Rituximab with Dose-Adjusted EPOCH (R-DA-EPOCH) with or without Autologous Stem Cell Transplantation (ASCT) As First Line Treatment in Patients with Aggressive B-Cell Lymphoma with MYC and BCL-2 and/or BCL-6 Gene Rearrangements or Increase Copy Number
Authors: Tucci Alessandra , Re Alessandro , Pagani Chiara , Guidetti Anna , Dodero Anna , Marino Fabrizio , Casaroli Ivana , Soverini Giulia , Daffini Rosa , Balzarotti Monica , Campostrini Giulia , Lorenzi Luisa , Balzarini Piera , Facchetti Fabio , Carlo-Stella Carmelo , Corradini Paolo , Rossi Giuseppe 
Published: November 2020

Introduction: We have previously reported short-term efficacy of six courses of R-DA-EPOCH in patients with aggressive B cell lymphomas carrying concomitant MYC and BCL-2 and/or BCL-6 rearrangement (DHL/THL) or gene increase copy number (ICN) (Tucci et al. Blood S1: 4154, 2017). Further experience with the same program has been described in the meantime in patients with aggressive lymphoma and c-MYC rearrangement, either as single hit or DHL/THL (Dunleavy et al. Lancet Haematol, 2018). We report here long-term results in a larger unselected series of DHL/THL with the aim to confirm our preliminary results and to define the role of consolidation with autologous stem cell transplantation (ASCT) after R-DA-EPOCH remission induction.
Methods: The study includes patients consecutively seen in four Italian centres. From January 2014, fit patients aged less than 80 years, with diffuse large B cell lymphoma (DLBCL), lymphoma with intermediate features between DLBCL and Burkitt (BCLU) or high grade lymphoma (HGBCL) histology, diagnosed as DHL or THL by fluorescent in situ hybridization (FISH), were treated with R-DA-EPOCH and central nervous system prophylaxis. Patients with MYC -ICN (three or more extra signals in more than 30% of nuclei, Schieppati et al. Haematologica, 2019) plus BCL-2 and/or BCL-6 gene rearrangement or ICN were also included. Pre-treatment with one cycle of R-CHOP was allowed in patients in need of urgent treatment, pending the results of FISH analysis. Consolidation with ASCT was planned in three of the four centres for stage II-IV patients aged less than 71 who reached at least a partial remission (PR) after six R-DA-EPOCH courses. Immunohistochemistry (IHC) was used to define cell of origin (COO) according to Hans' algorithm, double expressor cases (MYC and BCL-2 protein &gt;40% and 50% respectively) and Ki67 expression.
Results: Sixty-three patients were treated (51 DLBCL, 5 BCLU, 7 HGBCL, including 16 with histologic transformation from an indolent lymphoma). Their median age was 63 years (range 23-79) and 43 (68%) were males. Fifty-four (86%) had Ann-Arbor stage III/IV, 18 (28%) B symptoms and 41 (65%) high-intermediate/high risk score according to International Prognostic Index (IPI), with extranodal disease in 79% of patients, mainly in bone and gastrointestinal tract. According to FISH analysis, 34 cases were DHL, 10 THL and 19 c-MYC-ICN. According to IHC, 81% were of germinal center origin, 73% were double expressors and median Ki-67 was 91% (range 35-100%). Patients received a median of six courses of R-DA-EPOCH (range 1-6). Twelve patients were pre-treated with one R-CHOP course and 24 patients (17 in complete remission, 6 in PR and 1 with disease progression) received transplant consolidation (allogeneic SCT in one PR patient), according to the policy of the centre and eligibility criteria. In the entire cohort, the overall response rate was 81%, including 68% complete responses (CR) and 3y-PFS and OS were 67% and 69% respectively. Two patients died of infectious complications during chemotherapy. Of the 10 chemo-refractory patients, all have died of lymphoma. Median length of follow-up was 32 months. At univariate analysis, IPI &gt; 3 and THL were significantly associated with a worse outcome while cMYC-ICN and ASCT with a better OS. At multivariate analysis, only ASCT remained significantly associated with better survival (HR 0.146, IC 95% 0.032-0.667, p 0.013). Focusing on patients who achieved CR with R-DA-EPOCH, all 17 patients who underwent transplantation (100%) are alive (after a median of 27 months from transplant), versus 19 out of 24 patients (79%) who did not. Only one patient relapsed after ASCT and is alive after receiving CAR-T cells. 3y-OS and PFS of patients in CR after induction therapy who received or not ASCT consolidation were 100% vs 76% and 94% vs 72% respectively (Fig.1). Clinical characteristics of the two subgroups were similar except for median age that was lower in the former one (59 vs 69 years).
Conclusions: These results confirm the favourable outcome of patients with MYC and BCL-2 and/or BCL-6 rearrangements or gene ICN with R-DA-EPOCH therapy. The role of consolidative ASCT and its usefulness seems encouraging, but remains to be proven by prospective randomized studies. The poor outcome of chemo-refractory patients represents an unmet need and greater expansion of CAR-T cell programs could improve these results in the near future.

Disclosures
Tucci: Amgen: Consultancy. Carlo-Stella:Boehringer Ingelheim and Sanofi: Consultancy; Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca: Honoraria; ADC Therapeutics and Rhizen Pharmaceuticals: Research Funding. Corradini:Takeda: Consultancy, Honoraria, Other; BMS: Other; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; KiowaKirin: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Daiichi Sankyo: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Incyte: Consultancy; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for. Rossi:Janssen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Abbvie: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria.