Liposome-Encapsulated Doxorubicin Is Highly Active in Patients with B- as Well as T/NK-Cell Lymphomas and Cardiac Comorbidity or Older Age
Authors: Skrabs Cathri n C , Hauswirth Alexander , Eigenberger Karin , Einberger Christine , Raderer Markus , Sperr Wolfgang R , Knoebl Paul , Muellauer Leonhard , Uffmann Martin , Dieckmann Karin , Gaiger Alexander , Jaeger Ulrich 
Published: October 2019

Abstract
Conventional anthracyclines may have severe dose-limiting side effects in patients with pre-existing cardiac comorbidity, particularly if they are elderly. In routine practice, this will lead to dose reductions or preclude the use of anthracyclines. This may result in lower remission and shorter lymphoma-free or overall survival rates. Non-pegylated liposome-encapsulated doxorubicin (Myocet®) in combination with Rituximab, cyclophosphamide, vincristine and prednisone (R-COMP) has been shown to be effective with a low cardiotoxicity profile in patients with diffuse large B-cell lymphoma (DLBCL) (Rigacci et al., Hematol Oncol.2007;25:198–203). We have treated 37 lymphoma patients with pre-existing cardiac disorders or elderly patients with reduced general condition who were considered ineligible or high risk for anthracycline containing therapy. Thirty seven patients with various histologies were included: 20 DLBCL, 9 T-/NK cell lymphomas, 3 follicular lymphomas, 2 post-transplant lymphoproliferative disease (PTLD), 2 chronic lymphocytic leukemia (CLL) and 1 multiple myeloma (MM). Reasons for the use of liposome-encapsulated doxorubicin were: pre-existing cardiac disorders (N=19) including myocardial infarction, cardiomyopathy, reduced left ventricular ejection fraction LVEF (N=6), elevated B-type natriuretic peptide (BNP) levels (N=10, median 680 pg/ml), aortic valve problems, or heart transplantation; older age (N=12; median age 78 years); previous therapy with anthracyclines (N=3); other comorbity or reduced general condition (N=4). Twenty-nine patients (78%) were previously untreated. The following combination regimens were given: R-COMP (N=25), COMP (N=11), and BMD (N=1). The median number of Myocet® containing cycles administered was 5. For various reasons, liposome encapsulated doxorubicin was reduced to a dose of less than 50mg/m2 in 19 patients. High remission rates were observed for this poor risk population: Complete remission rates were 70% (14/20) for DLBCL and 57% (4/7 evaluable patients) for T-/NK cell lymphomas. 31 patients (83%) are still alive at 2–9 months after the end of therapy. Five patients died from progressive disease, one of unknown reasons. Thirteen patients with DLBCL are in continuous CR 3 months after the end of therapy (range 1–8 months). No major cardiac or gastrointestinal toxicity was observed. Of note, paravasation of liposome-encapsulated doxorubicin occurred in 2 patients, but resulted in mild inflammation only without tissue damage. Hematologic toxicity was comparable to that of conventional anthracycline containing regimens: CTC Grade 3 or 4 toxicity for leukocytopenia/neutropenia occurred in 22 patients (59%). Nineteen patients (51%) received G-CSF for primary or secondary prophylaxis in at least one cycle of treatment. We conclude that liposome-encapsulated doxorubicine is highly active in combination chemotherapy for B-cell lymphomas with low cardiac toxicity in patients with pre-existing cardiac disorders or older age. Moreover, we herewith report for the first time efficacy in T/NK-cell lymphomas in this high-risk population. A randomized study evaluating cardiac effects of substitution of conventional doxorubicin by liposome-encapsulated doxorubicin in combination chemotherapy (R-CHOP vs. R-COMP) is currently being conducted by the Austrian Cooperative Group on Cancer Drug Therapy (AGMT).