Addition of Brentuximab Vedotin to Gemcitabine in Relapsed or Refractory T-Cell Lymphoma: Results of a Lysa Multicenter, Phase II Study. "the TOTAL Trial"
Authors: Tournilhac Olivier , Hacini Maya , Bouabdallah Kamal , Laribi Kamel , Maerevoet Marie , Ysebaert Loic , Guidez Stephanie , Le Gouill Steven , André Marc , Dupuis Jehan , Thieblemont Catherine , Bachy Emmanuel , Daguindau Nicolas , Morschhauser Franck , Tricot Sabine , Feugier Pierre , Banos Anne , Lamy De La Chapelle Thierry , Chauchet Adrien , Gyan Emmanuel , Cartron Guillaume , Farhat Hassan , Camus Vincent , Drenou Bernard , Zerazhi Hacene , Sibon David , Nicolas-Virelizier Emmanuelle , Delette Caroline , Snauwaert Sylvia , Straetmans Nicole , Delarue Richard , Parrens Marie , Bossard Céline , De Leval Laurence , Gaulard Philippe , Damaj Gandhi Laurent 
Published: November 2020

Background
Peripheral T-cell lymphoma (PTCL) is a heterogeneous and accounts for approximately 10% of all lymphomas. Outcome of relapse/refractory (R/R) PTCL is poor with median progression-free survival (PFS) and overall survival (OS) of 3 and 6 months in the absence of stem-cell transplantation (SCT). [Mak, JCO, 2013]. Brentuximab vedotin (BV) monotherapy is approved for R/R systemic anaplastic large cell-lymphoma (ALCL) based on 86% overall response rate (ORR) and 57% complete remission (CR). [Pro, JCO, 2012]. In other CD30-positive (CD30+) R/R PTCL, the ORR of BV is 41%. Gemcitabine (G) used as monotherapy in control arm in the randomized phase 3 LUMIERE trial, provided ORR and CR rates of 35 and 22% respectively. [O'Connor, JCO, 2019]. Considering these results we designed a phase 2 study for R/R CD30+ PTCL combining G and BV with the primary end point to increase the ORR by 15%, compared to G monotherapy.
Patients (pts) and Methods:
Pts with histologically confirmed CD30+ (≥5%) PTCL who failed or were refractory to 1-3 prior lines of systemic therapy, with measurable disease and ECOG performance status &lt; 3 were eligible. Pts received an induction of 4 cycles of G-BV (28-days cycles; G: 1000 mg/m² at D1 and D15 plus BV: 1.8 mg/kg at D8). Pts with CR or partial remission (PR) and non-eligible for SCT, received BV maintenance 1.8 mg/kg at D1 (21-days cycles) up to 12 cycles. The primary endpoint was the ORR (CR + PR) according to Lugano criteria based on CT-scan. Secondary objectives included tolerance and safety, DOR, PFS, OS and impact of BV maintenance. Eligible pts were censored at time of SCT. (NCT03496779).
Results:
From April 2018 to October 2019, 71 pts were included. Pathology central review according to WHO 2017 criteria, so far available for 50 patients, confirmed angioimmunoblastic T-cell lymphoma (AITL) (22 ; 31%); nodal PTCL-TFH (5 ; 7%); PTCL-NOS (5 ; 7%); ALK- ALCL (10 ; 14.1%) ; ALK+ ALCL (4 ; 5.6%), Enteropathy associated T-cell lymphoma (EATL) (2 ; 2.8%); unclassified PTCL (2 ; 2.8%). There were 47 male and 24 female with a median age of 66 years (20-79) and 17 pts were &gt; 75 years. Median time from diagnosis to enrolment was 9.4 months (range, 6-21). Sixty-five pts (91.6%) presented with stage III-IV. The number of prior lines of therapy were 1 (57 pts), 2 (11 pts) or 3 (3 pts), all pts had received previous CHOP-like chemotherapy, 11 pts previous autologous SCT, 5 pts epigenetic modifiers and 39.4% were refractory to their last line of treatment prior to inclusion. The cut-off date of this analysis was 01/31/2020.
The 4 cycles of G-BV induction were completed in 45 pts (63%). The reasons for early discontinuation were progression (21 pts), death (3 pts) or adverse event (2 pts). In intention-to-treat analysis, the ORR at the end of induction (EOI) was 47.9% including CR (14 pts; 19.7%), PR (20 pts; 28.2%). PET performed in all patients reaching EOI showed overall and complete metabolic responses in 45.1 and 23.9%, respectively. During G-BV induction 58 pts (81.7%) had at least one G &gt; 3 adverse event (AE) including neutropenia (67.2%), thrombopenia (17.2%), infections (15.5%), peripheral neuropathy (PN) (5.2%) and cardiac event (5.2%). Overall PN of any grade was recorded in 8/71 patients (11%) during G-BV induction and caused BV withdrawal in one case.
Among the 34 responding pts after EOI, 27 pts began BV maintenance and 7 pts remain on maintenance at cut-off date. Eight pts were removed from the study due to SCT eligibility, either after the 4 GBV induction (4 pts) or after 1 or 2 maintenance BV cycles (4 pts).
With a median follow-up (FU) of 9.5 (0.5-19.4) months, median PFS is 4.5 months (95%CI [3.5 - 10]) and median OS is 12 months (95%CI [8.6 - NR]). Among the 34 patients in PR/CR after induction, the duration of response (DOR) is 12.8 months (95%CI [10.3 - NR]). At last FU were recorded 32 deaths. Disease status at time of death was PD (25 pts), CR (1 pt) NE or missing (6 pts).
Conclusion:
The addition of BV to G increases the overall response rate by 15% in the treatment of R/R CD30+ PTCL. OS data are encouraging for this overall R/R patient population but PFS is overall short and a longer FU is mandatory. Especially the DOR of pts achieving CR or PR after 4 cycles of G-BV exceeds 1 year on BV maintenance. This combination is generally well tolerated and this study suggests that G-BV combination could be an interesting alternative for R/R CD30+ PTCL.

Disclosures
Tournilhac: Janssen: Consultancy, Honoraria, Other: Travel grant; INNATE Pharma: Consultancy, Honoraria; GILEAD: Consultancy, Honoraria, Other: Travel Grant; ABBVIE: Consultancy, Honoraria, Other: Travle grant; Takeda: Consultancy, Honoraria, Other: Travel grant. Laribi:novartis: Honoraria, Research Funding; amgen: Research Funding; abbvie: Honoraria, Research Funding; takeda: Research Funding. Ysebaert:AbbVie: Consultancy; Roche: Consultancy; Janssen: Consultancy. Guidez:BMS: Honoraria; TAKEDA: Honoraria; Service Hématologie et Thérapie cellulaire CHU POITIERS: Current Employment; AMGEN: Honoraria; CELGENE: Honoraria; JANSEN: Honoraria. Le Gouill:Loxo Oncology at Lilly: Consultancy; Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria. André:Celgene: Other, Research Funding; Takeda: Consultancy; Bristol-Myers-Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Karyopharm: Consultancy; Gilead: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Consultancy, Research Funding; Amgen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Johnson & Johnson: Research Funding; CHU UCL Namur, site Godinne, Yvoir, Belgium: Current Employment; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Abbvie: Consultancy; Seattle Genetics: Consultancy. Dupuis:Henri Mondor University Hospital Creteil France: Current Employment. Thieblemont:Roche, Amgen, Kyte Gilead, Celgene, Abbvie, Novartis, Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche, Hospita: Research Funding; Cellectis: Speakers Bureau. Bachy:Beigene: Membership on an entity's Board of Directors or advisory committees; Roche, Gilead: Consultancy; Amgen: Research Funding; Roche, Celgene, Amgen, Janssen, Gilead, Novartis, Sanofi: Honoraria. Morschhauser:Celgene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; F. Hoffmann-La Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Servier: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Feugier:janssen: Consultancy, Honoraria, Research Funding; gilead: Consultancy, Honoraria, Research Funding; roche: Consultancy, Honoraria, Research Funding; astrazeneca: Consultancy, Honoraria, Research Funding; abbvie: Consultancy, Honoraria, Research Funding. Cartron:F. Hoffmann-La Roche: Consultancy, Honoraria; Abbvie: Honoraria; Jansen: Honoraria; Celgene: Consultancy, Honoraria; Sanofi: Honoraria; Gilead: Honoraria. Camus:ROCHE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); JANSSEN: Honoraria; AMGEN: Honoraria; PFIZER: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Sibon:takeda france: Consultancy. Snauwaert:roche: Other: travel; janssen: Other: travel; abbvie: Other. Delarue:BMS: Other: stock options ; Celgene/BMS: Current Employment. De Leval:Abbvie: Honoraria; Lausanne University Hospital & Lausanne University Institute of Pathology: Current Employment; Roche Diagnostics: Honoraria; Lunaphore Technologies SA: Consultancy, Honoraria. Gaulard:CHU Henri Mondor, Assistance Publique-Hôpitaux de Paris: Current Employment; TAKEDA: Consultancy, Honoraria, Research Funding; INNATE PHARMA: Research Funding; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company).