Non Pegilated Liposomal Doxorubicin (TLC-D99; Myocet ™) Can Be Safely and Effectively Used As Part of the R-COMP Regimen in Patients with Diffuse Large B-Cell Lymphoma Who Show Contraindications to Anthracyclines Due to Concomitant Moderate/Severe Heart Disease. Results of the HEART01 Phase II trial by the Fondazione Italiana Linfomi (NCT01009970)

R-CHOP is the standard treatment for Diffuse Large B-Cell Lymphoma (DLBCL) but is usually contraindicated in patients with concomitant heart disease due to the unsafe cardiac profile of doxorubicin. The encapsulation of doxorubicin into liposomes modifies its pharmacokinetic reducing its concentration in the heart. We conducted a multicenter phase II trial investigating activity and safety of R-COMP regimen where conventional doxorubicin was substituted with non-pegilated liposomal doxorubicin (TLC-D99; Myocet ™) in patients with DLBCL presenting with moderate/severe concomitant heart disease.

Main inclusion criteria were: age >18 years, diagnosis of DLBCL, no previous oncological treatments. Patients were also required to have cardiac disorder defined by at least one of the following: left ventricular ejection fraction (LVEF) < 50%, left ventricular hypertrophy, uncontrolled moderate/severe arterial hypertension, history of ischemic cardiopathy, clinically significant ventricular arrhythmia, atrial fibrillation (AF), pulmonary hypertension, moderate/severe mitral valvular disorder, moderate aortic valvular disorder. Enrolled patients received 6 courses of 3-weekly R-COMP (rituximab 375 mg/m², cyclophosphamide 750 mg/m², vincristine 1.4 mg/m², TLC-D99 50 mg/m², prednisone 40 mg/m²/day day 1–5). Cardiac function was monitored with LVEF and electrocardiogram (ECG) after cycle 3, at the end of treatment, and during follow-up. It was adopted a Bayesian sequential design that required the monitoring of complete reponse (CR) and cardiac events (CE) rates defined as primary endpoints. Response was defined according to international criteria (Cheson 2007). CE were defined as a LVEF < 25%, a LVEF reduction > 20% from baseline, or occurrence of significant cardiac disorder. Initial study assumptions were a CR rate of at least 70% and a rate of CE below 20%; with a power of 80% and a level of significance of 5%, the study sample was fixed at 50 patients. The proposed strategy would be considered as active and safe if at least 26 CRs and no more than 14 CEs were recorded at the end of the study.

Between 2009 and 2011, 51 patients were enrolled. One patient was excluded after registration due to violation of inclusion criteria. Median age was 77 years (range 53 – 91 years), 69% were male and 33% had stage IV disease. IPI score at study entry was 0–1 in 25%, 2 in 25%, and 3–5 in 50%. Sixty-three cardiac disorders were identified at baseline; the most frequent was ischemic cardiopathy (40%), followed by AF (17%), baseline LVEF <50% (16%), left ventricular hypertrophy (16%); 2 and 3 concomitant cardiac disorders were described in 4 patients; altered profiles at baseline ECG were detected in 38% patients. Median baseline LVEF was 58%. Treatment was completed in 76% of patients with a median dose intensity for TLC-D99 of 98%. R-COMP was interrupted prematurely due to lack of response (n=1), CEs (n=5), severe infection (n=2), deep venous thrombosis (n=1), renal failure (n=1), other toxicity (n=1), and patient's decision (n=1). As requested by the sequential Bayesian model, the CR rate and the rate of CE never fell outside activity and safety boundaries. In fact, 27 patients achieved a CR (55%; 95%CI=42–72%) and 6 CE were observed, which included significant LVEF reduction (2 patients), clinically significant s-troponine increase (2), hearth failure (1), and cardiac arrest (1). Median LVEF after cycle 3 and at the end of treatment was 59% (range 25–72%) and 56% (30–69%), without significant modifications from baseline values. Grade 3–4 hematological toxicity included neutropenia in 67% of pcases, anemia and thrombocytopenia in 10% each, and infections in 4%.

With a median follow-up of 13 months (range 1–28) 6 patients had lymphoma progression, 6 experienced relapse and 6 died without signs of lymphoma relapse/progression. Overall, 10 patients died due to lymphoma (2), severe infection (2), second cancer (1), hemorrhage (1), myocardial infarction (1), renal insufficiency (1), respiratory insufficiency (1), and unknown cause (1). The 1-year OS and PFS were 76% (95%CI: 58–87%) and 60% (95%CI: 42–74%), respectively.

The substitution of conventional doxorubicin with non pegilated liposomal doxorubicin (TLCD99-Myocet™) in the R-CHOP regimen is a safe and active option for patients with DLBCL presenting with concomitant moderate/severe cardiac disorders.

No relevant conflicts of interest to declare.