Acute Promyelocytic Leukemia Treatment Protocols

Acute promyelocytic leukemia (APL) is a distinct variant of acute myeloid leukemia (AML). It is classified as AML M3 by the old French-American-British (FAB) system and as APL with translocation between chromosomes 15 and 17—that is, t(15;17)—by the World Health Organization (WHO) classification system.

Although rapid confirmation of genetic diagnosis is mandatory, patients in whom APL is suspected (on the basis of clinical presentation and peripheral blood smear results) should be immediately hospitalized and their case managed as a medical emergency. ^[1]  

Patients with APL may be stratified into the following 3 risk categories on the basis of white blood cell (WBC) count and platelet count.:

• Low risk - WBC count < 10,000/µL and platelet count > 40,000/µL
• Intermediate risk - WBC count < 10,000/µL and platelet count < 40,000/µL\
• High risk -  WBC count > 10,000/µL

Treatment of APL includes induction therapy, consolidation therapy, and maintenance therapy. Protocols for these stages are provided below, as well as recommendations for management of relapse and for prophylaxis.

Induction therapy

The major component of induction therapy is all-trans retinoic acid (ATRA), which is commonly combined with other agents. ^{[2, 3, 4, 1]}

European LeukemiaNet regimen:

• For low- and intermediate-risk patients, induction therapy should consist of ATRA and arsenic trioxide  (ATO) without chemotherapy. ATRA and anthracycline-based chemotherapy is an option when ATO is contraindicated or unaffordable. 
• For high-risk patients, treatment is with conventional ATRA plus anthracycline-based chemotherapy; ATRA plus ATO with a certain amount of chemotherapy is a possible option, but ATO is not approved for use in high-risk patients.
• The ATRA dosage is 45 mg/m ²/day in 2 divided doses (25 mg/m ²/day in children and adolescents); the ATO dosage is 0.15 mg/kg/day IV until bone marrow remission occurs (maximum induction, 60 doses).
• Induction therapy should not be modified based on the presence of leukemia cell characteristics that have variably been considered to predict a poorer prognosis (eg, secondary chromosomal abnormalities, FLT3 mutations, CD56 expression, BCR3 PML-RARA isoform).
• Treatment with ATRA should be continued until terminal differentiation of blasts and achievement of complete remission.
• Therapy should not be modified on the basis of incomplete blast maturation (differentiation) detected up to 50 days or more after the start of treatment.

Several regimens that include chemotherapy are commonly used for induction therapy, including the European APL regimen, ^{[1, 5, 6]} the Programa para el Tratamiento de Hemopatias Malignas (PETHEMA) regimen, ^[7]  

North American Intergroup Study C9710 regimen ^[3] :

• ATRA 45 mg/m ²/day PO in 2 divided doses starting on day 1 and continuing until complete remission or a maximum of 90 days  plus
• Daunorubicin 50 mg/m ² IVP on days 3-6 plus
• Cytarabine 200 mg/m ²/day continuous IV infusion over 24 h on days 3-9

European APL regimen:

• Daunorubicin 60 mg/m ²/day IV as 15-30min infusion for 3d plus
• Cytarabine 200 mg/m ²/day IV as 24h continuous infusion on days 1-7 ^{[8, 9]}   plus
• ATRA 45 mg/m ²/day (25 mg/m ²/day for patients < 20y) in 2 divided doses (ATRA is started on day 1)
• For high-risk patients, the evidence favors the European APL regimen because it includes cytarabine ^[8]

PETHEMA regimen:

• Idarubicin 12 mg/m² IV bolus on days 2, 4, 6, and 8 (hold 8th dose in patients > 70y) plus

• ATRA 45 mg/m²/day (25 mg/m²/day for patients < 20y) in 2 divided doses (ATRA is started on day 1)

Consolidation therapy

Consolidation therapy is based on the potential risk of relapse in patients who undergo induction therapy. Its main goal is to convert morphologic and cytogenetic remission into durable molecular remission. ^[9]

Again, several regimens are commonly used for consolidation therapy, including the European LeukemiaNet regimen, the European APL regimen, and the PETHEMA regimen. ^[10]

European LeukemiaNet regimen

• For patients treated with chemotherapy-free induction regimens: Four courses of ATO (0.15 mg/kg/day 5 days per week, 4 weeks on 4 weeks off)  seven courses of ATRA (45 mg/m ² per day for adults; 25 mg/m ² per day for children, 2 weeks on 2 weeks off) are recommended.
• For patients treated with conventional ATRA plus chemotherapy: Two to three courses of anthracycline-based chemotherapy
• The addition of ATRA to chemotherapy in consolidation seems to provide a clinical benefit
• Consolidation for high-risk patients younger than 60 years with WBC counts > 10 x 10 ⁹/L should include at least one cycle of intermediate or high-dose cytarabine
• Molecular remission in the bone marrow should be assessed at completion of consolidation by reverse transcriptase polymerase chain reaction (RT-PCR) assay with a sensitivity of at least 1 in 10 ⁴.

European APL regimen:

• First cycle: daunorubicin 60 mg/m²/day IV as 15-30min infusion on days 1-3 plus  cytarabine 200 mg/m²/day IV as 24h infusion on days 1-7

• Second cycle: daunorubicin 45 mg/m²/day IV as 15-30min infusion on days 1-3 plus  cytarabine 1 g/m² every 12h on days 1-4

• ATRA administered concurrently with cycles above: ATRA 45 mg/m²/day (25 mg/m²/day for patients < 20y) in 2 divided doses for 15d with each 4-wk cycle of chemotherapy (especially for intermediate- and high-risk patients)

PETHEMA regimen:

• First cycle: idarubicin 5 mg/m² IV bolus on days 1-4

• Second cycle: mitoxantrone 10 mg/m² IV bolus on days 1-3

• Third cycle: idarubicin 12 mg/m² IV bolus for 1 dose

• ATRA administered concurrently with cycles above: ATRA 45 mg/m²/day (25 mg/m²/day for patients < 20y) in 2 divided doses for 15d with each 4-wk cycle of chemotherapy (especially for intermediate- and high-risk patients)

Maintenance therapy

After consolidation therapy, patients should be evaluated for molecular remission. For patients in whom PCR evaluation is negative, a combination of ATRA, 6-mercaptopurine (6-MP), and methotrexate is recommended. Current evidence suggests that maintenance therapy may not provide a significant benefit for patients who have molecular remission after consolidation therapy. The recommended maintenance regimen is 2y of the following ^[5] :

• ATRA 45 mg/m ²/day for 15d every 3mo plus
• 6-MP 60 mg/m ²/day PO plus
• Methotrexate 20 mg/m ² PO weekly

Relapse therapy

See the list below:

• If the European APL regimen or the PETHEMA regimen was used initially, use ATO induction and consolidation doses for treatment of relapse. ^[11]

• If molecular remission is achieved with salvage therapy, the patient should be considered for autologous stem cell transplantation. ^[12]

• If persistent molecular or hematologic disease is noted after salvage therapy, the patient should be considered for allogeneic stem cell transplantation if performance status is good and a human leukocyte antigen (HLA)–matched donor is available. ^[13]

• If ATO was used initially, consider a clinical trial or supportive care

Prophylactic intrathecal chemotherapy

See the list below:

• For high-risk patients, intrathecal chemotherapy is recommended for prophylaxis

• Cytarabine 50 mg plus  methotrexate 15 mg plus hydrocortisone 30 mg weekly for 5wk

Response criteria for leukemias

See the list below:

• Complete remission (CR): bone marrow blasts < 5% in aspirate with spicules, no evidence of extramedullary disease, transfusion independence, PCR negative, absolute neutrophil count (ANC) > 1000/µL (see the Absolute Neutrophil Count calculator) with platelet count > 100,000/µL

• CR with incomplete blood count recovery (CRi) or incomplete platelet count recovery (CRp): CR plus persistence of cytopenia (eg, underlying myelodysplastic syndrome [MDS] in the elderly)

• Partial remission (PR) or treatment failure: 5-25% blasts in bone marrow or 50% decrease in blasts and normalization of blood counts

Treatment of coagulopathy

Intracerebral and pulmonary hemorrhages are the most frequent causes of early death in patients with APL, both before intiation of treatment and shortly afterward. Thrombotic complications occur less commonly. Consequently, measures to counteract coagulopathy,  as follows, should be started immediately ^[1] :

• Montior activated partial thromboplastin time and thrombin time, as well as levels of fibrinogen and fibrinogen-fibrin degradation products, at least daily and more frequently if necessary.
• Transfuse fibrinogen and/or cryoprecipitate, platelets, and fresh frozen plasma immediately upon suspicion of APL, then daily or more than once a day if needed, to maintain the fibrinogen concentration above 100-150 mg/dL, the platelet count above 30– 50×10 ⁹ /L, and the international normalized ratio (INR) below 1.5.
• Continue supportive treatment during induction therapy until all clinical and laboratory signs of coagulopathy have resolved.
• Because of the high risk of hemorrhagic complications, avoid central venous catheterization, lumbar puncture, and other invasive procedures (eg, bronchoscopy) before and during remission induction therapy.
• The benefit of using heparin, tranexamic acid, or other anticoagulant or antifibrinolytic agents to reduce the hemorrhagic and thrombotic risk associated with the coagulopathy before and during remission induction therapy remains questionable. 

Special considerations

APL differentiation syndrome (also known as retinoic acid syndrome [RAS]) can occur within the first 21d of treatment and 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
• Hyperleukocytosis is common, but leukocyte counts may be normal

RAS should be treated with dexamethasone 10 mg IV every 12h for ≥ 3d. The benefit of prophylactic corticosteroids for prevention of RAS remains uncertain, but prophylactic corticosteroids can be considered in patients with WBC count > 5-10 x 10⁹ /L at presentation or in those whose WBC counts increase after the start of ATRA. ^[1]

Other considerations include the following:

• Infectious disease prophylaxis should be started to prevent viral and fungal infections due to the altered lymphocyte function induced by cytotoxic treatment

• Elderly patients (> 60y) have poorer outcomes with standard treatment; in the PETHEMA trial, the last dose of idarubicin was omitted during induction; consolidation should be altered to liposomal ATRA and ATO ^[14]

• Disease monitoring: Bone marrow biopsy should not be done until count recovery (40-50d after induction), because remission can take up to 40-50d

• Relapse monitoring: Check quantitative PML-RAR alpha PCR, ^[12] cytogenetics, and fluorescence in situ hybridization (FISH) for 15;17 translocation from the bone marrow at the end of consolidation treatment, then monitor peripheral blood quantitative PML-RAR alpha PCR every 3mo for 2y; the assay can be performed every 3-6mo for the next 3y; if a positive test result is obtained, repeat PCR testing from bone marrow in 2-4wk