Standard induction chemotherapy for non-acute promyelocytic (APL) AML typically involves a treatment regimen that includes cytarabine (Ara-C) and an anthracycline given for 7 and 3 days respectively (7 + 3) [31]. Lowenberg et al. performed a landmark study demonstrating survival improvement for patients ≥65 years of age treated with intensive induction therapy versus supportive care alone [32] with no difference in time spent hospitalized between the two groups. This study provided supporting evidence to offer curative chemotherapy to selected older adults with AML. Population-based data from Sweden and the US similarly show a survival advantage for treatment [25, 33].

In the decades since publication of the landmark Lowenberg trial, many subsequent elderly- specific studies have been conducted. Unfortunately, most have failed to improve upon the suboptimal treatment outcomes seen in the older population (Table 4.2). In most elderly-specific trials, CR rates range from 40 to 60 %, but median survival remains less than a year [22]. Several variations of induction therapy regimens designed to improve the balance of efficacy versus toxicity have been investigated. Dose-attenuation, to minimize toxicity, has not resulted in substantial improvement in outcomes [34, 35]. Investigation of various anthracyclines, such as mitoxantrone and idarubicin, and the addition of etoposide have not improved survival for older adults [28, 36–38]. Use of growth factors including granulocyte colony stimulating factor (G-CSF) and granulocyte macrophage colony stimulating factor (GM-CSF) to decrease duration of neutropenia has not consistently been shown to improve response rates or survival; likewise they do not clearly decrease costs [28, 36, 39–41]. Modulation of the multi-drug resistant efflux pump (MDR1) was pursued using a cyclosporine analog PSC-833 with standard induction chemotherapy in two randomized trials [42, 43]. There was no benefit in response rates or survival and an increased toxic death rate on the experimental arm of the Cancer and Leukemia Group B trial [42].

Investigation of high anthracycline dose intensity has led to a positive outcome in a subset of older adults. Specifically, 90 mg/m² of daunorubicin improved CR rates compared to 45 mg/m² (64 % versus 54 % respectively) for untreated older adults receiving a 7 + 3 regimen [44]. While there was no significant increase in toxicity with higher dosing, the improved CR rate did not translate into better OS. In subset analyses, benefits appeared limited to adults aged 60–65 years. In this subset of “young-old” patients, a survival benefit was noted. No randomized trial data is available regarding comparison of the commonly used 60 mg/m² dosing with 90 mg/m². Two studies have shown positive outcomes when adding gemtuzumab ozogamicin to induction therapy for AML. Gemtuzumab ozogamicin is a humanized anti-CD33 monoclonal antibody linked to calicheamicin which has demonstrated efficacy in the relapsed setting but its use in older adults was after it was voluntarily withdrawn from the US market following a negative trial in younger AML patients. Recent investigations, however, testing a lower dose schedule in combination with intensive induction, suggest that the combination may be efficacious and tolerable. A phase 3 study of 280 adults aged 50–70 with untreated AML showed improvement in relapse-free (23 % versus 50 %) and overall survival (42 % versus 53 %) with the addition of gemtuzumab [45]. Benefit was most evident among patients with favorable cytogenetics. A larger study of patients >50 years old with AML or high risk MDS similarly showed a survival advantage to the addition of gemtuzumab to two different induction regimens without significant increased toxicity [46]. These studies have renewed interest in use of this agent in the curative setting, particularly among those with good risk cytogenetics, although data remains limited for adults >70 years of age. At present, gemtuzumab remains unavailable in many healthcare systems.

Lower intensity regimens have been tested for older adults, particularly for those considered “unfit” for intensive chemotherapy or presenting with more indolent disease. Use of DNA hypomethylating agents (azacitidine and decitabine) has increased significantly in recent years [25]. These agents have demonstrated activity in MDS and subset analyses of patients with low blast count AML (20–30 %) included on MDS treatment trials show evidence of increased response and survival compared to standard care (a mix of low dose Ara-C, best supportive care or 7 + 3) [47]. A multi-center trial of decitabine versus supportive care or low dose Ara-C for adults ≥65 years with intermediate or poor risk cytogenetics reported a CR rate of 18 % for decitabine and, in an unplanned post-hoc analysis, a small survival benefit (median 7.7 versus 6.2 months) [48]. At present, neither drug is approved for treatment of AML by the US Food and Drug Administration but both have an indication approved by the European Medicines Agency. Another low intensity option is low dose Ara-C which has limited activity and can improve survival among patients not fit for intensive chemotherapy compared to supportive care [49]. Low intensity regimens have not been compared in a randomized fashion to intensive therapy for older adults nor have rigorous definitions of fit or unfit been used in clinical trials to optimize extrapolation of data in clinical practice.

Optimal post-remission strategies for older adults are also undefined [31, 50]. It is generally accepted that post-remission therapy or consolidation is needed to translate a complete remission into cure [31]. Typical post-remission treatment includes high dose cytarabine or hematopoietic stem cell transplantation. For older adults with favorable or intermediate risk AML in first CR, consolidation chemotherapy without transplant is typically pursued. In a randomized study of low, intermediate and high dose cytarabine for consolidation in patients who had achieved CR, younger patients benefited from dose escalation while older patients experienced more cerebellar toxicity and no benefit in disease free survival [27]. For younger patients, high dose cytarabine (3 g/m²) is a standard post-remission treatment option for good risk cytogenetics [31]. This treatment is too toxic for older adults and likely contributes to suboptimal outcomes seen in older adults with good risk cytogenetics. In elderly specific trials, lower dose Ara-C regimens as a single agent or in combination with an anthracycline have been tested [36, 51]. In this population, there is no clear evidence to date that multiple courses of consolidation or maintenance therapy improve outcomes when compared to a single course of consolidation therapy [34, 36, 51].