Is Liposome Encapsulated Doxorubicin Able to Reduce the Cardiotoxicity of Doxorubicin In the Treatment of DLBCL? A Randomised Study by the Austrian Working Party of Medical Oncology (AGMT-study NHL-14)

A combination of Rituximab with a chemotherapy regimen consisting of cyclophosphamide, vincristine, doxorubicin, and prednisone (R-CHOP) is the current standard treatment for diffuse large B-cell lymphoma (DLBCL). Doxorubicin is known to induce short-time and long-time cardiac toxicity. By encapsulating doxorubicin in liposomes the cardiac toxicity may be reduced. This is the 1^st randomised study comparing doxorubicin and liposome encapsulated doxorubicin in the 1^st line treatment of DLBCL.

Aim of the study was to reduce the cardiotoxicity of R-CHOP by substituting doxorubicin by liposome encapsulated doxorubicin. The primary endpoint was left ventricular ejection fraction (LVEF) measured by the Simpson method and NT-proBNP levels, respectively. Both parameters were measured before each treatment cycle and after the end of treatment. From December 2007 until July 2010 we performed a two arm prospective randomised study. In arm 1 patients were treated with rituximab 375 mg/m^2 iv day 1, cyclophosphamide 750 mg/m^2 iv day 1, liposome encapsulated doxorubicin (Myocet®) 50 mg/m^2 iv day 1, vincristine 2 mg iv day 1, and prednisolone 100 mg po day 1–5. In arm 2 the regimen was identical, but liposome doxorubicin was substituted by standard doxorubicin 50 mg/m^2 i.v. day 1. Treatment cycles were repeated every 2 to 3 weeks, due to the discretion of the treating physician. Six cycles were scheduled. This study was conducted in accordance with the “Good Clinical Practice” Guidelines and the Declaration of Helsinki and was reviewed by the independent ethics committees at the trial centres. All patients gave their written informed consent. Eighty-eight patients were registered, eight were excluded. In each arm 40 patients were eligible. Median age was 66 years (range 19–84 years), 64% of patients were older than 60 years. The two arms were balanced in respect to age, international prognostic index, smoking status, hypertension, NT-proBNP, and LVEF. At the time of the abstract submission 44 patients (24 and 20 in arm 1 and 2, respectively) had finished their treatment and were fully documented. The complete remission rate was 78.8% and 69.6% in arm 1 and 2, respectively. The two progressive lymphomas were in arm 2. We observed 26 and 32 serious adverse events in 19 and 24 patients in arm 1 and arm 2, respectively. Most of them had neutropenic fever. The mean relative difference in LVEF after the 6^th cycle was 2.98 and -3.92 in arm 1 and arm 2, respectively. Two of 24 (8.3%) and 5/20 (25%) had a more than 20% decline of their LVEF during treatment in arm 1 and 2, respectively. However, this was not statistically significant. The difference in median NT-proBNP levels were significantly different 73.1 and 97.2 pg/ml in arm 1 and 2, respectively (P=.0235).

In this 1^st analyses we did not observe any safety concerns in the two arms. The remission rate was as expected. The substitution of doxorubicin by liposome encapsulated doxorubicin seemed not to alter the efficacy of the treatment. With the limited data available the cardiotoxicity may be lower in the arm with liposome encapsulated doxorubicin. However, the primary endpoint of the study was not met, respective to the attenuation of acute anthracycline cardiac toxicity. A possible attenuation of the frequency and severity of chronic heart failure will need a much longer follow up.

The study was registered under the Eudract #: 2007–004970-24

Fridrik:Cephalon: Honoraria, Research Funding. Off Label Use: Liposome encapsulated doxorubicin in diffuse large B-cell lymphoma. Greil:Cephalon: Research Funding.