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On March 27, 2020, the "CSCO Anti-Lymphoma Alliance Tour Lecture-Tianjin Station" meeting was successfully held.
During the conference, Professor Liu Wei from the Hospital of Hematology of the Chinese Academy of Medical Sciences brought a wonderful report entitled "The Status of DLBCL Transplantation in the Era of CAR-T Treatment".
Yimaitong compiled the following for readers.
The status of transplantation in the treatment of DLBCL Professor Liu Wei said that autologous hematopoietic stem cell transplantation (ASCT) is still the treatment method for most patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).
What is more controversial is whether transplantation is required for first-line treatment of high-risk DLBCL patients.
The recommendations of different guidelines are different.
The NCCN guidelines no longer recommend first-line transplantation for high-risk DLBCL patients after 2019, but European and Chinese guidelines still recommend that high-risk patients can choose first-line ASCT.
For extremely high-risk patients with double-strike and triple-strike, NCCN guidelines and American Society for Transplantation and Cell Therapy (ASTCT) guidelines still recommend first-line ASCT.
Regarding allogeneic hematopoietic stem cell transplantation (allo-HSCT), it is currently used in most cases of relapsed/refractory patients with more than two lines or patients who relapse after ASCT.
Current status of CAR-T therapy Chimeric antigen receptor T cell therapy (CAR-T) is a new type of cellular immunotherapy technology that has developed very rapidly in recent years.
CAR-T immunotherapy is to equip T cells with molecules that can recognize specific tumor cells, which can cause the activation and proliferation of T cells after recognizing tumor cells, which can effectively kill tumor cells.
In 2017, the FDA approved two CAR-T products, one is Tisagenlecleucel and the other is Axicabtagene.
At present, with regard to the application of CAR-T in DLBCL, patients who have failed more than two lines or relapsed after ASCT choose CAR-T treatment.
Conventional treatment path for DLBCL The current conventional treatment path for relapsed/refractory DLBCL is: first assess whether the patient is suitable for transplantation.
Patients who are not suitable for transplantation can receive second-line salvage chemotherapy.
If the disease recurs after second-line salvage chemotherapy fails, CAR- T treatment, if the patient is not suitable for CAR-T treatment, you can choose some new drug clinical trials or palliative treatment, but the prognosis of such patients is very poor; for patients who are suitable for transplantation, they can receive second-line salvage chemotherapy.
If salvage chemotherapy is effective, proceed ASCT, if recurrence after transplantation, choose CAR-T treatment.
If recurrence after CAR-T treatment, clinical trials or palliative treatment will be carried out; for patients who are suitable for transplantation but the second-line salvage chemotherapy is ineffective, CAR-T treatment can be considered If CAR-T treatment fails, clinical trials or palliative treatment will be carried out.
The above-mentioned treatment route is recommended based on the existing clinical evidence, but there are still many problems in this recommended route that deserve further discussion.
For example, what is the effect of transplantation for patients who are in partial remission after salvaging chemotherapy? Should these patients choose transplantation or CAR-T treatment? After CAR-T treatment is relieved, should transplantation be performed sequentially? Should CAR-T rescue be given priority to patients who are not suitable for transplantation? And can CAR-T be directly treated after recurrence? Professor Liu Wei shared and discussed these questions.
The best curative effect after salvage treatment is only PR.
Does it affect the curative effect after ASCT? A retrospective study by the Dana Farbor Cancer Center observed the impact of DLBCL's failure to obtain complete remission (CR) before transplantation on the effect of transplantation.
The results showed that the 4-year progression-free survival (PFS) rate of PET-positive patients before transplantation was 32%.
In contrast, the 4-year PFS rate of patients with PET negative before transplantation was 64%.
This suggests that about 64% of patients with complete remission before transplantation can obtain sustained remission, while more than 70% of patients with residual before transplantation will relapse, and only 30% of patients have long-term benefits.
The study also showed that patients with 3 risk factors (PET-positive, age ≥60 years, symptomatic recurrence) are at greater risk of recurrence, and the 4-year PFS rate is 0.
Another study also showed that pre-transplant PET results are factors that affect PFS and overall survival (OS).
In this study, the 3-year PFS rates of Deauville 1-3 patients and Deauville 4 patients were 49% and 77%, respectively.
, The 3-year OS rate was 54% and 85%, respectively.
Therefore, patients with positive PET after salvage chemotherapy (ie partial remission [PR]) are more likely to have recurrence after transplantation if they are accompanied by the following factors: no CR from previous chemotherapy; recurrence within 1 year; symptomatic recurrence and lactate dehydrogenase (LDH) High; PET Deauville 5 points before transplantation.
These patients have a high risk of direct ASCT recurrence, and direct transplantation may not be suitable.
CAR-T may be a better choice.
Therefore, the previous recommendation for relapsed/refractory DLBCL before 2017 has always been to directly recommend ASCT for patients with PR or above.
After the advent of two CAR-T products in 2017, it is proposed that CAR-T treatment can be considered for PR patients.
Especially for the above-mentioned patients with high risk factors for recurrence.
After CAR-T treatment is relieved, should transplantation be performed sequentially? ASCT or allo-HSCT? Professor Liu Wei pointed out that CAR-T treatment patients are basically second-line and above patients who are resistant to chemotherapy.
According to previous views, these patients should consider allo-HSCT after CAR-T treatment is relieved.
Because these patients are relieved by cell therapy, and the effect of chemotherapy is not good, ASCT may not be a good choice after CAR-T treatment is relieved.
From the summary of DLBCL allo-HSCT, the biggest problem is the recurrence-free mortality of transplantation, that is, the risk of treatment-related death.
There are differences in the 3-year recurrence-free mortality data of different studies, about 17%-53%, and an average of 30% of patients will die without recurrence.
This suggests that even if the patient does not relapse, about 30% of patients will die from allo-HSCT-related complications.
The 3-year PFS rate in the overall population is about 30%, and among refractory patients, only about 20% of patients can be cured after allo-HSCT.
Regarding CAR-T treatment, ZUMA1, JULIET and other studies have shown that patients who maintain CR at 3 months after CAR-T treatment have an expected PFS rate of 72%-83% at 12 or 24 months, that is, the probability of recurrence is less than 30%.
This means that even if the patients in remission of CAR-T treatment do not undergo allo-HSCT, about 72%-83% of patients can continue to remission, but if allo-HSCT is sequential, the problem of recurrence is not considered, and the treatment-related death The rate is about 30%.
Therefore, the risks and benefits of allo-HSCT in these patients may need to be carefully considered.
Tumor burden is an important factor that affects the efficacy of CAR-T and the long-term survival of patients.
Professor Liu’s team conducted a study of ASCT combined with SNCT19 in the treatment of refractory large B-cell lymphoma, and ASCT was used to reduce tumor burden before CAR-T treatment.
The pretreatment, then combined with CAR-T to remove residual tumors.
The results showed that compared with CNCT19 treatment alone, the CR rate of patients receiving ASCT sequential CNCT19 infusion was significantly higher (37.
5% vs 70%), and the safety of ASCT sequential CNCT19 infusion was controllable.
10 patients completed a 3-month follow-up, the 1-year PFS rate was 66.
7%, and the 1-year OS rate was 77.
1%.
The study suggests that sequential CAR-T treatment after transplantation can bring more significant benefits to patients.
Should CAR-T rescue be given priority to patients who are not suitable for transplantation? The overall survival of patients who are not suitable for transplantation is poor.
The PARMA study showed that with a median follow-up of 63 months, the event-free survival (EFS) rate was 46% for patients with sequential ASCT after chemotherapy was effective, while the EFS rate for patients who did not have sequential ASCT after chemotherapy was effective was only 12%.
.
This suggests that although chemotherapy is sensitive, the long-term survival probability of patients is still very low if transplantation is not performed.
So, since the prognosis of these patients is very poor, whether CAR-T can be considered earlier, Professor Liu Wei said that more clinical studies are needed to confirm.
Can CAR-T treatment be carried out directly after recurrence? Due to the poor general state of patients with advanced lymphoma and high tumor burden, these may affect the efficacy of CAR-T, and multi-line treatment may also affect the successful preparation of CAR-T cells.
Therefore, the timing of CAR-T treatment should not be too late.
Regarding whether the second-line treatment of DLBCL is the first choice for transplantation or CAR-T, three studies are currently in progress, ZUMA-7, EBLINDA and RANSFORM studies.
These three studies compare the efficacy of salvage chemotherapy + ASCT and direct CAR-T in second-line treatment.
It may help the choice of second-line treatment in the future.
In fact, there will be many patients who are expected to save the poor efficacy of sequential ASCT in the rescue of chemotherapy, such as rituximab used in the early stage and/or relapse within 1 year, the best effect in the past is only PR, and IPI 3-5 points at the time of relapse, etc.
For these patients, whether CAR-T treatment should be advanced, this is also a question that needs to be considered in the future.
In addition, the ZUMA-12 study observed the efficacy and safety of CAR-T first-line (1.
5-line) treatment of high-risk large B-cell lymphoma.
The results showed that the median follow-up was 9.
5 months.
Among 27 patients with evaluable efficacy, overall The response rate (ORR) was 85%, and the CR rate was 74%.
Therefore, the earlier application of CAR-T is more likely to benefit patients, but further clinical studies are still needed to confirm.
In the end, Professor Liu Wei concluded: If relapsed/refractory DLBCL is rescued to obtain CR after chemotherapy, ASCT is still the first choice; if the rescue chemotherapy does not reach CR (PR/SD/PD), CAR-T treatment should be carried out as soon as possible.
Whether CAR-T therapy can replace ASCT as the first-line second-line therapy for DLBCL remains to be the result of clinical trials.
It is still uncertain whether allo-SCT is sequential after CAR-T treatment is effective.
Patients who still maintain the efficacy (especially CR) at 3 months after CAR-T can be observed and followed up.
Whether CAR-T therapy can be used for high-risk DLBCL 1-1.
5 line therapy is still awaiting the results of further clinical trials. Preliminary studies on ASCT combined with CAR-T therapy have shown that the safety is controllable, the proportion of continuous CR at 1-year follow-up is higher, and the efficacy is better than that of CAR-T therapy alone.
Professor Liu Wei, Deputy Chief Physician, Lymphoma Diagnosis and Treatment Center, Hospital of Hematology, Chinese Academy of Medical Sciences Member of the Hematopoietic Stem Cell and Cell Therapy Group of the Hematological Oncology Committee of the Chinese Anti-Cancer Association Member of the First Youth Committee of the CSCO Anti-Leukemia/Anti-Lymphoma Alliance Tianjin Anti-Cancer The deputy director of the Youth Committee of the Association's Lymphoma Professional Committee is good at precise diagnosis and prognostic stratified treatment of lymphoma, and has rich clinical experience in lymphoma hematopoietic stem cell transplantation and CAR-T treatment.
Presided over and participated in a number of international and domestic multi-center clinical researches on new drugs, and reported orally on the research results of autologous hematopoietic stem cell transplantation combined with CAR-T in the treatment of refractory B-cell lymphoma at the 61st American Hematology Annual Conference.
Poke "read the original text" and we will make progress together
During the conference, Professor Liu Wei from the Hospital of Hematology of the Chinese Academy of Medical Sciences brought a wonderful report entitled "The Status of DLBCL Transplantation in the Era of CAR-T Treatment".
Yimaitong compiled the following for readers.
The status of transplantation in the treatment of DLBCL Professor Liu Wei said that autologous hematopoietic stem cell transplantation (ASCT) is still the treatment method for most patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).
What is more controversial is whether transplantation is required for first-line treatment of high-risk DLBCL patients.
The recommendations of different guidelines are different.
The NCCN guidelines no longer recommend first-line transplantation for high-risk DLBCL patients after 2019, but European and Chinese guidelines still recommend that high-risk patients can choose first-line ASCT.
For extremely high-risk patients with double-strike and triple-strike, NCCN guidelines and American Society for Transplantation and Cell Therapy (ASTCT) guidelines still recommend first-line ASCT.
Regarding allogeneic hematopoietic stem cell transplantation (allo-HSCT), it is currently used in most cases of relapsed/refractory patients with more than two lines or patients who relapse after ASCT.
Current status of CAR-T therapy Chimeric antigen receptor T cell therapy (CAR-T) is a new type of cellular immunotherapy technology that has developed very rapidly in recent years.
CAR-T immunotherapy is to equip T cells with molecules that can recognize specific tumor cells, which can cause the activation and proliferation of T cells after recognizing tumor cells, which can effectively kill tumor cells.
In 2017, the FDA approved two CAR-T products, one is Tisagenlecleucel and the other is Axicabtagene.
At present, with regard to the application of CAR-T in DLBCL, patients who have failed more than two lines or relapsed after ASCT choose CAR-T treatment.
Conventional treatment path for DLBCL The current conventional treatment path for relapsed/refractory DLBCL is: first assess whether the patient is suitable for transplantation.
Patients who are not suitable for transplantation can receive second-line salvage chemotherapy.
If the disease recurs after second-line salvage chemotherapy fails, CAR- T treatment, if the patient is not suitable for CAR-T treatment, you can choose some new drug clinical trials or palliative treatment, but the prognosis of such patients is very poor; for patients who are suitable for transplantation, they can receive second-line salvage chemotherapy.
If salvage chemotherapy is effective, proceed ASCT, if recurrence after transplantation, choose CAR-T treatment.
If recurrence after CAR-T treatment, clinical trials or palliative treatment will be carried out; for patients who are suitable for transplantation but the second-line salvage chemotherapy is ineffective, CAR-T treatment can be considered If CAR-T treatment fails, clinical trials or palliative treatment will be carried out.
The above-mentioned treatment route is recommended based on the existing clinical evidence, but there are still many problems in this recommended route that deserve further discussion.
For example, what is the effect of transplantation for patients who are in partial remission after salvaging chemotherapy? Should these patients choose transplantation or CAR-T treatment? After CAR-T treatment is relieved, should transplantation be performed sequentially? Should CAR-T rescue be given priority to patients who are not suitable for transplantation? And can CAR-T be directly treated after recurrence? Professor Liu Wei shared and discussed these questions.
The best curative effect after salvage treatment is only PR.
Does it affect the curative effect after ASCT? A retrospective study by the Dana Farbor Cancer Center observed the impact of DLBCL's failure to obtain complete remission (CR) before transplantation on the effect of transplantation.
The results showed that the 4-year progression-free survival (PFS) rate of PET-positive patients before transplantation was 32%.
In contrast, the 4-year PFS rate of patients with PET negative before transplantation was 64%.
This suggests that about 64% of patients with complete remission before transplantation can obtain sustained remission, while more than 70% of patients with residual before transplantation will relapse, and only 30% of patients have long-term benefits.
The study also showed that patients with 3 risk factors (PET-positive, age ≥60 years, symptomatic recurrence) are at greater risk of recurrence, and the 4-year PFS rate is 0.
Another study also showed that pre-transplant PET results are factors that affect PFS and overall survival (OS).
In this study, the 3-year PFS rates of Deauville 1-3 patients and Deauville 4 patients were 49% and 77%, respectively.
, The 3-year OS rate was 54% and 85%, respectively.
Therefore, patients with positive PET after salvage chemotherapy (ie partial remission [PR]) are more likely to have recurrence after transplantation if they are accompanied by the following factors: no CR from previous chemotherapy; recurrence within 1 year; symptomatic recurrence and lactate dehydrogenase (LDH) High; PET Deauville 5 points before transplantation.
These patients have a high risk of direct ASCT recurrence, and direct transplantation may not be suitable.
CAR-T may be a better choice.
Therefore, the previous recommendation for relapsed/refractory DLBCL before 2017 has always been to directly recommend ASCT for patients with PR or above.
After the advent of two CAR-T products in 2017, it is proposed that CAR-T treatment can be considered for PR patients.
Especially for the above-mentioned patients with high risk factors for recurrence.
After CAR-T treatment is relieved, should transplantation be performed sequentially? ASCT or allo-HSCT? Professor Liu Wei pointed out that CAR-T treatment patients are basically second-line and above patients who are resistant to chemotherapy.
According to previous views, these patients should consider allo-HSCT after CAR-T treatment is relieved.
Because these patients are relieved by cell therapy, and the effect of chemotherapy is not good, ASCT may not be a good choice after CAR-T treatment is relieved.
From the summary of DLBCL allo-HSCT, the biggest problem is the recurrence-free mortality of transplantation, that is, the risk of treatment-related death.
There are differences in the 3-year recurrence-free mortality data of different studies, about 17%-53%, and an average of 30% of patients will die without recurrence.
This suggests that even if the patient does not relapse, about 30% of patients will die from allo-HSCT-related complications.
The 3-year PFS rate in the overall population is about 30%, and among refractory patients, only about 20% of patients can be cured after allo-HSCT.
Regarding CAR-T treatment, ZUMA1, JULIET and other studies have shown that patients who maintain CR at 3 months after CAR-T treatment have an expected PFS rate of 72%-83% at 12 or 24 months, that is, the probability of recurrence is less than 30%.
This means that even if the patients in remission of CAR-T treatment do not undergo allo-HSCT, about 72%-83% of patients can continue to remission, but if allo-HSCT is sequential, the problem of recurrence is not considered, and the treatment-related death The rate is about 30%.
Therefore, the risks and benefits of allo-HSCT in these patients may need to be carefully considered.
Tumor burden is an important factor that affects the efficacy of CAR-T and the long-term survival of patients.
Professor Liu’s team conducted a study of ASCT combined with SNCT19 in the treatment of refractory large B-cell lymphoma, and ASCT was used to reduce tumor burden before CAR-T treatment.
The pretreatment, then combined with CAR-T to remove residual tumors.
The results showed that compared with CNCT19 treatment alone, the CR rate of patients receiving ASCT sequential CNCT19 infusion was significantly higher (37.
5% vs 70%), and the safety of ASCT sequential CNCT19 infusion was controllable.
10 patients completed a 3-month follow-up, the 1-year PFS rate was 66.
7%, and the 1-year OS rate was 77.
1%.
The study suggests that sequential CAR-T treatment after transplantation can bring more significant benefits to patients.
Should CAR-T rescue be given priority to patients who are not suitable for transplantation? The overall survival of patients who are not suitable for transplantation is poor.
The PARMA study showed that with a median follow-up of 63 months, the event-free survival (EFS) rate was 46% for patients with sequential ASCT after chemotherapy was effective, while the EFS rate for patients who did not have sequential ASCT after chemotherapy was effective was only 12%.
.
This suggests that although chemotherapy is sensitive, the long-term survival probability of patients is still very low if transplantation is not performed.
So, since the prognosis of these patients is very poor, whether CAR-T can be considered earlier, Professor Liu Wei said that more clinical studies are needed to confirm.
Can CAR-T treatment be carried out directly after recurrence? Due to the poor general state of patients with advanced lymphoma and high tumor burden, these may affect the efficacy of CAR-T, and multi-line treatment may also affect the successful preparation of CAR-T cells.
Therefore, the timing of CAR-T treatment should not be too late.
Regarding whether the second-line treatment of DLBCL is the first choice for transplantation or CAR-T, three studies are currently in progress, ZUMA-7, EBLINDA and RANSFORM studies.
These three studies compare the efficacy of salvage chemotherapy + ASCT and direct CAR-T in second-line treatment.
It may help the choice of second-line treatment in the future.
In fact, there will be many patients who are expected to save the poor efficacy of sequential ASCT in the rescue of chemotherapy, such as rituximab used in the early stage and/or relapse within 1 year, the best effect in the past is only PR, and IPI 3-5 points at the time of relapse, etc.
For these patients, whether CAR-T treatment should be advanced, this is also a question that needs to be considered in the future.
In addition, the ZUMA-12 study observed the efficacy and safety of CAR-T first-line (1.
5-line) treatment of high-risk large B-cell lymphoma.
The results showed that the median follow-up was 9.
5 months.
Among 27 patients with evaluable efficacy, overall The response rate (ORR) was 85%, and the CR rate was 74%.
Therefore, the earlier application of CAR-T is more likely to benefit patients, but further clinical studies are still needed to confirm.
In the end, Professor Liu Wei concluded: If relapsed/refractory DLBCL is rescued to obtain CR after chemotherapy, ASCT is still the first choice; if the rescue chemotherapy does not reach CR (PR/SD/PD), CAR-T treatment should be carried out as soon as possible.
Whether CAR-T therapy can replace ASCT as the first-line second-line therapy for DLBCL remains to be the result of clinical trials.
It is still uncertain whether allo-SCT is sequential after CAR-T treatment is effective.
Patients who still maintain the efficacy (especially CR) at 3 months after CAR-T can be observed and followed up.
Whether CAR-T therapy can be used for high-risk DLBCL 1-1.
5 line therapy is still awaiting the results of further clinical trials. Preliminary studies on ASCT combined with CAR-T therapy have shown that the safety is controllable, the proportion of continuous CR at 1-year follow-up is higher, and the efficacy is better than that of CAR-T therapy alone.
Professor Liu Wei, Deputy Chief Physician, Lymphoma Diagnosis and Treatment Center, Hospital of Hematology, Chinese Academy of Medical Sciences Member of the Hematopoietic Stem Cell and Cell Therapy Group of the Hematological Oncology Committee of the Chinese Anti-Cancer Association Member of the First Youth Committee of the CSCO Anti-Leukemia/Anti-Lymphoma Alliance Tianjin Anti-Cancer The deputy director of the Youth Committee of the Association's Lymphoma Professional Committee is good at precise diagnosis and prognostic stratified treatment of lymphoma, and has rich clinical experience in lymphoma hematopoietic stem cell transplantation and CAR-T treatment.
Presided over and participated in a number of international and domestic multi-center clinical researches on new drugs, and reported orally on the research results of autologous hematopoietic stem cell transplantation combined with CAR-T in the treatment of refractory B-cell lymphoma at the 61st American Hematology Annual Conference.
Poke "read the original text" and we will make progress together
