Phase II, Randomised, Multicentre Study With Two Treatment Arms (R-COMP Versus R-CHOP) in Newly Diagnosed Elderly Patients (≥60 Years) With Non-localised Diffuse Large B-cell Lymphoma (DLBCL)/Follicular Lymphoma Grade IIIb.

Diffuse large B-cell lymphoma (DLBCL) is the most common histological subtype of non-Hodgkin's lymphoma (NHL). This is an aggressive lymphoma, with an incidence in Western countries estimated at 5-6 cases/100,000 inhabitants/year that increases with age.

Treatment for patients with DLBCL is currently based on immunochemotherapy, of which the R-CHOP regimen, which includes cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) in combination with the anti-CD20 monoclonal antibody rituximab and is administered every 21 days for a total of 6-8 cycles, is the most commonly used.

Cardiotoxicity is one of the undesirable effects that limit the use of anthracyclines, such as doxorubicin, as part of the CHOP regimen, which is caused by the formation of complexes between ferric ions and the anthracycline within the myocyte. Because of their oxidative properties, these complexes are toxic and produce highly reactive free radicals that damage the lipid membrane and lead to the cell death of myocytes. Several studies have linked the onset of cardiotoxicity with old age, high cumulative doses of doxorubicin, cardiovascular risk factors and previous heart disease, among others. Anthracycline-induced cardiotoxicity is cumulative and irreversible. Moreover, left ventricular dysfunction is an important late effect in patients with aggressive NHL who survive long term and, according to some studies, have received doxorubicin at doses higher than 200 mg/m². Cardiotoxicity may be silent or subclinical, which is usually detected as a decrease in left ventricular ejection fraction (LVEF), or clinical, with varying degrees of congestive heart failure (CHF). Depending on the symptoms, cardiotoxicity also differs between acute, subacute, late or chronic. The first is manifested at an early stage, usually as arrhythmia, transient ECG changes or pericarditis, among others, is usually reversible, is not detrimental to the continuation of treatment and is not associated with subacute and late toxicity.

Chronic cardiotoxicity could be early or late. Early-onset cardiotoxicity occurs within 1 year after anthracycline treatment and late-onset cardiotoxicity occurs more than 1 year after completion of anthracycline treatment. In the latter two, cardiotoxicity is associated with the lesion of cardiomyocytes and is therefore considered irreversible. The incidence of cardiotoxicity varies among different studies, depending on patient follow-up or the definition of cardiotoxicity used (acute, subacute or late).

In addition to clinical findings, the determination of LVEF or, more recently, the use of biomarkers, are the most commonly used methods to diagnose and assess cardiotoxicity. Regarding the identification of biomarkers, troponin I and N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP) are the most commonly used and investigated in the context of clinical studies. The advantages of using biomarkers include their minimally invasive identification, which is less expensive than echocardiography, and, unlike radionuclide ventriculography, they avoid irradiation of the patient. Furthermore, the interpretation of their results does not depend on the observer's experience, thus avoiding interobserver variability. Several studies have shown the role of troponins as indicators of early anthracycline-induced cardiotoxicity or other chemotherapeutic agents, which are able to predict impaired ventricular function and higher incidence of cardiac events in patients with elevated values of this marker compared with patients with normal troponin values. Regarding the use of brain natriuretic peptides such as NT-proBNP, several studies have shown a correlation between persistently high values of this biomarker and impaired heart function parameters, in particular LVEF.