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Aplastic anemia is a life-threatening bone marrow failure with a very high mortality rate if left untreated
.
Although the incidence rate is not high, China has a large population base, and the actual number of patients is relatively large
.
Since the establishment of antithymocyte globulin combined with cyclosporine as the standard immunotherapy for aplastic anemia in the 1980s, there has been a lack of important progress in the treatment of aplastic anemia in the past 30 years
.
On January 6, 2022, the New England Journal of Medicine (NEJM) published the results of the RACE trial in Europe, confirming that the standard immunotherapy regimen combined with eltrombopag in severe and very severe aplastic anemia improved the rate of hematologic response, speed and intensity
.
The editorial issued at the same time pointed out: "The results of this trial support the use of equine antithymocyte globulin, cyclosporine combined with eltrombopag as a new standard immunotherapy regimen for aplastic anemia
.
" "NEJM Medical Frontiers" is invited here The team of Professor Yu Li from the Second Affiliated Hospital of Nanchang University interpreted the study
.
To read the full text translation, please visit the official website of NEJM Medical Frontiers, APP or click on the WeChat applet picture
.
Fei Yan, Yu Li *Department of Hematology, The Second Affiliated Hospital of Nanchang University *Corresponding Author Acquired aplastic anemia is a primary bone marrow failure disease manifested by pancytopenia, which seriously affects the production and life of patients, even life-threatening
.
The most important pathogenesis of the disease is the hyperimmunity of T lymphocytes
.
The introduction of antithymocyte globulin (ATG) in the late 1970s, and the addition of cyclosporine to ATG in the 1980s, significantly improved hematopoietic recovery and survival in patients with severe or very severe aplastic anemia
.
In this way, cyclosporine combined with ATG has become the standard immunotherapy regimen for severe aplastic anemia, but the reduction in the number of residual stem cells in patients with aplastic anemia will limit the efficacy of standard immunotherapy
.
The survival status of aplastic anemia still has many unmet clinical needs to be solved: the hematopoietic response rate of patients after standard immunotherapy is only 42%-74%, and about 1/3 of patients with aplastic anemia are ineffective in standard immunotherapy.
Disease recurrence occurs in 20% to 40% of patients who respond to initial therapy
.
Therefore, how to improve the hematological response rate and long-term remission rate of patients with severe aplastic anemia is an urgent problem
.
There is still a long way to go in the development of new treatment options
.
Eltrombopag is an oral non-peptide thrombopoietin receptor agonist that acts on the transmembrane region of the thrombopoietin receptor to stimulate the differentiation of bone marrow hematopoietic stem cells, progenitor cells, precursor cells, etc.
Involved in the production of blood cells
.
In July 2012, the New England Journal of Medicine (NEJM) published the results of Olnes et al.
[1], demonstrating the efficacy of eltrombopag in patients with aplastic anemia refractory to standard immunotherapy
.
This is an investigator-initiated Phase 2, open-label, single-arm trial
.
Inclusion criteria were patients with severe aplastic anemia who failed to respond to standard immunotherapy at least 1 time, and who had completed standard immunotherapy for at least 6 months, platelet count ≤30,000/µl, age ≥18 years (core study phase) and ≥12 years old ( extended research phase)
.
Twenty-five patients received eltrombopag at a dose of 50 mg, which could be increased to a maximum dose of 150 mg per day for 12 weeks if needed, and continued eltrombopag in those in remission
.
The primary endpoint was hematologic remission and adverse effects after 12 weeks of eltrombopag treatment, and secondary endpoints included the incidence and severity of bleeding events
.
The results showed that the remission rate was 40%, and it was well tolerated, and the incidence of myelofibrosis was not significantly increased
.
Based on the results of this study, eltrombopag was approved by the US Food and Drug Administration (2014) and the European Medicines Agency (2015) for the treatment of severe aplastic anemia
.
In 2017, NEJM republished a study on Eltrombopag in the treatment of aplastic anemia [2]
.
This is a prospective phase 1/2 clinical trial of immunosuppressive therapy plus eltrombopag in aplastic anemia, enrolling 92 consecutive patients and divided into 3 cohorts
.
The 3 cohorts differed in the initiation and duration of eltrombopag administration (cohort 1 received eltrombopag from days 14 to 6 months, and cohort 2 received eltrombopag from days 14 to 3 months).
Popa, Cohort 3 received Eltrombopag from months 1 to 6)
.
The primary study endpoint was complete hematologic remission at 6 months
.
Secondary endpoints included overall response, survival, relapse, and evolution of bone marrow malignant clones
.
The 6-month complete response rate was 33% in cohort 1, 26% in cohort 2, and 58% in cohort 3
.
The 6-month overall response rates were 80%, 87%, and 94%, respectively
.
Complete and overall response rates in the combined cohort were higher than the center's historical data (complete response rate 10%, overall response rate 66%)
.
With a median follow-up of 2 years, the survival rate was 97%
.
One patient died of non-hematologic causes during the study period
.
The number of bone marrow cells, the number of CD34+ cells and the number of early hematopoietic progenitor cells were significantly increased in the experimental group
.
Recurrence rates and clonal evolution are similar to historical experience
.
Two patients developed severe rash, which led to early discontinuation of eltrombopag
.
In January 2022, the results of the third study were published in NEJM[3]
.
This is an investigator-initiated, multicenter, open-label, randomized phase 3 trial comparing equine ATG plus cyclosporine with or without eltrombopag in untreated patients with severe or very severe aplastic anemia
.
The patients were divided into immunosuppressive treatment group (group A, 101 cases, horse ATG 40 mg/kg, day 1-4; cyclosporine 5 mg/kg, starting from day 1, at least 12 months, and gradually tapering thereafter , and discontinued within 24 months) and immunosuppressive therapy + eltrombopag group (group B, 96 patients, immunosuppressive therapy plus oral eltrombopag, 150 mg, from day 14 to month 6 or complete remission at 3 months)
.
Complete remission at 3 months was 10% in group A and 22% in group
B.
At 6 months, the overall response rate (complete and partial) was 41% in arm A and 68% in arm
B.
The median time to first response was 8.
8 months (group A) and 3.
0 months (group B)
.
The incidence of serious adverse events was similar in the two groups
.
Figure 1.
Kinetics of Hematologic Remission [3] Cumulative Incidence of Remission Curves by Treatment Group
.
Shaded area represents 95% CI
.
Competing events include hematopoietic stem cell transplantation, any other treatment for aplastic anemia, clonal evolution, and death
.
Panel A shows the time to first remission
.
In Arms A and B, the cumulative incidence of first remission at 3 months was 25% (95% CI, 16 to 33) and 53% (95% CI, 43 to 63), respectively; at 6 months, the The rates were 45% (95% CI, 35 to 54) and 68% (95% CI, 58 to 77), respectively
.
Panel B shows the time to complete remission
.
In arm B, the median time to complete remission was 9.
1 months, while in arm A, less than 50% of patients had complete remission during the trial observation period
.
Eltrombopag stimulates stem cell proliferation, is it possible to increase the generation of malignant clones? The researchers conducted a prospective analysis of gene mutation frequencies
.
During a median follow-up of 24 months, 1 case in group A and 2 cases in group B developed abnormal karyotype, which was classified as myelodysplastic syndrome; the event-free survival rates were 34% and 46%, respectively
.
At baseline, somatic mutations were detected in 29% (group A) and 31% (group B) of patients; at 6 months, this increased to 66% and 55%, respectively, but did not affect hematologic response and 2-year Prognosis
.
Figure 2.
Somatic Mutations [3] Panel A shows the frequency of mutations and variant allele frequencies (VAF) at baseline, 6 months, and 24 months
.
Variant allele frequencies for mutations are shown on a log scale
.
Box and whisker plots for specific gene mutations are shown; whiskers represent ranges, sides of boxes represent interquartile ranges, and vertical lines within each box represent medians
.
Grey dots represent individual mutations, and vertical lines over some grey dots represent ranges (minimum and maxima)
.
Panel B shows the frequency of mutations (expressed as the number of cases with 1 or ≥2 mutations) in each group at different time points
.
Panel C shows the variant allele frequency of mutations in each group in patients screened (45 patients) and in patients with detectable mutations at all three time points (34 patients)
.
Figure 3.
Event-Free Survival and Stacked Cumulative Incidence Curves [3] Panel A shows Kaplan-Meier curves for event-free survival by treatment group
.
Shaded area represents 95% CI
.
In arm A, event-free survival was 59% (95% CI, 50 to 69) at 6 months; 41% (95% CI, 31 to 50) at 12 months; and 24 months, was 34% (95% CI, 24 to 44); in arm B, the event-free survival rates at these time points were 79% (95% CI, 71 to 87) and 56% (95% CI, 46 to 66), respectively ) and 46% (95% CI, 36 to 57)
.
Events included no response at 6 months, hematopoietic stem cell transplantation, any other treatment for aplastic anemia, clonal evolution, relapse, or death
.
Panel B shows the stacked cumulative incidence curves by event
.
The graph shows the total cumulative incidence of events (1 - event-free survival) according to the type of event that occurred
.
In Panel B, eltrombopag was reintroduced according to the protocol in the event of a relapse or weak hematologic response
.
The results of this study demonstrate that the addition of eltrombopag to standard immunosuppressive therapy improves the rate of hematologic response in previously untreated patients with severe aplastic anemia without additional toxic effects
.
Of course, since the follow-up time is only 2 years, it is difficult to draw a firm conclusion that Eltrombopag does not cause cancer
.
In the past three decades, aplastic anemia has seriously endangered human health as a blood disease with high mortality and low quality of life
.
Improving prognosis and quality of life has always been the core of exploration
.
Various previous clinical studies including replacement of equine ATG with rabbit ATG, alemtuzumab, or cyclophosphamide; addition of a third immunosuppressive drug such as mycophenolate mofetil or sirolimus; addition of hematopoietic growth to standard therapy factor, has not achieved good curative effect, or has certain carcinogenicity
.
Multiple clinical trials of eltrombopag in patients with aplastic anemia have shown higher quality, faster remission, and no increase in the occurrence of malignant clones, making it a powerful weapon for hematologists
.
We look forward to the early arrival of the next important therapeutic advance, making aplastic anemia a curable disease
.
Reference 1.
Olnes MJ, Scheinberg P, Calvo KR, et al.
Eltrombopag and improved hematopoiesis in refractory aplastic anemia.
N Engl J Med 2012;367:11-19.
2.
Townsley DM, Scheinberg P, Winkler T, et al.
Eltrombopag added to standard immunosuppression for aplastic anemia.
N Engl J Med 2017;376:1540-50.
3.
Peffault de Latour R, Kulasekararaj A, Iacbelli S, et al.
Eltrombopag added to immunosuppression in severe aplastic anemia.
N Engl J Med 2022;386 :11-23.
The author introduces Yu Li, doctor, chief physician, professor, doctoral/master tutor
.
Director of the Department of Hematology, the Second Affiliated Hospital of Nanchang University, member of the Standing Committee of the Hematology Branch of the Chinese Medical Doctor Association (the 5th session), Deputy Head of the China Castleman Disease Collaborative Group, Chairman of the Hematology and Oncology Professional Committee of the Jiangxi Anti-Cancer Association, and Hematology of the Jiangxi Medical Association Vice-chairman of the branch, vice-chairman of the Hematologist Branch of the Jiangxi Medical Association, director of the Jiangxi Anti-Cancer Association, chairman of the Youth Committee of the Hematology Branch of the Jiangxi Research Hospital Association, and deputy of the Jiangxi Research Hospital Integrated Traditional Chinese and Western Medicine Hematology Branch Chairman, Vice Chairman of Hematology Branch of Jiangxi Provincial Health Care Association
.
Fei Yan, Deputy Chief Physician, Head of aplastic anemia sub-specialist in the Department of Hematology, Second Affiliated Hospital of Nanchang University
.
He is currently a member of the Hematology Branch of Jiangxi Research Medical Association, a standing member of the Youth Committee of the Hematology Branch of Jiangxi Research Medical Association, and a member of the Hematology Branch of Jiangxi Health Care Association.
.
Vice-chairman of the Lymphoma Professional Youth Committee of Jiangxi Anti-Cancer Association
.
Copyright Information This article was translated, written or commissioned by the NEJM Frontiers in Medicine, jointly created by Jiahui Medical Research and Education Group (J-Med) and The New England Journal of Medicine (NEJM)
.
The full text of the Chinese translation and the included figures are exclusively authorized by the NEJM Group
.
If you want to reprint, please leave a message or contact nejmqianyan@nejmqianyan.
cn
.
Unauthorized translation is an infringement, and the copyright owner reserves the right to pursue legal responsibility
.
.
Although the incidence rate is not high, China has a large population base, and the actual number of patients is relatively large
.
Since the establishment of antithymocyte globulin combined with cyclosporine as the standard immunotherapy for aplastic anemia in the 1980s, there has been a lack of important progress in the treatment of aplastic anemia in the past 30 years
.
On January 6, 2022, the New England Journal of Medicine (NEJM) published the results of the RACE trial in Europe, confirming that the standard immunotherapy regimen combined with eltrombopag in severe and very severe aplastic anemia improved the rate of hematologic response, speed and intensity
.
The editorial issued at the same time pointed out: "The results of this trial support the use of equine antithymocyte globulin, cyclosporine combined with eltrombopag as a new standard immunotherapy regimen for aplastic anemia
.
" "NEJM Medical Frontiers" is invited here The team of Professor Yu Li from the Second Affiliated Hospital of Nanchang University interpreted the study
.
To read the full text translation, please visit the official website of NEJM Medical Frontiers, APP or click on the WeChat applet picture
.
Fei Yan, Yu Li *Department of Hematology, The Second Affiliated Hospital of Nanchang University *Corresponding Author Acquired aplastic anemia is a primary bone marrow failure disease manifested by pancytopenia, which seriously affects the production and life of patients, even life-threatening
.
The most important pathogenesis of the disease is the hyperimmunity of T lymphocytes
.
The introduction of antithymocyte globulin (ATG) in the late 1970s, and the addition of cyclosporine to ATG in the 1980s, significantly improved hematopoietic recovery and survival in patients with severe or very severe aplastic anemia
.
In this way, cyclosporine combined with ATG has become the standard immunotherapy regimen for severe aplastic anemia, but the reduction in the number of residual stem cells in patients with aplastic anemia will limit the efficacy of standard immunotherapy
.
The survival status of aplastic anemia still has many unmet clinical needs to be solved: the hematopoietic response rate of patients after standard immunotherapy is only 42%-74%, and about 1/3 of patients with aplastic anemia are ineffective in standard immunotherapy.
Disease recurrence occurs in 20% to 40% of patients who respond to initial therapy
.
Therefore, how to improve the hematological response rate and long-term remission rate of patients with severe aplastic anemia is an urgent problem
.
There is still a long way to go in the development of new treatment options
.
Eltrombopag is an oral non-peptide thrombopoietin receptor agonist that acts on the transmembrane region of the thrombopoietin receptor to stimulate the differentiation of bone marrow hematopoietic stem cells, progenitor cells, precursor cells, etc.
Involved in the production of blood cells
.
In July 2012, the New England Journal of Medicine (NEJM) published the results of Olnes et al.
[1], demonstrating the efficacy of eltrombopag in patients with aplastic anemia refractory to standard immunotherapy
.
This is an investigator-initiated Phase 2, open-label, single-arm trial
.
Inclusion criteria were patients with severe aplastic anemia who failed to respond to standard immunotherapy at least 1 time, and who had completed standard immunotherapy for at least 6 months, platelet count ≤30,000/µl, age ≥18 years (core study phase) and ≥12 years old ( extended research phase)
.
Twenty-five patients received eltrombopag at a dose of 50 mg, which could be increased to a maximum dose of 150 mg per day for 12 weeks if needed, and continued eltrombopag in those in remission
.
The primary endpoint was hematologic remission and adverse effects after 12 weeks of eltrombopag treatment, and secondary endpoints included the incidence and severity of bleeding events
.
The results showed that the remission rate was 40%, and it was well tolerated, and the incidence of myelofibrosis was not significantly increased
.
Based on the results of this study, eltrombopag was approved by the US Food and Drug Administration (2014) and the European Medicines Agency (2015) for the treatment of severe aplastic anemia
.
In 2017, NEJM republished a study on Eltrombopag in the treatment of aplastic anemia [2]
.
This is a prospective phase 1/2 clinical trial of immunosuppressive therapy plus eltrombopag in aplastic anemia, enrolling 92 consecutive patients and divided into 3 cohorts
.
The 3 cohorts differed in the initiation and duration of eltrombopag administration (cohort 1 received eltrombopag from days 14 to 6 months, and cohort 2 received eltrombopag from days 14 to 3 months).
Popa, Cohort 3 received Eltrombopag from months 1 to 6)
.
The primary study endpoint was complete hematologic remission at 6 months
.
Secondary endpoints included overall response, survival, relapse, and evolution of bone marrow malignant clones
.
The 6-month complete response rate was 33% in cohort 1, 26% in cohort 2, and 58% in cohort 3
.
The 6-month overall response rates were 80%, 87%, and 94%, respectively
.
Complete and overall response rates in the combined cohort were higher than the center's historical data (complete response rate 10%, overall response rate 66%)
.
With a median follow-up of 2 years, the survival rate was 97%
.
One patient died of non-hematologic causes during the study period
.
The number of bone marrow cells, the number of CD34+ cells and the number of early hematopoietic progenitor cells were significantly increased in the experimental group
.
Recurrence rates and clonal evolution are similar to historical experience
.
Two patients developed severe rash, which led to early discontinuation of eltrombopag
.
In January 2022, the results of the third study were published in NEJM[3]
.
This is an investigator-initiated, multicenter, open-label, randomized phase 3 trial comparing equine ATG plus cyclosporine with or without eltrombopag in untreated patients with severe or very severe aplastic anemia
.
The patients were divided into immunosuppressive treatment group (group A, 101 cases, horse ATG 40 mg/kg, day 1-4; cyclosporine 5 mg/kg, starting from day 1, at least 12 months, and gradually tapering thereafter , and discontinued within 24 months) and immunosuppressive therapy + eltrombopag group (group B, 96 patients, immunosuppressive therapy plus oral eltrombopag, 150 mg, from day 14 to month 6 or complete remission at 3 months)
.
Complete remission at 3 months was 10% in group A and 22% in group
B.
At 6 months, the overall response rate (complete and partial) was 41% in arm A and 68% in arm
B.
The median time to first response was 8.
8 months (group A) and 3.
0 months (group B)
.
The incidence of serious adverse events was similar in the two groups
.
Figure 1.
Kinetics of Hematologic Remission [3] Cumulative Incidence of Remission Curves by Treatment Group
.
Shaded area represents 95% CI
.
Competing events include hematopoietic stem cell transplantation, any other treatment for aplastic anemia, clonal evolution, and death
.
Panel A shows the time to first remission
.
In Arms A and B, the cumulative incidence of first remission at 3 months was 25% (95% CI, 16 to 33) and 53% (95% CI, 43 to 63), respectively; at 6 months, the The rates were 45% (95% CI, 35 to 54) and 68% (95% CI, 58 to 77), respectively
.
Panel B shows the time to complete remission
.
In arm B, the median time to complete remission was 9.
1 months, while in arm A, less than 50% of patients had complete remission during the trial observation period
.
Eltrombopag stimulates stem cell proliferation, is it possible to increase the generation of malignant clones? The researchers conducted a prospective analysis of gene mutation frequencies
.
During a median follow-up of 24 months, 1 case in group A and 2 cases in group B developed abnormal karyotype, which was classified as myelodysplastic syndrome; the event-free survival rates were 34% and 46%, respectively
.
At baseline, somatic mutations were detected in 29% (group A) and 31% (group B) of patients; at 6 months, this increased to 66% and 55%, respectively, but did not affect hematologic response and 2-year Prognosis
.
Figure 2.
Somatic Mutations [3] Panel A shows the frequency of mutations and variant allele frequencies (VAF) at baseline, 6 months, and 24 months
.
Variant allele frequencies for mutations are shown on a log scale
.
Box and whisker plots for specific gene mutations are shown; whiskers represent ranges, sides of boxes represent interquartile ranges, and vertical lines within each box represent medians
.
Grey dots represent individual mutations, and vertical lines over some grey dots represent ranges (minimum and maxima)
.
Panel B shows the frequency of mutations (expressed as the number of cases with 1 or ≥2 mutations) in each group at different time points
.
Panel C shows the variant allele frequency of mutations in each group in patients screened (45 patients) and in patients with detectable mutations at all three time points (34 patients)
.
Figure 3.
Event-Free Survival and Stacked Cumulative Incidence Curves [3] Panel A shows Kaplan-Meier curves for event-free survival by treatment group
.
Shaded area represents 95% CI
.
In arm A, event-free survival was 59% (95% CI, 50 to 69) at 6 months; 41% (95% CI, 31 to 50) at 12 months; and 24 months, was 34% (95% CI, 24 to 44); in arm B, the event-free survival rates at these time points were 79% (95% CI, 71 to 87) and 56% (95% CI, 46 to 66), respectively ) and 46% (95% CI, 36 to 57)
.
Events included no response at 6 months, hematopoietic stem cell transplantation, any other treatment for aplastic anemia, clonal evolution, relapse, or death
.
Panel B shows the stacked cumulative incidence curves by event
.
The graph shows the total cumulative incidence of events (1 - event-free survival) according to the type of event that occurred
.
In Panel B, eltrombopag was reintroduced according to the protocol in the event of a relapse or weak hematologic response
.
The results of this study demonstrate that the addition of eltrombopag to standard immunosuppressive therapy improves the rate of hematologic response in previously untreated patients with severe aplastic anemia without additional toxic effects
.
Of course, since the follow-up time is only 2 years, it is difficult to draw a firm conclusion that Eltrombopag does not cause cancer
.
In the past three decades, aplastic anemia has seriously endangered human health as a blood disease with high mortality and low quality of life
.
Improving prognosis and quality of life has always been the core of exploration
.
Various previous clinical studies including replacement of equine ATG with rabbit ATG, alemtuzumab, or cyclophosphamide; addition of a third immunosuppressive drug such as mycophenolate mofetil or sirolimus; addition of hematopoietic growth to standard therapy factor, has not achieved good curative effect, or has certain carcinogenicity
.
Multiple clinical trials of eltrombopag in patients with aplastic anemia have shown higher quality, faster remission, and no increase in the occurrence of malignant clones, making it a powerful weapon for hematologists
.
We look forward to the early arrival of the next important therapeutic advance, making aplastic anemia a curable disease
.
Reference 1.
Olnes MJ, Scheinberg P, Calvo KR, et al.
Eltrombopag and improved hematopoiesis in refractory aplastic anemia.
N Engl J Med 2012;367:11-19.
2.
Townsley DM, Scheinberg P, Winkler T, et al.
Eltrombopag added to standard immunosuppression for aplastic anemia.
N Engl J Med 2017;376:1540-50.
3.
Peffault de Latour R, Kulasekararaj A, Iacbelli S, et al.
Eltrombopag added to immunosuppression in severe aplastic anemia.
N Engl J Med 2022;386 :11-23.
The author introduces Yu Li, doctor, chief physician, professor, doctoral/master tutor
.
Director of the Department of Hematology, the Second Affiliated Hospital of Nanchang University, member of the Standing Committee of the Hematology Branch of the Chinese Medical Doctor Association (the 5th session), Deputy Head of the China Castleman Disease Collaborative Group, Chairman of the Hematology and Oncology Professional Committee of the Jiangxi Anti-Cancer Association, and Hematology of the Jiangxi Medical Association Vice-chairman of the branch, vice-chairman of the Hematologist Branch of the Jiangxi Medical Association, director of the Jiangxi Anti-Cancer Association, chairman of the Youth Committee of the Hematology Branch of the Jiangxi Research Hospital Association, and deputy of the Jiangxi Research Hospital Integrated Traditional Chinese and Western Medicine Hematology Branch Chairman, Vice Chairman of Hematology Branch of Jiangxi Provincial Health Care Association
.
Fei Yan, Deputy Chief Physician, Head of aplastic anemia sub-specialist in the Department of Hematology, Second Affiliated Hospital of Nanchang University
.
He is currently a member of the Hematology Branch of Jiangxi Research Medical Association, a standing member of the Youth Committee of the Hematology Branch of Jiangxi Research Medical Association, and a member of the Hematology Branch of Jiangxi Health Care Association.
.
Vice-chairman of the Lymphoma Professional Youth Committee of Jiangxi Anti-Cancer Association
.
Copyright Information This article was translated, written or commissioned by the NEJM Frontiers in Medicine, jointly created by Jiahui Medical Research and Education Group (J-Med) and The New England Journal of Medicine (NEJM)
.
The full text of the Chinese translation and the included figures are exclusively authorized by the NEJM Group
.
If you want to reprint, please leave a message or contact nejmqianyan@nejmqianyan.
cn
.
Unauthorized translation is an infringement, and the copyright owner reserves the right to pursue legal responsibility
.
