Untreated Adult Acute Myeloid Leukemia
The two-drug regimen of daunorubicin given in conjunction with cytarabine will result in a complete response rate of approximately 65%. Some physicians opt to add a third drug, thioguanine, to this regimen, although little evidence is available to conclude that this three-drug regimen is better therapy. One study suggested that the addition of etoposide during induction therapy may improve response duration. The choice of anthracycline and the dose-intensity of anthracycline may influence the survival of patients with acute myeloid leukemia (AML). Idarubicin appeared to be more effective than daunorubicin, particularly in younger adults, although the doses of idarubicin and daunorubicin may not have been equivalent.[2-5] No significant survival difference between daunorubicin and mitoxantrone has been reported.
In patients aged 60 years and younger, outcomes for those receiving daunorubicin (90 mg/m2/dose, total induction dosing at 270 mg/m2) were superior to those receiving more traditional dosing (45 mg/m2/dose; total dose = 135 mg/m2). Complete remission (CR) rate was 71% versus 57% (P < .001), and median survival was 24 months versus 16 months (P = .003). No randomized comparison data between daunorubicin at 270 mg/m2 and daunorubicin at 180 mg/m2, nor between daunorubicin at 270 mg/m2 and idarubicin, are available. However, two studies examined when idarubicin (36 mg/m2) versus daunorubicin (180 mg/m2 or 240 mg/m2) were administered to elderly patients. While overall survival (OS) was not impacted by the choice of anthracycline, the percentage of long-term disease-free survivors in a mixed-cure model did appear to be impacted (hazard ratio [HR], 0.8; 0.65–0.98). The addition of the CD33-directed immunotoxin gemtuzumab ozogamicin to cytarabine plus anthracycline or clofarabine plus anthracycline in patients aged 51 to 79 years led to a small increase in median survival (25% vs. 20%; HR, 0.87; 95% confidence interval [CI], 0.76–1.00; P = < .05). In contrast, gemtuzumab did not improve the 1-year survival rate of elderly patients receiving low-dose cytarabine, although the CR rate increased from 17% to 30% (odds ratio [OR], 0.48 (0.32–0.73); P = .006).
The role of high-dose cytarabine in induction therapy is controversial; randomized trials have shown prolongation of DFS [11,12] or no effect [13,14] compared with conventionally dosed cytarabine-based induction chemotherapy. Post hoc analyses of two negative trials suggested potential benefit for the intensified therapy in subsets of patients at high risk for treatment failure;[13,14] however, an analysis of a subset of patients with complex cytogenetic abnormalities treated in a randomized multicenter trial in Germany showed improvement in CR rate with minimal improvement in event-free survival (EFS) (CR, 56% vs. 23%; P = .04; median EFS, 1 month vs. 2 months; P = .04).[Level of evidence: 1iiDii]
AML arising from myelodysplasia or secondary to previous cytotoxic chemotherapy has a lower rate of remission than de novo AML. A retrospective analysis of patients undergoing allogeneic bone marrow transplantation (BMT) in this setting showed that the long-term survival for such patients was identical regardless of whether or not patients had received remission induction therapy (DFS was approximately 20%). These data suggest that patients with these subsets of leukemia may be treated primarily with allogeneic BMT if their overall performance status is adequate, potentially sparing patients the added toxic effect of induction chemotherapy.[Level of evidence: 3iiiDii]
Older adults who decline intensive remission induction therapy or are considered unfit for intensive remission induction therapy may derive benefit from low-dose cytarabine, administered twice daily for 10 days in cycles repeated every 4 to 6 weeks. The CR rate using this regimen was 18% compared with 1% for patients treated with hydroxyurea (P = .006). Survival with low-dose cytarabine was better than survival was with hydroxyurea (OR, 0.60; 95% CI, 0.44–0.81; P = .009).[Level of evidence: 1iiA]
Supportive care during remission induction treatment should routinely include red blood cell and platelet transfusions when appropriate.[18,19] Empiric broad spectrum antimicrobial therapy is an absolute necessity for febrile patients who are profoundly neutropenic.[20,21] Careful instruction in personal hygiene, dental care, and recognition of early signs of infection are appropriate in all patients. Elaborate isolation facilities (including filtered air, sterile food, and gut flora sterilization) are not routinely indicated but may benefit transplant patients.[22,23] Rapid marrow ablation with consequent earlier marrow regeneration decreases morbidity and mortality. Prophylactic oral antibiotics may be appropriate in patients with expected prolonged, profound granulocytopenia (<100/mm3 for 2 weeks). Norfloxacin and ciprofloxacin have been shown to decrease the incidence of gram-negative infection and time to first fever in randomized trials. The combination of ofloxacin and rifampin has proven superior to norfloxacin in decreasing the incidence of documented granulocytopenic infection.[25-27] Serial surveillance cultures may be helpful in such patients to detect the presence or acquisition of resistant organisms.
A long-term follow-up of 30 patients who had AML that was in remission for at least 10 years has demonstrated a 13% incidence of secondary malignancies. Of 31 long-term female survivors of AML or acute lymphoblastic leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.Acute Promyelocytic Leukemia
Special consideration must be given to induction therapy for acute promyelocytic leukemia (APL). Oral administration of tretinoin (all-trans-retinoic acid [ATRA]); 45 mg/mm2/day) can induce remission in 70% to 90% of patients with M3 AML. (ATRA is not effective in patients with AML that resembles M3 morphologically but does not demonstrate the t(15;17) or typical PML-RARA gene rearrangement.)[29-35] ATRA induces terminal differentiation of the leukemic cells followed by restoration of nonclonal hematopoiesis. Administration of ATRA leads to rapid resolution of coagulopathy in most patients, and heparin administration is not required in patients receiving ATRA. However, randomized trials have not shown a reduction in morbidity and mortality during ATRA induction when compared with chemotherapy. Administration of ATRA can lead to hyperleukocytosis and a syndrome of respiratory distress now known as the differentiation syndrome. Prompt recognition of the syndrome and aggressive administration of steroids can prevent severe respiratory distress. The optimal management of ATRA-induced hyperleukocytosis has not been established; neither has the optimal postremission management of patients who receive ATRA induction. However, two large cooperative group trials have demonstrated a statistically significant relapse-free and OS advantage to patients with M3 AML who receive ATRA at some point during their antileukemic management.[37,38]
A randomized study has shown that the relapse rate was reduced in patients treated with concomitant ATRA and chemotherapy compared with ATRA induction followed by chemotherapy given in remission (relative risk [RR] of relapse at 2 years, 0.41; P = .04).[Level of evidence: 1iiDii] This trial also showed a DFS benefit to maintenance therapy, which consisted of either 6-mercaptopurine plus methotrexate (RR of relapse, 0.41), intermittent ATRA (RR of relapse, 0.62), or a combination of all three drugs. The use of 6-mercaptopurine and methotrexate also produced an improvement in OS (RR of relapse, 0.36; P = .005). Two concurrent clinical trials separately conducted in Italy and Spain included ATRA plus anthracycline induction followed by three cycles of postremission and maintenance therapy. The two treatment protocols differed only in the addition of nonanthracycline drugs during postremission therapy cycles in the Italian study; doses of anthracyclines were identical between the two trials. Essentially identical relapse-free survival suggests that the nonanthracycline drugs (i.e., cytarabine, etoposide, and 6-thioguanine) may not contribute significantly to the outcome of patients with acute promyelocytic leukemia induced with ATRA plus anthracycline.[Level of evidence: 3iiiDii]
In contrast, a trial randomly assigned low-risk patients (age <60 years, white blood cell count [WBC] < 10,000/mm3) to receive 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 (CNS). Five-year event-free survival (EFS) was 89%.
In another trial, investigators used an ATO-based regimen, which included gemtuzumab ozogamicin (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-RARA (measured in bone marrow by polymerase chain reaction) in patients who achieve CR 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, DFS, 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.
Treatment options for remission induction therapy:
- One of the following equivalent combination chemotherapy regimens:
- Cytarabine plus daunorubicin.[47,48]
- Cytarabine plus idarubicin.[2-5]
- Cytarabine plus mitoxantrone.
- Dose-intensive cytarabine-based induction therapy.[11,12]
- Cytarabine plus daunorubicin plus thioguanine.
- Treatment of CNS leukemia, if present:
- Intrathecal cytarabine or methotrexate.
- Clinical trials.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with untreated adult acute myeloid leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References
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