In DLBCL Treatment, Cardiovascular Comorbidities Warrant Careful Consideration

Treating diffuse large B-cell lymphoma (DLBCL) can be particularly challenging in patients underlying cardiovascular comorbidities, since the most common first- and second-line therapies come with considerable cardiovascular toxicities, according to a report published in JACC CardioOncology.

However, newer targeted therapies and immunotherapies have been developed that appear to carry a lower risk of cardiovascular complications, according to the report, which suggests a collaborative approach between oncologists and cardiologists is essential to safely treat this patient group.

The traditional frontline therapy for people with DLBCL is chemotherapy containing the anthracycline doxorubicin. However, corresponding author Alex F. Herrera, MD, of City of Hope Medical Center in California, and colleagues, explained that anthracycline is associated with a number of cardiac toxicities, including cardiomyopathy and heart failure.

One option for patients at high risk of cardiovascular toxicities is striking doxorubicin from the rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen and replacing it with the less-toxic etoposide or gemcitabine (Gemzar). With such substitutions, the regimens are known as R-CEOP and R-GCVP, respectively.

Multiple studies have looked at R-CEOP compared to R-CHOP. Cumulatively, Herrera and colleagues wrote, the studies “suggest that substituting doxorubicin with etoposide may result in poorer long-term survival, but a sizable minority of patients appear to experience durable remission.”

A phase II study of R-GCVP found an overall response rate of 61.3% and a 2-year progression-free survival rate of 49.8%, the authors noted. A third regimen, using pixantrone instead of doxorubicin (R-CPOP), was found to have a somewhat lower response rate than R-CHOP, but similar survival outcomes with fewer cardiac events.

The authors explained that the use of cardioprotective therapies like neurohormonal modulators or statins can help reduce the cardiovascular risk.

For patients with relapsed or refractory cases, autologous stem cell transplantation (auto-SCT) and anti-CD19 chimeric antigen receptor (CAR) T-cell therapy have become common strategies following salvage chemotherapy. However, the authors said the high-dose chemotherapy used alongside stem-cell transplantation brings with it a significant risk of heart failure and coronary artery disease. Meanwhile, CD19-directed CAR-T therapy has been linked with a risk of hypotension, pulmonary edema, heart failure, arrhythmia, and cardiac arrest, they said.

“[R]elapsed DLBCL patients with significant cardiovascular comorbidities would benefit from cardiac consultation and comanagement by cardiologists/cardio-oncologists to further assess cardiac risk and determine eligibility for intensive therapies such as auto-SCT and CAR-T-cell therapy,” they said.

Herrera and colleagues said a number of targeted agents and immunotherapy options are currently under investigation, and those may prove to be better options for some patients.

One of them is the antibody drug conjugate loncastuximab tesirine (Zynlonta), which targets CD19. It has demonstrated an overall response rate of 48.3% in trials, but it also comes with a significant risk of serious adverse events, the authors said. The second-generation Bruton’s tyrosine kinase inhibitors acalabrutinib (Calquence) and zanubrutinib (Brukinsa) have demonstrated an improved cardiovascular safety profile in patients with chronic lymphocytic leukemia, the authors noted, thought it is not yet clear if that same safely profile would translate to the setting of relapsed or refractory lymphoma.

The authors noted that, in addition to cardiovascular risks conveyed by the therapies themselves, many patients with cardiovascular comorbidities are already considered frail and thus less tolerant of certain treatments.

While Herrera and colleagues said significant work is being done to develop new therapies, there is yet to be a clear curative option for these patients.

“Hence, developing improved treatments for the DLBCL patients with cardiac conditions both in the frontline and relapsed setting is a significant unmet need,” they said.

Reference

Kambhampati S, Herrera AF, Rhee JW. How to treat diffuse large B-cell lymphoma: oncologic and cardiovascular considerations. JACC CardioOncol. 2023;5(3):281-291. Published June 20, 2023. doi:10.1016/j.jaccao.2023.05.001