Mi Qi Xing Xie Feng Jifeng and Professor Qiu Lugui: Turn the tide, and Pola will guide the repeated progress of DLBCL

Patients with DLBCL progress repeatedly, and there is a lack of better options for posterior line therapy

Over the years, the classical R-CHOP regimen has significantly improved the response rate and survival of DLBCL patients, but there are still treatment challenges with high relapse or refractory rates, which is closely related to the clinical failure of approximately 73% of patients with R/R DLBCL to achieve remission with second- and ^{later-line therapy1}
.
The poor clinical prognosis and limited treatment options available in these patients, especially in patients with recurrent DLBCL, have very high heterogeneity of late-line treatment regimens, so there is an urgent need for new and effective treatment options to improve patient survival
.

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

There is currently no recognized standard treatment plan for patients with DLBCL who relapse and progress after second-line treatment, and the need for more effective treatment has not been met, whether it is immunochemotherapy, hematopoietic stem cell transplantation (HSCT), CAR-T therapy, most patients quickly enter the next recurrence or refractory treatment, and nearly one-third (31.
0%) of patients need to receive back-line therapy in the short term (median time 5.
8 months).
^2,3
。

The efficacy of immunochemotherapy regimens as first-line standard therapy in the latter line has been very limited, with median overall survival (OS) of only 7.
7 months and 4.
4 months in patients receiving third-line and fourth-line immunochemotherapy, respectively, and only 6.
3% to 9.
4% of patients achieving complete remission (CR), and the survival prognosis is worrying, and more effective treatment options are urgently needed to improve this ^situation4
。

Autologous hematopoietic stem cell transplantation (ASCT) is the second-line standard of care for patients with R/R DLBC, although approximately 50% of patients still relapse after ASCT clinically, and patients with three risk factors (PET-positive [i.
e.
, PR], age ≥ 60 years, symptomatic recurrence) are at greater risk of post-transplantation5,6
.
Patients with DLBCL who relapse/progress after ASCT will face a very poor prognosis, with a median OS of less than 10 ^months7 and extremely limited back-line treatment methods, and can only receive salvage treatments such as allo-HSCT, enrollment in clinical trials, and CAR-T therapy, and new treatments
are urgently needed.

* PR: Partial remission; allo-HSCT, allogeneic hematopoietic stem cell transplantation; CAR-T, chimeric antigen receptor T cells

Fig.
1 Overall median OS of patients with R/R DLBCL who progressed after ASCT in a retrospective study (left); OS in patients who progressed < 1 year after ASCT versus OS in patients who progressed ≥ 1 year after ASCT (right)

CAR-T cell therapy, as one of the treatment options for relapse/progression of DLBCL after ASCT, also has a certain treatment failure rate
.
Patients who fail after CD19 CAR-T cell therapy have a poor prognosis, with less than 25% responding to subsequent treatment and an average OS of only 3.
6 ^months8
.
For patients with R/R DLBCL who have failed CAR-T cell therapy, how to choose follow-up treatment is a difficult problem
for clinicians.

Although new drugs and therapies have been emerging in recent years, their accessibility in China is poor, and new drugs such as Tafasitamab and Loncastuximab tesirine have not been approved for marketing in China, while CAR-T therapy has been approved for marketing, but the price is so high that most patients cannot afford it, and as the number of treatment lines increases, the higher the cumulative treatment cost for patients, ^{the heavier} the economic
burden9.
How to meet the needs of patients with repeated progress for innovative treatments and seek more accessible and effective drugs has become the direction of
many researchers.

Turning the tide, Pola provides guidance to patients with recurrent progressive R/R DLBCL

In recent years, in order to meet the treatment needs of patients with R/R DLBC, various new drugs and therapies have been approved for marketing
.
Pola, the world's first ADC drug targeting CD79b, was accelerated by the US FDA for the treatment
of R/R DLBCL in 2019 due to its excellent performance in the GO29365 study.
In this pivotal study, the Pola-BR regimen not only increased the optimal CR rate of patients with R/R DLBCL from 20% to 57.
5%, but also significantly increased BOR (70.
0% vs 32.
5%) and reduced the risk of death by 58%¹⁰
.

*Pola-BR: Pola, bendamustine, rituximab; BOR, the best overall response rate

Fig.
2 BOR and CR rate results of Poola-BR and BR

Post-hoc subgroup survival analyses showed consistent survival benefits
across all clinical and biological subgroups.
In randomized controlled cohort analysis, Pola-BR also brought considerable efficacy in the later line of R/R DLBC, with BOR and CR rates of 50.
0% and 42.
2%, respectively, which means that patients with more previous treatment lines can still benefit from Pola-BR, and most patients in response can achieve CR depth, promising longer ^survival11
。 R/R DLLBCL THAT RELAPSES/PROGRESSES AFTER ASCT CAN STILL BE TREATED WITH POLA-BR OR CAN REVERSE THE VERY POOR PROGNOSIS
.

Fig.
3 Results of optimal response rate of Pola-BR in patients treated with multiple lines

Breaking the treatment trap, Pola has demonstrated therapeutic potential in a number of real-world studies around the world

Since Pola was approved for the treatment of DLBCL, a large amount of real-world research data
has been accumulated in various countries and regions around the world.
As an extension of clinical research data, Pola has also demonstrated tangible efficacy in real-world studies, providing new treatment options
for patients with recurrent DLBCL.

An Israeli real-world study retrospectively analyzed the efficacy of the Pola regimen in R/R DLBC previously treated with second-line or more treatments, confirming that the real-world benefit of the Pola regimen was comparable to that of the GO29365 study (ORR, 61%; CR rate, 40%)¹²
.

The high response rate of the Pola regimen has also been demonstrated in real-world studies in China, and in patients with multi-line recurrence, the Pola regimen still achieves an ORR of 52.
5% in 70% of high-risk patients with R-IPI≥3, with a CR rate of 25%¹³
.
Compared with the CR rate of less than 10% in patients with multi-line relapse, the therapeutic potential of the Pola regimen is self-evident
.

*R-IPI, revised international prognosis index; ORR, overall response rate

By improving patient remission rates, Pola-BR is expected to lead to improved survival, and may be an ideal treatment option for patients with DLBCL with multi-line relapse.

Patients in the study had a median OS of 8.
5 months and an estimated 1-year OS rate of 35.
9%, with patients achieving CR/PR after Pola achieving a longer survival and a median progression-free survival (PFS) of 30.
2 ^months13
.

Fig.
4 PFS results of multi-line relapsed patients who achieved remission after treatment with Pola regimen

For patients with DLBCL who relapse/progress after ASCT, the Pola regimen is still an option to bridge allo-HSCT.

In a real-world study in Germany, 50% of patients successfully underwent allo-HSCT after bridging with the Pola regimen, promising additional survival ^benefits14
.
At the same time, it was found that the response rate of the Pola regimen did not decrease with the increase of the patient's treatment line (second-line ≥versus third-line: 54.
5% versus 43.
8%; P = 0.
6), indicating that Pola maintains high therapeutic activity in patients with recurrent ^{progression14}
.

Fig.
5 Results of the allo-HSCT bridging scheme in a real-world study in Germany

A real-world UK study confirmed that more than 40% of patients with R/R DLBCL who have failed CAR-T can achieve relief from salvage therapy with the Pola-BR ^regimen15
.
Patients with CAR-T failure can still benefit from salvage therapy with Pola-BR, which has also been confirmed
by a large-scale multicenter study in the United States.
In a range of single- or multi-agent salvage regimens, Pola-BR salvage therapy after CAR-T failure had a better response rate than other salvage regimens (ORR, 73%; CR rate, 40%)¹⁶
.

Fig.
6 Data of different salvage treatment regimens after CAR-T treatment failure in real-world studies in the United States

Both clinical trials and real-world explorations have proven that the Pola regimen is a promising treatment option for patients with recurrent progression of DLBCL, especially in the real-world world where patients
are worse off and have more previous treatment lines.
Pola, a rising star, provides new, measurable and accessible treatment options
for patients with recurrent progression who are confused about the road ahead.