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Impact of rituximab on treatment outcomes of patients with angioimmunoblastic T-cell lymphoma; a population-based analysis

Open AccessPublished:October 05, 2022DOI:https://doi.org/10.1016/j.ejca.2022.09.008

      Highlights

      • Epstein–Barr virus-positive B-cells are present in most angioimmunoblastic T-cell lymphomas.
      • The effect of rituximab when added to CHO(E)P remains unknown.
      • Nearly half of patients with angioimmunoblastic T-cell lymphoma (44%) at population level received rituximab.
      • There is no progression-free survival and overall survival difference between patients treated with or without rituximab.

      Abstract

      Background

      Patients with angioimmunoblastic T-cell lymphoma (AITL) are treated with cyclophosphamide, doxorubicin, vincristine and prednisone with or without etoposide (CHO(E)P). In the majority of cases, Epstein–Barr virus (EBV)-positive B-cells are present in the tumour. There is paucity of research examining the effect of rituximab when added to CHO(E)P. In this nationwide, population-based study, we analysed the impact of rituximab on overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) of patients with AITL.

      Methods

      Patients with AITL diagnosed between 2014 and 2020 treated with ≥one cycle of CHO(E)P with or without rituximab were identified in the Netherlands Cancer Registry. Survival follow-up was up to 1st February 2022. Baseline characteristics, best response during first-line treatment and survival were collected. PFS was defined as the time from diagnosis to relapse or to all-cause-death. OS was defined as the time from diagnosis to all-cause-death. Multivariable analysis for the risk of mortality was performed using Cox regression.

      Findings

      Out of 335 patients, 146 patients (44%) received R–CHO(E)P. Rituximab was more frequently used in patients with a B-cell infiltrate (71% versus 89%, p < 0·01). The proportion of patients who received autologous stem cell transplantation (ASCT) was similar between CHO(E)P and R–CHO(E)P (27% versus 30%, respectively). The ORR and 2-year PFS for patients who received CHO(E)P and R–CHO(E)P were 71% and 78% (p = 0·01), and 40% and 45% (p = 0·12), respectively. The 5-year OS was 47% and 40% (p = 0·99), respectively. In multivariable analysis, IPI-score 3–5, no B-cell infiltrate and no ASCT were independent prognostic factors for risk of mortality, whereas the use of rituximab was not.

      Interpretation

      Although the addition of rituximab to CHO(E)P improved ORR for patients with AITL, the PFS and OS did not improve.

      Kewords

      1. Introduction

      Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive, mature T-cell lymphoproliferative neoplasm that is classified as one of the peripheral T-cell lymphomas (PTCL) [
      • Swerdlow S.H.
      • Campo E.
      • Harris N.L.
      • et al.
      Mature T- and NK-cell neoplasms.
      ]. AITL is one of its most prevalent subtypes in Europe and North America, accounting for 13–36% of PTCL diagnoses [
      • Ellin F.
      • Landström J.
      • Jerkeman M.
      • Relander T.
      Real-world data on prognostic factors and treatment in peripheral T-cell lymphomas: a study from the Swedish lymphoma registry.
      ,
      International T-cell Lymphoma Project
      International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes.
      ,
      • Petrich A.M.
      • Helenowski I.B.
      • Bryan L.J.
      • Rozell S.A.
      • Galamaga R.
      • Nabhab C.
      Factors predicting survival in peripheral T-cell lymphoma in the USA: a population-based analysis of 8802 patients in the modern era.
      ,
      • De Leval L.
      • Parrens M.
      • Le Bras F.
      • et al.
      Angioimmunoblastic T-cell lymphoma is the most common T-cell lymphoma in two distinct French information data sets.
      ].
      AITL primarily presents itself as generalised nodal disease with also frequent involvement of the skin, spleen, liver and bone marrow. The disease is often accompanied by paraneoplastic phenomena due to immune dysregulation, including pruritic skin rash, pleural effusion, ascites and arthritis. Anti-smooth muscle antibodies, rheumatoid factor, circulating immune complexes and cold agglutinins with haemolytic anaemia can be observed [
      • Siegert W.
      • Nerl C.
      • Agthe A.
      • et al.
      Angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma: prognostic impact of clinical observations and laboratory findings at presentation.
      ,
      • Dogan A.
      • Attygalle A.D.
      • Kyriakou C.
      Angioimmunoblastic T-cell lymphoma.
      ,
      • Lachenal F.
      • Berger F.
      • Ghesquières H.
      • et al.
      Angioimmunoblastic T-cell lymphoma: clinical and laboratory features at diagnosis in 77 patients.
      ,
      • Mourad N.
      • Mounier N.
      • Brière J.
      • et al.
      Clinical, biologic, and pathologic features in 157 patients with angioimmunoblastic T-cell lymphoma treated within the groupe d'Etude des lymphomes de l'Adulte (GELA) trials.
      ].
      AITL originates from T-follicular helper cells (TFH) [
      • De Leval L.
      • Rickman D.S.
      • Thielen C.
      • et al.
      The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells.
      ,
      • Piccaluga P.P.
      • Agostinelli C.
      • Califano A.
      • et al.
      Gene expression analysis of angioimmunoblastic lymphoma indicates derivation from T follicular helper cells and vascular endothelial growth factor deregulation.
      ]. TFH are a subset of CD4+ T-cells that are formed from naïve T-cells under the influence of antigen recognition. In healthy individuals, TFH are involved in germinal centre formation and support B-cells in the development of high affinity antibodies [
      • De Leval L.
      • Rickman D.S.
      • Thielen C.
      • et al.
      The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells.
      ,
      • Ahearne M.J.
      • Allchin R.L.
      • Fox C.P.
      • Wagner S.D.
      Follicular helper T-cells: expanding roles in T-cell lymphoma and targets for treatment.
      ,
      • Delfau-Larue M.
      • de Leval L.
      • Joly B.
      • et al.
      Targeting intratumoral B cells with rituximab in addition to CHOP in angioimmunoblastic T-cell lymphoma. A clinicobiological study of the GELA.
      ,
      • Crotty S.
      T follicular helper cell differentiation, function, and roles in disease.
      ]. In the majority of patients (66–91%), Epstein–Barr virus (EBV)-positive, CD20-positive B-cells are present in the tumour infiltrate while the neoplastic T-cells are EBV negative [
      • De Leval L.
      • Parrens M.
      • Le Bras F.
      • et al.
      Angioimmunoblastic T-cell lymphoma is the most common T-cell lymphoma in two distinct French information data sets.
      ,
      • Lachenal F.
      • Berger F.
      • Ghesquières H.
      • et al.
      Angioimmunoblastic T-cell lymphoma: clinical and laboratory features at diagnosis in 77 patients.
      ,
      • Mourad N.
      • Mounier N.
      • Brière J.
      • et al.
      Clinical, biologic, and pathologic features in 157 patients with angioimmunoblastic T-cell lymphoma treated within the groupe d'Etude des lymphomes de l'Adulte (GELA) trials.
      ,
      • Anagnostopoulos I.
      • Hummel M.
      • Finn T.
      • et al.
      Heterogeneous epstein-barr virus infection patterns in peripheral T-cell lymphoma of angioimmunoblastic lymphadenopathy type.
      ,
      • Weiss L.M.
      • Jaffe E.S.
      • Liu X.F.
      • et al.
      Detection and localization of epstein-barr viral genomes in angioimmunoblastic lymphadenopathy and angioimmunoblastic lymphadenopathy-like lymphoma.
      ,
      • Dobay M.P.
      • Lemonnier F.
      • Missiaglia E.
      • et al.
      Integrative clinicopathological and molecular analyses of angioimmunoblastic T-cell lymphoma and other nodal lymphomas of follicular helper T-cell origin.
      ,
      • Tokunaga T.
      • Shimada K.
      • Yamamoto K.
      • et al.
      Retrospective analysis of prognostic factors for angioimmunoblastic T-cell lymphoma: a multicenter cooperative study in Japan.
      ,
      • Chiba S.
      • Sakata-Yaganimoto M.
      Advances in understanding of angioimmunoblastic T-cell lymphoma.
      ]. The exact role that EBV plays in the course of AITL is still unknown. The EBV-positive CD20-positive B-cell infiltrate is likely to be a manifestation of the immunocompromised state of the patient rather than being a dominant driver of lymphomagenesis of AITL [
      • Ahearne M.J.
      • Allchin R.L.
      • Fox C.P.
      • Wagner S.D.
      Follicular helper T-cells: expanding roles in T-cell lymphoma and targets for treatment.
      ]. Clonal B-cell expansion can result in B-cell lymphomas [
      • Swerdlow S.H.
      • Campo E.
      • Harris N.L.
      • et al.
      Mature T- and NK-cell neoplasms.
      ].
      Patients are treated with either cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or with the same regimen with additional etoposide (CHOEP). CHOEP is favoured in some countries for the treatment of PTCL, but the evidence supporting this treatment strategy in AITL is controversial [
      • Ellin F.
      • Landström J.
      • Jerkeman M.
      • Relander T.
      Real-world data on prognostic factors and treatment in peripheral T-cell lymphomas: a study from the Swedish lymphoma registry.
      ,
      • Schmitz N.
      • Trümper L.
      • Ziepert M.
      • et al.
      Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German high-grade non-hodgkin lymphoma study group.
      ,
      • Deng S.
      • Lin S.
      • Shen J.
      • Zeng Y.
      Comparison of CHOP vs CHOPE for treatment of peripheral T-cell lymphoma: a meta-analysis.
      ]. Recently, in a large population-based analysis, there was no effect of etoposide on the outcome in patients with AITL below 65-years of age [
      • Brink M.
      • Meeuwes F.O.
      • Van der Poel M.W.M.
      • et al.
      Impact of etoposide and ASCT on survival among patients < 65 years with stage II-IV PTCL; a population-based cohort study.
      ]. Complete remission (CR) is achieved in 70% of patients, however, relapses frequently occur [
      • Savage K.J.
      • Chhanabhai M.
      • Gascoyne R.D.
      • Connors J.M.
      Characterization of peripheral T-cell lymphomas in a single north american institution by the WHO classification.
      ]. The prognosis of patients with AITL is poor, with a median 5-year overall survival (OS) of 32–36% [
      • Ellin F.
      • Landström J.
      • Jerkeman M.
      • Relander T.
      Real-world data on prognostic factors and treatment in peripheral T-cell lymphomas: a study from the Swedish lymphoma registry.
      ,
      International T-cell Lymphoma Project
      International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes.
      ,
      • Petrich A.M.
      • Helenowski I.B.
      • Bryan L.J.
      • Rozell S.A.
      • Galamaga R.
      • Nabhab C.
      Factors predicting survival in peripheral T-cell lymphoma in the USA: a population-based analysis of 8802 patients in the modern era.
      ,
      • Savage K.J.
      • Chhanabhai M.
      • Gascoyne R.D.
      • Connors J.M.
      Characterization of peripheral T-cell lymphomas in a single north american institution by the WHO classification.
      ]. Patients who progress or relapse have a dismal outcome with a 3-year OS of less than 10% [
      • 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.
      ]. In younger patients, consolidation with high-dose chemotherapy and autologous stem cell transplantation (ASCT) is often performed in chemo-sensitive disease. However, the impact of ASCT remains a matter of debate [
      • Schmitz N.
      • Trümper L.
      • Ziepert M.
      • et al.
      Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German high-grade non-hodgkin lymphoma study group.
      ,
      • 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.
      ].
      It has been postulated that targeting CD20-positive B-cell infiltrates in AITL with the anti-CD20 monoclonal antibody rituximab (R) might improve outcome. However, this hypothesis has only been studied in non-randomised, small series–the largest study containing 25 patients [
      • Delfau-Larue M.
      • de Leval L.
      • Joly B.
      • et al.
      Targeting intratumoral B cells with rituximab in addition to CHOP in angioimmunoblastic T-cell lymphoma. A clinicobiological study of the GELA.
      ,
      • Joly B.
      • Frenkel V.
      • Gaulard P.
      • et al.
      Rituximab in combination with CHOP regimen in angioimmunoblastic T-cell lymphoma (AITL). preliminary results in 9 patients treated in a single institution.
      ,
      • Joly B.
      • Plonquet A.
      • Grare M.
      • et al.
      Rituximab in combination with CHOP regimen in angioimmunoblastic T-cell lymphoma: results of the phase II RAIL trial—a prospective study of the groupe d'etude des lymphomes de l'adulte (GELA).
      ]. While these studies do not show a clear clinical advantage, rituximab is regularly used in daily practice given its biological rationale.

      1.1 Objective

      This nationwide, population-based study analysed the impact of rituximab on best response, progression-free survival (PFS) and OS of patients with AITL treated with CHO(E)P.

      2. Material and methods

      2.1 Registry and study population

      The nationwide population-based Netherlands Cancer Registry (NCR) is maintained and hosted by the Netherlands Comprehensive Cancer Organisation (IKNL) and has nationwide coverage of at least 95% of all malignancies since 1989. The NCR relies on comprehensive case notification through the Nationwide Histopathology and Cytopathology Data Network and the Nationwide Registry of Hospital Discharges (i.e. inpatient and outpatient discharges). Information on dates of birth and diagnosis, sex, topography and morphology, hospital type of diagnosis and first-line therapy is routinely recorded by trained registrars of the NCR through retrospective medical records review. Information on the last known vital status for all patients (i.e. alive, dead or emigration) is obtained through annual linkage with the Nationwide Population Registries Network that holds vital statistics on all residents of the Netherlands. Since 1st January 2014, detailed information on diagnostic and treatment characteristics for all haematological malignancies diagnosed in the Netherlands is recorded in the NCR.
      Patients with AITL were identified from the NCR, using the International Coding system of Disease–Oncology (ICD-O) of the World Health Organization (WHO) morphology code 9705/3. The status of EBV+ B-cell infiltrates was retrieved by NCR clerks based on the information in the pathology reports. All patients diagnosed with AITL between 2014 and 2020 who received at least one cycle of CHO(E)P either with or without rituximab were included. Patients who were treated differently, not treated at all or patients who were diagnosed through autopsy were excluded from all analyses. The registry clerks went through the digital pathology reports of the included patients, thereby depending on key words or terms regarding (EBV+) B-cell infiltrate, used by the pathologists. Terms like ‘B-cell infiltrates and/or EBV present/observed/positive/+’ were registered as ‘positive’ in the NCR, whereas terms like ‘B-cell infiltrates and/or EBV absent/negative/-’ were registered as ‘negative’. If no information on B-cell infiltrate or EBV could be retrieved, registry clerks registered ‘unknown’. Registry clerks were blinded for treatment regimen as well as for outcome. Survival follow-up was available through 1st February 2022.
      According to the Central Committee on Research involving Human Subjects (CCMO), this type of observational study does not require approval from an ethics committee in the Netherlands. The Privacy Review Board of the NCR approved the use of anonymous data for this study.

      2.2 End-points

      The primary end-point was OS, which was defined as the time between AITL-diagnosis and all-cause-death. Patients alive were censored on February 1st, 2022. The secondary end-points were PFS and best response, i.e. CR, partial response (PR) or stable/progressive disease (SD/PD), to first-line treatment, as such routinely collected by trained registrars of the NCR through retrospective medical record review. Best response was determined by physician assessment, using the Lugano classification as of 2014 onward. PFS was defined as the time between AITL-diagnosis and tumour progression or all-cause-death, whichever occurred first.

      2.3 Statistical analyses

      Descriptive statistics were used to present patient and treatment characteristics between patients who received R–CHO(E)P and patients who received CHO(E)P. The Pearson chi-square test was used to compare categorical covariables, and the Kruskal–Wallis test was used to compare non-normally distributed continuous covariables between the two treatment groups. A p-value below 0.05 was considered statistically significant.
      The Kaplan–Meier method served to estimate OS, and the log-rank test to examine differences in survival distributions. OS was calculated for the two treatment groups. Then, the impact of age, sex, Ann Arbor stage, LDH, extranodal localisation, WHO Performance score, IPI-score, EBV status, type of chemotherapy and ASCT as a time-varying covariate on risk of mortality was evaluated using univariable and multivariable Cox proportional hazard regression analysis.
      The results from the Cox regression analyses produce hazard ratios (HRs) with associated 95% confidence intervals (CIs). The proportional hazard assumption was tested based on the Schoenfeld residuals. All covariables, presented as patient and clinicopathological factors in Table 1, were introduced in the multivariable regression model simultaneously, thereby using a backward selection method to exclude covariables with a p-value below 0·05. All analyses were performed using STATA/SE 17.1 (StataCorp LP, College Station, Texas, USA).
      Table 1Characteristics of patients treated with R–CHO(E)P vs. CHO(E)P.
      R–CHO(E)PCHO(E)Pp-value
      No.%No.%
      Number of patients (% row)1464418956
      Female sex523679420.25
      Age at diagnosis
       Median age at diagnosis (years, range)69 (27–85)67 (28–88)0.57
       18-60422962330.43
       >601047112767
      Clinicopathological factors
      Ann Arbor stage0.33
       1-275137
       3-41369317593
      Unknown3210
      Elevated LDH8860104550.56
      WHO Performance score0.87
       0-162427640
       2-418122212
       Unknown66459148
      >1 Extranodal localisation (yes)201428150.32
      IPI-score0.61
       0-267469249
       3-579549751
      EBV status<0.01
       B-cell infiltrate+, EBV+110759952
       B-cell infiltrate+, EBV-21144419
       No B-cell infiltrate14103820
       Unknown1184
      First-line treatment
      Type of chemotherapy0.95
       CHOP946412164
       CHOEP52366836
      Number of CHO(E)P cycles0.36
       <635245831
       ≥61107512968
       Unknown1121
      Stem cell transplantation0.36
       No1027013772
       Autologous44305027
       Allogenic0021

      3. Results

      3.1 Patient characteristics

      Between 2014 and 2020, 462 patients were newly diagnosed with AITL in the Netherlands; 87 (19%) patients did not receive first-line therapy, whereas 375 (81%) patients did. The group that received first-line treatment (n = 375) was treated with CHO(E)P (n = 189, 50%) or R–CHO(E)P (n = 146, 39%); 40 (11%) were treated with other types of chemotherapy. For the current study, 335 patients treated with CHO(E)P with (n = 146, 44%) or without (n = 189, 56%) rituximab were included for analyses and their clinical factors are presented in Table 1. In the CHO(E)P group, B-cell infiltrates were less frequently observed than in the R–CHO(E)P group (71% and 89%, respectively; p < 0·01). In 69% and 84%, respectively, the B-cell infiltrates were EBV+. There were no significant differences in the remaining patient factors such as age and sex or clinical factors related to Ann Arbor stage and IPI-score (Table 1).

      3.2 First-line therapy

      Rituximab was given in 44% (n = 146) of patients treated with CHO(E)P (Table 1). Between 2014 and 2020, the addition of rituximab to CHO(E)P increased from 36% in 2014 to 53% in 2016, thereafter decreased to 47% in 2020 (Supplementary Fig. 1). CHOP was preferred over CHOEP in both treatment groups (64% in both) (Table 1).

      3.3 Outcome

      The best overall response rates (ORR; CR + PR) for patients who received CHO(E)P and R–CHO(E)P were 71% and 78%, respectively (p = 0·01) (Fig. 1). CR was more frequently observed in patients treated with R–CHO(E)P (65% versus 53%, respectively, p = 0·02). There was no significant difference in patients proceeding to ASCT between patients receiving CHO(E)P and R–CHO(E)P (27% versus 30%, p = 0.36). The 2-year PFS for all patients was 42% and was not statistically different between patients treated with CHO(E)P and R–CHO(E)P (40% and 45%, p = 0·12; Fig. 2A). The 5-year OS for the entire cohort was 43% and was not statistically different between patients treated with CHO(E)P and R–CHO(E)P (46% and 40%, p = 0·99; Fig. 2B). For patients not proceeding to ASCT, we observed no significant difference in outcome between patients treated either with or without rituximab (5-year OS 29% and 33%, p=0·55) (Fig. 2C). HRs and corresponding 95% CIs of univariable and multivariable analyses for OS is presented in Fig. 3. The risk of mortality was similar for patients treated with CHO(E)P and R–CHO(E)P (HR, 1.04; 95%CI, 0.77–1.39; p = 0·81). In multivariable analysis, IPI-score 3–5 (HR 1.59, p < 0·01), the absence of a B-cell infiltrate (HR 2.32, p < 0·01) and no ASCT (HR 3.00, p < 0·01) were independent prognostic factors for the risk of mortality, whereas rituximab treatment was not (Fig. 3). HRs and corresponding 95% CIs for the risk of relapse are presented in Supplementary Fig. 2.
      Fig. 1
      Fig. 1Response to treatment according to regimen; R–CHO(E)P versus CHO(E)P.
      Fig. 2
      Fig. 2A. Progression-free survival for patients treated with R–CHO(E)P versus CHO(E)P B. Overall survival for patients treated with R–CHO(E)P versus CHO(E)P. C. Overall survival for patients not proceeding to ASCT, according to R–CHO(E)P and CHO(E)P.
      Fig. 3
      Fig. 3Forest plot of univariable and multivariable analysis for the risk of mortality.

      4. Discussion

      The hypothesis that targeting CD20-positive B-cell infiltrates in AITL with rituximab might improve outcome has been studied only in small non-randomised studies. While these studies showed no clear advantage, rituximab has been widely used in the Netherlands in the first-line treatment of AITL between 2014 and 2020. Rituximab was even used in patients without clear evidence of an (EBV+) B-cell infiltrate (10%). This finding in itself is remarkable. This might have occurred due to rare occurrence and lack of clinical trials in PTCL. For clinicians, conjecture may play a role in the treatment choice–since outcomes are poor – even more so because rituximab is generally well tolerated.
      In this largest population-based cohort study to date assessing the impact of rituximab on the treatment of AITL, the CR rates were higher in the rituximab group. However, this neither translated into an increased percentage of patients going into ASCT consolidation nor did it translate into a statistically significant difference in 2-year PFS or 5-year OS. Therefore, if rituximab would be of added value in the treatment of AITL, its effect is only short-lived. While rituximab is generally considered to have a tolerable safety profile, there is an increased risk of contracting infections. Especially during the COVID pandemic, a lack of response to SARS-CoV-2 RNA vaccines has been observed in patients receiving rituximab [
      • Haggenburg S.
      • Lissenberg-Witte B.I.
      • van Binnendijk R.S.
      • et al.
      Quantitative analysis of mRNA-1273 COVID-19 vaccination response in immunocompromised adult hematology patients.
      ].
      Although not available for every case, the absence of a B-cell infiltrate was associated with an inferior outcome, whereas hitherto the presence or absence of an EBV + B-cell infiltrate in the tumour was not associated with survival outcomes in all, but one study. This effect might have been revealed due to our larger sample size [
      • Mourad N.
      • Mounier N.
      • Brière J.
      • et al.
      Clinical, biologic, and pathologic features in 157 patients with angioimmunoblastic T-cell lymphoma treated within the groupe d'Etude des lymphomes de l'Adulte (GELA) trials.
      ,
      • Delfau-Larue M.
      • de Leval L.
      • Joly B.
      • et al.
      Targeting intratumoral B cells with rituximab in addition to CHOP in angioimmunoblastic T-cell lymphoma. A clinicobiological study of the GELA.
      ,
      • Tokunaga T.
      • Shimada K.
      • Yamamoto K.
      • et al.
      Retrospective analysis of prognostic factors for angioimmunoblastic T-cell lymphoma: a multicenter cooperative study in Japan.
      ,
      • Iqbal J.
      • Wright G.
      • Wang C.
      • et al.
      Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma.
      ]. In patients with AITL, a high EBV viral load in plasma or serum may be found. Patients with a detectable EBV viral load in peripheral blood seem to have an inferior prognosis [
      • Delfau-Larue M.
      • de Leval L.
      • Joly B.
      • et al.
      Targeting intratumoral B cells with rituximab in addition to CHOP in angioimmunoblastic T-cell lymphoma. A clinicobiological study of the GELA.
      ,
      • Kim Y.R.
      • Kim S.J.
      • Cheong J.W.
      • et al.
      Pretreatment epstein-barr virus DNA in whole blood is a prognostic marker in peripheral T-cell lymphoma.
      ]. Although it seems plausible to administer rituximab in patients with elevated EBV plasma loads, there is no evidence to support this practice in AITL.
      The 5-year OS in the current study is significantly higher than other past cohorts of patients with AITL [
      • Ellin F.
      • Landström J.
      • Jerkeman M.
      • Relander T.
      Real-world data on prognostic factors and treatment in peripheral T-cell lymphomas: a study from the Swedish lymphoma registry.
      ,
      International T-cell Lymphoma Project
      International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes.
      ,
      • Petrich A.M.
      • Helenowski I.B.
      • Bryan L.J.
      • Rozell S.A.
      • Galamaga R.
      • Nabhab C.
      Factors predicting survival in peripheral T-cell lymphoma in the USA: a population-based analysis of 8802 patients in the modern era.
      ,
      • Savage K.J.
      • Chhanabhai M.
      • Gascoyne R.D.
      • Connors J.M.
      Characterization of peripheral T-cell lymphomas in a single north american institution by the WHO classification.
      ]. This is likely due to the fact that patients in the current study received at least one cycle of CHO(E)P. Patients that were treated otherwise or were not treated at all were excluded. The prognosis of AITL remains poor. In our cohort, 57% of patients did not manage to finish their treatment with six cycles of (immuno-) chemotherapy (data not shown), likely due to lack of response, toxicity, infections or poor performance status. Therefore, more effective first-line treatments for AITL are urgently needed.
      There are several agents that offer perspective for further research. For an overview, see Table 2. Despite 63–75% of AITL cases express CD30 at the cell surface, patients with AITL do not seem to benefit from the anti-CD30 antibody drug conjugate brentuximab vedotin combined with CHP [
      • Horwitz S.
      • O'Connor O.A.
      • Pro B.
      • et al.
      Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial.
      ]. While PD1 is expressed on the majority of neoplastic TFH in AITL, a phase II clinical trial with nivolumab was terminated prematurely due to several patients showing hyper-progressive disease [
      • Bennani N.N.
      • Pedersen L.D.
      • Atherton P.
      • et al.
      A phase II study of nivolumab in patients with relapsed or refractory peripheral T-cell lymphoma.
      ]. Epigenetic regulators such as TET2, DNMT3A and IDH2 are frequently mutated in AITL. Targeting these epigenetic regulators could bear potential. In a subgroup analysis of a phase III trial, romidepsin had a marginal benefit when added to CHOP in AITL patients [
      • Bachy E.
      • Camus V.
      • Thieblemont C.
      • et al.
      Romidepsin plus CHOP versus CHOP in patients with previously untreated peripheral T-cell lymphoma: results of the ro-CHOP phase III study (conducted by LYSA).
      ]. Azacitidine showed promising results when added to CHOP [
      • Ruan J.
      • Moskowitz A.J.
      • Mehta-Shah N.
      • et al.
      Multi-center phase II study of oral azacitidine (CC-486) plus CHOP as initial treatment for peripheral T-cell lymphoma (PTCL).
      ]. Several targeted strategies have been studied in relapsed PTCL. Inhibition of phosphatidylinositol 3-kinase (PI3K) can lead to antitumour effects in lymphoma by blocking mitogenic and survival signalling within the tumour, its microenvironment and to activate immune responses [
      • Chiba S.
      • Sakata-Yaganimoto M.
      Advances in understanding of angioimmunoblastic T-cell lymphoma.
      ,
      • Horwitz S.M.
      • Koch R.
      • Porcu P.
      • et al.
      Activity of the PI3K-d,g inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma.
      ,
      • Wang L.
      • Qin W.
      • Huo Y.J.
      • et al.
      Advances in targeted therapy for malignant lymphoma.
      ]. Duvelisib showed promising results in a phase I trial in patients with relapsed/refractory PTCL [
      • Horwitz S.M.
      • Koch R.
      • Porcu P.
      • et al.
      Activity of the PI3K-d,g inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma.
      ]. The JAK/STAT pathway is known to be activated in PTCL [
      • Wang L.
      • Qin W.
      • Huo Y.J.
      • et al.
      Advances in targeted therapy for malignant lymphoma.
      ]. However, few patients with AITL seem to have a JAK2 or STAT3 mutation so it is unclear how relevant these findings are for patients with AITL [
      • Odejide O.
      • Weigert O.
      • Lane A.A.
      • et al.
      A targeted mutational landscape of angioimmunoblastic T-cell lymphoma.
      ,
      • Moskowitz A.J.
      • Ghione P.
      • Jacobsen E.
      • et al.
      A phase 2 biomarker-driven study of ruxolitinib demonstrates effectiveness of JAK/STAT targeting in T-cell lymphomas.
      ]. Cerdulatinib is an oral dual SYK/JAK inhibitor that has demonstrated responses in relapsed/refractory PTCL, especially AITL with an ORR of 55% of which 41% achieved CR [
      • Horwitz S.M.
      • Feldman T.A.
      • Hess B.T.
      • et al.
      A phase 2 study of the dual SYK/JAK inhibitor cerdulatinib demonstrates good tolerability and clinical response in relapsed/refractory peripheral T-cell lymphoma and cutaneous T-cell lymphoma.
      ]. Cyclosporine has been used in relapsed/refractory AITL in order to suppress the hyperactive state of the immune system. In a literature review, an excellent ORR of 86% has been found. However, no data on its use in first-line treatment are available and its report is prone to publication bias [
      • Omoto A.
      • Fuji S.
      Cyclosporine for angioimmunoblastic T-cell lymphoma: a literature review.
      ].
      Table 2Agents of interest in future research in AITL.
      RegimenStudy populationDesignOutcomeFuture plans
      Brentuximab-CHP [
      • Horwitz S.
      • O'Connor O.A.
      • Pro B.
      • et al.
      Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial.
      ]
      PTCL (n = 452)

      AITL n = 54
      Randomised phase III study of the CD30 monoclonal antibody brentuximab + CHP (A-CHP) versus CHOP in first-line patientsA-CHP: ORR 83% (PTCL)

      CHOP: ORR 72% (PTCL)

      HR 0.87 for OS (CI 0.29–2.58) favouring A + CHP in AITL
      Nivolumab [
      • Bennani N.N.
      • Pedersen L.D.
      • Atherton P.
      • et al.
      A phase II study of nivolumab in patients with relapsed or refractory peripheral T-cell lymphoma.
      ]
      PTCL (n = 12)

      AITL n = 6
      Phase II study of the PD-1 inhibitor nivolumab in relapsed/refractory patientsHalted due to hyperprogression in 4 patientsA randomised study of gemcitabine, oxaliplatin versus nivolumab, gemcitabine, oxaliplatin (the NIVEAU study for patients with relapsed/refractory aggressive lymphoma, not eligible for high-dose chemotherapy (ClinicalTrials.gov Identifier:NCT03366272).
      Romidepsin + CHOP [
      • Bachy E.
      • Camus V.
      • Thieblemont C.
      • et al.
      Romidepsin plus CHOP versus CHOP in patients with previously untreated peripheral T-cell lymphoma: results of the ro-CHOP phase III study (conducted by LYSA).
      ]
      PTCL (n = 421)

      AITL n = 195
      Randomised phase III study of the HDAC inhibitor romidepsin + CHOP (Ro-CHOP) versus CHOP in first-line patientsRo-CHOP: ORR 83% (PTCL)

      CHOP: ORR 72% (PTCL)

      Ro-CHOP: OS 51,8 months (PTCL)

      CHOP: OS 42,9 months (PTCL) (P = 0.477)

      HR 0.69 (0.48–1.00)AITL: PFS 19,5 months (Ro-CHOP) versus 10.6 months (CHOP); HR 0.69 (CI 0.48–1.00); P = 0.046
      Azacitidine [
      • Ruan J.
      • Moskowitz A.J.
      • Mehta-Shah N.
      • et al.
      Multi-center phase II study of oral azacitidine (CC-486) plus CHOP as initial treatment for peripheral T-cell lymphoma (PTCL).
      ]
      PTCL (n = 21)

      PTCL-TFH n = 17; AITL n = 16
      Phase II study of CHOP + hypomethylating agent azacitidine in first-line patientsORR 76,5%; CR 76,5%

      Estimated 1-yr OS for all patients was 74.4% (95%CI of 48.8%–100.0%), with 1-yr OS for PTCL-TFH at 88.9% (95%CI of 68.4%–100.0%)
      A randomised phase II study comparing CHO(E)P with CHO(E)P + oral azacitidine and CHO(E)P + duvelisib is for CD30 negative PTCL (including AITL) is being performed at the moment (ClinicalTrials.gov Identifier:NCT04803201).
      Duvelisib [
      • Horwitz S.M.
      • Koch R.
      • Porcu P.
      • et al.
      Activity of the PI3K-d,g inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma.
      ]
      PTCL (n = 16)

      AITL n = 3
      Phase I study of the PI3K inhibitor duvelisib in relapsed/refractory patientsAITL: one CR, one PR and one response rate n/aA randomised phase II study comparing CHO(E)P with CHO(E)P + oral azacitidine and CHO(E)P + duvelisib is for CD30 negative PTCL (including AITL) is being performed at the moment (ClinicalTrials.gov Identifier:NCT04803201).
      EnasidenibPTCL n = 21A phase 1/2, dose-escalation study of the IDH-2 inhibitor enasidenib in relapsed/refractory patientsn/a(ClinicalTrials.gov Identifier:NCT02273739).
      Ruxolitinib [
      • Ruan J.
      • Moskowitz A.J.
      • Mehta-Shah N.
      • et al.
      Multi-center phase II study of oral azacitidine (CC-486) plus CHOP as initial treatment for peripheral T-cell lymphoma (PTCL).
      ]
      PTCL (n = 45)

      AITL (n = 9)
      A phase 2 study of the JAK1/2 inhibitor ruxolitinib in relapsed/refractory patientsORR 33%
      Cerdulatinib [
      • Horwitz S.M.
      • Feldman T.A.
      • Hess B.T.
      • et al.
      A phase 2 study of the dual SYK/JAK inhibitor cerdulatinib demonstrates good tolerability and clinical response in relapsed/refractory peripheral T-cell lymphoma and cutaneous T-cell lymphoma.
      ]
      PTCL (n = 60) and CTCL

      AITL n = 22
      A phase 2 study of the dual SYK/JAK inhibitor cerdulatinib in relapsed/refractory patientsPTCL: ORR 35%

      AITL: ORR 55% (41% CR)
      Cyclosporine [
      • Omoto A.
      • Fuji S.
      Cyclosporine for angioimmunoblastic T-cell lymphoma: a literature review.
      ]
      AITL (n = 26)Literature review of case series and case reports of the calcineurin inhibitor cyclosporine in relapsed/refractory patientsORR 86%A phase II trial studying cyclosporine in relapsed/refractory AITL has been terminated due to slow accrual (ClinicalTrials.gov Identifier:NCT00070291)
      Abbreviations: CI: confidence interval; CR: complete response; HR: hazard ratio; ORR: overall response rate; OS: overall survival; PFS: progression-free survival.
      Our study has several limitations. The pathological diagnosis of AITL (and PTCL in general) is difficult [
      International T-cell Lymphoma Project
      International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes.
      ]. Due to the design of our study, a central pathology review has not been possible so there is potential misclassification. However, an underestimation of AITL cases is most likely and therefore has limited impact on the primary outcome measure. Moreover, there are no guidelines on when the pathologist should regard a specimen as having an (EBV+) B-cell infiltrate. Furthermore, the reasoning of the treating physician why rituximab was either added to or withheld from the treatment regimen is unknown. Finally, the number of patients analysed in our study is not sufficiently powered to fully exclude small differences (HR 0.74). Despite these limitations, cancer registries remain the standard for population-based analysis of treatment outcomes in real world populations.

      5. Conclusion

      In this large group of patients with AITL, the addition of rituximab to CHO(E)P did not improve ORR, PFS or OS. To our knowledge, this study reports the largest nationwide and population-based cohort published on this subject thus far. Although widely used, our data do not support the routine use of rituximab in the first-line treatment of AITL.

      Funding

      None declared.

      Authorship

      MN and MB designed the study. MB collected the data. MB, MN and FM analysed the data. FM, MB and MN wrote the paper. All authors revised the manuscript and accepted its final version.

      Conflict of interest statement

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgements

      The authors would like to thank the registrars of the Netherlands Cancer Registry (NCR) for their dedicated data collection. The nationwide population-based NCR is maintained and hosted by the Netherlands Comprehensive Cancer Organisation (IKNL).

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

      References

        • Swerdlow S.H.
        • Campo E.
        • Harris N.L.
        • et al.
        Mature T- and NK-cell neoplasms.
        in: WHO classification of tumours of hematopoietic and Lymphoid Tissues. Revised 4th ed. IARC, 2017: 345-422
        • Ellin F.
        • Landström J.
        • Jerkeman M.
        • Relander T.
        Real-world data on prognostic factors and treatment in peripheral T-cell lymphomas: a study from the Swedish lymphoma registry.
        Blood. 2014; 124: 1570-1577
        • 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: 4124-4130
        • Petrich A.M.
        • Helenowski I.B.
        • Bryan L.J.
        • Rozell S.A.
        • Galamaga R.
        • Nabhab C.
        Factors predicting survival in peripheral T-cell lymphoma in the USA: a population-based analysis of 8802 patients in the modern era.
        Br J Haematol. 2015; 168: 708-718
        • De Leval L.
        • Parrens M.
        • Le Bras F.
        • et al.
        Angioimmunoblastic T-cell lymphoma is the most common T-cell lymphoma in two distinct French information data sets.
        Haematologica. 2015; : e361-e364
        • Siegert W.
        • Nerl C.
        • Agthe A.
        • et al.
        Angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma: prognostic impact of clinical observations and laboratory findings at presentation.
        Ann Oncol. 1995; : 659-664
        • Dogan A.
        • Attygalle A.D.
        • Kyriakou C.
        Angioimmunoblastic T-cell lymphoma.
        Br J Haematol. 2003; 121: 681-691
        • Lachenal F.
        • Berger F.
        • Ghesquières H.
        • et al.
        Angioimmunoblastic T-cell lymphoma: clinical and laboratory features at diagnosis in 77 patients.
        Medicine. 2007; 86: 282-292
        • Mourad N.
        • Mounier N.
        • Brière J.
        • et al.
        Clinical, biologic, and pathologic features in 157 patients with angioimmunoblastic T-cell lymphoma treated within the groupe d'Etude des lymphomes de l'Adulte (GELA) trials.
        Blood. 2008; 111: 4463-4470
        • De Leval L.
        • Rickman D.S.
        • Thielen C.
        • et al.
        The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells.
        Blood. 2007; 109: 4952-4963
        • Piccaluga P.P.
        • Agostinelli C.
        • Califano A.
        • et al.
        Gene expression analysis of angioimmunoblastic lymphoma indicates derivation from T follicular helper cells and vascular endothelial growth factor deregulation.
        Cancer Res. 2007; 67: 10703-10710
        • Ahearne M.J.
        • Allchin R.L.
        • Fox C.P.
        • Wagner S.D.
        Follicular helper T-cells: expanding roles in T-cell lymphoma and targets for treatment.
        Br J Haematol. 2014; 166: 326-335
        • Delfau-Larue M.
        • de Leval L.
        • Joly B.
        • et al.
        Targeting intratumoral B cells with rituximab in addition to CHOP in angioimmunoblastic T-cell lymphoma. A clinicobiological study of the GELA.
        Haematologica. 2012; 97: 1594-1602
        • Crotty S.
        T follicular helper cell differentiation, function, and roles in disease.
        Immunity. 2014; 41: 529-542
        • Anagnostopoulos I.
        • Hummel M.
        • Finn T.
        • et al.
        Heterogeneous epstein-barr virus infection patterns in peripheral T-cell lymphoma of angioimmunoblastic lymphadenopathy type.
        Blood. 1992; 80: 1804-1812
        • Weiss L.M.
        • Jaffe E.S.
        • Liu X.F.
        • et al.
        Detection and localization of epstein-barr viral genomes in angioimmunoblastic lymphadenopathy and angioimmunoblastic lymphadenopathy-like lymphoma.
        Blood. 1992; 79: 1789-1795
        • Dobay M.P.
        • Lemonnier F.
        • Missiaglia E.
        • et al.
        Integrative clinicopathological and molecular analyses of angioimmunoblastic T-cell lymphoma and other nodal lymphomas of follicular helper T-cell origin.
        Haematologica. 2017; 102: e148-e151
        • Tokunaga T.
        • Shimada K.
        • Yamamoto K.
        • et al.
        Retrospective analysis of prognostic factors for angioimmunoblastic T-cell lymphoma: a multicenter cooperative study in Japan.
        Blood. 2012; 119: 2837-2843
        • Chiba S.
        • Sakata-Yaganimoto M.
        Advances in understanding of angioimmunoblastic T-cell lymphoma.
        Leukemia. 2020; 34: 2592-2606
        • Schmitz N.
        • Trümper L.
        • Ziepert M.
        • et al.
        Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German high-grade non-hodgkin lymphoma study group.
        Blood. 2010; 116: 3418-3425
        • Deng S.
        • Lin S.
        • Shen J.
        • Zeng Y.
        Comparison of CHOP vs CHOPE for treatment of peripheral T-cell lymphoma: a meta-analysis.
        OncoTargets Ther. 2019; 12: 2335-2342
        • Brink M.
        • Meeuwes F.O.
        • Van der Poel M.W.M.
        • et al.
        Impact of etoposide and ASCT on survival among patients < 65 years with stage II-IV PTCL; a population-based cohort study.
        Blood. 2022; 140: 1009-1019
        • Savage K.J.
        • Chhanabhai M.
        • Gascoyne R.D.
        • Connors J.M.
        Characterization of peripheral T-cell lymphomas in a single north american institution by the WHO classification.
        Ann Oncol. 2004; 15: 1467-1475
        • 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: 1970-1976
        • 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. 2008; 27: 106-113
        • Joly B.
        • Frenkel V.
        • Gaulard P.
        • et al.
        Rituximab in combination with CHOP regimen in angioimmunoblastic T-cell lymphoma (AITL). preliminary results in 9 patients treated in a single institution.
        Blood. 2005; 106: 2686
        • Joly B.
        • Plonquet A.
        • Grare M.
        • et al.
        Rituximab in combination with CHOP regimen in angioimmunoblastic T-cell lymphoma: results of the phase II RAIL trial—a prospective study of the groupe d'etude des lymphomes de l'adulte (GELA).
        J Clin Oncol. 2010; 28: 8049
        • Haggenburg S.
        • Lissenberg-Witte B.I.
        • van Binnendijk R.S.
        • et al.
        Quantitative analysis of mRNA-1273 COVID-19 vaccination response in immunocompromised adult hematology patients.
        Blood Adv. 2022; 6: 1537-1546
        • Iqbal J.
        • Wright G.
        • Wang C.
        • et al.
        Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma.
        Blood. 2014; 123: 2915-2923
        • Kim Y.R.
        • Kim S.J.
        • Cheong J.W.
        • et al.
        Pretreatment epstein-barr virus DNA in whole blood is a prognostic marker in peripheral T-cell lymphoma.
        Oncotarget. 2017; 8: 92312-92323
        • Horwitz S.
        • O'Connor O.A.
        • Pro B.
        • et al.
        Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial.
        Lancet. 2019; 393: 229-240
        • Bennani N.N.
        • Pedersen L.D.
        • Atherton P.
        • et al.
        A phase II study of nivolumab in patients with relapsed or refractory peripheral T-cell lymphoma.
        Blood. 2019; 134: 467
        • Bachy E.
        • Camus V.
        • Thieblemont C.
        • et al.
        Romidepsin plus CHOP versus CHOP in patients with previously untreated peripheral T-cell lymphoma: results of the ro-CHOP phase III study (conducted by LYSA).
        J Clin Oncol. 2022; 40: 242-251
        • Ruan J.
        • Moskowitz A.J.
        • Mehta-Shah N.
        • et al.
        Multi-center phase II study of oral azacitidine (CC-486) plus CHOP as initial treatment for peripheral T-cell lymphoma (PTCL).
        ASH Annual Meeting. 2020;
        • Horwitz S.M.
        • Koch R.
        • Porcu P.
        • et al.
        Activity of the PI3K-d,g inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma.
        Blood. 2018; 131: 888-898
        • Wang L.
        • Qin W.
        • Huo Y.J.
        • et al.
        Advances in targeted therapy for malignant lymphoma.
        Signal Transduct Target Ther. 2020; 5: 1-46
        • Odejide O.
        • Weigert O.
        • Lane A.A.
        • et al.
        A targeted mutational landscape of angioimmunoblastic T-cell lymphoma.
        Blood. 2014; 123: 1293-1296
        • Moskowitz A.J.
        • Ghione P.
        • Jacobsen E.
        • et al.
        A phase 2 biomarker-driven study of ruxolitinib demonstrates effectiveness of JAK/STAT targeting in T-cell lymphomas.
        Blood. 2021; 138: 2628-2637
        • Horwitz S.M.
        • Feldman T.A.
        • Hess B.T.
        • et al.
        A phase 2 study of the dual SYK/JAK inhibitor cerdulatinib demonstrates good tolerability and clinical response in relapsed/refractory peripheral T-cell lymphoma and cutaneous T-cell lymphoma.
        Blood. 2019; 134: 466
        • Omoto A.
        • Fuji S.
        Cyclosporine for angioimmunoblastic T-cell lymphoma: a literature review.
        Expert Rev Hematol. 2019; 12: 975-981