2022CSH| Professor Qingqing Cai: Progress in the treatment of NK/T-cell lymphoma

The 17th National Hematology Academic 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 well-known experts at home and abroad to talk about the latest progress
in the field of blood diseases.
On this occasion, Professor Cai Qingqing of the Affiliated Cancer Hospital of Sun Yat-sen University was invited to be interviewed to talk about the basic and clinical research progress
of Zhongshi in the field of NK/T cell lymphoma.

NK/T-cell lymphoma is a type of T-cell lymphoma with poor prognosis and difficult treatment
.
Can you tell us about the current treatment status of NK/T-cell lymphoma?

NK/T-cell lymphoma is a class of lymphopoietic system tumors with strong aggression and high degree of malignancy
.
Over the past decade, asparaginase-based combination regimens have improved the efficacy of NK/T-cell lymphoma, but the prognosis for advanced patients remains poor
.
The principles of early and late treatment of NK/T-cell lymphoma are different, with a combination of radiotherapy and chemotherapy recommended in the early stage, while chemotherapy is the main treatment in the
advanced stage.

Overall, early stage patients require risk stratification therapy, and in patients with no risk factors in stage I, radiation therapy alone can achieve better results
.
Stage I with risk factors and stage II patients, radiotherapy and chemotherapy comprehensive therapy is the standard treatment, radiotherapy and chemotherapy mode includes chemotherapy sequential radiotherapy, sandwich radiotherapy chemotherapy or sequential chemotherapy after radiotherapy, etc.
, and the current chemotherapy sequential radiotherapy is the most clinically selected mode, which can reduce the incidence
of bone marrow suppression and oral mucositis.
The chemotherapy regimen containing asparaginase is the most effective systemic chemotherapy regimen for NK/T-cell lymphoma, and the high-efficiency and low-toxicity chemotherapy regimen such as P-GemOx, DDGP, AspaMetDex, mSMILE, etc.
, is a widely used treatment plan
at this stage.

Patients with advanced and recurrent refractory NK/T-cell lymphoma have a poor prognosis, with a 5-year overall survival rate of only about 30%, and chemotherapy is recommended as the main treatment
.
The P-GemOx protocol has shown comparable efficacy to the AspaMetDex regimen, with less toxicity and easier clinical application
.
The SMILE protocol has also shown good clinical efficacy in advanced and relapsed refractory NK/T-cell lymphoma, but side effects such as hematological toxicity and renal impairment are relatively significant and are now less commonly used
.
With the advent of PD-1 monoclonal antibody, NK/T-cell lymphoma has gradually entered the era of
immunochemotherapy.
Clinical study results show that Pabolizumab, navuriumab, sindilizumab, tirelizumab, etc.
can achieve an overall effective rate
of 57% to 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.

Medical Pulse Communication: The Cancer Prevention and Control Center of Sun Yat-sen University 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 Zhongzhong in this field?

Our lymphoma team has been exploring
the field of NK/T-cell lymphoma for nearly two decades.
Our team found that if mutations in the ECSIT gene V140A in NK/T-cell lymphoma can easily induce clinical hemophagocytic syndrome, dexamethasone combined with thalidomide can alleviate hemophagocytic syndrome to some extent (2018, Nature Medicine).

Because Ann Arbor staging does not accurately reflect the extent of disease invasion of NK/T-cell lymphoma, our lymphoma team has created a new staging system for NK/T-cell lymphoma, CA Stage, which is able to more accurately distinguish patient prognosis (2020, Leukemia
).
For patients with clinical stage I NK/T-cell lymphoma, the choice of treatment with combination chemoradiotherapy or radiotherapy alone is inconclusive, 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 predictive labels that enable high-precision prognostic stratification to guide high-risk patients to choose combination chemoradiotherapy while low-risk patients can receive radiotherapy alone (2021, Blood
).

Ten years ago, the middle swollen lymphoma team pioneered the high-efficiency and low-toxicity P-GemOx (pemantose, gemcitabine, oxaliplatin) protocol, 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 for the treatment of NK/T-cell lymphoma showed that the efficacy of the P-GemOx regimen was comparable to that of the AspaMetDex regimen, but the toxicity was less severe and the use was simpler
。 For early stage patients, we further created a combination chemoradiotherapy model of first-line P-GemOx chemotherapy sequential radiotherapy, which significantly improved the 5-year survival rate of early patients and reduced treatment-related toxicity, and was adopted and popularized by the Chinese Society of Clinical Oncology (CSCO) lymphoma guidelines (2021, American Journal of Hematology
).

However, prognosis remains poor in patients with advanced NK/T-cell lymphoma, and there is an urgent need to explore new treatment modalities to prolong their survival
.
Our team created an immunochemotherapy regimen of PD-1 monoclonal antibody combined with P-GemOx, which increased CR rates to 80% in advanced patients and was well tolerated (2020, Signal Transduction and Targeted Therapy
).
The efficacy of this new model of immunochemotherapy was also validated
in a prospective, multicenter Phase II clinical study.

For patients with relapse relapse, a phase II clinical study initiated by our lymphoma team showed that the histone deacetase inhibitor cedabenamide can achieve good efficacy in some patients and can be used as one of the options for patients with refractory relapse (2017, ASH).

Another clinical study showed a 52.
4% efficacy of mitoxantraquinone hydrochloride liposomes in relapsing refractory NK/T cell lymphoma, showing promising results for further exploration of combined applications (2021, ASH
).
In addition, by analyzing the clinical features and therapeutic efficacy of patients with central nervous system invasion of NK/T-cell lymphoma, we found that the addition of new drugs such as anti-PD-1 monoclonal antibody and sidabenamide on the basis of traditional chemotherapy drugs (HDMTX, asparaginase) may further improve patient prognosis (2021, ASH).

You have rich clinical experience in the treatment of NK/T-cell lymphoma, can you please combine the research results of your team and talk about which new drugs or new therapies may have good development potential in the field of NK/T-cell lymphoma? And what new directions are worth exploring in the development of drugs to treat NK/T-cell lymphoma?

With the deeper 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 samples have shown that PD-L1 monoclonal antibody, CD38 monoclonal antibody, CD30 monoclonal antibody and antigen-specific EBV cytotoxic T lymphocyte therapy for NK/T cell lymphoma also has initial efficacy
.
In addition, other immune checkpoint inhibitors such as TIGIT, LAG-3, VISTA, CD47 monoclonal antibody, PI3K inhibitors and other signaling pathway inhibitors and antibody-coupled drugs also have potential therapeutic value
in NK/T cell lymphoma.
Although some of these drugs may have satisfactory results, more evidence from larger samples is needed to validate their survival benefits and elucidate long-term toxicity
before clinical application.

At present, we are not clear about the molecular genetics and immune mechanisms of NK/T-cell lymphoma, as well as the molecular mechanism of the role of anti-tumor drugs and immune drugs, and actively explore the mechanism of NK/T cell lymphoma resistance, which is expected to improve existing treatment methods and help determine new NK/T cell lymphoma treatment strategies
.

Professor Cai Qingqing

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

• Professor, Chief Physician, Doctoral Supervisor

• Leader of the lymphoma group of the Oncology Branch of the Guangdong Medical Association

• Chairman of the Lymphoma Professional Committee of Guangdong Precision Medicine Applied 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 Association of Women Physicians

• In the past 5 years, he has published 20 SCI treatises in STTT, Blood, Leukemia, CCR, etc.
  , and presided over the National Natural Key Fund and a number of national natural surface funds

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