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Dose intensity for induction in AML
Disease-related factors
Primary predictors of response to chemotherapy in AML are molecular and cytogenetic factors and these will be used to guide selection of upfront chemotherapy in the years to come. For instance, in patients 75 years and older treated with IC in the AML Cooperative Group (AMLCG)-1999 trial, the average number of mutations was four and 83% of patients had a mutation in at least one of the following genes: TET2, DNMT3A, NPM1, SRSF2, ASXL1, TP53, and SF3B1.79 While NPM1 and FLT3-internal tandem duplication did not significantly affect OS, adverse-risk cytogenetics (according to the MRC) and IDH1 mutations were associated with poor prognosis and chemorefractoriness.79 Overall prognosis was poor with intermediate-risk patients having a 3-year survival rate of 10-15% and no patients with unfavorable- risk AML being alive at 3 years.79 While in this study, NPM1 mutations did not influence survival, an earlier study demonstrated that NPM1 mutations in octogenari- ans were associated with improved survival after IC.80 In addition, the CR rate for favorable-risk disease in older patients ranges from 89-95% for CBF-AML to 69% for CEBPA-double mutant disease, with CR rates for NPM1- mutated AML falling in between.81 Furthermore, 3-year OS differs: 47% versus 21% for CBF-AML versus CEBPA- double mutant AML, respectively.81 Given the relatively high CR rate, older patients with favorable-risk AML could be considered for intensive induction. In AML patients aged 70-79 years old with PS 0-2, worse cytoge- netic risk is associated with higher early mortality, but with IC improving early mortality relative to palliation only.4 This supports the pursuit of chemotherapy in patients over 70 years old, but unfortunately does not pro- vide guidance as to the optimal regimen.
In older AML patients with good-risk profiles such as those with NPM1 mutations82 or CBF, IC may have the potential to achieve long-term survival or even cure. Early studies demonstrating high response rates of NPM1- mutated AML to venetoclax combinations73,76 suggest that the addition of venetoclax to IC (7+3 or 5+2, etc.) may improve outcomes in the future. On the other hand, older patients with IDH1-mutated AML are unlikely to benefit from IC and have excellent response rates to azacitidine/venetoclax. In AML patients with chromo- some 5 and/or chromosome 7 abnormalities,83 MDS-relat- ed changes,84 and in those with low blast counts,85 HMA therapy has been associated with improved OS when compared with intensive cytarabine-based chemotherapy, supporting HMA-based therapies such as HMA/veneto- clax in these populations. Similarly, those with monoso- mal karyotypes86-89 or other adverse cytogenetics who are 75 years and older have essentially 0% 3-year survival with IC79 and should be considered primarily for HMA/venetoclax. Patients with secondary AML or AML with MDS-defining cytogenetics also do poorly with stan- dard IC and may benefit from initial therapy with azaciti- dine/venetoclax if they have not previously been treated with HMA. If they are refractory to HMA or HMA/vene- toclax, CPX-351 rather than 7+3 induction can be consid- ered, as can the addition of venetoclax to HMA in HMA refractory patients.
TP53-mutated AML is a particular challenge given that it is associated with a 2-year OS rate of 9%.90 Lower-inten- sity therapy has been associated with equivalent response
rates to those in patients treated with higher-intensity therapy, but with less toxicity.91,92 For that reason, IC is less frequently employed in patients with TP53 mutations and clinical trials exploring HMA combinations such as those with venetoclax, magrolimab, or eprenetapopt93 are being pursued specifically in this population. Given the poor prognosis of this subgroup to all approved therapies, patients should consider clinical trials if available.
A subgroup of patients who should primarily be consid- ered for IC would be those with highly proliferative AML in whom a delay to CR or effective disease control may lead to excess early mortality. Proliferative leukemia is often associated with CBF, NPM1-, or FLT3-mutated AML, which responds well to initial 7+3 alone or in com- bination with a targeted agent and supports the use of IC if a delay to determining molecular and cytogenetic fea- tures is not feasible. Given the risk of tumor lysis syn- drome with venetoclax, cytoreduction to a white blood cell count <20x109/L is preferred prior to initiation and if this is achieved by hydroxyurea then the resulting mucosi- tis may limit oral chemotherapy options and result in missed doses. Thus, if patients are candidates for IC and have proliferative disease, we generally recommend inten- sive IC.
In addition to age, cytogenetic and molecular risks, and features of proliferative disease, another important con- sideration when selecting upfront therapy is candidacy for subsequent HCT. The vast majority of older adults have intermediate- or poor-risk cytogenetics, in whom HCT is associated with a survival benefit. Yet, patients may be deemed unfit for HCT at the time of diagnosis because of disease burden affecting PS, but may become candidates for HCT once treated.94 However, given that CR is often considered a pre-requisite for HCT, strategies with the highest rates of achieving CR are those that should be pur- sued. While median survival rates after HMA and IC are similar for patients 60 years and older, the CR rate is sig- nificantly lower.67,95-99 Given that patients are more likely to undergo HCT if they reach a CR,100 then achieving a CR should be a primary goal if HCT is the destination. However, upfront intensity may not be required if less intensive therapy can achieve a CR without affecting PS. This strategy has been associated with success in early tri- als of azacitidine/venetoclax in whom some patients went on to HCT.101 However, to understand which therapy best achieves CR would require an upfront trial of 7+3 versus HMA/venetoclax rather than comparisons of HMA/vene- toclax and HMA alone. Thus, there is more work to be done.
Patients’ fitness
One of the primary reasons for a patient not being eligi- ble for IC is being categorized as “unfit.” However, lack of a widely utilized consensus definition of what fitness entails often means that this is a subjective clinical assess- ment. An Italian consensus group provided a definition of unfit that is similar to many criteria used in clinical trial enrollment and includes “(i) age over 75, (ii) congestive heart failure with an ejection fraction ≤50%, (iii) DLCO ≤65% or FEV1 ≤65%, lung neoplasm, or requiring oxygen, (iv) hemodialysis, or renal cancer and age over 60, (v) liver cirrhosis Child B or C or liver function tests >3 times nor- mal values, or age over 60 with biliary or liver cancer or
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