Professors Wu Depei and Zhang Xi: Concentric relay, continuing hope, innovative ADC drug Pola opens up a new pattern suitable for transplanted R/R DLBCL treatment

Every opening of the unknown world has the brave foresight of pioneers; Every journey of sneaking in the dark night, there is a little lamp man fearlessly leading the way
.
The series of reports "Solving the Puzzle Star - Unlocking the New Standard for DLBCL Cure" digs deep into the difficult problems in the treatment of diffuse large B-cell lymphoma (DLBCL) and explores the clinical unmet needs; Combined with clinical research and Chinese and foreign real-world treatment experience, we will jointly explore a new standard
for accurate diagnosis and treatment of DLBCL.
Polatuzumab Vedotin (Pola) is transformed into Pole Star, which is guided by the biggest names in the field to help optimize diagnosis and treatment strategies to improve the survival
of DLBCL patients in China.

Patients with relapsed or refractory (R/R) DLBCL are only about 10% more likely to achieve long-term cure from second-line standard therapy, and up to 60%-70% of patients do not respond
to salvage chemotherapy.
In the era of new drugs, how to optimize the rescue treatment plan before transplantation? How can transplant-appropriate patients with R/R DLBCL reduce recurrence rates after transplantation? What is the role of the innovative drug Pola?

Patients suitable for transplantation of R/R DLBCL have unfinished needs, and the current treatment needs to be optimized

As the pioneer of the era of immunochemotherapy in the field of lymphoma, rituximab (R) has revolutionized DLBCL therapy, and its combination chemotherapy for first-line therapy can cure about 50-60% of patients with new-treatment DLBCL, but there are still about 40%-50% of patients who are refractory or relapse
.
Treatment options for patients with R/R DLBCL are limited and new treatments
are urgently needed.

High-dose salvage chemotherapy sequential autologous hematopoietic stem cell transplantation (HDC-ASCT) has long been a second-line standard of care for patients with first-time relapse of DLBCL and can significantly prolong the survival of patients, while patients with R/R DLBCL have only a 10% chance of obtaining a long-term cure from second-line standard ^therapy1,2
。 Whether pre-transplant salvage therapy achieves complete remission (CR) is the key to affecting the transplant effect, but the CR rate of conventional salvage R chemotherapy regimens is less than 30%, and even in patients suitable for ASCT, about half of patients still have no or poor response to salvage therapy, affecting the development and efficacy of subsequent ^{transplants3,4}
.

Figure 1 CR rate of commonly used salvage chemotherapy regimens

Although many patients successfully receive transplants, they are still at risk of recurrence, with approximately 50% of patients having a recurrence after transplantation with a very poor prognosis and a greater risk of recurrence after transplantation in patients with 3 risk factors (positive PET [i.
e.
, PR], age ≥ 60 years, symptomatic ^relapse5,6
.
Since the PARMA study established ASCT's status as standard treatment, the recurrence rate of ASCT has ^{not improved7} despite scholars exploring multiple strategies aimed at improving
prognosis7.
Patients with DLBCL who recur/progress again after HDC-ASCT will face the dilemma of extremely poor prognosis, with a median OS of less than 10 ^months8 and extremely limited treatment methods, and can only receive salvage treatment such as allo-SCT, enrolled clinical trials, and CAR-T treatment, and new treatment methods
are urgently needed.

* PR: partial remission; OS, total lifetime; Allo-SCT, allogeneic hematopoietic stem cell transplantation; CAR-T, chimeric antigen receptor T cells

Figure 2 Overall median OS in patients with R/R DLBCL progression after ASCT in retrospective studies (left); OS in patients who < 1 year after ASCT versus those who ≥ 1 year after ASCT (right)

CAR-T cell therapy, as one of the treatment options for DLBCL that recurs/progresses again after HDC-ASCT, also has a certain failure rate
.
Nearly half (49%) of patients failed treatment in the first month after CAR-T cell infusion, with early progression with ≥2 extranodal lesions, elevated lactate dehydrogenase (LDH), and tumor burden (TMTV) as key factors for early ^progression9
.
Patients who failed to respond to CD19 CAR-T cell therapy had a poor prognosis, less than 25% were effective for subsequent treatment, and the average OS was only 3.
6 ^months10
.
For patients with R/R DLBCL who have failed CAR-T cell therapy, how to choose subsequent treatment is a difficult problem for clinicians
.

20% to 35% of patients with DLBCL are associated with MYC and BCL2 co-expression, or double-expressing lymphoma (DEL), which is associated with poor prognosis and is a group
of concern in clinical treatment.

Studies have shown that after bridging ASCT by R-ICE salvage therapy, the short-term overall response rate (ORR) and CR rate of DEL patients were similar compared with non-DEL patients, but the long-term progression-free survival (PFS) rate and OS rate were significantly lower (median follow-up for 20 months, 3-year PFS rate: 6% vs 33%, P=0.
044; 3-year OS rate: 39% vs 56%, P=0.
03), suggesting that DEL patients had a poor effect on salvage therapy, Better salvage regimens need to be ^explored11
.

* R-ICE: rituximab, ifosfamide, carboplatin, etoposide

Figure 3 After the R-ICE salvage treatment bridged ASCT, the PFS and OS differences between DEL and non-DEL

With concentric relay, Pola opens the Walk of Fame for transplantation of R/R DLBCs

Achieving CR before transplantation is significant for patient outcomes and can significantly improve patient survival, and pre-transplant salvage therapy is critical
for patients with R/R DLBCL.
In recent years, new drugs have been launched, and Pola, the world's first ADC drug targeting CD79b, has performed well in the key study of GO29365, and its combined protocol Pola-BR has not only increased the optimal CR rate of patients with R/R DLBCL from 20% to 57.
5%, but also significantly improved the optimal overall response rate (BOR) (70.
0% vs 32.
5%), with good ^safety12
。 Although the study included all non-transplantable patients, the high remission rate of Pola-BR suggests that the drug may help transplantable patients achieve deeper remission prior to transplantation, thereby enabling transplantation
.

*Pola-BR: Pola, phendamustine, rituximab

Figure 4 BOR and CR rate results of Pola-BR and BR

Post-event subgroup survival analysis showed a consistent survival benefit
across all clinical and biological subgroups.
In randomized control cohort analyses, Pola-BR also resulted in significant survival benefit for DEL patients, with PFS prolonged by 4 times (7.
03 months vs 1.
40 months) and OS prolonged by nearly 1 times (8.
9 months vs 4.
6 months), and in the future Pola may be a new treatment option for DEL ^patients13
.

Figure 5 PFS and OS results of Pola-BR and BR in DEL and non-DEL patients, respectively

In addition, regardless of the number of treatment lines or refractory status of the patient, Pola-BR can bring good efficacy, most patients in remission can reach the depth of remission to reach CR, of which second-line treatment and relapse patients show excellent CR rate, indicating that compared with frontline treatment to deepen the response, for subsequent transplantation or CAR-T treatment provides a better basis
.
R/R DLBCL that recurs/progresses again after HDC-ASCT, and Pola-BR can still be selected for treatment, is expected to reverse the dilemma of extremely poor prognosis14
.

Figure 6 Remission rate of Pola-BR in multi-line, refractory and non-refractory patients

The real world proves that Pola continues its hope for a suitable transplantation of R/R DLBCs

Based on the high remission rates demonstrated by the Pola protocol in the GO29365 study, Pola has certain advantages
both as a pre-transplant bridging treatment and as a post-transplant maintenance therapy.
Pola protocol bridging transplantation can improve the transplant success rate of patients; Post-transplant maintenance therapy with the Pola regimen is expected to reduce the recurrence rate after transplantation; At the same time, the Pola protocol also offers new treatment options for patients with DLBCL who have progressed/relapsed after transplantation
.

A Greek real-world study suggested that about 40% of patients with R/R DLBCL who were not suitable for ASCT due to insensitivity to front-line therapy could transition to ASCT¹⁵
after Pola-BR treatment.

Figure 7 Results of a Greek real-world study in which patients with ASCT were not suitable for treatment with Pola-BR

In addition to transforming treatment outcomes that are not suitable for transplant patients, the Pola protocol can also improve the success rate
of bridging transplants.
In real-world studies in Germany and China, 30% to 50% of patients successfully transplanted after Pola protocol bridging, compared with the survival benefit of patients who failed to transplant, especially those with PR above ^16,17
after bridging therapy.

Figure 8 Results of a Pola protocol bridging transplantation in a real-world study in Germany and China

Based on Pola's excellent performance in the real world, researchers are exploring the benefits of Pola-BR as a pre-ASCT salvage treatment for transplantable R/R DLBCL patients (NCT04535102).

In addition, the exploration of Pola in B-cell lymphoma as maintenance therapy after CR or ASCT is also under way (NCT04491370
).
It is believed that in the near future, there will be more evidence to support the benefits
of Pola in portable R/R DLBCL.

UK real-world studies confirm that more than 40% of patients with R/R DLBCL can still achieve remission from salvage therapy with the Pola-BR ^regimen18
after CAR-T failure.
Patients who fail CAR-T can still benefit from Pola-BR salvage therapy, which has also been confirmed
by large-scale multi-center studies in the United States.
In a range of single- or multi-drug combination salvage regimens, the remission rate of Pola-BR salvage therapy after CAR-T failure was better than that of other salvage regimens (ORR, 73%; CR rate, 40%) ¹⁹
.

Figure 9 Data on different salvage regimens after CAR-T treatment failure in real-world studies in the United States

Through the experience at home and abroad, it is not difficult to see that the Pola combination program is a salvage treatment option with considerable efficacy for transplantable R/R DLBCL patients, creating conditions for transplantation and further improving the survival
of patients.
At the same time, the Pola combination protocol remains clinically beneficial
in patients with CAR-T failure.
The eagle flies in the sky, the long dragon leaps into the sky, and Pola's performance as a "magic bullet" in the field of targeted therapy is worth looking forward to in the
future.

The First Affiliated Hospital of Soochow University

Professor Wu Depei

HDC-ASCT is the second-line standard of care for patients with the first recurrence of DLBCL, which can significantly prolong the survival time of patients, but only about 10% of patients with R/R DLBCL can achieve long-term remission after transplantation, and the efficacy of salvage chemotherapy is an important influencing factor
.
In order to deepen the remission of salvage therapy and improve the survival of patients with transplantable R/R DLBCL, researchers have carried out many explorations
.
The key study GO29365 confirms that the Pola-BR protocol can significantly improve the CR rate of patients with R/R DLBCL, which means that transplantable patients have a further improvement in transplant success and the likelihood of long-term survival, and that all clinical and biological subgroups have a consistent survival benefit, which is of great significance
for patients with R/R DLBCL who are treated with multiple lines, including DEL patients.
It is expected that Pola will be available as soon as possible to benefit more patients with
transplantable R/R DLBCL.

Army Medical University Shinbashi Hospital

Professor Zhang Xi

Although many patients with R/R DLBCL successfully receive transplants, they are still at risk of recurrence, and many current treatment strategies have failed to improve the recurrence rate
of ASCT.
Based on the high remission rate of the Pola combination scheme in the GO29365 study and many real-world studies, it can not only be used as an ASCT bridging treatment, further improve the success rate of ASCT, reduce the recurrence rate after ASCT, but also serve as an effective rescue treatment after CAR-T treatment failure, bringing more clinical benefits
to patients with R/R DLBCL.
The Pola regimen as a salvage treatment before ASCT and maintenance therapy after ASCT are also being explored, and it is expected that more research results will prove the clinical benefits
of the Pola regimen in the future.

Professor Wu Depei

• Chief physician, professor, doctoral supervisor

• Director of the Department of Hematology, First Affiliated Hospital of Soochow University

• Executive Deputy Director of the National Clinical Medical Research Center for Hematological Diseases

• Deputy Director of Jiangsu Institute of Hematology

• Director of the Institute of Hematopoietic Stem Cell Transplantation of Soochow University

• Member of the 13th National Committee of the Chinese People's Political Consultative Conference

• Chairman of the Hematology Branch of the Chinese Medical Association

• Vice President of the Hematology Branch of the Chinese Medical Doctor Association

• Vice Chairman of the Expert Committee of China Hematopoietic Stem Cell Donor Database

• Editor-in-chief of the Chinese Journal of Hematology

Professor Zhang Xi

• Chief physician, professor, postdoctoral supervisor; Distinguished Professor of Changjiang Scholars

• Director of the Hematology Medical Center of the Army Military Medical University Xinqiao Hospital

• Director of the Blood Disease Center of the People's Liberation Army of the Chinese

• Vice Chairman of China Hematology Specialty Alliance

• Standing Committee Member of Hematology Branch of Chinese Medical Association and Deputy Leader of Hematopoietic Stem Cell Application Group

• He is a member of the Standing Committee of the Hematology Branch of the Chinese Medical Doctor Association

• Vice Chairman of the Hematology and Oncology Committee of the Chinese Anti-Cancer Association

• Standing Committee Member of Experimental Hematology Committee of Chinese Society of Pathophysiology

• Chairman of the 5th and 6th Chongqing Medical Association Hematology Committee

• Presided over 39 national, provincial and ministerial projects; 85 SCI papers, up to 44.
  5; 5 editors/associate editors; The first person to complete the project won 1 second prize of the National Science and Technology Progress Award, 1 first prize of the Chinese Medical Science and Technology Award, and 1 second prize of the Chongqing Municipal Science and Technology Progress Award; Wrote 4 industry guides and co-edited 28 items; Won 32 national invention patents

• He has won the China Cancer Young Scientist Award, the Army's Outstanding Scientific and Technological Personnel Pacesetter, the Chongqing Chief Expert Studio and the Chongqing Municipal Innovation Group Leading Expert, the Chongqing Chief Medical Expert, the Chongqing Municipal Science and Technology Innovation Leading Talent, the Tianfu Scholar Distinguished Expert, the Army's Top Talent, and the First Batch of Army Science and Technology Talents; JHO, Leukemia, Science Bulletin and other editorial board and review experts

References:

1.
Friedberg JW.
Hematology Am Soc Hematol Educ Program 2011; 2011:498–505

2.
Gisselbrecht C, et al.
J Clin Oncol 2010; 28:4184–90

3.
Gisselbrecht C, et al.
J Clin Oncol 2010; 28:4184–90

4.
Crump M, et al.
J Clin Oncol 2014; 32:3490–6

5.
Crump M, et al.
Blood.
2017 Oct 19; 130(16):1800-1808.

6.
Armand P, Welch S, Kim HT, et al.
Br J Haematol.
2013; 160:608–617.

7.
Gisselbrecht C, et al.
J Clin Oncol 2010; 28:4184–90

8.
Nagle SJ, et al.
Am J Hematol.
2013.

9.
Vercellino L, et al.
Blood Adv.
2020; 4(22):5607-5615.

10.
John H Baird , et al.
Blood.
2021 Apr 29; 137(17):2321-2325.

11.
Allen J, et al.
Ther Adv Hematol.
2018 Apr; 9(4):81-87.

12.
Sehn LH, et al.
Blood Adv.
2022 Jan 25; 6(2):533-543

13.
Sehn LH, et al.
J Clin Oncol.
2020 Jan 10; 38(2):155-165.

14.
Sehn LH, et al.
ASH 2020 poster; Abstr P3020

15.
Dimou M, et al.
Hematological oncology vol.
39,3(2021):336-348.

16.
Liebers N, et al.
Blood Adv.
2021 Jul 13; 5(13):2707-2716.

17.
Wang YW, et al.
Ann Hematol.
2022 Feb; 101(2):349-358.

18.
M Northend, et al.
2021 ICML Abstract 174.

19.
Joanna C.
Zurko, et al.
2021ASH Oral 884.

Puzzle Star Solution | Prof.
Zhao Weiying and Prof.
Yanyan Liu: How to break through the R/R DLBCL puzzle? Chinese and foreign experiences unlock new scenarios

Zhu Jun and Professor Guo Ye: Pola's three major offensive tools (1) - MMAE bystander effect lays the foundation for breaking through DLBCL heterogeneity

Puzzle Star Solution | Professor Ma Jun: The ultra-classical effect, the more the level of healing, 1L DLBCL treatment is ushering in a new standard

Puzzle Star Solution | Zhang Huilai, Professor Tao Rong: Pola's three major offensive tools (2) - CD79b innovative target accurate breakthrough, DLBCL's world-first "magic bullet" to lead the new channel

Puzzle Star Solution | Professor Huang Huiqiang: Pola sends charcoal in the snow to help patients with non-transplantable R/R DLBCL rekindle hope

Poke "Read the original article" to see more