Professor Wu Depei on World AML Day: Interpreting the New Trend of R/R AML in Precision Targeted Therapy

Acute myeloid leukemia (AML) is the most common type of leukemia in adults and has historically had a high mortality rate
.

With the deepening of medical research, the treatment of AML has developed rapidly in recent years
.

However, the treatment of patients with relapsed or refractory (R/R) AML still faces enormous challenges
.

FLT3 mutation is one of the most common genetic mutations in AML, which seriously affects the prognosis of patients
.

A new generation of FLT3 inhibitor, gilritinib, is a precision targeted drug for the treatment of FLT3-mutated R/R AML patients, which has significantly improved the survival of R/R AML patients
.

Therefore, it is of epoch-making significance to explore the role of such drugs in the era of precision targeted therapy
.

On the occasion of World AML Day, this article will interpret the new development trend of R/R AML precision targeted therapy, help the development of AML diagnosis and treatment in China, and hope that more AML patients will benefit! Professor Wu Depei Chief Physician, Professor, Doctoral Supervisor Director of Hematology Department of the First Affiliated Hospital of Soochow University Executive Deputy Director of National Clinical Research Center for Hematological Diseases Deputy Director of Jiangsu Hematology Research Institute Deputy Director of Soochow University Clinical Medicine Research Institute of Soochow University Hematopoiesis Director of Stem Cell Transplantation Institute Member of the 13th National Committee of the Chinese People's Political Consultative Conference Chairman of the Chinese Medical Association Hematology Branch Standing Committee Member of the Chinese Medical Association Internal Medicine Branch Vice President of the Chinese Medical Doctor Association Hematologist Branch Challenges, treatment effects need to be improved AML is characterized by high genetic and clinical heterogeneity and high mortality1, according to the 2021 National Cancer Institute Surveillance, Epidemiology and Outcomes Database (SEER) accurate estimates, new cases of AML20 , 240 cases, and 11,400 deaths2, and the morbidity and mortality are increasing year by year3
.

In China, the incidence of AML is about 2.
57/100,000 people, and the mortality rate is about 1.
57/100,000 people per year4.
The morbidity and mortality remain high
.

Since the 1970s, the "7+3" (cytarabine, d1-7+daunorubicin, d1-3) intensive induction regimen has officially entered the field of AML and has become the standard first-line induction regimen for AML1
.

However, R/R AML still lacks standard treatment options, and the prognosis of patients is poor, and the treatment faces great challenges5
.

For most R/R AML patients, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only cure, and the 4-year survival rate of HSCT in R/R AML patients is only 20-35%5
.

Patients who achieved complete remission (CR) prior to HSCT had more favorable outcomes 5
.

R/R AML treatment should help achieve CR and create conditions for HSCT
.

Pioneering and innovation: FLT3 inhibitors help AML treatment, and precise targeted therapy sets sail.
With the emergence of next-generation sequencing technology and the continuous discovery of new gene mutations, the treatment of AML has undergone earth-shaking changes, and the research and development of various targeted drugs has gradually Push to clinical 1
.

However, the treatment of R/R AML remains the most challenging, and new treatment strategies are urgently needed5
.

FLT3 mutation is an independent risk factor for poor prognosis of AML.
There are many gene mutations in AML patients, such as FLT3, NPM1, IDH1/2, etc.
Among them, FLT3 gene is particularly important
.

FLT3 is a gene encoding FLT3 receptor tyrosine kinase 6, and by binding to its ligand, it plays an important role in promoting the proliferation and differentiation of hematopoietic cells during early hematopoiesis
.

FLT3 gene mutation leads to autophosphorylation of FLT3 receptor tyrosine kinase, which continuously activates the signal transduction pathway of cell proliferation and inhibits cell apoptosis, which can lead to the malignant proliferation of immature cells in the process of hematopoiesis, resulting in malignant hematological diseases.
1
.

FLT3 gene mutation is one of the most common genetic alterations in AML patients7, the most common FLT3 mutation is the internal tandem repeat (ITD) of the receptor juxtamembrane domain, with a mutation frequency of 30%; followed by the tyrosine kinase domain (TKD) ) point mutation with a mutation frequency of 7%8
.

Patients with FLT3-mutated R/R AML have generally poorer outcomes compared with those without mutations: a study of 109 patients with FLT3 mutations and 221 patients without mutations comparing FLT3 treated at MD Anderson Cancer Center from 1995-2004 Data from patients with mutated R/R AML showed that the median OS was 32 weeks vs 72 weeks (p < 0.
001) in the two groups, respectively (Figure 1)
.

Figure 1 OS of R/R AML patients National Comprehensive Cancer Network (NCCN) guidelines (2022.
v1), Chinese Society of Clinical Oncology (CSCO) guidelines 2021 and Chinese adult acute myeloid leukemia (non-acute promyelocytic leukemia) diagnosis and treatment The guidelines (2021 edition) all pointed out that FLT3 mutation affects prognosis, and FLT3-ITD hypermutation (allele ratio ≥0.
5) is associated with poor prognosis 11-13
.

Since FLT3 mutations are the most common genetic mutations in protein-coding regions and are associated with poor prognosis, FLT3 is one of the important targets for precise targeted therapy in AML7
.

FLT3 inhibitors open up a new pattern of precision-targeted therapy for FLT3-mutated AML patients With the discovery of important targets for precision-targeted therapy for AML such as FLT3, FLT3 inhibitors and other precision-targeted drugs bring light to patients with FLT3-mutated AML (Figure 2)
.

First-generation FLT3 inhibitors include Lestaurtinib, Sunitinib, Midostaurin,
etc.

In recent years, more selective and effective second-generation FLT3 inhibitors, such as Quizartinib, gilritinib, and Crenolanib, have entered clinical trials and demonstrated significant therapeutic effects
.

Compared with first-generation inhibitors, second-generation FLT3 inhibitors selectively target and inhibit FLT3, with better efficacy and greater specificity
.

Figure 2 The development history of FLT3 inhibitors The only FLT3 inhibitor approved in China for the treatment of R/R AML The second-generation FLT3 inhibitor geritinib was approved in the United States as early as 2018 for the treatment of R/R AML with FLT3 mutations patients, enabling a breakthrough in the treatment of FLT3-mutated R/R AML
.

Geritinib is a novel, highly selective, oral FLT3 inhibitor that inhibits FLT3-ITD and FLT3-TKD mutations with high selectivity and inhibits the FLT3 receptor by simultaneously binding to the active conformation and inactive construct of the FLT3 kinase domain signaling, resulting in the inhibition of AML cell growth, reduction in cell proliferation and induction of apoptosis (Figure 3)
.

In addition to the highly selective inhibition of FLT3-ITD and FLT3-TKD mutations, gilritinib also showed inhibitory activity against the receptor tyrosine kinase AXL 7
.

AXL is upregulated and activated in malignant cells including AML, and its high expression has been reported to be associated with poor prognosis 7
.

Figure 3 Geritinib Mechanism of Action Due to its unique mechanism of action, geritinib monotherapy in patients with FLT3-mutant R/R AML showed positive efficacy and a satisfactory safety profile 14
.

The ADMIRAL study is an international, multicenter, open-label, phase III randomized clinical study of 371 patients ≥18 years of age with FLT3-mutated R/R AML, comparing geritinib versus salvage chemotherapy in the treatment of FLT3-mutated R/R AML patient outcomes 15
.

The results showed that median OS was significantly prolonged in the geritinib arm compared with salvage chemotherapy (9.
3 months vs 5.
6 months, p < 0.
001) (Figure 4), and regardless of prior FLT3 inhibitor use, FLT3 mutations All patients benefited from geritinib (Figure 5); the event-free survival (EFS) was significantly prolonged in the geritinib group (2.
3 months vs 0.
7 months, p < 0.
001); Complete response (CR) rates were 21.
1% vs 10.
5% in the chemotherapy group, CR and partial hematologic recovery (CR/CRh) rates were 34% vs 15.
3%, and overall response (ORR) rates were 67.
6% vs 67.
6% 25.
8%; the gilritinib-treated group did not show greater toxicity in the first 30 days after treatment compared with the chemotherapy group
.

In addition, for patients who did not continue to receive hematopoietic stem cell transplantation after induction of remission, the median OS for geritinib and salvage chemotherapy was 8.
3 months vs 5.
3 months, respectively, which was similar to the median OS for all patients; HSCT The median OS was 16.
2 months in patients who continued oral geritinib maintenance therapy after transplantation, compared with 8.
4 months in patients who did not receive geritinib maintenance therapy after transplantation, suggesting that patients who received HSCT received oral geritinib Maintenance therapy can significantly prolong survival
.

Fig.
4 Median OS of geritinib vs salvage chemotherapy in R/R AML patientsFig.
5 Subgroup analysis of OS with geritinib in patients with FLT3 mutation The regulatory agency (NMPA) approved it for the treatment of patients with FLT3-mutated R/R AML in 2021, marking the first targeted therapy for FLT3-mutant R/R AML patients in China and pioneering the development of FLT3-mutated R/R AML.
A new era of precision targeted therapy in China, and it has been approved by the European Society for Medical Oncology (ESMO) guidelines16, NCCN guidelines (2022.
v1)11, CSCO guidelines 202112 and Chinese guidelines for the diagnosis and treatment of relapsed and refractory acute myeloid leukemia (2021 edition)17 It is unanimously recommended by domestic and foreign authoritative guidelines as the first choice for the treatment of patients with FLT3-mutated R/R AML
.

In the ascendant: Giritinib benefits Chinese patients and opens a new era of precise targeted therapy in China.
Giritinib not only showed excellent efficacy in the single-agent treatment of FLT3-mutated R/R AML, but also combined with azacitidine + veneclax therapy The composite CR rate of FLT3-mutated R/R AML unsuitable for strong induction chemotherapy was also as high as 67%18, and the improved composite CR rate of FLT3-mutated AML who received extensive treatment in combination with veneclax was as high as 83.
8%19
.

In addition, the combination of gilritinib and standard chemotherapy, azacitidine, veneclax, etc.
in the treatment of newly diagnosed AML patients also achieved good curative effect 20-22
.

One year after its launch in China, gilritinib has filled the unmet medical needs of Chinese patients with FLT3-mutated R/R AML, benefiting many Chinese patients with FLT3-mutated R/R AML
.

On the occasion of World AML Day, we look forward to the application of gilritinib in induction therapy, consolidation therapy, and maintenance therapy to further improve the survival and prognosis of AML patients, so as to benefit more AML patients! Reference 1.
Fiorentini A, Capelli D, Saraceni F, et al.
The Time Has Come for Targeted Therapies for AML: Lights and Shadows.
Oncol Ther.
2020 Jun;8(1):13-32.
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National Cancer Institute.
Surveillance , Epidemiology, and End Results (SEER) Program.
National Cancer Institute; Bethesda, MD, USA: 2021.
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Cancer Stat Facts: Leukemia—Acute Myeloid Leukemia (AML).
[EB/OL].
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cancer.
gov/ statfacts/html/amyl.
html available at 2020.
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Li Ya, Chen Yu, Li Junmin.
Advances in the treatment of elderly acute myeloid leukemia [J].
Internal Medicine Theory and Practice, 2019,14(06): 391-394.
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Thol F, Heuser M.
Treatment for Relapsed/Refractory Acute Myeloid Leukemia.
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2021 Jun 1;5(6):e572.
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Liesveld JL, et al.
Acute myelogenous leukemia.
In: Williams Hematology, 9th ed.
, Kaushansky K, et al.
New York, NY: McGraw-Hill Education, 2016.
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Kiyoi H, Kawashima N,