The induction of remission of APML by trans-retinoic acid (ATRA) is associated with the differentiation of immature promyelocytes into mature granulocytes, followed by the restoration of normal hematopoiesis as the patient enters remission. Data in support of this mechanism include:
• The absence of bone marrow hypoplasia during induction with ATRA
• The persistence of Auer rods in morphologically mature granulocytes
• The persistence of t(15;17) in morphologically mature granulocytes
• The appearance of immunophenotypically unique intermediate cells that express both mature and immature cell surface antigens (CD33+, CD16+ cells), indicating their origin from leukemic promyelocytes.
Dose of trans-Retinoic Acid
Dose range: 10-100 mg/m2/day.
Most commonly employed dose: 45 mg/m2/day in a single or two equally divided doses
Time required to induce remission: 1-3 months (median time to remission, 44 days); resolution of APML-associated coagulopathy is frequently the first sign of response to ATRA
Range of duration of remission: 1-23 months (median duration of remission, 3-5 months).
The unique pharmacologic feature of ATRA leads to the resistance of APML cells to ATRA and, for this reason, ATRA is not useful as a maintenance agent in the therapy of APML. ATRA does not cross the blood-brain barrier. Therefore, ATRA is ineffective in the treatment of CNS involvement with APML.
The side effects of ATRA include skin dryness, itching, peeling, angular stomatitis, headache, pseudotumor cerebri, hypertriglyceridemia, and hypercholesterolemia. The following side effects occur only in patients with APML:
2. Hematologic a. Marked leukocytosis b. Thrombosis
3. Gastrointestinal: Hepatic liver enzymes and bilirubin level elevations
4. Cardiovascular a. Congestive heart failure b. Fluid overload c. Pericardial effusion
5. Pulmonary: Retinoic acid syndrome, which is characterized by respiratory distress, fever, pulmonary infiltrates radiographically, pleural effusion, weight gain, death due to progressive hypoxemia, and multiple-organ failure. Prompt treatment with dexamethasone (12 mg every 12 hours for 3 days) stops the progression of this syndrome.
ATRA treatment is associated with leukocytosis involving a count of 20,000/mm3 or more leukocytes in 50% of patients with APML. The peripheral WBCs comprise myeloblasts, promyelocytes, intermediate cells (CD33+, CD16+ cells), and neutrophils. Nuclear shrinkage, nuclear elongation, and marked nuclear and cytoplasmic vacuolation characterize the granulocytic cells.
Management of Acute Promyelocytic Leukemia with ATRA
1. Treat with ATRA as described previously (45 mg/m2/day in a single or equally divided doses).
2. Perform surveillance coagulation studies periodically and treat as follows:
a. Disseminated intravascular coagulation (DIC): Treat with platelet and fresh frozen plasma transfusion to maintain a platelet count of 50,000/mm2 or more and a fibrinogen level of at least 100 mg/dL. Heparin is indicated for patients with marked or persistent elevation of fibrin degradation products.
b. Fibrinolysis: The use of epsilon-aminocaproic acid is reserved for patients with life-threatening hemorrhages.
3. After the induction of remission with ATRA, the patient should be treated with three cycles of the cytosine arabinoside and anthracycline regimen commonly employed in the treatment of AML. Daunorubicin 60 mg/m2/day IV bolus for 3 days and cytarabine 200 mg/m2/day by continuous infusion IV for 7 days. This chemotherapy is repeated after hematologic recovery. After recovery then the second course is followed by daunorubicin 45 mg/m2/day IV bolus for 3 days with cytarabine 1 g/m2 every 12 hours for 4 days. Maintenance therapy consists of ATRA 45 mg/m2/day for 15 days every 3 months and 6-mercaptopurine 90 mg/m2/day and methotrexate 15 mg/m2/week orally for 2 years.
The use of reverse transcriptase polymerase chain reaction (RT-PCR) for detecting PML-RARa fusion transcripts may be helpful for the identification of patients with MRD, and it is possible that they may benefit from further antileukemic therapy.
Studies are now under way to investigate the use of arsenic as a differentiation inducer in APML.
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