Untreated Adult AML
The two-drug regimen of cytarabine given in conjunction with daunorubicin (the so-called 7+3 induction therapy) 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 disease-free survival (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] The hypomethylating agents decitabine and azacitidine are used commonly in this population of older adults, particularly in the United States. Although approval of the drugs by the U.S. Food and Drug Administration is for a myelodysplastic syndrome indication, the registration studies leading to approval included patients with 20% to 30% myeloblasts, or what would now be considered oligoblastic AML.[18,19]
One phase III trial randomly assigned 485 AML patients older than 65 years to receive decitabine (n=242) or their preferred choice (n=243) of either supportive care (n=28) or low-dose cytarabine (n=215). Although rates of CR + CRp (CR with incomplete platelet recovery) were more than double in the decitabine arm (17.8%) compared with the treatment-choice arm (7.8%) (P = .001), median OS was not significantly improved for patients receiving decitabine (7.7 months) compared with the treatment of choice (5.0 months) (HR for death for decitabine, 0.85; 95% CI, .69–1.04; P = .11).
Preliminary results from a phase III trial randomly assigned AML patients older than 65 years to azacitidine compared with conventional care regimens of best supportive care, low-dose cytarabine, and 7+3 AML-type induction chemotherapy and similarly showed a nonsignificant difference in median OS for patients receiving azacitidine (10.4 months) versus conventional care (6.5 months) (HR for death for azacitidine, 0.84; 95% CI, .69–1.02; (P = .08).
In sum, low-dose cytarabine, decitabine, azacitidine, or best supportive care can be considered equivalently effective treatment approaches for older AML patients who decline traditional, 7+3 induction chemotherapy.
Supportive care during remission induction treatment should routinely include red blood cell and platelet transfusions when appropriate.[22,23] Empiric broad spectrum antimicrobial therapy is an absolute necessity for febrile patients who are profoundly neutropenic.[24,25] 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.[26,27] 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.[29-31] 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.
Treatment options for remission-induction therapy
- One of the following equivalent combination chemotherapy regimens:
- Treatment of central nervous system leukemia, if present:
- Intrathecal cytarabine or methotrexate.
- Clinical trials.
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.)[37-43] 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.[45,46]
The C9710 (NCT00003934) trial randomly assigned patients receiving ATRA and anthracyclines to two cycles of consolidation with or without arsenic trioxide (ATO). Event-free survival (EFS), the primary endpoint, was significantly better for patients assigned to receive ATO consolidation, with an 80% EFS rate compared with a 63% EFS rate at 3 years (stratified log-rank test, P < .0001). The secondary endpoint, survival, was better in the ATO arm, with an 86% survival rate compared with an 81% survival rate at 3 years (P = .059) The inclusion of ATO led to outcomes for higher-risk patients that were equivalent to the outcomes for lower-risk patients. A phase II study showed that incorporation of ATO in the primary management of APL patients could reduce the total amount of therapy administered.
Investigators at the University of Texas MD Anderson Cancer Center 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%.
This approach was investigated in a randomized, noninferiority trial that compared ATO plus ATRA with an ATRA-anthracycline-based regimen in patients with lower-risk APL. With median follow-up of 34.4 months, 2-year EFS rates were 97% in the ATRA-ATO group and 86% in the ATRA-chemotherapy group (95% CI for the difference, 2%–22%). OS was also better with ATRA-ATO (P = .02).
Most current regimens for the treatment of APL include some form of maintenance therapy, particularly for patients with higher-risk APL. A meta-analysis of randomized trials has indicated that maintenance clearly improves DFS but not OS; however, these studies did not include ATO-containing trials.
- ATRA plus ATO.
- ATRA plus anthracycline, followed by ATO-based consolidation therapy.
Current 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.
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