Acute Promyelocytic Leukemia

APL was first described as an entity in the late 1950s in Norway and France as a hyperacute fatal illness associated with a hemorrhagic syndrome.[2] In 1959, Jean Bernard et al described the association of APL with a severe hemorrhagic diathesis that led to disseminated intravascular coagulation (DIC) and hyperfibrinolysis. By 1973, there were reports of complete remissions with treatment of the disease by daunorubicin.

In 1974, Leo Sachs pioneered research on leukemic cell differentiation in vivo. Dr. Zhen Yi Wang, a Chinese hematologist, shared data on the efficacy of all-trans retinoic acid (ATRA) in his APL patients during a visit to France in 1985. In 1990, several publications linked a translocation between chromosomes 15 and 17 to the pathology of APL. In the early to mid 1990s, arsenic trioxide (ATO) was added to the treatment regimen. A potentially fatal complication of ATRA treatment, called retinoic acid syndrome, was also described. Over the past 50 years, APL has transformed from a highly fatal disease to a highly curable one.[3]

Acute promyelocytic leukemia (APL) is defined by its cytogenetic properties. Over 95% of cases are characterized by a balanced translocation between chromosome 17q21 and chromosome 15q22. This leads to an abnormal fusion protein called PML-RARA. This translocation can be detected by karyotyping or fluorescence in situ hybridization (FISH) studies, and the transcript can be detected by polymerase chain reaction (PCR) techniques. PML-RARA represses genes responsible for hematopoiesis and activates super-enhancer genes responsible for specific characteristics of APL.[4]

The retinoic acid alpha receptor gene (RARA) is encoded by the long arm of chromosome 17. It is mainly expressed in hematopoietic cells and has an important role in regulating gene expression. In the absence of retinoid acid, RARA is bound by nuclear corepressor factor, and this causes transcriptional repression. In the presence of retinoic acid, RARA is activated and terminal differentiation of promyelocytes occurs.

The promyelocytic gene (PML) is encoded by the long arm of chromosome 15 and is expressed ubiquitously. PML is thought to be involved in apoptosis and tumor suppression.

There are three possible isoforms caused by PML-RARA translocations. The breakpoint in chromosome 17 is consistently found in intron 2, but varies in chromosome 15. The three breakpoints on the PML gene can occur at intron 3 (L form), intron 6 (S form), and exon 6 (V form). The S form is reportedly associated with a shorter remission duration and overall survival compared with the L form.[5]

The fusion gene product causes the retinoic acid receptor to bind more tightly to the nuclear co-repressor factor. Therefore, the gene cannot be activated with physiologic doses of retinoic acid. In about 5% of cases, rearrangements of chromosome 17q21 with other gene partners occur. These include the following:

• PZLF (promyelocytic zinc finger) t(11;17)(q23;q21)
• NPM (nucleophosmin) t(5;17)(q35;q12-21)
• NuMa (nuclear mitotic apparatus) t(11;17)(q13;q21)
• STAT5b (17;17)(q11;q21)

Yin et al identified a novel fusion between RARA and the interferon regulatory factor 2 binding protein 2 (IRF2BP2) genes.[6] Cao et al reported on a new karyotype: 46,XY; t(7;16)(q31'q22), t(15;17)(q22;q21).[7]

It is important to note that the nature of the fusion partner significantly impacts the disease characteristics and response to therapy. For example, APL with PLZF-RARA is not sensitive to retinoic acid and is less sensitive to chemotherapy.[8]

About 40% of APL cases also express additional chromosomal abnormalities (trisomy 8 and isochromosome 17). These do not appear to impact the overall prognosis.

In the United States, acute promyelocytic leukemia (APL) accounts for 5-15% of all adult leukemias.[9] Approximately 30,800 cases of acute leukemia are diagnosed yearly in the US, and about 1000 of those are APL. The annual incidence of APL in Italy is approximately 0.6 per 1 million people.

Douer noted that the APL-specific PML/RARA gene rearrangement is different in Latinos and non-Latinos, and that the incidence rate of  APL is higher in patients originating in Latin America.[10]  In contrast, Matasar et al reported that lifetime incidence rates of APL were not higher in US Hispanics than in whites, but the age distribution among Hispanics was significantly different from that in non-Hispanic whites, with greater incidence rates for children ages 1-19 years and adults ages 20-44 years. Blacks had lower lifetime incidence rates than non-Hispanic whites, Hispanics, and Asians.[11]

The incidence of APL in males and females is equal.[10] The median age of onset of APL is about age 40 years.

Unlike most leukemias, acute promyelocytic leukemia (APL) has a very good prognosis, with long-term survival rates up to 90% following treatment.[12]  However, the incidence of early death remains high, with 29% of APL patients dying within 30 days of their diagnosis; in 35% of those early deaths, the patient never received all-trans retinoic acid (ATRA) therapy.[13] The most common causes of early death in APL are hemorrhage, differentiation syndrome (DS), and infection.[14, 15]

The white blood cell (WBC) count is viewed as an important index associated with prognosis in APL. The National Comprehensive Cancer Network (NCCN) uses WBC counts to classify patients as either low risk (WBC ≤10,000/μL) or high risk (WBC >10,000/μL).[16] In addition to higher WBC counts, the following have also been identified as risk factors for early death[15, 14] :

• Increased serum creatinine level
• Older age
• Male sex
• Elevated fibrinogen level

Molecular and immunophenotypic features associated with a higher risk of relapse include expression in APL blasts of the stem/progenitor cell antigen CD34, the neural adhesion molecule (CD56), and the T cell antigen CD2. Often, the expression of these markers is associated with a high WBC count.[17]

Since the early 1990s, there have been reports of extramedullary relapse to the skin and central nervous system with APL that are associated with a poor prognosis.

A retrospective analysis examined the outcome of 155 patients with the microgranular variant (M3V) of APL who were treated with ATRA-based therapy in three clinical trials. The analysis revealed no difference in incidence of complications, survival, and response compared with patients who had classical M3 morphology, when outcomes were adjusted for the WBC count or the relapse risk score.[18]

A long-term observational study of 1025 patients with APL in first complete remission found that therapy-related myeloid neoplasms (t-MNs) are a rare but severe complication. Therapy for APL in these patients consisted of ATRA plus anthracycline chemotherapy. Further research is needed to determine how to decrease the frequency of t-MN following ATRA plus anthracycline-based therapy.[19]

Most of the signs and symptoms of acute promyelocytic leukemia (APL) are also seen in cases of acute myelogenous leukemia (AML). These include the following:

• Fatigue, weakness, and dyspnea related to anemia

• Easy bruising or bleeding caused by thrombocytopenia or coagulopathy

• Fever and infection related to leukopenia

Most patients with APL present with pancytopenia. About 10-30% of patients present with leukocytosis.[20]

APL differs from AML in that most patients present with coagulopathy. The coagulopathy has been described as disseminated intravascular coagulation (DIC) with associated hyperfibrinolysis. APL has been associated with low levels of plasminogen, alpha2-plasmin inhibitor, and plasminogen activator inhibitor 1 found in fibrinolytic states. There is increased expression of annexin II, a receptor for plasminogen and plasminogen-activating factor, on the surface of leukemic promyelocytes.[21] This leads to overproduction of plasmin and fibrinolysis.

It is important to treat the coagulopathy as a medical emergency. In 40% of untreated patients, pulmonary and cerebral hemorrhages can occur. It takes 5-8 days for coagulopathy to improve with treatment.

The physical examination can reveal pallor, petechiae, and areas of ecchymoses. Bleeding from the gums may be evident. A flow murmur can be heard in patients with severe anemia. Neurologic deficits or headaches may be present if central nervous system (CNS) involvement has occurred.

According to National Comprehensive Cancer Network (NCCN) guidelines, multidisciplinary testing (immonohistochemistry, cytochemistry, and molecular genetic analysis) are needed to diagnose APL in accordance with the 2016 WHO classification system. An APL diagnosis requires APL morphology and one of the following[16] :

• t(15:17) by cytogenetics, or
• Promelocytic leukemia (PML)/retinoic acid receptor alpha (RARA) by molecular testing

Patients are further classified as low risk (white blood cell [WBC] count ≤10,000/μL) or high risk (WBC >10,000/μL)[16]

If major neurologic signs or symptoms are present, appropriate brain imaging studies should be performed to detect meningeal disease, chloromas, or central nervous system (CNS) bleeding.[16]

The initial laboratory workup of acute promyelocytic leukemia (APL) should include the following:

• Complete blood cell (CBC) count with differential
• Peripheral blood smear
• Comprehensive metabolic profile for baseline renal and liver function tests,
• Electrolyte levels
• Prothrombin time (PT) and activated partial thromboplastin time (aPTT)
• Fibrinogen assay

Many authorities recommend lumbar puncture at diagnosis of acute promyelocytic leukemia (APL) in high-risk patients who present with a very high WBC count. In these cases, the CNS may serve as a sanctuary site warranting intrathecal therapy. Coagulopathy should be corrected first, and lumbar puncture may sometimes be delayed until after induction therapy.

The cerebrospinal fluid (CSF), in addition to undergoing routine chemical and hematologic studies, should be cytospun and examined by a pathologist trained in examination of fluid cytospins. Flow cytometry of CSF should be done to look for the abnormal clonal cells.

In addition, cardiac function should be examined by echocardiography or scintigraphy before the administration of anthracyclines.

A bone marrow biopsy with aspirate should be performed immediately. The sample should be sent for flow cytometry and cytogenetics. Fluorescent in situ hybridization (FISH) for the translocation or reverse transcription–polymerase chain reaction (RT-PCR) for the PML-RAR alpha transcript should also be done. The typical phenotype of acute promyelocytic leukemia (APL) is myeloperoxidase positive and CD33 positive, human leukocyte antigen (HLA)-DR negative.

Acute promyelocytic leukemia (APL) has the following morphologic variants[14] :

• Hypergranular (classic M3)
• Microgranular (M3v)
• Hyperbasophilic
• PLZF-RAR alpha (M3r)

The hypergranular subtype has frequent Auer rods, clumps of granular material containing lysosomes, peroxidase, lysosomal enzymes, and large crystalline inclusions (see the image below). Auer rods can be seen in other types of AML, but they are usually seen in APL. The nucleus is folded or bilobed, and the cytoplasm contains prominent azurophilic granules. The bone marrow is usually hypercellular. The cells stain intensely for Sudan black and myeloperoxidase, but not for periodic acid–Schiff (PAS) and HLA-DR.

Regularly hypergranular subtype of acute promyelocytic leukemia. Image courtesy of Dr. William Kocher.

The microgranular variant also has a folded nucleus, but the cytoplasm has fine, dusky granules and Auer rods are rare. It is seen in 25% of cases of APL.

The hyperbasophilic subtype shows an increased nucleocytoplasmic ratio and strongly basophilic cytoplasm with blebs. There are few granules and no Auer rods.

The PLZF-RAR alpha variant has regular, condensed chromatin in the nucleus. There are fewer granules and rare Auer rods compared with the hypergranular subtype.

Patients with acute leukemia should be treated in centers staffed by specially trained physicians and nurses. Availability of supportive care, such as platelet transfusion therapy, and a well-equipped laboratory is also crucial.

Given the frequent abrupt onset of acute promyelocytic leukemia (APL) and the risk of severe hemorrhagic events, immediate institution of all-trans-retinoic acid (ATRA) and/or arsenic trioxide (ATO) treatment and supportive therapy is indicated, to avoid early death. Current recommendations strongly suggest starting these measures upon clinical suspicion of APL and before genetic confirmation of the diagnosis.[16]

APL treatment has three phases: induction, consolidation, and maintenance. There is debate among experts about the ideal induction therapy, the best initial treatment for the elderly, the subset of patients most likely to benefit from maintenance therapy, and the most effective regimen for relapsed disease. These issues are the subject of ongoing clinical trials (see ClinicalTrials.gov).

ATRA is an important agent in all three phases of APL treatment.[22] ATRA can lead to terminal differentiation of malignant promyelocytes into mature neutrophils. However, ATRA alone cannot eradicate the malignant clone. Achievement of complete hematologic and molecular remission requires the addition of ATO or chemotherapy.[23, 24]

Resistance to ATRA has been seen with cytogenetic variants of APL, especially cases with the PLZF-RARA mutation. However, resistance may also develop as a secondary event in PML-RARA APL.

An interventional radiology consultation should be made for placement of a peripherally inserted central catheter (PICC) line. A gynecology consultation should be obtained for women with acute promyelocytic leukemia (APL) who have heavy vaginal bleeding or who are pregnant at the time of diagnosis.

In patients with acute promyelocytic leukemia (APL) who are at low or intermediate risk (ie, those with a white blood cell count [WBC] of 10,000/μL or less), current guidelines from the National Comprehensive Cancer Network (NCCN) recommend all-trans-retinoic acid (ATRA), 45 mg/m2 in divided doses daily until clinical remission, plus arsenic trioxide (ATO), 0.15 mg/kg IV daily until bone marrow remission. Alternative regimens (all category 1) are as follows[16] :

• ATRA plus daunorubicin (50 mg/m2 x 4 days or 60 mg/m2 x 3 days) and cytarabine (200 mg/m2 x 7 days)

• ATRA plus idarubicin (12 mg/m2 on days 2, 4, 6, and 8)

• ATRA plus ATO (0.3 mg/kg IV on days 1–5 of cycle one and 0.25 mg/kg twice weekly in weeks 2–8 or until clinical remission)

A randomized phase III study by Lo-Coco et al demonstrated that ATRA plus ATO is not inferior to ATRA plus chemotherapy for the induction therapy of patients with low- to intermediate-risk APL. The 2-year disease-free survival rate was 97% (95% confidence index [CI], 94-100%) in the ATRA–ATO group and 90% (95% CI, 84-97%) in the ATRA–chemotherapy group (P = 0.11). The 2-year cumulative incidence of relapse was 1% (95% CI, 0-4%) in the ATRA–ATO group and 6% (95% CI, 0-11%) in the ATRA–chemotherapy group (P = 0.24).[25]

In high-risk patients (WBC >10,000/μL), the NCCN recommends the following regimens for induction therapy[16] :

• ATRA plus daunorubicin and cytarabine

• ATRA plus age-adjusted idarubicin plus ATO

• ATRA plus idarubicin 

For patients who are unable to tolerate anthracyclines, the NCCN recommends ATRA plus ATO.

Idarubicin has been shown to be slightly more effective than daunorubicin in younger patients with acute myelogenous leukemia (AML). The combination of ATRA with chemotherapy improves long-term survival and results in 85-90% complete remission rates.

The most effective and least toxic induction chemotherapy combination with ATRA has not been established. The PETHEMA (Programa de Estudio y Tratamiento de las Hemopatías Malignas)[26] and European APL 2000[27] groups showed comparable and high complete remission rates with different induction chemotherapy regimens. The main difference was the addition of cytarabine by the APL 2000 group. The addition of cytarabine causes more myelosuppression, but the APL 2000 group reported a higher relapse risk when it was omitted.[27]

Prognostic factors were identified in 2000 by the Italian Group for Adult Hematologic Diseases (GINEMA) and Spanish PETHEMA group in a 217-patient multivariate analysis.[28] These researchers proposed risk stratification based on WBC and platelet count, as follows:

• Low risk - WBC < 10,000/μL and platelets >40,000/μL

• Intermediate risk - WBC < 10,000/μL and platelets < 40,000/μL

• High risk - WBC >10,000/μL and platelets < 40,000/μL

In the PETHEMA study (LPA 96 and 99), 426 patients with newly diagnosed APL were given induction therapy with ATRA and idarubicin (AIDA regimen). The study was started in 1996 and was called LPA 96. However, the study was modified after 1999 (LPA 99) to give intermediate- and high-risk patients consolidation with ATRA and higher doses of anthracyclines. The complete remission rate was 90%. All of the patients received 2 years of maintenance therapy. The 3-year risk of relapse was lower in the LPA 99 arm (8.7% vs 20.1%).

In the French-Belgian-Swiss study (APL 2000)< study, 413 patients younger than age 75 years with newly diagnosed APL were randomized to ATRA followed by chemotherapy versus ATRA with concurrent chemotherapy. The first arm had to achieve remission with ATRA before chemotherapy, with 7 days of cytarabine at 200 mg/m2 and 3 days of daunorubicin at 60 mg/m2. The second arm had chemotherapy added on day 3. These patients were then randomized to four different maintenance arms: observation, ATRA, chemotherapy, or ATRA with chemotherapy.

The complete remission rate was 92%. The results revealed that the early addition of chemotherapy lead to significantly better survival, and the lowest relapse risk was seen in patients with ATRA and chemotherapy maintenance.

Ades et al compared results of the French-Belgian-Swiss group and the PETHEMA group for patients younger than 65 years and concluded that in both groups, patients with WBC < 10,000/μL had similar 3-year survival rates.[29] However, for patients with WBC >10,000/μL, the complete remission rates and 3-year free survival rates were higher in the APL 2000 trial, and risk of relapse was lower. These findings were statistically significant and suggested a beneficial role for cytarabine for induction chemotherapy in high-risk patients.

De la Serna et al reported on the incidence, time of occurrence, and prognostic factors of induction failure in a population of 732 patients with APL.[30] The most common causes of induction failure included hemorrhage, infection, and APL differentiation syndrome (a rapid rise in WBC count during APL treatment, resulting in hyperleukocytosis). A multivariate analysis showed that certain pretreatment factors correlated with these adverse events. For example, elevated creatinine levels, presence of high peripheral blood blasts, and coagulopathy increased the risk of death.

Infection was seen more frequently in men older than 60 years and patients who had fever at presentation.[30] APL differentiation syndrome was linked to a lower serum albumin level and an Eastern Cooperative Oncology Group (ECOG) score >1.

In low- and intermediate-risk patients, the NCCN recommends continuing induction therapy until count recovery occurs, then proceeding to consolidation therapy. In high-risk patients receiving ATRA/ATO, induction is continued until count recovery and bone marrow remission are demonstrated. In high-risk patients receiving other regimens, count recovery and lumbar puncture results are indications for proceeding to consolidation therapy.[16]

For consolidation therapy in acute promyelocytic leukemia (APL), the National Comprehensive Cancer Network (NCCN) recommends basing the choice of regimen on the agents used for induction therapy. For example, patients who received all-trans-retinoic acid (ATRA) plus arsenic trioxide (ATO) would continue to receive ATRA/ATO, while those treated with ATRA plus chemotherapy would for the most part continue to receive those agents. In some cases, mitoxantrone may be added.[16] Another consolidation regimen consists of 2 years of 6-mercaptopurine (6-MP), methotrexate, and ATRA.

Retrospective studies by the independent groups GINEMA and PETHEMA showed statistically improved outcomes when ATRA was added to chemotherapy for 15 days. The PETHEMA group used three cycles of consolidation with idarubicin to mitoxantrone to idarubicin, but with higher doses of idarubicin for intermediate- to high-risk patients. The APL 2000 group used daunorubicin and cytarabine in differing doses for two cycles of consolidation.

Montesinos et al reported that of 918 patients who achieved complete remission with induction and consolidation therapy with ATRA and anthracycline-based chemotherapy, 17 patients developed therapy-related myeloid neoplasms (t-MN) or secondary acute myelogenous leukemia.[31]

The 6-year cumulative incidence of these complications overall was 2.2%. In subgroups of APL in low-, intermediate-, and high-risk patients, the 6-year incidence was 5.2%, 2.1%, and 0%, respectively. The study shows that t-MN is a relatively infrequent, long-term, and severe complication after first-line treatment of APL with ATRA and anthracycline-based regimens.[31]

Powell et al investigated the role of ATO in consolidation therapy.[32] In their study, 481 patients all underwent the same induction regimen with daunorubicin, cytarabine, and ATRA. They were then randomized to consolidation treatment with either two cycles of daunorubicin and ATRA or two 25-day courses of ATO. At 3 years, event-free survival and disease-free survival were significantly better for the ATO consolidation arm (P< 0.0001), but the difference in overall survival was not statistically significant (P = 0.59).

The role of maintenance therapy remains uncertain, especially for patients with low-risk APL who achieve molecular remission at the end of consolidation treatment. Most of the studies demonstrating benefit from maintenance therapy were conducted before the introduction of ATRA, ATO, or cytarabine for consolidation.[16]

The European APL group randomized patients to intermittent ATRA alone, ATRA plus 6-mercaptopurine (6-MP) and methotrexate, or observation. They found an improved overall survival in patients receiving ATRA or ATRA plus chemotherapy. Currently, the three-drug regimen of ATRA 45 mg/m2 daily given 15 days every 3 months, oral PO) 6-MP 60 mg/m2 once daily, and methotrexate 20 mg/m2 PO once weekly are administered for 2 years. Patients should be monitored for abnormal liver function and myelosuppression during this time period.

APL disease monitoring is usually done by reverse transcription polymerase chain reaction (RT-PCR) assay for the PML-RARA fusion transcript.[33] The RT-PCR assay can establish the diagnosis of APL when cytogenetics and fluorescence in situ hybridization (FISH) fail. The assay is useful for detecting minimal residual disease (MRD). The International Working Group recommends that the goal of treatment is complete molecular remission, which is evidenced by the absence of the fusion transcript using RT-PCR at a sensitivity threshold of 10-4.

Due to the lower sensitivity of the RT-PCR assay, the peripheral blood RT-PCR needs to be monitored every 3 months for the first 2 years. Then, the assay can be performed every 3-6 months for the next 3 years. The highest risk of relapse is in the first 2 years. Bone marrow samples may be more sensitive for detecting MRD, but peripheral blood samples are considered equivalent.

Avissati et al published the results of a 12-year follow-up for different maintenance regimens among patients who achieved a complete molecular remission (PML-RARA negative on RT-PCR) at the end of consolidation. In this study, 586 patients who were RT-PCR negative after consolidation were then randomized to four maintenance arms: (1) oral 6-MP and intramuscular methotrexate, (2) ATRA, (3) alternating oral 6-MP and intramuscular methotrexate with ATRA, or (4) observation alone. After 4 years, the chemotherapy alone arm was discontinued.[34]

The estimated 12-year disease-free survival was 68.9%; no difference in disease-free survival was found among all of the arms. This study raises the question of whether maintenance therapy should be done in patients who achieve a complete molecular remission at the end of consolidation.[34]

Patients have resistant APL if they have not achieved complete molecular remission at the end of consolidation therapy. Individuals have relapsed disease if they achieve molecular remission, but monitoring by RT-PCR assay shows positivity on consecutive samples. This can occur in up to 30% of patients. ATO is recommended in relapsed or refractory APL.[35]

In relapsed APL, ATO shows high antileukemic activity, especially for patients who have a relapse within 1 year of receiving ATRA. Several studies in China from 1996 to 1999 showed complete remission rates of 52-96% with ATO monotherapy in relapsed APL. Soignet et al showed a complete remission rate of 85% in a multicenter study of 40 patients with APL.[36] After two cycles of ATO, 78% of patients had no evidence of the leukemic clone.

Analysis of 72 patients with APL treated with ATO alone showed a good overall survival in the good-risk group, as defined in the study, at 100% for the study period. Single-agent ATO in the management of newly diagnosed cases of low-risk APL is safe and is associated with durable responses compared with standard therapy with anthracyclines, which likely would be required in high-risk cases.[37]

ATO is well tolerated in elderly persons and has antileukemic effects at low doses. Adverse effects of ATO include the following[38] :

• Prolongation of the QTc interval
• Hepatotoxicity
• Nausea and vomiting
• Fluid retention
• Itching and rash
• APL differentiation syndrome

Gemtuzumab ozogamicin, a humanized anti-CD33 antibody linked to an antitumor antibiotic,[39] was approved in May 2000 for first recurrence of AML but was withdrawn from the US market in June 2010 when no improvement in clinical benefit was observed and after a greater number of deaths occurred in the group of patients who received gemtuzumab compared with those receiving chemotherapy alone. In addition, the rate of veno-occlusive disease was shown to be increased in the postmarket setting. Gemtuzumab ozogamicin had been highly effective in molecular or overt relapsed APL.[40, 41]

Bone marrow transplantation

Because the cure rate for acute APL is high, bone marrow transplantation (BMT) is not the first option for these patients, but it should be offered to those with relapsed APL.[42, 43] BMT is associated with significant transplant-related mortality, especially with allogeneic transplants. Patients who achieve molecular remission with salvage therapy should be offered high-dose chemotherapy, followed by autologous stem cell transplantation (SCT) for consolidation. Patients who have persistent molecular or hematologic disease after salvage therapy should be offered allogeneic SCT if they have a good performance status and an HLA-matched donor can be found.

Other alternatives would include enrollment in a clinical trial if transplantation is not an option. Date from the Center for International Blood and Marrow Transplant Research (CIBMTR) show that the majority of patients undergo SCT in the second or subsequent remissions. Three-year overall survival (OS) was 73% for autologous SCT and 61% for allogeneic SCT.

The role of maintenance therapy after SCT has not been established. Transplantation-related mortality is improving over time with improved techniques and conditioning regimens. The role of transplantation in high-risk patients (WBC >10,000/μL) will need further investigation.

In patients who have central nervous system (CNS) involvement or who are at higher risk for CNS relapse, intrathecal chemotherapy is usually given in five doses. The regimen is a combination of cytarabine (50 mg), methotrexate (15 mg), and hydrocortisone (30 mg), given weekly for 5 weeks. For prophylaxis, one dose is given during induction, and four doses are given during consolidation.[44]

Although APL in patients older than 60 years is sensitive to chemotherapy, these patients have higher death rates in complete remission.[45, 46] The PETHEMA group omitted one dose of idarubicin for induction chemotherapy in patients older than age 70 years. In the European APL93 trial, 18.6% of elderly patients with APL died, mainly from sepsis, during consolidation or maintenance treatment.

Although these patients can be treated with ATRA and a less intensive dose of chemotherapy, the consolidation regimen should be altered to liposomal ATRA or ATO. These drugs can also be used in combination.

A neutropenic diet should be ordered for leukopenic or neutropenic patients. No fresh fruits or flowers should be allowed in the patient's room.

The patient's activity should be limited in cases of severe thrombocytopenia (platelet count < 10,000/μL). These patients are at increased risk of spontaneous bleeding, and the potential for falls should be minimized.

The most important complications of acute promyelocytic leukemia (APL) are bleeding diathesis secondary to underlying coagulopathy (5%), infection (2.3%), and differentiation syndrome (1.4%).[30] The coagulopathy should be monitored closely to prevent early mortality. Infection can occur at any time and should be treated promptly with antibiotics. Patients with differentiation syndrome should be treated with intravenous steroids to prevent treatment-related mortality.

ATRA helps to rapidly control the disseminated intravascular coagulation (DIC) associated with APL. It is important to note that the treatment of disseminated intravascular coagulation (DIC) should also include platelet transfusions to maintain the platelet count at about 20,000/μL and cryoprecipitate to maintain a fibrinogen level at least above 100-150 mg/dL.[16, 12]

About 25-50% of patients who receive ATRA develop differentiation syndrome, typically within the first 21 days of treatment. This disorder was initially termed retinoic acid syndrome (RAS), but was subsequently found to occur in APL patients treated with ATO or other cytotoxic drugs. Differentiation syndrome is characterized by the following:

• Fever
• Hypotension
• Weight gain
• Respiratory distress
• Serositis with pleural or pericardial effusions
• Hypoxemia
• Radiologic infiltrates
• Acute kidney injury
• Hepatic dysfunction

For high risk patients (WBC >10,000/μL), prophylaxis against differentiation syndrome is with corticosteroids (prednisone or dexamethasone) with the dose tapered over several days.

A high degree of clinical suspicion for differentiation syndrome should always lead to initiation of dexamethasone therapy at the first sign of symptoms of respiratory compromise. Temporary discontinuation of ATRA therapy should be considered until hypoxia resolves. Cytoreduction, hydroxyurea, and anthracycline are recommended for difficult-to-treat differentiation syndrome.[16]

Hyperleukocytosis is common in differentiation syndrome, but leukocyte counts may also be normal. Gemtuzumab or anthracyclines (idarubicin and daunorubicin) can be used to control the leukocyte count if necessary.[12]

In those patients who are not treated initially with chemotherapy, a rapid increase in WBC count may follow ATRA use. These patients should be promptly treated with chemotherapy to avoid clinical hyperleukocytosis.

Other side effects of ATRA include the following:

• Headache
• Nasal stuffiness
• Dry, red skin
• Pseudotumor cerebri (rare)

No risk factor has been identified for primary acute promyelocytic leukemia (APL). It is still unclear whether there are certain forms of environmental or occupational exposure that predispose susceptible individuals to APL.

Secondary APL may follow treatment with cytotoxic agents (especially mitoxantrone) or radiotherapy. Secondary APL accounts for 10-20% of cases. The evolution of treatment strategies for primary cancers has reduced the incidence of secondary APL in breast cancer patients but increased it in prostate cancer patients. Characteristics and outcomes of secondary APL are similar to those of primary APL.[47]

Guidelines on acute promyelocytic leukemia (APL)  have been published by the following organizations:

• National Comprehensive Cancer Network (NCCN) ^[16]  
• European LeukemiaNet (ELN). ^[48]  

National Comprehensive Cancer Network recommendations

According to the NCCN, multidisciplinary testing (immonohistochemistry, cytochemistry and molecular genetic analysis) are needed to diagnose APL in accordance with the 2016 WHO classification system. An APL diagnosis requires APL morphology and either:

• t(15:17) by cytogenetics, or
• Promelocytic leukemia (PML)/retinoic acid receptor alpha (RARA) by molecular testing

Patients are further classified as low risk (WBC ≤10,000/μL) or high risk (WBC >10,000/μL)[16] .

Induction treatment 

For patients who are at low risk, NCCN lists the following regimens[16] :

• All-trans-retinoic acid (ATRA), 45 mg/m2 in divided doses daily until clinical remission, plus arsenic trioxide (ATO), 0.15 mg/kg IV daily until bone marrow remission; alternatively, ATO may be given in a dose of 0.3 mg/kg IV on days 1–5 of week 1 and 0.25 mg/kg twice weekly during weeks 2–8

• In the ATRA-ATO regimen, an ATRA dose of 25 mg/m2 may be used in children and adolescents.

• If arsenic is unavailable or contraindicated, ATO can be replaced with idarubicin 12 mg/m2 on days 2, 4, 6, and 8 (category 1) or with a single dose of gemtuzumab ozogamicin 9 mg/m2 on day 5

The NCCN recommends proceeding with consolidation if the blood count has recovered by day 28 (platelet count > 100,000/μL, absolute neutrophil count [ANC] > 1,000/μL). Bone marrow (BM) aspirate and biopsy may be considered to document morphologic remissionl, but is optional. If a full course of induction treatment is not given or counts have not recovered by day 28–35, a BM aspirate and biopsy is recommended to document morphologic remissionl.

In patients who are at high risk and able to tolerate anthracyclines, NCCN recommends a choice of one of the following preferred regimens[16] :

• ATRA plus age-adjusted idarubicin (6–12 mg/m2 on days 2, 4, 6, 8) and ATO (0.15 mg/kg on days 9–36 as 2 h IV infusion) 

• ATRA plus ATO 0.15 mg/kg/d IV; plus a single dose of gemtuzumab ozogamicin 9 mg/m2 given on day 1,  2, 3, or 4

• ATRA plus ATO 0.3 mg/kg IV on days 1–5 of week 1 and 0.25 mg/kg twice weekly on weeks 2–8 (category 1); plus a single dose of gemtuzumab ozogamicin 6 mg/m2 may be given on day 1, 2,3, or 4

Other recommended regimens are as follows:

• ATRA plus daunorubicin 50 mg/m2 × 4 days (IV days 3–6) plus cytarabine 200 mg/m2 × 7 days (IV days 3–9)

• ATRA plus daunorubicin (60 mg/m2 x 3 days) and cytarabine (200 mg/m2 × 7 days)

• ATRA plus idarubicin (12 mg/m2 on days 2, 4, 6, 8)

In patients who are at high risk and unable to tolerate anthracyclines, the NCCN recommends ATRA plus ATO. Induction is continued until count recovery and bone marrow remission are demonstrated. BM aspirate and biopsy are recommended at day 28 to document remission, with lumbar puncture considered before proceeding with consolidation.[16]

Consolidation Therapy

For consolidation therapy, the NCCN recommends basing the choice of regimen on the agents used for induction therapy. For example, patients who received ATRA/ATO would continue to receive that regimen, while those treated with ATRA plus chemotherapy would for the most part continue to receive those agents. In some cases, mitoxantrone may be added.[16]  

NCCN guidelines note that the role of maintenance therapy remains uncertain, especially for patients with low-risk APL who achieve molecular remission at the end of consolidation treatment. Most of the studies demonstrating benefit from maintenance therapy were conducted before the introduction of ATRA, ATO, or cytarabine for consolidation.[16]

European LeukemiaNet recommendations

ELN recommendations for management of APL are as follows[48] :

• Immediately admit patients with suspicion of APL to the hospital, initiate ATRA, and manage coagulopathy. Confirmation of APL by genetic diagnosis should follow.
• Monitor coagulation parameters at least daily until all signs of coagulopathy have disappeared.
• Initiate transfusions immediately and continue them to maintain appropriate fibrinogen concentration, platelet count, and international normalized ratio.
• Start cytoreductive therapy with ATRA upon suspicion of APL. High-risk patients should also receive chemotherapy, and low-risk patients may receive antileukemic agents upon genetic diagnosis of APL. In view of the demonstrated efficacy of ATRA/ATO, the ELN recommends its use for low-risk patients as well as for patients not receiving chemotherapy.
• After consolidation therapy, perform a bone marrow molecular assessment to confirm complete response (CR) with negative minimal residual disease (MRD). The ELN does not recommend routine monitoring after induction therapy or in low-risk patients with CR and negative MRD after consolidation.
• In high-risk patients, monitor MRD every 3 months for up to 3 years after consolidation.
• In low-risk patients, the ELN does not recommend maintenance therapy after consolidation.
• Continue maintenance therapy in high-risk patients receiving ATRA and chemotherapy who showed clinical benefit.
• Elderly patients with good clinical conditions should receive the same treatment as younger patients, with a small dose reduction similar to the treatment of low-risk patients with APL.
• Patients with evidence of molecular or hematologic relapse after consolidation should be crossed over according to the previously used treatment: patients who previously received ATRA plus ATO should receive ATRA plus chemotherapy and vice versa. Perform autologous hematopoietic stem cell transplantation in patients who have achieved second molecular remission, have negative MRD, or are have negative results on polymerase chain reaction (PCR) testing.
• Tthe patient’s individual genetic variants of APL should inform treatment: Patients with ATRA-sensitive variants should be treated with ATRA and anthracycline chemotherapy, while those with ATRA-resistant variants might not benefit from ATRA treatment.

The goals of pharmacotherapy are to induce remission, prevent complications, and reduce morbidity in patients with acute promyelocytic leukemia (APL). All-trans-retinoic acid (ATRA) should be prescribed on both an inpatient and outpatient basis. Patients should also be on prophylactic antifungal and antiviral medications during treatment, as these individuals have altered lymphocyte function due to both the underlying leukemia and cytotoxic therapy.

Class Summary

Antineoplastic agents inhibit cell growth and proliferation.

Arsenic trioxide (Trisenox)

May cause DNA fragmentation and damage or degrade the fusion protein PML-RAR alpha. Used in APL patients who have the presence of the t(15;17) translocation or PML/RAR-alpha gene expression. It is indicated also for induction of remission and consolidation in patients with APL who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy and in combination with tretinoin for treatment of adults with newly diagnosed low risk APL.

Idarubicin (Idamycin)

Used for induction or consolidation therapy. Topoisomerase-II inhibitor. Inhibits cell proliferation by inhibiting DNA and RNA polymerase.

Tretinoin (Vesanoid)

Induces maturation of acute promyelocytic leukemia cells in cultures. Used in both induction and maintenance phases for patients with acute promyelocytic leukemia.

Cytarabine (Cytosar-U)

Converted intracellularly to active compound cytarabine-5'-triphosphate, which inhibits DNA polymerase. Cell cycle S phase specific. Blocks the progression from G1 to S phase and in turn kills cells that undergo DNA synthesis in S phase of cell proliferation cycle.

Mitoxantrone (Novantrone)

Used for induction or consolidation therapy. Inhibits cell proliferation by intercalating DNA and inhibiting topoisomerase II.

Daunorubicin (Cerubidine)

Anthracycline antibiotic. Binds to nucleic acids by intercalation between base pairs of DNA, interfering with DNA synthesis. Causes inhibition of DNA topoisomerase II. Half-life is 14-20 h (23-40 h for active metabolite). Used in the induction phase of treatment.

Gemtuzumab (Mylotarg)

Antibody-drug conjugate for newly diagnosed and relapsed or refractory CD33-positive acute myeloid leukemia. Gemtuzumab originally received accelerated approval in 2000; it was voluntarily withdrawn from the US market in 2010 after a confirmatory trial failed to show clinical benefit and reported an elevated rate of fatal toxicity, but was approved again in 2017 at a lower, fractionated dose. Gemtuzumab carries a black box warning for hepatotoxicity, including severe or fatal veno-occlusive disease.