Anemia, Diamond-Blackfan
Conditions
Keywords
Chelation, Ribosomopathy, Erythroid Aplasia, Iron Homeostasis, Hemoglobin Synthesis, Heme Synthesis
Brief summary
Background: Diamond-Blackfan anemia (DBA) is treated with steroids. But some people cannot take steroids, or steroids don t work. Other patients must get blood transfusions regularly which are time consuming and can have significant side effects. The drug eltrombopag can increase red blood cells. Researchers want to see if it can help people with DBA and, if so, for how long. Objective: To study the safety and efficacy of eltrombopag in people with DBA who have not responded to steroids or could not take them. Eligibility: People ages 2 and older with DBA who did not respond to steroids or could not take them, or their disease has returned despite taking them Design: Participants will be screened with: Medical and medicine history Physical exam MRI: Participants will lie in a machine that takes pictures of the liver. Blood and urine tests Bone marrow biopsy: A thin needle will remove a marrow sample from the participant's hip bone. Electrocardiogram Participants will take eltrombopag pills once daily for 24 weeks. They will have blood taken every 2 weeks. Participants will have visits 6 months. At 6 months, they will repeat all the screening tests and also have: Quality-of-life questionnaire Neurodevelopmental test (for participants younger than 18 years) If participants blood cell counts improve, they may keep taking eltrombopag for up to 3 more years. If so, they will have blood taken every 4 weeks. They will visit NIH every 6 months and repeat the above tests. Participants will be monitored for up to 3 years after they stop taking eltrombopag. They will visit NIH 6 months after treatment ends. If participants blood counts go down after treatment ends, they may restart the drug....
Detailed description
Diamond-Blackfan anemia (DBA) is a heritable bone marrow failure (BMF) syndrome characterized by selective erythroid defects typically presenting within the first year of life as a normochromic, macrocytic anemia with reticulocytopenia. More than half of all DBA cases are associated with either inherited or spontaneous mutations in ribosomal proteins, making DBA a prototypic ribosomopathy. Furthermore, although the primary presentation is isolated anemia, as life expectancy has improved, progressive defects in other lineages have now been identified, consistent with a long-term stem cell defect. Current standard of care for DBA is the use of systemic corticosteroids, the mechanism of which is unclear, although only half show an initial response. Even when a response to steroids is observed, long-term steroid therapy carries significant morbidity, especially in children or in combination with transfusion-associated iron overload, and thus most cannot tolerate high-dose steroids long-term. Responses are rare with second-line immunomodulatory agents. Yet other than allogeneic hematopoietic stem cell transplantation in those patients with healthy matched donors, there are no alternative therapies. In one model for DBA pathogenesis, the defects lead to an overabundance of the iron-carrying moiety heme in primitive erythroid cells, unbound by protein. Free heme is toxic to cells, likely exacerbated over time by iron overload due to transfusions. Ongoing work with eltrombopag (EPAG) has shown that it is capable of acting as a potent iron chelator, including intracellular iron, with evidence that this effect of EPAG can reverse the impact of excess heme and elevated reactive oxygen species. Furthermore, in a recent trial of EPAG for moderate aplastic anemia or hypoproliferative unilineage cytopenias, we identified a robust response to EPAG in the one DBA patient enrolled in this clinical trial. This response has been durable over more than three years since study entry, but requires continuous EPAG to maintain transfusion independence. From these data, we hypothesize that EPAG may be able to improve production of red blood cells in DBA patients via chelation of iron and subsequent reduction in heme synthesis, resulting in decreased toxicity to bone marrow stem cells and developing erythroid cells. We will conduct a single-arm, pilot trial in patients with steroid-refractory or steroid-intolerant DBA, treating with a fixed dose of EPAG for 6 months to assess safety and efficacy at improving hematological manifestations of DBA. Responders at 6 months will be able to continue EPAG on the extension part of this protocol for an additional 3 years. We will examine the hematologic, molecular, cytogenetic and clonal responses to EPAG in responders and non-responders alike. Translational studies will examine the mechanism of activity of EPAG in DBA through its effects on iron metabolism, erythroid differentiation, apoptosis, global transcriptome and TPO signaling pathways in patient's hematopoietic stem and progenitor cells (HSPCs).
Interventions
DRUGEltrombopag
Eltrombopag will be administered to participants 12 years of age an above will receive the adult dose of 150 mg by mouth daily. Participants between ages of 6 and 11 years old will start at 75 mg by mouth daily, and children 2 and 5 years of age will start at 2.5 mg/kg, not to exceed 75 mg by mouth daily. To adjust for the higher expected exposure in participants of East Asian and South East Asian ancestry, the starting dose for East Asian and South East Asian participants 12 years of age and above will be 75 mg by mouth once daily. For East Asian and South East Asian participants between 6 and 11 years of age, the starting dose will be 37.5 mg once daily by mouth, and for children between 2 and 5, the starting dose will be 1.25 mg/kg by mouth.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: In order to be participate in this study, individuals must meet all of the following criteria: * Diamond-Blackfan anemia defined as anemia presenting on or before the third year of life with reticulocytopenia and greatly reduced or absent bone marrow erythroid precursors, supported by, but not requiring either: * familial history * gene mutation testing demonstrating a known disease-causing mutation or a mutation of disease-associated gene in combination with clinical characteristics of DBA * Patients with late-onset DBA (diagnosed after the third year of life) may also be included if gene mutation testing confirms a disease -causing mutation as above. * Clinically-significant anemia as defined as either: * hemoglobin less than 9.0 g/dL * red cell transfusion of at least 2 units PRBC for adults or 30 cc/kg for children (whichever is less) in the eight weeks prior to study enrollment * Relapsed and/or steroid-refractory or intolerant of systemic corticosteroids * Age greater than or equal to 2 years * Weight greater than or equal to 12 kilograms * Residence within the United States of America or territories, or able to reside within the US or its territories while on drug during trial participation
Exclusion criteria
Individuals meeting any of the following criteria will not be eligible for participation in this study. However, having met
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants That Responded to Eltrombopag | 6 months (24 weeks +/- 14 days) | Participants that responded to Eltrombopag as defined by: Response to treatment will be defined by one or more of the following: * Erythroid response for subjects with a pretreatment hemoglobin less than 9 G/dL will be defined as an increase in hemoglobin by \>1.5 G/dL from enrollment baseline, and/or * A reduction in the units of PRBC transfusions by at least 50% during the eight consecutive weeks prior to response assessment - compared with the pretreatment transfusion number in the previous 8 weeks. |
| Time (Weeks) to Response | 6 months (24 weeks +/- 14 days) | Time-to-response in weeks will also be measured according to the time from Eltrombopag initiation to the first time the patient met criteria for response. Response to treatment will be defined by one or more of the following: * Erythroid response for subjects with a pretreatment hemoglobin less than 9 G/dL will be defined as an increase in hemoglobin by \>1.5 G/dL from enrollment baseline, and/or * a reduction in the units of PRBC transfusions by at least 50% during the eight consecutive weeks prior to response assessment - compared with the pretreatment transfusion number in the previous 8 weeks. |
| Number of Adverse Events | 6 months (24 weeks +/- 14 days) | Number of Adverse Events Toxicity profile as measured by using the Common Terminology Criteria for Adverse Events (CTCAE version 5.0) for grade 2 and above. According to https://ctep.cancer.gov/, CTCAE is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. CTCAE grades are defined as: Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental activities of daily living. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4 Life-threatening consequences; urgent intervention indicated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Change Absolute Neutrophil Count | Baseline, Month 3 | Median Change Absolute Neutrophil Count as measured by serial CBC assessments |
| Number of Participants That Experienced Relapse | 6 months up to 27 months | Number of Participants that experienced Relapse during extension phase. Relapse is defined as no longer meeting response criteria. Response criteria is defined as: Response to treatment will be defined by one or more of the following: * Erythroid response for subjects with a pretreatment hemoglobin less than 9 G/dL will be defined as an increase in hemoglobin by \>1.5 G/dL from enrollment baseline, and/or * A reduction in the units of PRBC transfusions by at least 50% during the eight consecutive weeks prior to response assessment - compared with the pretreatment transfusion number in the previous 8 weeks. |
| Number of Participants That Experienced Clonal Evolution | 6 Months and Up to 27 months | Number of participants that experienced clonal evolution according to cytogenetic, mutational or flow cytometric markers |
| Number of Participants That Responded to Eltrombopag | 3 Months | Number of Participants That Responded to Eltrombopag. As determined by the response to treatment, which will be assessed based on one or more of the following criteria: Erythroid response for subjects with a pretreatment hemoglobin less than 9 G/dL will be defined as an increase in hemoglobin by \>1.5 G/dL from enrollment baseline, and/or A reduction in the units of PRBC transfusions by at least 50% during the eight consecutive weeks prior to response assessment - compared with the pretreatment transfusion number in the previous 8 weeks. |
| Neurodevelopment in Pediatric Patients | At baseline and Month 6 | Neurodevelopment in pediatric patients as measured by validated neurodevelopmental measurements |
| Number of Participants With Iron Overload | Month 6 | Number of participants with Iron overload. Iron overload as measured by serial ferritin levels, T2\* MRI measurements and bone marrow iron staining |
| Number of Adverse Events During the Extension Phase | 6 months Up to 27 months | Number of Adverse Events Toxicity profile as measured by using the Common Terminology Criteria for Adverse Events (CTCAE version 5.0) for grade 2 and above. According to https://ctep.cancer.gov/, CTCAE is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. CTCAE grades are defined as: Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental activities of daily living. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4 Life-threatening consequences; urgent intervention indicated. |
| Number of Participants With Robust Response to Eltrombopag | 3 Months, 6 Months, Up to 27 Months | Number of Participants with Robust Response to Eltrombopag regardless when it is achieved. Best response is defined as robust response or not robust response. Robust response to treatment will be defined both: * Stable hemoglobin (two consecutive measurements at least 2 weeks apart) greater than 10 g/dL, and * Transfusion independence for the previous 8 weeks |
| Median Change in Platelet Count | Baseline, 3 months | Median Change in Platelet Count as measured by serial CBC assessments |
Countries
United States
Participant flow
Recruitment details
Participants were recruited and enrolled from February 2020 through August 2022 at the National Institutes of Health (NIH) (Bethesda, MD).
Participants by arm
| Arm | Count |
|---|---|
| Refractory Diamond-Blackfan Anemia in Eltrombopag Participants with Refractory Diamond-Blackfan Anemia will be administered Eltrombopag. Participants 12 years of age an above will receive the adult dose of 150 mg by mouth daily. Participants between ages of 6 and 11 years old will start at 75 mg by mouth daily, and children 2 and 5 years of age will start at 2.5 mg/kg, not to exceed 75 mg by mouth daily.
To adjust for the higher expected exposure in participants of East Asian and South East Asian ancestry, the starting dose for East Asian and South East Asian participants 12 years of age and above will be 75 mg by mouth once daily. For East Asian and South East Asian participants between 6 and 11 years of age, the starting dose will be 37.5 mg once daily by mouth, and for children between 2 and 5, the starting dose will be 1.25 mg/kg by mouth. | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Initial Phase (Day 0 to Month 6) | Lack of Efficacy | 14 |
Baseline characteristics
| Characteristic | Refractory Diamond-Blackfan Anemia in Eltrombopag |
|---|---|
| Age, Categorical <=18 years | 7 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Number of participants with Iron Overload | 14 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 13 Participants |
| Region of Enrollment United States | 15 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 15 |
| other Total, other adverse events | 2 / 15 |
| serious Total, serious adverse events | 2 / 15 |
Outcome results
Primary
Number of Adverse Events
Number of Adverse Events Toxicity profile as measured by using the Common Terminology Criteria for Adverse Events (CTCAE version 5.0) for grade 2 and above. According to https://ctep.cancer.gov/, CTCAE is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. CTCAE grades are defined as: Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental activities of daily living. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4 Life-threatening consequences; urgent intervention indicated.
Time frame: 6 months (24 weeks +/- 14 days)
Population: Analysis includes number of adverse events with grade 2 events and above
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Number of Adverse Events | Acute inception without sepsis/Acute viral syndrome | 1 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Number of Adverse Events | Myalgia | 1 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Number of Adverse Events | Headache | 0 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Number of Adverse Events | Nausea | 0 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Number of Adverse Events | Chills | 1 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Number of Adverse Events | Sepsis | 0 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Number of Adverse Events | Arthralgia | 1 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Number of Adverse Events | Dysphagia | 1 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Number of Adverse Events | Fever | 1 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Number of Adverse Events | Flu-like symptoms: COVID/flu | 0 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Number of Adverse Events | Back pain | 1 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Number of Adverse Events | Elevated alanine transaminase | 0 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag With Grade 3 Adverse Events | Number of Adverse Events | Headache | 2 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag With Grade 3 Adverse Events | Number of Adverse Events | Acute inception without sepsis/Acute viral syndrome | 0 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag With Grade 3 Adverse Events | Number of Adverse Events | Back pain | 0 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag With Grade 3 Adverse Events | Number of Adverse Events | Elevated alanine transaminase | 1 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag With Grade 3 Adverse Events | Number of Adverse Events | Myalgia | 0 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag With Grade 3 Adverse Events | Number of Adverse Events | Dysphagia | 0 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag With Grade 3 Adverse Events | Number of Adverse Events | Arthralgia | 1 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag With Grade 3 Adverse Events | Number of Adverse Events | Nausea | 1 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag With Grade 3 Adverse Events | Number of Adverse Events | Flu-like symptoms: COVID/flu | 1 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag With Grade 3 Adverse Events | Number of Adverse Events | Fever | 1 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag With Grade 3 Adverse Events | Number of Adverse Events | Sepsis | 1 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag With Grade 3 Adverse Events | Number of Adverse Events | Chills | 1 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag With Grade 4 Adverse Events | Number of Adverse Events | Sepsis | 0 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag With Grade 4 Adverse Events | Number of Adverse Events | Headache | 0 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag With Grade 4 Adverse Events | Number of Adverse Events | Arthralgia | 0 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag With Grade 4 Adverse Events | Number of Adverse Events | Back pain | 0 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag With Grade 4 Adverse Events | Number of Adverse Events | Chills | 0 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag With Grade 4 Adverse Events | Number of Adverse Events | Dysphagia | 0 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag With Grade 4 Adverse Events | Number of Adverse Events | Fever | 0 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag With Grade 4 Adverse Events | Number of Adverse Events | Flu-like symptoms: COVID/flu | 0 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag With Grade 4 Adverse Events | Number of Adverse Events | Acute inception without sepsis/Acute viral syndrome | 0 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag With Grade 4 Adverse Events | Number of Adverse Events | Myalgia | 0 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag With Grade 4 Adverse Events | Number of Adverse Events | Nausea | 0 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag With Grade 4 Adverse Events | Number of Adverse Events | Elevated alanine transaminase | 0 Adverse Events |
Primary
Participants That Responded to Eltrombopag
Participants that responded to Eltrombopag as defined by: Response to treatment will be defined by one or more of the following: * Erythroid response for subjects with a pretreatment hemoglobin less than 9 G/dL will be defined as an increase in hemoglobin by \>1.5 G/dL from enrollment baseline, and/or * A reduction in the units of PRBC transfusions by at least 50% during the eight consecutive weeks prior to response assessment - compared with the pretreatment transfusion number in the previous 8 weeks.
Time frame: 6 months (24 weeks +/- 14 days)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Participants That Responded to Eltrombopag | Response to Treatment | 1 Participants |
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Participants That Responded to Eltrombopag | No Response to Treatment | 14 Participants |
Primary
Time (Weeks) to Response
Time-to-response in weeks will also be measured according to the time from Eltrombopag initiation to the first time the patient met criteria for response. Response to treatment will be defined by one or more of the following: * Erythroid response for subjects with a pretreatment hemoglobin less than 9 G/dL will be defined as an increase in hemoglobin by \>1.5 G/dL from enrollment baseline, and/or * a reduction in the units of PRBC transfusions by at least 50% during the eight consecutive weeks prior to response assessment - compared with the pretreatment transfusion number in the previous 8 weeks.
Time frame: 6 months (24 weeks +/- 14 days)
Population: Analysis includes only participants that responded to eltrombopag
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Time (Weeks) to Response | 15 weeks |
Secondary
Median Change Absolute Neutrophil Count
Median Change Absolute Neutrophil Count as measured by serial CBC assessments
Time frame: Baseline, Month 3
Population: Analysis includes those participants that completed baseline and month 3 visits
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Median Change Absolute Neutrophil Count | 0.7 K/uL |
Secondary
Median Change in Platelet Count
Median Change in Platelet Count as measured by serial CBC assessments
Time frame: Baseline, 3 months
Population: Analysis includes those participants that completed baseline and month 3 visits
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Median Change in Platelet Count | 83.0 K/uL |
Secondary
Neurodevelopment in Pediatric Patients
Neurodevelopment in pediatric patients as measured by validated neurodevelopmental measurements
Time frame: At baseline and Month 6
Population: Data was not collected and there are no future plans to collect the data. The analysis could not be completed due to insufficient staffing to carry out the required tasks.
Secondary
Number of Adverse Events During the Extension Phase
Number of Adverse Events Toxicity profile as measured by using the Common Terminology Criteria for Adverse Events (CTCAE version 5.0) for grade 2 and above. According to https://ctep.cancer.gov/, CTCAE is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. CTCAE grades are defined as: Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental activities of daily living. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4 Life-threatening consequences; urgent intervention indicated.
Time frame: 6 months Up to 27 months
Population: All participants that participated within the extended phase of the clinical trial
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Number of Adverse Events During the Extension Phase | Grade 2 | 0 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Number of Adverse Events During the Extension Phase | Grade 3 | 0 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Number of Adverse Events During the Extension Phase | Grade 4 | 0 Adverse Events |
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Number of Adverse Events During the Extension Phase | Grade 5 | 0 Adverse Events |
Secondary
Number of Participants That Experienced Clonal Evolution
Number of participants that experienced clonal evolution according to cytogenetic, mutational or flow cytometric markers
Time frame: 6 Months and Up to 27 months
Population: Analysis post 6 months only includes those participants that met criteria for extension phase of the study
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Number of Participants That Experienced Clonal Evolution | 6 months | 0 Participants |
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Number of Participants That Experienced Clonal Evolution | Up to 27 months | 1 Participants |
Secondary
Number of Participants That Experienced Relapse
Number of Participants that experienced Relapse during extension phase. Relapse is defined as no longer meeting response criteria. Response criteria is defined as: Response to treatment will be defined by one or more of the following: * Erythroid response for subjects with a pretreatment hemoglobin less than 9 G/dL will be defined as an increase in hemoglobin by \>1.5 G/dL from enrollment baseline, and/or * A reduction in the units of PRBC transfusions by at least 50% during the eight consecutive weeks prior to response assessment - compared with the pretreatment transfusion number in the previous 8 weeks.
Time frame: 6 months up to 27 months
Population: All participants that participated within the extended phase of the clinical trial
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Number of Participants That Experienced Relapse | 0 Participants |
Secondary
Number of Participants That Responded to Eltrombopag
Number of Participants That Responded to Eltrombopag. As determined by the response to treatment, which will be assessed based on one or more of the following criteria: Erythroid response for subjects with a pretreatment hemoglobin less than 9 G/dL will be defined as an increase in hemoglobin by \>1.5 G/dL from enrollment baseline, and/or A reduction in the units of PRBC transfusions by at least 50% during the eight consecutive weeks prior to response assessment - compared with the pretreatment transfusion number in the previous 8 weeks.
Time frame: 3 Months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Number of Participants That Responded to Eltrombopag | Response to Treatment | 0 Participants |
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Number of Participants That Responded to Eltrombopag | No Response to Treatment | 15 Participants |
Secondary
Number of Participants With Iron Overload
Number of participants with Iron overload. Iron overload as measured by serial ferritin levels, T2\* MRI measurements and bone marrow iron staining
Time frame: Month 6
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Number of Participants With Iron Overload | 15 Participants |
Secondary
Number of Participants With Robust Response to Eltrombopag
Number of Participants with Robust Response to Eltrombopag regardless when it is achieved. Best response is defined as robust response or not robust response. Robust response to treatment will be defined both: * Stable hemoglobin (two consecutive measurements at least 2 weeks apart) greater than 10 g/dL, and * Transfusion independence for the previous 8 weeks
Time frame: 3 Months, 6 Months, Up to 27 Months
Population: Analysis post 6 months only includes those participants that met criteria for extension phase of the study
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Number of Participants With Robust Response to Eltrombopag | 3 months : Robust Response | 0 Participants |
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Number of Participants With Robust Response to Eltrombopag | 3 months : Not Robust Response | 15 Participants |
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Number of Participants With Robust Response to Eltrombopag | 6 months : Robust Response | 0 Participants |
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Number of Participants With Robust Response to Eltrombopag | 6 months : Not Robust Response | 15 Participants |
| Refractory Diamond-Blackfan Anemia in Eltrombopag | Number of Participants With Robust Response to Eltrombopag | Up to 27 months : Robust Response | 0 Participants |