 November 2022 2681 ARTICLE - ASCT as consolidation of first-line treatment for PTCL A. M. García-Sancho et al. largest prospective trial evaluating ASCT in first-line was not improve PFS when compared with active observation carried out by the Nordic Lymphoma Group (NLG T-01 in PTCL patients who achieved CR1 after receiving CHOP- study) in which patients with de novo PTCL were treated like induction chemotherapy, but these results were also with CHOEP-14 x 6 followed by BEAM/BEAC and ASCT, limited by the small sample size (n=20 transplanted pa- leading to long-term PFS in 44% of patients.8 In the Italian tients). In contrast, in another observational study (COM- experience, patients who attained CR before ASCT had PLETE)14 that directly compared the outcomes of ASCT significantly better outcomes than patients who did not and non-ASCT in patients with nodal PTCL in CR1, ASCT achieve CR, in terms of OS (48% vs. 22% at 10 years, emerged as one of the variables most strongly associated P<0.0001) and event-free survival (47% vs. 11%, P<0.0001). with favorable OS (HR=0.37; 95% CI: 0.15-0.89), whereas However, these studies are very difficult to interpret be- an advanced stage was associated with poor OS (HR=2.65; cause they did not include a control group of patients who 95% CI: 1.08-6.55), in line with our results. However, this did not undergo transplantation. In the absence of ran- study was limited not only by the small number of pa- domized clinical trials, no definitive consensus has there- tients who proceeded to transplantation (n=36), but also fore been reached about the role of ASCT as upfront by the relatively short duration of follow-up (median of consolidation for PTCL patients. ~34 months). Retrospective comparisons of ASCT versus observation in Similar to the COMPLETE study, the present study directly first remission have produced conflicting results.1,9,11-15 Fos- compared the results of ASCT and non-ASCT in patients sard et al.9 analyzed a cohort of 269 patients with nodal in CR1, but in a much larger series (103 ASCT and 71 non- PTCL other than ALK-positive ALCL in CR (n=217) or PR ASCT cases) and with longer follow-up (>60 months). In (n=52) after induction. The patients were divided into two our series, clinical characteristics differed between the groups, ASCT and non-ASCT, based on the physicians’ two groups, as a significantly higher proportion of patients decision before starting induction treatment (intention- in the transplant group had adverse prognostic factors, to-treat), according to the information collected in the such as advanced stage or increased LDH level. This indi- medical records. Neither the Cox multivariate model nor cates that baseline risk factors, especially stage, could the propensity score analysis revealed a survival advan- play a significant role in determining whether to proceed tage for ASCT as a consolidation procedure for patients in with ASCT in CR1. Nevertheless, it is remarkable that the response after induction. However, in a study from the ASCT group was associated with superior PFS in the over- Swedish Lymphoma Registry,1 upfront ASCT was associ- all series, even though a significantly higher proportion of ated with a superior OS (HR=0.58, P=0.004) and PFS patients in the ASCT group had more adverse prognostic (HR=0.56, P=0.002) compared with the outcomes of pa- factors than the non-ASCT group. Consistent with what tients treated without ASCT in an intention-to-treat Park et al. found in the COMPLETE study,14 in our study we analysis of 252 patients with nodal PTCL or enteropathy- observed a significant influence of upfront ASCT on OS, associated T-cell lymphoma (excluding ALK-positive especially in patients with advanced-stage disease, ALCL), although no adjustment for response status after whereas the benefit was less evident in patients with li- induction was made. mited-stage disease. These results should be interpreted The design of our study differs from that of the two pre- with caution because of the small sample sizes available viously mentioned, since we selected the patients in CR1, for these subanalyses. who are likely to benefit the most from ASCT, rather than As a secondary objective, we assessed the survival of pa- using a design that enabled an analysis based on the in- tients undergoing ASCT in PR after first-line therapy. Our tention to treat. Since transplantation is usually per- results indicate that a significant proportion of patients in formed several weeks after remission is achieved, rather PR could benefit from transplantation, although, once than immediately after, patients who experienced pro- again, these results must be interpreted with caution due gressive disease within 3 months of the initiation of the to the very small sample size investigated in this sub- last cycle of first-line chemotherapy were not considered analysis. Recent studies16,17 have shown that patients with to be responders, and were excluded from the analysis to relapsed or refractory diffuse large B-cell lymphoma in PR limit a potential bias. Other retrospective studies have after salvage therapy could still benefit from ASCT, but, to also analyzed the role of ASCT in patients who achieve CR our knowledge, this subject has not been specifically in- after induction treatment. Abramson et al.13 showed a vestigated in patients with PTCL; it warrants being ad- benefit favoring ASCT in first remission, but this dis- dressed in future studies. appeared in multivariate analysis when adjusting for CR In all the studies that we have discussed, including our to initial chemotherapy as well as stage, LDH, and hypo- own, the response to induction therapy is assessed mainly albuminemia, although these results were limited by the by computed tomography.18 The impact of upfront ASCT small number of patients who proceeded to transplanta- in patients with PTCL in complete metabolic response has tion (n=33). In a single-center study11, upfront ASCT did not been rigorously investigated. In a retrospective study, Haematologica | 107 November 2022 2682 ARTICLE - ASCT as consolidation of first-line treatment for PTCL A. M. García-Sancho et al. the prognostic significance of 18F-fluorodeoxyglucose Takeda, Eusa Pharma and Novartis. SB reports honoraria positron emission tomography–computed tomography and/or non-financial support from Gilead, Janssen, Novar- (PET/CT) responses to induction chemotherapy was tis and Roche. The remaining authors have no relevant studied in 96 patients with PTCL from two centers. In the conflicts of interest to disclose. 59 patients with final response Deauville scores of 1–2, there was no statistically significant difference in the PFS Contributions and OS between the transplanted and non-transplanted AMGS, DC, MB and MF were responsible for the design and patients. In addition, of the 37 patients with a final PET/CT conduct of the study; AMGS, MLP, MC, and MB analyzed response score of 3–4, the PFS rate was equally poor in and interpreted the data; AMGS drafted the report, which transplanted and non-transplanted patients. The study all co-authors critically revised for significant scientific was limited by the small number of patients who pro- content; MLP, GG, SN, CP, LP, AG, ID, MBO, JMS, MJR, JMM, ceeded to transplantation in the overall series (n=37) and EC, AIJU, IJ, LO, EGT, CM, AD, RA, NH, MJP, JLJ, MS, AR, SGV, by the interpretation of the Deauville scale, since only pa- and SB contributed research data to the study; all co- tients with a score of 1–2 were considered to have shown authors contributed to data analysis and interpretation, a complete metabolic response, whereas the international and approved the submitted and final versions. consensus regards patients with scores of 1–3 as showing a complete response.19,20 Therefore, further studies are Acknowledgments needed to define the role of PET/CT in patients with PTCL AWe are grateful to Ángel Cedillo and Ana Méndez, from treated with upfront ASCT. the Grupo Español de Linfomas y Trasplante Autólogo de The observational nature of this study means that it is Médula Ósea (GELTAMO), and Fondazione Italiana Linfomi prone to unintentional bias and the effects of confounding (FIL), for their research support. Our thanks to Phil Mason variables. There are three major limitations to the study. for correcting the grammar and spelling errors of this ar- First, no central histological diagnostic review was under- ticle. taken. Second, in the non-ASCT group, the decision not to proceed to transplantation was taken well into the Data-sharing statement treatment of some patients, based mainly on the patients’ Any requests for study data and protocol will be reviewed general condition, which could have been associated with by the study management group and GELTAMO/FIL. Only subsequent worse survival. Finally, the response to first- requests that have a methodologically sound basis and line treatment was determined by the treating physician whose proposed use of the data has been approved by the supported by an imaging investigation; however, response applicable ethics committees and regulatory authorities criteria could have changed over time and imaging inves- will be considered. tigations were not specifically reviewed for this study. Overall, and bearing in mind the study’s limitations, the Collaborators data presented here support the use of ASCT as a con- In addition to the authors, the following investigators col- solidation strategy for patients with PTCL other than ALK- laborated in the present study: M. Manni (CHIMOMO De- positive ALCL in CR1. Our analyses suggest that some partment, University of Modena and Reggio Emilia, Modena, subgroups of patients, especially those with advanced- Italy), F. Merli (Hematology Unit, Azienda Unità Sanitaria stage disease, might benefit more than others. Given the Locale-IRCCS, Reggio Emilia, Italy), I. Ceberio (Hematology limitations of any retrospective study and the lack of con- Department, Hospital Universitario Donostia, San Sebas- sensus about the procedure, a large collaborative ran- tián, Spain), M. Pedreño (Department of Clinical Hematol- domized trial should be conducted to enable definitive ogy, Hospital Dr. Peset, Valencia, Spain), M.J. conclusions to be drawn. Rodríguez-Salazar (Hematology Department, Hospital Uni- versitario de Canarias, Santa Cruz de Tenerife, Spain), M. Disclosures Casanova (Hematology Department, Hospital Costa del AMG-S reports consulting fees, honoraria and/or non-fi- Sol, Marbella, Spain), E. de Cabo (Department of Hematol- nancial support from Roche, Celgene/BMS, Morphosys, ogy, Hospital de El Bierzo, León, Spain), A.J.M. Ferreri (Lym- Kyowa Kirin, Clinigen, Eusa Pharma, Novartis, Gilead, Ser- phoma Unit, Department of Onco-Haematology, IRCCS San vier, Incyte, Janssen and Takeda. SN reports honoraria from Raffaele Scientific Institute, Milano, Italy), E. González- Takeda. CP reports consulting fees, honoraria and/or non- Barca (Clinical Hematology Department, ICO-Hospital financial support from Roche, Janssen, Celgene/BMS, In- Duran i Reynals, IDIBELL, Barcelona, Spain), A.M. D’Arco cyte and Kyowa Kirin. J-MS reports consulting fees and/or (Onco-hematology Unit, Hospital A. Tortora, Pagani, Sa- honoraria from Roche, Janssen, Gilead-Kite, BMS-Celgene, lerno, Italy), A. Muntañola (Hematology Department, Hos- Novartis, Lilly, Incyte, Beigene and Takeda. RA reports con- pital Mútua de Terrassa, Terrassa, Spain), P. Sánchez-Godoy sulting fees, honoraria and/or non-financial support from (Hematology Department, University Hospital Severo Haematologica | 107 November 2022 2683 ARTICLE - ASCT as consolidation of first-line treatment for PTCL A. M. García-Sancho et al. Ochoa, Madrid, Spain.), J. Pérez de Oteyza (Hospital Uni- tiago de Compostela, Spain), A. Suárez-Cabrera (Hematol- versitario Madrid Sanchinarro, Madrid, Spain), M. Rodrí- ogy Department, Hospital Universitario de Gran Canaria guez-Calvillo (Department of Hematology, Hospital Doctor Negrín, Las Palmas de Gran Canaria, Spain), M.A. Complex Navarre, Pamplona, Navarra, Spain), M. Roig (De- Canales (Hematology Department, Hospital Universitario partment of Hematology, Hospital General Universitario de La Paz, Madrid, Spain), C. Cuéllar (Hematology Department, Valencia, Valencia, Spain), C. Stelitano (Department of Hospital de la Santa Creu i Sant Pau, Barcelona, Spain), Hematology, Grande Ospedale Metropolitano Bianchi Mel- M.J. 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