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The risk of cardiovascular (CV) adverse events (AEs; CVAEs) and heart failure is elevated in patients with non-Hodgkin lymphoma (NHL), and survivors of NHL, when compared with the general population and other patient groups. This marked increase is believed to be associated with the frontline treatments currently employed in the NHL setting. Components of the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and rituximab plus CHOP (R-CHOP) regimens are thought to be particularly cardiotoxic. Specifically, cyclophosphamide and doxorubicin have been linked to left ventricle dysfunction.
Marijke Linschoten, Janine A. M. Kamphuis, and colleagues at the University of Utrecht, NE, carried out a meta-analysis to determine the frequency of CVAEs in patients with NHL that had received CHOP or R-CHOP as a frontline therapy and to identify potential risk factors. Below is a summary of the findings, recently published in Lancet Hematology.1
Table 1. Characteristics of the 137 studies eligible for analysis1
CHOP, cyclophosphamide + doxorubicin + vincristine + and prednisone; CV, cardiovascular; CVAE, cardiovascular adverse event; IQR, interquartile range; R-CHOP, rituximab + CHOP; SD, standard deviation |
|
Study characteristics (N = 137 studies) |
|
---|---|
Number of patients receiving frontline treatment CHOP R-CHOP CHOP + R-CHOP |
21,211 9,541 11,293 377 |
Median follow-up, months (IQR) |
39.0 months (25.5–52.8) |
Mean cycle interval, days (SD) |
19.9 (3.4) |
Mean number of cycles (SD) |
6.3 (1.3) |
Number of studies reporting Grade 1–2 CVAEs Grade 3–4 CVAEs Overall heart failure Treatment-related CV death Treatment discontinuation due to heart failure |
23 77 38 118 51 |
Sub-group analysis
Table 2. Factors influencing the development of Grade 3–4 CVAEs and overall heart failure1
CHOP, cyclophosphamide + doxorubicin + vincristine + prednisolone; R-CHOP, rituximab + CHOP *Meta-regression †Tested with a fixed-effect model across subgroups ‡Analysis was done with data of % of females per study group, rather than comparing the proportion of adverse events or occurrence of heart failure between men and women |
||||
|
Number of subgroups of treatment |
Regression coefficient treatment (95% CI) |
Relative risk (95% CI) |
p |
---|---|---|---|---|
Grade 3–4 CVAEs |
||||
Age, years < 65 (young) ≥ 65 (old) Old vs young |
91 58 33 — |
0.39 (0.21–0.57) — — — |
— — — 3.18 (2.54–3.98) |
< 0.0001* < 0.0001† — — |
Sex, % female‡ |
92 |
0.24 (0.09–0.40) |
— |
0.0023* |
Overall heart failure |
||||
Screening No Yes |
44 30 14 |
— 0.017† — |
||
Number of cycles ≤ 6 (low) > 6 (high) High vs low |
46 31 15 — |
4.99 (0.66–9.32) — — — |
— — — 1.78 (1.43–2.23) |
0.024* 0.31† — — |
Conclusion
Although the proportion of patients that developed Grade 3–4 CVAEs was relatively low, this multi-study analysis underpins frontline treatment with CHOP and/or R-CHOP as a contributing factor towards heart failure. Older (≥ 65 years) age and female sex significantly influenced the establishment of Grade 3–4 CVAEs, while the number of treatment cycles had a significant impact on the development of overall heart failure. Additionally, when active cardiac function screening took place following treatment with CHOP/R-CHOP, an increased number of patients with overall heart failure were identified. These data may encourage clinicians to monitor cardiac events in patients receiving frontline chemotherapy for NHL, as treating pre-symptomatic individuals could halt the progression to serious cardiac AEs. Additionally, as the study uncovered the negative impact older age has on the risk of developing CVAEs, and given the increased prevalence of NHL with age, the use of alternative less cardiotoxic frontline treatments could be beneficial. The authors noted a number of limitations associated with the study, including the lack of access to individual patient data, inter-study heterogeneity, exclusion of potentially applicable studies, and a lack of uniform CVAE toxicity grading across the analysis.
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