Ignite Creation Date:
2024-05-06 @ 6:02 PM
Last Modification Date:
2024-10-26 @ 2:40 PM
Study NCT ID:
NCT05520749
Status:
COMPLETED
Last Update Posted:
2023-02-15
First Post:
2022-08-26
Brief Title:
Efficacy and Safety of Luspatercept A Study by Fondazione Italiana Sindromi Mielodisplastiche
Sponsor:
Fondazione Italiana Sindromi Mielodisplastiche-ETS
Organization:
Fondazione Italiana Sindromi Mielodisplastiche-ETS
Study Overview
Official Title:
Efficacy and Safety of Luspatercept in Adult Patients With Transfusion-dependent Anemia Due to Very Low- Low- and Intermediate-risk IPSS-R Myelodysplastic Syndrome With Ring Sideroblasts a Retrospective Multicenter Study by FISiM-ETS
Status:
COMPLETED
Status Verified Date:
2023-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
FISiM-Luspa
Brief Summary:
Myelodysplastic syndromes MDS are a group of malignancies characterized by reduced differentiation and increased apoptosis of hematopoietic progenitor cells leading to ineffective hematopoiesis Treatment of MDS varies according to prognosis Patients with low IPSS-R risk have a low probability of progression to acute myeloid leukemia AML and the treatment is aimed at controlling cytopenia and improving quality of life QOL Anemia is the most common disease feature occurring in 80-85 of low-risk patients 40 of whom eventually become RBC transfusion-dependent TD
Luspatercept is a recombinant fusion protein that selectively binds to ligands belonging to the transforming growth factor-beta TGF-beta superfamily Luspatercept binds to GDF11 GDF8 activin B and other ligands This binding leads to inhibition of Smad23 signaling which is abnormally high in disease models of ineffective erythropoiesis such as MDS resulting in erythroid maturation and differentiation
Luspatercept is now approved for the treatment of adult patients with TD anemia due to very low- low- and intermediate-risk MDS with ring sideroblasts who had an unsatisfactory response to or are ineligible for erythropoietin-based therapy
FISiM Fondazione Italiana Sindromi Mielodidplastiche promotes a multicenter retrospective observational study to collect information on the efficacy and safety of luspatercept in a real world Italian population of adult patients with transfusion-dependent anemia due to very low- and intermediate-risk MDS with ring sideroblasts
Luspatercept is a recombinant fusion protein that selectively binds to ligands belonging to the transforming growth factor-beta TGF-beta superfamily Luspatercept binds to GDF11 GDF8 activin B and other ligands This binding leads to inhibition of Smad23 signaling which is abnormally high in disease models of ineffective erythropoiesis such as MDS resulting in erythroid maturation and differentiation
Luspatercept is now approved for the treatment of adult patients with TD anemia due to very low- low- and intermediate-risk MDS with ring sideroblasts who had an unsatisfactory response to or are ineligible for erythropoietin-based therapy
FISiM Fondazione Italiana Sindromi Mielodidplastiche promotes a multicenter retrospective observational study to collect information on the efficacy and safety of luspatercept in a real world Italian population of adult patients with transfusion-dependent anemia due to very low- and intermediate-risk MDS with ring sideroblasts
Detailed Description:
Myelodysplastic syndromes MDS are a group of malignancies characterized by reduced differentiation and increased apoptosis of hematopoietic progenitor cells leading to ineffective hematopoiesis The incidence of MDS ranges from 15 to 4 cases per 100000 individuals per year Prognosis is determined by a number of factors including age cytogenetic abnormalities and cytopenia as determined by the Revised International Prognostic Scoring System IPSS-R but also by the occurrence of molecular aberrations eg gene mutations and red blood cell RBC transfusion dependence
Treatment of MDS varies according to prognosis Patients with low IPSS-R risk have a low probability of progression to acute myeloid leukemia AML and the treatment is aimed at controlling cytopenia and improving quality of life QOL whereas patients with high-risk disease have a shorter life expectancy and treatment is aimed at modifying the natural course of the disease
Anemia is the most common disease feature occurring in 80-85 of low-risk patients 40 of whom eventually become RBC transfusion-dependent TD
Besides lenalidomide which is exclusively approved for patients with deletion of chromosome 5q erythropoiesis-stimulating agents ESAs constitute the first option for patients with low risk disease Patients who do not respond to ESAs have very limited options and ultimately require long-term RBC transfusions Chronic transfusions lead to secondary iron overload and have a deleterious effect on the patients QOL
On April 26 2019 Celgene Europe BV applied for a marketing authorization via the European Medicines Agency EMA centralized procedure for luspatercept trade name Reblozyl Luspatercept is a recombinant fusion protein that selectively binds to ligands belonging to the transforming growth factor-beta TGF-beta superfamily Luspatercept binds to GDF11 GDF8 activin B and other ligands This binding leads to inhibition of Smad23 signaling which is abnormally high in disease models of ineffective erythropoiesis such as MDS resulting in erythroid maturation and differentiation
The review of the benefit-risk balance was conducted by the Committee for Medicinal Products for Human Use CHMP and the positive opinion was issued on April 30 2020 The indication approved in the EU is as follows Reblozyl is indicated for the treatment of adult patients with TD anemia due to very low- low- and intermediate-risk MDS with ring sideroblasts who had an unsatisfactory response to or are ineligible for erythropoietin-based therapy
The clinical development program for luspatercept in MDS consists of 3 clinical trials including the phase 3 randomized double-blind placebo-controlled study ACE-536-MDS-001 MEDALIST and 2 supportive phase 2 open-label single-arm trials A536-03 and A536-05
In the MEDALIST trial adult patients with very low low or intermediate IPSS-R risk MDS with ring sideroblasts who required RBC transfusions were randomized 21 to luspatercept 1mgkg or placebo by the SC route every 3 weeks16 In both treatment groups best supportive care could be used when clinically indicated including RBC transfusions or iron chelation therapy but excluding ESAs or other MDS-directed agents The primary endpoint of the trial was the proportion of subjects who were RBC transfusion-independent RBC-TI over any 56-day period from week 1 to week 24
In the MEDALIST trial 229 subjects very low low or intermediate IPSS-R risk MDS with ring sideroblasts were randomized 153 to luspatercept and 76 to placebo ITT population Forty-nine 214 patients discontinued from the study with no differences between arms Patients baseline characteristics and prior medication use were well balanced across treatment arms The percentage of responders RBC-TI during 56 d through week 24 was 3791 versus 1316 P 00001 for patients receiving luspatercept versus placebo respectively Table 1 When the assessment period was extended to 84 days the proportion of responders was 3333 versus 1184 through week 48 and 2810 versus 789 through week 24
The safety database comprised 571 subjects who received luspatercept The mean luspatercept treatment duration was 49 weeks median 456 Treatment emergent adverse events TEAEs were documented in 953 of patients in the pooled luspatercept group compared to 912 of patients in the placebo group Incidence rates of serious TEAEs 238 versus 150 grade 3 TEAEs 349 versus 259 and TEAEs leading to permanent drug discontinuation 88 versus 36 were higher in the pooled luspatercept group In the MDS cohort the most frequent TEAEs leading to discontinuation were progression to high-risk MDS transformation to AML general physical deterioration and sepsis Fatal TEAEs were observed in 18 versus 26 of patients receiving luspatercept versus placebo The most frequently reported TEAEs 15 in the MDS group were fatigue diarrhea nausea cough dizziness hypertension peripheral edema headache viral upper respiratory tract infection and back pain
Overall luspatercept significantly reduced red blood cell RBC transfusion requirements in patients with MDS with ring sideroblasts and had a generally manageable tolerability profile in clinical trials Thus luspatercept is an emerging treatment option in adults with transfusion-dependent anaemia due to MDS
Despite that luspatercept is approved based on data of safety and efficacy from a large randomized clinical trial the authors know that especially for human diseases arising in elderly people features of subjects included in those randomized trials often do not reflect those of the population in which a therapy is intended to be used Compliance to treatment and safety in clinical trials can also differ from real world settings Consequently in order to drive clinical decision-making process data from randomized clinical trials should be integrated with evidence generated in a real world setting
To date no information is available on the efficacy and safety luspatercept in the treatment of MDS in real world populations FiSIM Fondazione Italiana Sindromi Mielodisplastiche promotes a multicenter retrospective observational study to collect information on the efficacy and safety of luspatercept in a real world Italian population of adult patients with transfusion-dependent anemia due to very low- and intermediate-risk MDS with ring sideroblasts who had an unsatisfactory response to or are ineligible for erythropoietin-based therapy
Treatment of MDS varies according to prognosis Patients with low IPSS-R risk have a low probability of progression to acute myeloid leukemia AML and the treatment is aimed at controlling cytopenia and improving quality of life QOL whereas patients with high-risk disease have a shorter life expectancy and treatment is aimed at modifying the natural course of the disease
Anemia is the most common disease feature occurring in 80-85 of low-risk patients 40 of whom eventually become RBC transfusion-dependent TD
Besides lenalidomide which is exclusively approved for patients with deletion of chromosome 5q erythropoiesis-stimulating agents ESAs constitute the first option for patients with low risk disease Patients who do not respond to ESAs have very limited options and ultimately require long-term RBC transfusions Chronic transfusions lead to secondary iron overload and have a deleterious effect on the patients QOL
On April 26 2019 Celgene Europe BV applied for a marketing authorization via the European Medicines Agency EMA centralized procedure for luspatercept trade name Reblozyl Luspatercept is a recombinant fusion protein that selectively binds to ligands belonging to the transforming growth factor-beta TGF-beta superfamily Luspatercept binds to GDF11 GDF8 activin B and other ligands This binding leads to inhibition of Smad23 signaling which is abnormally high in disease models of ineffective erythropoiesis such as MDS resulting in erythroid maturation and differentiation
The review of the benefit-risk balance was conducted by the Committee for Medicinal Products for Human Use CHMP and the positive opinion was issued on April 30 2020 The indication approved in the EU is as follows Reblozyl is indicated for the treatment of adult patients with TD anemia due to very low- low- and intermediate-risk MDS with ring sideroblasts who had an unsatisfactory response to or are ineligible for erythropoietin-based therapy
The clinical development program for luspatercept in MDS consists of 3 clinical trials including the phase 3 randomized double-blind placebo-controlled study ACE-536-MDS-001 MEDALIST and 2 supportive phase 2 open-label single-arm trials A536-03 and A536-05
In the MEDALIST trial adult patients with very low low or intermediate IPSS-R risk MDS with ring sideroblasts who required RBC transfusions were randomized 21 to luspatercept 1mgkg or placebo by the SC route every 3 weeks16 In both treatment groups best supportive care could be used when clinically indicated including RBC transfusions or iron chelation therapy but excluding ESAs or other MDS-directed agents The primary endpoint of the trial was the proportion of subjects who were RBC transfusion-independent RBC-TI over any 56-day period from week 1 to week 24
In the MEDALIST trial 229 subjects very low low or intermediate IPSS-R risk MDS with ring sideroblasts were randomized 153 to luspatercept and 76 to placebo ITT population Forty-nine 214 patients discontinued from the study with no differences between arms Patients baseline characteristics and prior medication use were well balanced across treatment arms The percentage of responders RBC-TI during 56 d through week 24 was 3791 versus 1316 P 00001 for patients receiving luspatercept versus placebo respectively Table 1 When the assessment period was extended to 84 days the proportion of responders was 3333 versus 1184 through week 48 and 2810 versus 789 through week 24
The safety database comprised 571 subjects who received luspatercept The mean luspatercept treatment duration was 49 weeks median 456 Treatment emergent adverse events TEAEs were documented in 953 of patients in the pooled luspatercept group compared to 912 of patients in the placebo group Incidence rates of serious TEAEs 238 versus 150 grade 3 TEAEs 349 versus 259 and TEAEs leading to permanent drug discontinuation 88 versus 36 were higher in the pooled luspatercept group In the MDS cohort the most frequent TEAEs leading to discontinuation were progression to high-risk MDS transformation to AML general physical deterioration and sepsis Fatal TEAEs were observed in 18 versus 26 of patients receiving luspatercept versus placebo The most frequently reported TEAEs 15 in the MDS group were fatigue diarrhea nausea cough dizziness hypertension peripheral edema headache viral upper respiratory tract infection and back pain
Overall luspatercept significantly reduced red blood cell RBC transfusion requirements in patients with MDS with ring sideroblasts and had a generally manageable tolerability profile in clinical trials Thus luspatercept is an emerging treatment option in adults with transfusion-dependent anaemia due to MDS
Despite that luspatercept is approved based on data of safety and efficacy from a large randomized clinical trial the authors know that especially for human diseases arising in elderly people features of subjects included in those randomized trials often do not reflect those of the population in which a therapy is intended to be used Compliance to treatment and safety in clinical trials can also differ from real world settings Consequently in order to drive clinical decision-making process data from randomized clinical trials should be integrated with evidence generated in a real world setting
To date no information is available on the efficacy and safety luspatercept in the treatment of MDS in real world populations FiSIM Fondazione Italiana Sindromi Mielodisplastiche promotes a multicenter retrospective observational study to collect information on the efficacy and safety of luspatercept in a real world Italian population of adult patients with transfusion-dependent anemia due to very low- and intermediate-risk MDS with ring sideroblasts who had an unsatisfactory response to or are ineligible for erythropoietin-based therapy
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None