Liposomal doxorubicin in place of doxorubicin hydrochloride to prevent anthracycline-induced cardiomyopathy in elderly patients with Hodgkin lymphoma

Abstract

Although anthracycline-based chemotherapy provides the best outcomes for Hodgkin lymphoma (HL) patients,¹ reducing the use of doxorubicin hydrochloride is desirable to lower the risk of anthracycline-induced cardiac dysfunction, especially in the elderly.^2-4 The most common clinical manifestation of cardiotoxicity is a dose-dependent cardiomyopathy (CMP) leading to chronic heart failure (HF). According to recent reports,^2-4 the cut-off to prevent cardiotoxicity is 210 mg/m². Data from oncology literature indicate that about 5% of patients receiving >210 mg/m² of cumulative anthracycline will develop overt HF 10–20 years after treatment, increasing to 10% when mediastinal radiotherapy is added.^2-4 However, this incidence is likely underestimated, since over half of elderly patients show some degree of cardiac dysfunction.^2-4 The 2022 Task Force for Cancer Treatments and Cardiovascular Toxicity of the European Society of Cardiology (ESC) Guidelines⁴ strongly recommend systematic echocardiographic monitoring, including strain rate imaging with measures of global radial and circumferential strain (global longitudinal strain [GLS]) in addition to left ventricular ejection fraction (LVEF) for exploring subclinical signs of impaired ventricular function. The authors advocate diagnosis of anthracycline-induced CMP in the asymptomatic phase, that is, at the onset when GLS declines ≥15% from baseline and/or LVEF falls ≥10% to 40%–49%, allowing early modern HF treatment.^2-4

We read with interest the multicenter phase II study by Bröckelmann et al. reporting the outcomes of 49 elderly (median age: 66 years) classic-HL patients with advanced-stage treated frontline between 2015 and 2017, with six cycles of B-CAP, consisting of Brentuximab Vedotin (1.8 mg/kg i.v. Day 1), cyclophosphamide (750 mg/m² i.v. d1), doxorubicin (50 mg/m² i.v. d1), and prednisone (100 mg po Days 2–6) at 3-weekly intervals.⁵ The maximum dose level of antineoplastic drugs was maintained in 86% of patients, and the mean relative dose intensity, defined as the relative dose over relative duration, was 93%. Ten patients (20%) received consolidative 30-Gy radiotherapy to residual nodal masses (RNMs) with 2-deoxy-2[F-18] fluoro-D-glucose (FDG) uptake in positron emission tomography/computed tomography (PET/CT) scans after completion of B-CAP treatment. At 3 years, progression-free survival (PFS) and overall survival (OS) were 64% and 91%, respectively, with a median follow-up of 35 months. Any grade heart toxicity (according to the National Cancer Institute Common Terminology Criteria for Adverse Events) was reported in 10% of patients (N = 5), with grade 1–2 in 6% (N = 3) and grade 3 in 4% (N = 2). The authors conclude that the B-CAP regimen led to early and sustained improvements in health-related quality of life, that is, fatigue, dyspnea, insomnia, or loss of appetite as well as in role and social functioning. Despite relevant adverse prognostic factors for cardiac dysfunction (range of age of 60–84 years, and a cumulative anthracycline dose >210 mg/m²), no data on echocardiographic monitoring during and after anticancer treatment were provided.⁵

Advances in liposome technology led to the development of Myocet^TM, a stable doxorubicin formulation encapsulated in a nonpegylated liposomal membrane of phosphatidylcholine and cholesterol (nonpegylated liposomal doxorubicin [NPLD]).^{6, 7} Liposomal entrapment modifies doxorubicin pharmacokinetics and enables targeted delivery to neoplastic tissue, as shown in mouse and human carcinoma models.⁸ A key feature of NPLD is that liposomal formulation spares cardiac tissue with tight endothelial junctions, reducing adverse events and improving tolerability.⁹ We previously published¹⁰ encouraging preliminary multi-center efficacy and safety results on the upfront MVD regimen for elderly patients with advanced-stage c-HL. The protocol consists of 1-day outpatient i.v. infusions of NPLD (25 mg/m²) plus standard Vinblastine and Dacarbazine for a total of 6 cycles (12 i.v. administrations, every 2 weeks), followed by irradiation of RNMs with size ≥2.5 cm at CT scans. Mature results (in terms of longer follow-up)¹⁰ are now available from a retrospective series of 50 older adults (median age, 69 years; range, 60–89 years; two-third of patients with at least two of the traditional cardiac risk factors, that is, hypertension [N = 38], hyperlipidemia [N = 35], diabetes mellitus [N = 30], tobacco use [N = 20], obesity [N = 10], and/or history of heart disease [N = 18]) receiving MVD ± irradiation during the period from 2013 to 2023 in tertiary hospitals in the bay of Naples (Italy). The median dose intensity was 92%. Seventeen patients (34%) received consolidation radiotherapy (mediastinal in 3 cases) for RNMs with Deauville score ≥3 at FDG-PET. At the 6-year median follow-up, the PFS and OS of the entire population were 82% (95% confidence interval [CI], 0.72–0.934) and 88% (95% CI, 0.794–0.975), respectively. All patients underwent systematic cardiac monitoring by expert echocardiographers of the cardio-oncology units.^{11, 12} Complete GLS and LVEF evaluations were available for 45 patients at baseline, interim, end-of-treatment (EoT), and 6–12 months of follow-up (Figure 1). At baseline (chemotherapy start), there were 10 patients (22%) with measurements of GLS worse than −20% (they had LVEF measurements ≥50%); the echocardiographic assessment showed a median result of GLS of −20% and a median result of LVEF of 60%. At the interim assessment, the median result of GLS was −21% and the median result of LVEF was 60%. At EoT assessment, the median result of GLS was −21% and the median result of LVEF was 60%. At the 6- and 12-month follow-up, the median result of GLS was −21.6% and −22% and the median result of LVEF was 60% and 61%, respectively. According to the cancer therapy-related cardiovascular damage definitions of ESC 2022 Guidelines,⁴ most changes were minimal, with a reduction of 10% from baseline in the median values of GLS and LVEF at each time point compared with the baseline. Only three patients showed ≥15% GLS reduction (Figure 1A) and six patients showed ≥10% LVEF reduction (Figure 1B) as compared to the baseline. Despite older age, comorbidities, and cumulative dose of anthracycline >250 mg/m² (relevant adverse prognostic factors for cardiac dysfunction), any grade cardiotoxicity occurred in 10% of patients (N = 5), with grade 1–2 in 6% (N = 3) and grade 3 in 4% (N = 2). Among them, two patients experienced grade 3 atrial fibrillation, fully reversible with medical therapy.

These findings, consistent with the Italian Agency of the drug (AIFA) recommendations,¹³ support frontline use of NPLD-based regimens in elderly HL patients due to their favorable safety and efficacy profile.^{10-12, 14}

In conclusion, substituting conventional doxorubicin with the liposomal formulation may help prevent anthracycline-induced cardiomyopathy in elderly patients with HL.

Marco Picardi: Conceptualization; writing—original draft; methodology; validation; visualization; writing—review and editing; formal analysis; project administration; data curation; supervision; resources; funding acquisition. Annamaria Vincenzi: Conceptualization; writing—original draft; methodology; validation; visualization; writing—review and editing; formal analysis; project administration; supervision; data curation; resources; investigation; software. Novella Pugliese: Conceptualization; writing—original draft; methodology; validation; visualization; writing—review and editing; software; formal analysis; project administration; data curation; supervision; resources; investigation. Claudia Giordano: Conceptualization; investigation; writing—original draft; methodology; validation; visualization; writing—review and editing; software; formal analysis; project administration; data curation; supervision; resources. Maria Prastaro: Data curation; writing—review and editing; writing—original draft; methodology; validation; visualization; formal analysis. Roberta Esposito: Data curation; writing—review and editing; writing—original draft; methodology; validation; visualization; formal analysis. Fabrizio Pane: Conceptualization; investigation; funding acquisition; writing—original draft; methodology; validation; visualization; writing—review and editing; formal analysis; project administration; supervision; resources; data curation.

The authors declare no conflicts of interest.

This research received no funding.