Current treatment strategy of acute promyelocytic leukemia

Abstract

Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML). The prognosis of APL has changed from the worst among the AMLs to currently the best. The application of all-trans retinoic acid (ATRA) in the induction therapy of APL decreases the high mortality of newly diagnosed patients, thereby significantly improving the response rate. ATRA combined with anthracycline-based chemotherapy is the current standard treatment, and for high-risk patients, high doses cytarabine have a beneficial effect on relapse prevention. In recent years, the indications of arsenic trioxide (ATO) therapy for APL have been extended from the salvage therapy for relapse patients to the first-line treatment of de novo APL. The introduction of both ATRA and ATO represents great achievements in translational medicine. In this review article, we discuss the therapeutic strategies for this disease, including the initial approaches to newly diagnosed patients, prevention, and treatment of side effects and relapse to ensure the best and timely treatment for each newly diagnosed APL patient.

Keywords

acute promyelocytic leukemia / all-trans retinoic acid / arsenic trioxide

Introduction

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML). This relatively rare hematologic malignancy accounts for approximately 5%-8% of all AML cases. According to the French-American-British (FAB) classification, APL is also morphologically categorized as AML-M3, whereas in the WHO classification, it is classified as “acute promyelocytic leukemia with t(15;17)(q22;q12), (PML/RARα) and variants.” APL used to be the leukemia with the highest mortality rate mainly because of hemorrhagic diathesis before the introduction of all-trans retinoic acid (ATRA) for the APL treatment. Cytogenetically, APL is mostly characterized by t(15;17) translocation, which fuses the promyelocytic leukemia (PML) gene on chromosome 15 to the retinoic acid receptor α (RARα) gene on chromosome 17, resulting in the chimeric gene encoding PML-RARα fusion protein. About 90% of the APL patients bear the typical t(15;17) translocation and PML-RARα fusion. However, some rarer molecular subtypes may be identified, such as t(11;17)(q23;q21), t(11;17)(q13;q21), t(5;17)(q35;q21) and dup(17) (q21.3;q23), leading to promyelocytic leukemia zinc finger protein (PLZF)-RARα [1], NuMA-RARα [2], NPM1-RARα [3] and STAT5b-RARα [4] fusions, respectively, as well as others more recently described [5,6]. The identification of these molecular fusions usually predicts poor response to ATRA induction.

In the 1990s, an ancient drug mainly based on traditional Chinese medicine, arsenic trioxide (As₂O₃ or ATO), was shown to be effective in inducing complete remission (CR) in both relapsed and newly diagnosed APL patients [7–9]. Moreover, since the beginning of the 21st century, several clinical trials have demonstrated a safe treatment for newly diagnosed APL patients with an encouraging long-term survival rate of over 90%. The therapy marked another milestone in the treatment of APL, which was once considered the “most malignant form of acute leukemia,” and became a curable disease after that. Both ATRA and ATO have been applied to clinical practice based on bench-to-bedside studies conducted by investigators throughout the world, which represent the achievements of translational medicine. In this review, some major issues involved in the APL therapy are discussed.

ATRA/chemotherapy

Induction therapy

Historically, chemotherapy (CT) with anthracycline-cytosine arabinoside (Ara-C) was the only treatment that obtained CR rates of 65%-80%, but 5-year event-free survival (EFS) rates of only 35%-45% [10,11]. The deterioration of coagulopathy during chemotherapy because of the release of azure granules in the malignant cells is the main reason for patient deaths. In the mid-1980s, the introduction of ATRA as a cancer differentiation inducer dramatically improved the outcomes of de novo APL patients, with CR rates increasing to roughly 90% [12]. ATRA specifically targets the PML-RARα transcripts, releases the dominant transcription repressor, and induces specific differentiation of promyelocytes. This also initiated a brand new century of differentiation therapy for malignancies.

During induction therapy with ATRA, some patients may develop APL differentiation syndrome (DS), which would be life threatening without appropriate early management. Physicians should carefully monitor this syndrome when one of the following clinical manifestations of unknown origin develops: dyspnea, fever, weight gain, peripheral edema, acute renal failure, congestive heart failure, pulmonary infiltration or pleuropericardial effusion (demonstrated by chest radiography). With the increase in experience of physicians dealing with this syndrome, most episodes of DS could be prevented or managed successfully early at its onset. The incidence of APL DS was about 10% in the patients treated by ATRA combined with chemotherapy induction, and the mortality rate was only up to 2%–3% [13,14]. The mechanism of APL DS remains unclear, and the major specific treatment includes the early use of intravenous dexamethasone at a dose of 10 mg q12 h for at least 4 days, as well as chemotherapy. However, if the patient presents with high-risk disease (WBC>10 × 10⁹/L), ATRA with chemotherapy should be started concurrently.

Consolidation/maintenance therapy

The role of ATRA in consolidation therapy remains controversial as most of the consolidation therapy of APL consists of 2–3 courses of chemotherapy without ATRA, which yields molecular remission rates of 95%. Several large-scale randomized clinical trials, especially two randomized trials of a European APL Group [15,16] and the North American Intergroup [17], demonstrated that the combination of ATRA and chemotherapy might further improve the long-term outcomes of APL patients, increasing the 5-year disease-free survival (DFS) rate to 74%. Several other clinical trials have also attempted to optimize the time schedule of the administration of ATRA and anthracycline-based chemotherapies [18,19]. Hence, intermittent ATRA combined with CT maintenance has been widely accepted to reduce the incidence of APL relapse and achieve significantly better survival rates than continuous CT maintenance. Recently, the European APL Group updated their long-term outcomes of APL after treatment with ATRA and chemotherapy [20]. In their APL 93 trial, which included 576 newly diagnosed APL patients, with a median follow-up of 10 years, the 10-year survival rate was 77%. Maintenance treatment with both intermittent ATRA and continuous 6-mercaptopurine plus methotrexate significantly reduced the 10-year cumulative incidence of relapse to 13.4% compared with either ATRA or chemotherapy alone (Pβ<0.001). The maintenance particularly benefited patients with higher initial WBC counts.

For repeated intensified chemotherapy, several arguments are still ongoing, especially among patients who have achieved completed molecular remission after consolidation therapy. The Japan Adult Leukemia Study Group (JALSG) conducted a randomized study (APL97) [21] and demonstrated no benefit on disease-free survival.

Arsenic trioxide (ATO)

Arsenic is an ancient drug that has been effective in treating several diseases. However, because of concerns regarding its toxicity, the administration of arsenic is only anecdotal. In the 1970s, a group from Harbin Medical University in China first used arsenic compounds to treat malignancies. Since the 1990s, groups from Harbin [22] and Shanghai Institute of Hematology (SIH) [23] reported favorable responses of APL patients given ATO intravenously. In the SIH experience, for 47 relapsed and 11 newly diagnosed APL patients, the CR rates were 85.1% and 72.7%, respectively. After that, several groups worldwide further confirmed that ATO was highly effective as a single agent inducing complete hematologic and, in some cases, molecular responses in APL patients. Moreover, the ATO treatment significantly improved the survival in both the relapsed and newly diagnosed patients[9,24–26]. Thus, the administration of ATRA combined with anthracycline-based chemotherapy for remission induction followed by consolidation or maintenance chemotherapy/ATRA was established as the standard front-line therapy in APL, whereas the ATO was considered as the standard treatment for relapsed patients.

In the SIH studies on the cellular and molecular mechanisms of action of ATO, ATO exerts dose-dependent dual effects on APL cells [27]. It induces the apoptosis of APL cells under high concentrations while promoting differentiation under low concentrations. ATO also directly degrades the PML-RARα fusion transcript, leading to the eradication of acute promyelocytic leukemia-initiating cells [28]. More recently, it was further revealed by investigators of SIH that arsenic controls the fate of the PML-RARα oncoprotein by directly binding the PML, and subsequently induces PML oligomerization, which increases its interaction with the small ubiquitin-like protein modifier (SUMO)-conjugating enzyme UBC9, resulting in enhanced SUMOylation and degradation [29].

ATRA/ATO/chemotherapy regimen for de novo APL

Given the successful therapeutic practices of ATO in APL, several working groups administered ATO as a single agent for first-line therapy, which produced better effects compared with ATRA alone [9,26,30]. Both ATRA and ATO induce the degradation of PML-RARα fusion protein but through distinct pathways, with ATRA targeting the RARα and ATO targeting the PML moieties of the fusion protein. A synergistic effect was found in animal models without aggravating the side effects [31-34]. These results encouraged us to conduct a randomized clinical study on newly diagnosed APL, which combined ATRA with ATO and/or chemotherapy in induction, intensive chemotherapy in consolidation, and ATRA combined with ATO and low-intensity chemotherapy in maintenance. The ATRA/ATO combination for the remission (with maintenance) therapy of APL yielded better results than either of the two drugs used alone in terms of the quality of CR and the status of disease-free survival. Our CR rate was 94.1%, whereas the 5-year event-free survival and the overall survival rates were 89.2% and 91.7%, respectively [35,36] (Fig. 1). A number of trials have also been carried out internationally in newly diagnosed patients, combining ATRA with ATO and/or chemotherapy or gemtuzumab ozogamicin (GO) [37,38]. Recently, Powell et al. studied the role of arsenic as consolidation treatment for 481 patients in first remission. The addition of ATO consolidation significantly improved event-free and disease-free survival in adults with newly diagnosed APL [39].

Prognostic factors

Prognosis evaluation will enable physicians to distinguish high-risk patients in the early stage of treatment in order to adjust the protocol accordingly and yield better outcomes. Most studies worldwide have concluded that the initial WBC count is the most important prognostic factor. A joint study of the Spanish PETHEMA and Italian GIMEMA cooperative groups reported that for the patients given ATRA with idarubicin as induction, anthracycline-based chemotherapy as consolidation, and ATRA with low-dose chemotherapy (6-MP and MTX) as maintenance treatment, patients could be further divided into low-, intermediate-, and high-risk groups depending on the WBC and PLT counts, with WBC<10 × 10⁹/L, PLT>40 × 10⁹/L as “low-risk” group of recurrence, WBC>10 × 10⁹/L as “high-risk,” and WBC<10 × 10⁹/L, PLT<40 × 10⁹/L as “intermediate-risk,” with distinctive Radio Frequency Systems curves (P<0.000 1) [40]. This simple predictive model may be used for risk-adapted therapy in APL.

More recently, the European APL Group reported their experience of improved outcomes of APL with high WBC counts over the past 15 years [41], as demonstrated by the better CR rates and 5-year cumulative incidence of relapse (CIR). Whereas in the APL 93 trial, increased WBC counts were significantly associated with higher CIR and shorter survival, this was not the case in the APL 2000 trial. Better initial supportive care and combined maintenance treatment have contributed to this improvement. With ATRA/ATO combination therapy, the prognosis was not influenced by the initial WBC count, distinct PML-RARα types, or FLT3 mutations, which is consistent with their findings.

Other prognostic factors, such as gender, PML-RARα transcript type, FLT3 mutations, CD56, and others [17,42], have also been reported, but have not reached a consensus.

The role of cytarabine

The traditional protocol of chemotherapy for APL was the DA regimen, specifically anthracycline combined with cytarabine. However, the leukemic cells of APL patients were discovered to be most sensitive to anthracyclines. A CR rate of 60%-80% was achieved by anthracycline monotherapy, including idarubicin and daunorubicin, whereas therapy-related toxicity was significantly reduced with the omission of cytarabine. A prospective large-scale randomized trial conducted by the Italian GIMEMA Cooperative Group reported no significant difference in CR rate between the two groups using anthracyclines with or without cytarabine, whereas the 7-year EFS was significantly higher in the anthracycline monotherapy group [43].

The role of cytarabine in APL therapy remains controversial. The European APL Group reported superior survival rates for patients younger than 60 years with WBC counts less than 10β×10⁹/L with the addition of cytarabine to ATRA and anthracyclines in a randomized trial (APL 2000) [44]. To better understand the role of cytarabine in treatment of APL, the investigators performed a joint analysis of patients younger than 65 years included in the PETHEMA LPA 99 trial, where no Ara-C in addition to ATRA, high cumulative dose idarubicin, and mitoxantrone, and APL 2000 trial, where patients received Ara-C in addition to ATRA, and lower cumulative doses of daunorubicin [45]. They found that in patients with high WBC counts, the addition of cytarabine may be beneficial in terms of CR rate and survival, but in patients with lower initial WBC counts, anthracyclines alone may be sufficient. The dosage and schedule of anthracyclines involved in these trials with controversial results differed from each other, resulting in a slightly complicated comparison. More recently, the Spanish PETHEMA group reported their latest progress in the LPA 2005 trial using the risk-adapted treatment of APL based on ATRA and anthracycline with the addition of cytarabine in consolidation therapy for high-risk patients, which also demonstrated a superior result with the addition of cytarabine for high-risk APL [46]. The German Acute Myeloid Leukemia Cooperative Group also reported their experience with double induction using ATRA and intensified chemotherapy including high-dose Ara-C followed by prolonged maintenance therapy reducing the relapse risk in high-risk patients [47]. Most of the literature up to now suggest at least one cycle of intermediate or high-dose cytarabine in younger patients with high WBC counts before maintenance treatment.

Humanized anti-CD33 monoclonal antibodies (gemtuzumab ozogamicin, GO)

Gemtuzumab ozogamicin is an antibody-drug conjugate consisting of cytotoxic calicheamicin and a humanized mouse anti-human-CD33 antibody. Several small-scale clinical administration of GO to relapsed [48] or newly diagnosed APL [49] showed its effectiveness in eliminating MRD.

Recently, Ravandi et al. of the M. D. Anderson Cancer Center in the US examined the outcome of patients with newly diagnosed APL patients treated with ATRA and ATO with or without GO, but without traditional cytotoxic chemotherapy. They used GO only for patients who presented with high-risk disease, or developed WBC counts more than 30β×β10⁹/L during induction. The CR rate was 92% with a 3-year overall survival of 85% [37].

Hematopoietic stem cell transplantation

Given that ATRA-based therapy is highly effective in APL, especially in newly diagnosed patients and most of the patients who have relapsed for the first time could be induced successfully to second CR, stem cell transplantations (either allogeneic or autologous) are not currently recommended for patients experiencing their first remission despite the lack of randomized trial results. As far as therapy-related mortality is concerned, reserving this kind of curative treatments with life-threatening complications to the second remission period is reasonable. Several investigations have indicated that autologous transplantation is very effective for patients who have relapsed after ATRA treatment and achieved second molecular remission, whereas allogeneic transplantation is risky concerning the higher transplantation-related mortality (TRM) and despite of the lower recurrence rate [50]. However, for those who have continuous positive PCR results, allogeneic transplantation should be considered in case suitable donors are available [51].

In patients with relapsed APL, the best therapeutic choice following remission induction remains undetermined. Thirugnanam et al. reported that consolidation with autologous SCT is associated with a significantly superior clinical outcome compared with single ATO and ATO/ATRA-based maintenance regimens [52]. A group from Japan also suggested that autologous hematopoietic stem cell transplantation (HSCT) may be preferable to allogeneic HSCT for APL in CR2 or CR3 [53].

Supportive care

Supportive measures are critical, especially in the first days of APL treatment for those with hemorrhagic diathesis. Although the introduction of ATRA significantly ameliorates severe bleeding, some patients complained of serious bleeding when seeking for medical assistance [54]. For the prevention and treatment of bleeding complications, appropriate measures should be taken, such as determination of blood cell count, fibrinogen level, prothrombin time, and partial thromboplastin time twice daily, transfusions of fibrinogen, fresh frozen plasma, and platelet concentrates as needed to maintain the platelet count at more than 30β×β10⁹/L and fibrinogen level at more than 1.5 g/L. The use of heparin has been typically abandoned, except in major deep vein thrombosis, which is very rare. In addition, starting the anti-infectious therapy in a timely and appropriate manner is necessary for newly diagnosed APL patients who develop leukocytopenia after chemotherapy to prevent severe infections.

Although favorable results have been achieved, prospective randomized studies are still warranted to define the role of HSCT in the treatment of relapsed APL compared with ATRA/ATO/chemotherapy/GO because long-term survival may also be achieved using these approaches without increasing the therapy-related mortality.

In summary, APL has been characterized by high early mortality, but with the efforts of researchers worldwide, it has become the most curable AML subtype. Currently recommended treatment options include ATRA combined with anthracycline-based chemotherapy and/or ATO as induction therapy, anthracycline-based consolidation therapy, and maintenance with ATRA-based therapy. Patients on first relapse are to be re-treated with ATO and/or ATRA. After the second hematologic remission, autologous stem cell transplantation can be used for patients with molecular remission, whereas allogeneic transplantation can be applied for fusion gene-positive patients while a suitable HLA-matched donor is available.

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