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Dose intensity for induction in AML
allogeneic HCT if this is not achieved. While adding GO to induction for patients with intermediate-risk AML was associated with a small improvement in OS, we typically recommend consolidation with HCT in first CR patients. Given the potential for sinusoidal occlusive syndrome after GO and HCT, we reserve GO for patients with CBF-AML, who derive the most benefit44 and for whom we do not routinely recommend HCT in first CR. Aside from increas- ing the risk of sinusoidal occlusive syndrome, GO also pro- longs the duration of cytopenias after 7+3, but is otherwise well tolerated.
FLT3 (tyrosine kinase domain or internal tandem dupli- cation)-mutated AML is another subtype in which addi- tions to 7+3 are becoming standard of care. Midostaurin is a protein kinase inhibitor that targets FLT3 and other pro- tein kinases. The phase III Ratify trial demonstrated that patients receiving 7+3 in combination with midostaurin 50 mg twice daily on days 8-21 compared with 7+3 in combi- nation with placebo had a 4-year OS of 51.4% versus 44.3%, respectively.45 Like GO, midostaurin is also added to consolidation cycles. Midostaurin is well tolerated with rash, nausea, abdominal pain, and diarrhea as the most fre- quent, but often manageable, side effects. However, in patients over 60 years old receiving midostaurin, cardiac toxicity (22%), arrthymias (10%), and pulmonary compli- cations (14%) were more common than antipicated.46 Given the success of midostaurin, the addition of more potent FLT3 inhibitors to induction is being explored in ongoing studies. For instance, 7+3 plus gilteritinib was associated with a composite CR rate of 93.9% in early tri- als.47 We anticipate that additional FLT3 inhibitors will be approved for use in combination with induction in the near future. While not yet approved in combination with 7+3 or 5+2, the addition of venetoclax to IC is also being explored, with promising early results discussed below.
The argument for intensity in older fit popula- tions
In a Swedish registry study of older AML patients, early death was dependent on PS and age, but patients adminis- tered intensive therapy had a lower early death rate regard- less of age.48 At the time, HMA use was rare or non-exis- tent49 so patients treated with hydroxyurea, lower-dose cytarabine, or best supportive care comprised the majority of the comparator group.49 In a study by Bories et al. the OS of patients 60 years and older between 2007-2010 who were selected by their physician to receive IC, or if unfit for IC then azacitidine, or if unfit for azacitidine then best supportive care, was 18.9, 11.3, and 1.8 months, respec- tively.50 One of the limitations of such studies is that PS, disease features, and co-morbidity influence how patients are selected for a given therapy. To adjust for these differ- ences, a propensity score matching analysis that included age, secondary versus de novo AML, bone marrow blast per- cent, and cytogenetics demonstrated an improvement in OS for IC when compared to azacitidine from 6 months after treatment initiation.50 However, PS and co-morbidi- ties were not different between the IC and azacitidine groups and thus not matched. This highlights the subjec- tivity of fitness; clinicians utilized criteria other than PS and co-morbidity to deem the patient unfit for IC. In a multi- center retrospective analysis of 1,295 patients aged 65 years and older treated between 2008-2012, Sorror and col-
leagues tried to account for this type of selection bias by using an AML-composite model51,52 score and found that those who received IC had longer survival than those who received a HMA, including the subset of patients aged 70- 79 years old.53 While this study importantly demonstrates the continued role for IC, the authors acknowledge that it does not include the latest generation of moderate-intensi- ty options. For instance, azacitidine/venetoclax was associ- ated with a composite CR rate of 66.4%, compared with 28.3% for single-agent azacitidine, and has the potential to rival the CR rate of IC in older patients and those with sec- ondary AML.3
Another potential advantage of IC is the ability to achieve cure in a small number of patients without need for ongoing HMA therapy or consolidation HCT. For instance, in a study by Heiblig et al. the median OS for AML patients 70 years and older receiving IC, HMA, or best supportive care was 12.4 months, 11.5 months and 2.6 months and the 3-year OS was 27%, 17%, and 6%, respectively. While median OS was similar after IC and HMA, patients receiving HMA were exceedingly unlikely to live beyond 3 years, whereas a very small number of patients receiving IC survived beyond 10 years.54 As such, in patients who are not candidates for HCT, upfront inten- sive options have the potential for long-term survival and may be considered. While some may argue that patients not fit for IC upfront would by definition not be candidates for bone marrow transplantation, OS improvements asso- ciated with IC even in poor PS patients contradict this dogma. Furthermore, in older or frail patients, the pro- longed stress of HCT may be more difficult to withstand than a single month of intensive treatment.
Clofarabine
Clofarabine is another moderate-intensity regimen explored in older AML patients who were considered unfit for intensive induction55 and at doses of 20 mg/m2 was asso- ciated with a CR/CR with incomplete hematologic recov- ery (CRi) rate of 48%, 30-day mortality of 18%,56 and a median disease-free survival of 37 weeks.55 Based on encouraging phase II results, a phase III ECOG ACRIN-led intergroup trial in newly diagnosed AML patients 60 years and older investigated the use of clofarabine 30 mg/m2 for 5 days compared with daunorubicin 60 mg/m2 days 1-3 and cytarabine 100 mg/m2 days 1-7 and demonstrated similar CR rates, but significantly inferior OS for clofarabine-treat- ed patients (HR=1.41).57 For patients with high-risk cytoge- netics there was no difference in OS between the arms. The authors reached the conclusion that 7+3 induction was still the standard for older fit patients.57 Clofarabine in combina- tion with daunorubicin has also been compared to cytara- bine and daunorubicin, but with no significant differences in remission or survival outcomes.58
The argument for attenuated intensity in older or unfit patients
Attenuated doses of the combination of anthracycline and cytarabine have not been shown to be of more value in older patients who are fit for induction.59-61 However, for patients unfit for IC, lower intensity options have been explored. One of the earliest utilized lower-intensity ther-
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