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From March 19 to 21, 2021, the 4th China Chronic Lymphocytic Leukemia Conference was successfully held in Tianjin.
At the meeting, Professor Yi Shuhua from the Hospital of Hematology, Chinese Academy of Medical Sciences introduced the "Progress in Diagnosis and Treatment of Fahrenheit Macroglobulinemia/Lymphoplasmacytic Lymphoma".
Yimaitongxian organized the following for readers.
Professor Yi Shuhua said that lymphoplasmacytic lymphoma/Wahrenheit's macroglobulinemia (LPL/WM) is a rare B-lymphocyte monoclonal proliferative disease.
According to an epidemiological statistics in 2014 (as shown in the figure below) ), mainland China is expected to have about 434 new cases each year.
Professor Yi Shuhua then emphasized that about 90% to 95% of LPL is WM.
Diagnosis and Difficulties of LPL/WM Professor Yi Shuhua introduced that the diagnostic criteria of WM mainly include the following: first, the detection of monoclonal IgM in the serum (regardless of the quantity); second, the plasma cell-like or the like in the bone marrow The small lymphocytes differentiated by plasma cells are invaded by the trabecular space (regardless of the number); third, their immunophenotypes are: slgM+, CD5-, CD10-, CD11c-, CD19+, CD20+, CD22+, CD23-, CD25+, CD27+, FMC7+, CD79a+, CD103-, CD38/138+.
Because about 10%-20% of cases can express CD5, CD10 or CD23, WM cannot be excluded based on immunophenotype alone; fourth, except for other known types of lymphoma; fifth, the occurrence of MYD88 L265P mutation in WM The rate is as high as 90%, but its positive detection rate is related to the detection method and the proportion of tumor cells in the specimen.
The MYD88 L265P mutation can also be found in other small B-cell lymphomas, diffuse large B-cell lymphomas, etc.
Therefore, the MYD88 L265P mutation It is an important marker for the diagnosis and differential diagnosis of WM, but it is a non-specific diagnostic index.Professor Yi Shuhua said that although LPL/WM currently has many clinical features, it does not have specific protein phenotypes or gene mutations.
In the clinical diagnosis process, there are still many difficulties (as shown in the figure below), which require doctors to make integrated judgments.
It is worth noting that “the small lymphocytes of plasma cell-like or plasma cell differentiation in the bone marrow are invaded by the trabecular space” is not a unique clinical manifestation of LPL/WM, and differential diagnosis is required; at the same time, if the patient is immune to MYD88 mutant CLL The phenotype is more atypical.
” It can be judged based on the results of bone marrow biopsy.
If the bone marrow biopsy shows small B-cell lymphoma with plasma-like differentiation, and tends to lymphoplasmacytic lymphoma, it can be diagnosed as LPL.
It needs to be emphasized that because the clinical characteristics of LPL/WM are not typical, patients may be diagnosed with different results in different hospitals.
At present, the clinical LPL/WM diagnosis has not yet standardized procedures, which is the focus of future work.
LPL/WM treatment progress First, Professor Yi Shuhua emphasized that not all LPL/WM need treatment.
The indications for treatment of LPL/WM are as follows; asymptomatic patients are followed up every 3-6 months.
Subsequently, Professor Yi Shuhua said that the current recommendation for LPL/WM treatment is to participate in well-designed clinical studies.
Other preferred treatment options include: 1) BR regimen: bendamustine + rituximab; 2) BTK inhibitor: ibrutinib ± rituximab or zebutinib as a single agent; 3) RCD : Rituximab + cyclophosphamide + dexamethasone; 4) VRd: bortezomib + rituximab + dexamethasone.
Subsequently, Prof.
Yi Shuhua explained the efficacy of the above treatment schemes by analyzing several authoritative clinical trials.
The BR regimen BR regimen induction therapy for initial treatment of WM has currently announced the results of two clinical trials: StiL NHL1-2003 trial compared the BR regimen with the R-CHOP regimen.
The overall response rate (ORR) of the BR regimen was 92.
7%, medium The disease-free survival (PFS) was 69.
5 months, which was significantly better than the R-CHOP program (28.
1 months), and the 5-year OS rate was 80.
1%.The StiL NHL7-2008 trial explored the effectiveness of maintenance therapy.
The ORR of WM maintenance therapy was 91.
4%, and the median PFS was 78.
0 months.
Among them, the median PFS of 179 patients who only received BR was 65.
3 months.
The results are similar to StiL NHL1- The 2003 trial was close, but the median OS in the StiL NHL7-2008 trial was not reached, and the 5-year OS rate is expected to be 78%.
How to choose treatment options for BR, RCD and BDR? The Mayo Clinic has conducted research on BR, RCD and BRD (bortezomib, dexamethasone, and rituximab) regimens, and the results show that the BR regimen is superior to the RCD regimen and the BRD regimen (as shown in the figure below).
A retrospective study by Harvard University showed that there was no significant difference in the treatment response rate of the three programs (as shown in the figure below), and the CR rate of the BR program was higher.
RCD vs BCD for initial treatment of WM patients Professor Yi Shuhua’s team conducted a randomized controlled study on the RCD regimen and BCD regimen for the treatment of WM patients.
The results showed that the ORR of the two regimens was similar, and the RCD regimen had a higher deep remission rate.
, PFS is also better than BCD program.
Therefore, Professor Yi Shuhua believes that the RCD program is a better choice for Chinese patients.
Progress in new drugs for LPL/WM treatment Professor Yi Shuhua introduced that LPL/WM new drug treatment is the current trend, but with the exception of BTK inhibitors and BCL-2 inhibitors, other new drugs are still far from clinical application.
Ibrutinib and Zebutinib Ibrutinib is the first BTK inhibitor.
There are clinical studies in the treatment of newly treated and relapsed/refractory patients.
Data show that ORR is above 90%, initial treatment The patient can reach 100%; the main response rate (MRR) is above 70%, and can reach 83% in the newly treated patients; the very good partial response (VGPR) rate is about 20%.
The ASPEN study is the world's first head-to-head study of Zebutinib in the treatment of WM.
The ASPEN clinical trial divided patients into two cohorts: cohort 1 (relapsed/refractory or untreated WM patients with MYD88 L265P mutation) and cohort 2 (MYD88 wild-type patients).
In 2019, the results of these two cohorts were announced.
The results of cohort 1 showed that Zebutinib improved the treatment effect of MYD88 mutant WM patients compared with Ibrutinib, but did not reach a statistically significant difference.
The results of cohort 2 showed that Zebutinib had a better effect on MYD88 wild-type patients, but follow-up data need to be further supplemented in the follow-up.
Oral combined targeted therapy for initial treatment of WM clinical trial (ZID clinical trial) Professor Yi Shuhua emphasized that the treatment of BTK inhibitors in clinical patients cannot be discontinued.
Once the drug is discontinued, the disease will rebound.
Therefore, explore multiple drugs Combination therapy in order to achieve better clinical efficacy is the focus of future research.
In order to achieve deep relief, the team of Professor Yi Shuhua designed the ZID test of "Zebutinib + Ishazomib + Dexamethasone" (as shown in the figure below), using oral combined targeted therapy for initial treatment of WM patients.
Since proteasome inhibitors can target plasma cells and BTK inhibitors can target B cells, the combination of drugs can achieve the purpose of full oral administration, discontinuation of the drug, and deep relief, while avoiding the resistance of Zebutinib.
It is expected to be able to Obtain better curative effect.
At present, 15 patients are enrolled in the trial, and the first 6 patients have reached a 100% effective rate.
Finally, Professor Yi Shuhua said that there are currently many clinical trials of LPL/WM in progress.
I believe that with the deepening of clinical research, more treatment plans will be approved for clinical use in the future, so that more patients can get more efficient and effective treatment.
Reassuring, economical treatment.
Professor Yi Shuhua Doctor of Medicine, Associate Chief Physician, Master's Tutor, Hematology Hospital of Chinese Academy of Medical Sciences (Institute of Hematology), Member of the 11th Committee of Lymphocytic Diseases Group of Hematology Branch of Chinese Medical Association, China Anti-Cancer Association Hematology Oncology Major Committee Youth Member, Secretary-General, Chinese Society of Immunology, Member of the Hematology and Immunology Branch of the Chinese Society Hope National Medical Center postdoctoral stamp "read the original", we make progress together
At the meeting, Professor Yi Shuhua from the Hospital of Hematology, Chinese Academy of Medical Sciences introduced the "Progress in Diagnosis and Treatment of Fahrenheit Macroglobulinemia/Lymphoplasmacytic Lymphoma".
Yimaitongxian organized the following for readers.
Professor Yi Shuhua said that lymphoplasmacytic lymphoma/Wahrenheit's macroglobulinemia (LPL/WM) is a rare B-lymphocyte monoclonal proliferative disease.
According to an epidemiological statistics in 2014 (as shown in the figure below) ), mainland China is expected to have about 434 new cases each year.
Professor Yi Shuhua then emphasized that about 90% to 95% of LPL is WM.
Diagnosis and Difficulties of LPL/WM Professor Yi Shuhua introduced that the diagnostic criteria of WM mainly include the following: first, the detection of monoclonal IgM in the serum (regardless of the quantity); second, the plasma cell-like or the like in the bone marrow The small lymphocytes differentiated by plasma cells are invaded by the trabecular space (regardless of the number); third, their immunophenotypes are: slgM+, CD5-, CD10-, CD11c-, CD19+, CD20+, CD22+, CD23-, CD25+, CD27+, FMC7+, CD79a+, CD103-, CD38/138+.
Because about 10%-20% of cases can express CD5, CD10 or CD23, WM cannot be excluded based on immunophenotype alone; fourth, except for other known types of lymphoma; fifth, the occurrence of MYD88 L265P mutation in WM The rate is as high as 90%, but its positive detection rate is related to the detection method and the proportion of tumor cells in the specimen.
The MYD88 L265P mutation can also be found in other small B-cell lymphomas, diffuse large B-cell lymphomas, etc.
Therefore, the MYD88 L265P mutation It is an important marker for the diagnosis and differential diagnosis of WM, but it is a non-specific diagnostic index.Professor Yi Shuhua said that although LPL/WM currently has many clinical features, it does not have specific protein phenotypes or gene mutations.
In the clinical diagnosis process, there are still many difficulties (as shown in the figure below), which require doctors to make integrated judgments.
It is worth noting that “the small lymphocytes of plasma cell-like or plasma cell differentiation in the bone marrow are invaded by the trabecular space” is not a unique clinical manifestation of LPL/WM, and differential diagnosis is required; at the same time, if the patient is immune to MYD88 mutant CLL The phenotype is more atypical.
” It can be judged based on the results of bone marrow biopsy.
If the bone marrow biopsy shows small B-cell lymphoma with plasma-like differentiation, and tends to lymphoplasmacytic lymphoma, it can be diagnosed as LPL.
It needs to be emphasized that because the clinical characteristics of LPL/WM are not typical, patients may be diagnosed with different results in different hospitals.
At present, the clinical LPL/WM diagnosis has not yet standardized procedures, which is the focus of future work.
LPL/WM treatment progress First, Professor Yi Shuhua emphasized that not all LPL/WM need treatment.
The indications for treatment of LPL/WM are as follows; asymptomatic patients are followed up every 3-6 months.
Subsequently, Professor Yi Shuhua said that the current recommendation for LPL/WM treatment is to participate in well-designed clinical studies.
Other preferred treatment options include: 1) BR regimen: bendamustine + rituximab; 2) BTK inhibitor: ibrutinib ± rituximab or zebutinib as a single agent; 3) RCD : Rituximab + cyclophosphamide + dexamethasone; 4) VRd: bortezomib + rituximab + dexamethasone.
Subsequently, Prof.
Yi Shuhua explained the efficacy of the above treatment schemes by analyzing several authoritative clinical trials.
The BR regimen BR regimen induction therapy for initial treatment of WM has currently announced the results of two clinical trials: StiL NHL1-2003 trial compared the BR regimen with the R-CHOP regimen.
The overall response rate (ORR) of the BR regimen was 92.
7%, medium The disease-free survival (PFS) was 69.
5 months, which was significantly better than the R-CHOP program (28.
1 months), and the 5-year OS rate was 80.
1%.The StiL NHL7-2008 trial explored the effectiveness of maintenance therapy.
The ORR of WM maintenance therapy was 91.
4%, and the median PFS was 78.
0 months.
Among them, the median PFS of 179 patients who only received BR was 65.
3 months.
The results are similar to StiL NHL1- The 2003 trial was close, but the median OS in the StiL NHL7-2008 trial was not reached, and the 5-year OS rate is expected to be 78%.
How to choose treatment options for BR, RCD and BDR? The Mayo Clinic has conducted research on BR, RCD and BRD (bortezomib, dexamethasone, and rituximab) regimens, and the results show that the BR regimen is superior to the RCD regimen and the BRD regimen (as shown in the figure below).
A retrospective study by Harvard University showed that there was no significant difference in the treatment response rate of the three programs (as shown in the figure below), and the CR rate of the BR program was higher.
RCD vs BCD for initial treatment of WM patients Professor Yi Shuhua’s team conducted a randomized controlled study on the RCD regimen and BCD regimen for the treatment of WM patients.
The results showed that the ORR of the two regimens was similar, and the RCD regimen had a higher deep remission rate.
, PFS is also better than BCD program.
Therefore, Professor Yi Shuhua believes that the RCD program is a better choice for Chinese patients.
Progress in new drugs for LPL/WM treatment Professor Yi Shuhua introduced that LPL/WM new drug treatment is the current trend, but with the exception of BTK inhibitors and BCL-2 inhibitors, other new drugs are still far from clinical application.
Ibrutinib and Zebutinib Ibrutinib is the first BTK inhibitor.
There are clinical studies in the treatment of newly treated and relapsed/refractory patients.
Data show that ORR is above 90%, initial treatment The patient can reach 100%; the main response rate (MRR) is above 70%, and can reach 83% in the newly treated patients; the very good partial response (VGPR) rate is about 20%.
The ASPEN study is the world's first head-to-head study of Zebutinib in the treatment of WM.
The ASPEN clinical trial divided patients into two cohorts: cohort 1 (relapsed/refractory or untreated WM patients with MYD88 L265P mutation) and cohort 2 (MYD88 wild-type patients).
In 2019, the results of these two cohorts were announced.
The results of cohort 1 showed that Zebutinib improved the treatment effect of MYD88 mutant WM patients compared with Ibrutinib, but did not reach a statistically significant difference.
The results of cohort 2 showed that Zebutinib had a better effect on MYD88 wild-type patients, but follow-up data need to be further supplemented in the follow-up.
Oral combined targeted therapy for initial treatment of WM clinical trial (ZID clinical trial) Professor Yi Shuhua emphasized that the treatment of BTK inhibitors in clinical patients cannot be discontinued.
Once the drug is discontinued, the disease will rebound.
Therefore, explore multiple drugs Combination therapy in order to achieve better clinical efficacy is the focus of future research.
In order to achieve deep relief, the team of Professor Yi Shuhua designed the ZID test of "Zebutinib + Ishazomib + Dexamethasone" (as shown in the figure below), using oral combined targeted therapy for initial treatment of WM patients.
Since proteasome inhibitors can target plasma cells and BTK inhibitors can target B cells, the combination of drugs can achieve the purpose of full oral administration, discontinuation of the drug, and deep relief, while avoiding the resistance of Zebutinib.
It is expected to be able to Obtain better curative effect.
At present, 15 patients are enrolled in the trial, and the first 6 patients have reached a 100% effective rate.
Finally, Professor Yi Shuhua said that there are currently many clinical trials of LPL/WM in progress.
I believe that with the deepening of clinical research, more treatment plans will be approved for clinical use in the future, so that more patients can get more efficient and effective treatment.
Reassuring, economical treatment.
Professor Yi Shuhua Doctor of Medicine, Associate Chief Physician, Master's Tutor, Hematology Hospital of Chinese Academy of Medical Sciences (Institute of Hematology), Member of the 11th Committee of Lymphocytic Diseases Group of Hematology Branch of Chinese Medical Association, China Anti-Cancer Association Hematology Oncology Major Committee Youth Member, Secretary-General, Chinese Society of Immunology, Member of the Hematology and Immunology Branch of the Chinese Society Hope National Medical Center postdoctoral stamp "read the original", we make progress together
