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The 24th National Conference on Clinical Oncology and the 2021 CSCO Academic Annual Conference will be held on September 25-29, 2021.
At this conference, Professor Cai Qingqing from the Affiliated Tumor Hospital of Sun Yat-sen University presented "Progress in the Treatment of Diffuse Large B-Cell Lymphoma" Reported on the subject
.
On this occasion, Yimaitong invited Professor Cai Qingqing to accept an interview to share the progress of the treatment of diffuse large B-cell lymphoma (DLBCL)
.
Yimaitong: First of all, could you please introduce the current status of DLBCL treatment? What are the difficulties in the treatment of DLBCL? Professor Qingqing Cai DLBCL is a group of heterogeneous diseases.
The current R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) as the first-line standard treatment for DLBCL still cannot be shaken.
However, about 15% of patients receiving R-CHOP regimen are initially refractory, another 20%-25% of patients relapse after initial remission (mostly within 2 years), and about 73% of patients relapse after first-line treatment /Refractory patients do not respond to follow-up salvage treatment or cannot receive autologous hematopoietic stem cell transplantation (ASCT), so relapsed/refractory patients are currently the main difficulty in the treatment of DLBCL
.
In addition, for special populations, such as elderly patients who are frail or have high-risk factors (double/triple hits, CD5 positive, etc.
), there are problems with poor chemotherapy tolerance or insufficient first-line standard treatment intensity
.
Therefore, to further optimize the first-line treatment and develop high-efficiency and low-toxicity treatment programs for these patients is also the focus of researchers
.
Yimaitong: At present, many studies are still exploring how to further improve the efficacy of R-CHOP in patients with DLBCL.
Could you please introduce any progress that deserves attention in related studies? One of the ideas of Professor Qingqing Cai to improve the efficacy of the R-CHOP program is to add new targeted drugs to the R-CHOP program
.
Currently available clinically targeted drugs include BTK inhibitor ibrutinib, immunomodulator lenalidomide and histone deacetylase inhibitor chidamide
.
At the ICML conference this year, the results of a precision individualized treatment study of DLBCL guided by gene stratification by Professor Zhao Weilai’s team from Shanghai Ruijin Hospital was reported.
-After CHOP treatment, patients were divided into six genetic subtypes based on 18 gene mutations, BCL-2 translocation and BCL-6 fusion: MCD, BN2, N1, EZB, TP53 and NOS
.
MCD and BN2 patients receive ibrutinib, N1 and NOS patients receive lenalidomide, EZB patients receive chidamide, and TP53 patients receive the demethylating drug decitabine, followed by the standard R-CHOP regimen Treatment
.
A total of 128 patients were enrolled in the study, each of 64 patients.
The complete response (CR) rate and total response rate (ORR) of the R-CHOP-X group were 85% and 91%, respectively, while the R-CHOP group was 65 % And 72%
.
With a median follow-up of 14.
1 months, the 1-year progression-free survival (PFS) rate and overall survival (OS) rate of patients in the R-CHOP-X group were 96% and 98%, respectively, and those in the R-CHOP group were 79% and 94, respectively %
.
The research results show that the R-CHOP-X program guided by genotype is expected to improve the efficacy of DLBCL patients
.
In fact, the traditional International Prognostic Index (IPI) score is not enough to meet the current clinical needs in terms of prognostic stratification and guiding treatment.
This topic has also recently been published in the British Journal of Cancer and British Journal of Haematology.
Related research was published on the paper, and the Nomogram prognostic model and immune score prognostic model based on clinicopathological factors and transcriptome sequencing were constructed.
Its prognostic prediction performance is significantly better than the traditional IPI score, which has the value of clinical application
.
In addition, the antibody-drug conjugate Polatuzumab vedotin (Pola), which targets the B cell receptor CD79b, is effective in treating relapsed and refractory (R/R) DLBCL.
Past Phase Ib/II studies suggest that Pola and R-CHP regimens (Rituximab, cyclophosphamide, doxorubicin, and prednisone) The ORR of the combined treatment of newly-treated DLBCL patients was 89%, and the 2-year PFS rate was 83%
.
In view of this, a multi-center phase III randomized POLARIX study of Pola+R-CHP vs R-CHOP for the treatment of newly treated DLBCL patients was carried out in 2017.
The study is expected to end in 2026.
The results of the study are expected to rewrite the R-CHOP program for nearly 20 years.
First-line standard treatment status
.
Yimaitong: CAR-T therapy is currently a hot spot therapy in the treatment of lymphoma.
Could you please introduce what breakthroughs have been made by CAR-T therapy in R/R DLBCL? Prof.
Qingqing Cai’s JULIET study and TRANSCENT study confirmed the effectiveness and safety of tisa-cel and liso-cel in the treatment of R/R DLBCL.
These two CAR-T cells were also approved by the U.
S.
Food and Drug Administration (FDA) in 2017.
For the treatment of R/R DLBCL
.
The current CAR-T targets are mainly CD19, and most of them are single targets.
However, the lack of targeted CD19 epitopes may lead to the failure of CAR-T treatment.
Therefore, the current research on CAR-T mainly focuses on dual targets or multiple targets.
Targeted CAR-T treatment development
.
For example, the domestic Prof.
Han Weidong’s team recently published a phase I/II study in the top journal blood and leukemia, using CAR-T cells targeting CD19 and CD20 to treat R/RB cell lymphoma, with an ORR of 78% and a median PFS of 27.
6.
Month
.
In addition, last year’s ASCO and ESMO meeting reported the results of a phase I/II study of CD19/CD22 dual-targeting CAR-T cells (AUTO3) combined with PD-1 monoclonal antibody for the treatment of R/R DLBCL, using different doses of AUTO3 alone or in combination The ORR of pembrolizumab-treated patients was 68%, the CR rate was 54%, and the duration of complete remission was long.
At a median follow-up of 6 months, 93% of patients still maintained CR
.
The above two dual-target CAR-T treatments have relatively small side effects, and the cytokine release syndrome (CRS) is mostly grade 1-2, and the incidence of neurotoxicity is low
.
The above research results show that dual-target CAR-T therapy is better than previous single-target therapy, which further enhances the therapeutic effect of CAR-T in R/R DLBCL patients
.
Yimaitong: Could you please share with me what other new drugs or treatments are worth paying attention to in the field of DLBCL treatment? Professor Qingqing Cai aimed at DLBCL patients who are not suitable for transplantation.
Our research group is also currently carrying out a phase II clinical study of Cedaraniline combined with R-Gemox (CR-Gemox) to save the treatment of sequential Cedaraniline maintenance therapy.
The preliminary research results are also Reported at the 2020 ASH Annual Meeting
.
The results of the study showed that the CR-Gemox regimen in the treatment of R/R DLBCL patients had an ORR of 60.
9%, a CR rate of 34.
8%, and a median PFS of 7.
4 months.
It also showed a good therapeutic effect in patients with dual expression, ORR and CR The rates were 66.
6% and 33.
3%, respectively, and the overall toxicity was controllable.
The main grade 3-4 adverse reaction was thrombocytopenia
.
The study is still ongoing, and 39 patients have been enrolled
.
In terms of new targeted drugs, in addition to drugs that target CD19 and CD79b, new therapeutic drugs for other targets have also been developed and put into use
.
This year’s EHA conference reported the results of a phase II study of the CD37 antibody conjugate drug Naratuximab emtansine (Nara) in the treatment of R/RB cell lymphoma
.
CD37 is a lymphocyte surface marker, and B-cell non-Hodgkin's lymphoma (B-NHL) including DLBCL highly expresses CD37
.
Preclinical studies suggest that Nara and rituximab have a synergistic anti-tumor effect on B-NHL
.
Phase I clinical studies have also confirmed the safety and effectiveness of Nara monotherapy in DLBCL
.
A total of 100 patients were enrolled in this phase II study, including 80 DLBCL and 20 other NHL
.
Among 76 patients with evaluable R/R DLBCL, the ORR was 44.
7% and the CR rate was 31.
6%
.
With a median follow-up of 15 months, the median duration of response (DOR) was not reached, 82% of patients had adverse events ≥ grade 3, mainly hematological toxicity, and 8 patients were discontinued due to adverse events
.
The above results preliminarily confirmed the efficacy and safety of Nara in R/R DLBCL, and CD37 will also become a new target for R/R/DLBCL treatment
.
Professor Cai Qingqing, Chief Physician, PhD Supervisor, Deputy Director of the Department of Internal Medicine, Sun Yat-sen University Tumor Hospital, Head of the Lymphoma Group of the Oncology Branch of the Guangdong Medical Association, Deputy Chairman of the Youth Committee of the Oncology Branch of the Chinese Medical Association, Lymphoma Major, China Medical Education Association Deputy Chairman of the Committee, Deputy Chairman of the Lymphoma Professional Committee of the Guangdong Provincial Association of Women Physicians, Deputy Chairman of the Guangdong Anti-Cancer Association, Hematological Oncology Committee, Deputy Chairman of the Youth Committee, Beijing Cancer Prevention and Treatment Society, Deputy Chairman of the Lymphoma Immunization Committee, and published 79 SCI articles , Published 19 SCI papers in Blood, Leukemia, CCR, etc.
as a (co-) corresponding author in the past 5 years, presided over a number of national natural funds and provincial funds stamped "Read the original text", we make progress together
At this conference, Professor Cai Qingqing from the Affiliated Tumor Hospital of Sun Yat-sen University presented "Progress in the Treatment of Diffuse Large B-Cell Lymphoma" Reported on the subject
.
On this occasion, Yimaitong invited Professor Cai Qingqing to accept an interview to share the progress of the treatment of diffuse large B-cell lymphoma (DLBCL)
.
Yimaitong: First of all, could you please introduce the current status of DLBCL treatment? What are the difficulties in the treatment of DLBCL? Professor Qingqing Cai DLBCL is a group of heterogeneous diseases.
The current R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) as the first-line standard treatment for DLBCL still cannot be shaken.
However, about 15% of patients receiving R-CHOP regimen are initially refractory, another 20%-25% of patients relapse after initial remission (mostly within 2 years), and about 73% of patients relapse after first-line treatment /Refractory patients do not respond to follow-up salvage treatment or cannot receive autologous hematopoietic stem cell transplantation (ASCT), so relapsed/refractory patients are currently the main difficulty in the treatment of DLBCL
.
In addition, for special populations, such as elderly patients who are frail or have high-risk factors (double/triple hits, CD5 positive, etc.
), there are problems with poor chemotherapy tolerance or insufficient first-line standard treatment intensity
.
Therefore, to further optimize the first-line treatment and develop high-efficiency and low-toxicity treatment programs for these patients is also the focus of researchers
.
Yimaitong: At present, many studies are still exploring how to further improve the efficacy of R-CHOP in patients with DLBCL.
Could you please introduce any progress that deserves attention in related studies? One of the ideas of Professor Qingqing Cai to improve the efficacy of the R-CHOP program is to add new targeted drugs to the R-CHOP program
.
Currently available clinically targeted drugs include BTK inhibitor ibrutinib, immunomodulator lenalidomide and histone deacetylase inhibitor chidamide
.
At the ICML conference this year, the results of a precision individualized treatment study of DLBCL guided by gene stratification by Professor Zhao Weilai’s team from Shanghai Ruijin Hospital was reported.
-After CHOP treatment, patients were divided into six genetic subtypes based on 18 gene mutations, BCL-2 translocation and BCL-6 fusion: MCD, BN2, N1, EZB, TP53 and NOS
.
MCD and BN2 patients receive ibrutinib, N1 and NOS patients receive lenalidomide, EZB patients receive chidamide, and TP53 patients receive the demethylating drug decitabine, followed by the standard R-CHOP regimen Treatment
.
A total of 128 patients were enrolled in the study, each of 64 patients.
The complete response (CR) rate and total response rate (ORR) of the R-CHOP-X group were 85% and 91%, respectively, while the R-CHOP group was 65 % And 72%
.
With a median follow-up of 14.
1 months, the 1-year progression-free survival (PFS) rate and overall survival (OS) rate of patients in the R-CHOP-X group were 96% and 98%, respectively, and those in the R-CHOP group were 79% and 94, respectively %
.
The research results show that the R-CHOP-X program guided by genotype is expected to improve the efficacy of DLBCL patients
.
In fact, the traditional International Prognostic Index (IPI) score is not enough to meet the current clinical needs in terms of prognostic stratification and guiding treatment.
This topic has also recently been published in the British Journal of Cancer and British Journal of Haematology.
Related research was published on the paper, and the Nomogram prognostic model and immune score prognostic model based on clinicopathological factors and transcriptome sequencing were constructed.
Its prognostic prediction performance is significantly better than the traditional IPI score, which has the value of clinical application
.
In addition, the antibody-drug conjugate Polatuzumab vedotin (Pola), which targets the B cell receptor CD79b, is effective in treating relapsed and refractory (R/R) DLBCL.
Past Phase Ib/II studies suggest that Pola and R-CHP regimens (Rituximab, cyclophosphamide, doxorubicin, and prednisone) The ORR of the combined treatment of newly-treated DLBCL patients was 89%, and the 2-year PFS rate was 83%
.
In view of this, a multi-center phase III randomized POLARIX study of Pola+R-CHP vs R-CHOP for the treatment of newly treated DLBCL patients was carried out in 2017.
The study is expected to end in 2026.
The results of the study are expected to rewrite the R-CHOP program for nearly 20 years.
First-line standard treatment status
.
Yimaitong: CAR-T therapy is currently a hot spot therapy in the treatment of lymphoma.
Could you please introduce what breakthroughs have been made by CAR-T therapy in R/R DLBCL? Prof.
Qingqing Cai’s JULIET study and TRANSCENT study confirmed the effectiveness and safety of tisa-cel and liso-cel in the treatment of R/R DLBCL.
These two CAR-T cells were also approved by the U.
S.
Food and Drug Administration (FDA) in 2017.
For the treatment of R/R DLBCL
.
The current CAR-T targets are mainly CD19, and most of them are single targets.
However, the lack of targeted CD19 epitopes may lead to the failure of CAR-T treatment.
Therefore, the current research on CAR-T mainly focuses on dual targets or multiple targets.
Targeted CAR-T treatment development
.
For example, the domestic Prof.
Han Weidong’s team recently published a phase I/II study in the top journal blood and leukemia, using CAR-T cells targeting CD19 and CD20 to treat R/RB cell lymphoma, with an ORR of 78% and a median PFS of 27.
6.
Month
.
In addition, last year’s ASCO and ESMO meeting reported the results of a phase I/II study of CD19/CD22 dual-targeting CAR-T cells (AUTO3) combined with PD-1 monoclonal antibody for the treatment of R/R DLBCL, using different doses of AUTO3 alone or in combination The ORR of pembrolizumab-treated patients was 68%, the CR rate was 54%, and the duration of complete remission was long.
At a median follow-up of 6 months, 93% of patients still maintained CR
.
The above two dual-target CAR-T treatments have relatively small side effects, and the cytokine release syndrome (CRS) is mostly grade 1-2, and the incidence of neurotoxicity is low
.
The above research results show that dual-target CAR-T therapy is better than previous single-target therapy, which further enhances the therapeutic effect of CAR-T in R/R DLBCL patients
.
Yimaitong: Could you please share with me what other new drugs or treatments are worth paying attention to in the field of DLBCL treatment? Professor Qingqing Cai aimed at DLBCL patients who are not suitable for transplantation.
Our research group is also currently carrying out a phase II clinical study of Cedaraniline combined with R-Gemox (CR-Gemox) to save the treatment of sequential Cedaraniline maintenance therapy.
The preliminary research results are also Reported at the 2020 ASH Annual Meeting
.
The results of the study showed that the CR-Gemox regimen in the treatment of R/R DLBCL patients had an ORR of 60.
9%, a CR rate of 34.
8%, and a median PFS of 7.
4 months.
It also showed a good therapeutic effect in patients with dual expression, ORR and CR The rates were 66.
6% and 33.
3%, respectively, and the overall toxicity was controllable.
The main grade 3-4 adverse reaction was thrombocytopenia
.
The study is still ongoing, and 39 patients have been enrolled
.
In terms of new targeted drugs, in addition to drugs that target CD19 and CD79b, new therapeutic drugs for other targets have also been developed and put into use
.
This year’s EHA conference reported the results of a phase II study of the CD37 antibody conjugate drug Naratuximab emtansine (Nara) in the treatment of R/RB cell lymphoma
.
CD37 is a lymphocyte surface marker, and B-cell non-Hodgkin's lymphoma (B-NHL) including DLBCL highly expresses CD37
.
Preclinical studies suggest that Nara and rituximab have a synergistic anti-tumor effect on B-NHL
.
Phase I clinical studies have also confirmed the safety and effectiveness of Nara monotherapy in DLBCL
.
A total of 100 patients were enrolled in this phase II study, including 80 DLBCL and 20 other NHL
.
Among 76 patients with evaluable R/R DLBCL, the ORR was 44.
7% and the CR rate was 31.
6%
.
With a median follow-up of 15 months, the median duration of response (DOR) was not reached, 82% of patients had adverse events ≥ grade 3, mainly hematological toxicity, and 8 patients were discontinued due to adverse events
.
The above results preliminarily confirmed the efficacy and safety of Nara in R/R DLBCL, and CD37 will also become a new target for R/R/DLBCL treatment
.
Professor Cai Qingqing, Chief Physician, PhD Supervisor, Deputy Director of the Department of Internal Medicine, Sun Yat-sen University Tumor Hospital, Head of the Lymphoma Group of the Oncology Branch of the Guangdong Medical Association, Deputy Chairman of the Youth Committee of the Oncology Branch of the Chinese Medical Association, Lymphoma Major, China Medical Education Association Deputy Chairman of the Committee, Deputy Chairman of the Lymphoma Professional Committee of the Guangdong Provincial Association of Women Physicians, Deputy Chairman of the Guangdong Anti-Cancer Association, Hematological Oncology Committee, Deputy Chairman of the Youth Committee, Beijing Cancer Prevention and Treatment Society, Deputy Chairman of the Lymphoma Immunization Committee, and published 79 SCI articles , Published 19 SCI papers in Blood, Leukemia, CCR, etc.
as a (co-) corresponding author in the past 5 years, presided over a number of national natural funds and provincial funds stamped "Read the original text", we make progress together
