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Professor Fu Chengcheng: Seliniso double-effect attack, anti-tumor and potential anti-COVID-19 effect!

 Last Update: 2023-02-03
 Source: Internet
 Author: User

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With the advancement of various epidemic policies one by one, China's epidemic prevention and control measures are more accurate, and the mobility of social personnel is gradually increasing, which also means that the overall development of the national epidemic is relatively rapid, and the incidence of new crowns has risen
sharply.
Patients with hematologic cancers tend to have lower immune function and are more susceptible to COVID-19 than healthy people, and once infected, COVID-19 affects the diagnosis and treatment of their primary ^disease1.

Celiniso (trade name: Xivio ^®) can effectively inhibit virus proliferation and pro-inflammatory cytokine release when treating the new coronavirus, while activating the release of anti-inflammatory cytokines, and has shown a certain efficacy
in some patients with COVID-19 infection.
The International Myeloma Foundation (IMF) recommends celiniso as one of
the potential treatment options for COVID-19.
In addition, as the world's first potent and oral nuclear output protein inhibitor, celinisol has strong anti-tumor activity and controllable
safety.
While exerting its anti-myeloma effect, celiniso also has the potential to treat the new coronavirus, or it can bring treatment gospel
to patients with multiple myeloma (MM) combined with COVID-19 infection.
On this occasion, Yimaitong specially invited Professor Fu Chengcheng of Suzhou First People's Hospital to interpret how Seliniso has a double effect and played a dual role in the anti-tumor and anti-epidemic battle, so as to feed readers!

To add insult to injury, the unmet needs of MM patients have doubled under the pandemic

With the prevention and control measures of the epidemic in China becoming more precise and open, the incidence of new crowns has risen sharply, affecting a wide range, and the risk of infection of patients with blood tumors has gradually increased
.
Patients with haematological tumors have lower basal immune function and are more immunodeficient and at increased risk of COVID-19 if they are or have recently completed high-dose ^{chemotherapy2}
.
It can be seen that patients with hematological tumors in the epidemic themselves are facing a more serious situation
.

MM is a malignant disease in which clonal plasma cells proliferate abnormally, which cannot be cured and requires ongoing treatment
.
MM patients are ^{immunocompromised3} and studies have shown that MM patients have a higher risk of viral infection than the general ^population4
.
In terms of prognosis, advanced age, high risk, and kidney disease are the adverse prognostic factors for MM patients infected with the new ^crown5
.
After MM patients were infected with the new crown, the incidence of severe disease was twice that of non-tumor patients, 8% vs.
4%,
respectively.
In addition, the mortality rate of MM patients infected with the new crown is also significantly higher than that of non-MM patients, and the study statistics show that the mortality rate of new crown patients hospitalized with MM infection in Spain and France is as high as 34% and 39%, respectively (Figure 1)^6,7
.

With the opening up of China's new crown epidemic control, the risk of new crown infection faced by MM patients in China has greatly increased, and how to effectively prevent COVID-19 infection and reduce the severe disease rate and mortality rate after COVID-19 infection while fighting tumor is very important
for MM patients.

Figure 1.
Risk of infection in MM patients and prognosis of new crown infection

Make a big difference – Celiniso has potential anti-coronavirus effects thanks to its superior mechanism

In terms of mechanism, XPO1-mediated protein or RNA output is necessary for viral replication, and celiniso, as the world's first potent, oral nuclear output protein inhibitor, can bind to XPO1 to inhibit protein and RNA output
.
In virus-associated immunopathopathies, as observed in influenza viruses, MERS-CoV, etc.
, celiniso prevents IκB nuclear output
by activating NF-κB (IκB) signaling to release pro-inflammatory cytokines.
In addition, celiniso can inhibit the interaction
between SARS-CoV-2 ORF6 and IFN-induced mRNA nuclear output complex (NUP98-RAE1 complex).
Thus, celiniso effectively inhibits viral proliferation and pro-inflammatory cytokine release while activating anti-inflammatory cytokine release for potential anti-COVID-19 effects (Figure 2)^8,9
.

Figure 2.
The role of celiniso in the transport of genetic material and proteins and the regulation of immune responses in COVID-19 or other viruses

Celiniso has not only demonstrated its effective antiviral ability in basic research, but also verified its efficacy
in clinical studies.
In a phase II single-blind randomized low-dose oral seliniso for severe COVID-19, the SARS-CoV-2 PCR conversion rate was 36.
4% in the celiniso group and 19.
6% in the placebo group, and the incidence of adverse events in the treatment of COVID-19 in celiniso was comparable to that in the placebo group.
The main hematologic adverse events were hyponatremia and neutropenia
.

Figure 3.
Efficacy of celiniso in the treatment of severe COVID-19

A real-world case shows the potential role
of celiniso in treating COVID-19 infection.
In a patient with five-drug exposure/triple refractory MM who was infected with COVID-19 and treated with hydroxychloroquine and azithromycin, the patient's C-reactive protein was persistently elevated, indicating uncontrolled
disease.
Subsequently, the patient's temperature dropped rapidly and continued to return to normal, and C-reactive protein continued to drop to normal levels
.

Figure 4.
Seliniso treats patients with MM and COVID-19 infection

Unlimited potential – Seliniso could be a potential treatment option for COVID-19

The XPO1 inhibitor celiniso has been officially approved for use in patients with R/R MM in December 2021, and its combination regimen has been approved by the 2022 V5 version of NCCN guideline 10, the 2021 ESMO guideline 11, the 2021 IMWG guideline 12, the 2022 CMDA guideline ¹³, and the 2022 CSCO guideline ¹⁴The 2022 CACA guideline ¹⁵ is recommended for patients
with first-time recurrence or R/R MM.
For patients with MM with poor prognostic factors, Celiniso is also a reliable treatment option:

For older (≥65 years) patients with MM, BOSTON studies showed progression-free survival (PFS) of up to 21 months in older patients using XVd16;
For patients with high-risk MM in the 1-3 lines, the BOSTON study results show that the XVd regimen can extend PFS to 12.
9 months
when used in high-risk patients.
In patients with either 1 or ≥ 2 cytogenetic abnormalities, XVd regimens reduce the risk of disease progression or ^death17;
For patients with renal insufficiency MM, because celiniso is not metabolized through the kidneys and does not need to adjust the dose, it can also bring efficacy
.
The BOSTON study showed that the XVd regimen for patients with CrCl 40–60 mL/min had PFS of up to 16.
62 ^months18
.

In addition, celiniso has a mechanistic basis for the treatment of the new coronavirus, and its potential anti-COVID-19 effects have also been demonstrated in clinical trials and real-world cases, and the IMF recommends celinisol as one of the potential treatment options for COVID-19.

For patients with MM and COVID-19 infection, the potential anti-COVID-19 efficacy of celiniso may bring additional benefits
to patients.

*X: Seliniso; V: bortezomib; D: Dexamethasone

Expert reviews

MM is currently an incurable disease, and most patients face problems such as
limited treatment options and poor treatment effects, and will eventually lead to the dilemma of recurrence and refractory treatment.
Since the outbreak of COVID-19 at the end of 2019, the high incidence of vaccination without effective antibodies, higher susceptibility to infection, higher rates of severe disease and higher mortality rates have made the survival challenges faced by MM patients more severe
.
Therefore, patients with hematological tumors urgently need to effectively prevent new crown infection in the process of anti-tumor, or choose anti-COVID-19 treatment strategies
that can effectively prevent severe disease after infection with COVID-19.

Launched in 2021, with its good efficacy and safety in anti-tumor, celinisol has been recommended by a number of domestic and foreign guidelines for patients with first-time recurrence or R/R MM
.
In the fight against the new coronavirus, celiniso can effectively inhibit viral proliferation and pro-inflammatory cytokine release, while activating anti-inflammatory cytokine release, with potential anti-COVID-19 effects, and the IMF also recommends celinisol as one of the potential treatment options for COVID-19.

Seliniso can not only exert potential anti-new coronavirus effects while effectively and safely treating MM, but also reduce the treatment burden of patients, and is a treatment option
worth considering for patients with MM and COVID-19 infection.

Prof.
Fu Chengcheng

Deputy Director and Chief Physician of the Department of Hematology, The First Affiliated Hospital of Soochow University
Associate Professor, Doctoral Supervisor
Deputy leader of plasma cytology group, blood branch of Chinese Medical Association
Member of Myeloma Expert Committee of Hematology Branch of Chinese Medical Doctor Association
Member of Hematology and Oncology Branch of Chinese Anti-Cancer Association
Member of the Targeted Therapy Committee of the Association of Women Physicians
Deputy leader of the Multiple Myeloma and Related Diseases Professional Group of the Association of Women Physicians
Hematology and Oncology Branch of Jiangsu Anti-Cancer Society, Hematology Branch of Jiangsu Medical Association, Deputy Leader of Plasma Cell Disease Group of Jiangsu Research Hospital Association
Director and Standing Committee Member of Hematology Professional Committee of China Medical Education Association
Member of the Asia-Pacific Myeloma Network
Member of the International Myeloma Association
As the project leader, he has successively won the Key Talent Fund of Science and Education Rejuvenation and Health of Jiangsu Provincial Department of Health, the National Natural Science Foundation of China, the Natural Science Foundation of Jiangsu Province, and the Fund
of Hematological Oncology Professional Committee of the Chinese Anti-Cancer Association.
He has won the second prize of scientific and technological progress of the Ministry of Education and the Ministry of Science and Technology, and the new technology introduction award of Jiangsu Province

Note: Silvio ^® is the trade name
of Celiniso.
In December 2021, China's National Medical Products Administration (NMPA) approved Antengene's new drug application for celinisol for the treatment of previously treated relapsed or refractory multiple myeloma (R/R MM)
in combination with dexamethasone for the treatment of at least one proteasome inhibitor, one immunomodulator, and one anti-CD38 monoclonal antibody.

In June 2020, the US Food and Drug Administration (FDA) approved celinisol for the treatment of patients with diffuse large B-cell lymphoma (DLBCL) above the third line; In addition, Seliniso has also received multinational approval for the treatment of patients
with relapsed and refractory DLBCL.

The content of the article is only for academic communication of medical and health professionals, if you are a non-medical and health professional, please take the initiative to withdraw from browsing and reading, otherwise the risks and consequences arising therefrom should be borne
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References:

1.
HU Xichun, HU Zhihuang, WANG Biyun, et al.
Novel coronavirus pneumonia and antitumor drug treatment[J].
Chinese Journal of Oncology,2022,32(6):499-511.

2.
Leng Tongai, et al.
Effect of novel coronavirus pneumonia on prognosis and treatment strategies of patients with hematological tumors[J].
Chinese Journal of Experimental Hematology,2022,30(2):645-648.

3.
Chari, Ajai et al.
Blood vol.
136,26 （2020）: 3033-3040.

4.
Blimark C, et al.
Haematologica.
2015; 100:107–13.

5.
Ajai Chari, et al.
Blood.
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6.
Martinez-Lopez Jet al.
medRxiv.
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7.
Salje H, et al.
Science.
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8.
Nature.
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9.
Drug Discov Today.
2020 Oct; 25（10）:1775-1781

10.
NCCN Clinical Practice Guidelines in Oncology（NCCN Guidelines®）for Multiple Myeloma.
2022 Version 5.

11.
Dimopoulos M A, et al.
HemaSphere, 2021, 5（2）: e528.

12.
Moreau P , et al.
The Lancet Oncology, 2021, 22（3）:e105-e118.

13.
Hematologist Branch of Chinese Medical Doctor Association, etc.
Guidelines for the diagnosis and treatment of multiple myeloma in China (revised in 2022)[J].
Chinese Journal of Internal Medicine,2022.

14.
Guidelines Working Committee of Chinese Society of Clinical Oncology.
Guidelines for the diagnosis and treatment of malignant hematological diseases of the Chinese Society of Clinical Oncology (CSCO) 2022[M].
Beijing: People's Medical Publishing House, 2022.
168-171.

15.
National Anti-Cancer Association.
Guidelines for integrated diagnosis and treatment of cancer in China.
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16.
Grosicki S, et al.
Lancet.
2020; 396(10262):1563-1573.

17.
Richard S, et al.
Am J Hematol.
2021 Sep 1; 96(9):1120-1130.

18.
Delimpasi S, et al.
Am J Hematol.
2022 Mar 1; 97(3):E83-E86.

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