Authors:

Maria Teresa Voso

Luca Guarnera

Abstract

Acute Promyelocytic Leukaemia (APL) is a rare and highly aggressive condition, once considered the most severe and incurable acute myeloid leukaemia (AML). Since its initial description in the 1950s, significant progress has been made in understanding the disease, including the identification of the leukemic transformation process, the t(15;17) translocation, and the rearrangement of the retinoic acid receptor alfa (RARA) with the PML gene in the 1970s. The late 1980s witnessed the introduction of targeted drugs, namely all-trans retinoic acid (ATRA) and subsequently arsenic trioxide (ATO), both of which were derived from traditional Chinese medicine. This treatment, characterised by manageable side-effects, revolutionised the prognosis of APL, inducing durable and profound remissions in the vast majority of patients, dramatically reducing the rate of relapse and late events as secondary malignancies, and improving quality of life.

The history of APL demonstrated, for the first time in the field of haematology, that a comprehensive understanding of the genetic underpinnings can result in the development of safe and effective treatments, yielding tangible benefits for patients. These remarkable outcomes have paved the way for the gradual transition from conventional chemotherapy to a chemo-free ATRA/ATO treatment in APL.

Current and future research is now focused on addressing some unresolved issues, including APL-like AMLs (AMLs with an APL-like phenotype and/or RAR gene translocations, but lacking the characteristic t(15;17) translocation) and the management of the initial hours/days following APL diagnosis, which continues to be associated with a high mortality rate.

Introduction

APL is a rare subtype of acute myeloid leukaemia, characterised by the typical balanced t(15;17)(q24;q21) translocation, leading to the pathological PML/RARA rearrangement ^[1]. The aggressive features and haemorrhagic diathesis typical of APL were first described in 1957 by L. Hillestad ^[2]. A few years later, Bernard and colleagues published a case series of 20 patients, reporting poor responses and dismal outcomes after cytotoxic treatment ^[3]. In the 1970s and 1980s, the genetic features of APL were elucidated and the leukaemogenic process was characterised, allowing the development of targeted therapy and paving the way for current APL management.

The first significant breakthrough in the history of APL management is represented by the introduction of anthracyclines into clinical practice. Despite the recognised short-term and long-term toxicities of the chemotherapy agents, there was a significant improvement in outcomes, with long-term survival rates ranging from 25 to 50% ^[4][5]. Concurrently, following a period of 20 years from the initial documentation of APL, Rowley and colleagues identified in 1977 the balanced chromosomal translocation responsible for APL, involving chromosomes 15 and 17 ^[1]. The biological bases of APL leukemogenesis were identified several years later. Notably, in 1988, the initial experiences with ATRA monotherapy were documented, including a report from China on a case series of 24 patients, all of whom achieved complete remission (CR) ^[6]. These results subsequently prompted numerous researchers to investigate the mechanisms of action of this compound. Consequently, in 1990, de Thé et al. and Borrow et al. identified the genes involved in the pathological rearrangement: PML, localized on chromosome 15, and RARA, localized on chromosome 17 ^[7][8]. This groundbreaking finding paved the way in 1992 for the PCR-based APL transcript detection, allowing for early diagnosis and MRD monitoring ^[9][10]. In the same year, Fenaux et al. conducted a pilot study on 26 patients, evaluating the efficacy and safety of ATRA in combination with chemotherapy, which resulted in CR in 25 patients ^[11]. Subsequent to this, in 1997, the seminal AIDA trial corroborated these findings on a substantial cohort of 240 patients, with 229 (95%) attaining hematologic CR. Furthermore, this trial highlighted the important clinical role of MRD monitoring for PML/RARA, with 159 of 162 patients (98%) achieving molecular CR at the end of consolidation therapy ^{[12] [13]}. In 2000, a collaborative effort between the Spanish PETHEMA (Programa Español de Tratamientos en Hematología) and Italian GIMEMA cooperative groups analysed 217 patients receiving AIDA chemotherapy and developed a straightforward yet highly effective blood count-based relapse risk score, which is still in use today to stratify patients at initial diagnosis[Sanz risk Score: Low risk: ≤ 10 10⁹/L white blood cells (WBC) and platelets > 40 10^{9/L; Intermediate risk: ≤ 10 10}9/L 10^{9/L WBC and platelets ≤ 40 10}9/L; High risk: >10 10^9/L WBC] ^[14].

The introduction of ATRA in the clinical armamentarium has led to a more in-depth understanding of one of its major side effects (shared with ATO), namely the differentiation syndrome (DS; previously known as ATRA syndrome). This potentially life-threatening complication arises from the unblocking of differentiation of APL blasts. It is characterised by various signs and symptoms, including unexplained fever, weight gain, peripheral oedema, dyspnoea with interstitial pulmonary infiltrates, pleuropericardial effusion, hypotension, and acute renal failure, and requires prompt intervention ^[15]. The most extensive study on this subject, conducted by the PETHEMA group, analysed data from nearly 800 patients receiving ATRA/Chemotherapy. In this study, Montesinos and colleagues reported a DS prevalence of 24.8%, occurring at a median of 12 days after starting the ATRA treatment, with a bimodal distribution: the first peak during the first week of treatment and the second in the third week ^[15]. The study noted a mortality rate of 11% in patients with severe DS, while no deaths were observed in cases of moderate DS ^[15]. While there is consensus on the use of corticosteroids at the earliest manifestations of DS, steroid prophylaxis is still the subject of debate. A retrospective analysis by PETHEMA showed a significant reduction of severe DS, but no differences in terms of DS-related mortality ^{[15] [16]}.

The chemo-free approach

In 1997, another agent, arsenic trioxide (ATO), targeting PML, was tested by Chinese researchers in APL patients relapsed after ATRA-chemotherapy. CR was achieved in 9 of 10 (90%) patients treated with ATO monotherapy, and in all five patients treated with ATO in combination with ATRA or chemotherapy ^[17]. These results prompted several groups to further investigate this combination. The Italian-German Phase III APL0406 trial, which was designed by Francesco Lo-Coco on the basis of MD Anderson Cancer Center's (US) ATRA/ATO schedule, was performed in collaboration with the German-Austrian AML study group and the Study Alliance Leukemia group, coordinated by Uwe Platzbecker. The study randomly assigned newly diagnosed patients with standard-risk APL (including low and intermediate-risk APL with WBC counts of ≤ 10,10⁹ /L at the time of disease onset) to receive the ATRA/ATO chemo-free combination in induction and during four consolidation cycles, or the standard AIDA regimen (consisting of ATRA/Idarubicin in induction, followed by three consolidation ATRA-chemotherapy cycles and two years of maintenance). The experimental arm initially included 77 patients, all of whom achieved complete remission (CR), in contrast to 75 patients in the control arm, where CR was achieved in 74 patients. At a two-year follow-up, patients treated with the ATRA/ATO regimen exhibited superior overall survival (OS) (99% vs. 91%) and event-free survival (EFS) (97% vs. 86%), without substantial differences in terms of relapse rate ^[18]. The trial final results on the extended series including 276 patients and published in 2017 confirmed the survival advantage and also showed benefits in terms of incidence of relapse ^[19]. After a median follow-up period of 40.6 months, the EFS and cumulative incidence of relapse (CIR) were 97.3% and 1.9% for ATRA/ATO vs. 80% and 13.9% for ATRA-Chemotherapy. This finding was further corroborated by the outcomes of OS, with a median follow-up of 50 months showing 99.2% vs. 92.6% for the respective groups ^[19]. The favourable outcomes associated with ATRA-ATO treatment were further validated at long-term, confirming an increasing advantage over time, with no late relapses or cases of secondary malignancies ^[20]. It should be noted that these exceptional results were paired with studies on short- and long-term quality of life (QoL), led by Fabio Efficace at GIMEMA, which confirmed the ATRA/ATO regimen as the preferred first-line treatment in this subset of patients ^{[21] [22]}. These data led to the approval by the FDA and EMA, in 2016 and 2018, respectively, of the ATRA/ATO combination as first-line treatment in standard-risk APL.

In the field of European trials on APL, the NCRI UK group published the AML17 trial in 2018, which compared a modified ATRA/ATO schedule to AIDA as front-line treatment for APL, irrespective of disease risk. The study confirmed the efficacy of the chemo-free regimen in terms of 4-year event-free survival (EFS) and complete response (CIR) (91% vs. 70% and 1% vs. 18%, respectively). Additionally, it demonstrated that there were no significant differences in overall survival (OS) between the two treatment arms in high-risk patients ^[23].

The sporadic cases of relapse after targeted therapies prompted studies on the mechanisms of resistance, which led to the identification of several mutations affecting PML:RARA, able to induce resistance to either ATO or ATR ^{[24] [25] [26] [27]}.

Finally, in 2024, there were exciting updates for the development of a chemo-sparing schedule for all patients. A large multicentre study undertaken within the European HARMONY Project, including 1438 APL patients from both clinical trials and national registries, substantiated the superiority of ATRA/ATO over ATRA/chemotherapy with respect to OS, EFS and CIR, irrespective of age, risk stratification and treatment context (clinical trial vs. real-life setting) ^[28]. Furthermore, the initial results of the Pan-European APOLLO trial, which compared ATRA/ATO in combination with two doses of idarubicin in induction followed by four consolidations vs. AIDA Chemotherapy in high-risk APL, were presented at the Congress of the European Society of Haematology. The study demonstrated the activity of ATRA-ATO in high-risk APL and its significant impact on EFS at two years of follow-up (89% vs. 72% for AIDA) ^[29]. The publication of the complete results of the trial is eagerly awaited.

Conclusions

Over the past three decades, there has been a paradigm shift in the management of APL, with a transition from a predominantly aggressive approach to one that is increasingly focused on achieving a cure. The advent of targeted therapies has led to unprecedented rates of remission, a marked reduction in relapses, and a substantial enhancement in quality of life. The story of APL is a prototype of precision medicine and an outstanding demonstration of the central role of translational studies in modern oncology.

Reference Research Centre

Sapienza and Tor Vergata Universities, Rome, Italy