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Initial treatment of acute promyelocytic leukemia in adults

Initial treatment of acute promyelocytic leukemia in adults
Literature review current through: Jan 2024.
This topic last updated: Jun 10, 2022.

INTRODUCTION — Acute myeloid leukemia (AML) refers to a group of hematopoietic neoplasms involving cells committed to the myeloid lineage. Acute promyelocytic leukemia (APL) is a biologically and clinically distinct variant of AML. APL was classified as AML-M3 in the older French-American-British (FAB) classification system and is currently classified as acute promyelocytic leukemia with t(15;17)(q24.1;q21.1); PML-RARA in the World Health Organization classification system [1]. (See "Molecular biology of acute promyelocytic leukemia".)

Without treatment, APL is the most malignant form of AML, with a median survival of less than one month [2]. Registry data suggest that many patients die before reaching an experienced hematologist. Thus, those patients who enroll in prospective clinical trials may already be a selected subset. However, with modern therapy, APL is associated with the highest proportion of patients with AML who are cured of their disease. The treatment of APL is distinct from that of other types of AML and is comprised of several stages which, in total, may span one to two years of treatment (table 1) [3]:

Remission induction

Consolidation

Maintenance

The treatment of APL in adults will be reviewed here. While not specifically discussed, treatment programs described below appear to be equally effective in children, after minor modifications [2,4-6]. The clinical features, diagnosis, and prognosis of APL in adults are discussed separately, as is the treatment of patients with relapsed or resistant disease. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults" and "Treatment of relapsed or refractory acute promyelocytic leukemia in adults".)

EMERGENCY PRETREATMENT EVALUATION — APL represents a medical emergency with a high rate of early mortality, often due to hemorrhage from a characteristic coagulopathy [7]. Among nearly 1000 patients who enrolled on prospective clinical trials that included early use of all-trans retinoic acid (ATRA; tretinoin) for APL, the incidence of early hemorrhagic death was 3.7 percent [8]. Population-based surveys that included less highly selected APL patients indicate an early death rate of 17 to 29 percent [7,9,10]; the increased rate of death in the population-based surveys include additional causes of death (eg, infections, differentiation syndrome, thrombotic events), but also highlight the importance of early diagnosis and prompt treatment with ATRA.

It is critical to start treatment with ATRA without delay as soon as the diagnosis is suspected based on cytologic criteria, and before definitive confirmation of the diagnosis has been made by genetic, cytogenetic, or immunostaining methods [11]. If the diagnosis is not confirmed, ATRA can be discontinued and treatment changed to that used for other types of acute myeloid leukemia (AML). (See "Acute myeloid leukemia: Induction therapy in medically fit adults" and "Acute myeloid leukemia: Management of medically unfit adults" and "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults", section on 'Pathologic features'.)

Patients with suspected APL should undergo studies to evaluate for disease extent and comorbidities as described for other patients with AML. While important, these studies should not interfere with the rapid initiation of ATRA-based therapy. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Pretreatment'.)

INDUCTION

Choice of regimen — Induction therapy aims to reduce the total body leukemia cell population from approximately 1012 to below the cytologically detectable level of about 109 cells. A key component of this therapy is the use of all-trans retinoic acid (ATRA), which promotes the terminal differentiation of malignant promyelocytes to mature neutrophils (picture 1). However, ATRA must be combined with other agents since remissions induced by ATRA therapy alone are short-lived with a median duration of only about 3.5 months [12].

The largest experience has been with ATRA combined with anthracycline-based chemotherapy (table 2). Randomized trials suggest that the combination of ATRA plus arsenic trioxide (ATO) yields equivalent and perhaps superior outcomes compared with standard regimens combining ATRA with chemotherapy. The great majority of these results are derived from clinical studies in low-risk APL and intermediate-risk APL. There is still relatively limited information on the comparative value of combination treatment with ATRA plus ATO in patients with high-risk APL. In addition, there is limited availability of ATO worldwide.

Our preferred induction regimen is informed by risk stratification based on white blood cell (WBC) count at presentation:

Low- or intermediate-risk APL – Initial WBC count ≤10,000/microL (≤10 x 109/L)

High-risk APL – Initial WBC count >10,000/microL (>10 x 109/L)

Selection of induction therapy is also informed by the ability of the patient to tolerate anthracycline-based therapy, and the availability of ATO:

Low- or intermediate-risk APL – For most low- or intermediate-risk patients with newly diagnosed APL, we recommend ATRA plus ATO rather than ATRA plus anthracycline-based chemotherapy. This preference places a high value on the lesser toxicity (eg, myelosuppression, cardiac toxicity), fewer deaths during induction therapy, fewer relapses, and reduced risk of secondary leukemia with this combination, and less value on the longer clinical experience and robustness of the clinical trials with ATRA plus chemotherapy [13]. Where ATO is not available for initial use, a standard ATRA plus anthracycline regimen is the recommended alternative for remission induction. Patients who receive induction with ATRA plus chemotherapy benefit when ATO is used for post-remission therapy. (See 'ATO plus ATRA' below.)

High-risk APL – There is less certainty regarding the preferred approach for patients with a high WBC count at presentation. International studies are underway comparing ATRA plus ATO versus ATRA plus chemotherapy in this setting. ATRA plus chemotherapy remains the recommended initial therapy for high-risk APL until more data are available regarding the early use of ATO in this small subset. When ATRA plus ATO is used for patients with high-risk APL, the WBC count often rises and raises concerns regarding hyperleukocytosis and differentiation syndrome. In clinical trials, gemtuzumab ozogamicin (GO) effectively reduced the rising WBC count in these situations, but GO is not currently readily available. Cytotoxic chemotherapy with either hydroxyurea or an anthracycline has been used for leukocytosis in this setting, but prospective studies have not yet been reported. These agents may add toxicities and it is not clear whether substitution of these agents for GO impacts efficacy. (See 'ATRA plus chemotherapy' below.)

Primary resistance to treatment with induction therapy that contains ATRA is unusual except for patients with the rare APL variant t(11;17). Such patients are generally treated as if they had a non-APL variant of AML. (See "Acute myeloid leukemia: Induction therapy in medically fit adults" and "Molecular biology of acute promyelocytic leukemia", section on 'Variant translocations'.)

ATO plus ATRA — ATO, alone or in combination with ATRA, is capable of producing complete molecular remissions (as defined by the absence of the PML-RARA fusion transcript using reverse transcription polymerase chain reaction [RT-PCR]) in previously untreated APL [14-22]. Where ATO is available for front-line use, we recommend ATRA plus ATO for newly diagnosed APL with low or intermediate risk (ie, those with initial WBC count ≤10,000/microL). It is also our preferred therapy for patients, such as older adults, who are not able to tolerate anthracycline-based therapy. ATO plus ATRA is administered until marrow remission, but should not exceed 60 days.

Use of ATO plus ATRA in patients with high-risk APL (initial WBC count >10,000/microL) without comorbidities is controversial, as the evidence supporting its use in this population is less robust. In high-risk disease, induction therapy with ATRA plus chemotherapy (table 2) [4,23], followed by post-remission therapy with ATO is standard; this approach has not been directly compared with ATO plus ATRA for high-risk disease. (See 'Is there a role for ATO in post-remission therapy?' below.)

The Intergroup APL0406 trial randomly assigned 263 adults with newly diagnosed low- or intermediate-risk APL to ATRA plus ATO (ATRA-ATO) versus ATRA plus chemotherapy (ATRA-CHT) [24,25]. In the experimental arm, ATRA (45 mg/m2) plus ATO (0.15 mg/kg) was administered daily until complete remission (CR), followed by consolidation with intermittent ATRA and ATO for seven and four courses, respectively. In the ATRA-CHT arm, patients received ATRA and idarubicin induction therapy, followed by three cycles of consolidation therapy with ATRA plus chemotherapy, and maintenance therapy with low dose chemotherapy and ATRA; the ATRA-CHT arm did not incorporate ATO into the post-remission therapy. At a median follow-up of more than 40 months, ATRA-ATO resulted in the following, when compared with ATRA-CHT:

Similar rates of hematologic CR (100 versus 97 percent).

Fewer deaths during induction therapy (0 versus 4 patients).

Superior estimated four-year event-free survival (EFS; 97 versus 80 percent), cumulative incidence of relapse (2 versus 14 percent), and overall survival (OS; 99 versus 93 percent).

Two relapses and one death in CR in the ATRA-ATO arm, and 15 relapses and 5 deaths in the ATRA-CHT arm.

Similar rates of moderate/severe differentiation syndrome (17 versus 13 percent). (See 'Differentiation syndrome' below.)

Less severe (grade 3/4) thrombocytopenia, neutropenia, and febrile neutropenia; less gastrointestinal toxicity and cardiac function abnormalities; but higher rates of severe (grade 3/4) elevation of liver function tests (which resolved with temporary discontinuation of ATO and/or ATRA), QTc prolongation (but no life-threatening cardiac arrhythmias), and reversible peripheral neuropathy.

Analysis of the 35 older adults (age 60 to 70) included in the study reported that, among the 16 patients receiving ATRA-ATO, there were no deaths and one relapse at 27 months [23]. In comparison, 3 of the 19 patients who received ATRA-CHT died (one each from differentiation syndrome, pulmonary embolism, and bronchopneumonia).

These results suggest that for patients with low/intermediate-risk APL, ATO plus ATRA is not inferior (and perhaps is superior) compared with ATRA-CHT. ATRA-ATO is associated with less toxicity, fewer deaths during induction therapy, and fewer short- and long-term relapses.

All risk groups of APL were represented in the United Kingdom's AML17 trial, in which 235 adults were randomly assigned to received ATRA plus ATO versus ATRA plus idarubicin (AIDA) [26]. An initial dose of gemtuzumab ozogamicin (GO, 6 mg/m2) was offered to the 30 patients with high-risk disease (ie, total WBC count >10,000/microL at presentation). The dose and schedule of ATO was less intensive than that used in the APL0406 trial described above. There was no difference in overall quality of life between the arms, the study's primary endpoint. At a median follow-up of 30 months, when compared with AIDA, ATRA plus ATO resulted in the following:

Similar rates of CR (94 versus 89 percent) and confirmed molecular negativity (91 versus 88 percent).

Similar mortality at 30 days (4 versus 6 percent) and 60 days (5 versus 9 percent).

Similar estimated rates of survival at four years (93 versus 89 percent).

Superior estimated EFS at four years (91 versus 70 percent).

Lower cumulative rates of molecular relapse (0 versus 27 percent) and morphologic relapse (1 versus 18 percent) at four years.

An average of 7 fewer days in hospital, 5 fewer units of blood, 4 fewer units of platelets, and 10 fewer days of intravenous antibiotics.

With median follow-up >67 months, compared with AIDA, five-year OS (92 versus 86 percent) and relapse-free survival (RFS; 96 versus 86 percent) were superior with ATRA plus ATO [27]. There were no relapses in patients treated with ATRA plus ATO who were negative for measurable residual disease (MRD) after consolidation therapy; in contrast, 20 percent relapsed within five years among those who received AIDA and were MRD negative after consolidation.

These beneficial results were seen across all patient populations. These positive results were also seen in those with high-risk disease although there were only small numbers of high-risk patients in the trial. GO is not available in most of the world. Cytotoxic chemotherapy with either hydroxyurea or an anthracycline is often used for leukocytosis in this setting. However, these agents may add toxicities and it is not clear whether the resulting mild to moderate leukocytosis needs to be treated with a cytoreductive agent and whether substitution of these agents for GO impacts efficacy in this setting. While some groups propose the use of dexamethasone as prophylaxis against differentiation syndrome, it is unclear whether this results in superior outcomes when compared with protocols that treat differentiation syndrome once symptoms develop. (See "Differentiation syndrome associated with treatment of acute leukemia".)

Several smaller prospective trials have shown durable responses extending over longer periods of time:

Two prospective trials evaluated single agent intravenous ATO administered until CR or for a maximum of 60 days, with variable use of ATO consolidation [15,18,19,28]. Morphologic CR was attained in 86 percent. Estimated rates of disease-free survival (DFS) and OS at five years ranged from 67 to 80 and 64 to 74 percent, respectively. The best outcomes were seen in patients with a WBC count <5,000/microL and platelet count >20,000/microL. DFS improved with increasing number of consolidation cycles.

A prospective trial evaluated ATRA and ATO, with or without GO in 82 patients with newly diagnosed APL [29]. Ninety percent of patients achieved a CR. At a median follow-up of 25 months, the three-year estimated rate of OS was 86 percent, and was 100 percent for the subset of 22 patients who had both a WBC count <5,000/microL and a platelet count >20,000/microL at the time of diagnosis. Toxicity was mild and reversible, and, after remission induction, treatment could be given on an outpatient basis. Side effects of ATO include fluid retention, differentiation syndrome, peripheral sensory neuropathy, and electrocardiographic abnormalities. (See "Treatment of relapsed or refractory acute promyelocytic leukemia in adults".)

Another prospective trial of ATRA plus ATO in 85 patients with newly diagnosed APL followed for a median of 70 months reported a CR rate of 94 percent with five-year EFS and OS rates of 89 and 92 percent, respectively [17].

The Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study was a non-randomized phase 2 trial that evaluated a combination of ATRA, ATO, and idarubicin in 124 patients with newly diagnosed APL [30]. At a median follow-up of 4.2 years, estimated five-year rates of DFS (95 percent) and OS (94 percent) were superior to those of historical controls not treated with ATO.

Most trials of ATO plus ATRA have used intravenous ATO. Initial results suggest that the combination of an oral formulation of tetra-arsenic tetra-sulfide (As4S4) plus ATRA results in similar clinical outcomes. A multicenter, unblinded, phase III trial of 242 patients with previously untreated low/intermediate-risk APL randomly assigned therapy with ATO plus ATRA versus As4S4 plus ATRA [31]. At a median follow-up of 39 months, As4S4 plus ATRA resulted in similar rates of CR (99 versus 97 percent), DFS at two years (98 versus 96 percent), and OS at three years (99 versus 97 percent). Oral As4S4 is not commercially available at this time. Several smaller prospective trials have shown durable responses extending over longer periods of time.

ATRA plus chemotherapy — The concurrent administration of ATRA plus cytotoxic chemotherapy produces a CR in 80 to 95 percent of patients of all ages with APL [24,32-35]. The median time to CR ranges from 38 to 44 days, but may be as long as 90 days. Almost all treatment failures are due to early mortality (approximately 10 percent) [36]. If an ATRA-based regimen of induction, consolidation, and maintenance is used, rates of two-year OS range from 69 to 88 percent. Rates of 10-year OS range from 58 to 85 percent [37].

This combination is supported by randomized trials that demonstrated that patients who received both ATRA and chemotherapy had superior rates of CR and DFS when compared with patients who received chemotherapy alone [32,33]:

A randomized controlled trial comparing induction with daunorubicin/cytarabine alone or in combination with ATRA was stopped early when the first interim analysis showed lower relapse rates with the addition of ATRA [32]. When compared with those treated with chemotherapy alone, patients who received chemotherapy plus ATRA had a significantly higher rate of EFS at 12 months (79 versus 50 percent) and a lower relapse rate (19 versus 40 percent). ATRA was also associated with a higher CR rate (91 versus 81 percent), but this did not achieve statistical significance, possibly because early termination of the study limited the number of patients enrolled. OS was similar in the two groups.

A second randomized trial within the US Intergroup studied various combinations of remission induction (ATRA alone versus chemotherapy with daunorubicin plus cytarabine) plus maintenance therapy (daily ATRA for one year versus observation), all in combination with a consolidation chemotherapy program in 350 patients with previously untreated APL [33]. CR rates were similar after initial induction (approximately 70 percent). At a median follow-up of 6.2 years, estimated rates of five-year DFS for the various treatment combinations were [38]:

Chemotherapy induction plus two cycles of consolidation chemotherapy followed by observation – 16 percent

Chemotherapy induction plus two cycles of consolidation chemotherapy plus ATRA maintenance – 47 percent

ATRA induction plus two cycles of consolidation chemotherapy followed by observation – 55 percent

ATRA induction plus two cycles of consolidation chemotherapy followed by ATRA maintenance – 74 percent

The duration of coagulopathy appears shortened when ATRA is added to induction chemotherapy (eg, three days compared with six days with chemotherapy alone) [32,39,40]. The addition of chemotherapy to ATRA helps to control hyperleukocytosis that occurs in up to 50 percent of patients treated with ATRA alone. In this way, the combination of ATRA plus chemotherapy limits complications that may occur when either agent is used alone.

For patients with newly diagnosed APL, we recommend induction therapy with ATRA plus anthracycline-based chemotherapy rather than treatment with either ATRA or chemotherapy alone. Multiple trials have investigated the optimal means of combining ATRA and chemotherapy during induction. These are described in the following sections.

Of interest, a randomized study in 1075 patients <60 years of age was unable to identify any subgroup of patients with non-APL acute myeloid leukemia (AML) likely to derive a significant survival benefit from the addition of ATRA to chemotherapy [41]. Preliminary data suggest that among patients with non-APL AML, those with mutations in the nucleophosmin-1 (NPM-1) gene may benefit from ATRA when combined with induction chemotherapy.

Choice of chemotherapy — Anthracycline-based regimens typically used for the treatment of AML have been administered to patients with APL, initially alone and then as a base for regimens employing ATRA. There have been no direct comparisons between agents, but the best results have been obtained when ATRA was combined with daunorubicin and cytarabine or with idarubicin (table 2) [5,32,38,42-47]. APL is especially susceptible to anthracycline therapy because of low expression of the drug efflux pump p-glycoprotein (MDR-1) on the cell membrane of the leukemic cells [48].

The prospective randomized trials described in the previous sections using a combination of daunorubicin, cytarabine, and ATRA for induction therapy reported CR rates of 80 to 95 percent [5,32,38,44]. A prospective, randomized trial that investigated whether cytarabine could be eliminated from this regimen found that patients who received cytarabine had similar CR rates but fewer relapses and improved survival, when compared with patients who did not receive cytarabine [45,49,50].

A retrospective analysis of patients treated with ATRA plus idarubicin induction reported a CR rate of 91 percent [51]. The most common causes of early mortality were hemorrhage (5 percent), infection (2.3 percent), and differentiation syndrome (1.4 percent). Lethal bleeding occurred most frequently in the first week of therapy while deaths due to infection or differentiation syndrome were spread throughout the course of induction treatment. (See 'Differentiation syndrome' below.)

In the prospective ATRA, idarubicin, and intravenous ATO in APL trial (the Australian APML4 trial), of 124 patients with newly diagnosed de novo APL who underwent induction with ATRA, intravenous ATO, and four doses of age-adjusted idarubicin, 118 (95 percent) attained a hematologic CR [52]. The four deaths (3.2 percent) during induction were due to myocardial ischemia, intracerebral hemorrhage (two patients), and cerebral edema. Following two cycles of consolidation with ATRA and intravenous ATO, all patients achieved a molecular CR and received two years of maintenance therapy with ATRA, oral methotrexate, and mercaptopurine. DFS at two years was 98 percent.

There is less experience reported in the literature using other anthracyclines or anthracycline derivatives. However, one cooperative group has produced excellent outcomes with successive induction and consolidation cycles using idarubicin and ATRA followed by mitoxantrone plus ATRA without the use of cytarabine [35].

Timing of chemotherapy — Several trials have demonstrated better outcomes when chemotherapy is administered with ATRA during induction (simultaneous administration) rather than postponing chemotherapy until a CR is achieved with ATRA (sequential administration).

The largest of these was a prospective randomized trial that compared sequential and simultaneous administration of ATRA and chemotherapy in 413 patients with newly diagnosed APL [5]. In the simultaneous program, combination chemotherapy with daunorubicin and cytarabine was added on the third day of ATRA therapy while chemotherapy was postponed until after achievement of CR in the sequential arm. While the rates of CR were similar in the two treatment groups, patients who received simultaneous therapy had significantly lower rates of relapse at two years (6 versus 16 percent) and a trend toward lower rates of differentiation syndrome (11 versus 20 percent) when compared with those who received sequential therapy. After a median follow-up of 10 years, this lower relapse rate persisted, but lost its statistical significance (13 versus 22 percent, respectively) [37].

Length of ATRA treatment — There is some evidence to suggest that ATRA should be continued during induction until CR is achieved. A prospective trial of 239 patients with APL receiving standard chemotherapy were randomly assigned to therapy with ATRA at a dose of 45 mg/m2 per day either for five days before the start of chemotherapy (short course) or starting with the first day of chemotherapy and continuing daily until attainment of CR, up to a maximum of 60 days (extended ATRA) [44]. For those patients with a presenting WBC count <10,000/microL, extended ATRA resulted in improved CR rates (94 versus 76 percent), reduced relapse rates (13 versus 35 percent at 4 years), and superior OS (80 versus 57 percent at 4 years). There was no benefit of extended ATRA for those with a presenting WBC count >10,000/microL.

Administration and side effects — For chemotherapy-based induction, we prefer the combination used in the North American Intergroup study C9710: daily ATRA (45 mg/m2/day orally divided into two doses), starting on day 0, followed by seven days of cytarabine by continuous infusion (200 mg/m2 per day) and four days of daunorubicin (50 mg/m2 per day), both starting on day 3, although other combinations can be used. Children and adolescents should receive a reduced dose of ATRA (25 mg/m2 per day) in combination with chemotherapy [4]. ATRA is continued throughout the period of pancytopenia until a CR is obtained.

This regimen results in severe pancytopenia in all patients and therefore requires transfusion support and antibiotics as needed. Daily laboratory testing generally includes a complete blood count and chemistries with renal function, glucose, and electrolytes. Calcium, phosphorus, and uric acid levels should be monitored until normal. Liver function tests should be assessed at least weekly. Coagulation parameters, including fibrinogen, D-dimer, PT, aPTT, and platelet counts, should be monitored closely. (See 'Monitoring during therapy and supportive care' below.)

Common non-hematologic side effects include stomatitis (mostly mild), reversible alopecia, nausea and vomiting (25 percent severe), and diarrhea (mostly mild). Daunorubicin can be associated with cardiac arrhythmias and heart failure; a flu-like syndrome and rash due to cytarabine may be seen during induction. (See "Infusion reactions to systemic chemotherapy", section on 'Anthracyclines and related agents' and "Infusion reactions to systemic chemotherapy", section on 'Cytarabine'.)

Drug toxicities due to ATRA are generally minor. Headache is common; pseudotumor cerebri has been described but is rare. Nasal stuffiness, dry red skin, chapped lips, transient elevations in serum aminotransferases and bilirubin, and hypertriglyceridemia can occur, but rarely require an alteration in treatment. However, there are two serious and specific complications that can result from ATRA treatment of APL: differentiation syndrome and hyperleukocytosis. These are discussed in more detail below. (See 'Differentiation syndrome' below and 'Hyperleukocytosis' below.)

Evaluating response to induction — The goal of remission induction treatment in APL is the attainment of a morphological CR with recovery of normal hematopoiesis, followed by a molecular remission. Sometimes molecular remission is attained only after completion of consolidation therapy. Premature evaluation of response may be misleading and is discouraged. A "day 14" bone marrow exam during induction is rarely informative and is not necessary. Blasts and promyelocytes may remain elevated in the marrow for many weeks and the reverse transcription polymerase chain reaction (RT-PCR) signal of the fusion gene may remain detectable during a slow decline. Primary resistance, however, is very uncommon.

An initial impression of response to induction therapy can be obtained with a bone marrow aspiration and biopsy performed after approximately 30 to 35 days when patients recover their absolute neutrophil count (>1000/microL) and platelet count (>100,000/microL) and become independent from red cell transfusions. An earlier evaluation, such as that generally done for other variants of AML (eg, on day 14), is not recommended since it may result in over treatment (ie, there may be delayed clearance of malignant promyelocytes from the marrow even after they have lost their proliferative potential) [4]. Of importance, information attained in such an early evaluation generally cannot be used to determine failure of a response to induction therapy. Response definitions are presented separately. (See 'Evaluating response after consolidation' below and "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Introduction'.)

Patients who achieve a hematologic CR with induction therapy proceed directly to consolidation therapy. Patients who achieve a partial response after the initial course may achieve a CR after additional therapy. Primary induction failure is rare, but those who do not eventually achieve a hematological CR should be treated with regimens for resistant disease. (See "Treatment of relapsed or refractory acute promyelocytic leukemia in adults".)

CONSOLIDATION — Approximately 90 percent of patients with newly diagnosed APL will achieve a hematological complete remission (CR) with induction therapy. However, without additional therapy, virtually all of these patients will relapse. Consolidation therapy is directed at leukemia cells that survived induction therapy but are not detectable by conventional tests thereby converting patients with morphologic and cytogenetic CR into a more durable molecular remission and eventually a cure.

After induction with ATRA plus ATO — For patients with APL who achieve a CR with arsenic trioxide (ATO) plus all-trans retinoic acid (ATRA), we suggest ATO-based consolidation.

Administer ATO (0.15 mg/kg/day intravenously daily for five days per week during weeks 1 to 4 of each eight-week cycle) for four cycles, in combination with ATRA. Other doses and schedules have been described. Details of consolidation should be guided by the protocol on which induction therapy was based.

No randomized trials have directly addressed the role of consolidation after induction with ATRA plus ATO. The prospective trials that have investigated the use of ATO plus ATRA used different consolidation approaches. As examples:

In the randomized Intergroup APL0406 trial that compared ATO plus ATRA versus ATRA plus chemotherapy in adults with newly diagnosed low- or intermediate-risk APL, consolidation therapy consisted of intermittent ATRA and ATO for seven and four courses, respectively [24,25].

In the AML17 trial that confirmed the noninferiority of ATRA plus ATO compared with ATRA plus chemotherapy in all risk groups of APL, consolidation consisted of intermittent ATRA and ATO, administered over three months [26].

After chemotherapy-based induction — Standard consolidation after chemotherapy-based induction consists of two cycles of an anthracycline (daunorubicin or idarubicin) plus ATRA. More recently, data suggest an important role for ATO. For patients who achieve a CR with ATRA plus chemotherapy induction, we recommend two cycles of consolidation therapy with ATO followed by two cycles of daunorubicin plus ATRA rather than daunorubicin plus ATRA or daunorubicin therapy alone. Patients who underwent induction therapy with ATO plus ATRA may continue with ATO-based consolidation, but the evidence supporting this approach is still very limited [15]. (See 'ATO plus ATRA' above.)

Is there a role for ATRA in post-remission therapy? — The additional benefit attained from adding ATRA to consolidation therapy may vary according to the patient's risk of relapse as determined by white blood cell (WBC) and platelet counts at presentation. The duration of ATRA therapy during induction and the specific chemotherapy used also have an impact on outcome. While there may be a low-risk population that does not require ATRA as part of their consolidation therapy, this remains to be confirmed in prospective, randomized trials. For the time being, we recommend ATRA to be included in consolidation treatment. For all patients with APL who achieve a hematologic CR with induction, we recommend two cycles of consolidation therapy with ATO followed by two cycles of additional consolidation chemotherapy with three days of daunorubicin plus seven days of ATRA (table 1). This regimen was shown to be superior to a standard post-remission regimen that did not contain ATO in the randomized North American Intergroup study C9710. In Europe, where ATO is not so readily available for APL patients in first CR, other consolidation regimens described below have provided similar excellent outcomes.

A retrospective comparison of two prospective non-randomized Spanish trials that included 732 patients investigated the need for ATRA in the consolidation phase [53,54]:

In both of these trials, patients underwent induction therapy with ATRA and idarubicin followed by anthracycline-based consolidation and maintenance with ATRA. The main difference between the two protocols was the incorporation of ATRA into consolidation therapy in the second protocol as follows:

The 172 patients treated from 1996 to 1999 (LPA96 study) did not receive ATRA therapy as part of their consolidation.

The 560 patients treated after November 1999 (LPA99 study) received ATRA in addition to the other scheduled consolidation unless they had low-risk disease as defined by a WBC count <10,000/microL and platelets above 40,000/microL.

Both protocols achieved CR in 90 percent of patients. Patients who received ATRA as part of their consolidation therapy had significantly lower rates of clinical and molecular relapse:

Low-risk patients who received consolidation that did not contain ATRA had 93 to 97 percent disease-free survival (DFS) at three years.

Intermediate-risk patients (WBC count <10,000/microL but platelets <40,000/microL) had superior rates of DFS at three years (97 versus 82 percent) when ATRA was added to their consolidation.

Of the high-risk patients (WBC count >10,000/microL), only 77 percent were alive and free of relapse at three years even when ATRA was incorporated.

While these results suggest excellent outcomes for low-risk patients treated without ATRA in consolidation, it does not rule out the possibility that ATRA may provide additional benefit to these patients. In addition, this study illuminates the poor outcomes for high-risk patients even when ATRA is incorporated.

Is there a role for ATO in post-remission therapy? — ATO provides an important contribution for consolidation. A randomized trial in North America investigated the safety and utility of two courses of ATO (0.15 mg/kg per day for five days each week for five weeks) followed by consolidation with ATRA plus daunorubicin versus consolidation with ATRA and daunorubicin alone in 518 adults with newly diagnosed APL achieving CR or partial remission (PR) following a standard ATRA-containing induction program. At a median follow-up of 54 months, the following results were reported [55]:

The CR rate for adults was 90 percent, using the identical induction regimen in each treatment arm.

Three-year event-free survival (EFS; 80 versus 63 percent) and DFS (90 versus 70 percent) were both significantly higher for those receiving ATO consolidation. There was a trend toward improved overall survival (OS; 86 versus 81 percent) that did not reach statistical significance.

This study provides evidence from a large randomized controlled trial regarding the place of ATO in the current management of APL. While the results are consistent with an additive value of ATO, the outcome in the control group (ie, those treated with ATRA plus chemotherapy but no ATO for consolidation) was not as good as that reported in other studies with different entry criteria and chemotherapy regimens, making conclusions less convincing. Importantly, however, treatment outcomes in high-risk patients (eg, WBC count >10,000/microL) were markedly improved on the ATO-containing treatment arm of this randomized study. ATO may eliminate pre-existing subclones of APL that have acquired mutations in the ligand binding domain of PML-RARA, making them relatively resistant to ATRA and responsible for relapse.

For patients with APL who achieve a CR with induction, the most widely prescribed post-remission therapy in North America uses two cycles of consolidation chemotherapy with ATO followed by two cycles of daunorubicin plus ATRA rather than daunorubicin plus ATRA alone [55].

Can post-remission therapy be risk-adapted? — Patients with APL can be risk-stratified for relapse into three groups based on WBC and platelet counts at diagnosis [56]:

Low-risk disease (WBC count <10,000/microL and platelets >40,000/microL)

Intermediate-risk disease (WBC count <10,000/microL but platelets <40,000/microL)

High-risk disease (WBC count >10,000/microL and platelets <40,000/microL)

Using current regimens, there is little difference in outcomes between the low-risk and intermediate-risk groups. Induction therapy followed by consolidation with ATRA plus an anthracycline and standard maintenance results in three-year DFS rates of approximately 97, 97, and 77 percent for those with low-, intermediate-, or high-risk disease, respectively [53,54]. Prospective studies have begun to investigate whether therapy can be altered based on risk as determined by these criteria. The goal of such studies is to decrease the treatment toxicity for those with low-risk disease while preserving their excellent outcomes and to improve outcomes among those with high-risk disease.

As an example, a prospective trial examined the use of risk-adapted therapy in 372 adults with APL in first CR after induction with ATRA plus idarubicin [57]. Consolidation was adjusted according to risk. Patients with low- or intermediate-risk disease were assigned fewer doses of mitoxantrone during consolidation, while patients with high-risk disease had cytarabine added to consolidation. When compared with historical matched controls, patients with low- and intermediate-risk disease had shorter durations of neutropenia and thrombocytopenia. DFS and OS rates at three years were not significantly different. Alternatively, patients with high-risk disease demonstrated a significantly lower rate of relapse at three years (11 versus 26 percent).

Another single-arm prospective trial of risk-adapted therapy included 453 adults with APL in first CR after induction with ATRA plus idarubicin [46]. Patients with low- or intermediate-risk disease (WBC count <10,000) were assigned to consolidation with three anthracycline-based courses, while patients with high-risk disease (WBC count >10,000) had cytarabine-based consolidation. When compared with historical matched controls, patients with low- and intermediate-risk disease had significantly improved DFS rates at six years (86 versus 77 percent) and a lower cumulative incidence of relapse (11 versus 20 percent), but similar rates of OS (89 versus 85 percent). Patients with high-risk disease had superior OS at six years (83 versus 61 percent), DFS (85 versus 50 percent), and a lower cumulative incidence of relapse (9 versus 50 percent).

Longer follow-up and studies of these approaches that incorporate newer agents (eg, ATO) are needed before risk-adapted therapy can be widely implemented.

Evaluating response after consolidation — After the completion of consolidation, the response to treatment is again evaluated with a bone marrow aspirate and biopsy. This sample should be tested for the PML-RARA fusion transcript using reverse transcription polymerase chain reaction (RT-PCR). The goal of APL treatment is the achievement of a molecular CR (CRm), as defined by the absence of the PML-RARA fusion transcript using RT-PCR methods with a sensitivity threshold of at least 10-3 or 10-4 [58].

A CRm takes time to achieve. It is usually attained only after completion of consolidation therapy, although it may occur more promptly if ATO is used for consolidation. Therefore, RT-PCR need not be attempted immediately after completion of induction treatment, as this premature evaluation may give a misleading interpretation of response failure. Patients who achieve CRm should proceed directly to maintenance therapy. Patients who have a positive RT-PCR test at the conclusion of the planned consolidation sequence should have a second bone marrow aspirate and biopsy with RT-PCR testing repeated in four weeks. If this second test is negative, the patient may proceed to maintenance therapy. If the second RT-PCR is still positive, the patient should proceed to treatment for resistant disease. (See "Treatment of relapsed or refractory acute promyelocytic leukemia in adults".)

MAINTENANCE

Is maintenance necessary? — Initial randomized trials demonstrated that maintenance therapy decreases the incidence of relapse and improves disease-free survival (DFS) among patients who have undergone induction with all-trans retinoic acid (ATRA) plus chemotherapy followed by consolidation therapy. As described above, induction and consolidation therapy have since evolved to include arsenic trioxide (ATO) in addition to ATRA (with or without chemotherapy) based on studies that suggest improved event-free survival (EFS) and overall survival (OS) with this approach. As such, the role of maintenance therapy among patients who achieve a molecular complete remission (CRm) after initial therapy that incorporates ATO and ATRA is controversial and likely depends to a considerable extent on the precise induction and consolidation treatment. Although the issue remains unresolved, initial studies suggest that patients who receive ATO as part of their induction and/or consolidation do not need maintenance after a CRm is achieved. Patients who do not have access to ATO for induction or consolidation should receive maintenance therapy. (See 'Is there a role for ATO in post-remission therapy?' above.)

Following ATRA plus ATO — There are limited data regarding the role of maintenance therapy following the use of ATRA plus ATO as part of the induction and/or consolidation therapy for APL. Until further data are available, we suggest observation rather than maintenance therapy for those patients with low- or intermediate-risk APL who achieve a CRm with a regimen that includes both ATRA and ATO (with or without chemotherapy) [24,25,59]. Maintenance may reasonably be administered to those who are willing to accept the increased toxicity and cost in return for a potential yet unproven decrease in the risk of relapse; for all other patient populations, we suggest observation.

Support for this approach comes from the following trials that have demonstrated good clinical outcomes without maintenance in this population:

The Intergroup APL0406 randomized phase III trial that demonstrated the noninferiority of ATRA plus ATO compared with ATRA plus idarubicin (AIDA) in newly diagnosed low- or intermediate-risk APL did not include maintenance therapy for those treated with ATRA plus ATO [24,25]. In the experimental arm, ATRA plus ATO was administered daily during induction until complete remission (CR) followed by consolidation with intermittent ATRA and ATO for seven and four courses, respectively.

Similarly, the AML17 trial confirming the noninferiority of ATRA plus ATO compared with AIDA in all risk groups of APL did not include maintenance therapy for those treated with ATRA plus ATO [26].

In a noninferiority study (S0521), 105 adults with newly diagnosed low- or intermediate-risk APL underwent induction with ATRA plus chemotherapy followed by consolidation that included ATO [59]. The 68 patients who achieved CRm were randomly assigned to observation alone or maintenance therapy with ATRA, 6-MP, and methotrexate. After a median follow-up of 36 months, no patients who achieved CRm have relapsed.

Following ATRA plus chemotherapy — We suggest the use of maintenance therapy rather than observation alone after induction with ATRA plus anthracycline-based chemotherapy without ATO. This preference is largely based on the apparent low toxicity of maintenance therapy in combination with the potential, yet unproven, DFS benefit.

Initial randomized trials of ATRA plus chemotherapy demonstrated that, when compared with observation, patients assigned to ATRA maintenance demonstrated superior rates of DFS at five years (74 versus 55 percent, respectively) and a lower 10-year cumulative incidence of relapse (33 versus 43 percent) [37,38].

The benefit observed in these early trials has led to the frequent use of maintenance therapy in all patients with APL. However, maintenance therapy may not be necessary for all patients (eg, those in CRm following consolidation). Additional randomized trials are needed to answer the question regarding the need for maintenance therapy in APL and, if necessary, the best maintenance regimen.

The complexity of this issue was illustrated in these two randomized trials of maintenance therapy after the achievement of a CRm:

In a randomized trial involving 175 patients in CRm following induction and three cycles of consolidation chemotherapy, the addition of six courses of intensive maintenance chemotherapy, as compared with observation only, unexpectedly conferred significantly poorer six-year DFS (63 versus 80 percent) and OS (86 versus 99 percent) [60]. Of note, two patients on the intensive maintenance arm developed therapy-related myelodysplastic syndrome (MDS)/AML compared with none on the observation arm.

In another randomized trial including 586 patients with newly diagnosed APL in CRm after induction with ATRA and idarubicin followed by three cycles of intensive consolidation therapy, maintenance did not appear to improve DFS [61]. However, in this particular study, relatively high dose levels of cytarabine used in induction treatment may have obviated the need for maintenance therapy.

Most prospective studies have investigated various combinations of ATRA, 6-MP, and methotrexate for maintenance therapy. ATO has not been routinely incorporated into maintenance and remains investigational in this setting [62]. Prospective studies have evaluated both single agent ATRA and combination maintenance therapy [55,63]:

Single agent ATRA – ATRA 45 mg/m2 orally for seven days repeated every other week for one year.

Combination maintenance therapy – ATRA 45 mg/m2 orally daily on an intermittent schedule (eg, 15 days every three months or seven days every two weeks) plus 6-mercaptopurine (MP) 60 mg/m2 orally every evening plus methotrexate 20 mg/m2 orally per week as tolerated. All three medications are taken for one year, with doses adjusted according to the presence or absence of myelosuppression and/or liver function abnormalities. If there is unexpectedly severe or prolonged myelosuppression in patients taking 6-MP, the medication should be stopped and an analysis obtained for thiopurine methyltransferase activity. (See "Overview of pharmacogenomics", section on 'Thiopurines and polymorphisms in TPMT and NUDT15'.)

The preferred maintenance regimen likely depends to a considerable extent on the precise induction and consolidation treatment administered. For patients whose induction and consolidation therapy did not include ATO, we suggest single agent ATRA rather than combination therapy largely due to its decreased toxicity and complexity. Other clinicians prefer combination maintenance therapy due to greater experience with this regimen and the longer follow-up of patients treated with this regimen.

Monitoring response during maintenance — Once a CRm is achieved, patients are followed periodically with reverse transcription polymerase chain reaction (RT-PCR) for the PML-RARA fusion transcript in order to monitor for relapse. Monitoring for residual disease is most sensitive using bone marrow aspirate samples. Peripheral blood samples have not yet demonstrated equivalence to bone marrow samples, but they may allow monitoring for measurable residual disease (MRD) at more frequent intervals. This may be especially important when fluctuating levels have been noted.

We perform RT-PCR on the peripheral blood or marrow every three months for the first year of CR, since most relapses will occur during this time (table 1). If CRm is lost, the patient undergoes bone marrow evaluation for confirmation within two weeks and proceeds to therapy for relapsed disease. (See "Treatment of relapsed or refractory acute promyelocytic leukemia in adults".)

MONITORING DURING THERAPY AND SUPPORTIVE CARE — The management of cytopenias, infections, tumor lysis, menorrhagia, and other complications common to all patients with acute myeloid leukemia (AML) are presented separately. (See "Management of menorrhagia during chemotherapy" and "Acute myeloid leukemia: Overview of complications" and "Tumor lysis syndrome: Prevention and treatment", section on 'Clinical impact of tumor lysis syndrome' and "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Adjunctive care'.)

The following sections review complications that are specific to patients with APL.

Control of coagulopathy — APL is characterized by frequent and severe hemorrhage that can result from disseminated intravascular coagulation (DIC) and/or primary fibrinolysis. Treatment of the coagulopathy (DIC) associated with APL may be difficult and should be managed expectantly. Coagulation parameters, including fibrinogen, D-dimer, PT, aPTT, and platelet counts, should be monitored closely. Transfusions of platelets and cryoprecipitate or fresh frozen plasma are used to maintain the platelet count above 20,000 to 30,000/microL and the plasma fibrinogen concentration above 150 mg/dL [11,64]. Higher platelet counts of 30,000 to 50,000/microL may be beneficial to control overt bleeding. In addition, anecdotal evidence supports attempting to maintain the platelet count above 50,000/microL during periods of DIC, as reflected by falling fibrinogen or high D-dimer levels [65]. Our approach to the control of coagulopathy is mainly based on our own clinical experience and observations. There have been case reports using recombinant factor VIIa for the treatment of severe life-threatening hemorrhage [66,67].

Invasive procedures such as central venous catheterization, lumbar puncture, and bronchoscopy should be avoided before and during induction remission.

The role of heparin is controversial, and we suggest that it not be used for prophylaxis in this setting. Inhibitors of fibrinolysis should be considered only for those patients with life-threatening bleeding. This is discussed in more detail separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults", section on 'Coagulopathy and APL' and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Prevention/treatment of thrombosis'.)

Differentiation syndrome — The differentiation syndrome (previously "retinoid acid syndrome" or cytokine storm), occurs in one-quarter to one-half of patients with APL within 2 to 21 days after initiation of treatment and is seen more frequently in patients with a high white blood cell (WBC) count at diagnosis [68-70]. It can occur in the absence of all-trans retinoic acid (ATRA) and is characterized by fever, peripheral edema, pulmonary infiltrates, hypoxemia, respiratory distress, hypotension, renal and hepatic dysfunction, and serositis resulting in pleural and pericardial effusions. The symptoms of fever, hypotension, dyspnea, and pulmonary infiltrates can mimic sepsis. Sometimes, but not always, the cytokine syndrome is accompanied by hyperleukocytosis.

Early recognition and aggressive management with dexamethasone therapy (10 mg intravenously every 12 hours for three or more days) has been effective in most patients. This is largely based on our clinical experience and observations of a lower rate of mortality associated with differentiation syndrome when prompt dexamethasone treatment is added in prospective trials or if dexamethasone is given prophylactically in patients with high WBC counts at diagnosis [69]. Other therapeutic interventions such as temporary cessation of ATRA or arsenic trioxide (ATO), leukapheresis, or prompt institution of cytotoxic chemotherapy have not been effective after respiratory distress is established. ATRA or ATO can be restarted in most cases once the syndrome has resolved. This is discussed in more detail separately. (See "Differentiation syndrome associated with treatment of acute leukemia".)

Hyperleukocytosis — Hyperleukocytosis, likely due to the rapid maturation of a large mass of leukemic cells, occurs in up to 50 percent of patients treated with ATRA alone at induction. The marked increase in WBC count may result in leukostasis, but complications are uncertain and management is controversial. The frequency of hyperleukocytosis has decreased since most current remission induction regimens now combine ATRA with cytotoxic chemotherapy. Leukapheresis may exacerbate the underlying coagulopathy in APL and is therefore not used [68]. (See "Hyperleukocytosis and leukostasis in hematologic malignancies".)

Most investigators have advocated the prompt institution of full doses of induction chemotherapy with cytarabine and daunorubicin in all patients showing a rapid rise in the leukocyte count after starting ATRA therapy; this may include as many as 70 percent of cases [32]. When compared with those with a normal or decreased WBC count, patients with an elevated WBC count have a similar rate of complete remission, but have a higher rate of relapse and are more likely to develop the differentiation syndrome [69,71]. Some studies also report a higher induction death rate in patients with WBC count >10,000/microL.

Although formal proof is lacking, some investigators add corticosteroids for prevention of the differentiation syndrome when WBC counts are or rise above 10,000/microL. (See 'Differentiation syndrome' above.)

High intracranial pressure — Idiopathic intracranial hypertension (IIH), commonly called pseudotumor cerebri, can complicate the treatment of APL with ATRA. IIH is more common in children and adolescents treated with ATRA, and the incidence in this population decreased with the use of lower dose ATRA (eg, 25 mg/m2 per day) [4].

The diagnosis of IIH is suspected in patients with headache, papilledema, and/or vision loss. Evaluation includes a physical examination including evaluation of the optic nerve, lumbar puncture, and cerebral imaging studies. The diagnosis is confirmed in patients with increased intracranial pressure, normal cerebrospinal fluid, and negative cerebral imaging studies (eg, computed tomography or magnetic resonance imaging scan). Papilledema is common, but not necessary for the diagnosis. Some patients may require serial lumbar puncture or intracranial pressure monitoring to document sustained elevated pressures.

On occasion, the symptoms resolve after the initial diagnostic lumbar puncture. If this occurs, no further medical treatment is necessary. If symptoms persist, therapeutic options include the temporary discontinuation or dose reduction of ATRA, analgesics, and/or the administration of steroids and acetazolamide. (See "Idiopathic intracranial hypertension (pseudotumor cerebri): Clinical features and diagnosis" and "Idiopathic intracranial hypertension (pseudotumor cerebri): Prognosis and treatment", section on 'Carbonic anhydrase inhibitors'.)

SPECIAL SCENARIOS — The general treatment principles for APL apply to most disease presentations and patient populations. However, certain populations, particularly pregnant women, patients with therapy-related APL, and those with genetic variations of APL, require special consideration.

Pregnant women — Patients diagnosed with APL during pregnancy pose a distinct challenge requiring a team approach with a hematologist, obstetrician, and neonatologist. The treatment approach depends largely on the trimester of pregnancy during which APL is diagnosed [72].

First trimester — Both all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are considered to be highly teratogenic and are contraindicated during the first trimester of pregnancy. The critical factor in determining the treatment of women with APL in the first trimester of pregnancy is whether the pregnancy will be electively terminated once the patient is hemodynamically stable:

If the patient plans to terminate the pregnancy, then conventional therapy with ATRA plus chemotherapy can be started.

If elective termination of the pregnancy is unacceptable to the patient, the only available treatment option is the administration of chemotherapy alone.

As described in more detail above, when compared with patients who receive ATRA plus chemotherapy, patients treated with chemotherapy alone have inferior response rates and progression-free survival and higher relapse rates. Perhaps most importantly, the risk of hemorrhage due to coagulopathy is much higher in patients treated with chemotherapy alone. If treatment with chemotherapy alone is chosen, daunorubicin may be the preferred anthracycline for pregnant women. There is greater experience with daunorubicin administration during pregnancy and concerns over the lipophilic nature of idarubicin, which may increase placental transfer and fetal toxicity [4,72]. (See 'ATRA plus chemotherapy' above.)

If a remission is achieved with chemotherapy alone and the pregnancy continues normally, ATRA may be added during the second or third trimester. After delivery, breastfeeding is contraindicated during treatment with chemotherapy or ATO.

Second or third trimester — Two main options are available for women who are diagnosed with APL in the second or third trimester of pregnancy [4]:

Remission induction with ATRA alone with chemotherapy administration postponed until after delivery.

Simultaneous administration of ATRA plus chemotherapy as given for patients who are not pregnant at the time of diagnosis.

The immediate institution of simultaneous administration of ATRA plus chemotherapy offers the best chance of cure but is accompanied by the risk of an increased rate of spontaneous abortion, prematurity, low birth weight, neonatal neutropenia, and sepsis [4]. (See "Gestational breast cancer: Epidemiology and diagnosis".)

When compared with patients who undergo induction with ATRA plus chemotherapy, patients treated with ATRA alone have similar rates of remission, but higher rates of hyperleukocytosis during induction and higher rates of relapse. This treatment approach requires frequent monitoring with reverse transcription polymerase chain reaction (RT-PCR) after induction to monitor for relapse while awaiting delivery. Vaginal delivery is generally preferred since it is associated with a reduced risk of bleeding. After delivery, breastfeeding is contraindicated during treatment with chemotherapy or ATO. (See 'ATRA plus chemotherapy' above and 'Hyperleukocytosis' above.)

Therapy-related APL — An unknown percentage of patients treated with chemotherapy (especially mitoxantrone, anthracyclines, and other topoisomerase II inhibitors) and/or radiation therapy for malignant or non-malignant conditions will develop therapy-related APL (t-APL) [4,73]. Patients with t-APL appear to have a similar prognosis as de novo APL and benefit from standard APL therapy. As such, most patients with t-APL can be treated with standard APL therapy [74].

A percentage of patients with t-APL will have a history of anthracycline exposure or cardiac impairment that limits their ability to receive further treatment with anthracyclines. In such patients, alternative regimens, such as ATO plus ATRA may be used. (See 'ATO plus ATRA' above and "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)

Genetic variations of APL — The vast majority of patients with APL demonstrate the t(15;17)(q22;q12) translocation resulting in the PML-RARA fusion gene. Alternative fusion genes have been described that result in leukemias that would now be classified as "AML with a variant RARA translocation." The study of the treatment of patients with genetic variations of APL is complicated by the rarity of these conditions. Some appear to be sensitive to ATRA therapy while others are not.

In general, patients with variations identified as ATRA-sensitive are treated with standard ATRA-based therapy, as described above. Patients with variants known to be resistant to ATRA are treated with standard AML induction therapy. (See "Acute myeloid leukemia: Induction therapy in medically fit adults".)

The following variants have been identified as ATRA-sensitive:

NuMA-RARA and t(11;17)

NPM1-RARA and t(5;17)

FIP1L1-RARA

The following variants are ATRA-resistant or unknown:

STAT5B-RARA and interstitial chromosome 17 deletion – Resistant

PLZF/RARA and t(11;17) – Relatively resistant

PRKAR1A/RARA – Unknown

Patients with APL and additional cytogenetic abnormalities (eg, trisomy 8) or particular molecular abnormalities (eg, gene mutations in FLT3) are considered to have the same prognosis as standard APL. These molecular variants of APL are described in more detail separately. (See "Molecular biology of acute promyelocytic leukemia", section on 'Variant translocations'.)

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute promyelocytic leukemia".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

Basics topics (see "Patient education: Acute myeloid leukemia (AML) (The Basics)" and "Patient education: Leukemia in adults (The Basics)")

Beyond the Basics topics (see "Patient education: Acute myeloid leukemia (AML) treatment in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Acute promyelocytic leukemia (APL) represents a medical emergency with a high rate of early mortality. It is necessary to start treatment without delay as soon as the diagnosis is suspected based on cytologic criteria, and before definitive genetic, cytogenetic, or immunostaining confirmation of the diagnosis has been made. (See 'Emergency pretreatment evaluation' above.)

Treatment spans one to two years and comprises (table 1):

Remission induction

Consolidation

Maintenance

Induction therapy – For patients with newly diagnosed APL, we recommend induction therapy that incorporates all-trans retinoic acid (ATRA) (Grade 1A). (See 'Choice of regimen' above.)

Induction therapy is stratified according to risk category, based on white blood cell (WBC) count:

Low- or intermediate-risk APL (WBC ≤10,000/microL) – For most patients with newly diagnosed low- or intermediate-risk APL, we recommend ATRA plus arsenic trioxide (ATO) rather than ATRA plus anthracycline-based chemotherapy (Grade 1A). (See 'ATO plus ATRA' above.)

Where ATO is not available, ATRA plus an anthracycline is acceptable. (See 'ATRA plus chemotherapy' above.)

High-risk APL (WBC count >10,000/microL) – We consider either ATRA plus an anthracycline or ATRA plus ATO (with hydroxyurea or an anthracycline for a rising WBC count) acceptable.

Consolidation varies with the induction regimen (see 'Consolidation' above):

ATO plus ATRA – For complete remission (CR) after ATO plus ATRA, we suggest ATO-based consolidation (Grade 2C).

ATRA plus chemotherapy – For CR after ATRA plus chemotherapy, we recommend two cycles of consolidation therapy with ATO followed by two cycles of daunorubicin plus ATRA, rather than daunorubicin plus ATRA or daunorubicin therapy alone (Grade 1A). Other post-remission regimens using anthracyclines may be equally effective.

Maintenance varies according to prior therapy (see 'Maintenance' above):

After ATO – For patients who achieve a molecular CR (CRm) after receiving ATO as part of induction or consolidation therapy, we suggest observation rather than maintenance therapy (Grade 2C).

No prior ATO – For other patients, we suggest maintenance therapy rather than observation (Grade 2C).

For maintenance, we suggest the use of intermittent single agent ATRA rather than the combination of intermittent ATRA, 6-mercaptopurine (MP), and methotrexate (Grade 2B). (See 'Maintenance' above.)

Complications of APL treatment:

Disseminated intravascular coagulation (DIC) – The preferred approach is immediate initiation of ATRA followed quickly by chemotherapy. For patients with DIC, we suggest transfusions of platelets and cryoprecipitate to maintain the platelet count above ≥30,000 to 50,000/microL and plasma fibrinogen >150 mg/dL (Grade 2C). (See 'Control of coagulopathy' above.)

We suggest not using heparin in this setting because there is no proven benefit (Grade 2C). However, the best treatment approach is the immediate initiation of treatment with ATRA followed quickly by chemotherapy.

Differentiation syndrome – We recommend immediate treatment with dexamethasone (10 mg intravenously every 12 hours for ≥3 days) along with temporary cessation of ATRA, if severe symptoms were present (Grade 1B). ATRA can be restarted once the syndrome has resolved. (See 'Differentiation syndrome' above.)

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Topic 4498 Version 56.0

References

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