Acute Promyelocytic Leukemia
Tretinoin is used for remission induction in acute promyelocytic leukemia (APL), French-American-British classification M3 including the M3 variant, characterized by the presence of certain genetic markers (i.e., 15;17 chromosomal translocation and/or PML/RAR-α gene) in patients with relapsed or refractory disease following anthracycline-based chemotherapy or in patients for whom anthracycline therapy is contraindicated. Tretinoin also is added to induction with chemotherapy as initial treatment for APL in patients with previously untreated disease.
Tretinoin is indicated for induction of remission, and patients with disease in remission following completion of induction therapy should receive consolidation and/or maintenance therapy for APL. For patients with APL that fails to respond or relapses following induction therapy with anthracycline-based therapy and tretinoin, induction therapy with arsenic trioxide is recommended.
APL is associated with a translocation between the long arms of chromosomes 15 and 17 [t(15;17)]. The 15;17 translocation results in fusion of the genes for promyelocytic leukemia (PML) and retinoic acid receptor-alpha (RAR-α), leading to 2 reciprocal fusion transcripts, PML/RAR-α and RAR-α/PML; the PML/RAR-α fusion protein is thought to play a role in leukemogenesis. Although therapy with tretinoin may be initiated based on the morphologic diagnosis of APL, cytogenetic evaluation to confirm presence of the 15;17 translocation should be performed. If this genetic marker is absent, molecular diagnostic testing for the PML/RAR-α fusion protein should be performed. The response rate to tretinoin has been determined only in patients with the 15;17 translocation and/or the PML/RAR-α gene, and alternative therapy should be considered in patients with APL lacking these genetic markers. Limited evidence indicates that response to tretinoin is poor in patients with a variant t(11;17) chromosomal abnormality.
Induction regimens are used to rapidly reduce the tumor burden to achieve complete remission, which generally is defined as less than 5% leukemic blast cells in the bone marrow and normalization of peripheral blood cell counts. Conventional induction therapy for APL consists of a combination of cytotoxic agents (i.e., an anthracycline and cytarabine), and results in a complete remission in about 60-80% of patients. The rate of early mortality is relatively high in patients with APL undergoing induction therapy, mainly secondary to intracranial or pulmonary hemorrhage in association with disseminated intravascular coagulation, fibrinolysis, and thrombocytopenia. Induction therapy with cytotoxic agents often initially worsens coagulopathy associated with APL, and aggressive replacement of platelets and clotting factors is necessary; although low-dose heparin therapy is used by some clinicians for anticoagulation, other clinicians do not recommend this approach. In contrast, induction therapy with tretinoin typically results in improvement of the coagulopathy associated with APL, and prophylactic heparin therapy generally is not required. However, tretinoin therapy is associated with complications including leukocytosis and a syndrome of respiratory distress described as the retinoic acid-APL syndrome.
The optimal postremission management of patients with APL receiving remission induction therapy with tretinoin has not been established. Patients with disease in complete remission should receive consolidation and/or maintenance therapy for APL following completion of induction therapy. Because of hypercatabolism of tretinoin with prolonged administration
(see Pharmacokinetics), clinical resistance appears to result from continued therapy with the drug (see Pharmacology); however, the use of tretinoin in an intermittent maintenance regimen has been investigated.
Treatment for Relapsed or Refractory Disease
The current indication for tretinoin is based principally on the results from an open-label, single-arm trial and on data from 2 cohorts of compassionate cases treated in multiple centers under the direction of the National Cancer Institute. All patients received tretinoin 45 mg/m daily as a divided oral dose for up to 90 days or 30 days beyond attainment of a complete remission. In the clinical trial, tretinoin therapy was associated with a complete remission rate of 80% in the 20 patients with relapsed APL and 73% in the 15 patients with previously untreated APL; median survival was 10.8 months in the patients with relapsed disease. In the 2 cohorts of compassionate cases of APL, complete remission rates of 50-52% in patients with relapsed disease and 36-68% in patients with previously untreated disease were reported. The median time to achieve a complete remission was between 40-50 days (range: 2-120 days) in all patients studied. Most of the patients in these studies also received cytotoxic chemotherapy during the remission phase. The treatment outcomes observed with tretinoin in these patients compare favorably to the 30-50% complete remission rate and median survival of 6 months or less associated with cytotoxic chemotherapy alone in the treatment of relapsed APL.
Among 4 patients in whom cytogenetic analysis failed to detect the t(15;17) translocation, treatment with tretinoin resulted in a response in 3 patients. Although molecular genetic studies were not performed, these cases probably involved a masked translocation resulting in PML/RAR-α fusion. Responses to tretinoin have not been reported in cases of APL in which PML/RAR-α fusion has been shown to be absent. Although tretinoin has been used to induce second remissions in patients with APL that has relapsed following prior treatment with tretinoin, results have been inconsistent; continuous treatment with tretinoin results in resistance to the drug secondary to increased catabolism and decrease in plasma concentrations (see Pharmacokinetics), and response may be more likely for late relapse occurring after discontinuation of tretinoin therapy.
Limited data on the clinical use of tretinoin in children are available.
(See Precautions and Contraindications: Pediatric Precautions.). A complete remission rate of 67% (8 of 10 males and 2 of 5 females) was reported in 15 pediatric patients (age range: 1-16 years) receiving tretinoin induction therapy for APL.
Initial Treatment for Newly Diagosed Disease
Tretinoin is added to induction with chemotherapy as initial treatment for acute promyelocytic leukemia in patients with previously untreated disease. Although tretinoin has not been shown to increase the complete remission rate or lower morbidity and mortality during induction therapy for APL compared with cytotoxic chemotherapy, the results of 2 large randomized trials have demonstrated that relapse-free (and, in one of the studies, overall) survival is prolonged in patients with previously untreated APL who receive tretinoin as a part of their treatment. In a randomized, multicenter trial in 346 patients with newly diagnosed APL, induction therapy with tretinoin was shown to be superior to induction therapy with standard chemotherapy (daunorubicin and cytarabine) with similar rates of complete remission and early mortality but prolonged disease-free and overall survival resulting from a reduced rate of relapse. Another randomized trial was terminated early when the addition of tretinoin to induction therapy with daunorubicin and cytarabine was shown to result in an increased rate of event-free survival. Long-term follow-up shows that the results of these randomized trials have been maintained.
Based on these findings, most clinicians recommend the addition of tretinoin to induction with chemotherapy as initial treatment for acute promyelocytic leukemia. Although the optimal regimen for induction therapy has not been established, data from initial randomized trials suggests that tretinoin should be administered concurrently with anthracycline-based chemotherapy for newly diagnosed APL. In one of these randomized trials, the use of maintenance therapy (continuous low-dose chemotherapy with mercaptopurine and methotrexate) following induction and consolidation therapy for APL was shown to reduce the rate of relapse and increase the 2-year survival rate. Maintenance regimens including tretinoin have been shown to increase the rate of disease-free or event-free survival.
Acne, Photoaging, and Other Dermatologic Conditions
For topical uses, see Tretinoin 84:16.