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Recently, Professor Benjamin Watkins and others published a report aimed at evaluating Abatacept combined with calcineurin inhibitor (CNI) and methotrexate (MTX) to prevent acute graft resistance after allogeneic hematopoietic stem cell transplant (allo-HSCT) Results of a Phase II clinical study (ABA2 trial) on the efficacy of host disease (aGVHD).
Research background Allo-HSCT is an effective treatment for aggressive hematological malignancies and is usually the only cure.
For patients who lack a complete sibling donor, an unrelated donor (URD) is usually chosen.
The main problems in choosing URD for allo-HSCT are non-recurring mortality (NRM) caused by aGVHD, chronic GVHD (cGVHD) and the incidence of infection will increase.
The use of URDs that do not match HLA will further increase the above-mentioned risks.
The incidence of severe aGVHD is as high as 37%, and the NRM caused by aGVHD is as high as 45%.
Although some ethnic minority patients lack HLA-compatible URDs, most of them have HLA7/8 URDs available.
Therefore, it is particularly important to improve the safety of allo-HSCT in patients with such high-risk transplants.
Pre-clinical research data show that costimulatory blockers and cytotoxic T lymphocytes-4-immunoglobulin (Abatacept) can prevent GVHD; at the same time, the results also provide a theoretical basis for the first human study of Abatacept to prevent GVHD, and confirm The feasibility and safety of this method are discussed.
On the basis of the above content, Professor Benjamin Watkins and others have carried out a phase II clinical study (ABA2 trial) of Abatacept combined with standard CNI+MTX to prevent severe aGVHD, aiming to verify the following hypothesis: Abatacept can reduce the acceptance of HLA7/8 or 8/8 URD allo-HSCT patients are at risk of severe aGVHD, thereby improving the clinical outcome of transplant patients.
Research method Eligible allo-HSCT patients in the ABA2 trial received Abatacept or placebo combined with standard CNI (such as cyclosporine or tacrolimus) and MTX (15mg/m2 d+1 and 10mg/m2 d+3, + 6 and +11) Treatment.
Among them, CNI continued to be used until d+100 after transplantation, and patients who can tolerate it will gradually decrease and stop between d100-180 after transplantation.
For patients receiving Abatacept, four doses were administered at d-1, +5, +14, and +28, each with a dose of 10 mg/kg.
In the cohort of patients receiving HLA8/8 URD allo-HSCT, it was designed as a double-blind, placebo-controlled study.
Patients were randomized 1:1 to receive Abatacept combined with CNI+MTX (Abatacept group) or placebo combined with CNI+MTX (placebo group) ) Prevent GVHD.
The cohort of patients receiving HLA7/8 URD allo-HSCT was designed as an open-label, single-arm study and compared with a pre-set control cohort set by the International Center for Blood and Bone Marrow Transplantation Research (CIBMTR).
The primary endpoint of the study is the occurrence of severe (grade 3-4) aGVHD at transplantation d+100; the primary secondary endpoint is the non-severe aGVHD survival rate (SGFS) at transplantation d+180, and other secondary endpoints include patients after transplantation The occurrence of grade 3-4 aGVHD at d+180, the occurrence of grade 2-4 aGVHD at d+100 and +180, the cumulative incidence of cGVHD at 1 year, NRM, recurrence, recurrence-free survival (RFS), total Lifetime (OS), etc.
The results of the study in patients receiving HLA8/8 URD allo-HSCT, using Abatacept compared with placebo combined with CNI+MTX to prevent GVHD, can significantly reduce the incidence of aGVHD.
In the HLA8/8 URD allo-HSCT cohort, the incidence of grade 3-4 aGVHD in the Abatacept group vs.
the placebo group was 6.
8% vs 14.
8% (P=0.
13).
Patients receiving HLA7/8 URD allo-HSCT can also reduce the incidence of aGVHD compared with non-random matched cohorts.
In the HLA7/8 URD allo-HSCT cohort, using Abatacept combined with CNI+MTX to prevent GVHD, the incidence of grade 3-4 aGVHD in the intention-to-treat (ITT) population was 2.
3%; significantly lower than the aGVHD in the non-random matched cohort The incidence rate was 30.
2% (P<0.
001).
The study also conducted an exploratory analysis of other secondary aGVHD-related endpoints.
The results showed that compared with controls, Abatacept combined with CNI+MTX to prevent GVHD, all aGVHD-related secondary endpoints have significant benefits.
In the HLA8/8 URD allo-HSCT cohort, the d+180 SGFS after transplantation in the Abatacept group and the placebo group were 93.
2% vs 82%, respectively (P=0.
05).
In the HLA7/8 URD allo-HSCT cohort, the SGFS of d+180 after transplantation in the ITT population in the Abatacept group was 97.
7%; it was significantly better than the non-random matched cohort (58.
7%) that received CNI+MTX (P<0.
001).
Overall, the Abatacept group did not improve the patient's cGVHD condition compared with the placebo group.
In the HLA7/8 and 8/8 URD allo-HSCT cohorts, the cumulative incidence of young cGVHD in patients 1 with Abatacept included in the GVHD prevention program was 62.
0% and 51.
9%, respectively, while the non-randomized matched cohort and the placebo control group, respectively They were 45.
9% and 45.
3% (P=0.
74 and P=0.
55).
In the HLA 8/8 URD allo-HSCT cohort, the 1-year cumulative incidence of moderate to severe cGVHD in the Abatacept group and placebo group were 62.
0% and 51.
9% (P=0.
32); HLA7/8 URD allo-HSCT In the cohort, the cumulative incidence of moderate to severe cGVHD in patients with Abatacept included in the GVHD prevention program was 57.
9% at 1 year.
On the whole, the addition of Abatacept will not increase the recurrence rate of patients.
In the HLA7/8 URD allo-HSCT cohort, using Abatacept combined with CNI+MTX to prevent GVHD, the 2-year cumulative recurrence rate in the ITT population was 9.
3%, compared with 21.
4% in the non-random matched cohort.
In the HLA8/8 URD allo-HSCT cohort, the 2-year cumulative recurrence rate in the Abatacept group was 21.
5%, compared with 23.
6% in the placebo group.
In addition, in the HLA7/8 URD allo-HSCT cohort, the use of the GVHD prevention program containing Abatacept significantly improved the patients' NRM, RFS and OS.
In the HLA8/8 URD allo-HSCT cohort of surviving patients with a median follow-up time of 716 days, the data showed that the use of the Abatacept group to prevent GVHD compared with the placebo group did not significantly benefit patients' NRM, RFS and OS.
Research conclusions The research shows that for URD allo-HSCT patients, combined with Abatacept on the basis of CNI+MTX can reduce the incidence of aGVHD, increase SGFS, and has good safety.
References: Benjamin Watkins, Muna Qayed, Courtney McCracken, et al.
Phase II Trial of Costimulation Blockade With Abatacept for Prevention of Acute GVHD.
J Clin Oncol.
2021 Jan 15; JCO2001086.
Stamp "read the original text", we make progress together
Research background Allo-HSCT is an effective treatment for aggressive hematological malignancies and is usually the only cure.
For patients who lack a complete sibling donor, an unrelated donor (URD) is usually chosen.
The main problems in choosing URD for allo-HSCT are non-recurring mortality (NRM) caused by aGVHD, chronic GVHD (cGVHD) and the incidence of infection will increase.
The use of URDs that do not match HLA will further increase the above-mentioned risks.
The incidence of severe aGVHD is as high as 37%, and the NRM caused by aGVHD is as high as 45%.
Although some ethnic minority patients lack HLA-compatible URDs, most of them have HLA7/8 URDs available.
Therefore, it is particularly important to improve the safety of allo-HSCT in patients with such high-risk transplants.
Pre-clinical research data show that costimulatory blockers and cytotoxic T lymphocytes-4-immunoglobulin (Abatacept) can prevent GVHD; at the same time, the results also provide a theoretical basis for the first human study of Abatacept to prevent GVHD, and confirm The feasibility and safety of this method are discussed.
On the basis of the above content, Professor Benjamin Watkins and others have carried out a phase II clinical study (ABA2 trial) of Abatacept combined with standard CNI+MTX to prevent severe aGVHD, aiming to verify the following hypothesis: Abatacept can reduce the acceptance of HLA7/8 or 8/8 URD allo-HSCT patients are at risk of severe aGVHD, thereby improving the clinical outcome of transplant patients.
Research method Eligible allo-HSCT patients in the ABA2 trial received Abatacept or placebo combined with standard CNI (such as cyclosporine or tacrolimus) and MTX (15mg/m2 d+1 and 10mg/m2 d+3, + 6 and +11) Treatment.
Among them, CNI continued to be used until d+100 after transplantation, and patients who can tolerate it will gradually decrease and stop between d100-180 after transplantation.
For patients receiving Abatacept, four doses were administered at d-1, +5, +14, and +28, each with a dose of 10 mg/kg.
In the cohort of patients receiving HLA8/8 URD allo-HSCT, it was designed as a double-blind, placebo-controlled study.
Patients were randomized 1:1 to receive Abatacept combined with CNI+MTX (Abatacept group) or placebo combined with CNI+MTX (placebo group) ) Prevent GVHD.
The cohort of patients receiving HLA7/8 URD allo-HSCT was designed as an open-label, single-arm study and compared with a pre-set control cohort set by the International Center for Blood and Bone Marrow Transplantation Research (CIBMTR).
The primary endpoint of the study is the occurrence of severe (grade 3-4) aGVHD at transplantation d+100; the primary secondary endpoint is the non-severe aGVHD survival rate (SGFS) at transplantation d+180, and other secondary endpoints include patients after transplantation The occurrence of grade 3-4 aGVHD at d+180, the occurrence of grade 2-4 aGVHD at d+100 and +180, the cumulative incidence of cGVHD at 1 year, NRM, recurrence, recurrence-free survival (RFS), total Lifetime (OS), etc.
The results of the study in patients receiving HLA8/8 URD allo-HSCT, using Abatacept compared with placebo combined with CNI+MTX to prevent GVHD, can significantly reduce the incidence of aGVHD.
In the HLA8/8 URD allo-HSCT cohort, the incidence of grade 3-4 aGVHD in the Abatacept group vs.
the placebo group was 6.
8% vs 14.
8% (P=0.
13).
Patients receiving HLA7/8 URD allo-HSCT can also reduce the incidence of aGVHD compared with non-random matched cohorts.
In the HLA7/8 URD allo-HSCT cohort, using Abatacept combined with CNI+MTX to prevent GVHD, the incidence of grade 3-4 aGVHD in the intention-to-treat (ITT) population was 2.
3%; significantly lower than the aGVHD in the non-random matched cohort The incidence rate was 30.
2% (P<0.
001).
The study also conducted an exploratory analysis of other secondary aGVHD-related endpoints.
The results showed that compared with controls, Abatacept combined with CNI+MTX to prevent GVHD, all aGVHD-related secondary endpoints have significant benefits.
In the HLA8/8 URD allo-HSCT cohort, the d+180 SGFS after transplantation in the Abatacept group and the placebo group were 93.
2% vs 82%, respectively (P=0.
05).
In the HLA7/8 URD allo-HSCT cohort, the SGFS of d+180 after transplantation in the ITT population in the Abatacept group was 97.
7%; it was significantly better than the non-random matched cohort (58.
7%) that received CNI+MTX (P<0.
001).
Overall, the Abatacept group did not improve the patient's cGVHD condition compared with the placebo group.
In the HLA7/8 and 8/8 URD allo-HSCT cohorts, the cumulative incidence of young cGVHD in patients 1 with Abatacept included in the GVHD prevention program was 62.
0% and 51.
9%, respectively, while the non-randomized matched cohort and the placebo control group, respectively They were 45.
9% and 45.
3% (P=0.
74 and P=0.
55).
In the HLA 8/8 URD allo-HSCT cohort, the 1-year cumulative incidence of moderate to severe cGVHD in the Abatacept group and placebo group were 62.
0% and 51.
9% (P=0.
32); HLA7/8 URD allo-HSCT In the cohort, the cumulative incidence of moderate to severe cGVHD in patients with Abatacept included in the GVHD prevention program was 57.
9% at 1 year.
On the whole, the addition of Abatacept will not increase the recurrence rate of patients.
In the HLA7/8 URD allo-HSCT cohort, using Abatacept combined with CNI+MTX to prevent GVHD, the 2-year cumulative recurrence rate in the ITT population was 9.
3%, compared with 21.
4% in the non-random matched cohort.
In the HLA8/8 URD allo-HSCT cohort, the 2-year cumulative recurrence rate in the Abatacept group was 21.
5%, compared with 23.
6% in the placebo group.
In addition, in the HLA7/8 URD allo-HSCT cohort, the use of the GVHD prevention program containing Abatacept significantly improved the patients' NRM, RFS and OS.
In the HLA8/8 URD allo-HSCT cohort of surviving patients with a median follow-up time of 716 days, the data showed that the use of the Abatacept group to prevent GVHD compared with the placebo group did not significantly benefit patients' NRM, RFS and OS.
Research conclusions The research shows that for URD allo-HSCT patients, combined with Abatacept on the basis of CNI+MTX can reduce the incidence of aGVHD, increase SGFS, and has good safety.
References: Benjamin Watkins, Muna Qayed, Courtney McCracken, et al.
Phase II Trial of Costimulation Blockade With Abatacept for Prevention of Acute GVHD.
J Clin Oncol.
2021 Jan 15; JCO2001086.
Stamp "read the original text", we make progress together
