Introduction
Every unknown world opens up, pioneers bravely foresee; every journey of stealth in the dark night, there are those who light the lights to guide the way without fear. " Mixed Questions and Answers - Unlocking the New Standard for DLBCL cure" series of reports, digging deep into the difficult problems in the treatment of diffuse large B-cell lymphoma (DLBCL), and exploring unmet clinical needs; combining clinical research and real-world treatment experiences between China and foreign countries, we jointly explore new standards for accurate diagnosis and treatment of DLBCL. Polatuzumab Vedotin (Pola) is turned into Pole Star. Under the guidance of major experts in the field, it helps optimize diagnosis and treatment strategies in order to improve the survival of Chinese DLBCL patients.
This issue of the question
After the first-line treatment of classic R-CHOP, more than 30% of DLBCL patients face disease progression and mostly relapse within 2 years. Medium and high-risk subtypes are also difficult to benefit from R-CHOP treatment. After a long and tortuous exploration process, many explorations have failed one after another. How can the first-line DLBCL treatment achieve further breakthroughs?
Star solution expert
1L DLBCL demand is not met
Optimization and exploration are difficult to explore
DLBCL is an invasive disease with a poor prognosis compared with other lymphatic malignant tumors. 25 years ago, the emergence of the original rituximab made the R-CHOP protocol * and made milestone progress in the treatment of DLBCL. However, although R-CHOP significantly improves the prognosis of DLBCL patients, it is far from meeting the actual clinical needs.
*R-CHOP: Rituximab combined with cyclophosphamide, doxorubicin, vincristine, prednisone
Looking at the overall population of DLBCL, after R-CHOP first-line treatment, about 40% of the patients will have disease progression, and most of the progression occurs within the first two years after treatment [1]. After the disease progression, the survival outcomes of patients are often poor. 70% of patients die of lymphoma within 2 years of progression, and the 25-year and 10-year overall survival (OS) rates were only 25.0% and 8.6% of , respectively (Figure 1). The life expectancy of patients who did not progress in 2 years after first-line treatment may be close to the normal population [1].
Figure 1 Patients who were initially treated with R-CHOP were treated with OS
after the disease progression, while many subtypes cannot be cured from R-CHOP treatment due to the existence of DLBCL heterogeneity, such as: high IPI score (3 to 5 points), dual-expression lymphoma (DEL), elderly patients who cannot tolerate chemotherapy, etc. [2]. The survival of these patients needs to be improved (Table 1). Faced with these treatment status, DLBCL urgently needs new treatment strategies that can improve survival.
Table 1 Expected results of R-CHOP treatment in high-risk subgroup [2]
In the past 20 years, scholars in the field have explored many optimization programs based on R-CHOP, trying to redefine the first-line treatment standards for DLBCL, including adjusting dose density and intensity, maintaining treatment, and adding new targeted drugs to R-CHOP regimens (such as bortezomib, lenalidomide, ibrutinib, etc.) [3-6] in order to further improve the treatment effect, but these optimization explorations ended in failure (Figure 2).
Figure 2 Optimization exploration based on R-CHOP
took another approach
Pola innovative structure creates a powerful anti-tumor effect
After tortuous and long exploration, the DLBCL field finally ushered in the "magic bullet" CD79b antibody coupling drug (ADC) - Vipotuzumab Vedotin, Pola) . Pola is the first ADC drug approved for the treatment of DLBCL. It is mainly composed of anti-CD79b monoclonal antibody, the powerful cytotoxic drug monomethyl aorstatin E (MMAE), and a lysable linker (Figure 3). is ADC, which combines ideal targets, stable and only site-point cleavage linkers and powerful cytotoxic drug.
Figure 3 Drug structure of Pola
CD79b Target : CD79b is a highly expressed B cell receptor component in the vast majority of patients with malignant lymphoma, and is rarely or not expressed in normal tissues. The existence of CD79b antibody can enable Pola to accurately locate tumor cells, exert the toxic killing effect of MMAE on malignant B cells more efficiently, avoid "incorrect damage" to normal cells, and balance safety while improving the efficacy.
cleavable linker : cleavable linker is the key mechanism for payload release.Compared with non-lysed linkers, lysable linkers can be rapidly lysed after being delivered to target cells to release payloads, which is conducive to improving the anti-tumor efficacy of the drug.
MMAE: Compared with traditional chemotherapy drugs, ADCs often use new and more powerful cytotoxic drugs. The cytotoxic drug methyloritatin E (MMAE) carried by Pola is more easily passed through the cell membrane and can exert a bystander effect on nearby cells, thereby achieving repeated and continuous killing.
POLARIX research strength verification
Pola is expected to become the new standard for DLBCL treatment
With its precise and powerful characteristics, Pola's clinical trial in the front-line DLBCL population - the Global Phase III POLARIX study [7] shows excellent data, confirming that the Pola-R-CHP regimen has brought significant progression-free survival (PFS) benefits to patients with initial treatment DLBCL including high-risk factors while maintaining good safety characteristics.
Safety
Compared with the R-CHOP group, the introduction of Pola-R-CHP group did not impair the overall safety. The safety of the two groups was comparable. The common adverse reactions were peripheral neuropathy, nausea, neutropenia, etc. It is worth noting that the proportion of treatment courses in the Pola-R-CHP group is higher and there are fewer adverse events that cause dose reduction (Figure 4).
Figure 4 POLARIX study safety results
2-year PFS benefit
22-year PFS benefit
Compared with the R-CHOP group, the Pola-R-CHP group significantly improved the 2-year PFS rate by 6.5%, and further reduced the relative risk of disease progression, recurrence or death (76.7% vs 70.2%; HR, 0.73; P=0.02, Figure 5).
Figure 5 PFS
evaluated by POLARIX study investigators In patients with different high-risk factors (such as high IPI scores, elderly DEL, etc.), the Pola-R-CHP group maintained similar or higher PFS benefits, and the PFS rate increased by more than 6.5% in the 2-year period (Figure 6). The increase in the 2-year PFS rate means an improvement in survival outcomes in DLBCL patients and may reduce subsequent rescue treatment. Therefore, this result is of great clinical value and brings new drug choices and hope for cure patients with high-risk factors or high-risk molecular characteristics.
Figure 6 Analysis of the POLARIX study DEL population updated by the EHA and ASCO conference in different high-risk factors also confirmed the PFS advantages of Pola-R-CHP treatment. Further analysis of the effects of DEL and BCL2/MYC expression status on PFS in patients with initial treatment of DLBCL showed that the Pola-R-CHP regimen can reduce the impact of DEL status and BCL2 expression on the adverse prognosis of PFS, and is more conducive to prolonging the patient's PFS[8].
Figure 7 PFS
of DEL+ vs non-DEL population Based on the above outstanding research data, Pola has achieved a "qualitative" breakthrough in the first-line treatment of DLBCL, and its combined treatment plan - Pola-R-CHP is expected to set new treatment standards for front-line DLBCL.
Star explanation quotes
Harbin Hematopathy Oncology Research Institute
Professor Ma Jun
DLBCL, as one of the most common malignant lymphomas, seriously threatens the lives and safety of patients. Global cancer survival monitoring CONCORD-3 data shows that the survival rate of lymphoma patients in China is significantly lower than that in Europe, the United States and Japan. The OS in the five-year period was only 38.3% between 2010 and 2014, and DLBCL, as a highly aggressive subtype, may have a worse survival. After a long treatment exploration, the treatment of DLBCL has gradually evolved and has made great progress, but the long exploration attempts in the past 20 years are still unsatisfactory. What is exciting is that ADC is rising rapidly, and Pola's appearance is expected to break through this shackle.
Global Phase III POLARIX study is the first study to surpass the efficacy of R-CHOP regimen in Phase III clinical trials in all large-scale clinical studies worldwide in the past 20 years. In addition, the Pola-R-CHP regimen also benefited significantly in people with high-risk factors, breaking the deadlock of previous failures in exploration.I believe that as the research continues to be carried out, we can observe evidence of Pola's benefit in long-term survival, bringing more cures to DLBCL patients!
Professor Ma Jun
Chief physician, professor, doctoral supervisor
Director of Harbin Hematopathy Oncology Research Institute
Supervisory Board Supervisory Board of China Society of Clinical Oncology (CSCO)
Vice Chairman of Asian Society of Clinical Oncology
Chinese Society of Clinical Oncology leukemia Chairman of the Expert Committee
Head of the Expert Group of the National Health Commission's Capacity Building and Continuing Education Center Lymphoma Specialist Construction Project
Honorary Consultant of the Nursing Group of the Lymphoma Expert Committee of the Chinese Society of Clinical Oncology
- 979 went to the School of Medicine of the University of Tokyo, Japan and has been committed to the diagnosis and treatment of benign and malignant diseases of the blood system, especially in the industry for the treatment of leukemia and lymphoma. In 1982, the first in vitro pluripotent hematopoietic progenitor cell culture system was established in China to fill the domestic gap. Since 1983, sequential therapy for retinoic acid and arsenic trioxide has been used to treat more than 1,200 cases of acute promyelocytic leukemia, with a 10-year disease-free survival rate of 85%, reaching the international advanced level. He has published more than 200 papers and more than 40 monographs in domestic and foreign journals, and has won 20 national, provincial and municipal science and technology awards. It undertakes 8 national 863 major scientific research projects and 25 provincial and municipal scientific research projects.
References:
.Maurer MJ, Habermann TM, Shi Q, et al. Progression-free survival at 24 months (PFS24) and subsequent outcome for patients with diffuse large B-cell lymphoma (DLBCL) enrolled on randomized clinical trials. Ann Oncol. 2018;29(8):1822-1827. doi:10.1093/annonc/mdy203.- .Smith SM. Treatment of aggressive B-cell lymphomas. Hematol Oncol. 2017;35 Suppl 1:84-87. doi:10.1002/hon.2407.
- .Lue JK, O'Connor OA. A perspective on improving the R-CHOP regimen: from Mega-CHOP to ROBUST R-CHOP, the PHOENIX is yet to rise. Lancet Haematol. 2020;7(11):e838-e850. doi:10.1016/S2352-3026(20)30222-2. .Jeremy S, et al.2021 ASH Oral 523.
.Lamy T, Damaj G, Soubeyran P, et al. R-CHOP 14 with or without radiotherapy in nonbulky limited-stage diffuse large B-cell lymphoma. Blood. 2018;131(2):174-181. doi:10.1182/blood-2017-07-793984..Tilly H, Morschhauser F, Sehn LH, et al. Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma. N Engl J Med. 2022;386(4):351-363. doi:10.1056/NEJMoa2115304..Franck Morschhauser. 2022ASCO Abstract #7517; 2022EHA P1190.Edit: Evelyn
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