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Acute promyelocytic leukemia: What is the new standard of care?

Blood Reviews


Acute promyelocytic leukemia (APL) is one of the most exciting stories of modern medicine. Once a disease that was highly lethal, the majority of patients are now cured with the advent of molecularly targeted therapy with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). In many patients, chemotherapy can be omitted completely, particularly in patients with low- or intermediate-risk disease (white blood cell count ≤ 10,000/μl). Recent data show overall survival exceeding 90% with ATRA and ATO-based induction and consolidation strategies. In the uncommon patient in whom relapse does occur, most can still be cured with ATO and autologous hematopoietic cell transplantation. Remaining challenges in APL management include the rapid identification and treatment of newly diagnosed patients to decrease the early death rate, optimizing treatment strategies in high-risk patients (white blood cell count > 10,000/μl), and the role of maintenance therapy in lower risk patients.

Keywords: Acute promyelocytic leukemia, All-trans retinoic acid (ATRA), Arsenic trioxide (ATO), Coagulopathy, Early death, Differentiation syndrome.

1. Introduction

Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML) characterized by distinct morphologic and cytogenetic aberrations and a potentially life-threatening coagulopathy [1], [2], and [3]. APL is defined and driven by a specific balanced translocation, t(15;17), resulting in the fusion of PML (promyelocytic leukemia) and RARα (retinoic acid receptor-α) genes. This fusion yields an aberrant, oncogenic protein (PML-RARα) that blocks myeloid differentiation at the promyelocyte stage [4] and [5]. Clinically, the bone marrow blast percentage in APL can be variable, and patients often present with peripheral cytopenias, including a low or normal total white blood cell count (WBC). Bone marrow promyelocytes are considered blast equivalents, can be atypical and hyper-granular, and cytolysis after chemotherapy may contribute to the coagulopathy.

APL is a rare disease (approximately 1200–1500 cases/year in the United States), accounting for approximately 10–15% of all AML cases  [6] . Some cases of APL are therapy-related, occurring after exposure to cytotoxic chemotherapy (most commonly topoisomerase II inhibitors) or radiation (including radioactive iodine) for a first malignancy [7], [8], [9], [10], and [11]. Interestingly and unlike most other AML subtypes, outcomes in de novo and therapy-related APL appear to be essentially equivalent [12] . Historically, although outcomes were favorable relative to other AML subtypes, long-term overall survival (OS) was < 50% [13], [14], [15], and [16]. Many non-survivors died early in the disease course before or during induction chemotherapy from bleeding complications (most commonly cerebral hemorrhage). Relapse was common as well and required autologous or allogeneic hematopoietic cell transplantation (HCT) for sustained disease control. However, with the advent of therapies targeted to the retinoic acid receptor (RAR) over the last 1–2 decades, APL has undergone a remarkable transition from an often rapidly lethal disease with less than half of patients achieving long-term remissions to one of the most curable forms of leukemia, although early death remains a problem if treatment is delayed. In recently published reports, both event-free survival (EFS) and OS at 2–3 years have improved remarkably to approximately 90% or more [17] and [18].

This perspective will focus on contemporary therapy of APL with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), with or without chemotherapy, during all phases of treatment (induction, consolidation, and maintenance). We will also review indications for traditional cytotoxic chemotherapy using a risk-adapted approach, and discuss the treatment of relapsed disease in the era of targeted therapy. Lastly, we will address the emergent need for rapid administration of ATRA at first suspicion of APL, as this may be critical for preventing early death from catastrophic hemorrhage in what is now an imminently curable disease.

1.1. The evolution of APL therapy in the targeted era: what is the emerging treatment paradigm?

1.1.1. Induction

Before the development of ATRA, APL was treated with standard AML induction regimens including an anthracycline and cytarabine. Most patients achieved complete remission (CR) (approximately 70–80%), with the majority of non-CR patients dying from bleeding complications and occasionally refractory disease [13], [14], [15], and [16]. Of the patients who achieved CR, over half eventually relapsed. Two-year OS rates were approximately 30–40%.

The introduction of ATRA (which targets the RAR and induces terminal differentiation of APL blasts) into the treatment armamentarium in the late 1980s and early 1990s improved CR rates to as high as 90% (as a single agent), but early mortality remained high and APL differentiation syndrome (a syndrome manifested by fever, hypotension, fluid retention, and diffuse pulmonary infiltrates) often developed with a rapid rise in the WBC (see Table 1 ) [19], [20], [21], [22], [23], [24], [25], [26], [27], and [28]. In addition, the emergence of resistance and subsequent relapse was relatively common with ATRA monotherapy. Thus, studies were conducted showing that the ATRA plus chemotherapy was superior to ATRA alone with impressive CR rates of 90–95% [28] . Also, concurrent administration of ATRA plus chemotherapy was demonstrated to be more effective than sequential therapy and to decrease the risk of differentiation syndrome [29], [30], and [31]. Standard induction regimens for newly diagnosed APL began to include ATRA and an anthracycline (+/− cytarabine) [32] . While there is no prospective randomized comparison of idarubicin versus daunorubicin in APL, retrospective data have suggested that idarubicin may be superior to daunorubicin, but either is considered acceptable [33] . Historically, the PETHEMA group has shown outstanding outcomes with idarubicin and ATRA alone (without cytarabine), while in most APL trials using daunorubicin it has typically been given in combination with cytarabine, making direct comparison of the two anthracyclines difficult.

Table 1 Targeted agents in acute promyelocytic leukemia that have become the new standard of care: mechanism of action (MOA), dosing and schedule for each phase of therapy, and possible side effects.

New agent MOA Induction Consolidation Maintenance Possible side effects

Binds RAR, inducing terminal differentiation of APL cells 45 mg/m2/day until achievement of complete remission 45 mg/m2/day for 15 days per month for 7 cycles a 45 mg/m2/day for 15 days every 3 months for 2 years b Leukocytosis

Differentiation syndrome


(I.V.) c
Various; degrades PML-RARα fusion protein; activates pro-apoptotic pathways 0.15 mg/kg/day until achievement of complete remission 0.15 mg/kg/day for 5 days per week for 4 to 5 weeks, followed by 1 month off, repeat for 4 cycles N/A QT interval prolongation

GI: anorexia, nausea


Bone marrow suppression

a ATRA and ATO are given concurrently. Standard consolidation regimens may vary.

b Maintenance may not be indicated for low/intermediate-risk patients receiving ATRA and ATO-based induction and consolidation regimens. If maintenance therapy is used, ATRA may be given with oral methotrexate and 6-mercaptopurine.

c Oral formulations of ATO are in development.

While APL is exquisitely sensitive to anthracyclines [34] , the role of cytarabine remains less clear, particularly in the ATRA era. Cytarabine has been successfully omitted from induction regimens without a negative impact on response regardless of the presenting WBC, especially if ATRA is given with both induction and consolidation and idarubicin is used as the anthracycline of choice (the idarubicin and ATRA or “AIDA” regimen) [30] and [31]. The Medical Research Council (MRC) has reported less myelosuppression and equivalent outcomes with AIDA compared to ATRA, daunorubicin, and cytarabine [35] . Furthermore, with the subsequent discovery of the activity of arsenic trioxide (ATO) in APL, cytarabine and in certain cases even anthracyclines may no longer be required to cure most patients.

ATO, which degrades the PML-RARα fusion protein among other anti-leukemic properties including induction of apoptosis, was shown in the 1990s to have impressive clinical activity in relapsed or refractory APL when used as a single agent, with approximately 85% of patients responding after 2 cycles (see Table 1 ) [36], [37], and [38]. Subsequent studies demonstrated significant activity in newly diagnosed disease as well, with again approximately 85% of patients achieving CR, comparable to CR rates with ATRA plus chemotherapy [39] and [40]. While ATO is clearly the single most effective agent in APL, untreated patients with a relative leukocytosis (> 5000/μl) may have inferior outcomes with single agent ATO compared to ATRA plus chemotherapy, with lower 3-year EFS and increased early death in one study [40] . Lastly, it should be noted that ATO can cause QT interval prolongation (> 450 ms) and, potentially, cardiac dysrhythmias. Patients on ATO therapy should have regular monitoring of electrocardiograms (usually at the beginning of each cycle), additional QT prolonging agents should be avoided (such as azoles and fluoroquinolones), and potassium and magnesium levels should be maintained at normal values.

Building on pre-clinical data showing synergy of ATRA and ATO in vitro, studies combining the 2 agents with or without chemotherapy were undertaken [41] and [42]. A 3-arm clinical trial conducted in China comparing ATRA monotherapy, ATO monotherapy, and ATRA/ATO combination therapy showed superior outcomes with combination therapy: fewer relapses, faster achievement of CR, and greater reduction in PML-RARα transcript burden [43] . However, it should be noted that patients in this study did receive chemotherapy with consolidation and maintenance. Nonetheless, subsequent updates from this study showed durable remissions and minimal toxicity at 7 years, paving the way for ATRA/ATO combination therapy [44] . Further studies that stratified patients by risk groups showed that ATRA and ATO-based induction and consolidation therapy were highly effective in patients with low- or intermediate-risk disease (WBC ≤ 10,000/μl at initial presentation) with a CR rate of 96% and excellent long-term outcomes, despite the omission of chemotherapy from both induction and consolidation phases [45] and [46]. High-risk patients (WBC > 10,000/μl) had inferior outcomes on this study, despite the addition of idarubicin or gemtuzumab ozogamicin (GO) during induction. Overall, these 3 studies signified a remarkable advance in APL therapy with significant improvement in survival, although the early death rate (EDR) remained high (6–11%).

In addition, while the overall relapse rate in the ATRA/ATO era has decreased dramatically, a number of the relapses that do occur are often isolated to the central nervous system (CNS), a sanctuary site [47] . ATRA and ATO do cross the blood–brain barrier, but concentrations in the cerebrospinal fluid may not be high enough for significant anti-leukemic activity  [48] , possibly selecting for CNS relapse if intensive chemotherapy is not used, particularly in high-risk patients. In addition, prophylaxis with intrathecal methotrexate is also usually recommended for high-risk patients (after the achievement of CR), although there are no data to clearly establish if this strategy is protective.

In order to address some of these challenges, the Australasian Leukaemia and Lymphoma (ALLG) group conducted a trial treating 124 newly diagnosed APL patients with ATRA/ATO-based induction therapy that included a course of idarubicin for all patients [17] . Patients then received 2 courses of ATRA and ATO consolidation without chemotherapy followed by 2 years of maintenance therapy with ATRA, methotrexate, and mercaptopurine (all patients received maintenance). With minimal exposure to chemotherapy, 2-year failure-free survival was 88% and OS was 93% — only 2 patients relapsed and there were 4 early deaths. This study firmly established the role of ATRA/ATO combination therapy in APL and remains a standard current approach for the treatment of untreated APL patients, especially those with high-risk disease.

More recently, Lo-Coco and coworkers conducted a randomized phase III trial showing that ATRA and ATO induction therapy followed by 4 cycles of ATRA/ATO consolidation in low- or intermediate-risk patients (WBC ≤ 10,000/μl) is highly effective and superior to ATRA/chemotherapy-based induction, consolidation, and maintenance (no maintenance was given on the ATRA-ATO arm) [18] . Hydroxyurea was used to control the WBC in patients developing leukocytosis after exposure to ATRA (high-risk patients at diagnosis were excluded). The 2-year EFS rate was a remarkable 97% in the ATRA/ATO group compared to 86% in the ATRA/chemotherapy group (p = 0.02 for superiority) [ Fig. 1 ].


Fig. 1 These survival curves from Lo-Coco and colleagues show the excellent outcomes of ATRA-based therapy in general, and the superior outcomes of ATRA/ATO compared to ATRA/chemotherapy in low- or intermediate-risk patients (all patients on this study were low/intermediate-risk). source: From The New England Journal of Medicine. Lo-Coco F, Avvisati G., Vignetti M., et al., Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013;369:111–121. Copyright© 2013 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

In summary, ATRA and ATO are now the cornerstones of APL therapy and have dramatically improved outcomes. Based on prospective randomized trials, ATRA and ATO-based frontline therapy without chemotherapy can cure almost all patients who present with a low or normal WBC, has minimal toxicity, and can be considered the new standard of care in low- or intermediate-risk patients. However, if the WBC rises above 5000/μl after starting ATRA in a low- or intermediate-risk patient, then an anthracycline or hydroxyurea should be administered to reduce the WBC, which may ameliorate the coagulopathy and prevent APL differentiation syndrome. Lastly, patients with high-risk APL do appear to benefit from at least a short course of intensive chemotherapy during induction (+/− consolidation) and possibly also 1–2 years of maintenance therapy (see Maintenance section below).

1.1.2. Consolidation

Even with the advent of ATRA and ATO-based induction therapy, consolidation treatment is still needed to prevent relapse [49] . Risk-adapted approaches have been studied to help determine the optimal intensity and duration of post-remission therapy in both high-risk and low/intermediate-risk patients. Sanz and colleagues developed the initial prognostic system that serves as the basis for the modern risk-adapted approach: WBC > 10,000/μl (high-risk), WBC ≤ 10,000 μl with platelet count ≤ 40,000/μl (intermediate-risk), and WBC ≤ 10,000/μl with platelet count > 40,000/μl (low-risk) [50] . However, many of the large clinical trials conducted in the ATRA/ATO era have shown no difference in outcome between the low- and intermediate-risk subgroups, and these two risk categories can effectively be combined into a single low/intermediate-risk group defined by a presenting WBC of ≤ 10,000/μl (presenting platelet count no longer used for prognostic purposes).

Prior to the introduction of ATO, the addition of ATRA and also cytarabine to anthracycline-based consolidation therapy was shown to significantly reduce relapse rates in high-risk patients [51], [52], and [53]. In low- or intermediate-risk patients receiving ATRA and cytarabine, decreasing the anthracycline dose during consolidation was also better tolerated and did not impair clinical outcomes. Regardless, the excellent outcomes on these ATRA-based studies were achieved with the inclusion of either high doses of an anthracycline or the addition of cytarabine, particularly in high-risk patients, and cumulative anthracycline exposure remained a problem.

With the discovery of ATO, first-line ATRA-based consolidation regimens using ATO as a substitute for chemotherapy were developed [54] . The North American Intergroup has shown in a randomized trial (C9710) that adding ATO to consolidation significantly improved DFS and OS in all APL risk groups (all patients received at least 2 courses of daunorubicin consolidation) [55] . Subsequently, studies omitting chemotherapy and using only ATRA and ATO for consolidation reported excellent outcomes with 3-year OS of 85% [56] . An intriguing study conducted in India used only single-agent ATO for both induction and consolidation and reported outcomes comparable to historical controls in low- or intermediate-risk patients [57] . For high-risk patients, the 5-year relapse rate with ATO alone was higher than with chemotherapy.

Recently, randomized prospective data have shown that ATRA/ATO consolidation after ATRA/ATO induction achieves excellent outcomes in low- or intermediate-risk patients [18] . Therefore, in patients presenting with a WBC of ≤ 10,000/μl who do not have contraindications to ATO, a non-chemotherapy-based consolidation approach (as with induction) can be considered the new standard of care. In high-risk patients, ATRA/ATO combined with idarubicin for induction followed by ATRA/ATO consolidation without chemotherapy has demonstrated very favorable results and is commonly considered the regimen of choice in these patients [17] . Alternatively, a course of ATRA and idarubicin alone (without ATO) for induction followed by intermediate-dose cytarabine as the first consolidation is also an effective treatment strategy and can be used in high-risk patients (although this approach provides greater chemotherapy exposure) [51] . While cytarabine appears to benefit high-risk patients when incorporated into ATRA and anthracycline-based regimens, its role in combination with ATO, if any, is unknown.

1.1.3. Maintenance

The role of maintenance therapy in APL is still being elucidated, but likely benefits certain subgroups. It should be noted that maintenance therapy also carries some risk and has the potential to harm patients who are potentially cured. A study from Europe reported an 11% death rate in CR in elderly patients receiving maintenance therapy (mostly from myelosuppression-related sepsis) [29] . However, 2 more recent randomized trials have demonstrated substantial improvement in outcomes with ATRA-based maintenance. Tallman and colleagues for the North American Intergroup (E2491) reported lower relapse rates (22% vs. 39%) and improved 5-year DFS (61% vs. 36%) with ATRA maintenance [26] and [58]. The European APL (EAPL) group also demonstrated the benefit of ATRA-based maintenance when given with low-dose oral 6-mercaptopurine and methotrexate in a randomized study [29] . Follow-up data from the EAPL group showed that maintenance primarily benefits high-risk patients [59] .

The benefit of maintenance therapy may also depend and the type, intensity, and duration of prior induction and consolidation therapy as well as minimal residual disease (MRD) status (PML-RARα transcript positivity). For example, a study using 3 instead of 2 cycles of consolidation therapy in PML-RARα-negative patients did not confirm the benefit of ATRA-based maintenance therapy [53] . The role of maintenance therapy in low- or intermediate-risk patients who are MRD-negative after intensive induction and consolidation regimens including chemotherapy and ATO was recently examined by the North American Intergroup (S0521) [60] . Based on this study, maintenance appears to be unnecessary in this select group, as no relapses occurred in either the maintenance or observation arm after a median follow-up of 36 months [ Fig. 2 ].


Fig. 2 (A) Overall survival in low- or intermediate-risk patients treated with intensive regimens that included ATRA, ATO, and chemotherapy. (B) There was no difference in disease-free survival in patients who were MRD-negative after the completion of consolidation therapy, regardless of whether they received an additional 1 year of maintenance therapy with ATRA, methotrexate (MTX), and 6-mercaptopurine (6-MP) or were observed. source: This research was originally published in British Journal of Haematology. Coutre S.E., OthusM., Powell B., et al. Arsenic trioxide during consolidation for patients with previously untreatedlow/intermediate risk acute promyelocytic leukaemia may eliminate the need formaintenance therapy. Br J Haematol. 2014; Feb 14. doi: http://dx.doi.org/10.1111/bjh.12775 . ©2014 JohnWiley & Sons. Reprinted with permission.

In summary, the role of maintenance in low- or intermediate-risk patients receiving ATRA/ATO-based induction and consolidation without chemotherapy is not fully known, although recent work from Lo-Coco and colleagues would suggest that it is not needed [18] . In high-risk patients, an ATRA-based maintenance strategy incorporating low doses of 6-mercaptopurine and oral methotrexate (with careful monitoring of blood counts, especially in older patients) is generally recommended for 1–2 years depending on tolerability. As approaches to minimize or eliminate chemotherapy from APL regimens are further developed, maintenance therapy will likely continue to play an important role in high-risk or MRD-persistent patients. Conversely, the addition of ATO to frontline induction and consolidation strategies appears to have obviated the need for maintenance therapy in uncomplicated low- or intermediate-risk patients.

1.1.4. Relapsed disease

Over the last 1–2 decades, ATO has become the standard first-line therapeutic option for relapsed APL. Multiple studies have confirmed the activity and benefit of ATO in relapsed disease, with CR rates of approximately 80–90% and OS of 50–70% at 1–3 years [37], [61], [62], [63], and [64]. As upfront use becomes more common, it is unclear if ATO will remain as effective in the relapsed setting. The benefit of adding ATRA to ATO in the relapsed setting is also unclear, and a randomized trial from France showed no benefit, as many patients were likely ATRA-resistant at relapse [63] . The mechanism of secondary resistance to ATRA appears to be a novel missense mutation affecting the ligand-binding domain of the RARα region of the PML-RARα fusion protein [65] .

Upon achievement of CR2, autologous HCT is probably the best approach in younger patients. Other options include repetitive cycles of ATO with or without chemotherapy. However, transplantation likely provides the best chance to cure patients with relapsed APL. For example, autologous HCT can achieve up to 50–70% 5-year DFS in relapsed APL [66] . The choice between autologous and allogeneic HCT in relapsed APL can be a difficult one, and it depends on the patient age, suitability of potential allograft donors, and the extent of residual disease. The GIMEMA group and others have reported that patients with molecular MRD (PML-RARα-positivity) prior to hematopoietic cell collection subsequently relapsed after auto-transplantation, while those who were MRD-negative had sustained remission durations [67] and [68]. In MRD-negative patients in CR2, autologous HCT is typically preferred over allogeneic HCT given the excellent outcomes, better tolerability, and absence of graft-versus-host disease with this approach. In patients unfit for transplantation, repetitive courses of single agent ATO can also cure patients with relapsed disease, with 50% RFS at 17 months in one study [38] . In fact, although a recent report suggested that transplantation in CR2 may improve outcomes, non-transplant ATO-based therapy also cured a significant fraction (66%) of relapsed patients in this study [69] .

In patients with multiply relapsed or refractory APL, it is important to remember the anti-CD33 antibody–drug conjugate gemtuzumab ozogamicin (GO), while not commercially available in the United States, is highly active in APL and may be obtained on a compassionate use basis in the unusual case of multiply relapsed or refractory disease. Patients with multiply relapsed or refractory APL should also be considered for allogeneic HCT if the leukemic burden can be controlled, performance status and organ function are adequate, and a suitable donor can be identified.

1.1.5. MRD monitoring and pre-emptive therapy

Detection of bone marrow or peripheral blood leukemia-specific PML-RAR⍺ transcripts by conventional reverse transcriptase polymerase chain reaction (RT-PCR) testing – typically with sensitivity to detect up to 1 APL cell in 104 normal hematopoietic cells – after completion of consolidation and/or maintenance therapy has been associated with relapse [70] and [71]. More advanced PCR techniques such as real-time quantitative PCR (RQ-PCR) may be even more sensitive [72] . Thus, the use of MRD monitoring to detect residual disease or early relapse and guide pre-emptive therapy has been proposed. A study from the PETHEMA group has suggested that patients have better outcomes when treated in molecular relapse compared to frank, morphologic relapse [73] . However, this study was conducted before ATO became commercially available for the treatment of relapsed APL and ATO was not given on this protocol.

More recently, the MRC has shown that MRD-directed early intervention with single agent ATO may prevent progression to frank relapse [72] . In this study, which treated morphologically negative but MRD-positive patients with ATO monotherapy, the cumulative incidence of overt relapse was only 5%. However, most of the benefit appeared to be in high-risk patients. In general, serial monitoring of bone marrow samples with RT-PCR every 3 months for 36 months post-consolidation is a reasonable strategy in patients with high-risk APL. The role of strict MRD monitoring in low- or intermediate-risk patients is less clear. RT-PCR testing for fusion transcripts can also be performed on peripheral blood, and periodic sampling of blood (approximately every 3–6 months) for the first 3 years after consolidation therapy may be appropriate in lower risk patients.

1.1.6. Coagulopathy of APL and early death

Despite remarkable improvements in survival and decreased toxicity with ATRA and ATO-based therapy, early death (death within the first 30 days of treatment from hemorrhage or less commonly infection or differentiation syndrome) remains a major cause of treatment failure. Large cooperative group studies have reported an approximate 5–10% EDR within the first month of therapy [26], [29], [31], [35], and [74]; however, the true EDR may be higher given that many patients probably die before or early in the course of hospitalization (prior to registry on a clinical trial or even formal diagnosis of APL) [75], [76], and [77]. A recent study analyzing Surveillance, Epidemiology, and End Results (SEER) data reported an EDR of 18–21%, which is significantly higher than that reported on contemporary clinical trials [ Fig. 3 ] [78] . The EDR does not appear to have changed substantially in the ATRA era, which may be due to delayed diagnosis, delayed administration of ATRA when APL is first suspected, and/or inadequate supportive care. In fact, a recent retrospective analysis of 204 newly diagnosed APL patients demonstrated that delayed administration of ATRA leads to an increased EDR from hemorrhage, particularly in high-risk patients [79] .


Fig. 3 These two curves based on Surveillance, Epidemiology, and End Results (SEER) data show survival functions by diagnosis time periods and age groups. Whether stratified by diagnosis year or age, most APL-related deaths occur early in the disease course. Note that the advent of ATRA therapy in the 1990s did not impact the early death rate in this population-based study, possibly due to delays in ATRA administration at initial diagnosis. source: This research was originally published in Blood. Park J., Qiao B., Panageas K.S., et al. Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. Blood. 2011;118:1248–1254. ©The American Society of Hematology. Reprinted withpermission.

Almost all cases of fatal hemorrhage occur in the first month of APL therapy, and most of these (approximately 55%) occur within the first week of treatment and most of these within the first 24 h [80] and [81]. APL is a medical emergency and aggressive measures to support the coagulopathy and rapid initiation of ATRA should begin at first suspicion of APL. Rapid review of the blood smear is appropriate, but supportive measures and ATRA should not be delayed for bone marrow aspiration or specialty consultation. Standard supportive care measures include: cryoprecipitate or fibrinogen and platelets to maintain a fibrinogen of > 100–150 mg/dl and a platelet count > 50,000/μl and should persist throughout induction until signs of coagulopathy have resolved [32] and [82]. Fresh frozen plasma (FFP) may also be used if the prothrombin time and/or activated partial thromboplastin time are prolonged [83] .

It is important to educate emergency room physicians and internists regarding the rapid administration of ATRA at first suspicion of APL (suspicion of acute leukemia plus coagulopathy). ATRA has been shown to rapidly reverse signs of coagulopathy, reduce blood product consumption, and reduce the severity of bleeding [84] . Studies have also shown that the EDR at community hospitals without immediate access to specialty care is high, highlighting the need for patient transfer to centers with experience managing acute leukemia after they have been stabilized and the first dose of ATRA administered [85] . Emergency rooms and community hospitals should have mechanisms in place for the rapid procurement of ATRA and/or rapid transfer to a tertiary referral center once the patient is stabilized and supportive care initiated. The European LeukemiaNet has published guidelines that APL patients should be managed at large centers (> 500,000 patients/year) with a multidisciplinary team that treats ≥ 5 patients per year with intensive chemotherapy [32] . Lastly, while the full impact of ATRA on the EDR is yet to be fully elucidated, there is small to no risk of harm if ATRA is given for misdiagnosed APL and great potential benefit if the diagnosis is confirmed [26] and [86]. The impact of upfront ATO on the EDR is also unknown. In summary, rapid administration of ATRA, aggressively supporting the coagulopathy, and modulating the intensity of therapy (i.e., adding an anthracycline or hydroxyurea) in higher-risk patients may all be important for reducing the EDR in APL.

1.1.7. APL differentiation syndrome

About 50% of APL patients treated with ATRA will develop APL differentiation syndrome, which can be of varying clinical severity and potentially life-threatening [87] . APL differentiation syndrome is manifested by fever, hypotension, respiratory distress with pulmonary infiltrates, pleural and pericardial effusions, peripheral edema, and weight gain. The precise mechanism is not known, but is thought to be related to the release of vasoactive cytokines and chemotaxis of promyelocytes and blasts as they undergo rapid differentiation to neutrophils, causing a systemic inflammatory response and capillary leak syndrome. APL differentiation syndrome is typically associated with a high or rising WBC, but some patients will have a normal WBC [25] . Differentiation syndrome can be aborted or at least controlled with a pulse of high-dose Solu-Medrol or dexamethasone, which should be given at first suspicion of the syndrome and is potentially lifesaving. Delayed administration of corticosteroids is associated with poor outcomes [28] and [88], and when corticosteroid prophylaxis is administered in patients presenting with leukocytosis or with ATRA-associated leukocytosis, significant morbidity and death are rare [51] and [89]. Many investigators and clinicians now administer prophylactic dexamethasone (10 mg orally or intravenously twice daily) to high-risk patients or those who develop a relative leukocytosis on ATRA (WBC > 5000–10,000/μl).

2. Conclusion

The discovery of ATRA and ATO therapy for APL serves as a model for the implementation of rational targeted therapy in cancer, and illustrates how combinations of molecularly targeted agents that are synergistic or complimentary can cure disease and obviate the need for traditional cytotoxic chemotherapy. Although long-term survival of APL patients in the ATRA/ATO era has improved dramatically to 85–90% or higher, challenges still remain including the prevention of early death and improving outcomes (while concomitantly minimizing chemotherapy exposure) in high-risk patients. The North American Intergroup has recently completed a study using an ATRA/ATO-based induction that substitutes GO for traditional chemotherapy (S0535). Of note, patients on this study did receive chemotherapy (daunorubicin) with the second consolidation cycle and all patients receive maintenance therapy. Studies are also underway examining the optimal consolidation strategy for APL patients in CR2 (allogeneic HCT or autologous HCT or ATRA/ATO without transplantation). Synthetic retinoids, such as tamibarotene, have been under active investigation and may be effective in patients with ATRA-resistant APL [90] . Other areas for continued clinical exploration include the role of chemotherapy in low- or intermediate-risk patients who develop a leukocytosis after the initiation of ATRA (a not uncommon problem), and the role of maintenance therapy in different risk groups when ATO is used in the frontline setting. Lastly, oral formulations of ATO are currently being studied for clinical use, which should greatly reduce the not insignificant inconvenience associated with intravenous ATO schedules [91] and [92].

In summary, great strides have been made toward the cure of APL, which is one of the great accomplishments of modern medicine. Most patients are now cured (≥ 90%) with early disease detection and rapid initiation of ATRA, close clinical monitoring and supportive care in the initial stages, and ATRA/ATO-based induction and consolidation regimens. As remaining challenges, such as optimal therapy for high-risk patients, are addressed in the coming years, survival will likely approach 100%. Finally, the most important remaining challenge is likely the development of effective strategies for the rapid procurement and administration of ATRA and transfer to specialty care centers at initial presentation, to prevent early hemorrhagic death in what has now become the most curable subtype of acute leukemia in adults.

Practice points


  • Low- or intermediate-risk APL can be cured in most patients with ATRA/ATO and minimal or no chemotherapy, representing a new standard of care.
  • In high-risk patients, idarubicin or daunorubicin plus cytarabine should be incorporated into the therapeutic strategy.
  • APL is highly sensitive to high-dose chemotherapy and autologous HCT is very effective for relapsed disease.
  • The number one cause of treatment failure is now early hemorrhagic death, which likely can be greatly reduced with early detection and rapid initiation of ATRA, as well as aggressive supportive care measures to correct the coagulopathy.

Research agenda


  • Improved techniques for the prevention of early death (such as protocols for the rapid administration of ATRA at first suspicion of APL)
  • Refining indications for maintenance therapy in the ATO era
  • The development and clinical implementation of oral formulations of ATO

Conflict of interest statement

The authors have no conflict of interest to report.


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Leukemia Service, Memorial Sloan Kettering Cancer Center, USA

lowast Corresponding author at: University of Miami, Sylvester Comprehensive Cancer Center, 1120 NW 14th Street, Suite 610C, Miami, FL, 33136. Tel.: + 1 305 243 4860; fax: + 1 305 243 9161.

1 Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 380, New York, NY 10065, USA. Tel.: + 1 212 639 3842(Office); fax: + 1 212 639 3841.