Biweekly Rituximab, Cyclophosphamide, Vincristine, Non-Pegylated Liposome-Encapsulated Doxorubicin (Myocet®) and Prednisone (R-COMP-14) as Induction Treatment in Poor R-IPI Risk Elderly Patients with Diffuse Large B-Cell Lymphoma (DLBCL) and Pre-Existing Heart Disease.
Authors: Frigeri Ferdinando , Corazzelli Gaetano , Arcamone Manuela , Capobianco Gaetana , Lucania Anna , Becchimanzi Cristina , Marcacci Gianpaolo , Russo Filippo , Villa Maria Rosaria , Mastrullo Lucia , Pinto Antonio 
Published: October 2019

Abstract
Abstract 1664
Poster Board I-690

Background
Delivering of dose-dense R-CHOP represents a critical factor for improving response rate and survival outcomes in poor risk DLBCL patients (pts) but it may turn a very challenging goal to achieve in elderly pts with severe cardiac comorbidities. In this subset of pts, tachyarrhythmias, conduction disturbances, ventricular dysfunction, and a pericarditis-myocarditis syndrome, may occur during or immediately after the administration of doxorubicin hydrochloride, independently from total cumulative dose. This may lead to early treatment discontinuation and even death, strongly hampering the chance of receiving adequate chemotherapy. We have conducted a pilot study first exploring the feasibility of a dose-dense biweekly R-CHOP-like regimen including non-pegylated liposome-encapsulated doxorubicin in elderly pts at a high risk for both disease presentation and cardiac conditions. Liposomal anthracyclines, beyond the potential of a more selective uptake by lymphoma cells, may broaden the feasibility of a dose-effective treatment through a reduction of early and late cardiotoxicity.

Patients and Methods
Untreated pts with poor R-IPI risk DLBCL and moderate to high ‘life threat’ impact cardiopathy (NIA/NCI index) were scheduled to receive six courses of a R-COMP-14 regimen in which an equal dose (50 mg/sqm) of non-pegylated liposome-encapsulated doxorubicin (Myocet®) was substituted for doxorubicin hydrochloride within the R-CHOP platform. Treatment was given every two weeks with G-CSF support. Responses and endpoints were evaluated according to the International Harmonization Project with treatment failure defined as discontinuation of R-COMP-14 for any reason (e.g., disease progression, toxicity, initiation of new treatment without documented progression, or death).

Results
Thirty-seven pts, median age 72 years (r, 62-82) with pre-existing heart disease [history of myocardial infarction (n=10), atrial fibrillation (n=8), valve disease (n=6), conduction disturbances (n=9), hypertensive cardiomyopathy (n=4)] and R-IPI score ≥ 3, were accrued in this prospective study. Thirty-three pts were in advanced stage [stage IV (n=25) + stage III (n=8): 89%], 18 (49%) had B symptoms, 29 (78%) displayed abnormal LDH and 11 (30%) presented involvement of > 2 extra nodal sites. According to Charlson, median Comorbidity Index and Score were 5.5 (r, 2-8) and 8.5 (r, 5-11), respectively. Pre-treatment left ventricular ejection fraction (LVEF) ranged between 42% and 67% (median, 57%). One-hundred eighty-four total courses were delivered (median 6, range,1-8). The median time to recycling was 15.9 days (r, 13-29) and 67% of pts received the 6 scheduled courses. Hematologic toxicity was tolerable, with CTCAE v3.0 G3/G4 thrombocytopenia and G3/G4 infections being recorded in 6 (16%) 5 (12%) pts, respectively. Seventeen failures were documented; they were due to progression (n=2), early death (n=3), treatment discontinuation (n=6) and disease recurrence (n=6). Early deaths occurred at day +12, +13 of the 1st course and day + 18 of the 2nd course, accounting for a treatment mortality rate of 8%. Treatment was discontinued because of a > 15% reduction in LVEF occurring at the 3rd and 4th courses (n=3) and the occurrence of symptomatic arrhythmia (n=3). The overall response rate was 71 % (95% CI: 53-84) with 24 complete responses and 2 partial responses. Time to Treatment Failure and Time to Progression at 28 mo.s were 51% and 63%, respectively. Disease Free Survival was 69% at a median follow-up of 14 mo.s.

Discussion
The present study documented the attractive therapeutic potential of the R-COMP-14 regimen in the setting of poor-risk elderly DLBCL pts with moderate and high impact cardiac comorbidity, in terms of both response rate and time to progression. Survival endpoints were more than satisfactory in a such unfavourable cohort of subjects for which treatment recommendations are still controversial, also due to lack of international guidelines on cardioprotective agents and strategies. Although cardiac events have occured in a fraction of pts, very early and independently from cumulative doses, they did not substancially affect the feasibility of the regimen, provided that a close clinical monitoring was ensured. R-COMP-14 represents an active dose-dense therapeutic platform for pts with cardiac comorbidity.

Disclosures
No relevant conflicts of interest to declare.