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S.R. McCurdy and S.M. Luger
viral hepatitis, (vi) resistant infection, (vii) mental illness or cognitive impairment that is uncontrolled, (viii) ECOG PS ≤3 not related to leukemia, (ix) physician judgement.”102 The ninth criteria is critical, as a clinician’s gestalt judgment is often a reason that patients are felt to be ineligible for IC. However, the accuracy of this clinician assessment may differ by physician and by practice patterns. In a study by our group, we showed that in newly diagnosed AML patients over 60, a physician’s gestalt assessment was less likely to categorize patients as frail and more likely to cat- egorize patients as fit than objective measures of fitness.103 Specifically, academic clinicians categorized 37% of newly diagnosed older AML patients as fit, whereas only 17% were fit according to Fried’s frailty index.103
Another key component in determining fitness for IC is PS, which has been tied to early mortality after IC and has a synergistic relationship with age in predicting mortali- ty.11 The German cooperative group identified that the risk of early death after intensive chemotherapy was much higher (24%) in adults over 60 years old and that the CR rate was much lower (50%).104 Kantarjian et al. evaluated 446 non-CBF AML patients 70 years or older receiving intensive cytarabine-based induction and found that the CR rate was 45%, with an 8-week mortality of 36% and a median OS of 4.6 months, with 28% of patients alive at 1 year.105 They identified age ≥80 years, complex karyo- type, ECOG PS 2-4, and creatinine >1.3 mg/dL as risk fac- tors for mortality. The authors argued that a >30% 8- week mortality or a 3-year survival of <10% would pro- hibit the pursuit of IC.104 Even worse, patients with a PS of 3-4 had an 8-week mortality of 77% and a CR rate of 24%. Although this analysis identified patients at high risk of poor outcomes with IC, there was no comparison to less intensive therapies.
One of the drawbacks to the use of PS at the time of AML diagnosis as a predictor of outcomes is the inability to distinguish impairment due to AML from impairment due to comorbidities. To try to distinguish these factors, Klepin and colleagues used functional status 6 months prior to treatment as recalled by patients and found that it was not predictive of survival,106 which supports that the functional status at the moment, regardless of disease- related impairment, is relevant. If the AML is highly pro- liferative and limiting PS, perhaps intensive therapy to achieve a rapid reduction in disease burden is necessary. In fact, this could suggest that poor PS due to disease would be an indication for IC. We know that even in patients with poor PS, IC improves mortality when compared to best supportive care, but whether patients with poor PS would benefit from moderate intensity therapy over IC has yet to be determined.
Geriatric assessments have also been utilized to assess a patient’s fitness for IC. For instance, an abridged geriatric assessment was better associated with survival than Karnofsky Performance Scale (KPS) or a physical perform- ance test in older cancer patients107 and a 30-item geriatric assessment for hematologic malignancy performed well in another study.108 However, whether these metrics can be utilized to select therapy remains to be seen. In a study by Klepin et al., impaired cognition (defined by a modified mini-mental status examination score >77) and a short physical performance battery score <9 were associated with worse OS and increases in 30-day mortality to 23% versus 9.6% in patients 60 years and over receiving treat- ment with cytarabine-based chemotherapy.106 In contrast,
in a randomized trial in older patients treated with chemotherapy, geriatric assessment did not influence out- comes.109
Comorbidity scores represent another avenue for assessing fitness or potential to support treatment toxicity. As a quick measure of comorbidity, polypharmacy (≥4 medications versus ≤1) has been associated with 30-day mortality in older AML patients.110 More formal co-mor- bidity assessments include the hematopoietic cell trans- plantation- comorbidity index (HCT-CI)111 and the Charlson comorbidity index (CCI).112 Both of these tools were developed for patients in advanced stages of disease and may overemphasize the frailty of the AML patient at diagnosis.102 Nonetheless, in newly diagnosed AML patients 70 years and older receiving IC with 7+3, CCI was 0 in 68%, 1 in 13% and 2 in 16%, and patients with a score of >1 had an odds ratio of 0.29 of achieving CR (P=0.05). The HCT-CI, which performs well for predicting mortality after HCT, predicted early death after IC for AML in some,113 but not in other studies.103,106 Sorror and colleagues found that creating a model that added albumin <3.5 g/dL, platelet count <20x109 cells/L, lactate dehydro- genase level, age, and cytogenetic and molecular risk to form an AML composite model outperformed the HCT- CI, augmented HCT-CI, and KPS for predicting mortality with AML induction.114
One of the limitations of utilizing comorbidity to assess fitness for IC is that some patients may have well-com- pensated comorbidities that do not strongly influence out- comes whereas other patients may have few comorbidi- ties, but be frail due to lifestyle or genetics. We used Fried’s frailty phenotype to predict outcomes in newly diagnosed AML patients 60 years and older and found that 17% of patients were fit, 33% were pre-frail, and 50% were frail. All fit and pre-frail patient survived to 100 days, but the 100-day mortality was 51% for frail patients (P=0.01).102 In contrast, HCT-CI and clinician’s gestalt judg- ment were not significantly associated with mortality in our study. Interestingly, many of the frail patients who died received HMA-based therapy or best supportive care, whereas all four frail patients who were treated with IC with either 7+3 or CPX-351 survived.103 While this result needs to be validated in a larger population of patients, it is intriguing that fitness (or its inverse, frailty), while pre- dictive of mortality, may not be the ideal way to exclude AML patients from IC.
Summary
Fortunately, the treatment of AML is evolving rapidly. Ongoing clinical trials are evaluating the role of optimiz- ing intensive therapy with the addition of venetoclax, IDH inhibitors, or FLT3 inhibitors. In addition, the National Institutes of Health and national cooperative groups are developing a study to determine the optimal approach to induction and post-remission therapy using personalized diagnostics including a comprehensive molecular and cytogenetic screening. Based on disease characteristics, risk profile, age and fitness, patients will be assigned to an initial therapy to include evaluating the role of novel ther- apeutics. Remissions will be assessed for minimal residual disease by flow and subsequent therapy will depend on the depth of initial remission in addition to baseline dis- ease characteristics.
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