Treatment of Refractory Diamond-Blackfan Anemia With Eltrombopag
- Registration Number
- NCT04269889
- 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).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 15
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Refractory Diamond-Blackfan Anemia in Eltrombopag 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.
- Primary Outcome Measures
Name Time Method 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.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.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.
- Secondary Outcome Measures
Name Time Method Median Change in Platelet Count Baseline, 3 months Median Change in Platelet Count as measured by serial CBC assessments
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.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 weeksMedian 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 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.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
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States