First-line treatment options for elderly patients with acute myeloid leukemia from an international perspective: intensive chemotherapy versus non-intensive therapy

Fortunately, first-line use of demethylating agents in combination with veneer can significantly improve prognosis in elderly or unfit AML patients

Professor Nicholas J Short and Professor Hagop Kantarjian of MD Anderson Cancer Center in the United States reviewed retrospective and prospective data supporting intensive chemotherapy and low-intensity regimens containing Venekkura for the treatment of elderly patients with AML, as well as the MD Anderson Cancer Center's protocol for managing elderly or unfit AML patients

AML is primarily a senile disease, with a median age of 68 years

Demethylated drugs (i.

The oral BCL-2 inhibitor Venequera, approved in 2018, significantly improved outcomes in elderly or unfit AML patients and provided a tolerable and effective treatment option for these patients

A number of large retrospective studies support the use of intensive chemotherapy in elderly patients with AML, and these studies have shown that the prognosis of intensive chemotherapy is superior to palliative or supportive care

Given the curative potential of intensive chemotherapy, clinicians and leukemia researchers advocate using it for older patients
with AML who are suitable enough to receive chemotherapy.

This view is supported by American Hematological Society guidelines, which recommend that older patients with AML, if permitted, should receive intensive therapy
.

The National Comprehensive Cancer Network guidelines have some nuances, recommending intensive chemotherapy for elderly patients at low or intermediate risk of cytogenetic risk and venequera low-intensity therapy
for patients at high risk of cytogenetic risk.

Many experts in the field of AML also advocate that intensive chemotherapy
should still be used in some elderly patients.

While intensive chemotherapy offers a potential cure for a small percentage of older patients with AML, it also carries high risks, including treatment-related morbidity and mortality, both of which are often due
to complications of infection associated with bone marrow suppression.

In a retrospective analysis of 998 patients aged ≥ 65 years, newly diagnosed with AML and receiving intensive chemotherapy, factors associated with higher 8-week mortality included age ≥75 years, ecog fitness status score of ≥2, complex cytogenetic abnormalities, absence of treatment in a blood purification room, previous haematological disorders, and creatinine concentrations > 1.
3 mg/dL
.

8-week mortality was 50% in patients with 3 or more risk factors (25-30% of all patients) and 30% in patients with 1 or 2 risk factors (50-55%
of all patients).

Even in a small number of patients (about 20%) who did not have these adverse risk features, the 8-week mortality rate was 10%.


The study highlights the higher early mortality rates of most elderly AML patients who receive intensive chemotherapy
.

In addition, for many elderly AML patients who initially appear to be suitable for intensive therapy, the risk of intensive therapy remains too high to be acceptable
.

Most studies supporting the use of intensive chemotherapy in older patients with AML preceded the widespread use of demethylated drugs
.

Some retrospective study analyses have compared the results of
intensive chemotherapy and demethylated drug therapy.

A retrospective analysis of patients aged ≥70 years showed that, although there were more disease-related adverse features in the demethylated drug treatment group, compared with patients receiving intensive chemotherapy (median OS: 10.
8 months [95% CI: 8.
8-12.
5]), OS prolongation (median OS: 14.
4 months [95% CI: 11.
9-17.
2]) in patients receiving demethylated drugs (hazard ratio [HR]: 1.
35 [95% ]) CI：1.
10-1.
65]，P=0.
004）
。
In contrast, another study in similar populations (age ≥70 years) showed higher early mortality in the intensive chemotherapy group, but better
response rates, recurrence-free survival, and overall survival.

Retrospective analysis is prone to bias
when selecting patients with intensive chemotherapy (usually fit patients) or demethylated drugs (generally unfit patients).

In a large prospective observational study, the use of low-intensity treatment (mainly containing demethylated drugs) was associated with an increased risk of death compared with intensive chemotherapy; However, when the model was adjusted based on patient age and physician perceptions of a possible cure, the risk of death from intensive and non-intensive treatments was similar to
the patient's quality of life.

In prospective, randomized trials evaluating both treatments, more than 30 percent of elderly AML patients with protocellular protogenesis (≥65 years of age) were assigned to either azacytidine or a conventional treatment regimen (which may include intensive chemotherapy
).

Median OS in patients receiving azacytidine or intensive chemotherapy despite the older age of patients in the azacytidine group (azacytidine: 13.
3 months [95% CI: 7.
2-19.
9]; Intensive chemotherapy: 12.
2 months [95% CI: 7.
5-15.
1]) and 1-year OS rate (azacitidine: 56% [95% CI: 40-69]; Intensive chemotherapy: 51% [95% CI: 35-65]) similar
.

Based on the results of this prospective study and most retrospective studies, the response rates of the two treatments were similar to those of median OS in older patients with AML, although the potential cure rates for intensive chemotherapy may be higher
.

The inclusion of Venequera in first-line treatment options for elderly or unfit AML patients revolutionized treatment in this population
.

In the Phase III VIALE-A study, patients with newly diagnosed unfit AML (aged ≥75 years with significant clinical comorbidities or ECOG physical fitness status scores of ≥2) were randomly assigned to receive
azacitidine plus vernekorin plus placebo.

Azacytidine plus vinakela significantly increased the rate of complete remission (CR) and CR rate with incomplete recovery of hematology (azacitidine + venecola: 66.
4% [95% CI: 60.
6-71.
9]; Azacitidine + placebo: 28.
3% [95% CI: 21.
1-36.
3], P<0.
001) and improved median OS (azacitidine + venecrate: 14.
7 months [95% CI: 11.
9-18.
7]; azacitidine plus placebo: 9.
6 months [95% CI: 7.
4-12.
7], P<0.
001).
<b14>
Similarly, in the Phase III VIALE-C trial, low-dose cytarabine combined with veneercora improved the CR rate in elderly patients with unfit AML and the CR rate with incomplete recovery of hematologic hematology (low-dose cytarabine + wienecla: 48% [95% CI: 39-56]; Low-dose cytarabine + placebo: 13% [95% CI: 6-24], P<0.
001) and improved median OS (low-dose cytarabine + veneercora: 8.
4 months [95% CI: 5.
9-10.
1]; Low-dose cytarabine plus placebo: 4.
1 months [95% CI: 3.
1-8.
1], P=0.
04<b16>).

According to these two large randomized studies, demethylated drugs or low-dose cytarabine plus venequera are currently seen as the standard of care for
newly diagnosed unfit elderly patients with AML.

Given that the addition of venequera to demethylated drugs or low-dose cytarabine therapy significantly improves response rates and survival, the role of intensive chemotherapy in older patients with AML (aged 60-74 years but without significant clinical comorbidities) who do not meet the criteria for inclusion in VIALE-A or VIALE-C is increasingly questionable, The results showed a median OS of 14.
7 months for patients aged≥ 60 years treated with azacitidine plus verneclerol, significantly higher than historical expectations for patients receiving intensive chemotherapy, and the median OS for this subset of patients in prospective studies was about 12 months
.

Although there is a lack of definitive data to support the use of intensive chemotherapy or low-intensity regimens containing veneercer to treat older fit patients, there is evidence that demethylated agents plus venequera outcomes are similar to or may even be superior to intensive chemotherapy
.

The results of an ongoing randomized Phase II study comparing newly diagnosed AML patients (regardless of age) with intensive chemotherapy versus demethylated drugs plus veneerquera (NCT04801797) may help answer this question
.

Several studies have evaluated the efficacy of standard intensive chemotherapy plus veneerquera in young and older patients newly diagnosed with AML, and the initial results are encouraging
.

In young patients newly diagnosed with AML, the overall response rates of CLIA (cladribine, daunorubicin, and cytarabine) plus veneercora and FLAG-Ida (fludarabine, cytarabine, daunorubicin, and G-CSF) plus veneercora were 94% (47/50) and 97% (28/29), respectively, and the 1-year OS rates were 85% (95% CI: 75-97) and 94% (95% CI: 84-100), respectively, The safety of these regimens in patients over 65 years of age has not been studied
.

The CAVEAT study administered Vinekora plus a 5+2 chemotherapy regimen to 51 elderly patients with newly diagnosed AML (median age 72 years), 37/51 patients (73%) achieved CR or CR with incomplete hematologic recovery, and the median OS of the entire cohort was 11.
2 months (95% CI: 7.
3-20.
1).


Although there are currently relatively few data supporting elderly patients receiving intensive chemotherapy plus veneerquera, if these treatment regimens can be given safely, it may be a suitable option
for older patients with newly diagnosed fit.

Although demethylated drugs combined with veneerquera first-line therapy improved outcomes in elderly AML patients with unfit, the 2-year OS rate of this approach was only 30%-50%.


On the basis of demethylated drugs combined with veneerquera, new therapeutic advances
have been made.

In ≥ 60-year-old patients newly diagnosed with AML, the combination of clatrabine combined with a low-dose cytarabine and dicetabine alternating regimen yielded good results, and MD Anderson Cancer Center added venekra to the regimen
.

In a Phase II trial, 60 elderly patients (median age 68 years) newly diagnosed with AML received treatment with cladribine plus low-dose cytarabine + venekela, alternating with azacytidine + venequera
.

56/60 patients (93%) achieved CR or CR with incomplete haematological recovery, and of the 51 patients who could assess remission, 43 (84%) had a negative residual lesion
.

The 4-week mortality rate was 2% (1 in 60).


Nineteen patients (34% of those in remission) underwent an allogeneic hematopoietic stem cell transplant (HSCT)
at the time of the first remission.

The median FOLLOW-up was 20.
4 months, the median OS was not reached, and the estimated 2-year OS rate was 60% (95% CI: 48-77).


These results outperformed previous demethylated drugs in combination with venequera, but were studied in younger patients
who were more amenable to receiving consolidation allogeneic HSCT.

Triple therapies based on demethylated drugs and veneerk are being explored in clinical trials (table below), many of which are evaluating the addition of a novel experimental drug to the demethylated drug plus veneercora, and targeted combination therapies that have been shown to be effective in relapsed/refractory patients are also being explored
in first-line therapies.

For example, geritinib is a potent oral FLT3 inhibitor that has been approved as a monotherapy
for relapsed/refractory FLT3 mutant AML.

Data from a phase II trial of azacitidine, venequera and geritinib in combination with newly diagnosed FLT3 mutant AML patients with unfit have been reported, with good
interim results.

Of the 14 patients (median age 71 years) treated, all patients responded (13 [93%]CR) with a 6-month OS rate of 92%.


There have also been clinical trials of the combination of the IDH1 inhibitor evenib and the IDH2 inhibitor Enzeidipine with azacytidine or azacytidine plus vinakela in elderly or unfit AML patients with IDH1 or IDH2 mutations
.

In one randomized study, combination azacitidine with avenib improved CR rates in patients compared with azacytidine monotherapy (azacitidine + avonib: 47%; Azacytidine + placebo: 15%; OR: 4.
8 [95% CI: 2.
2-10.
5], P<0.
001) and median OS (azacitidine + evonibu: 24 months [95% CI: 11.
3-34.
1]; Azacytidine plus placebo: 7.
9 months [95% CI: 4.
1-11.
3]; HR：0.
44[95%CI：0.
27-0.
73]，P=0.
001）<b110>。
Of the 13 newly diagnosed patients with IDH1 mutant AML, 12 (92%) achieved CR or CR with incomplete haematological recovery after receiving triple regimens of azacytidine, venecolla and avonib, with an estimated 1-year OS rate of 71%.


Similarly good results
were observed in the new diagnosis and relapse/refractory IDH2 mutation AML with azacidine, veneerquera and encidipine.

table

MD Anderson Cancer Center's treatment of elderly patients newly diagnosed with AML is based primarily on the patient's age and cellular molecular characteristics (figure below
).

Available data suggest that in older patients with AML, demethylation agents combined with the venequera regimen can achieve similar or better efficacy to intensive chemotherapy, so MD Anderson Cancer Center uses a low-intensity regimen containing veneerquera rather than intensive chemotherapy to treat almost all patients
aged ≥ 65 years.

Low-intensity regimens are also commonly used in patients aged 60 to 64 years, but sometimes intensive chemotherapy in combination with Venequera, which is based on good efficacy
in younger fit patients.

MD Anderson Cancer Center conducted an analysis of early death predictors in newly diagnosed AML patients, and based on this analysis, only older patients with fit, age 60-64 years, good physical fitness, normal organ function, and no clinical or radiographic evidence of pneumonia at the beginning of treatment were retained as an intensive treatment regimen
.

fig

For elderly patients with defined molecular targets (i.
e.
, FLT3, IDH1, or IDH2 mutations) or unfit patients, MD Anderson Cancer Center is treated
with a triptych regimen of azacytidine (or desistatin) plus venecora plus geritinib (if there is a FLT3 mutation) or avenib (if there is an IDH1 mutation) or Enzeidipine (if there is an IDH2 mutation).

For elderly or unfit patients aged 60-69 years with no target abnormalities, MD Anderson Cancer Center uses clatrabin in combination with low-dose cytarabine and venecora, alternating with azacytidine and venecora, and the researchers believe that this regimen is superior to demethylated drugs alone in combination with venecora
.

Patients aged ≥70 years without target abnormalities are usually included in clinical trials
containing demethylated drugs and the Venequera triple regimen.

MD Anderson Cancer Center recommends fit patients aged ≤75 with molecular characteristics of intermediate- or high-risk cells to undergo allogeneic HSCT
at the time of the first remission.

Specific patients up to the age of 78 are also recommended for allogeneic HSCT evaluation
if they are particularly suitable.

Several analyses have shown a good prognosis for patients receiving allogeneic HSCT after receiving a low-intensity veneerk-containing regimen, and MD Anderson Cancer Center does not recommend changing first-line treatment based
on whether the patient is eligible for transplantation.

MD Anderson Cancer Center uses low-intensity treatment regimens containing venekera to treat newly diagnosed patients with AML, with the exception
of patients with core binding factor (CBF)-associated AML.

Older adults account for about 5-15%
of CBF-AML cases.

Because CBF-AML is very sensitive to high-dose cytarabine, MD Anderson Cancer Center uses the FLAG combined gemonumab ozogamicin regimen for fit patients aged ≤75 years, with appropriate dose adjustments
to the FLAG regimen based on age.

In view of the significant efficacy of gemmtuzumab ozogamicin, for elderly patients with significant clinical comorbidities or very poor physical status, a low-intensity regimen (i.
e.
, demethylated drugs + veneercora or cladribine and low-dose cytarabine + venecora) is used in combination with at least one dose of gemmtuzumab ozogamicin
.

Despite progress in including venequera in low-intensity treatment regimens for elderly or unfit AML patients, there are still some high-risk AML subsets with therapeutic challenges
.

These disorders include, but are not limited to: TP53 mutant AML, MECOM rearrangement AML (i.
e.
, inv[3][q21q26] or t[3; 3] [q21q26]), and AML caused by blood disorders previously treated with demethylated drugs
.

Analysis suggests that Venequera may not improve prognosis
in patients with TP53 mutant AML.

However, new drugs such as the anti-CD47 monoclonal antibody magrolimab show good early efficacy
in TP53 mutant AML and myelodysplastic syndrome (MDS).

Because these high-risk AML subgroups received very poor outcomes after intensive chemotherapy (historical response rates of <50% and median OS of 4-6 months), MD Anderson Cancer Center considered a low-intensity research strategy for all of these patients, including those<b18> younger than 60 years of age.

Effective and tolerable treatment options for elderly patients with AML have been an unmet need
in this field.

The development of low-intensity regimens with Venekla has improved survival in these patients, but their long-term outcomes remain unsatisfactory
.

New strategies containing demethylated drugs and venecla are expected to further improve response rates and survival in
these patients.

Although some progress has been made in recent years, some problems
remain.

For newly diagnosed elderly patients with AML, there is still a lack of clear consensus
on the choice of intensive and non-intensive therapy.

In addition, with the availability of data on long-lasting remission and long-term survival after demethylated drugs combined with veneerquera, can the use of this regimen be considered in younger patients? Low-intensity therapies containing Venekera are very high in response, so this regimen may be a reasonable way to safely transition patients to radical allogeneic HSCT, particularly those with high-risk cellular molecular signatures
who have not previously responded well to intensive chemotherapy.

Ultimately, in the rapidly evolving field of AML treatment, clinical trials involving patients of all ages remain a
priority in order to continue to advance and optimize the treatment of this challenging patient population.

References:

Nicholas J Short, Hagop Kantarjian.
Choosing between intensive and less intensive front-line treatment approaches for older patients with newly diagnosed acute myeloid leukaemia.
Lancet Haematol.
2022 Jul; 9(7): e535-e545.
doi: 10.
1016/S2352-3026(22)00167-3.

Poke "Read the original article" to see more