The Addition of Bortezomib to R-DHAP Does Not Improve the Response Pre-Stem Cell Transplantation Compared to Standard R-DHAP in Young Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Preliminary Results of the Phase II Randomized Trial FIL-VERAL12 of the Fondazione Italiana Linfomi
Authors: Chiappella Annalisa , Balzarotti Monica , Monagheddu Chiara , Cavallo Federica , Cabras Maria Giuseppina , Zanni Manuela , Califano Catello , Re Francesca , Congiu Angela Giovanna , Corradini Paolo , Olivieri Attilio , Liberati Anna Marina , Volpetti Stefano , Michieli Mariagrazia , Tucci Alessandra , Tani Monica , Nassi Luca , Mazza Rita , Novo Mattia , Pileri Stefano A , Ciccone Giovannino , Vitolo Umberto 
Published: November 2019

Background. The outcome of relapsed/refractory diffuse large-B cell lymphoma (DLBCL) patients after first line chemoimmunotherapy is poor, and the choice of the best salvage treatment is challenging. Acisplatin-containing regimen (DHAP, cisplatin, high-dose citarabine, dexamethasone) is worldwide accepted as induction pre-stem cell transplantation (SCT). Bortezomib had proven activity in aggressive lymphomas. On these bases, the Fondazione Italiana Linfomi designed the FIL-VERAL12 trial, aimed at evaluating whether the addition of bortezomib to rituximab-DHAP (BR-DHAP) increases complete response rate (CR, according to Lugano 2007 criteria) prior SCT compared to standard R-DHAP.
Methods. FIL-VERAL12 was a prospective, multicenter, two-arm randomized phase II trial (NCT01805557).The primary study endpoint wasCR after 4 courses of R-DHAP or BR-DHAP, assuming a 30% CR for the standard arm and a 50% CR in experimental arm. Inclusion criteria were: patients aged 18-65 years with relapsed/refractory DLBCL after first line chemoimmunotherapy, eligible to high-dose therapy. A centrally histological review and classification according to cell of origin profile was planned. Patients were stratified by relapsed or refractory and randomized 1:1 to receive: a) the standard salvage therapy R-DHAP every 28 days for 4 cycles and b) subcutaneous 1.5 mg/sqm bortezomib on days 1 and 4 of each 4-week cycle in addition to the same regimen. Restaging, mobilization and harvesting of peripheral stem cell were performed after the second course.
Results. From January 2013 to November 2018, 114 patients were screened; 108 eligible patients were enrolled into the trial and randomized to receive R-DHAP or BR-DHAP (54 patients in each arm). Principal clinical characteristics were: median age 57 years (IQR: 48;62); stage III/IV 81 patients (75%); IPI risk >3 32 (30%). All patients received rituximab and anthracycline-based regimens as first line treatment. Considering the time at relapse, 52 patients (48%) were registered as relapsed (median time at relapse 10.8 months, IQR: 6.9;20.9) and 46 (43%) as refractory (0.9 months, IQR 0.52;1.3); in the remaining 10 patients the data is missing at the time of this analysis. 51 (47%) patients completed the planned 4 cycles of therapy; 57 did not, due to progressive disease in 20, adverse events in 2, unknown causes in 35 cases. Intermediate response after 2 courses was: CR 16 (15%), partial response (PR) 37 (34%), stable disease (SD) 16 (15%); 24 (22%) were in progression (PD) and 15 (14%) were not available for response. At the end of treatment, the pre-ASCT response was: : CR 30 (28%), PR 10 (9%), SD 13 (12%), PD 38 (35%), NA 17 (16%). According to arm of randomization, the primary end point was not met, with CR 30% for R-DHAP and 26% for BR-DHAP (Pr 0.667). 38 patients performed a consolidation SCT, autologous SCT in 38, allogeneic SCT in 4. The addition of bortezomib to standard R-DHAP did not impact the mobilization: only one patient was poor mobilizer and the median number of CD34+ collected was 6.9 x 10^6 cells CD34/kg (IQR: 4.8; 9.7), with no differences between the two arms. No toxic deaths were recorded into the trial. On 294 cycles with data available, haematological and extra-haematological toxicities were: grade 3-4 neutropenia in 152 of 294 courses (52%), g 3-4 thrombocytopenia in 209 (71%); g 3-4 febrile neutropenia in 4 (1%), g3-4 infection in 5 (2%), g3-4 neurotoxicity in 5 (2%); the incidence of adverse events were similar in the two arms. At a median follow-up of 9.8 months, 12-months PFS was: overall 48.8% (38.4-58.4), 44.6% (30.4-57.8) and 53.1% (37.9-66.1) for R-DHAP and BR-DHAP, respectively (log rank, p 0.464). At a median follow-up of 15.9 months, 12-months OS was: overall 69% (58.2-77.7), 62.7% (46.4-75.3) and 75.1% (59.6-85.4) for R-DHAP and BR-DHAP, respectively (log rank, p 0.628).
Conclusions. In the FIL-VERAL12 phase II randomized trial, the addition of bortezomib to R-DHAP did not improve the outcome of relapsed/refractory DLBCL patients eligible to high-dose therapy plus SCT. This series of patients is mainly represented by true refractory patients after first line chemoimmunotherapy and the results underline the poor outcome of such patients. The treatment for these patients is still an unmet clinical need. The role of immunotherapies such as the integration of CAR-T therapy in this setting of patients should be investigated.

Disclosures
Chiappella: Teva: Speakers Bureau; Celgene: Other: advisory board, Speakers Bureau; Janssen: Other: advisory board, Speakers Bureau; Servier: Other: advisory board, Speakers Bureau; Roche: Speakers Bureau. Corradini:Amgen: Honoraria; Janssen: Honoraria, Other: Travel Costs; Servier: Honoraria; KiowaKirin: Honoraria; Sanofi: Honoraria; Gilead: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Takeda: Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; Celgene: Honoraria, Other: Travel Costs; AbbVie: Consultancy, Honoraria, Other: Travel Costs; BMS: Other: Travel Costs. Liberati:Novartis: Other: Clinical trial support; Janssen: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Roche: Other: Clinical trial support; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Celgene: Honoraria, Other: Clinical trial support; Bristol-Myers Squibb: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Nassi:Merck: Consultancy; Janssen: Consultancy; Takeda: Consultancy. Vitolo:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

OffLabel Disclosure:
the use of subcutaneous bortezomib is not registered in diffuse large B-cell lymphoma. Bortezomib was provided free by Janssen