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S.R. McCurdy and S.M. Luger
ized US intergroup trial, daunorubicin at a dose of 90 mg/m2 compared with 45 mg/m2 for AML patients younger than 60 years old was associated with a higher CR rate at 70% versus 57%, improvements in OS at 46.8% ver- sus 34.6%, and event-free survival at 40.8% versus 28.4%, respectively.17 However, the survival advantage was restricted to patients younger than 50 years old.18 With longer follow-up and additional analyses based on molec- ular classification, it was determined that in patients 50-60 years old who had either an FLT3-internal tandem duplica- tion or an NPM1 mutation higher anthracycline dose was associated with improved OS.19 Lowenberg and colleagues demonstrated that in patients aged 60-83 (median, 67) years old who received cytarabine 200 mg/m2 those receiv- ing an escalated dose of daunorubicin to 90 mg/m2 from 45 mg/m2 had a CR rate of 64% compared with 54%, but sur- vival endpoints did not differ.20 In the subgroup of patients aged 60-65 years old, the CR rate was 73% versus 51%, event-free survival was 29% versus 14%, and OS was 38% versus 23%, respectively, by anthracycline dose. In the Medical Research Council’s (MRC) AML15 randomized phase III trial that compared induction with two cycles of daunorubicin 90 mg/m2 to two cycles of 60 mg/m2, CR rate, toxicity, and OS were similar except for the subgroup of FLT3-mutated patients, in whom the higher dose provided a survival advantage.21,22 While toxicity increases with age for escalating anthracycline doses, higher doses should be considered for patients under 60-65 years old, particularly if FLT3-mutated and possibly if NPM1-mutated. Another important consideration is the choice of anthracycline. Idarubicin and daunorubicin have largely been used inter- changeably.23-25 However, a recent meta-analysis supports the preferential use of idarubicin over daunorubicin, partic- ularly when utilizing a high dose of anthracycline (daunorubicin 90 mg/m2 or equivalent).26
Cytarabine dose and CPX-351
The ideal dosing for cytarabine in combination with an anthracycline for induction is less controversial and appears to be 100-200 mg/m2/day typically administered as a 24-hour infusion.27 Dose escalations beyond 200 mg/m2/day have not been associated with further improvements, for instance, increasing the dose to 400 mg/m2/day did not improve survival.28 Lowenberg and col- leagues demonstrated that, when in combination with an anthracycline, high-dose cytarabine (1000 mg/m2 every 12 hours on days 1-5) was associated with no difference in outcomes, but a higher incidence of toxicity, prolonged hospitalization, and delayed hematologic recovery when compared to cytarabine 200 mg/m2/day as a continuous infusion for 7 days (7+3).29 Early mortality after high-dose cytarabine without an anthracycline was higher than after 7+3 and is of particular concern in patients with renal dys- function. Furthermore, the incidence of cerebellar toxicity is much greater with high-dose cytarabine, limiting its use to otherwise fit patients who are in need of a non-anthra- cycline-containing induction regimen due most often to baseline cardiac dysfunction (ejection fraction <45%30) or cumulative lifetime dose of anthracycline that would exceed doxorubicin 450-550 mg/m2 or equivalent.30,31
In 2017, CPX-351 (liposomal daunorubicin/cytarabine) was approved for patients with secondary AML as a method to improve the delivery of cytarabine based on a
fixed molar ratio. While CPX-351 did not improve survival beyond 7+3 for all newly diagnosed AML patients, a ran- domized trial comparing CPX-351 to standard 7+3 in patients aged 60-75 years with therapy-related AML, AML from prior MDS, or AML with MDS-defining cytogenetics demonstrated a significant improvement in median sur- vival of 9.56 versus 5.95 months (P=0.003), 2-year OS of 31.1% versus 12.3% and, a higher CR rate of 47.7% versus 33.3%, (P=0.016).15 However, the consolidation strategy for the control arm utilized cytarabine 100 mg/m2/day for 5 days and daunorubicin 60 mg/m2 on days 1 and 2 rather than high-dose cytarabine, which is the preferred consoli- dation regimen and can be utilized either as definitive ther- apy or as a bridge to hematopoietic cell transplantation (HCT). HMA/venetoclax, discussed more below, competes for the same population of older patients with secondary AML and produces a promising CR rate, thus we typically consider CPX-351 for patients with secondary AML in whom HMA or HMA/venetoclax has failed.
Triplet chemotherapy
We have established that chemotherapy intensity is important for treating AML with curative intent, however, until 2017, intensity beyond that established above failed to further improve survival due to improvements in relapse being offset by increased toxic deaths.32-34 Etoposide is one of the most widely utilized chemotherapy additions to standard induction, but has not been shown to improve survival when added to 7+335 or when utilized as part of time sequential therapy where the 68% CR rate and medi- an OS of 17.2 months36 are similar to the results associated with conventional 7+3 on clinical trial.37 The addition of cladribine, but not fludarabine, to 7+3 for AML patients aged 17-60 years was associated with improvement in OS in patients aged 50 to 60 years old, those with a leukocyte count at presentation above 50x109/L, and patients with an unfavorable karyotype.38 In contrast, in patients 60-77 years old, the addition of cladribine to 7+3 did not improve OS or CR.39 However, in a subgroup analysis of patients aged 60-65 years old with good- or intermediate-risk cyto- genetics there was an OS benefit with the triplet.39
Although the addition of a third standard cytotoxic agent to 7+3 has not been widely adopted, two Food and Drug Administration (FDA)-approved therapies have been shown to boost efficacy in specific populations without significant increases in toxicity: GO and midostaurin. GO is a monoclonal antibody to CD33 attached to the tradi- tional cytotoxic drug calicheamicin. Adding 3 mg/m2 of GO to 7+3 (daunorubicin 60 mg/m2) significantly improved the survival of patients with good-risk AML,40 leading to its approval for CD33+ AML. A subsequent meta-analysis demonstrated that adding GO to induction for CBF-AML produced a 20.7% absolute survival benefit at 6 years.41 GO in combination with 7+3 has also been explored for NPM1-mutated AML in which it was associ- ated with a reduction in relapse, but a higher early death rate (10.3% vs. 5.7%), which translated into no improve- ment in event-free survival.42 Subgroup analyses suggested a benefit in younger female and FLT3-negative patients, but given that the primary endpoint was not reached, we do not routinely add GO to induction or consolidation for NPM1-mutated AML and instead monitor patients closely for rapid minimal residual disease clearance43 and consider
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haematologica | 2021; 106(10)