**1. Acute myeloid leukaemia: a disease of older individuals**

Acute myeloid leukaemia (AML) is a heterogeneous group of malignant haematological diseases. It is predominantly a disease of older adults, with a median age at diagnosis of 68 years [1]. Indeed, 75% of the AML patients are older than 60 years (**Figure 1**). Besides a higher incidence of AML at older age, AML in older adults differs biologically and clinically from AML in younger adults [2]. AML in older adults is characterised by a markedly reduced long-term survival resulting from the combination of poor chemotherapeutic tolerance and inherent chemotherapy resistance compared with younger AML patients [3]. AML in older adults has a lower frequency of favourable core-binding chromosomal abnormalities and a higher incidence of complex aberrant karyotypes [4, 5]. These differences in clinical and cellular behaviour of AML in older adults suggest activation of different target genes by oncogenic events in aged stem or progenitor cells compared with younger stem or progenitor cells. Indeed a distinct gene-expression profile noted for older compared to younger adults with AML supports a molecular basis for disparities in outcome related to age [2, 5, 6]. In addition, more frequent comorbid conditions,

**Figure 1.**

*AML incidence rates by age at diagnosis (2013–2017).* Reproduced from: SEER Cancer Stat Facts: Acute Myeloid Leukaemia. National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/statfacts/html/ amyl.html

the decreased immune competence of older patients and psychosocial factors influence treatment outcome of AML in older adults. The effects of age on both disease- and patient-related factors result in a lower rate of disease remission, a higher incidence of early death during chemotherapy, and a reduced probability of longterm survival [2, 3]. In light of this, population based studies report a treatment percentage of only 30% in AML patients aged 65 and older [7, 8]. Indeed, regardless of treatment, outcomes for older AML patients are unsatisfactory, with median overall survival (OS) of 5–10 months and 5-year survival of about 10% [9–11]. In contrast with the progress made for younger adults with AML, the treatment in older adults has not improved significantly in recent decades, despite numerous efforts to find effective and tolerable treatments [12].

#### **2. Treatment options in older adults with AML**

The optimal treatment of older adults with AML in daily clinical practice remains challenging, and is dependent on patient characteristics (age, performance, comorbidities), disease characteristics (cytogenetic and molecular abnormalities, white blood cell count) and the preference of the patient [3]. Regular treatment options include: best supportive care (BSC), low-dose chemotherapy (e.g. low dose cytarabine (LDAC)), hypomethylating agents (HMA), and intensive chemotherapy (IC) (**Table 1**).

Population data from the Swedish Acute Leukaemia Registry suggest the majority of older patients should be considered candidate for antileukemic therapy [13]. However, only few prospective randomised studies in older AML patients are available to guide treatment decisions. A pivotal clinical trial, although with a limited number of patients (n = 60), showed that standard IC decreases early death rates and improves long-term survival compared with BSC [14]. Also LDAC and gemtuzumab ozogamicin (GO) have been reported to result in superior survival compared with BSC; although neither had an effect in patients with adverse cytogenetics [15, 16].

In addition to IC and LDAC, the armamentarium for the treatment of AML has been expanded in recent years with two cytosine analogues with DNA hypomethylating properties: azacitidine and decitabine. The hypomethylating agents (HMAs) azacitidine and decitabine have relatively mild side effects and are particularly feasible for the treatment of AML in older patients and patients with comorbidities.

**167**

with mutated *IDH1* or *IDH2*.

*Treatment of AML in Older Patients*

**Intensive chemotherapy** [9, 14, 30] **+ Gemtuzumab ozogamicin** [31, 32, 35, 36]

**New agents A. Venetoclax** + HMA [19] + LDAC [60]

**D. Glasdegib** + IC [65] + LDAC [66] **D. CPX-513** (68,67)

**Table 1.**

**B. IDH inhibitors** [61, 62]

**C. FLT3-inhibitors + IC** [33]

*Treatment options and outcomes for older AML patients.*

*DOI: http://dx.doi.org/10.5772/intechopen.94979*

Importantly, both azacitidine and decitabine have proven efficacy in patients with adverse cytogenetic abnormalities. Although not in their primary analyses, recent phase III trials have shown the superiority of azacitidine and decitabine treatment

**Response: CR/CRi (%)**

> 41–70 36–78

— — 66 48 30–40

> 78 —

40 17 53–67

**Low dose chemotherapy** [15] 18 4 — — **Hypomethylating agents** [17, 18, 40, 41, 44] 15–47 8–13 (25) 20–50 Not curative,

**Median OS (months)**

> 10–20 7–34

— — 14.7 8.4 11–13 —

> 14.7 8.8 15

**2-year OS (%)**

> 12–42 53

> > — — — — —

45.6

**5-year OS (%)**

> 10–30 36

unless consolidated with HCT

—

New combinations of HMAs with targeted drugs are being explored. Recently, the results of a phase 3 study of azacitidine in combination with venetoclax versus azacitidine alone in treatment-naïve adults with AML, who were ineligible for standard induction therapy, have been reported (VIALE-A trial; NCT02993523). This study confirmed the additive value of venetoclax to azacitidine treatment by an increase in remission rate from 28–66% and an increase in median OS from 9.6 months to 14.7 months [19]. The high remission rate which was achieved by adding venetoclax to azacitidine treatment is striking. Studies are ongoing to explore the added value of IDH1 or IDH2 inhibitors (ivosidenib or enasidenib) in combination with azacitidine and azacitidine plus venetoclax, for those older AML patients

Optimal treatment selection for older patients also requires consideration of treatment tolerance and life expectancy, derived from the evaluation of comorbidities, physical function and cognition [2]. Charlson comorbidity index >1 and haematopoietic cell transplantation comorbidity index (HCT-CI) >2 have been reported to be associated with lower remission rates, increased early mortality and decreased survival in patients treated with IC [20–22]. In a study on 177 patients aged ≥65 years who received IC the early death rates were 3% if the HCT-CI score was 0, 11% if the HCT-CI score was 1 to 2, and 29% if the HCT-CI score was ≥3 [20].

compared with conventional care for older AML patients [17, 18].

**2.1 Treatment selection: who is fit and who is not fit?**


#### **Table 1.**

*Acute Leukemias*

**Figure 1.**

amyl.html

the decreased immune competence of older patients and psychosocial factors influence treatment outcome of AML in older adults. The effects of age on both disease- and patient-related factors result in a lower rate of disease remission, a higher incidence of early death during chemotherapy, and a reduced probability of longterm survival [2, 3]. In light of this, population based studies report a treatment percentage of only 30% in AML patients aged 65 and older [7, 8]. Indeed, regardless of treatment, outcomes for older AML patients are unsatisfactory, with median overall survival (OS) of 5–10 months and 5-year survival of about 10% [9–11]. In contrast with the progress made for younger adults with AML, the treatment in older adults has not improved significantly in recent decades, despite numerous

*AML incidence rates by age at diagnosis (2013–2017).* Reproduced from: SEER Cancer Stat Facts: Acute Myeloid Leukaemia. National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/statfacts/html/

The optimal treatment of older adults with AML in daily clinical practice remains challenging, and is dependent on patient characteristics (age, performance, comorbidities), disease characteristics (cytogenetic and molecular abnormalities, white blood cell count) and the preference of the patient [3]. Regular treatment options include: best supportive care (BSC), low-dose chemotherapy (e.g. low dose cytarabine (LDAC)), hypomethylating agents (HMA), and intensive chemotherapy

Population data from the Swedish Acute Leukaemia Registry suggest the majority of older patients should be considered candidate for antileukemic therapy [13]. However, only few prospective randomised studies in older AML patients are available to guide treatment decisions. A pivotal clinical trial, although with a limited number of patients (n = 60), showed that standard IC decreases early death rates and improves long-term survival compared with BSC [14]. Also LDAC and gemtuzumab ozogamicin (GO) have been reported to result in superior survival compared with BSC; although neither had an effect in patients with adverse

In addition to IC and LDAC, the armamentarium for the treatment of AML has been expanded in recent years with two cytosine analogues with DNA hypomethylating properties: azacitidine and decitabine. The hypomethylating agents (HMAs) azacitidine and decitabine have relatively mild side effects and are particularly feasible for the treatment of AML in older patients and patients with comorbidities.

efforts to find effective and tolerable treatments [12].

**2. Treatment options in older adults with AML**

**166**

(IC) (**Table 1**).

cytogenetics [15, 16].

*Treatment options and outcomes for older AML patients.*

Importantly, both azacitidine and decitabine have proven efficacy in patients with adverse cytogenetic abnormalities. Although not in their primary analyses, recent phase III trials have shown the superiority of azacitidine and decitabine treatment compared with conventional care for older AML patients [17, 18].

New combinations of HMAs with targeted drugs are being explored. Recently, the results of a phase 3 study of azacitidine in combination with venetoclax versus azacitidine alone in treatment-naïve adults with AML, who were ineligible for standard induction therapy, have been reported (VIALE-A trial; NCT02993523). This study confirmed the additive value of venetoclax to azacitidine treatment by an increase in remission rate from 28–66% and an increase in median OS from 9.6 months to 14.7 months [19]. The high remission rate which was achieved by adding venetoclax to azacitidine treatment is striking. Studies are ongoing to explore the added value of IDH1 or IDH2 inhibitors (ivosidenib or enasidenib) in combination with azacitidine and azacitidine plus venetoclax, for those older AML patients with mutated *IDH1* or *IDH2*.

#### **2.1 Treatment selection: who is fit and who is not fit?**

Optimal treatment selection for older patients also requires consideration of treatment tolerance and life expectancy, derived from the evaluation of comorbidities, physical function and cognition [2]. Charlson comorbidity index >1 and haematopoietic cell transplantation comorbidity index (HCT-CI) >2 have been reported to be associated with lower remission rates, increased early mortality and decreased survival in patients treated with IC [20–22]. In a study on 177 patients aged ≥65 years who received IC the early death rates were 3% if the HCT-CI score was 0, 11% if the HCT-CI score was 1 to 2, and 29% if the HCT-CI score was ≥3 [20]. In addition, performance status, scored according to ECOG or WHO guidelines, has shown to be associated with survival in several studies [10, 23, 24].

To adequately assess fitness in older patients, beyond performance status and comorbidities, geriatric assessment (GA) is attracting more attention. GA is an approach to the evaluation of multiple patient characteristics (i.e. physical function, comorbid disease(s), cognitive function, psychological state, social support, polypharmacy, nutritional status) to help characterise individual patient complexity and discriminate among fit, vulnerable and frail patients. GA in older AML patients has been associated with treatment outcomes. In a single-institution prospective study conducted with AML patients ≥60 years of age treated with IC, geriatric assessment performed at diagnosis was associated with survival. In this study (n = 74, median age 68 years), impaired physical performance (measured as short physical performance battery (SPPB) score < 9) and impaired cognition (measured as modified mini-mental state (3MS) exam score < 77) were independently associated with OS, after accounting for other disease and patient characteristics [25]. In a study of 107 non-intensively treated AML patients, the scores for independence in activities of daily living and the Karnofsky score for performance status were associated with survival in multivariate analysis [21]. Although randomised data of comprehensive assessment of older AML patients are lacking, the above mentioned studies support the use of pre-treatment performance and comorbidity assessment in the setting of AML therapy.

#### **2.2 Treatment selection: predicting outcome with algorithms.**

Various studies have been undertaken with the aim to create prediction models for treatment effectiveness and to provide support for an educated treatment choice in the setting of AML. These algorithms include patient-specific factors (e.g. performance, comorbidity, body temperature, age) and disease-specific factors (e.g. cytogenetics, white blood cell counts, blast counts, primary or secondary leukaemia, haemoglobin level, platelet count, fibrinogen level, serum concentration of lactate dehydrogenase (LDH)) [23, 24, 26, 27]. However, most prediction models have not been successfully validated in independent cohorts of older patients. In addition, the data used to create most of these algorithms come from a patient population selected to receive intensive chemotherapy and therefore likely do not reflect the real world of older patients with AML. Although prediction models might be useful in identifying patients who are 'fit' for intensive chemotherapy, this does not automatically imply for AML patients with specific disease characteristics (or combinations) associated with poor outcome. This includes the high-risk AML subtypes with mutant *TP53*, complex cytogenetic abnormalities (in particular monosomal karyotype), mutations in *ASXL1* or *RUNX1* and high allelic burden *FLT3*-ITDs. An inclusive and validated prediction model for older AML patients has yet to be published.

#### **3. Treatment of patients considered to be fit**

The combination of anthracycline and cytarabine ('3 + 7') has been the standard of care for patients with AML for the last four decades [28]. However, the use of this regimen in older patients with AML does not yield similar results to those reported for younger patients, even in carefully selected patients. Although 50–60% of patients will attain a complete remission (CR), this does not translate into a similar survival benefit as for younger patients, with a 2-year survival of only 15–20% [3, 29]. To improve the outcome for older AML patients receiving intensive chemotherapy (IC)

**169**

*Treatment of AML in Older Patients*

(90 mg/m<sup>2</sup>

a higher (400 mg/m<sup>2</sup>

3 mg/m<sup>2</sup>

(3 mg/m<sup>2</sup>

a fourth course of treatment.

a higher dose of GO (6 mg/m<sup>2</sup>

*DOI: http://dx.doi.org/10.5772/intechopen.94979*

vs. 45 mg/m<sup>2</sup>

many studies have evaluated modifications of the traditional '3 + 7' combination. Strategies have included dose attenuation [9, 30], addition of gemtuzumab ozogamicin (GO) [31, 32], addition of midostaurin [33], addition of lenalidomide [34], and

The HOVON43 study assessed the effect of an escalated daunorubicin dose

tional '3 + 7' chemotherapy [9]. Median age was 67 years and 24% of patients had an unfavourable or very unfavourable cytogenetic risk. Although the CR rate was higher in the escalated-treatment group (64% vs. 54% [P = 0.002]), this did not translate into a survival benefit (2-year OS 31% vs. 26% [P = 0.16]). However, an unplanned post-hoc analysis showed that patients in the escalated-treatment group who were 60 to 65 years of age had higher CR rates and increased survival compared to patients aged 60 to 65 years in the conventional dose group (CR rates 73% vs. 51% and 2-year OS 38% vs. 23%, respectively). These data suggest the survival benefit of an escalated dose of daunorubicin was limited to the younger part of older patients. The MRC-AML-14 study randomised patients

receive the multidrug resistance modulator PSC-833 or not, and to receive three or four courses of treatment [30]. The CR rate was 54% and 5-year OS 12% for all patients, and no benefits were observed in either dose escalation groups, or from

Several studies investigated the addition of GO to standard chemotherapy to improve outcome in older AML patients. The MRC-AML-16-I study (addition of

significantly better in the GO arm (relapse 68% vs. 76%; survival 25% vs. 20%), although there was no difference in CR rate between both arms [31]. There was no difference in 30- or 60-day mortality and no major increase in toxicity with GO. The French ALFA-0701 trial investigated addition of fractionated doses of GO

in patients aged 50–70 years. The CR rate did not differ between both arms (81% in GO-arm vs. 75% in no GO-arm), but survival was increased in the GO-arm (median 34 vs. 19 months; 2-year OS 53.2% vs. 41.9%) [35]. However, in the EORTC-GIMEMA-AML17 trial, randomising patients to a course of GO (6 mg/m<sup>2</sup> on day 1 and 15) followed by IC or IC alone, a trend for inferior survival in the GO-arm was observed (median OS 7.1 vs. 10 months) [32]. Patients aged ≥70 years did significantly worse with GO due to the combined effect of increased induction mortality and poorer OS among those not achieving CR. This study incorporated

vs. 3 mg/m<sup>2</sup>

controlled trials, leading to re-approval in 2017 [36].

been associated with increased toxicity and after initial FDA approval in 2000 was voluntarily withdrawn in 2010 after safety concerns. Since then fractionated doses have been proved safe and efficacious in a large meta-analysis of five randomised

There is ongoing discussion whether older AML patients benefit from treatment with intensive chemotherapy. Retrospective analysis of the outcomes 446 older AML patients (≥70 years) treated with intensive chemotherapy between 1990 and 2008 showed that despite a reasonable CR rate of 45%, the median OS was only 4.6 months and 1-year survival 28% [37]. The surprisingly low median OS was due to high 4-week and 8-week mortality rates of 26% and 36%, and the authors concluded that intensive chemotherapy may not be beneficial to most older patients with AML, although some subgroups (e.g. CBF AML and good risk status) might benefit. In response to this, a Swedish group published updated outcomes of 998 unselected older AML patients, of who 55% received intensive chemotherapy

GO on day 1 of course 1) found 3-year relapse incidence and survival was

on day 1, 4, and 7) to standard chemotherapy and found similar results

) in older AML patients (> 60 years) receiving conven-

) dose of daunorubin,

) dose of cytarabine, allocation to

). GO, especially in higher doses, has

other attempts (e.g. growth factors, modulation of multidrug resistance).

four times to a higher (50 mg/m2) or lower (35 mg/m<sup>2</sup>

) or lower (200 mg/m<sup>2</sup>

#### *Treatment of AML in Older Patients DOI: http://dx.doi.org/10.5772/intechopen.94979*

*Acute Leukemias*

in the setting of AML therapy.

In addition, performance status, scored according to ECOG or WHO guidelines, has

To adequately assess fitness in older patients, beyond performance status and comorbidities, geriatric assessment (GA) is attracting more attention. GA is an approach to the evaluation of multiple patient characteristics (i.e. physical function, comorbid disease(s), cognitive function, psychological state, social support, polypharmacy, nutritional status) to help characterise individual patient complexity and discriminate among fit, vulnerable and frail patients. GA in older AML patients has been associated with treatment outcomes. In a single-institution prospective study conducted with AML patients ≥60 years of age treated with IC, geriatric assessment performed at diagnosis was associated with survival. In this study (n = 74, median age 68 years), impaired physical performance (measured as short physical performance battery (SPPB) score < 9) and impaired cognition (measured as modified mini-mental state (3MS) exam score < 77) were independently associated with OS, after accounting for other disease and patient characteristics [25]. In a study of 107 non-intensively treated AML patients, the scores for independence in activities of daily living and the Karnofsky score for performance status were associated with survival in multivariate analysis [21]. Although randomised data of comprehensive assessment of older AML patients are lacking, the above mentioned studies support the use of pre-treatment performance and comorbidity assessment

shown to be associated with survival in several studies [10, 23, 24].

**2.2 Treatment selection: predicting outcome with algorithms.**

Various studies have been undertaken with the aim to create prediction models

The combination of anthracycline and cytarabine ('3 + 7') has been the standard of care for patients with AML for the last four decades [28]. However, the use of this regimen in older patients with AML does not yield similar results to those reported for younger patients, even in carefully selected patients. Although 50–60% of patients will attain a complete remission (CR), this does not translate into a similar survival benefit as for younger patients, with a 2-year survival of only 15–20% [3, 29]. To improve the outcome for older AML patients receiving intensive chemotherapy (IC)

for treatment effectiveness and to provide support for an educated treatment choice in the setting of AML. These algorithms include patient-specific factors (e.g. performance, comorbidity, body temperature, age) and disease-specific factors (e.g. cytogenetics, white blood cell counts, blast counts, primary or secondary leukaemia, haemoglobin level, platelet count, fibrinogen level, serum concentration of lactate dehydrogenase (LDH)) [23, 24, 26, 27]. However, most prediction models have not been successfully validated in independent cohorts of older patients. In addition, the data used to create most of these algorithms come from a patient population selected to receive intensive chemotherapy and therefore likely do not reflect the real world of older patients with AML. Although prediction models might be useful in identifying patients who are 'fit' for intensive chemotherapy, this does not automatically imply for AML patients with specific disease characteristics (or combinations) associated with poor outcome. This includes the high-risk AML subtypes with mutant *TP53*, complex cytogenetic abnormalities (in particular monosomal karyotype), mutations in *ASXL1* or *RUNX1* and high allelic burden *FLT3*-ITDs. An inclusive and validated prediction model for older AML patients has

**168**

yet to be published.

**3. Treatment of patients considered to be fit**

many studies have evaluated modifications of the traditional '3 + 7' combination. Strategies have included dose attenuation [9, 30], addition of gemtuzumab ozogamicin (GO) [31, 32], addition of midostaurin [33], addition of lenalidomide [34], and other attempts (e.g. growth factors, modulation of multidrug resistance).

The HOVON43 study assessed the effect of an escalated daunorubicin dose (90 mg/m<sup>2</sup> vs. 45 mg/m<sup>2</sup> ) in older AML patients (> 60 years) receiving conventional '3 + 7' chemotherapy [9]. Median age was 67 years and 24% of patients had an unfavourable or very unfavourable cytogenetic risk. Although the CR rate was higher in the escalated-treatment group (64% vs. 54% [P = 0.002]), this did not translate into a survival benefit (2-year OS 31% vs. 26% [P = 0.16]). However, an unplanned post-hoc analysis showed that patients in the escalated-treatment group who were 60 to 65 years of age had higher CR rates and increased survival compared to patients aged 60 to 65 years in the conventional dose group (CR rates 73% vs. 51% and 2-year OS 38% vs. 23%, respectively). These data suggest the survival benefit of an escalated dose of daunorubicin was limited to the younger part of older patients. The MRC-AML-14 study randomised patients four times to a higher (50 mg/m2) or lower (35 mg/m<sup>2</sup> ) dose of daunorubin, a higher (400 mg/m<sup>2</sup> ) or lower (200 mg/m<sup>2</sup> ) dose of cytarabine, allocation to receive the multidrug resistance modulator PSC-833 or not, and to receive three or four courses of treatment [30]. The CR rate was 54% and 5-year OS 12% for all patients, and no benefits were observed in either dose escalation groups, or from a fourth course of treatment.

Several studies investigated the addition of GO to standard chemotherapy to improve outcome in older AML patients. The MRC-AML-16-I study (addition of 3 mg/m<sup>2</sup> GO on day 1 of course 1) found 3-year relapse incidence and survival was significantly better in the GO arm (relapse 68% vs. 76%; survival 25% vs. 20%), although there was no difference in CR rate between both arms [31]. There was no difference in 30- or 60-day mortality and no major increase in toxicity with GO. The French ALFA-0701 trial investigated addition of fractionated doses of GO (3 mg/m<sup>2</sup> on day 1, 4, and 7) to standard chemotherapy and found similar results in patients aged 50–70 years. The CR rate did not differ between both arms (81% in GO-arm vs. 75% in no GO-arm), but survival was increased in the GO-arm (median 34 vs. 19 months; 2-year OS 53.2% vs. 41.9%) [35]. However, in the EORTC-GIMEMA-AML17 trial, randomising patients to a course of GO (6 mg/m<sup>2</sup> on day 1 and 15) followed by IC or IC alone, a trend for inferior survival in the GO-arm was observed (median OS 7.1 vs. 10 months) [32]. Patients aged ≥70 years did significantly worse with GO due to the combined effect of increased induction mortality and poorer OS among those not achieving CR. This study incorporated a higher dose of GO (6 mg/m<sup>2</sup> vs. 3 mg/m<sup>2</sup> ). GO, especially in higher doses, has been associated with increased toxicity and after initial FDA approval in 2000 was voluntarily withdrawn in 2010 after safety concerns. Since then fractionated doses have been proved safe and efficacious in a large meta-analysis of five randomised controlled trials, leading to re-approval in 2017 [36].

There is ongoing discussion whether older AML patients benefit from treatment with intensive chemotherapy. Retrospective analysis of the outcomes 446 older AML patients (≥70 years) treated with intensive chemotherapy between 1990 and 2008 showed that despite a reasonable CR rate of 45%, the median OS was only 4.6 months and 1-year survival 28% [37]. The surprisingly low median OS was due to high 4-week and 8-week mortality rates of 26% and 36%, and the authors concluded that intensive chemotherapy may not be beneficial to most older patients with AML, although some subgroups (e.g. CBF AML and good risk status) might benefit. In response to this, a Swedish group published updated outcomes of 998 unselected older AML patients, of who 55% received intensive chemotherapy

between 1997 and 2006 and concluded that older patients do benefit from intensive treatment with a median OS in *de novo* AML of over 1 year [13]. This highlights that choosing the optimal treatment for older patients with AML remains challenging.
