Case review Professor Jin Jie: There is no way out of thousands of twists and turns, the peak circuit has turned into a good situation, and the geritinib headwind flips to reconstruct the new vitality of life for AML patients

Basic information

Patient, female, 34 years old

Adjunctive testing

• Blood count: WBC 128.

  
  

• Peripheral cell morphology: approximately 70% of blast cells

• Bone marrow cell morphology: primitive monocytes plus naïve monocytes account for 67%, bone marrow like considering AML-M5

• Immunophenotyping: The original myeloid cell population accounts for about 65.

  
  

• Mutational Genetic Testing: FLT3-ITD 154.

  
  

Diagnosis of the case

AML-M5（FLT3-ITD+，MPN1+，DNMT3A+）

Treatment progression

On November 2, 2020, he was given IA (demethorubicin, cytarabine) regimen chemotherapy, fever during hospitalization, and successively given piperacillintazobactam, cefoperazone sodium sulbactam sodium for injection, meropenem anti-infection, posaconazole, voriconazole oral preventive antifungal infection, blood trilogy decline after chemotherapy, bone marrow suppression with fever, recombinant human granulocyte stimulating factor, platelet transfusion and other symptomatic treatment

• Bone marrow cell morphology: 4% of primitive monocytes

• Minimal residual leukemia (MRD) test: MRD<0.
  01%

• Mutational genetic testing: FLT3-ITD 14.
  4%, DNMT3A 40.
  0%, NPM1 74.
  4%

On December 8, 2020, the results of bone puncture showed that monocytes were active, and the ratio of primitive monocytes plus naïve monocytes was 7%, suggesting recurrence
.

Due to the obvious consideration of bone marrow suppression with ineffective platelet transfusion and ineffective platelet transfusion, on December 10, 2020, va (veneclerra, azacytidine) regimen chemotherapy was switched to, and a review on January 26, 2021 showed:

• Bone marrow cell morphology: 7% of primitive monocytes plus naïve monocytes

• MRD detection: MRD 2.
  594%

• Mutational genetic testing: FLT3-ITD 5.
  0%, NPM1 1.
  5%

• Bone marrow cell morphology: 5.
  5% of primitive monocytes plus naïve monocytes

• MRD detection: MRD 3.
  055%

• Mutational genetic testing: FLT3-ITD 44.
  6%, NPM1 14.
  6%, DNMT3A 28.
  0%

On March 19, 2021, va regimen chemotherapy was again administered, and due to severe bone marrow suppression, the blood routine suggested WBC 0.
3×^{10 9}/L, Hb 51g/L, PLT 1×¹⁰⁹/L
.

Hematuria developed on April 18, 2021, with hematuria 400-500 mL
.

CT on 22 April 2021 suggests cerebellar hemorrhage with edema and subarachnoid hemorrhage
.

On April 19-20, 2021, dizziness, headache, sore throat, celecoxib capsules, tramadol extended-release tablets, dexamethasone and other pain relief symptomatic treatment, the effect is not good
.

Severe headache the next day, can not exclude cerebral hemorrhage, skull CT scan showed: left cerebellar hemisphere high density mass, cerebral sickle hyper-density shadow, considering platelet severe hypoplasia associated intracranial hemorrhage, urethral hemorrhage, mannitol + furosemide to reduce intracranial pressure, dexamethasone to reduce intracranial edema, and analgesia symptomatic, and infusion of group coagulation factor VII.
a hemostasis, May 28 suggests left cerebellar hemisphere hyper-density shadow, narrowing the scope of the previous lesion, decreasing density, and improving edema; The original subarachnoid cavity bleeds, and the present film is basically absorbed
.

After recovery of blood picture and improvement of symptoms, he will be discharged from the hospital, and his bone marrow will be reviewed on May 25, 2021:

• Bone marrow cell morphology: 20% of blast cells

• MRD detection: MRD 14.
  810%

On June 2, 2021, bridging transplantation was treated with geritinib 120 mg qd monotherapy, and on June 15, 2021, bone marrow was reviewed:

• Bone marrow cell morphology: no blast cells are seen

• MRD detection: MRD 10.
  33%

• Mutational genetic testing: FLT3-ITD 12.
  2%, NPM1 8.
  7%

From June 19, 2021, the FLAG (fludarabine, cytarabine, granulocyte colony stimulating factor) protocol was pretreated, and bone puncture was reviewed on June 24, 2021:

• Bone marrow cell morphology: bone marrow has a decrease in nucleated cells, no protoplasts are seen

• MRD detection: MRD 0.
  571%

On July 3, 2021, hemorrhagic again, hematuria with blood clots
.

Early infusion on July 4, 2021, parental total-phase hematopoietic stem cell transplantation (HSCT), +12 days platelet implantation, +20 days granular implantation, out of the warehouse on July 23, the situation is stable, MRD negative, gene negative
.

In September 2021, the maintenance treatment of geritinib was applied, and it has been maintained for one year, and the follow-up cr, MRD and gene negative have continued
.

Prof.
Huafeng Wang

• The First Affiliated Hospital of Zhejiang University School of Medicine, Ph.
  D.
  / Deputy Chief Physician / Master Supervisor

• Postdoctoral Fellow, City of Hope National Medical Center, USA

• Visiting scholar at Brown University in the United States and Royal Free Hospital in the United Kingdom

• Zhejiang Province 551 Talent Program Medical Rookie

• He is a young member of the Blood Disease Transformation Committee of the Chinese Anti-Cancer Association

• Secretary of the Hematology Branch of Zhejiang Medical Doctor Association

• Member of the leading innovation and entrepreneurship team in Zhejiang Province

• He has presided over a number of national, provincial and ministerial projects

• He has published more than 20 SCI papers, including 18 as the first author or corresponding author, published in Lancet Hematology, Leukemia, Clinical Transitional Medicine, Blood Cancer Journal and other journals, with a total impact factor of more than 120 points

• The international conference has made oral and abstract reports many times, and won the ASH Abstract Achievement Award at the American Hematology Annual Meeting 4 times

• Second Prize of Zhejiang Provincial Health Science and Technology Progress Award (3/10)

AML is one of the common hematologic malignancies in the clinic, and R/R AML has become a major challenge in clinical diagnosis and treatment due to the lack of standard treatment protocols
.

With the in-depth exploration of the pathogenesis of AML, stratified treatment has become the core of the formulation of
AML diagnosis and treatment strategies.

The treatment of R/R AML is stratified according to age, physical condition, mutated genes, etc.
, and for patients who are suitable for chemotherapy, induction chemotherapy regimen can be selected; If the patient is characterized by a genetic mutation such as a FLT3 mutation, a targeted drug such as a FLT3 inhibitor ^{can be selected1}
.

Minimal residual disease (MRD) during treatment follow-up also becomes the basic prognostic stratification index, failing to reach MRD negative or MRD recurrence is associated with disease recurrence and adverse ^outcomes2
.

FLT3 mutations are one of the most common mutations in patients with AML
.

In the past, treatment with AML was predominantly chemotherapy regimen, but patients with FLT3 mutation R/R AML had poor clinical benefit from salvage ^{chemotherapy3}
.

In recent years, the breakthrough of FLT3 inhibitor geritinib in the field of R/R AML has attracted much attention
.

An international, multicenter, open-phase III ADMIRAL ^study4 showed that geritinib monotherapy had a more significant benefit in response (complete response and complete response rate with partial haematological recovery, 34.
0% vs 15.
3%) and long-term survival benefit (median overall survival, 9.
3 months vs 5.
6 months, p<0.
001) compared with salvage chemotherapy.
And oral geritinib maintenance therapy in patients receiving HSCT significantly prolonged median survival (16.
2 months vs 8.
4 months, p=0.
024).


In addition, the analysis of the results of the ADMIRAL study subgroup showed that the most co-mutant genes were NPM1 (46.
6%) and DNMT3A (31.
0%), and the geritinib group showed a greater survival benefit
than the chemotherapy group in patients with co-mutations of NPM1 and DNMT3A.

The patient in this case is 33 years old, a young patient, accompanied by FLT3-ITD, DNMT3A, MPN1 mutations, and still relapses after induction therapy such as IA and VA regimen, HSCT is performed after geritinib monotherapy, and subsequent maintenance therapy with geritinib has been applied for one year, until continuous CR, MRD negative, and gene negative
.

This is a successful case
of geritinib monotherapy in patients with FLT3 mutations and other mutations with R/R AML.

Geritinib monotherapy has enabled patients with AML to survive longer, and it is believed that with more clinical exploration such as its combination therapy, it is expected to further improve the efficacy of AML and bring more clinical benefits
to patients with AML.

Professor Jin Jie

• Doctor of Medicine, Professor, Doctoral Supervisor

• Enjoy the special government allowance of the State Council and an advanced worker in the national health system

• Honorary Director of the Department of Hematology, The First Affiliated Hospital of Zhejiang University School of Medicine

• Director of the Key Laboratory of Hematological Oncology (Diagnosis and Treatment) of Zhejiang University

• Leader of the hematology department of the National Health Commission Clinical Key Discipline of Zhejiang First Hospital

• Director of Zhejiang Provincial Hematology Clinical Research Center

• Head of basic and clinical research on malignant blood diseases at the Cancer Research Institute of Zhejiang University

• Leader of Zhejiang Provincial Key Innovation Team - Innovation Team of Basic and Clinical Research on Leukemia

• Hematology Committee Chairman of the Chinese Association of Women Physicians

• Former Chairman of The Translational Medicine of Blood Diseases of the Anti-Cancer Association

• Vice Chairman of CSCO China Anti-Leukemia Alliance

• Standing Committee Member of Hematology Society of Chinese Medical Doctor Association

• Vice Chairman of the Integrative Hematology Society of the Chinese Medical Doctor Association

• Vice Chairman of the CSCO Anti-Leukemia Alliance

• Standing Committee Member of the CSCO Anti-Lymphoma Alliance

• Standing Committee Member of the Cross-Strait Hematology Society

• Standing Committee Member of the Hematology Society of the Chinese Health Promotion Association

• Former Chairman of the Hematology Branch of Zhejiang Medical Association

• President of hematology branch of Zhejiang Medical Doctor Association

• He has published more than 280 academic papers in SCI-included magazines such as Lancet Oncology, Cell, Blood, Leukemia, JHO, etc.
  , and won 1 second prize of national scientific and technological progress and 2 first prizes of zhejiang provincial science and technology progress as the first winner

References:

1.
Leukemia Lymphoma Group of Hematology Branch of Chinese Medical Association.
Chinese Guidelines for the Diagnosis and Treatment of Relapsed refractory acute myeloid leukemia (2021 edition)[J].
Chinese Journal of Hematology,2021,42(08):624-627.

2.
Heuser M, Freeman SD, Ossenkoppele GJ, et al.
2021 Update on MRD in acute myeloid leukemia: a consensus document from the European LeukemiaNet MRD Working Party.
Blood.
2021 Dec 30; 138(26):2753-2767.

3.
Cortes JE, Khaled S, Martinelli G, et al.
Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial.
Lancet Oncol.
2019; 20(7):984-997.

4.
Perl AE, Martinelli G, Cortes J, et al.
Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML.
N.
Engl.
J.
Med.
2019; 381:1728-1740.

*Clifettinib besylate has not been approved by the Chinese NMPA, this content is for clinical exchange only
.

The content of this article is for academic communication by medical and health professionals
only.

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