Acute promyelocytic leukemia medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Medical Therapy

APL is unique among the leukemias distinguished by its sensitivity to all-trans retinoic acid (ATRA), a derivative of vitamin A. Treatment with ATRA causes differentiation of the immature leukemic promyelocytes into mature granulocytes. ATRA is typically combined with anthracycline based chemotherapy resulting in a clinical remission in approximately 90% of patients.

ATRA therapy is associated with the unique side effect of retinoic acid syndrome. This is associated with the development of dyspnea, fever, weight gain, peripheral edema and is treated with dexamethasone. The etiology of retinoic acid syndrome has been attributed to capillary leak syndrome from cytokine release from the differentiating promyelocytes.

Treatment options for patients with relapsed disease include arsenic trioxide and allogeneic stem cell transplant. Monitoring for relapse using PCR tests for RARα allows early re-treatment which is successful in many instances.

Anti-leukemic Therapies

• All-trans retinoic acid: The introduction of all-trans retinoic acid has revolutionized the treatment paradigm and outcomes in acute promyelocytic leukemia. The 5-year mortality has decreased from 82% to 36% since the introduction of all-trans retinoic acid.
  • Mechanism of action: Induction of differentiation in leukemic blasts
  • Dosing: 45mg/m2 PO daily (typically 22.5mg/m2 PO divided twice daily), given on days 1-14 of a 28-day cycle (2 weeks on, 2 weeks off), for a total of 7 cycles
  • Adverse effects: The most unique adverse effect of all-trans retinoic acid is differentiation syndrome. This is characterized by weight gain, edema, hypoxia, dyspnea, and pulmonary infiltrates.
• Arsenic trioxide:
  • Mechanism of action: Induction of apoptosis in leukemic blasts
  • Dosing: 0.15mg/kg IV daily for days 1-30 of a 60-day cycle (4 weeks on, 4 weeks off), for a total of 4 cycles
  • Adverse effects: The adverse effects of arsenic trioxide include myelosuppression, liver dysfunction, QT interval prolongation, liver dysfunction.
• Gemtuzumab ozogamycin: This is an anti-CD33 antibody conjugated to the anti-tumor antibiotic calicheamicin. Gemtuzumab ozogamycin is FDA-approved for the treatment of patients with newly diagnosed acute myeloid leukemia expressing the CD33 antigen. Gemtuzumab ozogamycin shows efficacy in acute promyelocytic leukemia. This medication was originally approved in the year 2000 for relapsed acute myeloid leukemia, then was withdrawn from the marker a few years later, then re-introduced to the marker in 2017.
  • Mechanism of action: Antibody-dependent cell-mediated cytotoxicity towards leukemic blasts expressing the cell surface marker CD33
  • Dosing: 3 mg/m2 IV on days 1, 4, and 7 of the induction regimen
  • Adverse effects: The most unique adverse effect is hepatic venoocclusive disease, which is due to the ozogamycin component.
• Cytarabine: This is a cytotoxic chemotherapy that is used in high-risk acute promyelocytic leukemia along with all-trans retinoic acid.
  • Mechanism of action: Incorporation into DNA and disruption of DNA synthesis
  • Dosing: 100 mg/m2 IV infusion continuously for 7 days
  • Adverse effects: rash; myelosuppression (infections, fatigue, bleeding); cerebellar dysfunction; conjunctivitis
• Anthacyclines: These are cytotoxic chemotherapy agents that are used in high-risk acute promyelocytic leukemia along with all-trans retinoic acid.
  • Mechanism of action: intercalation into DNA; inhibition of topoisomerase II
  • Dosing: Idarubicin 12mg/m2 IV daily for 3 days, daunorubicin 60 mg/m2 or 90 mfg/m2 IV daily for 3 days
  • Adverse effects: The most unique adverse effect is cardiomyopathy. This can include arrhythmias in the acute setting and heart failure in the long-term setting. Patients who are at highest risk for cardiomyopathy from anthracyclines include those with pre-existing heart disease, diabetes, hypertension, and elderly patients. Mucositis is also a common adverse effect.

Supportive Therapies

• Cryoprecipitate transfusion: Cryoprecipitate is commonly given to patients with acute promyelocytic leukemia who have disseminated intravascular coagulation. Low fibrinogen levels (less than 100 mg/dl) warrant transfusion of cryoprecipitate. Cryoprecipitate contains factor I, factor VIII, and von Willebrand factor.
  • Adverse effects: Risks of cryoprecipitate transfusion include volume overload (low risk) and transfusion reaction. In rare cases, sepsis can occur from contaminated product.
• Packed red blood cell transfusion: Red blood cell transfusion is commonly done in patients with acute promyelocytic leukemia. Transfusion is indicated when the hemoglobin level decreases below 7 g/dl.
  • Adverse effects: Risks of red blood cell transfusion include volume overload, alloimmunization, iron overload, and infection (if the product is contaminated). Alloimmunization is usually prevents with clerical checks and proper blood banking techniques. Iron overload occurs after many repeated transfusion and can be prevented via the use of iron chelators such as deferiprone, deferasirox, and deferoxamine.
• Platelet transfusion: Platelet transfusion is indicated when the platelet count decreases to less than 10,000 cells per microliter. This low platelet count occurs especially when a patient received induction chemotherapy, such as cytarabine or anthacycline.
  • Adverse effects: Risks include sepsis (since platelet units are stored at room temperature and there is a high risk for contamination), volume overload, and thrombosis (less likely).
• Granulocyte colony stimulating factor (G-CSF): G-CSF is sometimes uses to help improve the neutrophil count in patients with acute promyelocytic leukemia. It is important to use G-CSF only when there is no active leukemia, as G-CSF can stimulate the proliferation of leukemic blasts. Patients who receive G-CSF are usually those who have had a favorable anti-tumor response to chemotherapy but have not recovered their normal blood counts. G-CSF helps enhance normal blood cell count recovery.
  • Adverse effects: bone pain; leukocytosis; injection site erythema and pain