Journal of Blood Research & Hematologic Diseases

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Review Article,  J Blood Res Hematol Dis Vol: 10 Issue: 1

Anthracycline Free Regimens in High Risk Acute Promyelocytic Leukemia: A Comprehensive Review

Praloy Basu*

1Department of Medical Oncology, Desun Hospital, Kolkata, West Bengal, India

*Corresponding Author: Praloy Basu,
Department of Medical Oncology, Desun Hospital, Kolkata, West Bengal, India
E-mail: dr.praloybasu@gmail.com

Received date: 13-Aug-2025, Manuscript No. jbrhd-25-169810; Editor assigned date: 16-Aug-2025, PreQC No. jbrhd-25-169810 (PQ); Reviewed date: 23- Aug-2025, QC No. jbrhd-25-169810; Revised date: 25-Aug-2025, Manuscript No. jbrhd-25-169810 (R); Published date: 23-Sep-2025, DOI: 10.4172/jbrhd.1000215

Abstract

Acute Promyelocytic Leukemia (APL), a distinct subtype of acute myeloid leukemia, has transitioned from a highly fatal to a highly curable disease due to the introduction of All-Trans Retinoic Acid (ATRA) and Arsenic Trioxide (ATO). Traditionally, high-risk APL patients, defined by a white blood cell count >10 × 10?/L, were treated with anthracycline-based chemotherapy combined with ATRA. However, long-term toxicities, particularly cardiotoxicity and secondary malignancies, have driven exploration into anthracycline-free regimens. Emerging evidence from randomised trials such as AML17 and MD Anderson studies demonstrate that ATRA+ATO, with adjunctive cytoreduction using Gemtuzumab Ozogamicin (GO) or hydroxyurea, achieves outcomes comparable to standard chemotherapy even in high-risk patients. Real-world data further validate the efficacy, safety and feasibility of these regimens, especially in resource-limited settings where oral ATO formulations improve accessibility. These regimens offer significantly reduced cardiotoxicity, myelosuppression and hospitalisation, enhancing patient quality of life. Nevertheless, challenges such as early mortality, optimal cytoreduction strategy and long-term toxicity of ATO persist. Guidelines from ELN, NCCN and GIMEMA now endorse ATRA+ATO-based approaches in high-risk APL. Future directions include integration of Minimal Residual Disease (MRD) monitoring oral ATO and artificial intelligence-driven personalization. This review highlights a paradigm shift in APL management, advocating for a move towards chemotherapy-free regimens that align curative potential with survivorship and quality-of-life goals in high-risk APL.

Keywords: Acute promyelocytic leukaemia, Anthracycline, Arsenic trioxide

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Keywords

Acute promyelocytic leukaemia; Anthracycline; Arsenic trioxide

Introduction

Acute Promyelocytic Leukaemia (APL) is a subtype of acute myeloid leukaemia (AML) that can be identified by the PML-RARA fusion gene which arises from the t(15;17) (q24;q21) translocation. Owing in a significant way to the development of differentiation therapy employing Arsenic Trioxide (ATO) and All-Trans Retinoic Acid (ATRA), this subtype of leukaemia has changed from being one of the most lethal to one of the most responsive [1,2].

Conventional APL treatment approaches have relied primarily on anthracycline-based chemotherapy in conjunction with ATRA, particularly for high-risk patients (defined as those whose initial white blood cell count is greater than 10 × 10^9/L). Despite their tremendous efficacy, anthracyclines have an array of risks, including long-term toxicity, cardiotoxicity and secondary cancers, which may restrict their usage in some patient populations [3,4].

Chemotherapy free or anthracycline-sparing regimens have become increasingly common in APL therapy in recent years. ATO and ATRA together can produce results that are on par with or better than those of conventional chemotherapy-based methods, even in high-risk categories, according to data from many trials [5-7].

This review explores the rationale, clinical evidence and future potential of anthracycline-free regimens in the management of high-risk APL. We highlight pivotal clinical trials, real-world experiences, toxicity profiles and implications for personalized treatment approaches in this unique leukemia subtype.

Literature Review

Historical context

One of oncology's rare success stories is the development of APL treatment over the past three decades. Disseminated Intravascular Coagulation (DIC) and major bleeding episodes were the main causes of APL's high early mortality rate prior to the development of All-Trans Retinoic Acid (ATRA) [8]. When added to traditional chemotherapy regimens, anthracyclines-particularly idarubicin and daunorubicin-were among the first drugs to substantially increase remission rates.

The introduction of ATRA in the 1980s was revolutionary because it caused terminal differentiation of promyelocytes, which led to remarkable therapeutic improvements [9]. After initially being given as a monotherapy, ATRA quickly integrated into protocols like AIDA, which created a new standard of treatment, that involved anthracycline-based induction regimens [10]. Over 90% of patients experienced Complete Remission (CR) with these regimens and over 80% of patients survived for the long term.

However, the initial enthusiasm surrounding anthracycline-based therapy was dampened by concerns about long-term damage, particularly cardiomyopathy and secondary leukaemia [11]. Paediatric and adolescent patients, who stood to lose the most from late therapy effects, were especially impacted by this. The need to balance efficacy with quality of life prompted exploration into chemotherapy-free options, especially as molecular understanding of APL deepened.

Mechanistic rationale for ATRA+ATO

The rationale for combining ATRA with Arsenic Trioxide (ATO) stems from their complementary mechanisms of action. ATRA induces differentiation of leukemic promyelocytes by degrading the co-repressor complexes associated with the RARA portion of the PML-RARA fusion protein [12]. Meanwhile, ATO facilitates the sumoylation and degradation of the PML moiety of the same fusion protein, promoting apoptosis of leukemic cells [13].

Moreover, ATO exhibits dose-dependent effects. At low concentrations, it induces partial differentiation, whereas at higher concentrations, it promotes apoptosis through mitochondrial pathway activation, Reactive Oxygen Species (ROS) generation and caspase activation [14]. When administered together, ATRA and ATO target both arms of the oncogenic fusion protein, resulting in dual inhibition and eradication of leukemic cells.

This combination also facilitates rapid clearance of minimal residual disease (MRD), as shown in molecular monitoring studies where early and deep molecular responses correlate with improved long-term survival [15]. Additionally, in vitro and in vivo studies have demonstrated that ATRA+ATO eradicates leukemic stem cell populations better than anthracycline-based regimens, potentially contributing to lower relapse rates [16,17].

Clinical trials in high-risk APL

Due to concerns regarding leukocytosis and differentiation syndrome, high-risk patients were not included in the early clinical trials of ATRA+ATO; however, this gap was filled by later research. The AML17 trial, which used Gemtuzumab Ozogamicin (GO) for cytoreduction in conjunction with ATRA+ATO, was the first major randomised study to include high-risk patients [18]. This regimen produced Event-Free Survival (EFS) rates comparable to those obtained with AIDA and CR rates over 90%. Anthracycline avoidance has been demonstrated to be feasible even in patients with leukocytosis in the more recent GIMEMA APL0406 study, which included exploratory cohorts of high-risk persons treated with hydroxyurea or cytoreduction, despite the trial's primary focus on standard-risk patients. Another noteworthy trial is the MD Anderson Cancer Center (MDACC) study, where ATRA+ATO plus minimal idarubicin (2 doses) yielded durable responses, prompting re-evaluation of how much chemotherapy is truly necessary [19-21].

The Japanese JALSG APL204 and the Chinese APL07 studies have also validated the use of arsenic-based therapies in high-risk APL, supporting global generalizability of the approach [22-26]. Importantly, these trials incorporated close monitoring and rapid cytoreduction strategies, underscoring the importance of disease burden control during induction [27-39].

Discussion

Real-world evidence

Real-World Evidence (RWE), which sheds light on treatment results outside of strictly regulated study settings, is supplementing clinical trials more and more. Even in community-based practices, anthracycline-free regimens, especially those that use oral ATO formulations, are practical and successful, according to registry data from Europe and Asia.

According to the SEER and HARMONY datasets, high-risk patients who receive ATRA+ATO along with cytoreductive drugs have comparable survival rates to those who receive conventional anthracycline regimens, but they also have a far fewer instances of hospitalisation and cardiotoxicity. Generic ATO has made it possible to adopt these regimens more widely in resource-constrained nations like India, with promising outcomes, confirming their affordability and accessibility [40].

These findings emphasize the importance of global collaboration and tailoring therapy to local contexts, especially where supportive care infrastructure may be limited. Early diagnosis, rapid initiation of therapy and careful electrolyte monitoring are key to minimizing early mortality in high-risk APL patients regardless of setting.

Toxicity and quality of life considerations

An important concern for long-term survivors is dose-dependent cardiotoxicity, even though anthracyclines like idarubicin and daunorubicin have remained effective at causing remission. Depending on cumulative dose, the process causes free radical generation and mitochondrial damage in cardiomyocytes, which can result in subclinical left ventricular dysfunction and overt heart failure in as many as 5%-10% of patients. This risk is particularly pronounced in paediatric, adolescent and elderly patients. In contrast, Arsenic Trioxide (ATO), while not free of toxicity, presents a different safety profile. The most common adverse effects include QTc prolongation, hepatic enzyme elevations and electrolyte imbalances. Despite being a class effect of ATO, QTc prolongation is usually reversible and can be lessened with dose breaks, magnesium and potassium supplements and careful ECG monitoring. Liver toxicity, if present, is typically transient and resolves with temporary dose hold [41].

Patients receiving ATRA+ATO typically experience fewer infectious complications and require shorter durations of hospitalization, as anthracycline induced myelosuppression is absent. This leads to better functional recovery and reduced need for growth factor support or transfusions.

Health-Related Quality of Life (HRQoL) has also been shown to improve significantly in patients managed with ATO-based regimens. A multicenter analysis demonstrated higher patient-reported physical and emotional well-being in the anthracycline-free arm compared to those receiving traditional chemotherapy. This underscores the importance of treatment selection not only for disease control but also for survivorship and long-term health outcomes.

Guidelines and recommendations

Recent updates to clinical practice guidelines reflect growing acceptance of anthracycline-free regimens in APL management. The 2022 European LeukemiaNet (ELN) guidelines endorse ATRA+ATO as the preferred frontline therapy for standard-risk APL and recommend its use in high-risk disease when combined with cytoreductive agents like GO or hydroxyurea.

Similarly, the National Comprehensive Cancer Network (NCCN) Guidelines Version 1.2023 advocate for ATRA+ATO in high-risk patients with leukocytosis, incorporating GO (3 mg/m² on day 1) or cytoreduction with hydroxyurea until WBC falls below 10,000/μL. These strategies are aimed at preventing APL differentiation syndrome and tumor lysis.

GIMEMA guidelines further reinforce this approach, advocating for individualized patient management that considers comorbidities, performance status and logistical considerations such as outpatient feasibility and access to supportive care.

These endorsements by international consortia mark a critical shift toward reducing treatment-related toxicity without compromising efficacy. Moreover, the inclusion of ATRA+ATO as a standard option in high-risk settings sets a precedent for rethinking the necessity of cytotoxic chemotherapy in molecularly defined leukemias.

Limitations and areas of uncertainty

Anthracycline-free regimens have limitations despite their promising outcomes. The management of early death, which continues to be the primary cause of treatment failure in APL, is one major challenge. Early mortality from haemorrhage or differentiation syndrome may be caused by inadequate leukoreduction, inadequate supportive care and delayed diagnosis. The best cytoreductive approach is still up for discussion. Although GO has demonstrated effectiveness in clinical trials, there are drawbacks, particularly in places with low resources, such as its restricted availability, high cost and possibility for hepatic Veno-Occlusive Disease (VOD). Although it is less expensive and safer, hydroxyurea is neither as selective or as effective as GO [42]. Additionally, the long-term safety of repeated ATO exposure is under investigation. Even though cardiotoxicity is uncommon, repeated exposure can affect hepatic function and QTc intervals. Long term follow-up in survivors is necessary due to concerns about reproductive toxicity, fertility and second malignancies. Lastly, particular populations like pregnant women, the extremely elderly or people with severe renal or hepatic impairment have little prospective data. Careful case-by-case analysis is necessary until robust information is obtained.

Future directions

Looking ahead, future strategies aim to refine and personalize APL treatment. Molecular monitoring of MRD using real-time quantitative PCR allows early identification of subclinical relapse, enabling timely intervention and possible treatment de-escalation in patients with deep and sustained responses.

The development of oral ATO formulations represents a major advancement, allowing outpatient delivery of therapy with equivalent bioavailability and tolerability. Trials conducted in China and Australia have shown that oral ATO plus ATRA is non-inferior to IV ATO, with advantages in cost, convenience and quality of life.

Other novel agents such as tamibarotene, a synthetic retinoid with greater selectivity for RARα, are being studied in relapsed/refractory APL and other AML subtypes with RARA overexpression. Additionally, next-generation formulations such as liposomal ATO and nanoparticle retinoids may further improve pharmacokinetics and reduce toxicity.

Integration of genomics into risk stratification and therapy selection may identify patients who could benefit from more or less intensive approaches. Artificial intelligence (AI)-based algorithms using clinical and genomic data are also under development to predict early mortality and relapse risk in APL, potentially guiding preemptive interventions [43,44].

Ultimately, the goal is to make APL treatment more accessible, less toxic and tailored to individual patient characteristics and healthcare system constraints.

Conclusion

The management of high-risk APL has undergone a paradigm shift with the introduction of anthracycline-free regimens centered on ATRA and ATO. Robust clinical trial data and real-world evidence support the efficacy and safety of these regimens, especially when combined with appropriate cytoreductive strategies like GO or hydroxyurea.

Reduced cardiotoxicity, lower hospitalization rates and improved patient-reported outcomes make these approaches particularly attractive for long-term survivorship. Early mortality, restricted availability to some drugs and the requirement for long-term safety data are still obstacles, nevertheless.

Ongoing studies into oral treatments, biomarkers and AI-based prediction tools will help to improve APL care as the profession shifts towards more focused, chemotherapy-free paradigms. For both standard-risk and high-risk APL, anthracycline-free regimens are on the verge of becoming the norm, balancing quality of life with oncologic cure.

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