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Idarubicin dose escalation increases leukemia-free survival in AML
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Patients with acute myeloid leukemia who received an increased cumulative dose of idarubicin during consolidation therapy demonstrated longer leukemia-free survival without an increase in nonhematologic toxicity than patients who received a standard dose, according to results of a phase 3 study.
“The Australian Leukemia & Lymphoma Group (ALLG) has previously explored the use of high doses of cytarabine during induction therapy,” Kenneth F. Bradstock, MB, PhD, from the Sydney Medical School at the University of Sydney in Australia, and colleagues wrote. “To further improve outcomes in adult AML by anthracycline dose escalation, the ALLG ... [examined] the impact on outcome of an increased idarubicin dose intensity during consolidation therapy after high-dose cytarabine-based induction.”
The analysis included 293 patients (median age, 45 years; range: 16-60) with previously untreated AML in complete remission after induction therapy. Patients received two cycles of consolidation therapy with 100 mg/m2 cytarabine daily for 5 days, 75 mg/m2 etoposide daily for 5 days and idarubicin 9 mg/m2 daily for either 2 days (standard arm; n = 146) or 3 days (intensive arm; n = 147).
Three-year leukemia-free survival served as the primary endpoint. Three-year OS, toxicity experienced from consolidation therapy and any effect on residual disease served as secondary outcomes.
Both groups were balanced for age, karyotypic risk and frequency of FLT3-internal tandem duplication (ITD) and NPM1 gene mutations. Twelve percent of all randomly assigned patients had adverse karyotype. Forty-two percent of 229 patients tested for NPM1 mutations tested positive, and 32% of 230 patients tested for FLT3-ITD mutations tested positive.
Overall, 120 patients (82%) in the standard arm and 95 patients (66%) in the intensive arm completed planned consolidation (P < .001). The median total dose of idarubicin administered during the two consolidation courses of therapy was 36 mg/m2 (range, 17-45) — or 99% (range, 47-125) of the protocol dose — among patients in the standard arm compared with 53 mg/m2 (range, 18-73) — or 98% (range, 33-136) of the protocol dose — among patients in the intensive arm.
Duration of grade 3 to grade 4 neutropenia was longer in the intensive arm in course one (median, 10 vs. 6 days; P < .001) and course two (median, 12 vs. 9 days; P < .001).
Duration of grade 3 to grade 4 thrombocytopenia also was prolonged in the intensive arm in course one (median, 20 vs. 14 days; P > .001) and course two (median, 21 vs. 15 days; P = .01).
There were no differences in grade 3 to grade 4 nonhematological toxicities between the arms.
Two deaths occurred in the intensive arm during consolidation therapy. No deaths occurred in the standard arm.
Over a median follow-up of 5.3 years (range, 0.6-9.9), 3-year leukemia-free survival was higher in the intensive arm than the standard arm (47% vs. 35%; HR = 0.74; 95% CI, 0.55-0.99).
The estimated median leukemia-free survival was 2.13 years (95% CI, 1.07 to > 9) among patients in the intensive arm compared with 0.93 years (95% CI, 0.80-1.49) among patients in the standard arm.
At 5 years, OS was 57% among patients in the intensive arm compared with 47% in the standard arm, which was not a significant difference.
The researchers did not observe any evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3-ITD and NPM1 gene mutation subgroups.
“An increased dose intensity of idarubicin during consolidation therapy ... represents a reasonable strategy to explore to further improve outcomes for this disease,” the researchers wrote. – by Melinda Stevens
Disclosures: Bradstock reports royalties from Westmead Hospital and travel accommodations and expenses from Amgen Australia. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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Jonathan M. Gerber
Substantial evidence suggests that higher induction doses of anthracyclines may improve outcomes in acute myeloid leukemia, particularly in select patient populations. The Australasian Leukemia & Lymphoma Group nicely explored whether similar dose escalation of anthracyclines during consolidation therapy also can improve outcomes in patients with AML aged 15 years to 60 years, in this prospective, randomized trial.
Three-year leukemia-free survival appeared higher in the group receiving more intensive anthracycline consolidation than in the standard arm (47% vs. 35%). Although researchers also reported higher 5-year OS in the intensive group, this did not reach statistical significance.
Notably, 35% of patients in the intensive group did not receive both planned consolidation cycles, including 19% due to toxicity. Interestingly, 3-year leukemia-free survival appeared highest in those patients who only received one of the two planned intensive consolidation cycles (69%), perhaps due to the impact of bone marrow transplantation (BMT). It should also be noted that no significant differences in survival occurred between patients in each treatment arm who underwent allogeneic BMT in first complete remission.
Although intensive anthracycline consolidation seemed to improve leukemia-free survival in this cohort of patients aged 60 years and younger, the outcomes still seem rather humbling. Even with more intensive therapy — and allowing for use of allogeneic BMT — most patients still relapsed, and OS did not significantly improve. Meanwhile, considerable toxicities precluded a planned second cycle in a sizeable fraction of the group assigned to intensive consolidation.
These results highlight the challenges in treating AML. We appear to be reaching a ceiling with conventional chemotherapeutic agents, encountering diminishing returns in terms of benefits — particularly OS — and increasingly limiting toxicities. These problems are further magnified in patients aged older than 60 years, who represent over half of all patients with AML and who typically harbor more resistant disease and are less able to tolerate intensive therapy. Novel approaches that are more effective, but less toxic, are greatly needed to treat this disease.
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