2022CSH Prof. Hui Wei: Progress in the treatment of acute myeloid leukemia with FLT3 mutation

The 17th National Hematology Academic Conference of the Chinese Medical Association was grandly opened in Shanghai on September 23-25, 2022, with the theme of "respect, inheritance, collaboration and innovation", and invited well-known experts at home and abroad to talk about the latest progress
in the field of blood diseases.
At this conference, Professor Wei Hui of the Blood Disease Hospital of the Chinese Academy of Medical Sciences introduced the treatment progress of acute myeloid leukemia (AML) with FLT3 mutation from the prognostic characteristics, chemotherapy progress
, and targeted drugs with FLT3 mutation under the topic of "Standardized Diagnosis and Treatment of AML with FLT3 Mutation".

Previous studies have demonstrated that compared with patients with FLT3 wild-type AML, the recurrence rate with FLT3 mutation is higher, the treatment effect after recurrence is poor, and the long-term survival is poor
。 The Cephalon 204 study showed that the overall response rate (ORR) after receiving chemotherapy was 12.
5% in 48 patients with AML with FLT3 mutation, and the median overall survival (OS) was only 3.
45 months; the results of the Hopkins study were very similar to those of the Cephalon 204 study, and the complete response (CR) rate of R/R with FLT3 mutation AML after receiving the cytarabine-containing rescue protocol was only 12%.
The median OS is only 6.
25 months
.
Professor Wei Hui said that traditional chemotherapy regimens and salvage therapies have limited efficacy in patients with FLT3 mutation AML, especially for patients with relapsed refractory disease
.

Previous clinical trials have confirmed that the traditional "7+3" regimen of daunorubicin increased from 45 mg/m2 to 90 mg/^m2 can significantly improve the long-term survival outcomes of patients in the cytogenetics group into the prognostic group and the middle group; Among them, the OS rate of the FLT3-ITD mutant subgroup was also significantly improved
.
The team of Professor Wang Jianxiang of the Chinese Academy of Medical Sciences Hematology Hospital published the results
of a clinical trial in the journal Clinical Cancer Research in 2020.
In this study, the HAD induction protocol for medium dose cytarabine was: high harringoline + cytarabine + daunorubicin; The dose of cytarabine on days 5-7 was increased to 1 g / m2,q12h; The experimental results showed that the medium-dose cytarabine HAD regimen significantly improved the recurrence-free survival (RFS) and OS of patients with AML as a whole compared with the traditional HAD induction regimen.
In the FLT3-ITD mutant subgroup, the efficacy of the medium-dose cytarabine HAD regimen was improved, but not significantly
.
Professor Wei Hui said that in the era of chemotherapy, the increase in chemotherapy dose can improve the long-term prognosis of patients with FLT3 mutation AML, but the effect is limited, so new drug development is particularly important
in the treatment exploration of AML with FLT3 mutation.

The results of the QuANTUM-First (NCT02668653) Phase 3 trial, published at the 2022 European Society of Hematology (EHA) conference, compared with a placebo group, evaluated the efficacy
of Quizartinib combined with a standard of care sequential single-agent Quizartinib consolidation therapy in patients with FLT3-ITD mutant AML 。 The results showed that the complete response rate (CRi) of hematological incomplete recovery in the Quizartinib and placebo groups was 16.
8% and 9.
6%, respectively, the CR rate was 54.
9% and 55.
4%, and the median OS was 31.
9 months and 15.
1 months (P=0.
03),
respectively 。 Professor Wei concluded that the second-generation FLT3 inhibitor Quizartinib combined with conventional standard therapy did not significantly improve the response rate, but significantly benefited patients with FLT3-ITD mutation AML for CR duration and OS, especially for patients who
did not receive hematopoietic stem cell transplantation.

Previous studies have confirmed that transplantation can improve long-term survival in patients with FLT3-ITD mutations, but compared with the FLT3 wild type, patients with mutations have lower leukemia-free survival (LFS) rates, higher cumulative recurrence rates (CIR), and transplant therapy does not eliminate the poor prognosis
of FLT3-ITD mutations.
The team of Professor Liu Qiqi of Southern Hospital of Southern Medical University published the results
of a trial of sorafenib maintenance therapy after transplantation in patients with AML with FLT3-ITD mutation in Lancet Oncology in 2020.
The study showed that sorafenib maintenance therapy significantly reduced recurrence rates in patients with mutations compared to placebo, thereby improving long-term survival
.
Professor Wei Hui concluded that in addition to domestic research, foreign studies have also confirmed that maintenance therapy with FLT3 inhibitors after transplantation can significantly improve
the survival of patients with FLT3-ITD mutation AML after transplantation.

The 2021 Journal of Clinical Oncology published the results of a clinical trial in which CR+CRi was 72%
higher in the subgroup with FLT3 mutation unfit AML compared to Venecra (VEN) plus low-dose cytarabine.
However, for long-term survival outcomes, other studies have confirmed that VEN+AZA does not significantly improve survival
in patients with FLT3-ITD mutant unfit AML compared with the placebo group.
The results of the 2022 LACEWING clinical trial, published in the journal BLOOD, evaluated the efficacy
of geretinib in combination with AZA in patients with initial diagnosis with FLT3 mutation unfit AML compared with single-agent AZA.
For efficacy results, the geretinib + AZA group was significantly better than the single-agent AZA group, with compound complete response rates (CRc) of 58.
1% and 26.
5%, respectively; However, for survival outcomes, there was no significant difference between the geretinib + AZA group and the single-drug AZA group, and the median overall survival was 9.
82 and 8.
87 months
, respectively.
Professor Wei concludes that in such patients, although the combined Venekla and Geretinib regimens have improved the response rate, neither has improved the long-term prognosis
.

In 2019, the New England Journal published a single-dose gerratinib comparing efficacy
of conventional salvage chemotherapy in patients with R/R AML with FLT3 mutation.
The results of the study showed that the remission rate was significantly better in the single-agent gerratinib group than in the traditional salvage chemotherapy group, with CR rates of 21.
1% and 10.
5%, respectively.
The overall survival of the single-agent gerratinib group was also significantly better than that of the traditional salvage chemotherapy group, with median OS of 9 months and 5 months
, respectively.
For the exploration of targeted drug combination regimens, a 2022 study published in the Journal of Clinical Oncology showed that the modified compound complete response rate (mCRc) in the VEN+ geritinib group improved to 75% compared with the single-agent geritinib (Admiral trial); For safety results, 80% of patients experienced grade 3-4 cytopenic events
.
Professor Wei Hui concluded that the combined VEN+ geretinib protocol has achieved significant efficacy in patients with R/R AML with FLT3 mutation, and hopes that future survival analyses will also achieve better results.
It is also important to note that the incidence of cytopenic events in this study is high, and the dosage regimen of subsequent studies needs to be further adjusted
.
In addition to the above-mentioned combined trials of dual-targeted drugs, joint trials of three-targeted drugs are also underway, hoping to bring new therapeutic light
to patients with R/R AML with FLT3 mutations.

Professor Wei Hui concluded that the overall efficacy of patients with FLT3 mutation AML was poor and long-term survival was poor
.
In the era of chemotherapy, the increase in the dose of chemotherapy drugs can improve the efficacy
.
But in today's era of targeted drugs, the exploration of targeted drug combination protocols is the way
forward for AML therapy with FLT3 mutations.

Professor Wei Hui

• Leukemia Diagnosis and Treatment Center, Institute of Hematology, Institute of Hematology, Chinese Academy of Medical Sciences, Chief Physician, Doctoral Supervisor

• Deputy Director of the National Clinical Research Center for Hematological Diseases

• He is a member of the Hematology Branch of the Chinese Medical Association and the deputy leader of the Leukemia Lymphoma Group

• Associate Editor-in-Chief, Hematological Oncology (IF:5.
  271)

• He graduated from China Medical University in 2000 with a master's degree

• He graduated from Peking Union Medical College in 2006 with a Ph.
  D.
  degree

• From 2010 to 2013, he worked as a postdoctoral fellow at the National Institutes of Health

• Mainly engaged in basic and clinical research on leukemia

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