Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) has improved the treatment results in DLBCL substantially. With more patients being cured from the lymphoma long term toxicity becomes an even more important issue. By replacing doxorubicin with non-pegylated liposomal encapsulated doxorubicin in the R-CHOP regimen (R-COMP) we tried to reduce the cardiotoxicity of R-CHOP in the 1st line treatment of DLBCL.
We randomized 88 patients with untreated DLBCL to one of two treatment arms. R-CHOP consisted of rituximab 375 mg/sqm, cyclophosphamide 750 mg/sqm, doxorubicin 50 mg/sqm, vincristine 2 mg, each iv. day 1 and prednisolone daily po for 5 consecutive days. Six cycles of chemotherapy and 8 cycles of rituximab were planned. In the R-COMP arm doxorubicin was replaced with non-pegylated liposomal encapsulated doxorubicin 50 mg/sqm iv day 1.
Forty and 39 patients were eligible in the R-COMP and R-CHOP arm, respectively. The two arms were well balanced with respect to age, smoking status, heart function, hypertension, and international prognostic index. The primary endpoint of the study was the left ventricular ejection fraction (LVEF) measured by the Simpson method at randomization, after each cycle and 8 weeks after the end of treatment. Mean and standard error were compared by the two-sample t test. Mean LVEF was significantly lower in the R-CHOP arm (62.29%) than in the R-COMP arm (63.56%) (P=.0333). Out of all LVEF measurements 10 (4.6%) vs. 31 (15.8%) were <55% in the R-COMP arm and R-CHOP arm, respectively (P<.001). The N-terminal proB-type of the natriuretic peptide (NT-proBNP) is a strong marker for heart failure. Levels of NT-proBNP began to rise in the R-CHOP arm after the 5th cycle and were significantly different after the end of treatment (median 73 pg/ml vs. 188.2 pg/ml) in the R-COMP arm and R-CHOP arm, respectively. Three (7.5%) and 12 (33.3%) patients had a NT-proBNP >450 pg/ml in the R-COMP arm and R-CHOP arm, respectively (P=.005). Side effects were lower in the R-COMP arm. We observed 26 and 40 severe adverse events in the R-COMP and R-CHOP arm, respectively (P=.029). Most of those were due to infection. The rate of grade 3 and 4 neutropenias was comparable in both arms giving evidence, that non-pegylated liposomal encapsulated doxorubicin was not under-dosed. Although the study was not powered to show differences in efficacy, we had no signal of lower efficacy. The remission rate was 97.5% (CR+CRu 75.0%) and 82.0% (CR+CRu 69.2%) with R-COMP and R-CHOP, respectively. The 3 cases progressing during treatment were in the R-CHOP arm.
Clinical heart failure usually appears after several years of treatment. The difference in LVEF may translate in a lower rate of clinical heart failure with longer follow-up.
Fridrik:Cephalon: Research Funding. Off Label Use: Non-pegylated liposomal encapsulated doxorubicin in the treatment of lymphoma. Willenbacher:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AESCA: Honoraria, Research Funding. Jaeger:Cephalon: Membership on an entity's Board of Directors or advisory committees. Greil:Cephalon: Research Funding.
Asterisk with author names denotes non-ASH members.