Acute Promyelocytic Leukemia Treatment Protocols 

Updated: Dec 30, 2015
  • Author: Sandy D Kotiah, MD; Chief Editor: Emmanuel C Besa, MD  more...
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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.

Patients with APL may be stratified into 3 risk categories on the basis of white blood cell (WBC) count and platelet count. Low risk is a WBC count < 10,000/µL and a platelet count > 40,000/µL; intermediate risk is a WBC count < 10,000/µL and a platelet count < 40,000/µL; high risk is a 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. [1] The combination of arsenic trioxide with ATRA may be considered for patients who are not candidates for anthracycline-based therapy. [2, 3]

Several regimens are commonly used for induction therapy, including the European APL regimen, [4, 5, 6] the Programa para el Tratamiento de Hemopatias Malignas (PETHEMA) regimen, [7] and, in specific populations, combination therapy with arsenic trioxide. [8]

North American Intergroup Study C9710 regimen:

ATRA 45 mg/m2/day PO in 2 divided doses starting on Day 1 plus  daunorubicin 50 mg/m2 IVP on days 3-6 plus  cytarabine 200 mg/m2/day continuous IV infusion over 24 h on days 3-9; 1 cycles until complete remission or a maximum of 90 days [2]

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 [9, 10] 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 [9]

PETHEMA regimen:

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

Arsenic trioxide and ATRA:

  • Arsenic trioxide and ATRA can be considered in frail or elderly patients
  • This combination can also be used in patients who are unable to tolerate anthracycline-based therapy
  • Recommended dosage is arsenic trioxide 0.15 mg/kg/day IV until bone marrow remission occurs (maximum induction, 60 doses) plus  ATRA 45 mg/m 2/day in 2 divided doses

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. [10]

Again, several regimens are commonly used for consolidation therapy, including the European APL regimen, the PETHEMA regimen, [11] and, in specific populations, combination therapy with arsenic trioxide.

European APL regimen:

  • First cycle: daunorubicin 60 mg/m 2/day IV as 15-30min infusion on days 1-3 plus  cytarabine 200 mg/m 2/day IV as 24h infusion on days 1-7
  • Second cycle: daunorubicin 45 mg/m 2/day IV as 15-30min infusion on days 1-3 plus  cytarabine 1 g/m 2 every 12h on days 1-4
  • ATRA administered concurrently with cycles above: ATRA 45 mg/m 2/day (25 mg/m 2/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/m 2 IV bolus on days 1-4
  • Second cycle: mitoxantrone 10 mg/m 2 IV bolus on days 1-3
  • Third cycle: idarubicin 12 mg/m 2 IV bolus for 1 dose
  • ATRA administered concurrently with cycles above: ATRA 45 mg/m 2/day (25 mg/m 2/day for patients < 20y) in 2 divided doses for 15d with each 4-wk cycle of chemotherapy (especially for intermediate- and high-risk patients)

Arsenic trioxide and ATRA:

  • Arsenic trioxide 0.15 mg/kg/day IV for 5d (M-F) per week every other month for 4 cycles plus  ATRA 45 mg/m 2/day PO in 2 divided doses for 2wk per month for 7 cycles [2]

Maintenance therapy

After consolidation therapy, patients should be evaluated for molecular remission. For patients in whom polymerase chain reaction (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.

  • Recommended regimen includes 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; administered for 2y [5]

Relapse therapy

See the list below:

  • If the European APL regimen or the PETHEMA regimen was used initially, use arsenic trioxide induction and consolidation doses for treatment of relapse [12]
  • If molecular remission is achieved with salvage therapy, the patient should be considered for autologous stem cell transplantation [13]
  • 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 [14]
  • If arsenic trioxide was used initially (eg, in elderly or frail patients), 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

Special considerations

See the list below:

  • Disseminated intravascular coagulation (DIC) should be treated with ATRA as soon as there is any suspicion of APL; platelet transfusions should be given to keep the platelet count above 20,000/µL and cryoprecipitate infusions given to keep the fibrinogen above 100-150 mg/dL
  • APL differentiation syndrome (also known as retinoic acid syndrome [RAS]) can occur within the first 21d of treatment and is characterized by fever, hypotension, weight gain, respiratory distress, serositis with pleural or pericardial effusions, hypoxemia, radiologic infiltrates, acute renal failure, and hepatic dysfunction
  • RAS is frequently associated with hyperleukocytosis but can occur with normal leukocyte counts; RAS should be treated with dexamethasone 10 mg IV every 12h for ≥ 3d
  • 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 arsenic trioxide [15]
  • 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, [13] 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