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Dose intensity for induction in AML
eligible for standard induction. What has been clearly demonstrated is that AML-directed chemotherapy improves survival for newly diagnosed patients when compared with best supportive care and that this benefit extends to the elderly and those with poor PS.4,5 In 1989, Lowenberg and colleagues performed a randomized trial of intensive induction chemotherapy (IC) versus best sup- portive care combined with mild cytoreductive therapy for relief of progressive symptoms in patients 65 years and older. Despite the concern that older patients would suffer from complications of intensive therapy, survival was significantly better in those treated with IC and fre- quency of hospitalization was not different between the treatment groups.6 Despite these early findings, histori- cally the majority of older adults with AML were not offered chemotherapy. For instance, SEER data for patients with AML aged 65 years and older from 1991- 1996 demonstrated that the median survival was 2.4 months with a dismal 2-year overall survival (OS) of 6%. While those receiving chemotherapy survived longer, only 34% of patients received chemotherapy.7 From 2000 to 2009, treatment rates for older AML patients increased from 35% to 50% and leukemia-directed therapy reduced the risk of death by 33% with a median OS of 18.9 months in those receiving IC, 6.6 months in those receiving HMA, and 1.5 months in patients receiving best supportive care.8 In a propensity matched analysis, patients 60 years and older who received IC had a median survival of 197 days whereas those receiving best sup- portive care had a median survival of 53 days.9 Furthermore, a randomized trial comparing IC to best supportive care demonstrated improvement in OS for patients over 65 receiving IC.10 The benefit of treatment also appears to extend to patients aged 70-79 years old, in whom a goal of achieving remission has been associated with improved survival.5
In one of the original studies of the interaction PS and age in AML, older age and poorer PS had a synergistic effect on early mortality after IC. Thirty-day mortality in patients ≥75 years old with Eastern Cooperative Oncology Group (ECOG) PS of 3 was 82% compared with 50%, 18%, and 14% for those ≥75 years old with PS of 2, 1, and 0, respectively.11 In AML patients aged 70-79 years old with PS 0-2 the 8-week mortality was 8% in those with intermediate-risk karyotype and 22% in those with high-risk karyotype, compared with 23% and 47% if given palliative therapy only.4 Interestingly, even in AML patients with an ECOG PS 3-4, 8-week mortality was shown to be 76% in those treated with palliation and 50% in those treated with intensive treatment,4 which suggests that even in those with a poor PS, treatment does not necessarily increase early mortality.
Whether, patients with a poor PS would fare better with less intensive therapy remains to be seen. It is pos- sible that the burden of their disease compromises their PS and that less intensive therapies, which take weeks or months to achieve remission, would not adequately con- trol their leukemia in time to reduce early mortality. For the first time, we have moderate intentsity therapies that offer similar complete resmission (CR) rates compared to IC, albeit with a delay to time of acheiving remission. Studies that compare therapy intensity in patients with poor PS, by fitness level, and by proliferative disease fea- tures are needed to determine the best approach in these high-risk patients.
When to treat?
Time from diagnosis to treatment was historically tied to survival outcomes, with increased mortality associated with delays in initiation of chemotherapy. In 2009, Sekeres et al. published that this was true for patients <60 years old, but not for those 60 years and older.12 For younger patients, delays beyond 5 days were associated with inferior sur- vival. Importantly, patients with a white blood cell count at diagnosis >50x109/L were excluded from the analysis. The authors hypothesized that older AML patients had biolog- ically different disease that was inherently more resistant to chemotherapy. Using chromosomal analysis to identify such patients would allow pursuit of alternatives to stan- dard IC. With further advances in the molecular and chro- mosomal categorization of AML, delaying therapy to allow individualization of treatment, particularly for older patients, is becoming more common. For instance, our group demonstrated that rapid fluorescence in situ hybridization testing could identify 86% of patients with myelodysplastic syndrome (MDS)-defining cytogenet- ics,13,14 a population that has been shown to benefit from CPX-351 (liposomal daunorubicin and cytarabine).15 In addition, rapid identification of core-binding factor (CBF) leukemia through fluorescence in situ hybridization or polymerase chain reaction analysis allows incorporation of gemtuzumab ozogamicin (GO) into induction, which has been shown to improve survival. For all FLT3-mutated patients, the addition of an FLT3 inhibitor to IC is now standard of care. With regard to molecular analyses, the initial management in older patients may change with the presence of an IDH or TP53 mutation. Delaying therapy to allow for genetic classification is, therefore, being increas- ingly employed.
Given the growing role of chromosomal and molecular testing to tailor initial therapy, Rollig et al. reviewed the outcomes of patients whose treatment was delayed to allow for personalized treatment choices. In their study, with 0-5, 6-10, 11-15, and >15 days from diagnosis to start- ing treatment, the 2-year OS was 51%, 48%, 44%, and 50%, respectively, with a 30-day mortality rate of approx- imately 4% in each group.16 Importantly, there was no dif- ference based on whether the initial white blood cell count was >50x109/L or ≤50x109/L. However, patients with a high white blood cell count, high bone marrow blast count, and/or high lactase dehydrogenase had a shorter time from diagnosis to treatment.16 The authors concluded that physicians were appropriately selecting those patients who could postpone therapy initiation and that advances in supportive care such as the use of anti-fungal agents may decrease early mortality to allow safe delays. In addition, stabilizing cytoreductive measures such as hydroxyurea and leukapharesis can be employed to allow informed treatment decisions. As such, we support rapid turnaround of fluorescence in situ hybridization testing for MDS-defin- ing cytogenetics and CBF, as well as molecular analysis for TP53, IDH, and FLT3 mutations. We anticipate that with time, as other genes become targets for leukemia therapy, the list of mutations necessary for rapid testing will grow.
Anthracycline dose
One of the often debated questions with regard to IC intensity is the ideal dose of anthracycline. In a random-
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