According to the recent International Consensus Classification on Myeloid Neoplasms, similar to all recurrent genetic abnormalities in AML [except for AML with t(9;22)(q34.1;q11.2)/BCR::ABL1], APL diagnostic criteria are currently recognized with the presence of at least 10 % of blasts in the bone marrow or blood plus specific genetic abnormalities.1,11 Two distinct subtypes [APL with classic t(15;17)(q24.1;q21.2)/PML::RARA and APL with other recurring RARA translocations] are included in AML with recurrent genetic abnormalities (Table 1).

The genetic alteration is directly related to impairment of myeloid maturation at the promyelocyte stage, often resulting in the accumulation of blasts with the appearance of abnormal promyelocytes in the bone marrow and/or peripheral blood, along with consequent cytopenias as well as a typical coagulopathy that manifests as a high risk of bleeding and requires rapid diagnosis and treatment to prevent early fatality.

The initial workup for the diagnosis of APL requires clinical information, medical history and physical examination combined with morphology of the cells, immunophenotyping, karyotype analysis and molecular genetic testing, as reviewed below.1,12,13

Based on the trials of the PETHEMA (Spanish Cooperative Group - Programa Español de Tratamientos en Hematología) and GIMEMA (Italian cooperative group - Gruppo Italiano Malattie Ematologiche dell'Adulto) groups, after remission induction, consolidation treatment has classically been adapted according to risk categories (low-, intermediate-, or high-risk).24 Low- and intermediate-risk categories (presenting platelet counts greater and lower than 40 × 103/μL, respectively) are characterized by WBC counts ≤10 × 103/μL at presentation. Patients presenting with WBC counts >10 × 103/μL are considered to be high-risk. More recently, the prognostic value of the WBC count at diagnosis has been recognized as the most important as it is associated not only with overall survival (OS) and relapse-free survival but also with rates of death and life-threatening complications before or during induction. Therefore, APL is currently stratified into two categories: high-risk (WBC count ≥10 × 103/μL) and low-risk (WBC count <10 × 103/μL), regardless of the platelet count.

Although differentiation therapy with ATRA and ATO is the rule for typical APL with t(15;17)/PML::RARA, in cases of rare RARA translocations, the sensitivity to those agents varies according to RARA rearrangements. For example, cases with t(11;17)/ZBTB16::RARA or der(17)/STAT5b::RARA are poorly responsive to ATRA and ATO.

DS is a common and life-threatening condition that can occur as a complication of treatment with ATRA or ATO. Both therapies induce the differentiation of leukemic blasts into mature cells and DS is an undesirable effect of these therapies. With an incidence of 2.5–37 % in patients treated with ATRA or ATO, it was first described in 1992.46,52–57

DS is characterized by a systemic inflammatory response and capillary leak syndrome. Differentiation of APL blasts induces the production of chemokines in the lung and ATRA stimulates leukemic cells to migrate towards alveolar epithelial tissues.58 Other inflammatory cells are attracted to this process, exacerbating it. Furthermore, by inducing the expression of beta integrins ATRA facilitates blast adhesion to the endothelium and subendothelium. Necropsy findings show diffuse neutrophilic infiltration and alveolar hemorrhage in the lungs, in addition to leukemia infiltration in several organs.59–60

Clinically, DS presents as dyspnea, pulmonary infiltrate on X-ray, fever, pleural or pericardial effusion, acute renal failure, hypotension, weight gain and edema.53 Infectious and cardiac etiologies must be ruled out, but if suspected, treatment must be initiated promptly. More rare manifestations include myocarditis, pericarditis, chest pain, pancreatitis, myalgia, and ocular manifestations with decreased visual acuity, retinal hemorrhage, and macular edema.

DS generally begins 7–12 days after starting ATRA treatment but can occur in around 40 days. About 50 % of cases occur in the first week of treatment and 50 % from the third week. Laboratory changes include leukocytosis, increased creatinine, and changes in troponin and pro-brain natriuretic peptide. Pulmonary infiltrate can be seen on chest X-ray in 80 % of severe cases. Pulmonary infiltrate, pleural effusion and ground-glass images or small pulmonary nodules can be seen by chest computed tomography. Some studies have shown that a WBC count >5–10 × 103/µL, elevated creatinine, and presence of coagulopathy are prognostic factors for the development of DS. In a recent publication, DS was involved in 12 early deaths (5.6 %) and thus was the second leading cause. Of these deaths, four resulted from DS alone, and eight were due to a combination of causes. The median time to DS-related early deaths was 10 days (range: 2–18 days). DS-associated deaths mainly occurred during the first weeks (10/12–83.3 % of patients).61 An incidence of DS was 5 % (18/180 patients) was reported in the Brazilian IC-APL study.30

Steroids are used to prevent DS, but there is no prospective evaluation of this benefit. Some protocols indicate prophylaxis if WBC count >5 × 103/µL or elevated creatinine (>1.4 mg/dL). A study from the Australian group used 1 mg/kg prednisone daily as prophylaxis for all patients treated with ATO and there was only one case of DS.43

Cytoreductive agents (hydroxyurea, chemotherapy or GO) can be used to control leukocytosis. The use of leukapheresis is not indicated due to the risk of hemorrhage.

Treatment must be started immediately if DS is suspected. In general, dexamethasone 10 mg every 12 h is used, in conjunction with treatment for infectious conditions and heart failure, when suspected. If there is no improvement after 24 h, the dose of dexamethasone can be increased to 10 mg every 6 h. ATRA and ATO should only be temporarily interrupted if the DS is severe, with severe respiratory failure, renal failure or when the patient requires admission to an intensive unit. After the condition has resolved, treatment with ATRA or ATO can be continued normally, within the protocol used to treat APL. Dexamethasone should be maintained until complete disappearance of signs and symptoms. Other support measures must be associated to treat signs or symptoms of fluid overload, dialysis, including mechanical ventilation, depending on the severity of each case.62

Pseudotumor cerebri (PTC) is a rare complication of ATRA in APL treatment, occurring more frequently in children.63–71 In a large series of 1034 APL patients enrolled in the PETHEMA Group trials, (APL96, APL99 and APL2005), the incidence of PTC was 3 % (30 cases during induction and 2 cases during consolidation). There was a higher rate of PTC in patients under 18 years old (13 %) and from 18 to 25 years, while in over 50-year-old patients it was 0.3 %. The rate of recurrence was 28 % after reinitiating ATRA.72 In 240 APL patients from the Intergroup Protocol 0129 (I0129), probable PTC occurred in 1.7 % of patients (ages: 4–24 years old) who received ATRA 45 mg/m2/day during induction or maintenance. The symptoms began 2–19 days after starting ATRA.73 There are also reports of PTC in patients treated with the ATRA plus ATO combined regimen74 and rare reports of PTC secondary to ATO.75

The following signs and symptoms suggest a diagnosis of PTC: headache, blurred vision, diplopia, and nausea and vomiting with bilateral papilledema characterized by increased intracranial pressure and the presence of papilledema, normal or diminished ventricles and normal cerebrospinal fluid (CSF). Diagnosis is made by the presence of papilledema, normal neurologic exam except for cranial nerve abnormalities, normal neuroimaging without evidence of hydrocephalus, mass, or structural lesion, and no abnormal meningeal enhancement on magnetic resonance images or by contrast-enhanced computed tomography, normal CSF composition, and elevated lumbar puncture opening pressure (≥250 mmHg or ≥280 mmHg for non-obese children). The diagnosis may also be made in the absence of papilledema if all of the above criteria are satisfied and the patient has unilateral or bilateral abducens nerve palsy. If there is neither papilledema nor a sixth cranial nerve palsy, the diagnosis can be suggested, but not confirmed with additional neuroimaging characteristics. Headache, although a common symptom, is not one of the criteria.73,76 In all cases there was an improvement of symptoms in 2–28 days after the suspension of ATRA, which was often reinitiated at a lower dose. Other therapies that have been utilized include corticosteroids, acetazolamide, mannitol, glycerin, topiramate, and therapeutic lumbar puncture.71,73,77 There is a report of the use of mannitol and acetazolamide together with the suspension of ATRA to decrease the CSF pressure thereby improving the headaches, diplopia, nausea and vomiting in two days and improvement of papilledema in seven days.78 Topiramate, an anticonvulsant and carbonic anhydrase inhibitor, may also be used in cases not responsive to acetazolamide to improve symptoms.74

The temporary suspension of ATRA/ATO is recommended when there is diagnostic suspicion of PTC in patients with APL. Symptomatic drugs may be used to abbreviate symptoms. ATRA/ATO can be reintroduced after improvement of the symptoms.

In the era of ATRA based treatment regimens, induction failures (failure to achieve morphological response) usually account for less than 1 % of cases.40,79–81 Morphological remission (less than 5 % of marrow blasts) should be confirmed at blood count recovery (platelet >100×103/µL and neutrophils > 1.5 × 103/µL)7 or 28 days after starting induction if no sign of count recovery.

Measurable residual disease (MRD) negativity after consolidation therapy is an essential goal of treatment. Due to kinetics and terminal differentiation, post-induction PML::RARA positivity is common and should not change clinical decisions. In a phase 3 study that compared ATRA plus ATO and ATRA plus Idarubicin, 27 % of patients (20 out of 74) in the ATRA plus IDA group remained MRD positive while 44 % (36 out of 82 maintained RT-qPCR positivity 60 days after induction.34 The adequate timepoint for assessing MRD using RT-PCR or RT-qPCR is at marrow recovery at the end of consolidation. Persistence of MRD positivity after consolidation or conversion from MRD negative to positive as identified by RT-qPCR is associated with morphologic relapse and is an important tool to predict relapse free survival while allowing for preemptive salvage treatment.82,83

RT-qPCR is the preferable testing method because of higher sensitivity; it is also less prone to contamination issues and easier to standardize.84 Once molecular response is confirmed, the European LeukemiaNet guidelines for the management of APL state that monitoring for relapse is cost effective principally for high-risk patients (WBC count >10 × 103/µL).82 Accordingly, the European LeukemiaNet MRD consensus document suggests monitoring every three months for 2–3 years after the end of consolidation only for high-risk APL. A minimum detection threshold of one mutated cell in 1000 cells (0.1 %) is recommended.85

Bone marrow remains the preferred sample for MRD testing, because of higher sensitivity and earlier positivity when compared to peripheral blood.82 However, peripheral blood is a reasonable alternative if used in shorter intervals (every 4–6 weeks). In the case of MRD conversion from negative to positive or when a 1log10 elevation occurs as determined by RT-qPCR in patients that were previously stable, the result must be confirmed using a bone marrow sample at least two weeks after.7,85,86

APL occurs in 0.06 cases per 100,000 per year in the pediatric population. This represents 5–10 % of cases of AML in this population. It shows gender equivalence. Similar to adults, it occurs more frequently in certain populations such as those in Latin America, China, Spain, and Italy. Under 5-year-old children have worse outcomes compared to those over 5 years old.87,88

Treatment regimens are based on those performed in adults with certain adaptations in the doses of ATRA due to the increased risk of neurological complications, such as pseudotumors, which occur in 15 % of cases compared to 3 % in adults. Therefore, in all protocols using ATRA in combination with chemotherapy, the dose is reduced to 25 mg/m2/day. Several multicenter studies, notably the Italian group (GIMEMA) and the Spanish group (PETHEMA), using ATRA in combination with idarubicin for induction followed by 3 cycles of consolidation associated with anthracyclines and maintenance for two years with mercaptopurine, methotrexate, and ATRA, showed excellent results. In the GIMEMA study, 96 % of patients achieved CR with PML::RARA negativity at the end of consolidation. OS was 89 %, and DFS was 75 %. Of note, WBC count >10 × 103/µL significantly reduced DFS.7,89

In this context, the PETHEMA group suggested that their regimen used until 1996, with an induction scheme of ATRA 25 mg/m2 divided in two doses until CR or 90 days, and idarubicin 12 mg/m2/day on Days 2, 4, 6, and 8 followed by consolidation (cycle 1: idarubicin 5 mg/m2/day on Days 1 to 4; cycle 2: mitoxantrone 10 mg/m2/day on Days 1 to 5; cycle 3: idarubicin 12 mg/m2/day on Day 1) was reinforced for higher-risk cases after 1999 during consolidation by the addition of ATRA 25 mg/m2 for 15 days and an increase in the idarubicin dose to 7 mg/m2/day on Days 1 to 4 in the first cycle and two consecutive days in the third cycle. After completing consolidation with PML::RARA negativity by RT-PCR, maintenance with mercaptopurine 50 mg/m2/day, methotrexate 15 mg/m2/week, and ATRA 25 mg/m2/day for 15 days every three months was carried out for two years, adapting doses to hematologic levels and changes in transaminases. The results showed an OS of 91 % ± 8 % and DFS of 89 % ± 12 %.90

An important concern in children is to reduce cardiotoxicity, which is linked to secondary neoplasms, because of their long life expectancy. A study from the International Consortium for Childhood APL evaluated a reduction in the dose of anthracyclines from 650 mg/m2 to 355 mg/m2 for standard risk and to 405 mg/m2 for high risk without a significant change in outcomes.87

As in adults, several studies have demonstrated the safety and efficacy of the combination of ATO and ATRA in children. The main difference from adults is the reduction of the ATRA dose to 25 mg/m2 following the same scheme adopted by the APL0406 study of adults. In high-risk patients, the use of low doses of anthracyclines or GO plays a crucial role. Additionally, a Chinese study has shown excellent results with an oral formulation of ATO.34,91,92

The management of APL is particularly challenging in elderly patients. General supportive measures should be given paying special attention due to the high risk of early mortality. According to Swedish registry data, early mortality rates reach up to 50 % among over 60-year-old patients compared to 15 % in younger patients.93

Within this context, the ATRA plus ATO combination is assumed to be even more beneficial for older patients due to its lower hematological toxicity and infection rates. This comes from limited, retrospective data, since over 70-year-old patients are infrequently included in clinical studies.94 According to the AML17, the arsenic dosage can be safely adjusted to twice weekly to prevent toxicity caused by this drug.34

Due to their underrepresentation in clinical studies, there is greater controversy regarding the optimal strategy for high-risk APL. In such cases, geriatric assessment could prove crucial and should replace chronological age as a decision-making factor. The assessment of geriatric domains, such as physical capacity, functionality, and comorbidities, will identify the more vulnerable patients who may benefit from exclusive treatment with ATRA plus ATO or from a combination with reduced doses of anthracyclines. The use of GO may be particularly appropriate for patients with a high risk for cardiac toxicity. Conversely, elderly patients without abnormalities in geriatric domains and compensated comorbidities should be considered for standard high-risk APL treatment, optimizing outcomes related to the control of the leukemia.95

The diagnosis of acute leukemia during pregnancy is a rare and dramatic condition, with 1:100,000 pregnancies described.96 APL during pregnancy is even more challenging due to its clinical characteristics that include the potential coagulopathy that may pose serious risks for both mother and fetus. The incidence is not well established and only based on rare case reports.97,98 A recent systematic review included 53 reports of individual cases, among which 92 patients were eligible for induction therapy, either with ATRA (32 %), ATRA and anthracycline (43 %), or anthracycline only;98 the CR rate was 89 %.98,99

Besides the increased risk of maternal and fetal death, intrauterine growth restriction, and malformations are additional risks when APL and pregnancy coexist so that the discussion needs to be discussed by the patient, family, and the medical multidisciplinary team.6,7,97,98 Medical termination of pregnancy is usually contraindicated upon diagnosis due to pancytopenia and coagulopathy, which are not controlled at that moment.6,7

If APL is diagnosed in the first trimester, therapeutic options are quite limited, and the risk of miscarriage is higher compared to the second or third trimesters (88 % versus 30 %).98 Although specific information regarding the teratogenicity of ATRA is not available, this effect is well demonstrated with other retinoids6 and, therefore, it should be avoided in the first trimester. Although anthracyclines may also increase the risk of miscarriage, fetal malformations, and low birth weight, chemotherapy is needed with the recommended anthracycline being daunorubicin, due to its well-known efficacy in APL, and the limited evidence against the use of idarubicin that has a greater ability to cross the placental barrier.6,100 Considering the benefits of the ATRA association with chemotherapy, the appropriate timing for introducing ATRA should be discussed individually.6

In the second and third trimesters, ATRA should be initiated immediately, as has been recommended by the European LeukemiaNet since 2009.6 It can be used with relative safety in the second and third trimesters of pregnancy with no cases of fetal malformations, although delayed fetal growth and fetal arrhythmia have been reported.101

ATO is genotoxic, teratogenic, and carcinogenic, as demonstrated by studies in animal models and environmental risk studies.99,102,103

Since it crosses the placental barrier, it is recommended to avoid its use throughout pregnancy.6 However, a report has described the use of ATRA and ATO during pregnancy with a favorable outcome for both mother and fetus, suggesting that this is a question of debate considering that this combination is currently the best therapeutic approach for APL.104

Another challenge is the choice of delivery type, which must be based on each patient's conditions. Vaginal delivery should be pursued whenever possible, as the risk of bleeding is higher in cesarean section.104

In summary, APL during pregnancy carries a high probability of miscarriage, prematurity, low birth weight, and respiratory distress syndrome at birth.98 Fetal viability is strongly influenced by gestational age, with a mortality rate of 87 % in the first trimester, 33 % in the second, and 7 % in the third.97,98 Pregnant women with adequate prenatal care can be diagnosed early and may have a better prognosis.

In conclusion, despite the demanding management, a multidisciplinary approach and careful monitoring of coagulopathy may offer a chance for CR and cure, regardless of gestational age at diagnosis.