Résumé
Background
Enteropathy-associated T-cell lymphoma (EATL), previously designated type 1 EATL, is a neoplasm of intraepithelial T cells that occurs in individuals with celiac disease (CD). It is a rare lymphoma, accounting for approximately 3% of all peripheral T-cell lymphomas (PTCLs). EATL may be preceded by refractory CD (RCD), defined as persistent or recurrent symptoms and signs of malabsorption with villous atrophy despite a strict gluten-free diet for more than 12 months. Currently, RCD is categorized into 2 types, based on immunophenotypic and molecular criteria. In RCD-II, intraepithelial lymphocytes (IELs) have an aberrant phenotype and a clonal TCR gene rearrangement. RCD-II is considered a low-grade lymphoma of intraepithelial T cells, with a high risk of transformation into EATL. CD or RCD may be diagnosed prior to or concomitant with EATL.
EATL has a poor prognosis due to perforation or obstruction of the bowel, sepsis, malnutrition and treatment resistance, with 2-year OS of 20% (de Baaij, CCR 2015). An EATL prognostic index (EPI) has been developed, that can distinguish 3 risk groups (de Baaij, CCR 2015).
Optimal treatment of EATL is an unmet need, and novel therapeutic approaches are required. Most EATLs are CD30+ and could be targeted by brentuximab vedotin (BV). Based on the encouraging activity and manageable safety profile of BV and CHP (cyclophosphamide, doxorubicin and prednisone) combination in CD30+ PTCLs, the EATL-001 phase 2 trial was initiated to assess the efficacy and safety of BV-CHP followed by HDT-ASCT for the frontline treatment of patients (pts) with EATL (ClinicalTrials.gov No. NCT03217643). Here we report the first results of the EATL-001 trial.
Methods
EATL-001 is an Investigator Initiated-Sponsored Research phase 2 study, on behalf of the CELAC (French NCI-labeled network of Centers of Expertise for Lymphomas Associated with Celiac disease). Key inclusion criteria were as follows: Newly diagnosed CD30+ (≥10% of neoplastic cells by central review) EATL (WHO 2016 criteria), 18-65 years, PS 0-3. Response was assessed according to the Lugano classification. Pts were scheduled to receive 4 cycles of BV+CHP as induction. Responding pts received 2 cycles of Etoposide (200 mg/m2) + Methotrexate (3 g/m2) followed by HDT-ASCT (BEAM conditioning regimen). The primary endpoint was 2-year PFS per investigator. Underlying CD/RCD diagnosis was based on uninvolved duodenal histology (including CMF and TCR gene rearrangement analysis of IEL), serology and HLA typing.
Results
A total of 14 pts were included between February 2018 and February 2021. The median age was 54 years (range, 34-65) and 64% were male. 11 pts (79%) had initial surgery for bowel obstruction (n=6) or jejunal perforation (n=5). All pts had CD, diagnosed prior to (n=4) or concomitant with (n=10) EATL. 9 pts (64%) had RCD-II. CD30 expression ranged from 10% to 100%, nine cases having 100% positivity. EPI was high-risk in 4 pts (29%), intermediate-risk in 6 pts (43%), and low-risk in 4 pts (29%).
Preliminary results by investigator assessment show an overall response rate following completion of the induction of 79% (11/14) with 64% (9/14) achieving a complete response. 3 pts had primary progressive disease (all had high-risk EPI), of which 2 died of the lymphoma. The 11 responding pts, still in response before intensification, underwent HDT-ASCT. 2 pts died of septic shock during HDT-ASCT. With a median follow-up of 2.1 years, there was no relapse and the 2-year PFS and OS for all pts were 63% and 68%, respectively.
The incidence of AEs was consistent with the known safety profiles of BV-CHP regimen.
Conclusions
EATL-001 is the first prospective phase 2 study dedicated to EATL. BV-CHP was well tolerated and induced high response rates, allowing the majority of patients to be transplanted. This novel therapeutic approach shows promising efficacy compared to historical controls.