2022CSH Prof. Li Wang: Advances in the treatment of diffuse large B-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.
At the conference, Professor Wang Li of Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine introduced the unmet diagnosis and treatment needs, treatment progress and precision treatment
of DLBCL under the title of "Treatment Progress of Diffuse Large B-cell Lymphoma (DLBCL)".

DLBCL is a common non-Hodgkin lymphoma (NHL) and currently about 40% of DLBCL patients cannot achieve cure with R-CHOP first-line chemotherapy regimens
.
Patients with non-curable DLBCL are often accompanied by adverse prognostic factors such as advanced age, extranodular invasion, double expression, and double strike
.
On the basis of the R-CHOP regimen, researchers have explored a variety of treatment options for DLBCL, such as R-CHOP+ ibratinib, R-CHOP+ lenalidomide, R-CHOP+ bortezomib, R-CHOP+ everolimus maintenance therapy, etc.
, but the biological heterogeneity of DLBCL limits the clinical benefits
of these regimens in patients with DLBCL.
IPI scores, onset and sites of involvement, cell origin, and molecular characteristics of patients with DLBCL can all lead to differences in prognosis
.
Professor Wang Li said that when whole-genome sequencing and other examination methods are more popular, and the biological background cognition is clearer, the individualized precision treatment of DLBCL patients will become feasible, and the prognostic outcome will be improved
.

With the aging of society, the number of elderly patients with DLBCL is increasing
.
The latest data from the National Cancer Institute shows that the age of onset of NHL, including DLBL, is concentrated in 65-74 years, in addition, various data at home and abroad also show that the age of onset of the disease is gradually increasing
。 A 2022 study (n=2445) by the team of Professor Zhao Weiguan of Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine published in the journal Frontier in Immunology showed that compared with young DLBCL patients, 1140 patients with > 60-year-old DLBCL had the characteristics of late disease staging, poor ECOG, elevated LDH, high extranodular involvement rate, and high double expression ratio, and PIM1, MYD88, BTG2, CD79B, TET2, Genes such as BTG1 have a high frequency of mutations and significantly worse
prognosis.

For the exploration of treatment in elderly patients with DLBCL, the results of the Smart Start trial were published in the journal
BLOOD in 2019.
This study explored the efficacy
of rituximab + lenalidomide + ibratinib (IR2) sequential IR2 + CHOP regimen in elderly patients with DLBCL.
The study found that after two cycles of IR2 treatment alone, patients were able to achieve ORR in 86%.

Based on this, Professor Zhao Weiying's team explored the efficacy of the IR2 protocol in elderly patients with DLBCL who could not receive unfit/chemotherapy, and the trial is still in progress, and the preliminary data results are very optimistic
.
In addition, in 2020, Prof.
Weichen Zhao's team published in the journal Clinical Epicgenetics the results
of a trial evaluating the use of cedabenamide combined with R-CHOP protocol for elderly patients with a > 60-year-old with an IPI score of 2-5 points.
The study enrolled a total of 49 patients, with a median age of 67 years, a CR rate of 86%, and an objective response rate (ORR) of 94%.

There were no significant differences in PFS and OS between dual-expressing lymphoma (DEL) and non-dual-expressed DLBCL in this study compared to historical controls
.
Professor Wang Li said that from the above trial results, the cedabenamide combined with R-CHOP scheme has excellent efficacy in elderly DLBCL patients, although the follow-up time is short, but the combination scheme can significantly improve PFS and OS in elderly patients with DEL; In addition, a national multicenter phase III randomized controlled study of cidabenamide plus R-CHOP is underway, with the hope that there will be better data outcomes in the future to support this protocol for older patients with
DLBCL.

Double-expressed lymphoma (DEL) mentioned above is a subtype of DLBCL with co-expression of c-MYC and BCL-2 proteins but not with rearrangement of both; In 2016, the WHO cited double expression as a poor prognostic factor for DLBCL and did not classify
it separately.
Multiple studies have demonstrated that the rate of complete response (CR) in patients with DEL after receiving the R-CHOP regimen is about 65%, the 5-year progression-free survival (PFS) rate is about 30%, and the 5-year overall survival (OS) rate is 30-36%; Patients with non-dual-expressed DLBCL had a CR rate of 84%, a 5-year PFS rate of 65%, and a 5-year OS rate of 68%
after receiving the R-CHOP regimen.
According to the data of Ruijin Hospital, the prognosis of DEL patients is also significantly worse than that of patients with non-bi-expression DLBCL
.
In 2022, Prof.
Weiyan Zhao's team published a basic study in the journal Clinical and Translational Medicine, and the RNA-seq results of DEL patients suggested that the expression of the AP-1 protein family was significantly upregulated
.
In addition, in the mouse human-derived tissue xenograft (PDX) model of DEL, cedabenamide combined with chemotherapy can specifically inhibit the transcriptional levels of the AP-1 protein family, thereby exerting a therapeutic effect
.
Professor Wang Li said that the results of the basic research also further support the exploration of the cedabenamide combined R-CHOP scheme in elderly DLBCL patients, and also hope that the program can bring better benefits
to patients with DEL subtypes.

In 2018, the New England Journal first proposed four genetic typings of DLBCL: 1.
MCD: MYD88^L265P and CD79B mutations are present at the same time; N1:NOTCH1 mutation; 3.
BN2: BCL6 fusion and NOTCH2 mutation; 4.
EZB: EZH2 mutation and BCL2 translocation
.
The latest review of the 2021 New England Journal divides DLBCL into 6 types through the lymphGen classification: EZB, ST2, BN2, A53, N1, MCD, of which the cell origin of the EZB and ST2 typing is mostly the germinal center B cell (GCB)-like cell, the cell origin of the A53, N1, MCD classification is mostly activated B cell (ABC)-like cell, and the cell origin of the BN2 classification is heterogeneous
。 Based on the above classifications, patients with DLBCL can select specific drugs in a targeted manner, such as PHOENIX trial data show that DLBCL with MCD and N1 typing can benefit from BTK inhibitors
。 The Guidance-01 clinical study conducted in China compared with the traditional R-CHOP regimen to explore the efficacy of R-CHOP combined with different drug regimens (R-CHOP+X) in patients with various subtypes of DLBCL, and the results showed that the CR rate, 1-year PFS rate and OS rate of R-CHOP+X regimen and R-CHOP regimen were 87% vs 66%, 96% vs 85% and 93% vs 73%, respectively, and the difference was statistically significant.
In addition, the MCD subtype and BN2 subtype benefit significantly from BTK inhibitors
.
Professor Wang Li said that the current subtype classification of DLBCL promotes the development of precision treatment and brings significant benefits to DLBCL patients.
The subtype segmentation of DLBCL is still being further explored and is expected to better guide clinical treatment options
.

Professor Wang Li concluded that DLBCL is a group of heterogeneous and aggressive lymphomas, and 40% of patients are still incurable; A series of improved explorations of R-CHOP regimens have failed to improve the prognosis of DLBCL patient populations, suggesting that treatment management of DLBCL requires more precise patient population
selection.
At present, the LymphGen classification provides a good new idea for the precise treatment of DLBCL, and it is hoped that there will be more and better classification methods in the future to bring treatment benefits
to DLBCL patients.

Professor Wang Li

• Chief Physician, Department of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine

• Ph.
  D.
  , School of Medicine, Shanghai Jiao Tong University, Ph.
  D.
  supervisor

• Postdoctoral Fellow, National Institute of Life and Health, France

• Member of the Lymphoma Committee of the Chinese Anti-Cancer Association

• Young member of the 11th Hematology Branch of the Chinese Medical Association

• He is a member of the Experimental Diagnostics Group of the Chinese Medical Association

• Young member of the Chinese Geriatric Hematology Lymphoma Group

• He has presided over 3 national natural science foundations and 4 provincial-level projects

• The main finishers have won 7 provincial and ministerial awards

• Shanghai Municipal Education Commission plateau peak talents

• Outstanding young medical talents in Shanghai

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