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Professor Zhou Daobin and Professor Li Zhiming: Searching for sand, Pola brings new treatment options to elderly patients with frailty/intolerance in DLBCL

 Last Update: 2022-11-01
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 Author: User

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Guide

Every unknown world is opened with pioneers who bravely foresee; Every journey of sneaking through the dark night is fearlessly led by the lighter
.
The series of reports "Solving the Problem - Unlocking the New Standard of DLBCL Cure" digs deep into the problems in the treatment of diffuse large B-cell lymphoma (DLBCL) and explores unmet clinical needs; Combined with clinical research and real-world treatment experience at home and abroad, we jointly explore the new standard
of precision diagnosis and treatment of DLBCL.
Polatuzumab Vedotin (Pola) is transformed into a North Star (Pole Star), which helps optimize diagnosis and treatment strategies under the guidance of leading experts in the field in order to improve the survival of
DLBCL patients in China.

This issue

DLBCL disease is highly heterogeneous, elderly or frail patients often cannot tolerate standard R-CHOP therapy, existing treatment regimens are difficult to balance efficacy and safety, and patients have a poor
prognosis.
After 20 years of unsuccessful R-CHOP+X explorations, can the innovative ADC drug Pola bring a new treatment option of "strong and low toxicity" to elderly frailty/intolerance patients?

Star solution expert

The need is "escalating", and elderly frailty/intolerance patients with DLBCL lack effective treatment options

DLBCL is an aggressive but curable lymphoma that is more common in older people, with a median age at diagnosis of 66 years [^1], and the International Prognostic Index (IPI) lists ≥ 60 years as a poor prognostic factor for DLBCL ^[2].
Older patients with DLBCL have a poor prognosis, with a 55-year survival rate of 79.
4 percent in the United States < 55-year-old patients but</b10>

Fig.
1 Survival of DLBCL patients of different ages

Older patients with DLBCL had higher molecular signature complexity and a significant increase in ABC subtypes

Disease molecular analysis spectroscopy showed that the molecular feature complexity of DLBCL increased with the age of onset ^[4].
In another retrospective analysis, the proportion of more refractory activated B cell (ABC) subtypes of DLBCL increased significantly with age (50-60 years vs.
>80 years: 33 versus 54 percent, P=0.
04) ^[5]
.

Elderly patients with DLBCL have many comorbidities and poor health

Older DLBCL patients tend to have more comorbidities, and statistics show that compared with DLBCL patients aged < 60 years, the proportion of comorbidities in patients aged 60 years ≥ 60 years (20% vs.
61%); If the patient is ≥ 70, the incidence of comorbidities can reach 85 percent ^[6].

In addition, older patients have reduced
tolerance to chemotherapy due to limited bone marrow reserve, altered drug metabolism, physical function, and/or cognitive impairment.
Data show that up to 30 percent of older (≥ 75 years) patients with DLBCL do not receive standard chemoimmunotherapy in first-line therapy due to frailty and comorbidities ^[7].

The treatment and management of elderly patients with DLBCL is challenging

The proportion of elderly patients with DLBCL decreases with age, and up to 25% of elderly people in Europe and the United States have not received any immunochemotherapy after being diagnosed with DLBCL ^[8]; Among people > 80 years of age, 33 percent do not receive treatment ^[9].

Some of the treated patients discontinued treatment due to poor tolerance, which led to poor survival outcomes
.
Studies have shown a 91% increased risk of death in patients treated < 6 cycles compared with 6 cycles of treatment; The risk of death increases by 103 percent in people > 80 years of age ^[8].

Similarly, the prognosis of elderly frail DLBCL patients who cannot tolerate standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and receive low-dose R-mini CHOP regimens does not achieve standard-dose clinical efficacy (Table ^{1) [7,10].}

Table 1 Comparison of efficacy of R-CHOP and R-mini CHOP

In order to improve the treatment outcomes of R-CHOP, researchers have explored several R-CHOP+X regimens or new therapies, including R-CHOP+ lenalidomide, R-mini CHOP+ lenalidomide, R-CHOP+ ibrutinib, rituximab + lenalidomide, but none of these explorations have been successful ^[11-14].

In conclusion, there is a significant unmet need for treatment in older patients with DLBCL who are frail/intolerant and urgently need highly effective and low-toxicity treatment options
.

Taking into account both "efficacy" and "safety", Pola brings a new treatment option to elderly patients with frailty/intolerance of DLBCL

In 2019, the world's first antibody drug conjugate (ADC) targeting CD79b, vepotuzumab (Pola), was born, which is rewriting the global DLBCL treatment landscape and bringing new treatment options
to elderly frailty/intolerance patients.

THE POLARIX STUDY COVERED PEOPLE UP TO 80 YEARS OF AGE, WITH A MORE PRONOUNCED BENEFIT > PATIENTS AGED 60 YEARS

The POLARIX study, the first breakthrough in first-line DLBCL therapy in more than 20 years, showed that the Pola-R-CHP regimen improved the 2-year progression-free survival (PFS) rate by 6.
5% and reduced the relative risk of disease progression, recurrence and death by 27%
compared with the R-CHOP regimen.
It is worth mentioning that the POLARIX study included a broad population of 18 to 80 years old, of which 70 percent of patients > 60 years of age, and the benefit was more obvious > elderly patients aged 60 years, ABC subtypes in older patients, and other patients with high-risk factors (Figure 2) ^[15].

Fig.
2 POLARIX study: Pola-R-CHP compared with R-CHOP's 2-year PFS rate

ANALYSIS OF THE POLARIX STUDY ASIAN SUBGROUP SHOWED A MORE PRONOUNCED BENEFIT IN ASIAN POPULATIONS

And this year's EHA/ASCO update of the POLARIX study Asian subgroup analysis showed that the relative risk of disease progression, recurrence, or death was reduced by 36% (HR 0.
64; 95% CI 0.
40-1.
03) with a median follow-up of 24.
2 months (HR 0.
64; 95% CI 0.
40-1.
03), and the benefit of the Pola-R-CHP regimen was more pronounced in the Asian population (Figure 3) ^[16].
。

Fig.
3 Results of POLARIX study of Asian populations

The introduction of Pola in the Pola-R-CHP regimen does not increase therapeutic toxicity

In terms of safety, the POLARIX study suggests that the introduction of Pola does not increase therapeutic toxicity
.
The overall safety profile of Pola-R-CHP was similar to that of R-CHOP, with no significant difference in the incidence of peripheral neuropathy (PN) at a relatively high incidence (Figure 4), and most PN events were grade 1 or 2, and fewer adverse events resulted in dose reduction in the Pola-R-CHP group, and a higher proportion of patients were able to receive a full course of treatment (Figure ^{5) [15].}
。

Figure 4 POLARIX STUDY: SAFETY SITUATION

Fig.
5 POLARIX study: proportion of full course treatment

Pola innovates the mechanism and takes into account the basis of "efficacy" and "safety"

Pola is one of the few drugs in many studies that has achieved a breakthrough in efficacy without increasing toxicity, which is inseparable
from Pola's innovative drug design.
Pola consists of anti-CD79b monoclonal antibody, payload monomethyl auratin E (MMAE), and cleavable linker vc (Figure 6).

CD79b antibody enables Pola to accurately locate tumor cells, and can lyse linkers to ensure the stable delivery of MMAE to target cells and avoid "accidental injury" of normal cells.
The lysable linker quickly lyses and releases MMAE after reaching the target cells, helping MMAE to exert a bystander effect on neighboring cells through the cell membrane and kill peripheral tumor cells, and the bystander effect is conducive to overcoming the heterogeneity of DLBCL tumors and maximizing the therapeutic effect ^[17].

Figure 6 Drug structure of Pola

Based on an innovative mechanism of action, breakthrough efficacy, and reliable safety profile, the Pola-R-CHP regimen is recommended by the 2022 CSCO Lymphoma Guidelines.

At present, Pola has been approved for relapsed, refractory and treatment-first DLBCL treatment in many countries and regions around the world, and is expected to be approved for marketing in China soon, which not only brings new choices and new hope
for DLBCL elderly frailty/intolerance patients, but also more DLBCL patients.

Star Quotes

Peking Union Medical College Hospital

Professor Daobin Zhou

At present, the standard regimen for first-line treatment of DLBCL is R-CHOP regimen, and the efficacy of R-CHOP in the treatment of elderly patients with DLBCL is also better than other regimens, but due to the many comorbidities and poor chemotherapy tolerance in elderly frail patients, severe cardiac and blood toxicity is obvious after treatment with R-CHOP regimen, which limits the use of R-CHOP in elderly patients
.
The lower dose intensity R-miniCHOP regimen, although the safety is increased, sacrifices efficacy and does not achieve the desired therapeutic effect
.
Therefore, elderly frailty/intolerance patients with DLBCL urgently need a strong and low-toxicity treatment regimen
.
The emergence of Pola can be said to be a "silver bullet", providing a new option
for DLBCL patients with limited treatment options.

Cancer Prevention and Treatment Center, Sun Yat-sen University

Professor Li Zhiming

DLBCL is the most common non-Hodgkin lymphoma in the older population, and its incidence increases with age, whereas treatment options for older patients with DLBCL who are frailty/intolerant are limited
.
The global phase III POLARIX study included 70% of patients >aged 60 years and showed that the Pola-R-CHP regimen benefited more significantly in elderly patients > 60 years of age, and the introduction of Pola did not increase treatment toxicity
.
The latest CSCO lymphoma guidelines also recommend the Pola-R-CHP regimen, which shows the recognition
of Pola's first-line treatment by experts nationwide.
We look forward to the launch of Pola in China, and believe that this powerful and low-toxicity ADC drug can become a reliable weapon for our doctors in the future, bringing more benefits
to DLBCL patients.
"

Prof.
Daobin Zhou

Director of the Department of Hematology, Chief Physician and Doctoral Supervisor of Peking Union Medical College Hospital
Vice President of Hematologist Branch of Chinese Medical Doctor Association
Chairman of Beijing Hematology Branch
Chairman of the Hematology and Immunology Branch of the Chinese Society of Immunology
Member of the Standing Committee of the Hematology Branch of the Chinese Medical Association
Editorial board member of Chinese Journal of Hematology, Basic Medicine and Clinical, Journal of Clinical Hematology and other journals
Main areas of expertise: hematological oncology, hematopoietic stem cell transplantation

Professor Li Zhiming

Professor, Chief Physician, Doctoral Supervisor, Cancer Prevention and Treatment Center, Sun Yat-sen University
Chairman of the Lymphoma Professional Committee of Guangdong Anti-Cancer Association
Standing member of the Youth Council of China Anti-Cancer Association
Deputy Secretary-General and Standing Committee Member of the Anti-Lymphoma Alliance of the Chinese Society of Clinical Oncology (CSCO).
Member of the Standing Committee of the Lymphoma Professional Committee of the Chinese Anti-Cancer Association
Secretary General and Standing Committee Member of the Lymphoma Professional Committee of the Chinese Geriatric Health Care Association
Vice Chairman of the Youth Committee of the Lymphoma Professional Committee of the Chinese Anti-Cancer Association
Vice Chairman of the Youth Committee of the Oncologist Branch of the Chinese Medical Doctor Association
Member of the Standing Committee of the Head and Neck Oncology Expert Committee of the Chinese Society of Clinical Oncology (CSCO).
Member of the Standing Committee of the Lymphoma Branch of the Chinese Medical Education Association
Deputy head of the Central Nervous System Lymphoma Group of the Neuro-Oncology Professional Committee of the Chinese Anti-Cancer Association
Vice Chairman of the Targeted and Individualized Therapy Professional Committee of Guangdong Anti-Cancer Association
Vice Chairman of the Tumor Immunology Professional Committee of Guangdong Society of Integrative Medicine
Vice Chairman of the Fertility Protection Professional Committee of Guangdong Health Management Society
Member of the Standing Committee of the Chemotherapy Professional Committee of Guangdong Anti-Cancer Association
Member of the Standing Committee of the Throat Oncology Professional Committee of Guangdong Clinical Medical Association
Member of the Nasopharyngeal Carcinoma Professional Committee of Guangdong Anti-Cancer Association
Vice Chairman of the Lymphoma Professional Committee of Guangzhou Anti-Cancer Association

References:

1.
Di M,Huntington SF, et al.
2021 Feb; 26(2):120-132.

2.
Zhou Z, et al.
Blood.
2014; 123(6):837-842.

3.
https://seer.
cancer.
gov/statfacts/html/dlbcl.
html (cited September 29, 2022).

4.
Klapper W, et al.
Blood.
2012; 119(8):1882-1887.

5.
Mareschal S, et al.
Haematologica.
2011 Dec; 96(12):1888-90.

6.
Paul A British Journal of Haematology, 2012, 157, 159–170.

7.
Adam J Olszewski, et al.
Blood 2020; 136 (Supplement 1): 43–45.

8.
Vicki A Morrison, et al.
J Geriatr Oncol.
2015 Mar; 6(2):141-52.

9.
Hamlin PA, et al.
Oncologist.
2014; 19(12):1249-1257.

10.
Park S, et al.
Clin Lymphoma Myeloma Leuk.
2019; 19(3):149-156.

11.
J Clin Oncol.
2017; 35(22):2473-2481.

12.
Oberic L, et al.
Blood, 2019, 134: 352.

13.
Younes A, et al.
J Clin Oncol.
2019; 37(15):1285-1295.

14.
Gini G, Tani M, Bassan R, et al.
Blood, 2021, 138: 305.

15.
Tilly H, et al.
Lymphoma.
N Engl J Med.
2022; 386（4）:351-363.

16.
Yuqin Song, et al.
2022ASCO Abstract #7558; 2022EHA P1192.

17.
Burke JM, et al.
Expert Rev Clin Pharmacol.
2020 Oct; 13（10）:1073-1083.

Past Review

Bridge Star Solution | Professor Zhao Weiyi and Professor Liu Yanyan: How to break through the R/R DLBCL problem? Chinese and foreign experience unlocks new solutions

Professor Zhu Jun and Guo Ye: Pola's three major offensive weapons (I) - MMAE bystander effect lays a mechanism foundation for breaking through DLBCL heterogeneity

Bridge Star Solution | Professor Ma Jun: The more classic the effect, the more curative, 1L DLBCL treatment is ushering in a new standard

Bridge Star Solution | Zhang Huilai and Professor Tao Rong: Pola's three major offensive weapons (II) - CD79b innovative target accurately broke the game, DLBCL world's first "magic bullet" to lead a new course

Bridge Star Solution | Professor Huang Huiqiang: Pola helps non-transplantable R/R DLBCL patients rekindle hope

Bridge Star Solution | Professor Wu Depei and Zhang Xi: Relay together, continue hope, and open up a new pattern of treatment suitable for transplanting R/R DLBCL

Bridge Star Solution | Professor Zhang Qingyuan: Pola's three major offensive weapons (3) - can cleave the linker, the guarantee of "strong and low toxicity" of ADC drugs

Bridge Star Solution | Feng Jifeng and Professor Qiu Lugui: Turn the tide, and Pola is the guide for the repeated progress of DLBCL

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