Lymphoma Patients Treated without Anthracyclines Have Negligible Risk of Cardiotoxicity: A Nationwide Cohort Study

Abstract

Objective: For more than two decades,CHOP (and later R-CHOP) has been the standard frontline treatment for diffuse large b-cell lymphoma (DLBCL). However, anthracycline-based chemotherapy regimens increase risk of cardiotoxicity with congestive heart failure (HF) being the best documented cardiovascular complication of anthracycline use. However, cardiotoxicity has also been associated with other chemotherapeutic drugs. In this nationwide cohort study, we compared the incidence of development of HF in patients with DLBCL or follicular lymphoma (FL) treated with or without anthracyclines.

Methods: DLBCL and FL patients > 16 years both receiving anthracycline in the form of R-CHOP/CHOEP or non-anthracycline chemotherapy regiments were identified in the Danish National Lymphoma Registry (LYFO) from 2000-2012. Anthracycline exposed patients were required to receive ≥3 cycles of R-CHOP or R-CHOEP upfront. The non-anthracycline exposed patients consisted of patients receiving non-anthracycline containing chemotherapy (such as CVP, CEOP and Bendamustine). Exclusion criteria were i) treatment with chemo therapy regimens more intensive than R-CHOP/CHOEP, ii) up-front high dose autologous stem cell transplantation and iii) the following heart comorbidities prior to the beginning of the study: HF (ICD-10 code: "I50"), Ischemic Heart Disease (ICD-10 code: "I20-I25"), Arrhythmic Heart Disease (ICD-10 code: "I48-I49") and Cardiomyopathy (ICD-10 code: "I42"). Information on heart comorbidities in our study population were retrieved from the Danish National Patient Registry. Patient follow-up started from 30 days after ended chemotherapy to minimize confounding by early HF on the planned number of R-CHOP treatments. Follow-up ended when HF occurred, on the day of emigration from Denmark, day of death or the end of the study on 31th. December 2014, whichever came first. Univariate and multivariable cox regression analyses were performed to assess the association between cumulative anthracycline treatments and HF (adjusted analysis included gender, age, Ann Arbor stadium, radiotherapy, comorbidities and type of lymphoma). Cumulative R-CHOP treatments were stratified into groups of "3-5", "6" and ">6" treatments. Cumulative incidence curves were computed to illustrate risk of HF over time according to number of treatments.

Results: The study included 2,696 patients; 2,007 received anthracycline and 689 received non-anthracycline containing chemotherapy. In total, 1979 patients were diagnosed with DLBCL and 717 with follicular lymphoma. Anthracycline users were slightly younger (median age 64.03 vs 65.2 years (p-value <0.01)), received radiotherapy more often (21.03% vs 6.82% (p-value <0.01)) and were more frequently diagnosed with DLBCL (87.94% vs 31.06% (p-value <0.01)) (table 1). For patients not treated with anthracycline, the cumulative risk of HF within 1, 5 and 8 years were 0%, 0.89% and 1.77%, respectively. For patients treated with 3- 5 cycles of R-CHOP/CHOEP, the corresponding cumulative risk were 0.54%, 4.58% and 5.18%. For patients treated with 6 cycles, the cumulative risks were 1.02%, 4.49% and 8.02 % and for patients treated with >6 cycles, the cumulative risks were 4.01 %, 7.86% and 9.33% (fig 1).

Compared to patients receiving non-anthracycline containing chemotherapy (reference), patients receiving anthracycline containing chemotherapy had a higher risk of developing HF during follow-up with adjusted hazard ratio (HR) of 3.73 (95% CI 1.38-10.09) for patients receiving 3-5 cycles, 4.38 (95% CI 1.83-10.48) for patients receiving 6 cycles, and 8.22 (95% CI 3.50-19.31) for patients receiving >6 cycles of anthracycline treatment.

Conclusion: This present studyconfirms that inclusion of anthracyclines in a multi-agent chemotherapy regimen is responsible for the increased risk of HF observed after treatment for lymphoma and that the rate of HF is correlated to the number of treatment cycles. Patients treated without anthracyclines had a negligible risk of HF supporting the safety of these regimens in patients considered at substantial risk of cardiotoxicity.

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