Rationale and design of the HOVON 170 DLBCL-ANTICIPATE trial: preventing anthracycline-induced cardiac dysfunction with dexrazoxane

Abstract

Background

Dexrazoxane has been studied for its ability to prevent anthracycline-induced cardiac dysfunction (AICD) in several trials but its use in clinical practice remains limited. This is related to the low to moderate quality of the generated evidence, safety concerns and restricted prescribing indications. Additional randomized trials are needed before this drug can be routinely integrated into cardio-oncology clinical practice.

Objectives

To describe the rationale and design of the HOVON 170 DLBCL – ANTICIPATE trial. This trial aims to establish the efficacy and safety of dexrazoxane for the primary prevention of AICD in patients diagnosed with Diffuse Large B-Cell Lymphoma (DLBCL) treated with six cycles R-CHOP₂₁ chemo-immunotherapy.

Methods

This is a multicenter, parallel-group, open-label, phase III trial, randomizing 324 patients between either no cardioprotective treatment or dexrazoxane from the first R-CHOP cycle. The primary and co-primary endpoints are the incidence of AICD within 12 months of registration and the percentage of patients with complete metabolic remission at the end-of-treatment PET-CT respectively. The trial is registered at the EU Clinical Trials Register (EU-CT number 2023-505377-32) and ClinicalTrials.gov (NCT06220032).

Results

The medical research ethics committee approved the trial in May 2024. Recruitment has started in September 2024 and is expected to last for three years.

Conclusions

This trial is poised to contribute crucial evidence concerning the efficacy and safety on the use of dexrazoxane in the primary prevention of AICD. The trial is anticipated to address critical knowledge gaps and offer important insights into the value of dexrazoxane in cardio-oncology practice.

Introduction

Diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma (NHL), is an aggressive but curable disease. With R-CHOP immunochemotherapy, the regimen that has been the standard frontline treatment for over two decades, with 60–70% of patients reach a 5-year progression-free survival, increasing to ≥ 75% for those who complete six cycles of treatment [1, 2].

The R-CHOP regimen is composed of the anti-CD20 monoclonal antibody rituximab combined with the chemotherapeutics cyclophosphamide, doxorubicin, vincristine, and prednisone [3]. Doxorubicin, one of the most used anthracyclines, is well-known for its cardiotoxicity, which is characterized by a loss of cardiomyocytes and the development of diffuse myocardial fibrosis [4]. In the absence of cardiac stem cells, the heart does not have regenerative capacity and the induced damage thereby is irreversible [5]. With a reduction in the proportion of normal myocardium, there is a decline in myocardial contractility that can, over time, progress to end-stage heart failure [6]. The cumulative incidence of symptomatic heart failure post treatment with the R-CHOP regimen has been reported around 5–10% within 5 years, rising to 26% in the elderly (≥ 65 years) after 8 years of follow-up [7–9]. In addition, heart failure is a significant cause of death among patients in complete remission [10].

Anthracycline-induced cardiotoxicity (AICD) is often considered a late side effect of cancer treatment due to the delayed onset of symptomatic heart failure. However, myocardial injury begins with the initial anthracycline exposure, marked by a troponin release that can be detected in some patients already after the first dose, and peaks at the end of anthracycline therapy [11, 12]. Of those patients that develop AICD, asymptomatic left ventricular systolic dysfunction can already be detected within the first year in 98% of affected patients [13]. Asymptomatic left ventricular systolic dysfunction increases the risk of developing heart failure by nearly fivefold (RR 4.6, 95% CI 2.2–9.8) compared to those with normal left ventricular systolic function [14]. For this reason, strategies to prevent AICD should ideally already start before the initial exposure to anthracycline agents.

Dexrazoxane has been investigated for its efficacy in the prevention of AICD in several randomized controlled trials in the past, all showing a cardioprotective effect [15]. Despite these findings, the use of dexrazoxane in clinical practice remains limited. This is largely related due to prescribing restrictions by the European Medicines Agency (EMA) and the Food and Drug Administration (FDA), which only approve its use for preventing chronic cumulative cardiotoxicity in advanced and/or metastatic breast cancer patients with a significant prior anthracycline exposure [16, 17]. Other factors contributing to its limited use are safety concerns, including a potential increased risk of hematologic toxicity and secondary cancers in children [15]. A large randomized controlled trial on the use of dexrazoxane is urgently needed to generate high-quality evidence and guide current cardio-oncology practice. In the current manuscript we present the rationale and study design of the HOVON 170 DLBCL – ANTICIPATE trial.

Methods

Design

The HOVON 170 DLBCL – ANTICIPATE trial (https://hovon.nl/en/trials/ho170) is an interdisciplinary investigator-initiated, national, parallel-group, open-label, phase III trial, that will be conducted in 25 hospitals in The Netherlands. The overall study design is depicted in the Central Illustration (Fig. 1). The trial is registered at the EU Clinical Trials Register (EU-CT number 2023-505377-32) and ClinicalTrials.gov register (NCT06220032). Ethical approval for the conduct of this trial has been obtained from the Medical Research Ethics Committee NedMec (reference number: D-24-500268). The trial will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.

Fig. 1.

Central Illustration: Overview of study flow, participating centres and schedule of assessments. * Patients switched to DA-EPOCH-R after one cycle of R-CHOP will be replaced and not receive any further follow-up in the context of the trial nor be included in the intention-to-treat analysis. The total number of patients included will therefor depend on the number of patients that switch to the DA-EPOCH-R regimen, a priori it is expected that 5–10% of patients will switch leading to an inclusion of 340–357 patients in total

Patient selection

Adult patients (≥ 18 years) with a confirmed histologic diagnosis of CD20⁺ DLBCL according to the 2022 WHO classification with Ann-Arbor stage II-IV or stage I with bulky disease (defined as a ≥ 10 cm mass), who are planned to receive six cycles of standard R-CHOP₂₁ (per cycle on day 1: rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², vincristine 1.4 mg/m² (max 2 mg), and on day 1–5: prednisolone 100 mg) will be considered for eligibility. Patients with follicular lymphoma grade 3B as well as those with double-hit lymphoma planned to receive R2-CHOP₂₁ (R-CHOP + lenalidomide) are also eligible. The most important exclusion criteria include any prior or present malignancy other than DLBCL that required or requires systemic therapy, planned treatment with mini-R-CHOP, non-diagnostic or poor echocardiographic imaging quality at baseline, and significant organ dysfunction including pre-existing cardiac disease defined as a baseline left ventricular ejection fraction (LVEF) < 50%, symptomatic heart failure or hospitalization for heart failure in the past year, refractory anginal symptoms, arrhythmia’s not controlled with optimal medical treatment, significant valvular dysfunction and non-ischemic cardiomyopathies. All in- and exclusion criteria are listed in Table 1.

Table 1.

Inclusion and exclusion criteria

Inclusion criteria
1.	Untreated patients with a confirmed histologic diagnosis of CD20+DLBCLg according to the 2022 WHOv classification:  - DLBCLg NOSr  - High-grade B-cell lymphoma NOSr  - High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 translocation when DA-EPOCH-Rf is not an option (note: it is allowed to include a patient pending the FISHi results).  - Follicular lymphoma  - T-cell/histiocyte-rich B-cell lymphoma (THRBCL)  - Untreated transformed lymphoma
2.	Planned treatment with 6 cycles of R-CHOP21. The following regimens are also allowed:  - Reversed R-CHOP21.  - Treatment with R2-CHOP21 (6 cycles of R-CHOP21 + lenalidomide 15 mg day 1–14) in case of double hit lymphoma if combined with G-CSF.  - Two additional administrations of rituximab after 6 cycles of R-CHOP21.  - Addition of high dose MTXq or MTXq-it for CNSd prophylaxis.
3.	Ann Arbor stages II-IV and stage I if the treatment plan is 6 cycles of R-CHOP21 in case of bulky disease (defined as ≥10 cm mass).
4.	Age ≥18 years.
5.	WHOv performance status ≤ 2, WHOv 3 performance status is allowed when considered directly related to the DLBCLg.
6.	Negative pregnancy test at study entry for women of childbearing potential.
7.	Female patient:  - Is either post-menopausal for at least 1 year before the screening visit or surgically sterile or;  - If of childbearing potential:   o Agrees to practice two effective methods of contraception at the same time from the time of signing the informed consent through at least 12 months after the last dose of protocol treatment or;   o Agrees to completely abstain from heterosexual intercourse.
8.	Male patient:  - Even if surgically sterilized (i.e. status post vasectomy) agrees to practice effective barrier contraception during the entire study period and through 12 months after the last dose of protocol treatment or;  - Agrees to completely abstain from heterosexual intercourse.
9.	Patient is able to adhere to the study visit schedule and other protocol requirements.
10.	Written informed consent.
Exclusion criteria
1.	Any of the following B-cell lymphomas according to the 2022 WHOv classification:  - CNSd involvement by DLBCLg (note: high CNS-IPId, o is allowed).  - Testicular DLBCLg.  - Primary mediastinal B-cell lymphoma.  - EBVh post-transplant lymphoproliferative disorder.
2.	Any prior malignancy or present malignancy other than DLBCLg that required or requires systemic therapy. Prior surgery or local radiotherapy is allowed in case the heart has not been exposed.
3.	Planned treatment with mini-R-CHOP.
4.	Pre-existing cardiac disease including:  - LVEFp <50% measured with echocardiography (2D or 3D).  - Symptomatic heart failure (NYHAs ≥II) or hospitalization for heart failure in the last year.  - Refractory anginal symptoms.  - Cardiac arrhythmias not controlled with optimal medical treatment, in case of atrial fibrillation the ventricular response rate needs to be < 110/bpm.  - Significant valvular dysfunction on echocardiography.  - Non-ischemic cardiomyopathy.
5.	Non-diagnostic/poor transthoracic echocardiography imaging quality at baseline.
6.	Severe pulmonary dysfunction defined as breathlessness at rest (COPDe GOLD III or IV) unless clearly related to DLBCLg.
7.	Severe neurological or psychiatric disease.
8.	Inadequate hematological function (ANCa <1.0 × 109/L or platelets < 75 × 109/) unless clearly related to DLBCLg.
9.	Significant hepatic dysfunction (serum bilirubin or transaminases ≥ 3x the upper limit of normal) unless related to lymphoma infiltration of the liver.
10.	Active hepatitis B or C infection (serology testing is required at screening).  - Patients positive for HBsAgk regardless of antibody status or HBsAgk negative but anti-HBcb positive are only eligible if HBV-PCR l, t is negative and patients are protected with lamuvidine or entecavir.  - Patients with positive hepatitis C serology are only eligible if HCV-(RNA)m, u is confirmed negative.
11.	Significant renal dysfunction (creatinine clearance < 30 ml/min after rehydration) or requiring dialysis.
12.	Active uncontrolled fungal, bacterial and/or viral infection.
13.	Patients known to be HIVn-positive.
14.	Breast feeding female patients.
15.	Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
16.	Participation in another clinical trial with anti-cancer therapy or a cardiovascular drug.

^aANC: Absolute neutrophil count; ^bAnti-HBc: ^cHepatitis B core antigen; ^dCNS: Central nervous system

^eCOPD: Chronic obstructive pulmonary disease; ^fDA-EPOCH-R: Dose adjusted EPOCH-R;

^gDLBCL: Diffuse large B-cell lymphoma; ^hEBV: Epstein Barr virus; ⁱFISH: Fluorescence in situ hybridization

^jG-CSF: Granulocyte colony stimulating fact ^kHBsAg: Hepatitis B surface antigen; ^lHBV: Hepatitis B virus; ^mHBC: Hepatitis C virus; ⁿHIV: Human immunodeficiency virus; ^oIPI: International prognostic index;

^pLVEF: Left ventricular ejection fraction; ^qMTX: Methotrexate; ^rNOS: Not otherwise specified;

^sNYHA: New York Heart Association; ^tPCR: Polymerase chain reaction; ^uRNA: Ribonucleic acid

^vWHO: World Health Organization

Intervention and randomization

Eligible patients will be randomized in a 1:1 ratio to receive either 6 cycles of R-CHOP₂₁ without dexrazoxane or 6 cycles of R-CHOP₂₁ with dexrazoxane prior to each doxorubicin infusion. Dexrazoxane will be administered from the first R-CHOP cycle in a 10:1 dexrazoxane-doxorubicin ratio infused 30 min prior to the infusion of doxorubicin.

The use of a placebo in the control arm was considered during the design of the trial but deemed infeasible due to the low pH of dexrazoxane in solution (pH 3.3 in Ringer’s lactate, pH 4.2 in sodium lactate 0.16 M). This low pH can cause irritation upon infusion, which jeopardizes the blinding process for patients as well as personnel. Administering a placebo with such a low pH was considered unethical.

Patients will be randomized centrally, with stratification by participating center, using a minimization procedure to ensure balance between the two arms.

Endpoints and definitions

The primary endpoint of the trial is the incidence of AICD within 12 months of randomization. AICD is defined as an absolute decline in LVEF from baseline of ≥10% points to < 50% on echocardiography (measured 2D). A LVEF decline of ≥10% points has been the most commonly accepted threshold value across literature to define cancer-therapy related cardiac dysfunction (CTRCD) [18]. The co-primary (safety) endpoint is the percentage of patients with complete metabolic remission (CMR) as assessed at the end-of-treatment ¹⁸F-FDG PET-CT 6–8 weeks after completion of the last R-CHOP₂₁ cycle (not including two potential additional doses of rituximab) to reassure that dexrazoxane does not influence the antineoplastic efficacy of doxorubicin. To declare the trial successful, it is deemed essential that the superiority of the addition of dexrazoxane on the primary endpoint and non-inferiority on the co-primary endpoint are both demonstrated (see statistical section for further details). Secondary endpoints include overall-, progression-free and event-free survival at 12-months, change in LVEF (2D and 3D) and global longitudinal strain (GLS), major adverse cardiovascular events (MACE), hospitalization for heart failure, New York Heart Association (NYHA) functional class, troponin release, and quality of life.

Clinical evaluation

Patients deemed potentially eligible by the treating hemato-oncologist are referred to a cardiologist for cardio-oncology screening including a transthoracic echocardiogram, electrocardiogram (ECG) and assessment of cardiac biomarkers (NT-proBNP and troponin). Patients meeting all eligibility criteria after screening that provide written informed consent will subsequently be randomized. During treatment with R-CHOP₂₁, troponin is measured at day 1 of every R-CHOP₂₁ cycle and an ECG is made at day 1 of cycle 2 and 4. At the end of treatment patients undergo a ¹⁸F-FDG PET CT-scan, transthoracic echocardiogram and ECG. A year after randomization the transthoracic echocardiogram and ECG are repeated.

Patient reported outcome measures (PROMS) will be used to evaluate self-reported side effects according to the following domains of the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE): gastrointestinal, cardio/circulatory, respiratory and miscellaneous (pain and swelling at injection site) [19]. Furthermore, the generic and disease-specific quality of life questionnaires QLQ-C30 and QLQ-NHL-HG-29 from the European Organization for Research and Treatment of Cancer (EORTC) will be used [20]. Patients will be asked to fill out these questionnaires at baseline, end of protocol treatment and 12-months after randomization. All clinical investigations related to the outcome assessments are depicted in the Central Illustration (Fig. 1).

Collection of biomaterial for ancillary studies

Peripheral blood samples, including serum, ethylenediaminetetraacetic acid (EDTA) plasma, EDTA cell pellet, and lithium heparin plasma, will be collected at the beginning and end of treatment and stored in a central biobank. These samples will be used for ancillary studies to enhance the understanding of the pathophysiological mechanisms behind AICD and to identify factors that modulate individual patient risk.

Long-term follow-up

All patients will be actively followed for 12 months after randomization. Beyond the first year, long-term follow-up data will be collected by linking the pseudonymized trial data with national registries, including but not limited to the Netherlands Cancer Registry (NCR) and Dutch Hospital Data (DHD). This linkage will allow for the assessment of long-term outcomes of trial participants, including the onset of secondary malignancies and hard cardiovascular endpoints including heart failure hospitalization and cardiovascular mortality.

Echocardiography imaging core laboratory and analysis

The local on-site measurement of echocardiographic parameters is a key feature of this trial. Uniform high-quality transthoracic ultrasound acquisition and measurements across trial sites is therefore of pivotal importance. Participating sites follow a training program prior to site activation and patient enrollment. During the training, the quality of ultrasounds, adherence to the echocardiogram protocol, and measurement accuracy is evaluated by two dedicated Cardiovascular Imaging (EACVI) certified cardiologists with specific training in cardio-oncology. During the conduct of the trial, these cardiologists form a core lab facility, where echocardiographic images from trial sites are sent to on a continuous basis during the patient recruitment period. The core lab cardiologists perform quality control checks to assess the imaging quality and protocol adherence. Furthermore, the core laboratory cardiologists will re-assess the echocardiography parameters related to the primary and secondary endpoints (i.e. 2D and 3D LVEF and GLS) while blinded to the locally performed measurements, supporting the reliability and validity of the study outcomes. In case of poor image acquisition, imaging protocol violations, or significant discrepancies between local and central measurements, the Sponsor will contact the trial site with direct feedback. Based on previous research on inter-observer variability of LVEF, an absolute difference of ≥10% points (2D) or ≥5% points (3D) between the locally and centrally performed LVEF measurements is considered as significantly different [21]. For GLS a relative difference of ≥15% is considered significant [18]. During the main analyses, a sensitivity analysis will be performed for the primary endpoint in the agreement between locally and centrally performed measurements regarding the classification of AICD.

Safety monitoring

Patients will be asked and monitored for adverse events by study personnel at every main study visit and through the PRO-CTCAE questionnaire. All adverse events of severity grade ≥2 will be registered until 30 days after the last administration of dexrazoxane. An increase in grade will be registered for all adverse events. To allow adequate monitoring of hematologic toxicity during treatment with R-CHOP₂₁, a decrease in grade is also registered for hematologic adverse events.

Cardiovascular disorders as well as pain at the injection site have been defined as adverse events of special interest (AESI) in this trial. For this reason, the occurrence of cardiovascular adverse events will be assessed until 12-months after randomization and for injection site reactions also grade 1 will be recorded as dexrazoxane is acidic in nature in solution and the extent of patient discomfort associated with this drug is unclear from previous studies.

Adverse events will be registered and graded in line with the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 with some adaptations to improve consistency of this classification system [22]. For example, in the CTCAE, a significant asymptomatic decline in LVEF from 60 to 35% can be graded as either grade 0, 1, or 3, depending on whether the researcher chooses the entry ‘left ventricular systolic dysfunction’, ‘heart failure’, or a ‘decline in ejection fraction’, respectively [23]. To promote more consistent grading, the ‘left ventricular systolic dysfunction’ entry has been removed from the electronic case report form. Additionally, for entries related to specific cardiovascular adverse events, more detailed information is collected upon registration of the event. This allows for better adjudication and more accurate determination of severity, causality, and treatment of the event.

Withdrawal criteria

Patients who die, progress or relapse during treatment, experience excessive toxicity, refuse or are incompliant to protocol treatment, appear to not be eligible in hindsight or become pregnant are withdrawn from protocol treatment. Furthermore, patients with a high-grade B-cell lymphoma with MYC +, BCL2 and/or BCL6 rearrangements as determined by fluorescence in situ hybridization (FISH) should, according to current clinical guidelines, be treated with either dose adjusted EPOCH-R (DA-EPOCH-R) or R2-CHOP. However, in many hospitals, the FISH results will not be immediately available at diagnosis. In such situations, it is common practice to start with a first cycle of R-CHOP pending the FISH results in the best interest of the patient. Patients switched to DA-EPOCH-R after one cycle of R-CHOP will be replaced and not receive any further follow-up in the context of the trial.

Data collection, management and study coordination

All data are gathered in an electronic case report form by trained data managers of the Netherlands Comprehensive Cancer Organization (IKNL) or experienced local data managers affiliated to the study site. The electronic case report form will document eligibility, efficacy, safety, compliance with the study protocol and parameters related to the primary and secondary endpoints. PROMS can be filled out by patients either digitally or on paper and the data will be collected within the Patient Reported Outcomes Following Initial treatment and Long-term Evaluation of Survivorship (PROFILES) registry [24]. For the imaging data, Digital Imaging and Communications in Medicine (DICOM) files of all the transthoracic echocardiograms and ¹⁸F-FDG PET-CTs are collected centrally at the Amsterdam UMC together with all ECGs in either DICOM format or Portable Document Format (PDF) as well as the (standardized) imaging reports generated locally as well as by the echocardiography core lab.

The Haemato Oncology Foundation for Adults in the Netherlands (HOVON) Clinical Operations oversees all operational aspects of this HOVON trial in collaboration with The Dutch Network for Cardiovascular Research (WCN). Before a site is activated, study monitors conduct remote site training. Once the site is activated, on- and off-site monitoring visits are carried out according to a study-specific monitoring plan. A steering committee, composed of multidisciplinary experts, provides clinical guidance on protocol development, study implementation and conduct as well as interpretation of results. An independent Data Safety and Monitoring Board (DSMB) is installed that will advise on safety and futility.

Statistical analyses

Data analysis for the primary endpoint will be performed according to the intention-to-treat principle for all patients apart from those switching to DA-EPOCH-R. The co-primary endpoint will be analysed in the as-treated population, so that if there is any difference in the proportion of patients with CMR between the control and intervention arm, this difference will not be diluted by patients allocated to the intervention but who did not receive it. Noninferiority will be assessed using the half-width of the confidence interval of the difference of the proportions. Using a group-sequential design with one interim analysis for futility when 30% of patients have been evaluated by ¹⁸F-FDG PET CT at the end of treatment (not including patients who switched to DA-EPOCH-R after the first cycle of R-CHOP), a sample size of 324 patients will provide approximately 90% power to detect a decrease in the incidence of AICD of 10.6 to 4.4% with the addition of dexrazoxane (superiority test with a one-sided alpha of 0.025). For the co-primary endpoint, the sample size is sufficient to obtain 80% power to test a non-inferiority margin of 10% points (non-inferiority test with a one-sided alpha of 0.05). Due to the replacement of patients that switch to DA-EPOCH-R after having received one R-CHOP cycle, the total number of patients included will depend on the number of patients that switch to the DA-EPOCH-R regimen. A priori it is expected that 5–10% of patients will switch to this regimen, leading to an inclusion of 340–357 patients in total. The number of patients switching to DA-EPOCH-R or discontinuing protocol treatment for other reasons will be regularly evaluated to determine the appropriate point for ending trial recruitment.

To declare the trial successful, it is deemed essential that the superiority of addition of dexrazoxane on the primary endpoint and non-inferiority on the co-primary endpoint are both demonstrated. Therefore, the study will not be stopped for efficacy at the interim analysis, and no adjustment of the alpha level is required at the time of the final analysis.

Results

The trial received approval from the medical research ethical committee in May 2024, and recruitment has started in September 2024, with an anticipated accrual duration of 3 years. The main results of the trial are expected in 2029.

Discussion

The development of cardio-oncology has in recent years been marked by significant advancements and growing recognition of the importance of managing cardiovascular health in patients with cancer and cancer survivors. Despite ongoing efforts to identify high-risk individuals and the growing number of hospitals with specialized cardio-oncology clinics focused on screening and monitoring for earlier detection and treatment of AICD, this toxicity remains a significant problem. Several trials have assessed the value of neurohormonal therapies (e.g. angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs) and mineralocorticoid receptor antagonists) for the primary prevention of AICD.²⁵ However, the results of these studies have been varying and a meta-analysis pooling aggregate data of 17 trials showed a marginal treatment effect at most [25].

In this context, there has been a resurgence of interest in dexrazoxane, a bisdioxopiperazine agent initially studied for its cardioprotective properties in the 1970s and 1980s in various mammalian species receiving anthracycline-antibiotic agents [26–30]. Following these pre-clinical studies, 13 randomized controlled trials have been conducted with dexrazoxane, eight of which involved adults which were published between 1992 and 2016 [15, 31–37]. A Cochrane meta-analysis pooling the results of seven adult trials demonstrated a significant reduction in the risk of both clinical heart failure (RR 0.22, 95% CI 0.11–0.43) and subclinical heart failure (RR 0.37, 95% CI 0.24–0.56) [15]. The analysis indicated no negative impact on survival or tumor response rate, although a possible increased risk of hematological toxicity was noted. The quality of evidence from these adult trials ranged from low to moderate [15]. In children, the meta-analysis contributed to recommendations by the Late Effects of Childhood Cancer Guideline Harmonization Group on the use of dexrazoxane for primary cardioprotection in patients who are expected to receive a cumulative doxorubicin- or equivalent dose of at least 250 mg/m² [38].

Limitations of previous randomized controlled trials

It is questionable to what extent the results of previous conducted trials justify the use of dexrazoxane in adults in current clinical practice. Firstly, dexrazoxane has almost exclusively been studied in adult patients with advanced or metastatic breast cancer. Only two studies have investigated its use in patients with other malignancies, including soft tissue sarcomas and non-Hodgkin lymphoma (sample size n = < 35) [32, 37]. A request to widen the indication to ´patients with cancer´ by the Marketing Authorization Holder of dexrazoxane was rejected by the EMA in 2016 in the absence of supporting data. Secondly, many trials used high cumulative anthracycline doses, which are not representative of those commonly used today [39]. Thirdly, there is a significant heterogeneity in the definition of AICD across trials, including symptomatic heart failure, subclinical heart failure with a decline in LVEF to < 45%, or absolute reductions in LVEF ranging between 5 and ≥ 20%, QT dispersion on ECG, or endomyocardial biopsy scores ≥ 2 according to the Billingham scale [15]. Most studies using subclinical heart failure as an endpoint used Multigated Acquisition scans (MUGA), which are limited to assessing LVEF and cannot evaluate other functional cardiac abnormalities. None of the trials measured more sensitive markers of AICD, such as GLS or cardiac biomarkers. Since the definition of mild asymptomatic CTRCD includes patients with a normal systolic function (LVEF ≥ 50%) with a new relative decline in GLS by > 15% from baseline and/or a new rise in cardiac biomarkers (defined as cTnI/cTnT > 99th percentile, BNP ≥ 35 pg/mL, NT-proBNP ≥ 125 pg/mL, or a new significant rise in cardiac biomarkers from baseline that exceeds the biological and analytical variation of the assay used), it is important that these parameters are measured [40].

Study strengths

The HOVON 170 DLBCL – ANTICIPATE trial is designed to overcome the limitations of previous studies and has several unique aspects. For the trial, we have invested significantly in establishing a robust national cross-disciplinary collaboration, involving investigator networks from both the field of (haemato-)oncology (HOVON) and cardiology (WCN). These investigator networks play an essential role in the Dutch ecosystem for the conduct of clinical studies. Patient recruitment and administration of the intervention are coordinated by the treating haemato-oncologist, while cardiologists are responsible for the cardiac screening and monitoring. Furthermore, we prioritized hospitals with established cardio-oncology clinics during the site selection process for the trial to ensure optimal cardio-oncologic care as well as streamlining patient recruitment.

With broad inclusion and exclusion criteria, the trial aims to reflect the diversity of patients with DLBCL seen in clinical practice who are considered fit to receive six cycles of R-CHOP. If dexrazoxane proves effective and safe, its use could be extended beyond advanced/metastatic breast cancer. Additional strengths of the trial include the establishment of an echocardiography core laboratory for training, feedback, and blinded re-evaluation of echocardiograms, which enhances the quality and reliability of the study endpoints [41, 42]. Linking trial data with national registries will enable cost-effective long-term follow-up, providing insights into hard clinical endpoints and mitigating selection and reporting bias.

Study limitations

Nevertheless, the trial also has some limitations. Firstly, only patients with DLBCL without pre-existing myocardial dysfunction will be recruited, and thereby the results are not generalizable to those with pre-existing myocardial dysfunction or heart failure. According to a recent study by Upshaw et al. using SEER-Medicare data of more than thirty thousand patients of 65 years and older with newly diagnosed DLBCL, 14% of patients had pre-existing heart failure [43]. This high-risk population was less likely to be treated with anthracyclines and had a higher lymphoma-related mortality at one year when compared to patients without heart failure (41.8% and 95% CI 40.5–43.2 vs. 29.6% and 95% CI 29.0-30.1). Among patients with pre-existing heart failure treated with anthracyclines in the first year, only 2.2% received dexrazoxane. Assessing the efficacy and safety of dexrazoxane in this high-risk patient population warrants further investigation and is beyond the scope of this trial. Another limitation is that the trial’s primary endpoint is based on 2D LVEF measurements rather than 3D LVEF. This decision was made as not all hospitals have access to the necessary equipment and software for 3D LVEF assessment. While 2D LVEF is less reproducible than 3D LVEF, using 2D LVEF as the primary endpoint ensures broader applicability. As all except four hospitals selected for the trial will measure both 2D and 3D, differences in the classification of patients for the primary endpoint using both techniques will be assessed.

Conclusions

HOVON 170 DLBCL – ANTICIPATE is a large randomized controlled phase III trial poised to contribute crucial evidence concerning the efficacy and safety on the use of dexrazoxane in the primary prevention of AICD among patients with DLBCL treated with R-CHOP immuno-chemotherapy. The trial is anticipated to address critical knowledge gaps and offer important insights into the value of dexrazoxane in cardio-oncology practice.

Abbreviations

¹⁸F-FDG PET-CT

Fluorodeoxyglucose F 18 - positron emission tomography - computed tomography

ACEi

Angiotensin-Converting Enzyme Inhibitors

AE

Adverse Events

AESI

Adverse Events of Special Interest

AICD

Anthracycline-Induced Cardiac Dysfunction

ANC

Absolute Neutrophil Count

ARB

Angiotensin Receptor Blocker

CMR

Complete Metabolic Response

CNS

Central Nervous System

CTCAE

Common Terminology Criteria for Adverse Events

CTRCD

Cancer Therapy Related Cardiac Dysfunction

DA-EPOCH-R

Dose-Adjusted EPOCH-R

DHD

Dutch Hospital Data

DICOM

Digital Imaging and Communications in Medicine

DLBCL

Diffuse Large B-Cell Lymphoma

DSMB

Data Safety and Management Board

EACVI

European Association of Cardiovascular Imaging

ECG

Electrocardiogram

EDTA

Ethylenediaminetetraacetic acid

EMA

European Medicines Agency

EORTC

European Organization for Research and Treatment of Cancer

FDA

Food and Drug Administration

FISH

Fluorescence In Situ Hybridization

GLS

Global Longitudinal Strain

HOVON

Haemato Oncology Foundation for Adults in the Netherlands

IKNL

Netherlands Comprehensive Cancer Organization

LVEF

Left Ventricular Ejection Fraction

MACE

Major Adverse Cardiovascular Events

MUGA

Multigated Acquisition Scan

NCR

Netherlands Cancer Registry

NHL

Non-Hodgkin Lymhpoma

NT-proBNP

N-terminal prohormone of brain natriuretic peptide

NYHA

New York Heart Association

PDF

Portable Document Format

PRO-CTCAE

Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events

PROMS

Patient Reported Outcome Measures

WCN

The Dutch Network for Cardiovascular Research

Author contributions

ML and AvR hold responsibility for the conceptualization, methodology and funding acquisition of the trial. EvW will perform the statistical analysis. AJT and LR are responsible for the echocardiography core laboratory. HC is the central pharmacist. HVW is the clinical project manager. SO will perform the quality of life analyses. AS and MBdR are managing directors of the involved investigator networks (WCN and HOVON respectively). FWA and MC have a supervisory role during trial conduct. ML drafted the manuscript. JG, EvA, HVW, MC, AJT, LR, SO, HC, MBdR, AS, FWA and AvR critically revised the manuscript. All authors read and approved the final manuscript.

Funding

This investigator-initiated trial is funded by the Dutch Cancer Society (project number 14657) and the Dutch Heart Foundation (02-001-2022-0126 Clinical Trials 2022). The pharmaceutical industry, including the current marketing authorization holder of dexrazoxane in the Netherlands (Clinigen B.V.), has no involvement in this trial. ML is supported by the Dutch Cancer Society (project number 14657). FWA is supported by UCL Hospitals NIHR Biomedical Research Centre and EU Horizon (AI4HF 101080430).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participat

Ethical approval for the conduct of this trial has been obtained from the Medical Research Ethics Committee NedMec (reference number: D-24-500268).

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.