Prof. Yan Xiaojing: Looking for the optimal treatment of DLBCL, I will search for the 2021 China Oncology Congress

Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma, rituximab (R) combined with CHOP (cyclophosphamide, doxorubicin, vincristine, strong pine) chemotherapy has significantly improved the remission rate and overall survival of DLBCL patients, but there are still many patients with relapse and refractory disease
.

In recent years, with the in-depth understanding of the pathogenesis of DLBCL and the continuous emergence of new drugs and new regimens, DLBCL patients have many new options
.

The 2021 China Conference on Oncology (CCO) was officially held from April 14th to 17th, 2022.
On this occasion, Yimaitong specially invited Professor Yan Xiaojing from the Department of Hematology of the First Affiliated Hospital of China Medical University to share the development of DLBCL treatment plan.
and optimization exploration
.

Yi Mai Tong: DLBCL has been rarely cured until now most patients can be cured by standard immunochemotherapy.
Can you tell us about the exploration process in these decades? Prof.
Yan Xiaojing The First Affiliated Hospital of China Medical University Before the 1970s, DLBCL was considered to be a rare and curable malignant tumor.
In 1972, Levitt M first reported the therapeutic effect of combined chemotherapy, and some patients with DLBCL obtained better results.
efficacy, but the overall efficacy is limited
.

Researchers have been optimizing the regimen of combination chemotherapy
.

In the 1980s, the combination regimens containing anthracyclines, such as CHOP regimens, made the cure rate of DLBCL reach 30% to 40%, laying the foundation for DLBCL combined chemotherapy regimens
.

The advent of the anti-CD20 monoclonal antibody rituximab in 1997 further increased the cure rate of DLBCL to 50% to 60%, changing the treatment situation of DLBCL.
R-CHOP has become the standard treatment for first-line DLBCL and is the treatment for DLBCL.
the cornerstone
.

Although the treatment regimen of R-CHOP significantly prolongs the overall survival (OS) and progression-free survival (PFS) of DLBCL patients, 40-50% of patients still face relapse or refractory in clinical application (R/R )
.

How to further improve the prognosis of these patients and ultimately improve the cure rate of DLBCL is a topic that researchers in the field continue to explore
.

Fig.
1 The road to cure of DLBCL patients Yimaitong: In recent years, what attempts have scholars in the field of DLBCL made to improve the efficacy of DLBCL and break through the ceiling of first-line treatment of R-CHOP? Professor Yan Xiaojing The First Affiliated Hospital of China Medical University In the exploration of first-line treatment, researchers have gone through different eras, from improving the intensity and density of chemotherapy to optimizing CD20 antibodies, to exploring maintenance therapy and combination new drugs, but most of the attempts All were negative and unsuccessful
.

For example, in the new era of targeted therapy, combining new targeted drugs (X) on the basis of R-CHOP chemotherapy regimen for first-line treatment is one of the main exploration directions to improve the efficacy of DLBCL.
These global multi-center clinical trials did not achieve significant benefit in the overall population, and the subgroup analysis found that IR-CHOP or R2-CHOP benefited in a subset of patients, suggesting differences in DLBCL
.

With the development of technologies such as large-scale sequencing, omics research, and bioinformatics analysis, especially a series of studies since 2017, people have gained a deeper understanding of the molecular mechanism of DLBCL and realized that DLBCL is actually a group of highly heterogeneous diseases
.

As far as tumor cells are concerned, the molecular typing of DLBCL has also changed from traditional GCB and ABC subtypes to 4, 5 to the current popular 7 classification; at the same time, scholars have also found that the tumor microenvironment and immune regulation are also involved in DLBCL.
morbidity
.

Therefore, the treatment of DLBCL ranges from various small molecule inhibitors targeting abnormal regulatory pathways, to immunomodulatory drugs, to antibody drugs and cell therapy targeting tumor cell surface antigens.
Various new drug development and clinical research emerge in an endless stream.
Some research results showed good efficacy
.

An antibody-drug conjugate (ADC) targeting CD79b, Polatuzumab Vedotin (Pola for short) is a rising star and has stood out in many R-CHOP+X explorations.
The efficacy of the treatment regimen Pola-R-CHP has been validated in the global phase III POLARIX study: the median follow-up of 28.
2 months, the relative risk of disease progression, recurrence or death in the Pola-R-CHP group compared with the R-CHOP group A 27% reduction, a significantly higher 2-year PFS rate (76.
7% vs 70.
2%; HR 0.
73; 95% CI 0.
57-0.
95; P<0.
02), and a significantly lower relative risk of events in the Pola-R-CHP group than in the R-CHOP group group, the 2-year event-free survival (EFS) rate was also significantly improved (75.
6% vs 69.
4%; HR 0.
75; 95% CI: 0.
58-0.
96; P=0.
02)
.

This global phase III double-blind randomized controlled trial showed that Pola-R-CHP was superior to R-CHOP standard treatment, setting a new benchmark for first-line treatment of DLBCL
.

Figure 2 Global Phase III POLARIX Study: PFS Results There are still some exploratory studies of R-CHOP+X and other therapies that have shown preliminary efficacy
.

For example: (1) Anti-CD19 monoclonal antibody: the combination of Tafasitamab ± lenalidomide regimen on the basis of R-CHOP initially showed an objective response rate (ORR) benefit in the first-MIND study in Phase Ib for newly treated DLBCL patients, The two regimens were well tolerated
.

(2) Precise treatment based on molecular typing: The heterogeneity of DLBCL and the complexity of molecular typing suggest that precise diagnosis and treatment is the future direction of DLBCL treatment.
The team of Prof.
Weili Zhao from Shanghai Ruijin Hospital explored the molecular typing-based approach in DLBCL patients.
The precision treatment of R-CHOP+X is carried out.
The preliminary results of the phase II trial will be published by ICML in 2021.
The research data shows that the ORR of patients receiving precision treatment is as high as 96%, of which the complete remission (CR) rate is 87%, excellent In the R-CHOP program (CR rate 66%, P=0.
003)
.

(3) Chimeric antigen receptor T (CAR-T) cell therapy: Phase II ZUMA-12 study showed that Axi-Cel first-line treatment of high-risk large B-cell lymphoma (LBCL) showed a higher ORR rate (89%) and CR rate (78%), with more than 70% of patients remaining in remission at data cutoff at a median follow-up period of 15.
9 months
.

The above progress has shown good remission benefits, and it is expected that the study data after extended follow-up and expansion of the trial population can further improve the cure rate of DLBCL
.

Yimaitong: About 30–40% of DLBCL patients relapse after first-line treatment, and these patients also have extremely high unmet medical needs
.

What are the new developments in the field of R/R DLBCL worth paying attention to? Professor Yan Xiaojing Some of the patients with R/R DLBCL in the First Affiliated Hospital of China Medical University can be relieved again by salvage chemotherapy, but about 50% cannot receive intensive chemotherapy due to age or complications.
Treatment is ineffective, these patients often have a poor prognosis, and the expected survival is generally less than half a year, so the treatment of R/R DLBCL patients is very difficult
.

The research and development of new drugs and new therapies has brought new treatment hope and options for R/R patients
.

Here we look at some of the research results
.

A phase Ib/II study (NCT02257567) showed that with a median follow-up of 48.
9 months in the randomized cohort, the Pola-BR arm significantly prolonged PFS compared with bendamustine, rituximab (BR) arm (9.
2 months vs 3.
7 months; HR, 0.
39; 95% CI, 0.
23-0.
66; P < .
0003) and OS (12.
4 vs 4.
7 months, HR, 0.
42; 95% CI, 0.
24-0.
72; P = .
001) 2-year PFS rate and 2-year OS rate reached 28.
4% and 38.
2%, respectively
.

It is worth noting that even patients who have received multiple lines of therapy or are refractory can benefit from Pola-BR
.

Figure 3 PFS and OS of the randomized cohortFigure 4 Best ORR, median PFS and median OS of the Pola+BR cohort according to the number of treatment lines and refractory status Another research hotspot for R/R lymphoma treatment is dual-antibody CD20/CD3 is one of the most promising dual-antibody target combinations in the field of R/R aggressive non-Hodgkin's lymphoma (aNHL), and a number of CD20/CD3 bispecific antibodies are under clinical research
.

Unlike most diabodies with a 1:1 structure, Glofitamab is a unique 2:1 fully humanized IgG1 bispecific antibody with enhanced tumor antigen affinity, rapid T cell activation and tumor cell activation Killing and potential in combination with other anti-CD20 antibodies
.

Study NP30179 (NCT03075696), a Phase I/II dose escalation/expansion study, showed high levels of Glofitamab monotherapy after pretreatment with otuzumab in R/R aNHL patients on multiple lines of therapy.
Anti-tumor activity and high response rate, ORR was 53.
7%, of which CR rate was 39.
4%
.

With a median follow-up of 12 months, Glofitamab monotherapy still had durable efficacy, with 72.
5% of patients sustaining CR
.

In terms of safety, no new safety signals were detected, and the most frequently reported adverse event was cytokine release syndrome (CRS), with an incidence of 58.
9%, mostly mild and limited to cycles 1 and 2
.

Figure 5.
The remission rate of aNHL cohort The remarkable remission rate of Glofit single drug in R/R DLBCL patients also laid the foundation for further clinical research of single drug and combination drug
.

Pola combined with Glofitamab, the MOA is unique and complementary, with little overlap in the toxicity profile of the two drugs
.

NP39488 (NCT03533283) is a phase Ib/II, open-label, multicenter, dose-escalation/expansion study, and the ORR of the two-drug combination therapy in all evaluable R/R DLBCL patients was 79.
6%, of which the CR rate was 51.
0%
.

The safety profile was consistent with that of single drug, most CRS events were grade 1, and no grade 3-4 CRS events were reported, supporting further confirmatory studies
.

Summary For the exploration of DLBCL, the footsteps of medical workers have never stopped
.

On the basis of the R-CHOP program, we should further explore innovative therapeutic drugs and innovative treatment models, formulate precise treatment plans, continuously reduce the incidence of R/R, and improve the clinical cure rate of DLBCL
.

Expert Profile Professor Yan Xiaojing Professor/Chief Physician, Doctoral Supervisor Director of Hematology Department of the First Affiliated Hospital of China Medical University National Special Support Program Young Top Talents Ministry of Education New Century Excellent Talents Outstanding Scientific and Technological Talents in Colleges and Universities Shenyang High-level Talents Leading Talents Youth Member of Hematology Branch of Chinese Medical Association Member of Hematology Branch of Chinese Medical Doctor Association Member of Hematology and Tumor Professional Committee of China Anti-Cancer Association Member of Standing Committee of Leukemia Branch of China Medical Education Association Lymphoma Branch Committee Member of the Youth Committee of the Hematology Rehabilitation Professional Committee of the Chinese Association of Rehabilitation Medicine, Member of the Lymphoma Branch of the Liaoning Anti-Cancer Association, Deputy Director of the Hematology Branch of the Liaoning Medical Association, Chairman of the Youth Committee of the Hematology Branch of the Liaoning Medical Association Reviewers and editorial board editors of domestic and foreign journals: Chole Review: Evelyn Typesetting: Uni Execution: Wenting Poke "read the original text", we will make progress together