R-COMP Vs. R-CHOP As First-Line Treatment for De Novo Diffuse Large B-Cell Lymphoma in Patients Older Than 60 Years: Preliminary Results from a Prospective Randomized Phase 2 Study from the Spanish Group Geltamo
Authors: Sancho Juan-Manuel , Gual Francisco , Fernández-Alvarez Rubén , González-García Esther , Grande Carlos , Jiménez-López Carmen , Gutierrez Norma C , Peñarrubia María-José , Batlle Ana , González-Barca Eva , Guinea-de-Castro Jose-Maria , Gimeno Eva , Peñalver Francisco-Javier , Fuertes Miguel A , Gayoso Jorge , Hernández-Rivas José-Ángel , Moraleda José-María , Virgili Lluis , Martín Alejandro 
Published: October 2019

Abstract
Background and objective. Anthracycline-induced cardiotoxicity is a major issue in the treatment of elderly patients with diffuse large B-cell lymphoma (DLBCL). The use of non pegylated liposomal doxorubicin (Myocet®)has been associated with less cardiotoxicity as compared to conventional doxorubicin in breast cancer, but its benefit in DLBCL has been investigated mostly in retrospective and single-arm prospective studies. The objective of this study was to evaluate the benefit, in terms of cardiac toxicity, of the substitution of conventional doxorubicin as part of R-CHOP therapy by the non pegylated liposomal doxorubicin (Myocet®, R-COMP arm) in older patients (≥60 years) with de novo DLBCL or grade 3b follicular lymphoma (FL).
Methods. This is a prospective randomized phase 2 trial (ClinicalTrials.gov Identifier: NCT02012088) of newly diagnosed patients with DLBCL or grade 3b FL ≥60 years old with baseline left ventricular ejection fraction (LVEF) > 55%. Patients were randomized to R-COMP or R-CHOP (in both cases every 21 days for a total of 6 cycles, with a dose of conventional doxorubicin or Myocet® of 50 mg/m2/cycle). The primary end-point was to evaluate the differences in subclinical cardiotoxicity between the two arms of treatment, defined by a decrease in LVEF to ≤ 55% at the end of treatment (measured by echocardiography at 1 and 4 months after the last cycle of chemotherapy). Secondary objectives were efficacy, safety and differences in the variations of cardiac biomarkers (troponin and N-terminal pro B-type natriuretic peptide [NT-proBNP]) through therapy in both arms of treatment.
Results.
Patient characteristics. A total of 91 patients from 15 Spanish hospitals were included, with a median age of 75 years (range 60-86), 49 (54%) were females. ECOG performance status was 2 in 15 (16%), stage III-IV in 68 (76%) and IPI 3-5 in 56 (63%). A total of 46 patients received R-COMP while 45 were treated with R-CHOP, without significant differences between arms regarding baseline characteristics.
Subclinical cardio-toxicity: No differences between arms were observed in the number of patients with LVEF ≤55% determined at the end of treatment or at 4 months (6 [15%] in those treated with R-COMP and 5 [14%] in the R-CHOP arm, p=0.966). However, a higher number of patients in R-CHOP arm increased troponin levels at cycle 6 of treatment (17 out of 24 evaluable patients [71%] in R-COMP group vs. 25 out of 25 evaluable patients [100%] in R-CHOP group, p=0.004) or at the end-of-treatment visit (13 out of 21 evaluable patients [62%] in R-COMP group vs. 20 out of 23 evaluable patients [87%] in R-CHOP group, p=0.05). No differences between both groups were observed in variations of NT-proBNP levels through treatment period and follow-up.
Serious adverse events (SAEs): With a median follow-up of 16 months (range 0.7-34), a total of 59 SAEs were reported in 37 patients (39 in 21 patients from R-COMP group and 20 in 16 patients from R-CHOP group), including 18 infections (12 in R-COMP and 6 in R-CHOP), and 14 episodes of febrile neutropenia (9 in R-COMP and 5 in R-CHOP). Four patients showed cardiovascular events: atrial fibrillation (n=1, R-COMP group), supraventricular tachycardia (n=2, R-CHOP group), and myocardial infarction (n=1, R-CHOP group). Efficacy: Overall response (OR) and complete remission (CR) were observed in 72 (96%) and 54 (72%) patients, respectively, without differences between R-COMP group (OR and CR rates of 97% and 72%) and R-CHOP group (OR and CR rates of 94% and 72%) (p=0.775). Conclusions. R-COMP is a feasible immunochemotherapy schedule for patients with de novo DLBCL older than 60 years. However, in our series, the use of non-pegylated doxorubicin instead of conventional doxorubicin was not associated with less decrease in LVEF measured by echocardiography, although the differences in troponin levels merits the need for further evaluation with a higher number of evaluable patients and longer follow-up.

Disclosures
Sancho: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion, Inc: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees. González-Barca:Roche: Honoraria; Gilead: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Martín:Janssen: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sevier: Honoraria, Membership on an entity's Board of Directors or advisory committees.