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Expert Review of Hematology
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ierr20
Non-intensive acute myeloid leukemia therapies
for older patients
Rodrick Babakhanlou & Farhad Ravandi-Kashani
To cite this article: Rodrick Babakhanlou & Farhad Ravandi-Kashani (2023): Non-intensive
acute myeloid leukemia therapies for older patients, Expert Review of Hematology, DOI:
10.1080/17474086.2023.2184342
To link to this article: https://doi.org/10.1080/17474086.2023.2184342
Published online: 02 Mar 2023.
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REVIEW
Non-intensive acute myeloid leukemia therapies for older patients
Rodrick Babakhanlou and Farhad Ravandi-Kashani
Department of Leukemia, the University of Texas, MD Anderson Cancer Center, Houston, Texas, USA
ABSTRACT
Introduction: Acute myeloid leukemia (AML) is an aggressive disease predominantly affecting the
elderly population. The elderly population represents a challenging group to treat and the prognosis is
generally poor with significantly worse treatment outcomes compared to the younger population.
While the goal of treatment for younger fit patients is cure and includes intensive chemotherapy and
stem cell transplantation, these strategies are not always feasible for elderly unfit patients due to
increased frailty, co-morbidities, and, subsequently, an increased risk of treatment-related toxicity and
mortality.
Areas covered: This review will discuss both patient- and disease-related factors, outline prognostica-
tion models and summarize current treatment options, including intensive and less intensive treatment
strategies and novel agents.
Expert opinion: Although recent years have seen major advances in the development of low-intensity
therapies, there is still a lack of consensus on the optimal treatment for this patient group. Because of
the heterogeneity of the disease, personalizing the treatment strategy is important and curative-
oriented approaches should be selected wisely, rather than following a rigid hierarchical algorithm.
ARTICLE HISTORY
Received: 05 Nov 2022
Revised: 13 Jan 2023
Accepted: 21 Feb 2023
KEYWORDS
Acute myeloid leukemia;
elderly population;
treatment options; low-
intensity therapy; targeted
therapy; hypomethylating
agents
1. Introduction
Acute myeloid leukemia (AML) is an aggressive disease pre-
dominantly affecting the elderly population, with a median
age of 68 years at diagnosis [1,2]. It is the most common acute
leukemia in adults and its incidence increases with advancing
age [3]. In Europe, a yearly incidence of 5–8 cases per 100.000
individuals is reported, while in the USA, 20.000 new cases of
AML are diagnosed each year [4,5]. The elderly population,
defined as an age over 60 years, represents a challenging
group to treat. The prognosis of AML in the elderly population
is generally poor, and treatment outcome is significantly
worse compared to the younger population [2,6–8]. This has
been attributed to various reasons, including both patient-
related and disease-related factors [7].
Older age is an adverse prognostic factor, which has been
associated with lower rates of complete remission (CR), a
reduced relapse free survival (RFS), disease free survival
(DFS), and even overall survival (OS) [3]. Moreover, older age
has been associated with a more resistant disease and an
increased risk of relapse compared to younger patients [3].
In addition, the biologic and cytogenetic profile of elderly
patients with AML differ from that of their younger counter-
parts with a higher incidence of adverse cytogenetic abnorm-
alities, higher multidrug resistance, and increased incidence of
secondary AML (sAML), resulting in poorer outcomes [3,4,9].
The majority of AML patients die from complications of their
disease or its treatment with a 5-year OS of less than 25% in
patients aged 60–65 years and <10% among patients
>70 years of age [6,9]. Despite advances in treatment
modalities for AML in younger patients, treatment in the
elderly remains challenging due to treatment-related toxicity
and treatment-related mortality (TRM) [3]. At present, there is
no standard treatment of choice for AML in the elderly popu-
lation and optimal treatment strategies remain controver-
sial [10].
This review will discuss prognostic factors for risk stratifica-
tion in elderly AML patients and review current treatment
options and novel therapies for the management of AML in
the older population.
2. Prognostic factors
When it comes to treatment, decision-making is a critical
component of care in elderly AML patients and needs to
incorporate tolerability and benefits of treatment, but also
predict toxicity and general suitability of the patient [6]. Due
to age-related comorbidities and an impaired general condi-
tion, the ability of elderly patients to tolerate intensive che-
motherapy significantly decreases, which necessitates a wise
selection of the patient population that will benefit from
intensive therapy.
The process of assessing the fitness level of elderly
patients helps to determine whether an intensive therapy
with a curative intent is suitable and incorporates both
patient-related and disease-related factors [4,11]. These fac-
tors are used for prognostication and can be used to esti-
mate response to treatment, risk of relapse, and OS in older
patients [6].
CONTACT Rodrick Babakhanlou rbabakhanlou@mdanderson.org Department of Leukemia, the University of Texas, MD Anderson Cancer Center, 515
Holcombe Blvd, Houston, Texas 77030, USA
EXPERT REVIEW OF HEMATOLOGY
https://doi.org/10.1080/17474086.2023.2184342
© 2023 Informa UK Limited, trading as Taylor & Francis Group
2.1 Patient-related factors
Increasing age is associated with a poor prognosis [12]. Most
trials consider the age of 60 as the cut-off between ‘younger’
and ‘older’ AML patients, which is arbitrary rather than evi-
dence-based [7]. Elderly patients suffer from physiologic
changes of ageing with an impaired functional status and a
reduced physical performance [3,11,13]. The impact of multi-
ple co-morbidities, polypharmacy, and altered pharmacody-
namics and pharmacokinetics limit the tolerance of intensive
chemotherapy and increase the risk of treatment-related toxi-
city and complications [3,11,13]. Elderly patients have an
increased risk of bleeding and a reduced tolerance to infec-
tions compared to their younger counterparts [3]. Moreover, it
is important to consider the psychosocial impact in the deci-
sion-making, including cognition and the presence of social
support [3].
2.2. Disease-related factors
With advancing age, leukemia cell biology changes with an
increased tendency to complex cytogenetics and unfavorable
karyotypes [6,11,12]. In the elderly population, AML commonly
arises from antecedent hematological disorders in the form of
sAML, which is associated with inferior response to treatment,
refractory disease, and higher TRM [3]. Moreover, elderly patients
have an overexpression of the multidrug resistance 1 gene
(MDR1), which encodes an efflux pump, contributing to the
removal of chemotherapeutics from the cell, resulting in an
increased treatment resistance [12].
2.3 Prognostication models
Due to underrepresentation of older patients in trials, there is
a lack of consensus on the optimal treatment for this patient
group. Hence, treatment approaches have been up to the
discretion of the treating physician. In order to evaluate the
best approach to treatment and to estimate fitness for inten-
sive chemotherapy in the elderly population, several prognos-
tic models based on retrospective analysis have been
published, incorporating various parameters, such as age,
cytogenetic abnormalities, genetic mutations, performance
status, laboratory abnormalities, comorbidities, and the pre-
sence of previous hematological disorders [14–20]. Only a few
have been validated prospectively, and there is currently no
gold standard to evaluate fitness levels and frailty.
Geriatric assessment is a feasible option to evaluate multi-
ple characteristics, such as physical function, comorbidities,
cognitive function, psychological state, polypharmacy, and
nutritional state, and could help identify unfit and frail
patients, and predict chemotherapy toxicity and survival
[21–23].
The Eastern Cooperative Oncology Group (ECOG) perfor-
mance status is another index to assess the patient’s general
condition [7]. Patients over the age of 75 years with an ECOG
of 3 or 4 undergoing chemotherapy, have a 30-day mortality
of over 50% [12].
The hematopoietic stem cell transplantation comorbidity
index (HCT-CI) is also an index correlated with the outcome
after intensive induction chemotherapy and is the most com-
monly being used [24]. This index is a measure of the presence
and severity of associated diseases, summarized on a point
scale with 0 points reflecting low risk, 1–2 points reflecting
intermediate risk and >3 points reflecting high risk [24].
In clinical practice, the choice depends on the practitioner
and his/her expertise and experience and the perception of
the patient’s condition. This approach is subjective and cer-
tainly needs to be replaced by more objective prediction
models.
At the MD Anderson Cancer Center, if the expected mor-
tality rate at 4–8 weeks is less than 10%, patients are being
offered intensive chemotherapy. If the mortality rate exceeds
10–20%, patients are being offered low-intensity chemother-
apy [15].
3. Treatment options
While the goal of treatment for younger fit patients is cure,
achieving this goal in elderly AML patients can be challenging
and is often not feasible due to both patient-related and
disease-related factors as discussed above [11–13,25].
Although achieving CR remains necessary for long-term DFS,
TRM remains a major limitation for intensive treatment in
elderly AML patients [26]. Moreover, it is crucial to factor in
secondary endpoints in this patient population, such as quality
of life (QoL), impact on supportive care, resource utilization,
and survival [25]. These aspects raise the question about the
choice of treatment, its intensity, or whether to apply palliative
and supportive care only. To assess the suitability of palliation
and supportive care approaches as a potential option to treat
AML in the elderly, a small clinical trial prospectively rando-
mized older patients over the age 65 years with newly diag-
nosed AML to either intensive chemotherapy vs. a ‘watch and
wait’ approach, which consisted of transfusion support and
cytoreductive chemotherapy in cases of leukocytosis [27].
While the number of days spend in hospital did not differ
between the groups, the median OS was significantly longer
in the group treated with intensive chemotherapy [27].
Moreover, the Swedish Acute Leukemia registry analyzed an
unselected elderly AML population over eight years compar-
ing intensive therapy vs. palliation. Their results showed that
Article highlights
●Older patients with AML constitute a proportionally large subgroup
that is difficult to treat
●The use of venetoclax and other targeted agents like IDH and FLT3
inhibitors as monotherapy or low-intensity combination have signifi-
cantly improved the outcomes
●Often the biological and chronological age of the patients are very
dyssynchronous and precise models to assess patient fitness, toler-
ability to therapy and risks of initial treatment mortality are required
to choose the right therapy intensity for an individual patient
●Older AML patients are better treated at high-volume AML centers
●More research is needed in order to understand which patient
population will benefit from curative approaches, and who will
benefit from moderate treatment or even supportive care.
2R. BABAKHANLOU AND F. RAVANDI-KASHANI
those who received treatment had a reduced death rate and
an improved OS compared to palliative therapy [28].
These data suggest that palliation alone results in worse
survival for older patients. Physicians treating elderly patients
with AML are faced with the challenge to choose the best
possible option and an appropriate selection of patients is
needed to evaluate which groups may benefit from more
intensive therapy.
Current FDA-approved treatment options of older AML
patients have been summarized in Table 1.
4. Intensive therapy
Since this review article is focused on the “non-intensive”
treatment options for elderly AML patients, this section on
“intensive” therapy will not be covered in depth, as other
papers have discussed this part in detail.
4.1 Anthracyclines and cytarabine
Since the 1970s, the traditional ‘7 + 3’ regimen has remained
the standard approach for patients with newly diagnosed
AML. This regimen consists of 7 days of cytarabine and
3 days of an anthracycline infusion [4,11].
Daunorubicin is the most commonly used anthracycline for
induction therapy in AML [29]. There has been a debate about
whether to use 90 mg/m2 or 60 mg/m2. Although 90 mg/m2
was shown to achieve higher rates of CR, it has also been
shown to be associated with higher levels of toxicity as well
[30]. Compared to daunorubicin 60 mg/m2 for induction ther-
apy, the results showed that the higher dose of 90 mg/m2 was
associated with an increased 60-day mortality without
improved OS at 2 years [29].
The ‘7 + 3’ regimen is successful in 40–60% of adults over
the age of 60 years and can be applied to older AML
patients [11].
4.2 Gemtuzumab ozogamicin
Gemtuzumab Ozogamicin (GO) is an anti-CD33 monoclonal
antibody conjugated to the cytotoxic agent calicheamicin
that contributes to single- and double stranded breaks in the
DNA. It is the only antibody approved by the FDA for the
management of AML [31]. The addition of GO to intensive
treatment regimens has been studied in several trials, how-
ever, with conflicting results [6]. In a randomized phase 3 trial,
GO was added to intensive chemotherapy on days 1, 4 and 7
during induction in patients aged 50–70 years of age with
AML [32]. The addition of GO was associated with an improved
event-free survival (EFS), OS, and RFS. However, GO was asso-
ciated with higher hematologic toxicity and increased rates of
infections [32]. Another trial randomly assigned 237 patients
to either GO (6 mg/m
2
on day 1 and 3 mg/m
2
on day 8) or
best supportive care (BSC) including hydroxyurea. The median
OS was 4.9 months in the GO group and 3.6 months in the
BSC group. Complete remission occurred in 27% of patients
who received GO. The results showed that single agent GO is a
possible option for the management of AML in the elderly
population [33]. A meta-analysis of trials using GO with che-
motherapy reported that GO did not improve CR, but certainly
did decrease the risk of relapse and was associated with an
improved OS [34].
This effect was particularly observed in patients with low-
and intermediate-risk cytogenetics. Hence, GO is likely to be
more suitable for fit patients and those with favorable
cytogenetics.
4.3 CPX-351
CPX-351 is a liposomal formulation that encapsulates cytara-
bine 100 mg/m2 and daunorubicin 44 mg/m2 at a 5:1 ratio,
which received its FDA approval in 2017 [4,11]. CPX-351 was
studied in a phase 2 trial of older patients with newly diag-
nosed de novo and secondary AML [35]. When compared to
conventional induction therapy, the addition of CPX-351
showed a non-significant trend toward higher remission
rates and an improved OS in patients with sAML [35]. Based
on those findings, a subsequent phase III randomized trial of
CPX-351 vs. 7 + 3 in newly diagnosed, elderly sAML patients
demonstrated a higher remission rate and an improved OS in
the CPX-351 arm [36]. Based on these findings, the FDA and
the European Medicines Agency (EMA) approved CPX-351 for
Table 1. FDA-approved therapies for older AML patients [4]
Drug Mechanism of action
Azacitidine Hypomethylating agent
Decitabine Hypomethylating agent
Gemtuzumab ozogamicin CD-33-specific antibody-drug conjugate
CPX-351 Liposomal formulation of cytarabine and daunorubicin at a fixed 5:1 ratio
Gilteritinib FLT3 Inhibitor
Ivosidenib IDH-1 inhibitor
Enasidenib IDH-2 inhibitor
Glasdegib Hedgehog inhibitor
Venetoclax BCL-2 inhibitor
Midostaurin Multitargeted Kinase Inhibitor
EXPERT REVIEW OF HEMATOLOGY 3
the treatment of adults with newly diagnosed, therapy-
related AML.
4.4 Allogeneic Hematopoietic Stem Cell transplantation
Allogeneic hematopoietic stem cell transplantation (HSCT) is
the most effective therapy to obtain durable remission in AML
[4]. Although the age range suitable for HSCT has been
extended to 70–75 years of age, only about 8% of older
patients with AML undergo HSCT, since HSCT is not available
to all patients with high-risk disease, due to lack of suitable
donors or the potential toxicity and mortality associated with
the procedure [2,4].
Allogeneic SCT is an accepted standard of care in first CR in
presence of an adverse AML karyotype at diagnosis, persistent
minimal residual disease (MRD) in CR and low-risk of SCT-
associated mortality, based on patient’s age and co-morbid-
ities [37].
In a prospective phase 2 study, 114 older patients with AML
in first CR patients were reported to have a DFS rate of 42%
and an OS rate of 48% at two years following reduced-inten-
sity conditioning transplant [38]. While retrospective studies
and meta-analysis support the idea of HSCT for the manage-
ment of AML in fit older patients, it is important to keep in
mind that less than 1 in 10 patients over the age of 60 years
undergo stem cell transplantation [39–42].
So far, those trials that have been focusing on HSCT in
older AML patients did not frequently include patients older
than 70 years of age, which makes it difficult to draw conclu-
sions about the safety of HSCT in AML patients in this age
group. Despite increasing expertise and safety of HSCT for the
management of AML, its exact value as a post-remission strat-
egy in older patients still needs to be determined [4].
5. Low-intensity treatment options
Low-intensity treatment strategies are reserved for patients,
who are unfit for intensive regimens [43]. The aim of low-
intensity treatment options is to reduce TRM and maintain a
QoL, but at the same time reduce disease activity. Elderly
patients with relapsed or refractory AML suffer from an unfa-
vorable outcome and a short median OS. Therapeutic options
in this patient population are limited. Current strategies for
elderly patients include Low dose Ara-C (LDAC), hypomethy-
lating agents, investigational and novel agents, and palliative
measures [43].
5.1 Low dose Ara-C
LDAC had been considered as the standard of care for older
unfit patients and has been utilized as a low-intensive therapy
since the 1960s [3,6]. It is given subcutaneously at a dose of
20 mg twice daily for 10 days and repeated every 4–6 weeks
[6]. The intention of this approach is to address symptoms of
leukocytosis and LDAC has shown to improve outcomes in
older patients without adverse cytogenetics compared to
hydroxyurea [6,44]. The UK AML14 trial randomized 201
patients with a median age of 76 years to LDAC or hydro-
xyurea with or without all-trans retinoid acid but was
prematurely stopped because of a superior survival in the
LDAC arm [44]. In a small proportion of patients CR have
been reported between 5% and 20% [45]. However, CR is
not durable and almost all patients will relapse.
5.2 Hypomethylating agents
Hypomethylating agents (HMA), such as azacitidine and deci-
tabine, are pyrimidine nucleoside analogues that inhibit aber-
rant methylation of the DNA. HMA have traditionally been
used for the management of the Myelodysplastic Syndrome
(MDS) but have also shown to have beneficial activity in AML
patients by inducing remission and prolonging OS [6,43,46–
48]. Since these agents are not associated with significant
organ toxicity, it makes them attractive for use in the elderly
AML patient, who are not considered to be fit for intensive
chemotherapy [6].
One of the early trials, the CALGB 9221, randomized 191
patients with high-risk MDS, of whom 23% qualified for AML,
to azacitidine (75 mg/m2 subcutaneously for 7 days every
28 days) vs. best supportive care. The response rate to azaci-
tidine was 60% with a CR rate of 7%. There was a significant
improvement in the QoL and the OS in the azacitidine
arm [47].
The AZA-001 study randomly assigned 358 patients with
high-risk MDS, of whom 31% progressed to AML at a later
stage with blast counts over 20%, to either azacitidine or
conventional care regimen (CCR), including best supportive
care, LDAC, or intensive chemotherapy. Azacitidine resulted
in a longer OS and less toxicity compared to CCR [46]. Even in
relapsed or refractory AML, azacitidine has produced
responses [49,50].
In the AZA-AML-001 study, 488 patients were randomized
to azacitidine (n = 241) for 7 days every 4 weeks versus three
predetermined conventional care regimens, including induc-
tion chemotherapy, LDAC, or supportive care [51]. In this
randomized phase 3 study, the response rate (CR+CRi) was
similar between the two arms. However, azacitidine was asso-
ciated with a better OS (24.5 months vs. 16 months, P = 0.05),
as well as shorter fewer hospitalizations [51]. Since this study
only enrolled patients with a white blood cell count of
<15.000/mm
3
, these findings cannot be generalized to all
elderly AML patients.
Decitabine is another hypomethylating agent that has been
shown to be beneficial in elderly patients with AML, who are
not able to tolerate intensive chemotherapy. Several phase III
studies have shown CR rates of 20–30% with decitabine in
elderly AML patients with intermediate to poor risk cytoge-
netics [52–54]. A large phase III study compared decitabine
(20 mg/m2 for 5 consecutive days every 28 days) with CCR
consisting of supportive care or subcutaneous cytarabine in
elderly patients >65 years of age with de novo or secondary
AML with intermediate or adverse cytogenetics [45].
Compared to CCR, decitabine was associated with higher
rates of CR and an increased median OS [45].
The ASTRAL-1 trial, a randomized phase 3 trial intended to
compare Guadecitabine against treatment of choice, which
included azacitidine, decitabine, or LDAC for the management
of newly diagnosed AML in elderly unfit patients ineligible for
4R. BABAKHANLOU AND F. RAVANDI-KASHANI
intensive chemotherapy [55]. This led to an indirect compar-
ison of azacitidine and decitabine. Azacitidine was given intra-
venously or subcutaneously at 75 mg/m
2
per day on days 1 to
7. Decitabine was given intravenously at 20 mg/m
2
per day on
days 1 to 5. There were no significant differences in the CR
rate and OS between both groups. Serious adverse events
leading to death seemed to be more frequent in the azaciti-
dine group. Data of this trial suggested that azacitidine and
decitabine can be used interchangeably among older and
unfit AML patients [55].
6. Novel agents and small molecules
6.1 Volasertib
Volasertib is a polo-like kinase (PLK) inhibitor that selectively
binds to the ATP binding pocket of the human PLK1 [6,56].
PLKs are involved in the regulation of cell-cycle progression
and mitosis and are overexpressed both in solid and hemato-
logic malignancies [6,56]. In a phase 2 trial, LDAC alone was
compared to LDAC in combination with volasertib in 87
patients not fit for intensive therapy [57]. Although toxicity
was greater in the combination arm, CR rates, EFS, and OS
were higher in the volasertib arm [57]. A randomized, double-
blind, placebo-controlled phase 3 trial was conducted to eval-
uate the efficacy and safety of volasertib combined with LDAC
in previously untreated older patients with AML, who were
considered unsuitable for intensive chemotherapy [56]. The
combination of volasertib with LDAC did not show a signifi-
cantly higher ORR compared to LDAC alone. In patients in the
ECOG 2 group, the addition of volaserib seemed to negatively
impact the ORR [56].
6.2 BCL-2 Inhibitors
The overexpression of B-cell lymphoma 2 (BCL-2) has been
associated with reduced CR rates, earlier relapse, and reduced
OS in patients with AML [58]. AML blasts and stem cells
depend on BCL-2 for survival. Venetoclax is a highly selective
BCL-2 inhibitor and has shown to induce apoptosis in AML
cells [59].
As a single agent, venetoclax (800 mg daily) demonstrated
modest activity in a cohort of 32 patients with relapsed and
refractory AML. The overall response rate was 15% with
another 19% of patients having reductions of blasts and a
median OS of 4.7 months [60]. The efficacy of venetoclax
was shown to increase markedly when combined with HMA
or LDAC. Venetoclax in combination with HMA or LDAC
received FDA approval in 2018 for treatment of AML in older
adults considered unfit for intensive chemotherapy [11].
Venetoclax was evaluated in a phase 1b escalation trial for
older patients, ineligible for intensive chemotherapy in com-
bination with either decitabine (20 mg/m2/day for 5 days) or
azacitidine (75 mg/m2/day for 7 days). The combination of
venetoclax with HMA achieved a CR rate of 73% and over 60%
in patients with poor-risk cytogenetics [61].
Based on those encouraging results, the VIALE-A trial ran-
domized 431 patients 75 years or older unfit for intensive
chemotherapy to therapy with azacitidine alone or in
combination with venetoclax [62]. The addition of venetoclax
resulted in a significantly longer survival (median survival 14.7
vs. 9.6 months), a better overall response rate (66.4% vs.
28.3%), and a higher CR rate (29.7% vs. 17.9%) [62].
In a phase Ib/II study, the combination of venetoclax
600 mg daily with LDAC in older adults showed a CR rate of
54% [63]. Ventoclax combination therapies with HMA or LDAC
have shown promising results and can be considered for
elderly AML patients not fit for intensive chemotherapy.
Another phase Ib study investigated the combination of
either azacitidine or decitabine with venetoclax in elderly AML
patients. The results showed a composite complete response
rate of 71% including a response rate of 88% among patients
with adverse risk cytogenetics and 82% in patients with IDH1/
2 mutations [64].
The landmark VIALE A trial has led to the cementing of the
combination of Ven +HMA/LDAC as the treatment of choice
for older/unit patients with AML. Improvement on the
responses and survival garnered in these trials depend on
reducing treatment toxicity along with adding on further tar-
geted therapies based on the AML mutational profile (e.g. IDH
inhibitors, FLT3 inhibitors, CD47 mAbs) .
6.3 Glasdegib
Glasdegib is a hedgehog pathway inhibitor. The hedgehog
(HH)/glioma associated oncogene homolog (GLI) signaling
pathway does have an important role in the embryonic devel-
opment. This pathway also seems to be crucial for certain
hallmarks in cancers, such as proliferative signaling, inflamma-
tion, immune evasion, metastasis, and replicative immortality
[65,66]. The overexpression of various HH/GLI components
amongst chemotherapy-resistant leukemic cell lines supports
the combination of chemotherapy with HH/GLI pathway inhi-
bitors [67]. Glasdegib is a selective oral inhibitor of the HH/GLI
pathway [67,68]. In a phase 1b trial, glasdegib (200 mg once
daily) was combined with LDAC, decitabine, or intensive che-
motherapy in patients with untreated AML and high-risk MDS,
resulting in CR rates of 8%, 28%, and 54%, respectively [69]. A
phase 2 multicenter study investigated LDAC alone vs. LDAC
in combination with glasdegib in 132 patients with AML or
high-risk MDS. The CR rates were 17% for the glasdegib arm
vs. 2% for the standard arm [69]. Based on these results, the
FDA approved glasdegib in combination with LDAC for the
management of newly diagnosed AML patients over the age
of 75 years of age.
6.4 IDH-Inhibitors
Isocitrate dehydrogenase (IDH) 1 and 2 gene mutations are
identified in 15–20% of cases in AML patients older than
60 years [70,71]. Ivosidenib and enasidenib target IDH1 and
IDH2 mutations, respectively, and were initially approved for
relapsed refractory AML [72,73]. Ivosidenib demonstrated
encouraging activity in relapsed refractory IDH1-mutated
AML with CR rates of 30.4% [73]. In patients with newly
diagnosed AML, who were not eligible for intensive che-
motherapy, ivosidenib monotherapy was associated with a
CR rate of 42.4% [74]. These studies led to the FDA approval
EXPERT REVIEW OF HEMATOLOGY 5
of ivosidenib for IDH1-mutated AML in relapsed refractory
AML patients over the age 75 years, not eligible for intensive
chemotherapy. Ivosidenib was combined with azacitidine in
23 patients with newly diagnosed IDH1-mutated AML in order
to exploit synergy, which resulted in a CR/CRh rate of 69.6%
[75]. This led to the phase 3 RCT AGILE (NCT03173248), com-
paring the combination of ivosidenib and azacitidine vs. aza-
citidine alone in patients with IDH1- mutated AML not eligible
for intensive chemotherapy. Enasidenib was evaluated in a
phase I/II trial in 239 patients with myeloid malignancies
carrying IDH2-mutations [76]. Among 174 patients with
relapsed refractory AML, the ORR was 40% with a CR rate of
19%. The median OS was 19.7 months among patients who
achieved CR [74]. Based on these results, the FDA approved
enasidenib for the treatment of relapsed refractory AML with
IDH2-mutation. In an open-label, phase 1b/2 trial, 101 patients
were assigned to either enasidenib in combination with aza-
citidine or azacitidine alone. The combination of enasidenib
with azacitidine was well tolerated and significantly improved
ORR compared to azacitidine alone [77].
Currently, a phase 3 study compares enasidenib efficacy in
patients over the age of 60 years with IDH2-mutated AML to
conventional care regimens (NCT02577406).
6.5 Nucleoside analogues
Clofarabine is a purine nucleoside analog that impairs the
synthesis and repair of DNA and activates apoptotic pathways
through disruption of mitochondrial pathways [78]. A rando-
mized controlled trial compared single agent clofarabine with
LDAC. Although the results showed a higher CR rate with
clofarabine, they did not translate into a better OS [79]. In
another randomized controlled trial, clofarabine in combina-
tion with LDAC was compared to clofarabine alone as induc-
tion therapy for older AML patients [80]. The results showed
an improved CR rate, OS rate, and EFS in the combination
group. A phase 2 single-arm trial investigated cladribine com-
bined with LDAC alternating with decitabine for the manage-
ment of AML in older unfit patients. A cohort of 118 patients
with a median age of 69 years was treated with cladribine plus
LDAC alternating with decitabine for up to 18 cycles. A CR rate
of 58% was achieved, with a median OS rate of 13.8 months
and a median DFS of 10.8 months [81].
In a prospective observational multicenter study, 117
patients with a median age of 70 years were enrolled to test
the efficacy and safety of LDAC and cladribine as first-line
treatment of elderly patients unfit for intensive chemotherapy
[82]. Adverse cytogenetics, ECOG PS > 2 and HCT-CI score >3
was observed in 43.5%, 60%, and 58% of patients, respectively.
A median OS was 21 months and 8.8 months in CR/CRi and PR
group, respectively. Advanced age (>75 years) and adverse
cytogenetics had a negative impact on OS. The authors con-
cluded that LDAC and cladribine to be a beneficial therapeutic
option with a predictable safety profile in elderly AML patients
not eligible for intensive chemotherapy [82].
Dual nucleoside analogues have been shown to improve
outcomes in patients with newly diagnosed AML. In older
patients, building on this treatment approach, low-intensity
regimens with LDAC and cladribine combined with venetoclax
alternating with 5-AZA were evaluated in a phase II study [83].
Among 60 patients with a median age of 68 years, a CR/Cri
rate of 93% was observed. The results showed that venetoclax
combined with CLAD/LDAC alternating with venetoclax and
AZA represents a safe and feasible lower intensity regimen for
newly diagnosed older patients with AML [83].
In a randomized, open-label, phase 3 multicenter study,
482 patients over the age of 70 years, who were not consid-
ered fit for intensive chemotherapy, were randomized to dec-
itabine alternating with sapacitabine vs. decitabine alone. The
results demonstrated an improved CR rate in the study group.
The median OS rate was better in the study group, although it
was not statistically significant [84].
6.6 FLT3-Inhibitors
Fms-like tyrosine kinase 3 (FLT3) is a cytokine receptor (CD135)
that belongs to the receptor tyrosine kinase class III [85,86].
This receptor is involved in the proliferation, differentiation,
and apoptosis of hematopoietic cells. Two different types of
FLT3 mutations have been observed in AML; the FLT3 internal
tandem duplication of the juxtamembrane domain FLT3-ITD,
and point mutations in the tyrosine kinase activating loop of
the kinase domain FLT3-TKD [85,86].
FLT3 mutations can be present in about 20% of AML
patients over the age of 65 years and can result in cell growth,
survival, and anti-apoptotic signaling [87]. While FLT3-ITD
mutations have been associated with adverse prognosis, the
impact of FLT3-TKD mutations in not entirely clear yet [88–91].
FLT3 inhibitors are classified in first- and second-generation
agents. First-generation agents include sorafenib, midostaurin,
and leustartinib, while second-generation agents include qui-
zartinib, crenolanib, and gilteritinib [86].
Several FLT3 inhibitors, such as sorafenib and lestaurtinib,
in combination with chemotherapy have shown improved CR
rates, however, without improvement of OS in patients
<65 years of age with diagnosis of de novo FLT3-mutated
AML [90,91]. Midostaurin is an oral first-generation FLT3 inhi-
bitor [85]. In a multicenter, double-blind, placebo-controlled,
phase III RATIFY study, which included 717 patients from the
age of 18–59 years with newly diagnosed AML with FLT3
mutations, the addition of midostaurin to chemotherapy, fol-
lowed by maintenance therapy with midostaurin showed bet-
ter EFS, DFS, and OS compared to placebo [92].
For older patients with AML, the combination of midos-
taurin and HMAs is under investigation in two phase II trials,
including azacitidine (NCT01093573) and decitabine
(NCT01846624). The combination of azacitidine and sorafenib
in older patients with FLT3-ITD AML resulted in a CR-CRi rate of
78% with a median survival was 8.3 months [93].
The phase 3 LACEWING trial combined Gilteritinib with
azacitidine in the frontline setting. Initial results showed a
marrow CR rate of 67% among the first 15 patients treated
prior to randomization [94].
Though FLT3 inhibitors as monotherapy or in combination
with low-intensity therapy, such as hypomethylating agents
combined with venetoclax, are a very promising proposition
for older, unfit patients with AML, the additive toxicities could
6R. BABAKHANLOU AND F. RAVANDI-KASHANI
be context specific to the patients’ age-related comorbidities
[95]. For example, quizratinib can be associated with QTc
prolongation, giltertinib can lead to GI toxicities, and sorafenib
can cause liver dysfunction or skin rash [96]. Thus, despite
their potent antileukemic effect, they have to be chosen wisely
in order to reduce toxicities and to improve therapy
compliance.
6.7 Antibody-based therapeutics
The advent of several targeted agents has revolutionized the
treatment of AML. Monoclonal antibodies (mAbs) targeting
cluster designation (CD) surface molecules may result in cru-
cial anti-leukemic effects [97]. Antibodies can be unconju-
gated, conjugated to immunotoxins or bispecific [98].
6.7.1 CD47
CD47 is a transmembrane protein that has been shown to be
overexpressed in malignant cells. Overexpression of CD47 is
associated with a poor prognosis and has been shown to have
anti-phagocytic effects [37,99]. Magrolimab is a humanized
anti-CD47 antibody that was shown to induce macrophage
phagocytosis of leukemia cells in vitro [37]. Since the combi-
nation of magrolimab with azacitidine increased pro-phagocy-
tic signals in AML cells and enhanced macrophage-induced
phagocytosis of leukemic cells in vitro, this combination was
evaluated in a phase 1b trial in 68 patients with previously
untreated MDS and AML, who were not eligible for intensive
chemotherapy [100,101]. Among 33 patients with MDS, the
ORR was 91% and among 25 patients with AML, the ORR was
64% [101]. Based on those results, a randomized phase 3 trial
in MDS (ENHANCE) is being planned (NCT03248479).
6.7.2. CD70
CD70 is the ligand for CD27, which belongs to the tumor
necrosis factor receptor superfamily and regulates adaptive
T-cell immune responses. The overexpression of CD70/CD27
in AML cells has been associated with a poor prognosis [102].
In preclinical studies, the inhibition of CD70/CD27 signaling
delayed disease progression and prolonged survival in AML
xenograft models [103]. Cusatuzumab is human αCD70 mono-
clonal antibody. In a phase 1/2 dose escalation trial, a single
dose cusatuzumab followed by a combination therapy with
azacitidine was evaluated in previously untreated elderly AML
patients. Among 12 enrolled patients, the ORR was 100%, and
the median time to response 3.3 months [102]. Further eva-
luation is underway.
7. Conclusion
Older patients with AML constitute a proportionally large
subgroup and the prevalence of AML in this age group is on
the rise. Clinical trials and studies including older adults over
the age of 75 years are still lacking. Despite expanding treat-
ment options for elderly AML patients, there is a lack of
consensus regarding the best treatment strategy in this age
group. There is evidence from clinical trials that older patients
do benefit from treatment compared to palliative approaches
only. However, one of the major challenges remains the
choice of treatment and the suitability of the patient. The
use of prognostication tools can support the assessment of
fitness for therapy, risks and benefits of treatment. Patients
ineligible for intensive chemotherapy may benefit from LDAC
or hypomethylating agents, despite a low durable remission.
Although the advent of multiple novel agents looks promising,
more research is needed to delineate the optimal therapeutic
approach in this age group.
8. Expert opinion
Acute myeloid leukemia (AML) is an aggressive disease pre-
dominantly affecting the elderly population. Older patients
with AML constitute a proportionally large subgroup that is
difficult to treat given their often more aggressive disease
biology, issues with therapy tolerance and inability to proceed
with stem cell transplantation. Nonetheless, the use of vene-
toclax and other targeted agents like IDH and FLT3 inhibitors
as monotherapy or low-intensity combination have signifi-
cantly improved the outcomes of these patients over the last
few years. Often, the biological and chronological age of the
patients are very dyssynchronous and precise models to assess
patient fitness, tolerability to therapy and risks of initial treat-
ment mortality are required to choose the right therapy inten-
sity for an individual patient. In patients >70 years of age with
newly diagnosed AML the 4-week mortality rate is 45–50%,
and the five-year survival rate is <5% [37]. While early mortal-
ity is reducing steadily from improvised, less intensive treat-
ment options, long-term survival remains dismal. To address
the issue of early mortality older AML patients are better
treated at high-volume AML centers often with easy access
to supportive care, physiotherapy, and occupational therapy
teams. The initial phases of therapy are especially high-risk
periods for fatal neutropenic infections and the treatment
framework should have necessary resources to address them
adequately.
Treatment regimens in older patients with AML should
include efficacious therapeutic combinations which are toler-
able, specifically based on the AML genomics and in line with
the patient’s comorbidities which are usually high in this
patient population. However, such decisions should also be
in conciliation with the patient’s wishes and should not sig-
nificantly affect their quality of life for small increments in
survival.
The management of AML in the older population is far from
perfect. More research is needed in order to understand which
patient population will benefit from curative approaches, and
who will benefit from moderate treatment or even supportive
care.
Funding
This paper was not funded.
Declaration of interest
F Ravandi receives honoraria, research funds, and/or consulting fees from
Astellas, Astra Zeneca, Xenocor, Prelude, Abbvie, Novartis, Syos, Amgen,
Celgene/BMS, and Astex/Taiho. The authors have no other relevant
EXPERT REVIEW OF HEMATOLOGY 7
affiliations or financial involvement with any organization or entity with a
financial interest in or financial conflict with the subject matter or materi-
als discussed in the manuscript apart from those disclosed.
Reviewer disclosres
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
Abbreviations
AML Acute Myeloid Leukemia
BCL-2 B-cell lymphoma 2
BSC Best supportive care
CCR Conventional Care Regimen
CD Cluster Designation
CR Complete remission
DFS Disease Free Survival
ECOG Eastern Cooperative Oncology Group
EFS Event free survival
GLI Glioma associated oncogene homolog
GO Gemtuzumab Ozogamicin
HCT-CI Hematopoietic stem cell transplantation comorbidity
index
HH Hedgehog
HMA Hypomethylating agents
HSCT Hematopoietic Stem Cell Transplantation
IDH Isocitrate Dehydrogenase
mAbs Monoclonal Antibodies
MDR1 Multidrug resistance 1
MDS Myelodysplastic Syndrome
MRD Minimal residual disease
ORR Overall response rate
OS Overall Survival
QoL Quality of Life
RFS Relapse Free Survival
sAML Secondary AML
TRM Treatment-related mortality
ORCID
Rodrick Babakhanlou http://orcid.org/0000-0002-1593-1380
Farhad Ravandi-Kashani http://orcid.org/0000-0002-7621-377X
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10 R. BABAKHANLOU AND F. RAVANDI-KASHANI
