Professor Zhang Zhizhi: Breaking through the dilemma, Seliniso brings new treatment options for PTCL and NK/T-cell lymphoma patients

Peripheral T-cell lymphomas (PTCLs) are a highly heterogeneous group of aggressive non-Hodgkin lymphomas (NHLs
) that account for 15% to 22% of NHL^[1].
According to the 2016 WHO classification, PTCL contains at least 29 subtypes, the most common of which are PTCL-non-specific (PTCL-NOS), vascular immunoblastic T-cell lymphoma (AITL), anaplastic macrocyte lymphoma (ALCL), and NK/T-cell lymphoma ^[2].

。 There are many similarities in the immunophenotype and functional characteristics of AITL, PTCL-NOS, and NK/T cell lymphoma, most of the biological behaviors and clinical manifestations are highly heterogeneous and aggressive, and patients with relapsed refractory patients lack efficient and specific treatment methods, and have a poor prognosis^[3], and there is an urgent need for highly effective and low-toxicity new drugs to improve the remission rate and prolong their survival in
these patients.

Nuclear output protein 1 (XPO1) is overexpressed in many malignancies, including PTCL, and increased expression of XPO1 has been shown to be associated with low patient survival ^[4
].
Selinisole (trade name: Sivio ^®) is the world's first oral selective nuclear output protein inhibitor (SINE) with a new mechanism that has been shown to provide effective relief
in patients with AITL, PTCL-NOS, and NK/T cell lymphoma.
Based on this, Professor Zhang Mingzhi of the First Affiliated Hospital of Zhengzhou University was specially invited to combine clinical experience, focus on clinical needs, and share the diagnosis and treatment status of PTCL, NK/T cell lymphoma and the clinical experience
of Selinisol.

First of all, could you briefly introduce the current treatment status of PTCL and NK/T cell lymphoma in China, and what unmet treatment needs these patients still have?

Professor Zhang Mingzhi

PTCL and NK/T-cell lymphoma have the characteristics of high invasion, rapid progression, high recurrence rate and mortality, the disease is common in middle-aged and elderly people, the diagnosis is mostly advanced, the existing treatment plan has a low cure rate, the overall prognosis is poor, the recurrence rate after first-line treatment is high, and the treatment progress lags far behind that of B-cell lymphoma ^[5].

。 When the disease progresses to refractory recurrence, the prognosis is worse, and conventional chemotherapy drugs are often chosen for salvage therapy, but the remission rate is low and the maintenance time is shorter, especially for most older patients and/or patients with multiple comorbidities who are not suitable for transplantation, there are still more unmet needs
.

• AITL is a subtype of PTCL with complex histological characteristics and unique biological characteristics, and there is growing evidence that AITL originates from the malignant transformation of follicular helper T cells (TFH) in the germination center, but the specific etiology and pathogenesis are still unclear ^[6].
  
  It is worth emphasizing that Epstein-Barr virus (EBV) infection has been established as the main driver/causative factor of PTCL, but the pathogenesis of specific diseases has not been established ^[5].
  
  

• Due to the complexity of PTCL and NK/T-cell lymphoma disease types and the large differences in prognosis of each type of disease, it is difficult to conduct large-scale clinical studies ^[5], resulting in the slow development of treatment in the
  direction of T-cell lymphoma.
  Currently, first-line treatment of PTCL usually uses CHOP-like regimens (cyclophosphamide, doxorubicin, vincristine, and prednisone), but overall efficacy is poor, with a 5-year overall survival (OS) rate of only 30% to 40%[⁷], and poor survival outcomes for both initial treatment and relapse/refractory (R/R) PTCL, with median progression-free survival (PFS) and OS of R/R PTCL being 3.
  1 months and 5.
  5 months^{, respectively[4]}
  。

• At present, it is generally believed that the first-line chemotherapy regimen containing anthracyclines (such as CHOP regimen) has only a good effect on anaplastic lymphoma kinase-positive anaplastic-large cell lymphoma (ALK+ALCL), but its prognosis for patients with NK/T-cell lymphoma and PTCL-NOS, AITL and other subtypes of PTCL is not optimistic; Modified CHOP regimens such as EPOCH (Changing the Way of Administration), Hyper⁃CVAD or ACVBP, CHOP/ICE, or CHOP/IVE have not shown better efficacy ^[5], and ideal, uniform standard regimens for each subtype of PTCL have not been established
  .
  

In short, the pathogenesis of NK/T cell lymphoma and PTCL subtypes of diseases is not yet clear, its clinicopathological characteristics are complex and diverse, aggressive, poor treatment effect, high recurrence rate, there are huge challenges in diagnosis and treatment, in order to solve the above unmet treatment needs, it is urgent to conduct in-depth research on the disease, explore chemotherapy drugs without cross-resistance to anthracyclines and more targeted small molecule drugs, which bring hope for the efficacy of the treatment of diseases and the survival and prognosis of patients
。

Medical Pulse Pass: R/R PTCL and NK/T cell lymphoma are still a type of disease that is difficult to treat, patients usually have a poor prognosis, as a clinical expert who has been working in the field for many years, can you please combine your clinical experience to talk about the current treatment strategies and new drug progress for R/R PTCL and NK/T cell lymphoma patients?

Professor Zhang Mingzhi

For R/R NK/T cell lymphoma and PTCL patients, guidelines such as the 2022 China CSCO Guidelines[⁸] and the National Comprehensive Cancer Network (NCCN)^[9] recommend that PTCL patients with PTCL-NOS, AITL, etc.
, prefer clinical trials or multi-drug chemotherapy, regardless of stage; The 2022 NCCN guidelines^[9] also recommend preferred clinical trials or multi-drug combination therapy
for patients with NK/T-cell lymphoma.
To date, clinical trials of new targeted drugs for a variety of different pathogenic mechanisms are in full swing to bring new treatment options and relief hope
to patients.

In recent years, with the emergence of new drugs, R/R NK/T CELL LYMPHOMA and PTCL new drug advances mainly include histone deacetylase inhibitors (HDACi), SYK/JAK signaling pathway dual inhibitors, PI3K inhibitors, PD-1 monoclonal antibodies, and XPO1 inhibitors Selinisol
.
A Phase I clinical study of Selinisol in combination with high-dose dexamethasone, ifosophosphamide, carboplatin, and etoposide (DICE^{) [4]} included 11 patients with a median age of 60 years of age with R/R PTCL and NK/T cell lymphomas, including 5 patients with AITL, 2 patients with PTCL-NOS, and 1 patient with NK/T-cell lymphoma, who had previously received a median 2-line regimen and 7 patients with primary refractory disease at the time of entry into the trial
。 Efficacy was evaluated after 2 cycles of treatment in 10 patients, and all of these 10 patients achieved remission, of which 9 (82%) achieved complete remission (CR) (95% CI, 48-98) and 1 (10%) achieved partial remission (PR).

Selinizol has some efficacy in the treatment of R/R PTCL and NK/T cell lymphoma, and it is worth further exploring and studying the efficacy and safety
of its combination therapy regimen in patients with R/R PTCL and NK/T cell lymphoma.

The TOUCH study is a multicenter, single-arm Phase Ib clinical study designed to explore the efficacy and safety of the Selinizol combination regimen in the treatment of R/R PTCL and NK/T cell lymphoma, and the results show that Selinizol has considerable prospects
in the treatment of such patients.
Could you please explain this study to us in terms of efficacy and safety?

Professor Zhang Mingzhi

The TOUCH study is a Phase 1b clinical study of R/R PTCL and NK/T cell lymphoma populations in China that evaluated the efficacy and safety of Selinizol combined with gemcitabine and oxaliplatin (GemOx) ^{regimens [10].}

。 As of September 14, 2021, a total of 26 patients received at least one cycle of treatment, of which 13 were PTCL-NOS, 7 were extranodal NK/T cell lymphoma, 5 were AITL, 1 was ALCL (ALK-), the median age was 53.
5 years, and 22 patients were stage
III/IV 。 With a median follow-up of 7.
3 months, the median number of treatment lines for patients was 2.
5, the ORR was 46.
2% for all patients, the CR rate was 26.
9%, the median DOR was 3.
3 months, and the median PFS was 2.
7 months, it was seen that the Selinisol combined with GemOx regimen showed good efficacy
in patients with R/R PTCL and NK/T cell lymphoma 。 In the PTCL-NOS and extranodal NK/T-cell lymphoma subgroups, patients had a more prominent remission and survival, with ORR rates of 53.
8% and 57.
1%, CR rates of 30.
8% and 28.
6%, respectively, median DOR of 3.
1 months, and median PFS of 4.
4 months and 4.
7 months
, respectively.
In terms of safety, the most common adverse events (TEAE) that occur during ≥ level 3 therapy are thrombocytopenia, neutropenia, anemia, diarrhea, etc.
, and most adverse events are well controlled
through dose adjustment and supportive care.

In summary, the Selinizol combined with GemOx protocol has shown good antitumor activity in patients with R/R PTCL and NK/T cell lymphoma, especially in patients with PTCL-NOS and extranodal NK/T cell lymphoma, where both ORR and PFS are high and overall safety is controllable
。 Therefore, the Selinisol combined with GemOx program is expected to provide a new treatment option for patients with R/R PTCL and NK/T cell lymphoma who have previously received multi-line therapy, and it is expected that other combined protocols of Selinisol will also make major breakthroughs
in the field of R/R PTCL and NK/T cell lymphoma in the future.

The emergence of new drugs has brought new hope to PTCL and NK/T cell lymphoma patients, what are your expectations or prospects for the treatment of PTCL and NK/T cell lymphoma in China?

Professor Zhang Mingzhi

In recent years, with the deepening of the understanding of the pathogenesis and pathological diagnosis of PTCL and NK/T cell lymphoma, the clinical treatment of PTCL and NK/T cell lymphoma has also become more and more important, and the targeted drugs represented by HDACi and verbtuximab (BV) have achieved certain efficacy in patients with PTCL and NK/T cell lymphoma, but it cannot be denied that there are fewer
targeted therapeutic drugs in PTCL and NK/T cell lymphoma.

• The efficacy of common targeted drugs such as PI3K inhibitors in this class of diseases has yet to be verified, and the published data show that PI3K inhibitors are not effective in the treatment of PTCL, and there is still much room for
  improvement 。 HDACi is a drug based on epigenetics research and development, in the PTCL and NK/T cell lymphoma treatment to undertake an important task, but in the clinic, patients in epigenetics in addition to histone acetylation, there are also some patients with histone methylation, DNA methylation and other changes, therefore, for epigenetics of drugs also need more precise design, in order to bring better clinical benefits
  to patients.
  

• In immunotherapy, such as PD-1 monoclonal antibody, from the current PD-1 monoclonal antibody monotherapy R/R PTCL patients efficacy data, PD-1/PD-L1 monoclonal antibody antibody antitumor activity is general, ORR is about 50%, CR rate is about 20%, in addition, PD-1 monoclonal antibody in PTCL treatment There are still many doubts, clinically only some patients show a certain efficacy, and some PTCL patients have even appeared "super progression" after using PD-1 antibody treatment.
  
  。 Therefore, how to further improve the mitigation rate, deepen the depth of mitigation and prolong PFS is an important direction of
  research.
  The new drugs developed for PTCL and NK/T-cell lymphoma have more or less problems such as unclear efficacy and obvious toxic side effects
  .
  New drugs such as CD52 monoclonal antibody and CD30 monoclonal antibody also need further in-depth research to verify their efficacy
  .
  

• As new drugs continue to emerge, more treatment options
  are available to patients.
  The novel small molecule targeted drug Selinizol provides rich clinical data for the treatment of PTCL and NK/T cell lymphoma, and a number of clinical studies of Selinisol combined with multiple regimens for the treatment of PTCL and NK/T cell lymphoma are also being conducted in our laboratory, such as Selinisol combination chemotherapy, PI3K inhibitors, PD-1 monoclonal antibody and CAR-T cell therapy
  。 Selinisole's new and unique mechanism of action makes it promising in the treatment of many types of hematologic malignancies, and the current basic research on Selinisole shows that it can reverse the resistance mechanism of tumors from multiple dimensions, such as resistance to chemotherapy, resistance to hormones, etc.
  , and even Selinizol helps to block the infection of EBV virus, which is precisely the causative factor
  of PTCL and NK/T cell lymphoma.
  We also believe that basic data from Seliniso, as well as data from clinical combination therapy, can lay the foundation
  for the treatment and even cure of more PTCL and NK/T-cell lymphoma patients.
  

Professor Zhang Mingzhi

• Chief physician, professor, doctoral supervisor

• Director of the Cancer Center of the First Affiliated Hospital of Zhengzhou University

• Director of Henan Lymphoma Diagnosis and Treatment Center

• Member of the Standing Committee of the Oncology Branch of the Chinese Medical Association

• Member of the Standing Committee of the Oncologist Branch of the Chinese Medical Doctor Association

• Leader of the Translational Medicine Professional Committee of the Oncology Branch of the Chinese Medical Association

• Vice President of the Chinese Lymphoma Federation of the Chinese Society of Clinical Oncology (CSCO).
  

• Deputy Director of the Lymphoma Branch of the Hematology and Oncology Committee of the Chinese Gerontology Society

• Vice Chairman of the China Precision Medicine Hematology Professional Committee

• The first president of the Cancer Branch of Henan Medical Doctor Association

• Deputy Director of Tumor Branch of Henan Medical Association

• Director of Lymphoma Professional Committee of Henan Anti-Cancer Association

• Outstanding talents of Henan Provincial Science and Technology Department, innovative talents of Henan Provincial Health Department

• He has undertaken 3 national natural science foundations, 19 provincial and departmental scientific research projects, published more than 310 academic papers (135 SCI articles), and won 6 provincial science and technology awards

Note: Sivio ^® is the trade name
of Seliniso.
In December 2021, China's State Drug Administration (NMPA) approved Deqi Pharmaceutical's Selinizol new drug marketing application to treat relapsed or refractory multiple myeloma (R/R MM) that has previously been treated with a proteasome inhibitor, an immunomodulator, and an anti-CD38 monoclonal antibody refractory to refractory multiple myeloma (R/R MM).


In June 2020, the U.
S.
Food and Drug Administration (FDA) approved Selinizol for the treatment of patients with third-line and above diffuse large B-cell lymphoma (DLBCL); In addition to this, Seliniso has been approved in several countries for the treatment of patients with
relapsed refractory DLBCL.

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Guidelines for the diagnosis and treatment of lymphoma (2022 edition) [J].
Medical Administration and Medical Authority, 2022.
[2] SWERDLOW S H, et al.
The 2016 revision of the World Health Organization classification of lymphoid neoplasms [J].
Blood, 2016, 127(20): 2375-90.
[3] ZHAO W L, et al.
How I diagnose and treat peripheral T cell lymphoma.
Zhonghua Xue Ye Xue Za Zhi, 2019, 40(5): 363-7.
[4] TANG T, et al.
Phase I study of selinexor in combination with dexamethasone, ifosfamide, carboplatin, etoposide chemotherapy in patients with relapsed or refractory peripheral T-cell or natural-killer/T-cell lymphoma [J].
Haematologica, 2021, 106(12): 3170-5.
Song Yuqin.
Diagnosis and treatment of peripheral T cell and NK cell lymphoma[J].
Chinese Oncology Clinical, 2014, 41(19): 5.
Li Tingting, et al.
Clinical features and prognosis of 84 cases of vascular immunoblastic T-cell lymphoma: single-center analysis[J].
Chinese Journal of Hematology, 2020, 41(11): 6.
Zhao Linjun, et al.
Progress in the treatment of recurrent refractory peripheral T-cell lymphoma.
Leukemia & Lymphoma,2020,29(02): 83-86.
[8] Guidelines Working Committee of Chinese Society of Clinical Oncology.
Guidelines for the diagnosis and treatment of CSCO lymphoma in 2022[J].
2022.
[9] HORWITZ S M, et al.
T-Cell Lymphomas, Version 2.
2022, NCCN Clinical Practice Guidelines in Oncology [J].
J Natl Compr Canc Netw, 2022, 20(3): 285-308.
[10] HUIQIANG HUANG E A.
Abstract#2452 XPO1 Inhibitor (ATG-010)Plus Chemotherapy per Investigator's Choice for Heavily Pretreated Patients with Relapsed or Refractory (R/R)Peripheral T-Cell Lymphoma(PTCL) and Extranodal NK/T-Cell Lymphoma (ENKTL):Preliminary Results from a Multicenter,Single- Arm,Phase Ib Study (TOUCH Trial) [J].
ASH, 2021.
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