2022CSH Professor Cai Qingqing: Treatment progress of NK/T-cell lymphoma

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The 17th National Hematology Conference of the Chinese Medical Association was grandly opened in Shanghai on September 23-25, 2022, with the theme of "Respect, Inheritance, Collaboration and Innovation", and invited famous experts at home and abroad to discuss the latest progress
in the field of blood diseases.
On this occasion, Yimaitong specially invited Professor Cai Qingqing of Sun Yat-sen University Cancer Hospital to be interviewed to talk about the progress of basic and clinical research in the field of NK/T-cell lymphoma
.

Medical Pulse: NK/T-cell lymphoma is a type of T-cell lymphoma
with poor prognosis and difficult to treat.
Could you please introduce the current status of NK/T-cell lymphoma treatment?

Professor Cai Qingqing: NK/T-cell lymphoma is a type of lymphoid hematopoietic system tumor
with strong aggression and high malignancy.
Asparaginase-based combination regimens have improved the efficacy of NK/T-cell lymphoma in the past decade, but the prognosis of advanced patients is still poor.

The principles of early and late treatment of NK/T-cell lymphoma are different, and a combination of radiotherapy and chemotherapy is recommended in the early stage, while chemotherapy is the main treatment in the
advanced stage.

In general, early patients need to be treated with risk stratification, and patients without risk factors in stage I can achieve good results with radiotherapy alone
.
Stage I with risk factors and stage II patients, radiotherapy and chemotherapy comprehensive treatment is the standard treatment, radiotherapy and chemotherapy mode includes chemotherapy sequential radiotherapy, sandwich radiochemotherapy or radiotherapy after radiotherapy, etc.
, and at present, chemotherapy sequential radiotherapy is the most clinically selected mode, which can reduce the incidence of
bone marrow suppression and oral mucositis.
Asparaginase-containing chemotherapy regimen is the most effective systemic chemotherapy regimen for NK/T-cell lymphoma, and high-efficiency and low-toxicity chemotherapy regimens such as P-GemOx, DDGP, AspaMetDex, mSMILE, etc.
, are widely used treatment options
at this stage.

Patients with advanced and relapsed refractory NK/T-cell lymphoma have a poor prognosis, with a 5-year overall survival rate of only about 30%, and chemotherapy is the main treatment recommendation
.
The P-GemOx regimen has shown comparable efficacy to the AspaMetDex regimen, with less toxicity and greater clinical application
.
The SMILE regimen has also shown good clinical efficacy in advanced and relapsed refractory NK/T-cell lymphoma, but the side effects such as hematologic toxicity and renal impairment are relatively significant, and are now rarely used
.
With the advent of PD-1 monoclonal antibody, NK/T-cell lymphoma has gradually entered the era of
immunochemotherapy.
The results of clinical studies showed that pembrolizumab, nivolumab, sindilimab, tislelizumab, etc.
can reach a total effective rate
of 57%~100% in recurrent NK/T-cell lymphoma.
PD-1 monoclonal antibody combined with P-GemOx immunochemotherapy has also achieved good efficacy in advanced NK/T-cell lymphoma, and the side effects are controllable, which can be used as a new treatment option
for patients with NK/T-cell lymphoma.

Yimaitong: Sun Yat-sen University Cancer Center has done a lot of research and exploration in the field of NK/T-cell lymphoma, can you please introduce the basic and clinical research and achievements of Zhong Wei in this field?

Professor Cai Qingqing: In the past two decades, our lymphoma team has been exploring
the field of NK/T-cell lymphoma.
Our team found that if the ECSIT gene V140A in NK/T-cell lymphoma is mutated, it is easy to induce clinical hemophagocytic syndrome, and dexamethasone combined with thalidomide can alleviate hemophagocytic syndrome to a certain extent (2018, Nature Medicine).

Since the Ann Arbor stage does not accurately reflect the extent of NK/T-cell lymphoma, our lymphoma team created a new staging system for NK/T-cell lymphoma, the CA stage, which can more accurately distinguish patient outcomes (2020, Leukemia).

For patients with clinical stage I NK/T-cell lymphoma, the choice of treatment combination radiotherapy or radiotherapy alone has never been conclusive, and there is currently a lack of suitable molecular typing to guide treatment options
.
Our team conducted an international multicenter study to create 7 SNP prediction labels that can achieve high-precision prognosis stratification and guide high-risk patients to choose combination chemoradiotherapy, while low-risk patients can receive radiotherapy alone (2021, Blood).

Ten years ago, the medium-swollen lymphoma team pioneered the high-efficiency and low-toxicity P-GemOx (pegaspartase, gemcitabine, oxaliplatin) regimen, which significantly improved the short-term efficacy and long-term survival of NK/T-cell lymphoma, and was recommended as a first-line standard treatment plan by NCCN guidelines and has been promoted and applied
nationwide 。 Subsequently, a multicenter randomized controlled clinical study of P-GemOx versus AspaMetDex in the treatment of NK/T-cell lymphoma was carried out, and the results showed that the efficacy of P-GemOx regimen was comparable to that of AspaMetDex regimen, but the toxic side effects were lighter and simpler
to use 。 For early-stage patients, we further created a combination radiotherapy model of first-line P-GemOx chemotherapy sequential radiotherapy, which significantly improved the 5-year survival rate of early-stage patients and reduced treatment-related toxicity, which was adopted and promoted by the Chinese Society of Clinical Oncology (CSCO) lymphoma guidelines (2021, American Journal of Hematology).

However, the prognosis of patients with advanced NK/T-cell lymphoma is still poor, and it is urgent to explore new treatment models to prolong their survival
.
Our team created an immunochemotherapy regimen with PD-1 monoclonal antibody combined with P-GemOx, which improved CR rates to 80% in advanced patients and was well tolerated (Signal Transduction and Targeted Therapy, 2020).

The efficacy of this new model of immunochemotherapy has also been verified
in prospective, multicenter phase II clinical studies.

For patients with relapse and refractory treatment, a phase II.
clinical study initiated by our lymphoma team showed that the histone deacetylase inhibitor cidarbenamide can obtain better efficacy in some patients and can be used as one of the options for patients with refractory recurrence (2017, ASH).

Another clinical study showed that mitoxantrone hydrochloride liposomal monotherapy was 52.
4% effective in relapsed and refractory NK/T-cell lymphoma, showing promising results for further exploration of combined applications (2021, ASH).

In addition, by analyzing the clinical characteristics and therapeutic efficacy of patients with central nervous system invasion in NK/T-cell lymphoma, we found that the addition of new drugs such as anti-PD-1 monoclonal antibody and cedarbenamide to traditional chemotherapy drugs (HDMTX, asparaginase) may further improve the prognosis of patients (2021, ASH).

You have rich clinical experience in the treatment of NK/T-cell lymphoma, could you please talk about which new drugs or new therapies may have good development potential in the field of NK/T-cell lymphoma based on your team's research results? And what new directions are worth exploring in the development of drugs for the treatment of NK/T-cell lymphoma?

Professor Cai Qingqing: With the in-depth exploration of the molecular genetics and immunopathogenesis of NK/T-cell lymphoma, immunotherapy and targeted therapy have also made significant progress, and the successful application of immune checkpoint inhibitors in NK/T-cell lymphoma is the most obvious example
.
Small studies have shown that PD-L1 monoclonal antibody, CD38 monoclonal antibody, CD30 monoclonal antibody and antigen-specific EBV cytotoxic T lymphocytes also have preliminary efficacy
in the treatment of NK/T-cell lymphoma.
In addition, other immune checkpoint inhibitors such as TIGIT, LAG-3, VISTA, CD47 monoclonal antibody, signaling pathway inhibitors such as PI3K inhibitors, and antibody conjugates also have potential therapeutic value
in NK/T-cell lymphoma.
While some of these drugs may have satisfactory results, more evidence from larger samples is needed to validate their survival benefits and clarify long-term toxicity
before clinical use.

At present, we are not clear about the molecular genetics and immune mechanism of NK/T-cell lymphoma, as well as the molecular mechanism of antitumor drugs and immune drugs, and actively exploring the mechanism of drug resistance in NK/T-cell lymphoma is expected to improve existing treatments and help identify new NK/T-cell lymphoma treatment strategies
.
Image

Prof.
Qingqing Cai

Deputy Director of Department of Internal Medicine, Sun Yat-sen University Cancer Hospital

Professor, chief physician, doctoral supervisor

Leader of the Lymphoma Group of the Oncology Branch of Guangdong Medical Association

Chairman of the Lymphoma Professional Committee of Guangdong Precision Medicine Application Society

Vice Chairman of the Youth Committee of the Oncology Branch of the Chinese Medical Association

Vice Chairman of the Lymphoma Professional Committee of the Chinese Medical Education Association

Vice Chairman of the Lymphoma Professional Committee of Guangdong Women Physicians Association

He has published a total of 80 SCI papers, and in the past 5 years, he has published 20 SCI papers in STTT, Blood, Leukemia, CCR, etc.
as a (co)corresponding author, and presided over the National Natural Key Fund and a number of National Nature Facet Funds
.