International Hematological Tumor Month Professor Hu Yu: Seeing the moon from the clouds, leading the targeting, and viewing the development trend of AML management of FLT3 mutation from the perspective of the change of guidelines

In recent years, the continuous optimization of the prognostic stratification system of acute myeloid leukemia (AML) and the continuous emergence of a variety of new targeted drugs have led to many updates

Professor Hu Yu

• Member of the 13th National Committee of the Chinese People's Political Consultative Conference

• President of Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology

• Director of the Institute of Hematology, Huazhong University of Science and Technology

• National Science Foundation for Outstanding Youth

• "Yangtze River Scholar" Distinguished Professor

• National model of teaching and educating people

• Second Prize of National Science and Technology Progress Award

• National Innovation Scramble Medal

• Ho Leung Ho Lee Foundation Award

• Chairman-designate of the Hematology Branch of the Chinese Medical Association (Leader of the Thrombosis and Hemostasis Group)

• Member of the Standing Committee of the Internal Medicine Branch of the Chinese Medical Association

• Vice President of the Hematology Branch of the Chinese Medical Doctor Association

• Vice Chairman of the Experimental Hematology Society of the Chinese Society of Pathophysiology

• Member of the Education Committee of the International Society for Thrombosis and Hemostasis

• Chairman of the Hematology Branch of Hubei Medical Association

• Editor-in-Chief of the Journal of Clinical Internal Medicine/Journal of Clinical Emergency Medicine

• Associate Editor, Chinese Journal of Hematology/Journal of Clinical Hematology

• Associate Editor, Chinese Hospital Management / Editorial Board Member of Chinese Journal of Hospital Management

• Associate Editor, Thrombosis Research/Thrombosis and Haemostasis

Looking internationally, in 2010, the European Leukemia Network (ELN) expert team defined the first cytogenetics-based AML prognostic stratification ^system1, and initially established the framework

Figure 1 Hierarchical changes in ELN prognosis (2017-2022)

Thanks to the development of molecular detection technology, the clinical application and value of minimal residual disease (MRD) have quickly attracted wide attention

Based on the domestic situation, with the continuous improvement of the medical system and the continuous improvement of the medical level, the Chinese Medical Association, CSCO^{7, 8}, etc.

FLT3 inhibitors have developed two generations of drugs, the first generation of inhibitors are relatively specific to FLT3, acting on a variety of kinases, and their anti-leukemia effect may not only come from FLT3 inhibition, but also from the inhibition

Table 1 Comparison of the characteristics of the first and second generation FLT3 inhibitors

Taking the second-generation FLT3 inhibitor gerratinib as an example, in terms of monotherapy, the ADMIRAL ^study10 showed that the rate of complete response (CR) in patients with FLT3-ITD mutation R/R AML was significantly higher than that of salvage chemotherapy (21.
1% vs.
10.
5%), and the median total survival (OS) and median disease-free survival (EFS) in patients with FLT3-ITD and TKD mutations were significantly longer (9.
3 months vs.
5.
6 months; 8.
3 months vs.
5.
3 months).


In terms of combination drugs, geretinib and Venectra treated patients with FLT3 mutation R/R AML who had previously received multiple therapy, and the improved CRc rate was as high as 84%, and the median progression-free survival (PFS) was 5.
1 months
.

Fig.
2 Comparison of overall survival in the geritinib group and salvage chemotherapy group in the ADMIRAL study

Based on good efficacy, ESMO guidelines, NCCN guidelines, and CSCO guidelines have recommended gerratinib for targeted therapy
in patients with relapsed FLT3 mutation AML.

Looking at the AML field, the status of targeted therapy has been clinically affirmed, and there is a trend of recommended treatment lines moving forward, domestic blood field workers should grasp the frontier dynamics, actively accumulate clinical experience and evidence-based medical evidence, and explore AML targeted therapy strategies
in line with China's clinical practice.

Focusing on the demand, the whole process management strategy of FLT3 mutation AML field is constantly explored

The improvement of the stratification system, the introduction of targeted drugs and the gradual maturity of hematopoietic stem cell transplantation technology have prolonged the overall survival of FLT3 mutant AML patients, and how to improve the survival of patients with better quality has become a topic of greater concern to our blood people, so it is of great significance to implement the whole process of management of FLT3 mutant AML patients
.

The efficacy of FLT3 inhibitors such as Midostaurin in induction therapy in patients with initial AML has been demonstrated
.

The results of a phase III clinical trial showed that chemotherapy combined with Midostaurin group OS and event-free survival (EFS) were significantly better than those in the chemotherapy ^group11, which also showed that targeted drugs are gradually gaining attention in first-line therapy.
Randomized trials of Midostaurin as part of intensive first-line therapy for AML with FLT3 mutation have been initiated, with follow-up results
expected.

Transplantation is still the only means to cure patients with FLT3 mutation R/R AML, and the application of FLT3 inhibitors in transplantation is also one of the topics of
clinical concern.

The ADMIRAL Phase III follow-up data released at the 2021 European Hematology Association (EHA) Annual ^Meeting12 shows that patients who have achieved compound complete remission before transplantation continue geretinib maintenance therapy after transplantation, with a 2-year recurrence rate of only 19%, and some patients have good safety in long-term treatment (≥ 24 months); Another ^study13 confirmed that patients who continued geretinib maintenance therapy after transplantation had significantly longer median overall survival (OS) than those who discontinued geretinib (16.
2 vs 8.
4 months; HR: 0.
387;95% CI: 0.
164, 0.
915) and well
tolerated.

A phase III clinical study (MORPHO) on the efficacy of geretinib for maintenance therapy in post-transplant patients is also underway, and we will wait and see
the results.

FLT3 inhibitors play an important role in the whole management of patients with FLT3 mutation AML, especially patients with FLT3 mutation R/R AML, and with the wide application of geretinib, its pivotal clinical value
has been highlighted.

Grasping the future, the road to accurate diagnosis and treatment of AML with FLT3 mutation still has a long way to go

Based on the development context of the FLT3 mutation AML field and the recent progress, the diagnosis and treatment in this field may have the following development directions in the future:

• Further improve the implementation of the precise prognosis layering system
  .
  
  In just 5 years, the ELN guidelines have updated the prognostic stratification system for AML, indicating that there are still more issues in the field of prognostic stratification that are worth exploring
  .
  
  The relationship between FLT3 mutations and other coexisting mutations, the influence of gene mutations on prognosis, the feasibility of MRD guidance treatment decisions, the construction of MRD dynamic stratification systems, and the establishment of guidelines for MRD need to be demystified
  .
  
  

• Study a variety of medication regimens or patterns
  .
  
  Clinically, the exploration of the combination regimen of FLT3 mutation inhibitors with chemotherapy drugs or other targeted drugs should be explored, and the possibility
  of early application of targeted drugs should be further explored.
  
  

• Accumulated experience
  in the whole process of management of AML patients with FLT3 mutation.
  
  Strategies for FLT3 inhibitors in induction therapy, post-chemotherapy, and post-transplant maintenance therapy still need more authoritative research validation; For some patients with FLT3 mutation AML who are not suitable for transplantation, replacing maintenance therapy with FLT3 inhibitors may also be a direction to be explored in the
  future.
  
  

summary

References:

1.
Döhner H, Estey EH, Amadori S, et al; European LeukemiaNet.
Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet.
Blood.
2010; 115(3):453-474.

2.
Daver, Naval et al.
“Targeting FLT3 mutations in AML: review of current knowledge and evidence.
” Leukemia vol.
33,2 (2019): 299-312.
 

3.
Arai, Y.
, Chi, S.
, Minami, Y.
et al.
FLT3-targeted treatment for acute myeloid leukemia.
Int J Hematol 116, 351–363 (2022).

4.
Döhner, Hartmut et al.
“Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel.
” Blood vol.
129,4 (2017): 424-447.
 

5.
Schuurhuis GJ, Heuser M, Freeman S, et al.
Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party.
Blood.
2018; 131(12): 1275-1291.

6.
The official website of the NCCN Guide

7.
Leukemia & Lymphoma Group, Chinese Society of Hematology, Chinese Medical Association.
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi vol.
42,8 (2021): 624-627.
 

8.
Guidelines for CSCO Malignant Hematological Tumors, 2022 Edition.

9.
Zhao, Jennifer C et al.
“A review of FLT3 inhibitors in acute myeloid leukemia.
” Blood reviews vol.
52 (2022): 100905.
 

10.
Perl, Alexander E et al.
“Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML.
” The New England journal of medicine vol.
381,18 (2019): 1728-1740.
 

11.
Döhner, Hartmut et al.
“Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel.
” Blood vol.
129,4 (2017): 424-447.
 

12.
Perl AE, Larson RA, Podoltsev NA, et al.
EHA Library.
J.
Levis M.
06/09/21; 325192; EP438.

13.
Maeda Y, Hosono N, Yokoyama H, et al.
EHA Library.
E Perl A.
06/09/21; 325195; EP441.

Poke "Read the original article" to see more