Professor Lin Yanjuan: Standing out, XPO1 inhibitors may bring new opportunities for the treatment of MDS patients

Many professionals often call MDS "pre-leukemia", which fully confirms the difficulty
of treating the disease.
As a big name in the industry who has been working in the field of MDS for many years, can you tell us about the current diagnosis and treatment status of MDS? What are the clinically unmet needs?

MDS is currently considered to be a heterogeneous myeloid clonal group of diseases
originating from hematopoietic stem cells.
Its diagnosis and typing have gone through several stages, the earliest is in 1982 FAB collaborative group proposed a morphology-based MDS typing system (type 5), in 2016 began to use WHO MDS diagnosis and classification, 2022 version of the updated classification (5th edition) added gene molecular characteristics, and MDS into two types of subtypes
with clear genetic abnormalities and clear morphology.
In addition, a clear distinction was made between MDS (MDS-LB) for low blasts and MDS (MDS-IB)
for blast pleasis.

Table 1 WHO MDS Classification 5th Edition (2022 Update)

In addition, the prognostic stratification of MDS has also undergone replacement and optimization, from the International Prognostic Points System (IPSS) to the revised International Prognostic Points System (IRSS-R), from focusing only on chromosomal abnormalities and multilineage blood cell changes to focusing on the degree of
cytopenia.
The current IPSS-M stratification adds some genetic factors
.

Table 2 MDS Revised International Prognostic Points System (IRSS-R)

Regarding the current treatment of MDS, it is mainly divided into two parts: lower risk group and higher risk group, and the treatment of lower risk group is mainly to support hematopoiesis, such as blood transfusion, use of erythropoietin, granulocyte colony-stimulating factor, androgens and immunosuppressants
.
Demethylation agents or chemotherapy can be used in the higher-risk group, and due to the higher overall age of onset and poor chemotherapy tolerance, demethylation agents
are now mainly considered.
For nearly 10 years since 2012, there has been no more effective treatment for MDS patients, and there are still a large number of unmet
clinical needs.

Yimaitong: With the deepening of people's research on tumor mechanisms, many different pathways and targets have been discovered, and a series of drugs have been developed and used in clinical practice to solve more problems
.
In response to this unresolved need in the field of MDS, do you think there are new drugs that may be effective in the clinic today? What are its main mechanisms?

At present, the use of demethylation drugs in the treatment of MDS is long, showing certain clinical efficacy, but it cannot achieve complete cure
.
There is still a large unmet
need for MDS patients who do not respond to or fail demethylation therapy.
With the deepening of the study of tumor mechanisms, scholars have discovered many different pathways and targets, developed a series of drugs, and used them to solve more problems in clinical practice
.
In response to this unsolved demand in the field of MDS, in recent years, the launch of many new drugs has brought new opportunities for MDS treatment, such as demethylation drugs (azacitidine, decitabine), immunomodulators (thalidomide, lenalidomide), Bcl-2 inhibitors (venetoclax), etc.
, and some such as CD47 monoclonal antibody and IDH1 inhibitors have not been widely used in clinical practice
.

Selective nuclear output protein inhibitors (SINE) offer certain advantages
over other treatment options.
Nuclear output protein 1 (XPO1) is a key nucleoplasmic transporter in cells, which inhibits the nuclear output of substrates by covalently binding Cys528 at the XPO1 binding site, promotes the intranuclear storage and activation of tumor suppressor proteins and other growth regulatory proteins, and downregulates the levels of various oncogenic proteins in the cytoplasm to induce apoptosis
of tumor cells.

Yimaitong: It is reported that Selinisol is the world's first oral selective nuclear output protein inhibitor (SINE) approved for marketing in China, which has been approved by the NMPA for the treatment of relapsed and refractory MM patients
at the end of 2021.
For MDS, is there any clinical exploration, can you give us a brief share?

The therapeutic exploration of Selinisol in the field of MDS mainly includes the following two studies
.
One study was on the treatment of demethylation drugs (HMAs) refractory to high-risk MDS or acute myeloid leukemia (AML)²
.
Patients received 3 weeks of oral treatment with celinisol (60 mg/BIW for 2 weeks, followed by a 1-week break).

The primary endpoint was overall response rate (ORR), and secondary endpoints included duration of response (DOR), disease stability, safety, and overall survival (OS).

The results of the study showed that of the 23 evaluable patients, the ORR was 26% (n=6) and 52% (n=12) achieved stable disease (SD).

The median DOR was 6.
3 months and the median OS was 8.
7 months
.
Subgroup analysis showed that patients who achieved complete myeloremission (mCR) or SD had a more pronounced improvement in survival compared with those in the inactive group, with OS of 9.
6 months and 7.
9 months
, respectively.
The most common grade 3 or 4 adverse events were thrombocytopenia and hyponatremia, which occurred in 8 and 5 patients
, respectively.
There were no treatment-related deaths
.
The results of this study confirm that celinisol is effective in the treatment of HMA-refractory MDS and AML, and adverse events are manageable with supportive care; Further research is needed to compare selinisosol with supportive care alone and to identify subgroups
of patients who may benefit most from treatment with selinisol.

Fig.
1 Clinical efficacy of celinisol in the treatment of HMA-refractory MDS

The second is a study of cerinisol plus azacitidine for MDS3
.
In the past, demethylating drugs, including azacitidine, have been used to treat MDS with some success; However, overall survival for patients with MDS remains low, so there is an urgent need to find new treatments
.
Selinisol is a nuclear output protein inhibitor that has been shown to have antitumor activity in some hematological tumors, blocking cell proliferation and inducing apoptosis
in a variety of tumor cell lines.
This study explored the effects of
combined administration of celinisol and azacitidine on two MDS cell lines, namely SKM-1 and MUTZ-1.
Cell proliferation tests were performed, the effects of each drug used individually and in combination were compared, apoptosis and cell cycle changes between groups were also analyzed, and western blots were performed to determine the potential mechanism
of action of combination therapy with celinisole and azacitidine.
The results showed that the combination of celinisol and azacitidine could synergistically inhibit MDS cell proliferation and block the cell cycle in the G2/M phase
.
In addition, MDS apoptosis is promoted, enhancing the accumulation of p53 in the nucleus, so that p53 is activated and functions
as a tumor suppressor protein.
It can be seen that the combination of cellinisol and azacitidine may be a promising treatment
in the field of MDS.

Another study is on the use of Eltanexor (ATG-016) in the field of MDS4
.
Eltanexor is a second-generation SINE compound with lower blood-brain barrier penetration and a wider therapeutic window than the first-generation, so it is better tolerated, can achieve higher frequency dosing and higher doses, longer exposure, and is intended to be developed for the treatment of patients with MDS above risk in IPSS-R who have failed HMA therapy
。 At the 2021 ASCO Annual Meeting, the latest data
from this study were presented.
The trial is a Phase I/II clinical study to evaluate the treatment of a single-agent Eltanexor in patients with
high-risk MDS.
Enrolled patients were divided into two dose groups: 10 mg daily (n=5) and 20 mg daily (n=10), administered 5 days a week in 28-day cycles
.
The results of the study showed that 15 of the 20 patients enrolled could be evaluated
.
The results showed that among the patients who could evaluate the efficacy, 7 (47%) obtained mCR and 5 (33%) obtained SD, with an overall disease control rate of 80%.

In the 10 mg dose group (n=5), 3 (60%) achieved mCR and 2 (40%) SD.

In the 20 mg dose group (n = 10), 4 (40%) achieved mCR and 3 (30%) SD.

Four of the 15 patients (26.
7%) achieved hematologic improvement
.
Survival analysis showed that the median OS (mOS) of 7 patients with mCR was 11.
86 months, which was significantly better than 8.
67 months for patients who did not reach mCR and significantly better than 3.
15 months
for patients with PD.
The mOS in patients with hematologically improved was 10.
58 months
.
The conclusion is that Eltanexor oral monotherapy is effective in patients with HMA-refractory high-risk MDS.

Yimaitong: In your opinion, what is the future of XPO1 inhibitors in the field of MDS? What other prospects do you have for MDS treatment?

There are two main prospect
prospects for the treatment of XPO1 inhibitors in the field of MDS.
First, through the clinical research data of patients with HMA-refractory MDS, it can be seen that the efficacy of XPO1 inhibitors alone can be expected; Secondly, the combined application of XPO1 inhibitors and demethylating drugs is also worth looking forward to
.
At present, many mutant genes related to MDS can be found through NGS detection, and in the future, combination therapy for one or more of these targets may appear and be applied in clinical practice
.
In addition, the combined application of XPO1 inhibitors with immunomodulators or immunotherapy (e.
g.
, CAR-T) as pre-transplant bridging therapy or post-transplant maintenance therapy is a direction
worthy of in-depth study and exploration.

Prof.
Yanjuan Lin

• Department of Hematology, Fujian Union Medical College, Chief Physician, Graduate Supervisor

• Postdoctoral fellow at Stanford University School of Medicine

• Member of China MDS/MPN Working Group

• Member of the MDS Academic Committee of the Chinese Gerontological Society

• Deputy head of the Red Group of the Hematology Branch of Fujian Medical Association

• Subspecialties: MDS/MPN, bone marrow failure disease, malignant hematological disease

• The first batch of millions of engineering talents in Fujian Province

• Winner of Fujian Youth Science and Technology Award

• He has published more than 50 papers in core journals and SCI

• He won one second prize and two third prizes of Fujian Province Science and Technology Progress Award

• Obtained a national invention patent

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

In June 2020, the U.
S.
Food and Drug Administration (FDA) approved Selinisole for the treatment of patients with third-line or above diffuse large B-cell lymphoma (DLBCL); In addition, Seliniso is also approved in multiple countries for the treatment of patients with
relapsed and refractory DLBCL.

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References:

1.
Guidelines for the diagnosis and treatment of myelodysplastic syndrome with blastocytosis (2022 edition)

2.
Taylor J,et al.
Lancet Haematol.
2020 Aug; 7(8):e566-e574.

3.
Guo Y, et al.
Invest New Drugs.
2022 Aug; 40(4):738-746.

4.
Sangmin Lee, et al.
JCO.
39, no.
15_suppl.