New treatment strategies for elderly patients with acute myeloid leukemia

The median age of newly diagnosed AML patients is 68 years old (mostly ≥65 years old).
The population is gradually aging and the incidence of elderly leukemia patients is increasing.
In order to improve the prognosis of this growing high-risk population, the exploration of safe and effective treatment methods has become a concern Focus
.

In recent years, the treatment of AML has progressed rapidly.
Compared with the use of demethylation drugs (HMA) alone, the combination of BCL-2 inhibitor Venecla and HMA has significantly improved the remission rate and overall survival (OS) rate of newly diagnosed AML patients
.

The development of small molecule inhibitors of FLT3, IDH1, and IDH2 provides a safe and effective treatment for a subset of patients defined by the genome
.

In addition, new oral maintenance therapy with bioavailable drugs has also been shown to extend the duration of remission and provide survival benefits
.

The joint program based on these new drugs and the research and development of new drugs are actively being explored
.

01Veneclax combination regimen: Venecla is a highly selective oral BCL-2 inhibitor, combined with azacitidine (AZA) to show significant anti-leukemia activity
.

The randomized phase III VIALE-A study confirmed the survival benefit of Venecla and AZA (compared to AZA alone)
.

Among 431 patients ≥75 years of age or unfit, the CR/CRi rates of the Venecla combined with AZA group and the AZA group alone were 66% and 28% (P<0.
001), and the median OS was 14.
7 months.
And 9.
6 months (HR 0.
66 [0.
52-0.
85]; P<0.
001)
.

However, according to the results of a randomized study, the combination of AZA and Veneclax is limited to patients ≥75 years old and unfit patients.
There are still unmet needs for patients 60-75 years old.
These patients may not be ideal candidates for intensive chemotherapy.
Benefit from the low-intensity and high-efficiency Vinekala joint program
.

The low-intensity dinucleoside analog combination regimen of Cladribine + low-dose cytarabine (LDAC) alternating AZA showed high CR rates and long-lasting OS in newly diagnosed patients with a median age of 69 years
.

In a long-term follow-up of 248 newly diagnosed AML patients with a median age of 69 years, the CR/CRi rate of the dinucleoside analog combination regimen (without venecla) was 66%, and the median OS was 12.
5 Months
.

In an ongoing phase II clinical trial, the CR/CRi rate of Venecla combined with cladribine + LDAC alternate AZA was 93%, the minimal residual disease (MRD) negative rate was 84%, and the early mortality rate was low.
The median OS has not been reached, and we look forward to better long-term results
.

02 Patients with NPM1 and IDH mutations in the new drug combination regimen have better curative effects after treatment with AZA+Veneclax
.

However, patients with FLT3 or TP53 mutations have a short duration of remission and a poor prognosis
.

The LACEWING study evaluating the FLT3 inhibitor gilteritinib combined with AZA in the treatment of AML patients did not prove a survival benefit.
The combination of FLT3 inhibitors and Venecla and AZA is currently being studied for the treatment of elderly AML patients with FLT3 mutations.
Observation of the triple regimen of gilteritinib showed that its early safety and efficacy were better
.

In addition, a new combination plan for TP53 mutant AML patients is also under study
.

In newly diagnosed MDS patients with TP53 mutations, the new small molecule inhibitor APR-246 (eprenetapopt) combined with AZA did not show a survival advantage.
A study to evaluate the efficacy of APR-246 combined with AZA and Vinekal is ongoing In
.

Therapeutic monoclonal antibodies are also used in combination therapy.
Magrolimab is an anti-CD47 monoclonal antibody that disrupts its interaction with macrophages SIRPα and acts as a macrophage checkpoint inhibitor
.

Based on its mechanism that affects the death of immune cells, the anti-leukemia activity of Magrolimab may not be related to the TP53 pathway
.

Researchers are conducting studies on Magrolimab combination regimens in the treatment of AML patients with adverse risks (including TP53 mutations).
Inhibitors of mutant IDH1 and IDH2 enzymes have been shown to be well tolerated and approved as a single agent as a treatment regimen for AML.
In combination with AZA or AZA+Venecla or intensive chemotherapy, promising results have been reported
.

03 Maintenance treatment of elderly patients after remission is an important need to reduce the risk of recurrence.
The randomized phase III QUAZAR AML-001 study showed that compared with placebo, CC-486 (an AZA oral preparation, given in a 28-day cycle) 14 days after treatment) has a survival benefit in post-remission treatment.
Among 472 patients ≥55 years of age who had first remission, the median OS of CC-486 was 24.
7 months, while the median OS of the placebo group was 14.
8 Month (P<0.
001)
.

Subgroup analysis confirmed the benefits of patients across subgroups, with elderly patients ≥65 years old and patients not receiving consolidation therapy benefiting the most
.

A new program that combines low-dose oral HMA with new small molecule drugs (including venacola, FLT3 inhibitors, and IDH inhibitors) has the potential to further expand these positive results and is currently under investigation
.

It should be noted that increasing the understanding of the biology of AML will help to rapidly develop new highly active drugs for the treatment of AML, and expand the opportunities for further innovation and exploration of new strategies to cure elderly AML patients
.

Reference source: Tapan Kadia.
2021 SOHO.
EXABS-132-AML.
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