2021 ASH big coffee talks about Professor Bai Ou's inventory of chidamine in the treatment of peripheral T-cell lymphoma

Peripheral T-cell lymphoma (PTCL) is a highly aggressive lymphoma with a high degree of malignancy, and the prognosis of its treatment is not optimistic
.

The team of Professor Bai Ou from Bethune First Hospital of Jilin University explored the study of Chidamide maintenance treatment of PTCL patients and was selected as a poster presentation at this year's ASH annual meeting
.

Yimaitong invited Professor Bai Ou to accept an interview to share with you the current status of PTCL treatment, transplantation status, and the research progress of Chidamide for the treatment of PTCL independently developed and produced in China
.

Yimaitong: Could you please introduce the current status of treatment of PTCL patients in my country? What are the treatment difficulties and what is the status of hematopoietic stem cell transplantation in its treatment? Professor Bai Ou’s PTCL is derived from mature T lymphocytes, which account for 5% of non-Hodgkin’s lymphomas in the United States and 21.
4% in China
.

The types of PTCL mainly include anaplastic large cell lymphoma (ALCL), follicular helper T cell PTCL (angioimmunoblastic T cell lymphoma [AITL]), peripheral T cell lymphoma non-specific type (PTCL-NOS), Extranodal NK/T cell lymphoma, nasal type (ENKTL), these four types account for 72% of PTCL
.

Other types include enteropathy-associated T-cell lymphoma (EATL), primary hepatosplenic γδ-cell lymphoma (HSTL), primary skin aggressive epidermal CD8-positive cytotoxic T-cell lymphoma, and breast prosthesis-related ALCL, which belong to PTCL The rare type in
.

At present, the treatment of PTCL still adopts CHOP or CHOP-like regimen (as shown in the figure below), among which CHOP-like regimen includes CHOEP regimen, DA-EPOCH regimen, ICE regimen and so on
.

What is the clinical effect of CHOP or CHOP-like regimen in the treatment of PTCL? A retrospective analysis of 22 centers around the world on 1,314 newly-treated PTCL patients from 1990 to 2002 (85% of patients received anthracycline-containing chemotherapy regimens) showed that the 5-year failure-free survival (FFS) rate of ALK+ ALCL patients and The overall survival (OS) rates were 60% and 70%
.

The 5-year FFS rate of ALK-ALCL, PTCL-NOS, AITL patients is 18%-36%, and the 5-year OS rate is 32%-49%, all of which are less than 50%
.

The results of other types (ATLL, EATL, HSTL) are even worse (as shown below)
.

Later, studies have performed autologous hematopoietic stem cell transplantation consolidation therapy for patients who are suitable for hematopoietic stem cell transplantation after first-line treatment, which only increases the progression-free survival (PFS) rate by about 10%
.

Therefore, the current prognosis of PTCL patients is very poor, and they cannot benefit significantly from anthracycline therapy like B-cell lymphoma
.

PTCL has limited benefits from anthracycline-based chemotherapy regimens, so the targeted therapy of PTCL has attracted much attention
.

Targeted therapy drugs include: anti-CD30 antibody drug conjugates (such as vebutuximab [BV]), anti-CD52 monoclonal antibodies (such as alemtuzumab), folic acid inhibitors (such as Pratroxa), Protein deacetylase inhibitors (HDACi; including first-generation romidepsin, second-generation belexstat and chidamide), PD-1 monoclonal antibody, immunomodulators (such as lenalidomide), proteasome inhibitors (e.
g.
, bortezomib), bispecific antibodies and the like
.

Yimaitong: Could you please introduce the role of histone deacetylase inhibitor chidamide in patients with relapsed and refractory PTCL and some important research progress? Professor Bai Ou Cedarbenamide is a new generation of HDACi independently developed and produced in China, which has strong accessibility in China
.

The unique benzamide chemical structure of Chidamide has a high degree of selectivity against the target and can bind to the target stably
.

A number of clinical studies have also been conducted at home and abroad to explore the efficacy and safety of chidamide as a single agent in the treatment of R/R PTCL
.

The key clinical research conducted in China is the CHIPEL study, which enrolled 79 patients with or above third-line treatment
.

With a median follow-up of 29 months, the overall response rate (ORR) of chidamide monotherapy for R/R PTCL was 28%, and the median OS was 21.
4 months
.

In addition, a real-world study from Japan at the ICML conference this year also explored the efficacy of chidamine as a single agent in the treatment of R/R PTCL.
A total of 55 patients with R/R PTCL were enrolled, 67% of whom were PTCL-NOS, 18 % Are AITL, 15% are other subtypes, and 64% of patients have previously received ≥2 line therapy
.

Among the 46 evaluable patients, the ORR was 46%, and the ORR of AITL patients reached 88%
.

The median duration of response (DOR) was 12 months, the median PFS was 6 months, and the median OS was 23 months
.

At present, the combined application of HDACi and new targeted drugs to treat R/R PTCL has also attracted much attention.
New targeted drugs that can be combined include PD-1 mAb, BV, bortezomib, pratroxa, azacitidine, And PI3K-δ/γ inhibitor Duvelisib and so on
.

Combination therapy can achieve a considerable ORR, up to 80%.
At the same time, the median PFS, DOR, and OS data are also improved compared with single-agent therapy
.

The above research results have also prompted HDACi to be included in the 2021 CSCO guidelines and the NCCN guidelines as an important recommendation for a type of evidence
.

There are also two clinical studies that are being enrolled, the results of which will have important guiding significance for the clinical practice of PTCL treatment
.

One is Chidamide combined with PD-1 monoclonal antibody for the treatment of relapsed and refractory AITL (SCRAT study), and the other is Chidamide combined with PD-1 monoclonal antibody and then combined with azacitidine to treat R/ R PTCL
.

It is hoped that the results of these two studies will provide better guidance for the treatment of PTCL patients
.

Yimaitong: What is the role of Chidamide in the first-line treatment of PTCL? What research and exploration is being carried out? Professor Bai Ou first introduced the exploration of new PTCL targeted drugs combined with first-line therapy
.

Including the combination of BV, azacitidine, romidepsin, lenalidomide and CHOP or CHOP-like regimens in standard PTCL treatment, compared with the exploration of CHOP regimens in first-line PTCL treatment
.

The preliminary results of these studies have obtained higher ORR, CR rate, PFS rate and OS rate
.

At the same time, there are also some first-line targeted drug combinations, such as romidepsin combined with lenalidomide, azacitidine combined with romidepsin, etc.
, which have also obtained good curative effects, with an ORR of 70%-75%, 2 The annual PFS rate is over 30%-40%, and the OS rate is close to 60%
.

In addition, at the ICML meeting this year, the team of Professor Huang Huiqiang from the Sun Yat-sen University Cancer Center announced the results of chidamide combined with CHOP regimen compared with CHOP regimen in the treatment of newly treated PTCL patients
.

The study performed case-control matching on 408 patients with PTCL.
A total of 22 patients treated with Chidamide combined with CHOP and 22 patients treated with CHOP control were included.
The dosage of Chidamide was 20 mg twice a week
.

The results showed that chidamide combined with CHOP was better than CHOP in ORR, CR rate and OS, but there was no significant statistical difference
.

The median PFS of chidamide combined with CHOP regimen group and CHOP regimen group were unreached and 14.
2 months (P=0.
035), which was statistically different, and the safety was acceptable
.

Therefore, the first-line treatment of PTCL with chidamide combined with CHOP is safe and reliable, and can significantly prolong the PFS of patients
.

At present, there are also two clinical studies on the first-line treatment of PTCL with chidamide combined with new targeted drugs.
One is chidamide combined with azacitidine and then combined with CHOP regimen compared with CHOP alone for the first-line treatment of PTCL patients, and the other One study was the first-line treatment of chidamide combined with azacitidine in patients with unfit (not suitable for transplantation) PTCL
.

Both of these clinical studies have begun to recruit patients, and the results of their studies will further guide clinical PTCL first-line treatment options
.

It is worth noting that after first-line chemotherapy and hematopoietic stem cell transplantation consolidation therapy, can patients use HDACi maintenance therapy to achieve better results? A study at the ASCO meeting in 2021 showed good results
.

The study divided patients into two cohorts, cohort 1 was transplanted in CR1, cohort 2 was transplanted in CR2, and romidepsin was used for maintenance treatment 42-80 days after transplantation
.

A total of 29 patients underwent maintenance treatment.
Of the 25 evaluable patients, 15 patients did not progress within 2 years, that is, the PFS rate at 24 months was 60%, which was significantly higher than the previous use of CHOP regimen alone or CHOP regimen for hematopoiesis PFS rate of stem cell transplant patients
.

Yimaitong: The study conducted by you and your team on the maintenance treatment of PTCL patients with chidamide was selected as the poster presentation of this year's ASH annual meeting.
Could you please briefly introduce the results and significance of this study? From 2016 to March 2021, Professor Bai Ou included a total of 50 patients with PTCL who were not suitable for transplantation.
Among them, 7 patients were followed up for less than 3 months.
Therefore, 43 patients were included in this evaluation.

.

The 43 patients included three different stratifications, as shown in the figure below
.

 The main pathological types of patients include AITL, ALK-ALCL, PTCL-NOS and NK/T cell lymphoma, accounting for 86.
3% of the total
.

The patients were mainly in the middle and high risk group, accounting for 62.
8%
.

The proportion of patients treated with 1-1.
5 lines was 83.
7%
.

The results showed that the ORR was 79.
1%, and the CR rate was 44.
2%
.

As of August 2021, the median follow-up was 12.
8 months
.

The median PFS and OS were not reached.
The 12-month PFS rate was 74.
9%, the 12-month OS rate was 88.
2%, the 18-month PFS rate was 67.
2%, and the 18-month OS rate was 79.
9%
.

At the same time, the study also conducted a subgroup analysis: age stratification analysis showed that after combined with Chidamide, there was no significant statistical difference in PFS and OS between patients >60 years old and <60 years old
.

In the pathological stratification analysis, the efficacy of AITL (21 cases), ALK-ALCL (4 cases) and PTCL-NOS (10 cases) were mainly analyzed.
The results showed that the PFS and OS results of AITL and ALK-ALCL patients were significant Better than PTCL-NOS patients
.

It further suggests that the combination of chidamide in clinical treatment focuses on AITL and ALK-ALCL patients, which is consistent with the results of the CHIPEL study
.

Some patients did not achieve CR after 4 courses of treatment.
On the basis of the original chemotherapy regimen, combined with Chidamide to continue treatment for 2 courses, and then the CHOP regimen was discontinued and Chidamide maintenance treatment was performed.
Some patients were observed The curative effect was improved and the remission deepened.
9 patients (64.
3%) improved from PR to CR, and 5 patients (35.
7%) improved from SD to PR
.

In terms of adverse events (AE), the most common grade 3/4 hematology AEs include neutropenia (39%), thrombocytopenia (30%), and anemia (23%)
.

Some patients, such as AITL and PTCL-NOS advanced patients, have poorer clinical status.
If you start treatment with Chidamide, the patients may have a more significant blood decline, or they may not be able to successfully complete all courses of treatment.
Therefore, these patients are in induction therapy.
Chidamide treatment was continued after 4 courses
.

The most common non-hematological AEs include gastrointestinal reactions and fatigue, which are both grade 1/2, and are generally well tolerated
.

The results of this research were shortlisted for the poster presentation of this year's ASH conference, and we look forward to your attention
.

Professor Bai Ou, Deputy Director, Department of Hematology, Bethune First Hospital, Jilin University, Head of the Lymphoma Specialist Alliance, Bethune First Hospital, Jilin University; Member of the Standing Committee of the Lymphoma Professional Committee of the Chinese Anti-Cancer Association CSCO Member of the Standing Committee of the Chinese Anti-Lymphoma Alliance (UCLI) Member of the Standing Committee of the 5th Clinical Chemotherapy Committee of the Chinese Anti-Cancer Association Member of the Standing Committee of the First Committee of the Hematology Branch of the Chinese Society of Geriatrics China Healthcare Member of the Standing Committee of the Oncology Branch of the International Exchange Promotion Association CSCO Member of the Chinese Anti-Leukemia Alliance (UCLI) stamp "Read the original text", we make progress together