Intensive remission induction chemotherapy should be considered by clinicians as the first choice for selected very old AML patients whenever feasible on clinical grounds. Early death in most studies does not seem to play a major role in the inferior outcome of elderly AML patients. The early death rate in intensively-treated patients has decreased considerably over the last 2 decades, most probably owing to better supportive care.
The median age of AML at diagnosis is 67 years with 54% of patients diagnosed at 65 years or older (and approximately a third diagnosed at >75 years of age) . Older AML, defined as patients aged >60 years, has been one of the most challenging subsets to stratify and derive treatment decisions .
The determinants of treatment success and failure remain partly understood. A combination of patient-related and specific disease-related factors are more common among this aging population and correlate markedly with treatment failure (i.e., primary resistance and relapse after induction therapy). They include comorbid conditions, performance status, decreased drug clearance and prolonged exposure to chemotherapeutics resulting from pharmacokinetic and pharmacodynamic changes, less tolerability to infections due to decreased immune competence of elderly patients, psychosocial factors (cognitive decline, social isolation, and, often, lack of caretakers), multidrug resistant abilities of the leukemia cells to expel the chemotherapeutics, antecedent hematologic disorders  (previous MDS, chronic myelomonocytic leukemia, myeloproliferative neoplasm), prior exposure to cytotoxic therapy for other disorders  and higher frequencies of adverse cytogenetics and unfavorable molecular aberrations .
The percentage of favorable cytogenetics (t(8;21), inv(16)/t(16;16), and t(15;17)) decreased to a low percentage
among the oldest age groups (<5% for patients older than 70 years;). No significant difference in frequency between patients who were not in the favorable or adverse cytogenetic group in different age groups. The rate of unfavorable risk cytogenetics increased continuously up to 36% in patients older than 85 years .
Chromosome 5 and 7 aberrations increase in the oldest age groups while complex karyotypes increase continuously up to 28% in the oldest age group. Trisomy 8 as a sole aberration was found more frequent in older patients than other age groups . Monosomal karyotype increased with age to 20% in patients older than 60 years . The median age of patients with chromosomal aneuploidy and TP53 mutations is 58 years as opposed to 49 years for the patients with aneuploidy alone. Chromosomal aneuploidy, and TP53 mutations are enriched in older AML (49% of >60 year-olds belong to either group) .
The high frequency of complex karyotypes and unbalanced aberrations in older patients indicates multiple genetic events, including epigenetic changes during a lifetime, a prolonged duration of exposure to environmental carcinogens which correlates with the number of mutations (especially in patients older than 60 years), and an accumulation of mutations from genetic error events in cell division. It has been demonstrated that clonal hematopoietic cells from normal individuals also accumulate mutations as a function of age .
RUNX1, ASXL1 and TP53 mutations (ELN adverse-risk category) are common in very old patient . The frequency of NPM1-positive cases increases up to 43% among 60-yearold
patients and decreases afterwards. The percentage of
NPM1/ FLT3-positive patients is lower (up to 19%), but the
age distribution remains similar to that for all NPM1-positive
Older AML patients can be offered one of the following
treatment options: standard induction treatment consisting
mostly of 3+7 regimen of an anthracycline and Ara-C;
hypomethylating agents; investigational drugs within a clinical
trial; low-dose Ara-C (LDAC); Best Supportive Care (BSC) with
oral cytostatic drugs like hydroxyurea and/or transfusions .
The choice between intensive, potentially curative chemotherapy
or a palliative therapeutic approach in old AML patients
should be guided by an evidence-based, individualized assessment
of the potential risks (e.g., treatment-related mortality)
and benefits of intensive chemotherapy .
The recommendation of intensive chemotherapy largely
depends on assessment of the clinical performance and medical
condition as judged by the medical doctor. Risk-scoring systems
could be instrumental in this regard. Geriatric assessments with
a focus on cognitive and physical function by either objective
measurements or self-reported measures have not been widely
studied. However, early studies suggest that they have added
value in comparison with performance status and comorbidity
evaluations, and thus they may improve the prediction of survival
in older patients receiving intensive chemotherapy .
Two models predict the probability of achieving a CR and
the risk for early death of untreated medically fit elderly AML
patients. The factors included in the first algorithm are body
temperature (≤38 °C and >38 °C), hemoglobin levels (≤10.3 and
>10.3 g/dL), platelet counts (≤28K, >28K - ≤53K, >53K - ≤10K
and >10K counts/mcL), fibrinogen levels (≤ 150 and >150 mg/
dL), age at diagnosis (60-64, >64-67, >67-72 and >72 years) and
the type of leukemia (de novo and secondary). The other model
includes performance score, age, platelet count, serum albumin,
presence or absence of secondary AML, WBC count, peripheral
blood blast percentage and serum creatinine (AUC 0.8-0.83) .
Patient registries and randomized trials suggest that
intensive induction therapy with 2 courses of cytarabine and
daunorubicin  can prolong OS at least in a subset of elderly
patients aged 70-79 years. A trial of induction chemotherapy
in this age group showed that favorable- and intermediate risk
cytogenetics, IDH1 wild type status and good performance
status may achieve relatively favorable OS, long-term survival
after induction chemotherapy compared to the adverse risk
group. The candidates’ patients might be those with absent
medical contraindications . Standard dose of cytarabine and
anthracycline with midostaurine may be considered in patients
with FLT3 positive mutation AML . Because many older
patients have some evidence of antecedent myelodysplasia, full
normalization of peripheral blood counts often does not occur
even if therapy clears the marrow blasts .
CR was achieved in 45% to 65% of older newly diagnosed
AML adults treated with standard ICT . No survival advantage
was observed in patients aged 65 to 70 years old who received
two intensive consolidation courses rather than one single
intensive consolidation course in the ALFA 9801 Trial .
RIC allogeneic HCT is considered an additional option for
postremission therapy in patients aged 60 years and older
with minimal comorbidities and in CR to induction therapy .
Prolonged survival has been reported in older patients receiving
AZA maintenance after achieving MRD negative remission after
HMAs is a backbone for combination strategies in older
patients and in those with adverse genetics or comorbidity that
make them at high risk for treatment failure and/or unacceptable
toxicity with standard intensive approaches . Both HMAs,
Decitabine (DAC) and Azacitidine (AZA) can improve median
and short-term OS compared with LDAC or Best Supportive Care
(BSC) only, even if the cure rates has not improved .
Favorable or NK-AML patients show CR rate of 18% with
subcutaneous LDAC (20 mg twice daily for 10 consecutive daily
every 4-6 weeks) and a survival benefit compared with CR rate of
1% with hydroxyurea at a dose that maintain WBC<10.000/mcL
. The combination of clofarabine and LDAC appears promising
in older patients who may not be suitable for standard induction
A wait-and-see approach with supportive care and cytoreduction
with hydroxyurea does not improve quality of life or prolong
survival of AML patients because none of the basic medical
problems are tackled .
• GO is a conjugate of an anti- CD33 monoclonal antibody
and the cytotoxic agent, calechiamicin. The cell surface
antigen CD33 is expressed in >90% of AML patients. The
FDA has made it available on a “compassionate use” basis for
patients with suboptimal responses, including persistence of
MRD after initial therapy .
• SGN-CD123A is an antibody-drug conjugate with the
antibody directed at CD123. CD123 is more restrictively
expressed in the healthy hematopoietic compartment,
which might decrease on-target off-leukemia toxicities. It
has been tested in relapsed/refractory AML in phase I trial
(NCT02848248) and in combination with AZA or DAC in
newly diagnosed older AML patients (CASCADE study) in phase III study (NCT02785900). Hepatotoxicity, including
veno-occlusive disease is a major concern, particularly when
combined with allogeneic HSCT before or after the treatment.
• CPX-351 (an encapsulation in nanoscale liposomes
of cytarabine and daunorubicin at a synergistic 5:1 molar
Ratio) may improve therapy of older patients with high-risk
features  and was also efficacious in older patients with
secondary AML .
• Treatment options of older adults with unfavorable
cytogenetic/ molecular markers, antecedent hematologic
disorder, or therapy-related AML include clinical trial, lowerintensity
therapy with HMA, standard infusional cytarabine
and anthracycline or clofarabine with or without standarddose
• Patients with adverse risk cytogenetics, IDH1 mutations
or poor performance status did not benefit from intensive
induction therapy and might fare better with alternative
strategies such as HMAs, or novel targeted agents that have
recently been approved or are currently under development
• Allogeneic HSCT is considered to be probably the best
option to prevent AML recurrence in selected patients with
intermediate- or adverse-risk AML .
How to manage older AML patients with high WBC at
diagnosis remains an open issue, because these patients appear
to poorly respond to both chemotherapy and HMAs. Combination
with kinase inhibitors represents an interesting approach
because they frequently present activating kinase mutations,
such as FLT3 internal tandem duplications .
The physically fit relapsed patients 60 years or older:
may be offered the following options: 1) therapy on a clinical trial
(strongly preferred); 2) chemotherapy followed by RIC allogeneic
HCT (transplant should be considered if the patient has entered
remission or in the context of clinical trial; 3) retreatment with
the initial successful induction regimen for patients with long
initial induction duration (relapse >12 months) .
The unfit relapsed elderly AML patients: are often
selected for clinical trials with new therapeutic agents . Many
new drugs have failed approval, partly because these drugs may
be tested in suboptimal setting. Relapsed/refractory AML in the
older patient population contains some of the most notoriously
resistant leukemias . AZA and DAC induce CR rates of 16% to
21% and median survival times of 6 to 9 months in older patients
with relapsed/refractory AML .
It remains unclear which genetic and clinical factors are
relevant to identify those elderly patients most likely to benefit
from, and least likely to be harmed by, induction chemotherapy
. The median OS in patients aged ≥75 years, regardless of
therapy type, was 4.3 months with a 3-year OS of 14%, compared
to a median OS of 10 months and a 3-year OS of 20% in patients
aged <75 years . The adverse outcomes associated with older
age are in part explained by the aggregation of poor cytogenetics
and, importantly, gene mutations .
Good-risk cytogenetics (core-binding factor leukemias) has
a distinctly favorable impact in older AML patients. Conversely,
Adverse-risk cytogenetics (MRC classification) are associated
with shorter OS . Monosomal karyotypes carry adverse
prognostic value . The 2-year OS was significantly decreased
among patients with monosomal karyotype compared with
patients without this abnormality (7% vs 22%). Similar
outcomes were observed within the subgroup of patients with
complex karyotype .
Chromosomal aneuploidy and TP53 mutations maintain an
independent adverse prognostic potential when age is accounted
Favorable molecular markers established in younger patients
(e.g., mutated NPM1 without or with low allelic ratio FLT3-ITD,
biallelic CEBPA mutations) have weaker prognostic relevance
in elderly patients . NPM1 and FLT3-ITD mutations had no
significant impact on OS . The impact of FLT3-ITD mutation
as a prognostic factor is reduced or absent in elderly patients .
Various studies have established the favorable effect of the
NPM1-mutant genotype in the absence of FLT3 gene mutations
for older AML patients treated with intensive chemotherapy
protocols . Alternately, in some studies, FLT3-ITD, DNMT3A,
and ASXL1 gene mutations seem to confer a negative effect on
response and survival in older patients with normal cytogenetics
Some driver gene mutations, such as DNA-methyltransferase
3A (DNMT3A), TET2, SRSF2, and ASXL1, may be detected in
seemingly healthy patients before overt AML development. Such
preleukemic clones are more frequent in older patients. Their
persistence during CR seems to represent a poor prognostic
factor associated with higher incidence of relapse in these
Gene-expression levels have to be evaluated in elderly AML
patients for their prognostic value. In addition, well-designed
clinical trials were recommended to include older AML patients
whenever possible. New drugs in fit, elderly AML patients and in
distinctly genomic-defined AML could be informative.