Acute myeloid leukemia (AML) is most common in older adults aged 65 to 74 years and has a higher mortality rate in people aged 65 years and older1. Elderly patients with AML have a poor prognosis due to poor physical performance status at diagnosis, high incidence of adverse cytogenetics, and high early mortality during intensive chemotherapy2. The vast majority of older patients are prone to relapse, and patients over 60 years of age are more refractory to treatment3. Therefore, the treatment of elderly AML patients still faces great risks and challenges. With the improvement of medical technology and the development of second-generation gene sequencing technology, more and more new drugs and therapies are gradually applied to the treatment of elderly AML. Geratinib is currently the only FMS-like tyrosine kinase-3 (FLT3) inhibitor approved in China in 2021 for the treatment of relapsed/refractory (R/R) AML, and multiple studies have shown that it can bring effective relief 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!
Case profile
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Basic information
Patient, female, 65 years old.
Current medical history: The patient suddenly developed fever in November 2020, with a temperature of up to 39.6 degrees and chest tightness. Blood routine at the local hospital showed WBC 168.61×109/L, MONO% 81%, HGB 98g/L, PLT 57×109/L, bone marrow cytology showed that prolaryomonocytes accounted for 89.5%, considering AML, M5 is likely, leukapheresis was given, followed by oral hydroxyurea descending cells, levofloxacin anti-infection. For further diagnosis and treatment, he came to our hospital after 10 days.
Anamnesis: anxiety disorders, long-term oral administration of milnacipran hydrochloride, haloperethine melitrecine tablets.
Physical examination: sternal tenderness.
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Auxiliary examinations
- 血常规：WBC 15.02×109/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]
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Case diagnosis
1.AML (M5, FLT3-ITD+, NPM1+, DNMT3A+, ASXL1+, CEBPA+, high risk)
2. Anxiety disorders
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After treatment
Relapse after the first treatment reaches complete response (CR).
Induction chemotherapy with IA regimen (nordaunorubicin + cytarabine) was initiated, and the patient developed grade IV myelosuppression during induction therapy, NEUT#0.05×109/L, HGB 54g/L, PLT 7×109/L, pulmonary infection, cardiac insufficiency, treated with meropenem, tigecycline, and voriconazole, improved, and considered adjusting the chemotherapy regimen.
- Bone marrow cytology: CR
- Flow cytometry: abnormal myeloid cell < 0.01%
- Genetic testing: FLT3-ITD(-)
- Karyotype: 46,XX[12]
After 3 cycles of azacitidine + Midostaurin* + venetoclax treatment, the efficacy was evaluated as CR, and the reexamination at cycle 5 suggested recurrence.
- Bone marrow cytology: blasts account for 13%
- Flow cytometry: abnormal myeloid cells 13%
- Genetic testing: FLT3-ITD(+)
CR after treatment with a combination regimen of giretinib
FLT3-ITD(+) at relapse, treated with geratinib + decitabine, and repeated after 2 cycles:
- Bone marrow cytology: blasts account for 7%
- Flow cytometry: abnormal myeloid cells 10%
Adjusted to jiretinib + venetoclax regimen treatment, the efficacy was assessed as CR, no fever or serious infection due to leukopenia, and well tolerated.
- Bone marrow cytology: CR
- Flow cytometry: abnormal myeloid naïve cells 2.49%
- Genetic testing: FLT3-ITD(-)
Prof. Xiaolin Zhang
- 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 Society of Pathophysiology
- Member of Leukemia Professional Committee of China Medical Education Association
- Member of the Standing Committee of Hematology Special Committee of Shandong Geriatrics Association
- Member and secretary of the Myelodysplastic Syndrome Group of Hematology and Oncology Branch of Shandong Anti-Cancer Association
Case reviews
AML is a disease that is more common in the elderly, and its incidence increases with age, and the adverse genetic mutations increase proportionally, resulting in a worse prognosis4. Currently, AML is still treated with standard chemotherapy regimens, with a 5-year survival rate of 35-35% for patients under 60 years of age and only 10-15% for patients over 60 years of age5. Despite improvements in chemotherapy in recent years, most patients with AML experience relapse/refractory treatment after achieving CR, and the prognosis for patients with relapsed/refractory (R/R) AML is extremely poor6. FLT3 mutations are one of the most common genetic mutations in AML patients, 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 FLT3 mutations and prior use of FLT3 TKIs.
FLT3 inhibitors are an effective clinical strategy for the treatment of FLT3-mutated AML. Geratinib is a selective, potent, oral FLT3 inhibitor with anti-FLT3-ITD and FLT3-TKD AML activities. Preclinical models of FLT3-mutated AML have shown a synergistic effect of giretinib with venetoclax. A multicenter, open-label, phase 1b dose escalation/dose expansion study (NCT03625505) published in the Journal of Clinical Oncology (IF=50.717) on July 18, 2022 showed that giretinib plus venetoclax was equally effective in patients with prior use of FLT3 TKIs, with 35 patients previously exposed to FLT3 Patients with FLT3-mutant R/R AML with TKI had a modified composite complete response (CRc) rate of 80% and a median overall survival (OS) of 9.6 months (95% CI, 4.2-11.6)7. It can be seen that the combination of girutinib and venetoclax to fight 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, advanced age and poor chemotherapy tolerance, relapsed after the early application of a first-generation FLT3 TKI, and then switched to geratinib to obtain CR, which was well tolerated. This is a successful case of a combination regimen for the treatment of FLT3-ITD mutant R/R AML with a previous FLT3 TKI drug. The emergence of targeted drugs and combination therapies such as girutinib has further expanded the treatment options for relapsed/refractory patients, which is expected to break the therapeutic dilemma in more AML fields and promote clinical practice innovation. It is expected that more new progress and breakthroughs will emerge in the future, helping the clinical treatment front to move forward and achieving more benefits for AML patients!
Prof. Hou Ming
- Director of Cancer Center and Director of Hematology Department of Qilu Hospital of Shandong University
- Director of Shandong Provincial Key Laboratory of Blood Immunology
- Taishan scholar, second-level professor and doctoral supervisor of Shandong University
- Member of the ITP International Working Group Guideline Development Expert Group
- Fellow member of ASH, member of 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
Bibliography:
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 has not been approved by the Chinese NMPA and this content is for clinical communication only.
The content of this article is for academic communication by medical and health professionals only.
Edit: May
Reviewed by Janet
Typesetting: moly
Execution: Quarterly year
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