Professor Jin Jie and Professor Li Jianyong: Pola may become the preferred future treatment of first-line high-risk DLBCL patients

The prognosis varies greatly between patients with DLBCL
.
Elderly patients with ABC subtype, double blow, double expression, and age > 60 years are difficult to cure from first-line R-CHOP as a high-risk subgroup, and the prognosis is poor, and there is currently no first-line standard treatment for these patients, and there is an urgent need for a better treatment ^regimen1
.

* R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone

Table 1 Expected outcomes of R-CHOP therapy in high-risk subgroups

Simultaneous overexpression of MYC and BCL2 proteins, known as "double expression", occurs in approximately 23% of treatment-naïve DLBCL, is more common in the ABC subtype, and has a significant adverse effect
on the survival prognosis of DLBCL patients.
Patients with dual-expression lymphoma had significantly lower 5-year overall survival (OS) rates (30% vs 75%, P<0.
0001)²
compared with other patients with DLBCL.

Lymphoma with MYC and BCL2 rearrangement is known as "double whammy" and occurs in approximately 5% to 10% of treatment-naïve DLBCL, and these patients may have a worse prognosis after treatment with R-CHOP3,4
.
For patients with double-expression and double-blow lymphoma, standard treatment plans have not been established at home and abroad, and how to improve the survival of these patients has become a thorny problem
.

According to the cell origin, DLBCL is mainly divided into germinal center B cell-like (GCB) and ABC subtypes
.
The ABC subtype is less effective than other types and may be associated with
an increased risk of central nervous system recurrence.
The cell origin of MCD classification in the lymphGen classification is mostly ABC-like cells, which has an unsatisfactory efficacy and poor prognosis for immunochemotherapy5
.

DLBCL has a higher proportion of older patients, with a median age at diagnosis of 66 ^years6
.
Elderly patients with many comorbidities, poor chemotherapy tolerance, high degree of disease invasion, high risk of recurrence, etc.
, can not tolerate high-intensity chemotherapy, and receiving a lower intensity R-CHOP regimen can not achieve the expected therapeutic ^effect7-9, and their adverse prognostic outcomes may be related to baseline health status and advanced toxicity of chemotherapy ^10-11
。 Therefore, the treatment of elderly patients with DLBCL needs to consider many factors such as treatment toxicity, treatment duration, and whether the patient can tolerate it to achieve the best benefit-risk ratio, and the current treatment options are ^limited12
.

It can be seen that R-CHOP has unmet clinical needs in high-risk patients such as ABC subtype, double blow, double expression, and elderly patients, and the cost of disease treatment will increase significantly with the increase of treatment line (especially when receiving new therapies in the later line), a retrospective cohort study using IQVIA administrative claims ^data13 With an average follow-up of 45 months, after first-line R-CHOP therapy, the cost of treatment for patients who have progressed and received transplantation and/or CAR-T therapy is approximately 10 times
that of progression-free patients.
Therefore, how to optimize the first-line treatment of high-risk patients and reduce the recurrence of progression is the focus
of clinical treatment.

In recent years, researchers have continued to explore new treatment options to improve the treatment outcomes of high-risk patients with DLBCL, among which ADC drugs, known as "magic bullets", have attracted much attention
in the field of DLBCL.

As the world's first ADC drug targeting CD79b, Pola's pivotal research POLARIX study is the first study to show the efficacy of surpassing R-CHOP in all phase III double-blind, randomized controlled trials in the world in more than two decades, and the Pola-R-CHP program has also "saved face"
for years of R-CHOP+X exploration.
The study confirmed that the Pola-R-CHP regimen significantly improved 2-year progression-free survival (PFS) (76.
7% vs 70.
2%, P = 0.
02), reduced the relative risk of disease progression, recurrence, or death by 27%¹⁴, and benefited more significantly in Asian ^{populations15}
。 In terms of safety, the overall safety profile of the two groups was comparable, and the proportion of patients in the Pola-R-CHP group who completed the full course of treatment was higher, and there were fewer adverse events
due to dose reduction or treatment interruption.

* Pola-R-CHP: vipotuzumab in combination with rituximab, cyclophosphamide, doxorubicin, prednisone

Although baseline showed a higher proportion of patients with double-hit lymphoma in the Pola-R-CHP group, the Pola combination regimen performed quite well
.
In the population with other high-risk factors, Pola-R-CHP regimen also showed significant improvement in PFS, and the 2-year PFS rate in high-risk patients such as ABC subtype, double expression, and elderly patients increased by more than 6.
5%, which improved the treatment outcome of these patients and is expected to reduce subsequent salvage treatment
.

Fig.
1 Two-year PFS rate increment for patients with different risk factors

Pola-R-CHP regimen can also reduce the effect of dual expression status and BCL2 expression on the poor prognosis of PFS, which has important clinical significance in patients with dual-expression lymphoma16
。 In the R-CHOP group, both univariate and multivariate analysis showed that patients with BCL2 expression had lower PFS than those without BCL2 expression (univariate HR 1.
96, 95% CI 1.
31-2.
93; multivariate HR 1.
74, 95% CI 1.
14-2.
66), however, no prognostic difference was detected in the Pola-R-CHP group, and no prognostic effect of MYC expression versus no expression was detected in either group
.

Fig.
2 PFS results of both groups of double-expressed and non-dual-expressed patients

Although there was no significant difference in complete response rates between the two groups in the POLARIX study, the Pola-R-CHP group prolonged event-free survival (EFS) compared with the R-CHOP group (2-year EFS rate 75.
6 versus 69.
4%, P = 0.
02), and fewer patients required subsequent anti-lymphoma therapy (23 versus 30 percent), suggested The early benefit of the Pola combination regimen for first-line treatment of DLBCL may help improve subsequent treatment outcomes and reduce the burden of treatment in ^{patients17,18}
.

Fig.
3 Comparison of the two groups receiving follow-up anti-tumor therapy

Pola's outstanding performance in POLARIX research is closely related to
its unique structure and innovative mechanism of action.
Pola is mainly composed of anti-CD79b monoclonal antibody, powerful cytotoxic drug monomethylorestatin E (MMAE), and cleavage linker, which has both targeted therapeutic selectivity and chemotherapy toxicity, and MMAE can not only kill cells expressing target antigens, but also exert a bystander effect on neighboring tumor cells, regardless of the expression of target antigens in neighboring cells, it can be repeated and continuously ^killed19,20
.

Figure 4 Bystander effect

Based on Pola's innovative mechanism and the bright data in the POLARIX study, the therapeutic potential of Pola in DLBCL is undoubted, and its combination therapy Pola-R-CHP is expected to bring more cures
to first-line DLBCL including ABC subtypes, double expression, double blow, elderly patients and other high-risk groups.

The First Affiliated Hospital of Zhejiang University School of Medicine

Professor Jin Jie

Although the advent of rituximab has greatly improved the survival prognosis of DLBCL patients, there are still some high-risk subgroups that have poor efficacy and poor prognosis for first-line treatment of R-CHOP
, such as double-expression, double-hit lymphoma, and elderly patients.
At present, NCCN and CSCO guidelines still recommend R-CHOP regimens for first-line treatment of elderly patients, but in clinical practice, we have found that elderly patients are often accompanied by comorbidities, most of them cannot tolerate high-dose chemotherapy regimens, and the efficacy of patients after drug reduction will be greatly reduced, and it is difficult to achieve both high efficiency and low toxicity
.
In recent years, the emergence of ADC drugs such as Pola has made it possible to treat elderly patients with DLBCL with
high efficiency and low toxicity.
We look forward to more research data on Pola in this segment of high-risk patients to demonstrate its therapeutic potential
in first-line DLBCL.

Jiangsu Provincial People's Hospital

Professor Li Jianyong

In addition to efficacy and safety, patients' willingness to treat and affordability of treatment costs are also important considerations for clinicians, and the economic burden of treatment is closely related
to patients' quality of life and happiness.
At present, 40% to 50% of DLBCL patients still have relapse/progression after first-line R-CHOP treatment, especially high-risk patients are at high risk of recurrence
progression.
For first-line treatment of high-risk patients, we often consider choosing a regimen that is affordable, tolerable, and brings the greatest benefit and lowest risk, and from the current data, the addition of Pola is still very promising
.
It is hoped that more ADC drugs such as Pola will be successfully developed in the future, providing high-efficiency and low-toxicity "magic bullets"
for DLBCL and even the entire lymphoma field.

Professor Jin Jie

• Doctor of Medicine, Professor, Doctoral Supervisor

• Director of the Department of Hematology, First Affiliated Hospital of Zhejiang University School of Medicine, discipline leader

• Enjoy the special government allowance of the State Council and the advanced worker of the national health system

• Director of the Key Laboratory of Hematology and Oncology (Diagnosis and Treatment) of Zhejiang University

• Director of Zhejiang Hematology Clinical Research Center

• He is the leader of the hematology department of Zhejiang First Hospital, a key clinical discipline of the National Health Commission

• Director of the International Scientific and Technological Cooperation Base for Research and Research of Malignant Blood Diseases

• Zhejiang Province Key Innovation Team - leader of basic and clinical research innovation team of leukemia

• Zhejiang Provincial Health Commission focuses on supporting disciplines and hematology leaders

• Chairperson of the Hematology Committee of the Chinese Association of Women Physicians

• Former Chairman of the Hematology Committee of the Anti-Cancer Association

• Vice Chairman of CSCO China Anti-Leukemia Alliance

• Deputy leader of the Red Blood Cell Disease Group of the Hematology Society of the Chinese Medical Association

• Member of the Standing Committee of the Chinese Society of Experimental Hematology and the Hematology Society of the Medical Doctor Association

• Vice Chairman of the Integrative Hematology Society of the Chinese Medical Doctor Association

• Member of the Standing Committee of CSCO China Anti-Lymphoma Alliance

• Member of the Standing Committee of the Cross-Strait Hematology Society and the China Health Promotion Association

• Member of Hematology Society of Chinese Medical Association

• Former Chairman of Hematology Branch of Zhejiang Medical Association

• President of Hematology Branch of Zhejiang Medical Association

• He has published 261 academic papers in SCI-indexed journals such as Lancet Oncology, Cell, and Leukemia, and won 1 second prize of National Science and Technology Progress Award and 9 prizes of Zhejiang Province Science and Technology Progress Award 1-3 as the first winner

Professor Li Jianyong

• Jiangsu Provincial People's Hospital Class A Distinguished Professor, Director of Hematology, Doctoral Supervisor, Postdoctoral Cooperative Supervisor

• Member of the Standing Committee of the Hematology Branch of the Chinese Medical Association and leader of the Lymphocyte Disease Group

• Chairman of the 4th Hematology and Oncology Professional Committee of the Chinese Anti-Cancer Association

• Vice Chairman of the Lymphoma Quality Control Expert Committee of the National Cancer Quality Control Center

• Leader of the Chinese Working Group on Chronic Lymphocytic Leukemia

• Vice Chairman of the CSCO Lymphoma Expert Committee

• Deputy leader of the lymphoma group of the Oncology Branch of the Chinese Medical Association

• Chairman of Hematology Branch of Jiangsu Geriatric Association

• President-elect of Hematologist Branch of Jiangsu Medical Association

• Chairman of the 7th Hematology Branch of Jiangsu Medical Association

• Chairman of Hematology Branch of Nanjing Medical Association

• Vice Chairman of China Hematology Specialty Alliance

• Vice Chairman of Hematology Branch of Chinese Hospital Association

References:

1.
Smith SM.
Hematol Oncol.
2017; 35 Suppl 1:84-87.

2.
Hwang J, et al.
Cancers (Basel).
2021 Jul 5; 13(13):3369.

3.
Petrich AM, et al.
Blood.
2014 Oct 9; 124(15):2354-61.

4.
Oki Y, et al.
Br J Haematol.
2014 Sep; 166(6):891-901.

5.
Schmitz R,et al.
N Engl J Med.
2018 Apr 12; 378(15):1396-1407.

6.
Di M,Huntington SF, et al.
2021 Feb; 26(2):120-132.

7.
LI Qiaobao, ZOU Liqun.
International Journal of Oncology,2021,48(5):317-320.

8.
Zhou Z, et al.
Blood.
2014; 123(6):837-842.

9.
Alden A Moccia,Catherine Thieblemont.
Eur J Intern Med.
2018 Dec; 58:14-21.

10.
https://seer.
cancer.
gov/statfacts/html/dlbcl.
html

11.
Shewade A, et al.
Blood, 2020, 136: 6-8.

12.
Vicki A Morrison, et al.
.
J Geriatr Oncol.
2015 Mar; 6(2):141-52.

13.
Rongrong Wang, et al.
ASH2021 P-3002.

14.
Tilly H, et al.
N Engl J Med.
2022; 386(4):351-363.

15.
Yuqin Song, et al.
2022ASCO Abstract #7558; 2022EHA P1192.

16.
Franck Morschhauser.
2022ASCO Abstract #7517; 2022EHA P1190

17.
Tilly H, et al.
2021 ASH abstract LBA-1.

18.
Kambhampati S, et al.
Blood.
2022 Jun 14:blood.
2022016624.

19.
Jin Y, et al.
Pharmacol Ther.
2022; 229:107917.

20.
Fu Z, et al.
Signal Transduct Target Ther.
2022; 7(1):93.
Published 2022 Mar 22.

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