Elderly AML specificities

“First, how does the hematopoietic system change with age, how does this lead to a spectrum of hematological conditions, and would it be possible to pharmacologically intervene in this process? Second, if hematological disease presents in an elderly patient, should this be treated differently than if it had occurred in a young patient?” ³

These are pertinent questions for which answers have so far eluted hematologists. They are of utmost importance because AML is primarily a disease of the elderly population with the incidence rising with age. According to the SEER population statistics, only 1.9 of 100,000 people under 65 years old develop AML, a number rising to 19.1 for the elderly population of 65 years and older (between 2009 and 2013) ⁹⁶ . Expectedly, the median age of patients with AML at the time of diagnosis is around 71 years old (indicated by the compulsory reports of population-based studies like the Swedish AML registry with about 3,363 adult AMLs) ^46,45,97 .

1.5.1 Survival of elderly AML patients

Overall, elderly patients with AML have a poor survival probability, as studies show that survival to AML decreases with advanced age (Figure 1.5.1) ^46,45,98 .

Although the goal of curing AML can only be reached using intensive

chemotherapies, the therapy choices for older patients also include less intensive

chemotherapy or supportive care. This depends on the doctors’ perception of the

patient’s condition (performance status, ECOG score, co-morbidities, and tolerance to

intensive chemotherapy). These patients are many times considered unfit for the

intensive chemotherapy for fear of the high rates of early death in initial treatment. For

instance, patients older than 75 years with an ECOG performance score of 3 (“capable

of only limited self-care; confined to bed or chair more than 50% of waking hours”) or

higher have a 30-day mortality rate of more than 50% ⁴⁴ .

Figure 1.5.1 Survival of

As a result, in the US 60% of AML patients 65 years or older have not received therapy 3 months after diagnosis ⁹⁹ . The lack of viable options leads clinicians in Europe to widely use the less intensive approaches in patients over 65 years old, like decitabine or azacitidine, for although the effectiveness of these hypomethylating agents is not well established, they are promising ^100,101 . They remain a viable option, having in mind that even with intensive chemotherapy only 50% of patients older than 60 years achieve complete remissions and 50% of those would have relapsed within 2 years ¹⁰² .

Advances in therapy in the elderly patients have been compromised by extrapolation of results from clinical trials that mostly use young patients (frequently younger than 60 years). Elderly patients tend to be excluded from clinical trials for many reasons. The selection bias is frequently due to strict criteria for entering trials with intent-to-treat and by the drop out due to the impossibility of many of this patients to begin treatments, to complete them, or to go through consolidation phases ¹⁰³ .

Therefore, we know little about how and why treatments work or not work in the

elderly group of AML patients. Higher rates of resistance to intensive chemotherapy

treatment regimens and high rates of relapse have been observed in the older patients

when compared to younger AML patients. Response rates were observed to decrease

with age (as well as the median overall survival) even when there were no

protocol-directed differences in dosing of patients ⁴⁴ . Moreover, in a recent study, the treatment

response of patients 57-59 years old to a full-dose chemotherapy proved to be no

different from 60-63 year’s patients receiving an attenuated-dose therapy ¹⁰⁴ . Therefore

it is regularly concluded that age is an important independent determinant of

therapy-response in AML.

1.5.2 Molecular characteristics of elderly AML

These facts have been attributed to several disease characteristics displayed by elderly AML when compared to young AML patients, like the fact that older patients are more likely to have adverse cytogenetics ^105,106 . Nevertheless, elderly AML patients irrespective of their cytogenetic group show an inferior outcome compared to younger patients with the same risk alterations ^106,107 .

In an effort to examine the phenotype of this disease a study analysed the status of oncogenic pathways in elderly AML in comparison to younger AML ¹⁰⁸ . They found older patients had a higher probability of RAS, Src, and tumor necrosis factor (TNF) pathway activation ¹⁰⁸ .

All of these data underscored the biological differences between AML in younger and older patients. Evidences that led us to postulate that elderly AML is a different entity for which a targeted treatment is needed and should be properly investigated.

As it remained an open question if additional molecular alterations have important contributes to the poor prognosis of AML in the elderly patients this was one focus of our project ¹ .

Meanwhile, attending to these indications in last two years some studies that sequenced genes known to be frequently mutated in AML have made a point in dividing their cohorts into young and elderly patients to look at frequencies of genetic alterations ^{34, 38,40} .

In general, it is now established the commonly mutated genes in older patients with AML included RUNX1, TET2, IDH2, ASXL1, SRSF2, TP53, BCOR and SF3B1 while WT1 mutations were more frequent in the younger patients ^1,34,38,40 .

Since the genetic profiles might explain some of the poor prognosis of elderly AML the origin of this very specific profiles should provide important information for new treatment design.

As age-related changes of the diseased hematopoietic system are found they

must be the result of the aged state of the HSCs. Therefore we should explore the

possible effects of age on the progenitor cells that give rise to the elderly AML.