Received: 28 April 2020 | Revised: 30 November 2020 | Accepted: 24 December 2020 DOI: 10.1002/cam4.3730 ORIGINAL RESEARCH R-COMP versus R-CHOP as first-line therapy for diffuse large B-cell lymphoma in patients ≥60 years: Results of a randomized phase 2 study from the Spanish GELTAMO group Juan-Manuel Sancho1 | Rubén Fernández-Alvarez2 | Francisco Gual-Capllonch3 | Esther González-García2 | Carlos Grande4 | Norma Gutiérrez5 | María-Jesús Peñarrubia6 | Ana Batlle-López7 | Eva González-Barca8 | José-María Guinea9 | Eva Gimeno10 | Francisco-Javier Peñalver11 | Miguel Fuertes12 | Mariana Bastos13 | José- Ángel Hernández-Rivas | José-María Moraleda | Olga García | Marc Sorigué1 | 14 15 1 Alejandro Martin5 1 Hematology Department, ICO-IJC-Hospital Germans Trias i Pujol, Badalona, Spain 2 Hematology Department, Hospital de Cabueñes, Gijón, Spain 3 Cardiology Department of Hospital Germans Trias i Pujol, Badalona, Spain 4 Hematology Department, Hospital Doce de Octubre, Madrid, Spain 5 Hematology Department, Hospital Universitario de Salamanca, IBSAL, CIBERONC, Salamanca, Spain 6 Hematology Department, Hospital Clínico de Valladolid, Valladolid, Spain 7 Hematology Department, Hospital Marqués de Valdecilla, Santander, Spain 8 Hematology Department, ICO-Hospital Durán i Reynals (Hospitalet de Llobregat, Barcelona, Spain 9 Hematology Department, Hospital Universitario de Araba, Vitoria, Spain 10 Hematology Department, Hospital del Mar, Barcelona, Spain 11 Hematology Department, Hospital Universitario Fundación de Alcorcón, Madrid, Spain 12 Hematology Department, Hospital Clínico Lozano Blesa, Zaragoza, Spain 13 Hematology Department, Hospital Gregorio Marañón, Madrid, Spain 14 Hematology Department, Hospital Universitario Infanta Leonor, Madrid, Spain 15 Hematology Department, Hospital Virgen de la Arrixaca, Murcia, Spain Correspondence Dr Juan-Manuel Sancho, Hematology Abstract Department, ICO-IJC-Hospital Germans The use of non-pegylated liposomal doxorubicin (Myocet®) in diffuse large B-cell Trias i Pujol, Universitat Autònoma lymphoma (DLBCL) has been investigated in retrospective and single-arm prospec- de Barcelona, C/Canyet S/N, 08916 Badalona Barcelona, Spain. tive studies. This was a prospective phase 2 trial of DLBCL patients ≥60 years old Email: jsancho@iconcologia.net with left ventricular ejection fraction (LVEF) ≥55% randomized to standard R-CHOP Funding information or investigational R-COMP (with Myocet® instead of conventional doxorubicin). The Teva Pharmaceutical Industries primary end point was to evaluate the differences in subclinical cardiotoxicity, de- fined as decrease in LVEF to <55% at the end of treatment. Secondary objectives This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. 1314 |  wileyonlinelibrary.com/journal/cam4 Cancer Medicine. 2021;10:1314–1326. | 20457634, 2021, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cam4.3730 by Readcube (Labtiva Inc.), Wiley Online Library on [23/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License SANCHO et al.    1315 were efficacy, safety, and variations of troponin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and LVEF along follow-up. Ninety patients were included, 45 in each group. No differences were observed in the percent- age of patients with LVEF <55% at end of treatment (11% in R-CHOP arm vs. 7% in R-COMP arm, p = 0.697) or at 4 months (10% vs. 6%, respectively, p = 0.667) and 12 months (8% vs. 7%, respectively, p = 1). However, a higher percentage of R-CHOP compared with R-COMP patients showed increased troponin levels in cycle 6 (100% vs. 63%, p = 0.001) and at 1 month after treat- ment (88% vs. 56%, respectively, p = 0.015). Cardiovascular adverse events were seen in five R-CHOP patients (nine episodes, four grade ≥3) and in four R-COMP patients (five episodes, all grade 1–2). No significant differences in efficacy were observed. In conclusion, R-COMP is a feasible immunochemotherapy schedule for DLBCL patients ≥60 years, with similar efficacy to R-CHOP. However, the use of non-pegylated doxorubicin instead of conventional doxorubicin was not associated with less early cardiotoxicity, although some reduced cardiac safety signals were observed. Trial registration: ClinicalTrials.gov Identifier: NCT02012088. KEYWORDS cardiotoxicity, diffuse large B-cell lymphoma, liposomal doxorubicin, N-terminal pro-B-type natriuretic peptide, troponin 1 | IN T RO D U C T IO N Several strategies have been proposed to decrease cardio- toxicity provoked by anthracyclines in elderly populations. The combination of the monoclonal anti-CD20 antibody rit- These include the administration of reduced doses or slow uximab plus chemotherapy with cyclophosphamide, doxoru- infusions of doxorubicin, use of cardioprotective agents or bicin, vincristine, and prednisone (R-CHOP) still constitutes substitution by other antineoplastic agents or by other less the standard first-line regimen for patients with diffuse large cardiotoxic anthacyclines, such as mitoxantrone, epirubicin, B-cell lymphoma (DLBCL).1 However, its use is limited es- or liposomal formulations of doxorubicin.10-14 Myocet® is a pecially in elderly patients due, among other reasons, to car- non-pegylated liposomal doxorubicin that demonstrated to diotoxicity derived from doxorubicin. Doxorubicin-induced be less cardiotoxic—with similar antitumoral activity—than cardiotoxicity is caused by the binding of the drug and the conventional doxorubicin in a phase 3 trial in patients with ferric ion, producing the formation of free radicals that pro- metastatic breast cancer.2 Due to its pharmacokinetic and vides lipid peroxidation and progressive myocyte damage.2 pharmacodynamics profiles, it has also been associated with The cumulative dose of doxorubicin appears to be the main less myelosuppression and mucositis.14 However, its activity factor involved in the development of cardiotoxicity, and al- in lymphoma patients has mainly been investigated in retro- though a threshold of 500 mg/m2 has been established as a spective and single-arm prospective studies.15-20 risk dose, some studies have described early cardiotoxicity Taking into account this background, we designed a clin- with doses of only 200 mg/m2.3,4 ical trial for patients ≥60 years old diagnosed with DLBCL In addition to clinical symptoms, determination of the left or grade 3b follicular lymphoma (FL) with normal cardiac ventricular ejection fraction (LVEF) by echocardiography or function, with the main objective of evaluating the possible cardiac scintigraphy (multi-gated acquisition [MUGA]) scan is benefits in terms of cardiac toxicity, of the substitution of the most frequent parameter employed to evaluate cardiotoxic- conventional doxorubicin by non-pegylated liposomal doxo- ity, and usually a decrease in LVEF precedes the development rubicin (Myocet®, R-COMP arm) as part of R-CHOP therapy. of congestive heart failure.3 In recent years, the measurement of cardiac biomarkers, especially troponin and N-terminal pro-B- type natriuretic peptide (NT-proBNP), has been proposed as a 2 | M ATERIAL S AND M ETHOD S method to detect early cardiotoxicity, and several studies have shown a relation between raised levels of cardiac biomarkers Prospective randomized phase 2 trial (ClinicalTrials.gov and left ventricular dysfunction, in particular with a decrease in Identifier: NCT02012088) of newly diagnosed patients LVEF, and the development of heart failure.4-9 ≥60 years old with non-localized DLBCL or grade 3b FL | 20457634, 2021, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cam4.3730 by Readcube (Labtiva Inc.), Wiley Online Library on [23/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 1316    SANCHO et al. with a baseline LVEF ≥55%. The trial was conducted ac- in both arms every 21 days for a total of six cycles. If the delay cording to Good Clinical Practice Guidelines and the 2008 in the administration of subsequent cycles was greater than revision of the Declaration of Helsinki. All patients provided 2 weeks due to toxicity, the patient was withdrawn from the written informed consent before participation in this study. study. Reductions of 25% and 50% in the doses of cyclophos- The requirements for the patients to be included were: age phamide and doxorubicin (in R-CHOP arm) or in the doses of ≥60 years, newly diagnosed non-localized DLBCL or grade cyclophosphamide and non-pegylated liposomal doxorubicin 3b FL (those with localized lymphoma were included in the (in R-COMP arm) were mandatory for patients without hema- presence of bulky disease) with at least one measurable lesion, tological recovery (minimum neutrophil count of 1 × 109/L and Eastern Cooperative Oncology Group (ECOG) performance platelet count of 75 × 109/L), after 1 or 2 weeks, respectively, of status of 0–2, adequate hematological, renal and hepatic pa- the 21-day period of the previous cycle. In the case of grade 3–4 rameters (unless secondary to lymphoma involvement), and neuropathy, discontinuation of vincristine was mandatory, but a baseline LVEF ≥55%. Patients with localized lymphoma, the patients were allowed to continue to participate in the trial history of transformed lymphoma, central nervous system and receive the remaining drugs of the chemotherapy schedule. (CNS) involvement, or positivity for hepatitis B or C vi- Primary prophylaxis of febrile neutropenia with granulocyte ruses or human immunodeficiency virus were excluded, as colony-stimulating factor was allowed according to the clinical were those with clinically significant cardiovascular disease, practice. CNS prophylaxis with intrathecal chemotherapy (ac- such as non-controlled arterial hypertension, non-controlled cording to clinical practice in the hospital) was recommended ventricular or supraventricular arrhythmias, symptomatic with each cycle of chemotherapy in the presence of increased ischemic heart disease (class II or higher according to the serum lactate dehydrogenase plus involvement of more than Canadian Cardiovascular Society criteria), past or present one extranodal site, or in patients with a high International history of congestive heart failure, LVEF <55%, moderate Prognostic Index (IPI) or in those with involvement of, at least, to serious left ventricular hypertrophy, and significant valve one of the following involved sites: paranasal sinus, Waldeyer's abnormalities. In addition, patients with no adequate window ring, epidural space, breast, kidney, or testes. Radiotherapy after to determine LVEF by echocardiography were also excluded. chemotherapy on residual mass in patients with baseline bulky Physical examination, standard blood tests, thoracic and disease was also allowed according to the physician's decision. abdominal computed tomography (CT) scan (and cervical if clinically indicated) plus positron emission tomography (PET) or combined PET/CT scan, and bone marrow biopsy 2.2 | Primary and secondary end points were performed at baseline and at the end of treatment. For the cardiac evaluation, an electrocardiogram (ECG) and The primary end point of the study was to evaluate the differences determination of the cardiac biomarkers troponin and NT- in subclinical cardiotoxicity, defined by a decrease in LVEF to proBNP in serum were performed at baseline, 48–72 h after <55% at the end of treatment (measured by echocardiography the third and sixth cycles of chemotherapy and at the end at 1 month after therapy), in patients receiving the standard of treatment (1 month after the last cycle of chemotherapy), R-CHOP regimen compared with those treated with R-COMP. and in the follow-up visits performed 4 and 12 months later Considering a non-superiority hypothesis test for two independ- in each participant institution according to local procedures. ent samples with a statistical power of 80%, a significance level The LVEF was measured by echocardiograpy at baseline, at of 5% and assuming a proportion of subclinical cardiac toxic- the end of treatment (1 month after the last cycle of chemo- ity in the reference and experimental groups of approximately therapy), and 4 and 12 months later. For LVEF determina- 15%22,23 and 5%,22,23 respectively, with 5% dropouts, 45 patients tion, the biplane Simpson's method from the apical acoustic in each treatment arm were necessary to be recruited. window was used,21 and the final result for the LVEF at each Secondary end points were efficacy in terms of overall evaluation point was the mean of three measurements. and complete response rates (ORR and CR) in all randomized patients, event-free survival (EFS), progression-free survival (PFS), overall survival (OS), and safety. Response to treat- 2.1 | Treatment ment was evaluated according to clinical, laboratory results and the evaluation of imaging techniques according to the Patients were randomized 1:1 to receive R-CHOP (rituximab criteria defined by Cheson et al.24 EFS was defined as the 375 mg/m2 [day 1], cyclophosphamide 750 mg/m2 [day 1], time from inclusion of the patients in the trial until treatment doxorubicin 50 mg/m2 [day 1], vincristine 1.4 mg/m2 [day 1, failure, including disease progression, treatment discontinua- capped at a maximum of 2 mg], and prednisone 60 mg/m2 [days tion, or death by any cause. PFS was defined as the time from 1–5]) or R-COMP (with the same drugs except for conventional inclusion into the trial until progression/relapse or death by doxorubicin being replaced by non-pegylated liposomal doxo- any cause. OS was defined as time from study inclusion to rubicin, Myocet®, at doses of 50 mg/m2 [day 1]), administered death by any cause. | 20457634, 2021, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cam4.3730 by Readcube (Labtiva Inc.), Wiley Online Library on [23/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License SANCHO et al.    1317 T A B L E 1 Baseline characteristics of R-CHOP arm R-COMP arm Overall series the overall series and divided by treatment (n = 45) (n = 45) p value (n = 90) arm Male, n (%) 17/45 (38%) 24/45 (53%) 0.138 41/90 (46%) Age (years), median 74 (60–84) 74 (60–86) 1 74 (60–86) (range) Baseline LVEF (%), 63 (55–81.4) 65 (55–87.1) 0.204 64 (55–87.1) median (range) Hypertension, n (%) 26/45 (58%) 17/44 (39%) 0.071 43/89 (48%) Diabetes, n (%) 7/45 (16%) 8/44 (18%) 0.741 15/89 (17%) Dyslipemia, n (%) 21/45 (47%) 15/44 (34%) 0.227 36/89 (40%) ECOG <2, n (%) 37/45 (82%) 38/45 (84%) 0.777 75/90 (83%) B symptoms, n (%) 20/45 (44%) 19/44 (43%) 0.904 39/89 (44%) Increased LDH level, 29/45 (64%) 23/45 (51%) 0.2 52/90 (58%) n (%) Extranodal 26/45 (58%) 26/45 (58%) 1 52/90 (58%) involvement, n (%) >1 extranodal site 12/45 (27%) 13/45 (29%) 0.814 25/90 (28%) involved, n (%) BM involvement, n (%) 11/44 (25%) 12/45 (27%) 0.857 23/89 (26%) Bulky disease, n (%) 11/44 (25%) 12/45 (27%) 0.857 23/89 (26%) Ann-Arbor stage, n (%) I–II 9/45 (20%) 10/45 (22%) 0.796 19/90 (21%) III–IV 36/45 (80%) 35/45 (78%) 71/90 (79%) IPI, (n %) 0–2 25/44 (57%) 26/44 (59%) 0.829 51/88 (58%) 3–5 19/44 (43%) 18/44 (41%) 37/88 (42%) Abbreviations: BM, bone marrow; ECOG, Eastern Cooperative Oncology Group; IPI, International Prognostic Index; LDH, lactate dehydrogenase; LVEF, left ventricular ejection fraction; WBC, white blood cells. Safety, with special attention to cardiovascular toxicity, variables, and median and range for quantitative variables. was evaluated according to clinical signs and laboratory pa- Comparisons of categorical variables between treatment rameters, and assessment of adverse events (AE) using ver- groups were studied using the Chi-square test or Fisher's sion 4.0 of the NCI-CTCAE scale for grading toxicity, as exact test, when necessary, while the median test was used to well as the variations in cardiac biomarkers troponin and NT- compare continuous variables. proBNP in both arms throughout the study. For the primary end point (evaluation of differences in The primary end point analysis was carried out in pa- subclinical cardiotoxicity), the percentage of patients in tients who received six cycles of treatment and in whom whom the LVEF decreased to <55% at the end of treatment post-treatment evaluation of LVEF was performed. Efficacy in each treatment group was compared using the Chi-square analyses were carried out on an intention-to-treat (ITT) test or Fisher's exact test, when necessary. The median LVEF population, defined as all randomized patients, and in the at the end of treatment, as well as at 4 and 12 months later, evaluable population, defined as ITT population excluding and the median of the differences between baseline and end patients who withdrew the trial without a response evalua- of treatment LVEF measures were compared by the nonpara- tion. The safety analysis was carried out in a safety popu- metric median test. Comparison of patients with variations in lation, which included all patients that received at least one cardiac biomarkers throughout the study was made by Chi- cycle of chemotherapy. square test or Fisher's exact test, when necessary. Regarding efficacy, OR and CR rates were compared using the Chi-square test or Fisher's exact test, whereas 2.3 | Statistical analysis EFS, PFS, and OS curves were plotted by the Kaplan–Meier method25 and compared by the log-rank test.26 Baseline demographic and clinical characteristics were A descriptive analysis of the reported AE (frequency described as frequency and percentage for categorical and percentage) was performed, and comparison between | 20457634, 2021, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cam4.3730 by Readcube (Labtiva Inc.), Wiley Online Library on [23/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 1318    SANCHO et al. treatment groups was made using the Chi-square test or flow chart of the patients along the study. Thirty-eight out Fisher's exact test. of 45 patients (84%) and 42/45 (93%) received six cycles of No imputation method was used for missing data. Two- R-CHOP and R-COMP, respectively, (p = 0.130) and were sided p values <0.05 were considered as statistically signif- included in the analysis of the primary end point. icant. All analyses were performed with SPSS v24 (SPSS Inc.). 3.1 | Subclinical cardiotoxicity: LVEF and cardiac biomarkers 3 | R E S U LTS Regarding the primary end point, no significant differences From October 2013 to February 2016, a total of 90 patients were observed between the R-CHOP and R-COMP arms in with DLBCL from 15 hospitals belonging to the Spanish the number of patients with a LVEF <55% determined at the GELTAMO group were prospectively included. Of these, 45 end (1 month) of treatment (11% [n =4/36] in the R-CHOP were randomized to the R-CHOP arm and 45 to the R-COMP arm vs. 7% [3/42] in the R-COMP arm, p = 0.697), or at arm, without significant differences between the two arms 4 months (10% [n =3/31] in the R-CHOP arm vs. 6% [2/33] in regarding baseline characteristics (Table 1). The median age the R-COMP arm, p = 0.667) or at 12 months (8% [n =2/24] of the entire series was 74 years (range 60–86), with ECOG in the R-CHOP arm vs. 7% [2/28] in the R-COMP arm, p = 1) <2 in 83%; 79% of patients were in advanced stage and 42% after therapy (Table 2). Furthermore, no differences were ob- had an intermediate to high IPI. The median LVEF at study served in an exploratory analysis comparing patients with a entry was 64% (range 55–87.1), and almost half of patients decrease in LVEF below 50% at the end of treatment or dur- had a previous history of hypertension. Figure 1 shows the ing follow-up (data not shown), as well as in the number of Enrolled n = 98 (Reasons for exclusion: 3 due to other Excluded: 8 lymphoma subtype, 2 due to localized disease, 1 due to no adequate window to determine LVEF, 2 due to physician criteria) Randomized n = 90 R-CHOP R-COMP n = 45 n = 45 Withdrawal by AE: 3 (subarachnoid hemorrhage, renal failure, atrial fibrilla on) Withdrawal by AE: 1 (worsening general condi on) Death by AE: 3 (gastrointes nal hemorrhage, sep c shock, worsening general condi on) Death by AE: 2 (sep c shock, abdominal Progression: 2 hemorrhage) Removal consent: 1 FINISHED TREATMENT FINISHED TREATMENT n = 36 n = 42 FIGURE 1 Flowchart of patients | 20457634, 2021, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cam4.3730 by Readcube (Labtiva Inc.), Wiley Online Library on [23/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License SANCHO et al.    1319 T A B L E 2 Subclinical cardiotoxicity R-CHOP arm R-COMP arm (LVEF) in both treatment arms throughout (n = 45) (n = 45) p value the treatment LVEF <55% at the end of treatment 4/36 (11%) 3/42 (7%) 0.697 (1 month), number of patients (%) LVEF <55% at 4 months of the end of 3/31 (10%) 2/33 (6%) 0.667 treatment, number of patients (%) LVEF <55% at 12 months of the end of 2/24 (8%) 2/28 (7%) 1 treatment, number of patients (%) Variation (difference) ≥10% in baseline 5/36 (14%) 4/42 (10%) 0.725 LVEF (%) compared with LVEF 1 month after the end of treatment: Variation (difference) ≥10% in baseline 4/31 (13%) 4/33 (12%) 1 LVEF (%) compared with LVEF 4 months after the end of treatment: Variation (difference) ≥10% in baseline 3/24 (12%) 2/28 (7%) 0.652 LEVF (%) compared with LVEF 12 months after the end of treatment: LVEF (%) at the end of treatment 61 (41–84.6) 63.9 (49–74) 0.820 (1 month), median (range) LVEF (%) at 4 months of the end of 61 (41–76) 63.7 (53.3–80) 0.129 treatment, median (range) LVEF (%) at 12 months of the end of 60.5 (43.2–84) 65 (52–80) 0.091 treatment, median (range) Variation (difference) in baseline LVEF (%) compared with LVEF 1 month after the end of treatment: Mean (SD) 1.6 (9.3) 2.3 (7.4) 0.793 Median (range) 2 (−23.6 to 24.7) 2.3 (−16.4 to 24.4) Variation (difference) in baseline LVEF (%) compared with LVEF 4 months after the end of treatment: Mean (SD) 3.7 (6.9) 1.6 (7.5) 0.841 Median (range) 3 (−13 to 28) 2 (−16.7 to 19.4) Variation (difference) in baseline LEVF (%) compared with LVEF 12 months after the end of treatment: Mean (SD) 1.3 (8.4) 0.4 (6.8) 0.592 Median (range) 3 (−20.3 to 16) 0.5 (−14 to 13) Abbreviations: LVEF, left ventricular ejection fraction; SD, standard deviation. patients with LVEF drop ≥10% at 1, 4, or 12 months after end of treatment (21/24 [88%] in the R-CHOP arm vs. treatment compared to baseline LVEF. Similarly, there were 14/25 [56%] in the R-COMP arm, p = 0.015), but not after also no significant differences between the two groups in the cycles 3 or at 4 and 12 months after treatment (Table 3). median LVEF determined at the end of treatment and at 4 and Regarding NT-proBNP, no differences were observed in 12 months, or in the variations in LVEF determined at differ- the percentage of patients with increased levels along the ent times compared to the baseline LVEF (Table 2). Finally, treatment period (in cycles 3 and 6) and follow-up (1, 4, no differences were detected in the primary end point (LVEF and 12 months after therapy) compared to the baseline lev- <55% at 1 month of treatment) considering all randomized els (Table 3). patients (9% [n =4/45] in the R-CHOP arm vs. 7% [3/45] in the R-COMP arm, p = 1). With respect to the cardiac biomarkers troponin and NT- 3.2 | Efficacy evaluation proBNP, a higher percentage of patients showed increased troponin levels (compared to baseline values) measured in OR and CR were observed in 77 (85.5%) and 56 (62%) out cycle 6 (24/24 [100%] in the R-CHOP arm vs. 17/27 [63%] of the 90 randomized patients, with no differences between in the R-COMP arm, p = 0.001) and at 1 month after the treatment groups (OR and CR in the R-CHOP arm in 36 | 20457634, 2021, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cam4.3730 by Readcube (Labtiva Inc.), Wiley Online Library on [23/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 1320    SANCHO et al. T A B L E 3 Cardiac biomarkers (troponin R-CHOP arm R-COMP arm and NT-proBNP) in both treatment arms (n = 45) (n = 45) p value throughout the treatment Troponin Increased troponin levels at cycle 3, 13/23 (57%) 12/26 (46%) 0.469 number of patients (%) Increased troponin levels at cycle 6, 24/24 (100%) 17/27 (63%) 0.001 number of patients (%) Increased troponin levels at end of 21/24 (88%) 14/25 (56%) 0.015 treatment (1 month), number of patients (%) Increased troponin levels at 4 months 16/21 (76%) 16/22 (73%) 0.795 after treatment, number of patients (%) Increased troponin levels at 12 months 10/15 (67%) 10/15 (67%) 1 after treatment, number of patients (%) NT-proBNP Increased NT-proBNP levels at cycle 3, 25/29 (86%) 32/34 (94%) 0.401 number of patients (%) Increased NT-proBNP levels at cycle 6, 27/29 (93%) 23/28 (82%) 0.253 number of patients (%) Increased NT-proBNP levels at end 14/29 (48%) 14/33 (42%) 0.644 of treatment (1 month), number of patients (%) Increased NT-proBNP levels at 14/25 (56%) 12/27 (44%) 0.405 4 months after treatment, number of patients (%) Increased NT-proBNP levels at 12/18 (67%) 6/17 (35%) 0.063 12 months after treatment, number of patients (%) Abbreviation: NT-pro-BNP, N-terminal pro B-type natriuretic peptide. [80%] and 28 [62%] patients, respectively; OR and CR in CI 48%–76%] for R-CHOP and R-COMP patients, respec- the R-COMP arm in 41 [91%] and 28 [62%] patients, re- tively, p = 0.083, and 2-year PFS of 59% [95% CI 44%–74%] spectively). We performed an additional efficacy analysis and 62% [95% CI 48%–76%] for RCHOP and R-COMP including only the 80 patients evaluable for efficacy; 38 patients, respectively, p = 0.505) (Figure 3).The 2-year OS in the R-CHOP arm (3 were excluded due to AE, 3 due to probability for the entire series was 74% (95% CI 65%–83%) death from AE, and the remaining patient due to withdrawal (Figure 2), but again without significant differences between of consent) and 42 in the R-COMP arm (2 were excluded the two groups (75% [95% CI 62%–88%] for R-CHOP pa- due to death from AE and the third patient due to AE). OR tients vs. 73% [95% CI 60%–86%] for R-COMP patients, and CR were observed in 77 (96%) and 56 (70%) out of 80 p = 0.751) (Figure 3). evaluable patients, respectively, again without differences between the R-CHOP and R-COMP groups (ORR of 95% vs. 98%, p = 0.498, and CR rate of 74% vs. 67%, p = 0.494, 3.3 | Safety respectively). With a median follow-up of 42 months (range 2.1–61.2) The main AEs reported by >5% of the patients are listed in for patients alive at the time of analysis, 15 patients in the Table 4. Overall, the most frequent non-hematologic AEs R-CHOP group had died (6 by lymphoma) and 14 in the were pain (53% of patients), fatigue (51%), infection (49%), R-COMP arm (10 by lymphoma).The 2-year EFS and PFS peripheral neuropathy (31%), constipation (29%). and py- probabilities for the entire series were 54% (95% confi- rexia (28%), with no differences between both arms. Non- dence interval [CI] 44%–64%) and 61% (95% CI 51%–71%) hematological grade 3–4 toxicity was also similar in both (Figure 2), respectively, without differences between the two groups, being infection the most frequent (five patients groups (2-year EFS of 46% [95% CI 31%–61%] vs. 62% [95% [11%] in the R-CHOP group and seven patients [16%] in the | 20457634, 2021, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cam4.3730 by Readcube (Labtiva Inc.), Wiley Online Library on [23/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License SANCHO et al.    1321 FIGURE 2 Event-free survival (EFS), progression-free survival (PFS), and overall survival (OS) probabilities for the overall series R-COMP group). Regarding grade 3–4 hematological toxic- group), myocardial infarction (n = 1, R-CHOP group), and ity, neutropenia was observed more frequently in R-CHOP heart failure (n = 1, R-CHOP group). patients (49% vs. 29%), but this was not translated into more incidence of febrile neutropenia, while thrombocytopenia and anemia were identical (Table 4). 4 | DISCUSSION Cardiovascular toxicity is described in Table 5. Fourteen cardiovascular AEs were observed in nine patients, nine AEs This study demonstrates that non-pegylated doxorubicin in- in five patients who received R-CHOP, and five AEs in four stead of conventional doxorubicin as part of the R-CHOP patients treated with R-COMP. Four cardiovascular AEs were regimen did not decrease the incidence of LVEF drop below of grade ≥3 (two cases of atrial fibrillation, one heart failure, 55% at the end of chemotherapy in patients ≥60 years old di- and one myocardial infarction), all of them in the R-CHOP agnosed with DLBCL with normal baseline cardiac function. group. Moreover, in this series, R-COMP was a feasible immuno- A total of 67 serious adverse events (SAEs) were reported chemotherapy schedule for patients ≥60 years of age with de in 39 patients (26 in 18 patients from the R-CHOP group novo DLBCL, with similar efficacy to R-CHOP. and 41 in 21 patients from the R-COMP group), including The main results of this study are concordant with a sim- 16 episodes of febrile neutropenia (6 in R-CHOP and 10 in ilar previous phase 3 trial by the Austrian AGMT group23 R-COMP), 14 infections (7 in each group), 6 episodes of that compared R-CHOP and R-COMP in 79 adult patients bleeding (2 in R-CHOP and 4 in R-COMP), and 4 episodes of with DLBCL and normal cardiac function. In the cited pyrexia (all in the R-COMP arm). Cardiovascular SAEs were study, a low-rate of cardiotoxicity was described in R-CHOP reported in only five patients: supraventricular tachycardia and R-COMP patients. However, while in the present study (n = 2, R-CHOP group), atrial fibrillation (n = 1, R-COMP no significant differences were observed in the percentage | 20457634, 2021, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cam4.3730 by Readcube (Labtiva Inc.), Wiley Online Library on [23/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 1322    SANCHO et al. F I G U R E 3 Event-free survival (EFS), progression-free survival (PFS), and overall survival (OS) probabilities by treatment group (RCHOP and R-COMP groups represented in the continuous and dashed lines, respectively) of patients with LVEF <55% at the end of treatment (with in another phase 2 trial of 75 patients with DLBCL treated only 11% and 7% of patients with a LVEF below <55% at with 8 cycles of R-COMP20; although LVEF measurements the end of the study in R-CHOP and R-COMP patients, decreased at most time points, the differences were not sig- respectively), the Austrian group reported higher measure- nificant, with a mean change from baseline to the end of ments of LVEF <50% throughout the study in R-CHOP treatment of −2.6%, very similar to that found in our study patients compared to the R-COMP group (15.8% vs. 4.6%, (Table 2). In addition, despite the lower number of mea- respectively, p < 0.001), despite similar baseline LVEF surements, the present study also suggests a lack of benefit values in both groups, a surprisingly finding since that in mid-term subclinical cardiotoxicity, with similar LVEF younger patients were included in the Austrian (median age measurements at 4 or at 12 months compared to baseline of 65 years and 38% of patients <60 years) compared to our LVEF in the R-CHOP and R-COMP arms. study (median age of 74 years and all patients over 60 years Cardiac biomarkers have been used as a complementary old), and age is a well recognized risk factor for cardio- method to detect subclinical cardiac toxicity.5-9 Troponin and toxicity. However, as in the present study, no differences NT-proBNP are related to early cardiac injury and heart fail- were observed in LVEF values at the end of treatment in ure, respectively. In the present study, only troponin levels the R-CHOP compared to the R-COMP group, suggest- more frequently increased in R-CHOP compared to R-COMP ing that the substitution of conventional doxorubicin by patients, although this increase was only detectable in cycle 6 non-pegylated doxorubicin does not seem to protect against and 1 month after the completion of treatment, but not at the anthracycline-derived subclinical cardiotoxicity, at least in other measurement times. This finding suggests the higher terms of LVEF decrease in DLBCL patients. Similar re- early cardiotoxicity in the R-CHOP arm with the cumula- sults regarding LVEF variations were described previously tive doses of conventional doxorubicin, but the absence of | 20457634, 2021, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cam4.3730 by Readcube (Labtiva Inc.), Wiley Online Library on [23/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License SANCHO et al.    1323 T A B L E 4 Number and percentage of patients with adverse events and toxicity (non-hematologic and hematologic) that occurred in >5% patients in the R-CHOP and R-COMP arms Non-hematologic toxicity Any grade Grade 3–4 R-CHOP R-COMP R-CHOP R-COMP Adverse event/toxicity Overall series (n = 45) (n = 45) p value (n = 45) (n = 45) Pain 48 (53%) 24 (53%) 24 (53%) 1 1 (2%) 1 (2%) Fatigue 46 (51%) 22 (49%) 24 (53%) 0.673 0 3 (7%) Infection 44 (49%) 21 (47%) 23 (51%) 0.673 5 (11%) 7 (16%) Peripheral neuropathy 28 (31%) 15 (33%) 13 (29%) 0.649 1 (2%) 0 Constipation 26 (29%) 13 (29%) 13 (29%) 1 1 (2%) 0 Pyrexia 25 (28%) 12 (27%) 13 (29%) 0.814 0 4 (9%) Edema 23 (26%) 14 (31%) 9 (20%) 0.227 0 1 (2%) Renal failure 21 (23%) 9 (20%) 12 (27%) 0.455 - - Diarrhea 20 (22%) 10 (22%) 10 (22%) 1 0 1 (2%) Hepatic toxicity 18 (20%) 6 (13%) 12 (27%) 0.114 1 (2%) 3 (7%) Nausea/vomiting 17 (19%) 8 (18%) 9 (20%) 0.788 - - Mucositis 16 (18%) 7 (16%) 9 (20%) 0.581 - - Hyperglucemia 14 (16%) 8 (18%) 6 (13%) 0.561 0 2 (4%) Anorexia 13 (14%) 6 (13%) 7 (16%) 0.764 - - Dyspnea 13 (14%) 4 (9%) 9 (20%) 0.134 0 4 (9%) Skin rash 13 (14%) 8 (18%) 5 (11%) 0.368 - - Hemorrhage 11 (12%) 5 (11%) 6 (13%) 0.748 1 (2%) 2 (4%) Hypotension 7 (8%) 4 (9%) 3 (7%) 1 - - Dizziness 6 (7%) 2 (4%) 4 (9%) 0.677 - - Thrombosis 5 (6%) 2 (4%) 3 (7%) 1 1 0 Hematologic toxicity Any grade Grade 3–4 R-CHOP R-COMP R-CHOP R-COMP Overall series (n = 45) (n = 45) p value (n = 45) (n = 45) Neutropenia 46 (51%) 27 (60%) 19 (42%) 0.092 22 (49%) 13 (29%) Febrile neutropenia 18 (20%) 7 (16%) 11 (24%) 0.292 7 (16%) 11 (24%) Anemia 36 (40%) 18 (40%) 18 (40%) 1 3 (7%) 3 (7%) Thrombocytopenia 16 (18%) 8 (18%) 8 (18%) 1 4 (9%) 4 (9%) differences in troponin levels at other time points of follow-up of them in the R-CHOP arm. These data are similar to those suggests later improvement. In fact, similar NT-proBNP val- of other published studies.16,17,20,23 In the phase 2 trial con- ues were observed in both arms not only throughout treat- ducted by Luminari et al.,20 15 out of 75 patients (21%) treated ment (after 3 and 6 cycles of treatment), but also during with R-COMP (median age 72 years) presented cardiac AEs follow-up (1, 4, and 12 months after therapy), conversely to (grade 3–4 in 3 patients, corresponding to cardiac ischemia, the aforementioned study by Fridrik et al,23 in which higher atrial fibrillation, and congestive heart failure), whereas in NT-proBNP values were detected in the R-CHOP arm at the Austrian phase 3 trial,23 a total of 9 cardiac SAEs were cycle 6 and after treatment. observed, again without differences between R-COMP (5 Overall, the frequency of cardiovascular and cardiac cardiac SAEs) and R-CHOP (4 cardiac SAEs). Other stud- events was low in both arms despite the advanced age of the ies with a lower number of patients treated with R-COMP patients and long-term follow-up, with a total of 14 events also described a low frequency of cardiac events.16,17 (9 in R-CHOP and 5 in R-COMP), 4 of being grade ≥3, all These results are consistent with the previous large phase 3 | 20457634, 2021, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cam4.3730 by Readcube (Labtiva Inc.), Wiley Online Library on [23/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 1324    SANCHO et al. T A B L E 5 Cardiovascular adverse events in the R-CHOP and respectively, that exceeds the planned 5% rate of drop- R-COMP arms outs and could decrease the ability of the study to detect R-CHOP R-COMP differences in subclinical cardiotoxicity, but in almost all Adverse event (n = 45) (n = 45) cases discontinuations were due to non-cardiac events. Atrial fibrillation 3a 1 Moreover, LVEF evaluation was done in each partici- Tachycardia 3 1 pant institution, subject to interobserver variability, al- Bradycardia/tachycardia 0 1 though all measurements were performed with the same Heart failure 2b 1 method.21 However, in addition to the comparisons of the differences in LVEF between the two groups at the end of Myocardial infarction 1c 0 treatment, we also analyzed the variations in LVEF along Atrioventricular block 0 1 the treatment, supporting the main findings of the study, Overall cardiovascular 9 5 which is also consistent with previous studies.20,23 Global events longitudinal strain (GLS) performed with echocardiog- a Grade 3 in two cases. raphy, another tool to detect subclinical cardiotoxicity, b Grade 3 in one case. was not performed routinely. Similarly, troponin and NT- c Causing death. proBNP biomarker measurements were not centralized, and thus, comparisons of cardiac biomarker values along the treatment and follow-up were made with respect to randomized study by a French group27 that compared CHOP baseline values in each patient. Nonetheless, the absence and R-CHOP (eight cycles in each arm) in patients between of significant variations of cardiac biomarkers supports 60 and 80 years old and described 8% of grade 3–4 cardiac the main finding of the study regarding the lack of sig- events in the R-CHOP arm, and with the randomized trial nificant LVEF changes in R-CHOP- and R-COMP-treated RICOVER-60 by a German group,28 in which grade 3–4 car- patients. The incidence of cardiotoxicity was quite low in diotoxicity was present in 3% of R-CHOP-14 patients (after the present study, as it has been observed in other contem- six or eight cycles). porary studies. However, a benefit of liposomal doxorubi- Non-cardiovascular toxicity was also similar in both the cin could be observed in selected patients with high risk of R-CHOP and R-COMP groups, in contrast to some of the cardiotoxicity (excluded in the design of the study), such findings reported by Fridrik et al.23 In fact, whereas in the as those with previous anthracycline administration, bor- study by the Austrian group the number of SAEs was higher derline LVEF (50%–55%) or another type of heart disease in R-CHOP compared to R-COMP patients (40 vs. 26, with preserved LVEF. p = 0.029) due to increased infections, this was not the case In conclusion, this randomized trial confirms that the use in our study, with more SAEs being observed in the R-COMP of liposomal doxorubicin instead of conventional doxorubi- group because of febrile neutropenia, bleeding and pyrexia cin in the R-CHOP regimen in older patients with DLBCL episodes, and despite a trend to higher incidence of neutro- and a previously normal LVEF does not compromise the ef- penia in R-CHOP patients. In any case, this trend to higher ficacy of the treatment, but neither does it appear to decrease neutropenia in the R-CHOP group observed in the present early cardiac toxicity, at least in terms of the primary end study supports a possible lower hematological toxicity with point. Although we observed some signs of reduced cardiac liposomal doxorubicin compared to conventional doxorubi- toxicity in the R-COMP group, short-term cardiotoxicity was cin due to its different pharmacokinetics.14 Moreover, no dif- also low in the R-CHOP group. Longer follow-up and addi- ferences were observed in the frequency of mucositis, an AE tional studies with a greater number of patients are needed to that could decrease with liposomal doxorubicin according to determine whether this drug could have benefits in late-onset other studies.15 cardiac toxicity. As could be expected, efficacy was similar in both arms, in accordance with previously published data.16,19,20,23 ACKNOWLEDGMENTS The CR rate was identical in both arms, but the ORR was This study was made possible by funding from TEVA higher in R-COMP compared to R-CHOP patients, although Pharmaceuticals. the differences were not significant. The EFS probability showed a trend to being higher in the R-COMP arm, but CONFLICT OF INTEREST PFS and OS were similar in both arms, and in line with JMS has received honoraria from Roche, Gilead, Janssen, other studies.19,20,23 Celgene, Servier, Novartis, Mundipharma, Sanofi, Kern- There are some limitations in this study that should be Pharma, and Takeda, and was a Member of the Board of mentioned. Primary end point was only assessed in 36/45 Directors or advisory committees for Roche, Janssen, Gilead, and 42/45 patients treated with R-CHOP and R-COMP, Celgene, Novartis, Bristol Myers, and Celltrion. NG has | 20457634, 2021, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cam4.3730 by Readcube (Labtiva Inc.), Wiley Online Library on [23/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License SANCHO et al.    1325 11. Yang F, Lei Q, Li L, et al. Delivery of epirubicin via slow infu- received honoraria from Roche and Janssen. EG has par- sion as a strategy to mitigate chemotherapy-induced cardiotoxicity. ticipated in advisory committees for Abbvie, Janssen, and PLoSONe. 2017;12:e0188025. Gilead. JAHR received honoraria and research funding from 12. Wiseman LR, Dexrazoxane SCM. A review of its use as a cardio- Roche, Janssen, Celgene, and Gilead. JMGDC received hon- protective agent in patients receiving anthracycline-based chemo- oraria from Novartis and Alexion y Pfizer. therapy. Drugs. 1998;56:385-403. 13. Armitage JO. The role of mitoxantrone in non-Hodgkin's lym- DATA AVAILABILIT Y STATEMENT phoma. Oncology (Willinston Park). 2002;16:490-502. 14. Allen TM, Martin FJ. Advantages of liposomal delivery systems The datasets used and/or analyzed during the current study for anthracyclines. Semin Oncol. 2004;31:161-181. are available from the corresponding author on reasonable 15. Levine AM, Tulpule A, Espina B, et al. Liposome-encapsulated request. doxorubicin in combination with standard agents (cyclophospha- mide, vincristine, prednisone) in patients with newly diagnosed ORCID AIDS-related non-Hodgkin's lymphoma: results of therapy and Juan-Manuel Sancho https://orcid. correlates of response. J Clin Oncol. 2004;22:2662-2670. org/0000-0001-7168-6538 16. Rigacci L, Mappa S, Nassi L, et al. 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