Untreated Adult Acute Myeloid Leukemia
In contrast, a trial randomly assigned low-risk patients (age < 60, white blood cell count [WBC] < 10,000/mm3) to receive all-trans -retinoic acid (ATRA) and daunorubicin as induction therapy, followed by daunorubicin consolidation and ATRA plus mercaptopurine plus methotrexate as maintenance therapy. Patients were randomly assigned to receive cytarabine in the induction and consolidation modules, or not. The trial was stopped at an early interim analysis following randomization of 172 patients. The cytarabine group demonstrated a superior 2-year relapse rate (4.7% vs. 15.9%, P = .011), 2-year EFS (93.3% vs. 77.2%, P = .002), and 2-year OS (97.9% vs. 89.6%, P = .007).[Level of evidence: 3iiiA] The latter study used a different chemotherapy platform than the one used by the Italian and Spanish groups, which reported no benefit to cytarabine.
Studies are beginning to examine the inclusion of arsenic trioxide (ATO) in the management of previously untreated patients. In one trial, 85 newly diagnosed patients were treated with ATRA plus ATO until remission; hydroxyurea or idarubicin and cytarabine were added if the WBC was greater than 10,000/mm3. This was followed by three cycles of consolidation (ara-C plus daunorubicin, plus cytarabine, and ara-C plus homoharringtonine) and maintenance with five cycles of sequential ATRA (1 month), ATO (1 month) and 6-mercaptopurine plus methotrexate (1 month). Eighty patients achieved remission with five induction deaths. Four relapses developed between 8 months and 39 months following remission attainment, all of which were in the central nervous system. Five-year event-free survival (EFS) was 89%.
In another trial, investigators used an ATO-based regimen, which included gemtuzumab ozogamycin (GO) as the only cytotoxic drug. Patients received ATRA plus ATO induction; patients also received a dose of GO if the WBC was greater than 10,000/mm3 on presentation or rose to over 30,000/mm3 during induction. Patients in remission received alternating months of ATO and ATRA for a total of seven cycles; GO was substituted if either ATO or ATRA were discontinued as a result of toxicity. Eighty-two patients were treated; seven patients died during induction, the remainder achieved remission. Three patients relapsed and four patients died during remission; thus EFS was approximately 76%.
Presence of the unique fusion transcript PML-RAR? (measured in bone marrow by polymerase chain reaction) in patients who achieve complete remission may indicate those who are likely to relapse early. In addition, a retrospective review of randomized trials from the Southwest Oncology Group suggested that the dose-intensity of daunorubicin administered in induction and postremission chemotherapy may significantly impact on remission rate, disease-free survival, and OS in patients with M3 AML. Although most patients currently receive ATRA in their induction therapy, for patients who do not, careful management of coagulopathy is required. Coagulopathy is occasionally a problem in patients undergoing induction with ATRA plus chemotherapy. This coagulopathy can lead to catastrophic intracranial bleeding but can be well-controlled with low-dose heparin infusion (in the setting of clotting) or with aggressive replacement of platelets and clotting factors.