A randomized trial of cardioprotective strategies in newly diagnosed diffuse large B-cell lymphoma and pre-existing cardiomyopathy or prior anthracycline exposure

Abstract Diffuse large B-cell lymphoma (DLBCL) is a common cancer with more than 25,000 new diagnoses each year in the United States alone. The anthracycline-containing chemotherapy regimens rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) and polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, prednisone (pola-R-CHP) are highly effective for DLBCL and are recommended as first-line treatment. However, anthracyclines increase the risk for heart failure (HF) and compromise necessary cancer treatment for patients with a reduced left ventricular ejection fraction (LVEF), history of HF, or prior anthracycline exposure - the risk of HF events after anthracycline exposure is higher in these patients but anthracycline-free regimens are associated worse lymphoma outcomes. Two cardioprotective strategies – dexrazoxane and liposomal doxorubicin - can prevent clinical HF in patients receiving anthracyclines. Clinical guidelines recommend these infusional cardioprotective strategies in patients treated with high cumulative anthracycline doses or who are high risk for HF, regardless of the malignancy. However, these strategies have not been well studied in patients with DLBCL, in patients with low LVEF or a history of HF and dexrazoxane and liposomal doxorubicin have never been compared with each other so it is uncertain which is preferred to prevent cardiotoxicity. Our primary objective for this project is to determine which infusional cardioprotective strategy is associated with lower risk of LVEF declines or HF events. Based on our preliminary data, we hypothesize that dexrazoxane is associated with superior cardioprotection and that anthracycline-based regimens with curative intent can be given safely in the setting of cardioprotection and close monitoring. We will test this hypothesis in a parallel group multisite randomized trial with 1:1 randomization to dexrazoxane given 30 minutes prior to each doxorubicin infusion or liposomal doxorubicin instead of doxorubicin in each cycle of chemotherapy among patients with DLBCL who are at very high risk for HF onset or worsening due to mildly reduced LVEF, a history of HF, or prior anthracycline treatment. Our primary endpoint will be LVEF at 3 months post-randomization adjusted for baseline LVEF value and key secondary endpoints will include HF events, cardiac biomarkers and lymphoma progression-free survival. We will also assess the toxicity, tolerability and patient-reported functioning using the patient reported outcomes- common terminology criteria for adverse events (PRO-CTCAE), clinician-reported CTCAE, health status questionnaires and measures of physical functioning in the two treatment arms.