Case evaluation Professor Hou Ming: The combination of two swords and walls has begun to show strength, the blade out of the sheath to accurately block elderly AML, and the treatment of FLT3 mutant AML by geratinib can be expected in the future

Acute myeloid leukemia (AML) is most common in older people aged 65 to 74 years, and mortality is higher in people aged 65 years and ^older1.

The prognosis of elderly patients with AML is poor due to poor performance status at diagnosis, high incidence of adverse cytogenetics, and high early mortality during intensive ^{chemotherapy2}
.
The vast majority of elderly patients are prone to relapse, and patients over 60 years of age are even more difficult to ^treat3
.
Therefore, the treatment of elderly AML patients still faces great risks and challenges
.
With the improvement of medical technology and the development of next-generation gene sequencing technology, more and more new drugs and new therapies are gradually applied to the treatment of
AML in the elderly.
Geratinib is currently the only FMS-like tyrosine kinase-3 (FLT3) inhibitor in China approved in 2021 for the treatment of relapsed/refractory (R/R) AML, and multiple studies have shown that it can bring effective remission
to patients with R/R AML.
In this issue, Professor Zhang Xiaolin of Qilu Hospital of Shandong University is invited to share the treatment experience of an elderly patient with FLT3 mutation AML, and Professor Hou Ming of Qilu Hospital of Shandong University is invited to comment on this case, hoping to bring you some enlightenment!

Basic information

Patient, female, 65 years old
.

Present history: the patient developed a sudden fever in November 2020 with a temperature of up to 39.
6 degrees and chest tightness
.
The blood routine of the local hospital showed WBC 168.
61×10 9/L, MONO% 81%, HGB 98g/L, PLT 57×10⁹/L, bone marrow cytology showed that projuvenile mononuclear cells accounted for 89.
5%, considering AML, M5 is more likely, leukocytes apheresis, followed by oral hydroxyurea-lowering cells, levofloxacin anti-infection
.
For further treatment, I came to our hospital
10 days later.

Anamnesis: anxiety, long-term oral administration of milnacipran hydrochloride, haloperithiton melitraxine tablets
.

Physical examination: sternal tenderness
.

Ancillary examination

• Blood routine: WBC 15.
  02×10 9/L, HGB 92g/L, PLT 20×10⁹/L

• Flow cytometry: abnormal myeloid naïve cells 43.
  63%

• Genetic testing: FLT3-ITD+, NPM1+, DNMT3A+, ASXL1+, CEBPA+, TET2+

• Karyotype: 46,XX[2]

Case diagnosis

AML (M5, FLT3-ITD+, NPM1+, DNMT3A+, ASXL1+, CEBPA+, High Risk)

2.
Anxiety disorders

After the treatment

Induction chemotherapy was started with IA regimen (nordaunorubicin + cytarabine), and the patient developed grade IV myelosuppression during induction therapy, NEUT^#0.
05×10 9/L, HGB 54g/L, PLT 7×10⁹/L, combined with pulmonary infection, cardiac insufficiency, treated with meropenem, tigecycline, voriconazole, improved, and considered adjusting the
。

• Myelocytology: CR

• Flow cytometry: abnormal myeloid cells < 0.
  01%

• Genetic testing: FLT3-ITD(-)

• Karyotype: 46,XX[12]

After 3 cycles of azacitidine + Midostaurin* + veneclaxla, the efficacy assessment was CR, and the relapse
was shown at the 5th cycle.

• Myeloid cytology: blasts at 13%

• Flow cytometry: abnormal myeloid cells 13%

• Genetic testing: FLT3-ITD (+)

FLT3-ITD (+) in relapse, treated with geratinib + decitabine regimen, repeat after 2 cycles:

• Myeloid cytology: blasts at 7%

• Flow cytometry: abnormal myeloid cells 10%

Adjusted to geratinib + venetoxla, the efficacy was assessed as CR, no fever or serious infection due to leukopenia, and well
tolerated.

• Myelocytology: CR

• Flow cytometry: abnormal myeloid naïve cells 2.
  49%

• Genetic testing: FLT3-ITD(-)

Professor Zhang Xiaolin

• Department of Hematology, Qilu Hospital, Shandong University

• Associate Chief Physician, Doctor of Medicine

• Postdoctoral fellow at the University of California, San Diego

• Member of the Experimental Hematology Professional Committee of the Chinese Pathophysiology Society

• Leukemia Professional Committee Member of Chinese Medical Education Association

• Member of the Standing Committee of the Hematology Committee of Shandong Geriatric Association

• Member and Secretary of the Myelodysplastic Syndrome Group of the Hematological Oncology Branch of Shandong Anti-Cancer Association

AML is a disease that occurs more often in older people, with an increasing incidence and proportional increase in adverse genetic mutations, resulting in a worse prognosis4
.
Currently, AML is still treated with standard chemotherapy regimens, with a 5-year survival rate of 30-35% for AML patients under 60 years of age and less than 10-15% for patients over 60 years of ^age5.

Despite improvements in chemotherapy in recent years, most patients with AML develop relapse/refractory CR and have a very poor prognosis for patients with relapsed/refractory (R/R) ^AML6
.
FLT3 mutations are one of the most common genetic mutations in patients with AML, and FLT3-ITD mutations are associated with higher recurrence rates and lower survival rates in patients with R/R ^AML7
.
Previous effective treatment options for older patients are very limited, particularly in older patients with R/R AML with FLT3 mutations and prior use of FLT3
TKIs.

FLT3 inhibitors are an effective clinical strategy
for the treatment of FLT3-mutant AML.
Geratinib is a selective, potent, oral FLT3 inhibitor with anti-FLT3-ITD and FLT3-TKD AML activities
.
Preclinical models of FLT3-mutant AML showed a synergistic effect
between geritanib and veneclaxla.
A multicenter, open-label, phase 1b dose-escalation/dose expansion study (NCT03625505) of geratinib plus venetoxrama in the treatment of R/R FLT3-mutant AML (NCT03625505) published in the Journal of Clinical Oncology (IF=50.
717) showed that geratinib plus venetinx was also effective in patients who had previously used FLT3 TKIs.
Modified composite complete response (CRc) rates were 80% and median overall survival (OS) was 9.
6 months (95% CI, 4.
2-11.
6)7 in 35 patients with FLT3 TKI-mutant R/R AML who were previously exposed to FLT3 ^TKIs.

It can be seen that the combination of geratinib and venetex in the fight against AML can further improve the efficacy and bring benefits
to more patients.

The patient in this case was a high-risk AML with FLT3-ITD mutation, who was advanced and poorly tolerated by chemotherapy, and relapsed after applying a generation of FLT3 TKI in the early stage, and then switched to geratinib to obtain CR, which was well
tolerated.
This is a successful case
of geratinib combination regimen in the treatment of FLT3-ITD-mutant R/R AML that had previously been treated with the FLT3 TKI drug.
The emergence of targeted drugs and combination therapies such as geratinib has further expanded the treatment options for relapsed/refractory patients, which is expected to break more treatment dilemmas in the AML field and promote clinical practice innovation
.
It is expected that more new progress and breakthroughs will emerge in the future to help the clinical treatment front move forward and achieve more benefits for AML patients!

Professor Hou Ming

• Director of Cancer Center and Director of Hematology Department of Qilu Hospital of Shandong University

• Director of Shandong Key Laboratory of Hematology and Immunology

• Taishan scholar, second-level professor and doctoral supervisor of Shandong University

• Member of the ITP International Working Group Guidelines Development Expert Group

• ASH Fellow and APSTH Executive Committee

• Member of the Standing Committee of the Hematology Branch of the Chinese Medical Association

• Member of the Standing Committee of the Experimental Hematology Society of the Chinese Pathophysiology Association

• Vice President of Hematologist Branch of Chinese Medical Doctor Association

References:

1.
SEER cancer stat facts: acute myeloid leukemia [Internet].
Bethesda, MD: National Cancer Institute; 2020.
Available from: http://seer.
cancer.
gov/statfacts/html/amyl.
html

2.
Webster JA, Pratz KW.
Acute myeloid leukemia in the elderly: therapeutic options and choice.
Leuk Lymphoma.
2018; 59(2):274-287.

3.
Kantarjian H, et al.
Acute myeloid leukemia: current progress and future directions.
Blood Cancer J.
2021 Feb 22; 11(2):41.

4.
Creutzig U, Kutny MA, Barr R, Schlenk RF, Ribeiro RC.
Acute myelogenous leukemia in adolescents and young adults.
Pediatr Blood Cancer.
2018 Sep; 65(9):e27089.

5.
Megías-Vericat JE, Ballesta-López O, Barragán E, Montesinos P.
IDH1-mutated relapsed or refractory AML: current challenges and future prospects.
Blood Lymphat Cancer.
2019 Jun 27; 9:19-32.

6.
Thol F, Ganser A.
Treatment of Relapsed Acute Myeloid Leukemia.
Curr Treat Options Oncol.
2020 Jun 29; 21(8):66.

7.
Naval Daver, Alexander E Perl, Joseph Maly, et al.
Venetoclax Plus Gilteritinib for FLT3-Mutated Relapsed/Refractory Acute Myeloid Leukemia.
J Clin Oncol.
2022 Jul 18; JCO2200602.

*Midostaurin is not approved by the Chinese NMPA, and this content is for clinical communication only
.

The content of this article is for academic communication of healthcare professionals only
.