Abstract
Objective:
Chronic myeloid leukemia (CML) is a malignancy driven by the BCR::ABL1fusion gene, with the e19a2 transcript being a rare variant, accounting for 0.4% of CML cases. Patients with the e19a2 transcript often show poor response to first-line treatment with imatinib, and no standard therapy has been established for this subtype.
Methods:
We report a case of a 28-year-old female with e19a2-positive CML. The patient exhibited poor response and tolerance to dasatinib. After 6 months, she achieved partial cytogenetic response (PCyR) but developed grade 3 pleural effusion. Following treatment discontinuation and prednisone therapy, the patient continued dasatinib (80 mg/d). At 12 months, the patient achieved complete cytogenetic response (CCyR), but BCR::ABL1 levels remained suboptimal, with recurrent pleural effusion. The patient was then switched to flumatinib (600 mg/d), achieving major molecular response (MMR) at 6 months and deep complete molecular response (MR4.5) at 24 months, with good tolerance.
Conclusion:
Flumatinib demonstrated excellent deep molecular response and good tolerability in e19a2-positive CML patients, suggesting that it may be one of the preferred treatment options for such patients.
Introduction
The BCR::ABL1 fusion gene is the primary molecular marker of chronic myeloid leukemia (CML) (1). The typical BCR::ABL1 transcripts are e13a2 and e14a2, which encode the p210 BCR::ABL1 protein. However, e19a2 is a rare variant that encodes the p230 BCR::ABL1 protein. The breakpoint cluster region (BCR) is located between exons 17 and 20 in the μ region, producing a fusion protein with a molecular weight of 230 kDa (2). Since Saglio et al. first reported the e19a2 variant in 1990, the number of related cases has gradually increased (3). Before the advent of tyrosine kinase inhibitors (TKIs), the treatment of CML mainly relied on allogeneic stem cell transplantation, chemotherapy, and interferon. However, chemotherapy and interferon treatment could only achieve limited hematologic responses, while allogeneic stem cell transplantation was limited by the availability of matched donors and treatment-related complications.
The introduction of the first-generation TKI, imatinib, in 2001 significantly improved the prognosis of CML patients. However, approximately 20% of patients develop resistance, leading to the emergence of second-generation TKIs (4). Although second-generation TKIs often provide deeper molecular responses (MR), they are also associated with adverse events such as pleural effusion, cytopenias, and vascular spasms or occlusive events, as well as pulmonary arterial hypertension (1). This case report discusses an e19a2-positive CML patient who showed poor response and tolerability to dasatinib but achieved a favorable molecular response following treatment with flumatinib.
Case presentation
A 28-year-old female patient, during the Chinese New Year in 2020, experienced a gradual decrease in appetite while staying at home due to the COVID-19 pandemic, resulting in a weight loss of approximately 10 kg by July 2020. Subsequently, the patient developed worsening fatigue and nausea, accompanied by vomiting after eating, and eventually sought medical attention. On examination: anemia-like appearance, spleen tip 10 cm below the rib margin. No enlarged superficial lymph nodes were palpated, and no suspicious masses were detected. Laboratory tests showed: white blood cell count of 314.45 × 109 g/L, with eosinophils at 1%, basophils at 11%, hemoglobin at 86 g/L, and platelet count at 524 × 109 g/L. Peripheral blood analysis showed 5% blast cells. Ultrasound revealed splenomegaly (thickness 6.5 cm, length 22.8 cm), with Sokal risk score indicating intermediate risk (1.18), EUTOS score indicating high risk (117.0), and ELTS score indicating intermediate risk (1.76) (see Table 1). Ultrasound of the spleen revealed a thickness of 6.5 cm and length of 22.8 cm. Bone marrow aspiration showed hypercellularity with 7% blast cells (see Figure 1A). Neutrophil alkaline phosphatase (N-ALP) positivity rate was 2.00% (see Figure 1B). Fluorescence in situ hybridization (FISH) showed BCR::ABL1 fusion signals in 40% of cells (see Figures 1G,H). Cytogenetic analysis revealed a karyotype of 46, XX, t(9; 22)(q34; q11.2)/47, XX, t(9; 22), +der (22)t(9; 22) (see Figure 1I).
Table 1
| Date | WBC count(X10 9 /L) | Hemoglobin (g/L) | Platelet count(X10 9 /L) | Ultrasound of the spleen | BCR::ABL1 level of the e19a2 transcript | Cytogenetic response | Other characteristics | Intervention | Efficacy evaluation | Adverse reactions | |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Thickness | Length | ||||||||||
| 2020.07 (Baseline) |
314 | 86 | 524 | 6.5 cm | 22.8 cm | 62.50% | 100% | Sokal score:1.18 EUTOS score high-risk:117.0 ELTS score intermediate risk: 1.76 |
DS 100mg/d | _ | _ |
| 2020.08 (Month 1) |
18.58 | 91 | 176 | _ | _ | _ | _ | _ | _ | _ | _ |
| 2020.10(Month 3) | 5.19 | 96 | 128 | _ | _ | 46.87% | 100% | _ | DS 100 mg/d | CHR | _ |
| 2021.01(Month 6) | 5.13 | 110 | 105 | 4.5 cm | 16 cm | 3.84% | 25% | _ | DS, followed by pleural drainage, diuretics, and prednisone treatment. Subsequently, 80 mg/d. | PCyR | Grade 3 pleural effusion. |
| 2021.07(Month 12) | 3.63 | 93 | 82 | 3.8 cm | 11 cm | 0.17% | 0% | _ | Discontinued DS, switched to FM, and simultaneously administered iron supplements. | CCyR | Second occurrence of grade 3 pleural effusion, cytopenia, rash, and iron-deficiency anemia (possibly caused by excessive menstrual bleeding). |
| 2022.01(Month 18) | 6.75 | 112 | 172 | _ | _ | 0.1% | _ | _ | _ | MMR | In the early stage of flumatinib treatment, mild gastrointestinal discomfort occurred and resolved quickly. |
| 2022.07(Month 24) | 9.17 | 112 | 195 | _ | _ | 0.04% | 0% | _ | FM | _ | _ |
| 2023.01(Month 30) | 10.02 | 126 | 207 | _ | _ | 0.01% | _ | _ | _ | MR 4.0 | _ |
| 2023.07(Month 36) | 6.06 | 100 | 182 | _ | _ | 0% | 0% | _ | FM | MR 4.5 | _ |
The patient's laboratory test results and treatment response
ABL1, Abelson murine leukemia viral oncogene homolog 1; BCR, break point cluster; CCyR, complete cytogenetic response; CHR, complete hematological response; DS, dasatinib; EUTOS, European Treatment and Outcome Study; ELTS, EUTOS long‐term survival; FM, flumatinib; MR, molecular responses; MMR, major molecular responses; PCyR, partial cytogenetic response; WBC, white blood cells.
Figure 1
Laboratory examination of the patient. (A) Patient's bone marrow cell morphological analysis (1000x). (B) Patient's cytochemical staining (1000x). (C) CD41 (1000x). (D) Peroxidase staining (1000x). (E) Specific esterase staining (1000x). (F) Nonspecific esterase staining (1000x). (G,H) FISH analysis–normal control and patient’s image, respectively.
Using a dual color and dual fusion BCR-ABL1 probe, the BCR (22q11) gene is marked with green, the ABL1 (9q34) gene is marked with red, and the BCR::ABL1 fusion gene is represented by a yellow or red, green superimposed signal. The negative signal is a 2 red and 2 green signal modes. The ISCN result of this patient is nuc ish (ABL1, BCR) × 3 (ABL1 con BCR × 2) [221/500]/(ABL1, BCR) × 4 (ABL1 con BCR × 3) [2000/500], indicating a positive detection rate of 84.2% for the BCR-ABL1 fusion gene. Among them, 40% of positive cell fusion signals increased with the addition of a fusion copy. ABL1 (9q34), Abelson murine leukemia viral oncogene homolog 1 is located on chromosome; 9q34BCR (22q11), breakpoint cluster region gene is located on chromosome 22q11; FISH, fluorescence in situ hybridization.
I Chromosome Analysis Karyotype Description 46,XX,t(9;22)(q34;q11.2) (5)/47,XX,t(9;22),+der(22)t(9;22) (6).
Bone marrow biopsy indicated active marrow proliferation with fibrosis, and reticulin staining was graded as MF-2 (see Figure 2). The BCR/ABL P210 fusion gene was negative, the BCR/ABL P190 fusion gene was negative, and the BCR/ABL P230 fusion gene was positive, confirming the diagnosis of e19a2-positive CML.
Figure 2
Bone marrow biopsy pathology of the patient (400X).
In July 2020, the patient began treatment with dasatinib at a dose of 100 mg/d. After 3 months of treatment, the patient achieved complete hematological response (CHR), but no cytogenetic response (CyR) was observed, with BCR::ABL1 > 10%. After 6 months, the patient achieved partial cytogenetic response (PCyR) with BCR::ABL1 < 10%, but grade 3 pleural effusion developed. The spleen thickness reduced to 4.5 cm and the length reduced to 16 cm. The tuberculin test was negative, and no acid-fast bacilli or fungi were detected. Liquid-based cytology showed proliferation of mesothelial cells and lymphocytes, but no malignant changes were observed. The pleural effusion was attributed to a side effect of dasatinib. The patient discontinued dasatinib treatment and was given diuretics and prednisone (40 mg/d). According to the 2020 European LeukemiaNet (ELN) guidelines, the treatment evaluation was in the warning zone, and a change in therapy was recommended. However, the patient chose to continue dasatinib treatment with a dose reduction to 80 mg/d. After 12 months, the patient achieved complete cytogenetic response (CCyR) with BCR::ABL1 reduced to 0.17%, but did not reach the optimal response. The spleen thickness further reduced to 3.8 cm and the length reduced to 11 cm. The patient developed grade 3 pleural effusion again, along with skin itching, cytopenia, and iron-deficiency anemia (possibly due to excessive menstrual bleeding). She resumed prednisone therapy, underwent pleural drainage, and received iron supplementation. The pleural effusion resolved after discontinuing dasatinib.
In July 2021, the patient switched to treatment with flumatinib at a dose of 600 mg/d. After 6 months, the patient achieved major molecular response (MMR), with BCR::ABL1 at 0.1%. After 18 months, the patient reached MR4.0, and at 24 months, BCR::ABL1 was undetectable, indicating achievement of MR4.5. During the early phase of flumatinib treatment, the patient experienced mild gastrointestinal side effects, which resolved quickly, and she tolerated the treatment well without recurrence of pleural effusion. The molecular response remained stable. At the same time, she resumed her daily activities, and her quality of life significantly improved.
Patient’s perspective
The patient expressed satisfaction with the treatment outcome.
Discussion
CML is a malignancy caused by clonal mutations of hematopoietic stem cells, characterized by the BCR::ABL1 fusion gene. CML is usually detected during physical exams or blood tests, and the presence of Ph chromosome abnormalities is confirmed by routine cytogenetic analysis, fluorescence in situ hybridization (FISH), or molecular studies (1). The typical BCR::ABL1 transcripts are e13a2 and e14a2, which encode the p210 fusion protein. Rare transcripts such as e19a2, e14a3, e1a2, and e13a3 account for 0.4, 0.3, 0.9, and 0.1% of CML cases, respectively. Other rare transcripts, including e1a3, e6a2, and e2a2, have also been reported (7). The e19a2 transcript encodes the p230 fusion protein, which differs clinically from the more common p210 isoform. Initially, the e19a2 subtype was often observed in neutrophilic CML, presenting with a benign clinical course. However, it has later been found predominantly in typical CML patients, some of whom exhibit more aggressive clinical manifestations. Patients with the p210 transcript tend to reach treatment goals more rapidly and have a lower treatment failure rate. In contrast, patients with the p230 transcript generally take longer to respond and have a higher risk of treatment failure. However, these patients show better responses to second-generation TKIs (2GTKIs) (2).
In the early stages, CML patients with the e19a2 transcript were treated with interferon and hydroxyurea, but these treatments only induced hematological responses, and most patients died due to disease progression. These patients also showed poor responses to the first-generation TKI imatinib, with most failing to achieve or maintain deep MR, leading to continued disease progression (2). Studies comparing patients with the p230 transcript to those with the p210 transcript revealed significant differences in treatment outcomes. The 1-year CCyR rate for p230 was 44.4%, while for p210 it was 87.9%; the 1-year MMR rate for p230 was 48.6%, compared to 6.3% for p210; and the 2-year event-free survival (EFS) rate for p230 was 94.4%, compared to 69.1% for p210 (8). These findings are consistent with another study’s results (5).
Due to the lower efficacy of imatinib in achieving MMR, 2GTKIs, such as nilotinib and dasatinib, have become the preferred first-line treatment options. Currently, the guidelines recommend the use of imatinib, dasatinib, bosutinib, and nilotinib as first-line TKIs for CML (1). Although the number of reported cases is limited, some studies show that second-generation TKIs can induce deeper molecular responses more quickly. In one study, 10 patients receiving nilotinib (300 mg daily, divided into two doses) as first-line treatment showed good therapeutic effects: one patient achieved MR4.5 within 3 months and maintained it for 31 months, while the other patients achieved MMR within 2 to 6 months. Similarly, two patients treated with dasatinib (100 mg daily) reached MMR within 6 months, with the duration of MMR ranging from 3 months to 43 months (9, 10).
Our patient initially received dasatinib treatment and achieved CCyR at 12 months with BCR::ABL1 < 1%. However, due to suboptimal response, recurrent pleural effusion, rash, and poor tolerance, the treatment was switched to flumatinib. After 6 months of flumatinib treatment, the patient achieved MMR and reached MR4.5 at 24 months, with only mild side effects. This response is consistent with the ELN guidelines for CML treatment (11).The patient’s laboratory test results and treatment response (see Table 1 and Figure 3).
Figure 3
Laboratory test results and treatment response over treatment period. (A) Blood cell counts. (B) Spleen characteristics. (C) BCR::ABL1 level of e19a2 transcript. (D) Cytogenic response.
Due to its trifluoromethyl and imidazole ring structure, nilotinib demonstrates better lipophilicity and ATP-binding affinity, but its long-term use is associated with cardiovascular risks (12). Dasatinib, as a dual inhibitor of ABL and SRC kinases, has a lower specificity for the shape and charge of the binding sites, which makes it more likely to induce pleural effusion with lymphocytic infiltration. These immune-mediated effects are thought to be caused by SRC inhibition (13). The advent of the third-generation TKI, ponatinib, provides hope for overcoming the T315I mutation, but the second-phase PACE trial reported a cumulative incidence of arterial occlusive events of 31% in chronic-phase CML patients (6). Therefore, although ponatinib remains effective, its use requires careful risk assessment.
Flumatinib, optimized from imatinib, binds more strongly to the hydrophobic pocket of the tyrosine kinase domain, enhancing its stability and efficacy (14). In vitro studies have shown that flumatinib exhibits excellent inhibitory activity against BCR::ABL1 kinase point mutations (15). In a phase III clinical trial (FESTnd) evaluating newly diagnosed CML patients, flumatinib was mainly associated with mild adverse events (AEs) such as diarrhea, which typically lasted only 1–2 days. The incidence of grade 3 or higher adverse events was low, including grade 3 rash, diarrhea, and thrombocytopenia (all <1.5%). Rare cardiovascular events, such as atrial fibrillation or stroke (in individual cases) (16, 17), were also reported. In our case, the patient responded rapidly and completely to flumatinib, with no severe side effects. Compared to other second-generation TKIs, flumatinib provides excellent efficacy, overall good tolerability, and fewer serious adverse events (16, 17), making it a feasible treatment option for patients with underlying cardiovascular disease or poor physical condition. A summary of related literature is provided in Table 2.
Table 2
| S. no | Authors and year | Title | Country | Total study population | Patient characteristics | Intervention | Main findings | Study conclusions |
|---|---|---|---|---|---|---|---|---|
| 1 | Yunfan Yang et al. (2024) | Safety and efficacy of flumatinib as later-line therapy in patients with chronic myeloid leukemia | China | 336 | Patients with CP- CML previously treated with TKI | Flumatinib 600 mg once daily |
|
Flumatinib was effective and safe in patients resistant to other TKIs. |
| 2 | Xiaoshuai Zhang et al. (2024) | Comparison of the Efficacy Among Nilotinib, Dasatinib, Flumatinib and Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia Patients: A Real-World Multi-Center Retrospective Study | China | 2,496 | Patients with CP- CML receiving initial 2G-TKI | Nilotinib (n = 512), dasatinib (n = 134), flumatinib (n = 411) or imatinib (n = 1,439) |
|
Efficacy (PFS and OS) among the 4 TKIs were comparable. |
| 3 | Li Zhang et al. (2021) | Flumatinib versus Imatinib for Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia: A Phase III, Randomized, Open-label, Multi-center FESTnd Study | China | 394 | Patients aged 18–75 years, ECOG performance of 0–2, and Ph + CP-CML within 6 months of diagnosis | 1:1 to flumatinib 600 mg once daily (n = 196) or imatinib 400 mg once daily (n = 198) |
|
Patients treated with flumatinib achieved significantly higher response rates, along with faster and deeper response. |
| 4 | Ya-Qin Jiang et al. (2021) | Clinical Effect of Tyrosine Kinase Inhibitors in the Treatment of P230 Chronic Myeloid Leukemia | China | 11 | Patients with e19a2 transcript (P230) CML-CP | Imatinib 400 mg, qd (n = 4), nilotinib 300 mg, bid (n = 5), dasatinib 100 mg, qd (n = 2) | MMR was obtained within
|
For patients with imatinib resistance, deeper molecular response, and MMR in a short time was achieved with 2G-TKIs |
| 5 | Mengxing Xue et al. (2019) | Clinical characteristics and prognostic significance of chronic myeloid leukemia with rare BCR-ABL1 transcripts | China | 40 | Patients with CML having rare BCR-ABL1 transcripts | Imatinib, nilotinib, dasatinib |
|
Patients with e19a2 transcript had a high rate of early optimal response to TKIs. |
| 6 | Jorge E. Cortes et al (2018) | Ponatinib efficacy and safety in Philadelphia chromosome–positive leukemia: final 5-year results of the phase 2 PACE trial | Republic of Korea, UK, Australia, Sweden, Spain, Netherlands, Italy, Germany, France, Singapore, Belgium | 267 | Patients with CP- CML resistant or intolerant to dasatinib or nilotinib, or who had the BCR-ABL1 | Starting dose of 45 mg ponatinib once daily, and dose reductions to 30 mg or 15 mg once daily |
|
Ponatinib was safe and effective, irrespective of dose reductions, in patients with heavily pretreated CP-CML |
| 7 | Ya-Zhen Qin et al. (2018) | Prevalence and outcomes of uncommon BCR-ABL1 fusion transcripts in patients with chronic myeloid leukemia: data from a single center | China | 4750 | Patients with CML and uncommon BCR-ABL1 transcripts | Imatinib, nilotinib or dasatinib | Patients with the e19a2 transcript had low probabilities of 2-year EFS (P = 0.0004) and PFS (P = 0.0067) | Patients with the e19a2 or e1a2 transcript had poor treatment outcomes. |
| 8 | Sudha Sazawal et al. (2017) | Chronic myeloid leukemia with a rare fusion transcript, e19a2 BCR-ABL1: A report of three cases from India | India | 03 | Patients with p230 fusion protein and diagnosed with CML-CP. | Imatinib 400 mg per day | All patients achieved MMR at 12 months | Imatinib demonstrated significant efficacy in patients with e19a2 fusion transcript |
| 9 | Marianna Greco et al. (2013) | Early Complete Molecular Response to First-Line Nilotinib in Two Patients with Chronic Myeloid Leukemia Carrying the p230 Transcript | Italy | 02 | Patients with p230 transcript, diagnosed with CML-CP, who achieved fast and deep CMR with nilotinib | Nilotinib 600 mg per day |
|
Nilotinib is recommended as frontline agent for the treatment of CML with e19a2 fusion transcript |
| 10 | Gaku Oshikawa et al. (2010) | Clonal evolution with double Ph followed by tetraploidy in imatinib-treated chronic myeloid leukemia with e19a2 transcript in transformation | Japan | 01 | Patient with e19a2 transcript CML | Imatinib |
|
CML progressed in 2 years despite imatinib therapy |
| 11 | Mondal et al. (2006) | e19a2 BCR–ABL fusion transcript in typical chronic myeloid leukemia: a report of two cases |
India | 02 | Patient with e19a2 transcript CML | The first patient was treated with hydroxyurea and progressed to the accelerated phase, followed by imatinib therapy. The second patient was treated with hydroxyurea |
|
The disease progression of the e19a2 fusion transcript type may resemble that of typical CML |
| 12 | Ayda Bennour et al. (2010) | E355G mutation appearing in a patient with e19a2 chronic myeloid leukemia resistant to imatinib | Tunisia | 01 | CML patients with the e19a2 transcript, accompanied by the E355G mutation | Initially treated with hydroxyurea, followed by adjustment to imatinib (initial dose of 400 mg, later increased to 800 mg), and subsequently adjusted to nilotinib 400 mg, all taken once daily. | After imatinib treatment, the disease progressed. Gene mutation analysis revealed that the patient carried the E355G mutation, which is associated with imatinib resistance. The treatment was adjusted to nilotinib, and after 3 months, the patient achieved MCyR. | The E355G mutation leads to imatinib resistance in the patient but makes them sensitive to second-generation tyrosine kinase inhibitors, such as nilotinib. |
Summary of the included studies.
ALT, alanine transaminase; CCyR, complete cytogenetic response; CHR, complete hematologic response; CMR, complete molecular response; ECOG, Eastern Cooperative Oncology Group; FFS, failure-free survival; EFS, event-free survival; MCyR, major cytogenetic response, MMR, major molecular response; MR4/DMR, log molecular response or deep molecular response; OS, overall survival; PFS, progression-free survival; Ph + CP-CML, philadelphia chromosome-positive chronic myeloid leukemia in chronic phase; qd, every day; 2G-TKI, second-generation tyrosine-kinase inhibitor.
Since this is the first detailed case report describing the use of flumatinib in treating CML patients with the rare e19a2 transcript, further research is required in larger sample cohorts to validate its efficacy and safety, addressing the limitations of single-case studies.
Statements
Data availability statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
Ethics statement
The studies involving humans were approved by The Third People’s Hospital of Datong. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author contributions
YF: Writing – original draft. LZ: Data curation, Writing – review & editing. JG: Data curation, Writing – review & editing. XL: Data curation, Writing – review & editing. CM: Data curation, Writing – review & editing. JQ: Data curation, Writing – review & editing. HM: Data curation, Writing – review & editing. YZ: Supervision, Writing – review & editing. HW: Supervision, Writing – review & editing.
Funding
The author(s) declare that no financial support was received for the research and/or publication of this article.
Conflict of interest
JG was employed by Tianjin Union Precision Medical Diagnostics Co. Ltd.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The authors declare that no Generative AI was used in the creation of this manuscript.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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Summary
Keywords
chronic myeloid leukemia, e19a2 transcript, second-generation tyrosine kinase inhibitor, flumatinib, molecular response
Citation
Feng Y, Wang H, Zhang L, Gong J, Liu X, Mu C, Qiao J, Meng H and Zhang Y (2025) Molecular response of a patient with e19a2-positive chronic myeloid leukemia to flumatinib: a case report and literature review. Front. Med. 12:1515002. doi: 10.3389/fmed.2025.1515002
Received
22 October 2024
Accepted
11 February 2025
Published
17 March 2025
Volume
12 - 2025
Edited by
Eleni Gavriilaki, Aristotle University of Thessaloniki, Greece
Reviewed by
Oscar Gonzalez Ramella, Civil Hospital of Guadalajara, Mexico
Yanquan Liu, Guangdong Medical University, China
Updates
Copyright
© 2025 Feng, Wang, Zhang, Gong, Liu, Mu, Qiao, Meng and Zhang.
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*Correspondence: Yaqing Feng, 3442187166@qq.com
†These authors have contributed equally to this work and share first authorship
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.