A Study to Determine Whether Therapy With Daclizumab Will Benefit Patients With Bone Marrow Failure
Study Details
Study Description
Brief Summary
Participants in this study are suffering from rare and serious blood disorders. In aplastic anemia, the bone marrow stops producing red blood cells, platelets, and white blood cells. In pure red cell aplasia, the bone marrow stops producing red cells, and in amegakaryocytic thrombocytopenic purpura, the bone marrow stops producing platelets.
Current treatment approaches for these disorders include bone marrow transplant and/or immunosuppression. However, bone marrow transplant is not always possible, and immunosuppression has serious side effects.
This study will investigate whether daclizumab can be used to treat these disorders. Daclizumab is a genetically engineered human antibody that blocks the interleukin-2 receptor on immune cells. It has been used successfully in many transplant patients to reduce the rate of organ rejection.
Participants will undergo a complete history and physical examination. A bone marrow aspiration and biopsy will be performed to confirm the type of bone marrow failure. About 5 tablespoons of blood will be drawn for baseline tests and research purposes. Daclizumab will be administered every 2 weeks by vein in a 30-minute infusion. The first dose will be given at NIH and the next four may be given at NIH or by the participant's primary hematologist. The treatment will last 8 weeks. Participants must also see their referring physician or NIH physicians every 2 weeks for blood counts. In the fourth and eighth weeks of the study and at the 3-month follow-up visit, 2 tablespoons of blood will be drawn at NIH. At the 1-month follow-up visit to NIH, 5 tablespoons of blood will be drawn and another bone marrow aspiration and biopsy performed.
Risks from bone marrow aspiration and biopsy and blood draws include discomfort. Daclizumab is usually well-tolerated; however, it may weaken immunity against certain bacteria and viruses.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Detailed Description
Many bone marrow failure syndromes in humans are now recognized to result from immunological mechanisms. These diseases include aplastic anemia; single hematopoietic lineage failures such as pure red cell aplasia, Diamond Blackfan Anemia, agranulocytosis, and amegakaryocytic thrombocytopenic purpura; and some types of myelodysplasia. Patients with these conditions, who may suffer variable degrees of anemia, leukocytopenia, and thrombocytopenia, alone or combination, have been shown to respond to a wide variety of immunosuppressive agents, ranging from corticosteroids to cyclosporine (CSA) and antithymocyte globulin (ATG). However, except for severe aplastic anemia, which has been shown to be appropriately treated with either bone marrow transplantation or a combination of ATG and CSA, single agents or regimens have usually not been applied systematically to other immune-mediated hematologic diseases. In an effort to discover other and especially less toxic treatments for immunologically-mediated bone marrow diseases, we seek to apply a new therapy, a humanized anti-interleukin-2 receptor (lL-2R) monoclonal antibody (mAb ), to a subset of patients with bone marrow failure. Anti-IL-2R mAb acts against activated lymphocytes, thus sharing an important mechanism of action with ATG. However, the mAb is much less toxic than ATG and may be administered to outpatients at relatively infrequent intervals (every 2 weeks).
The primary objective is to test the efficacy of anti-IL-2R mAb (daclizumab), we propose to treat four groups of patients: 1) moderate aplastic anemia, 2) single lineage failure states including pure red cell aplasia or Diamond Blackfan anemia, 3) relapse of severe aplastic anemia and 4) refractory severe aplastic anemia not responding to both horse and rabbit ATG/CsA. Subjects will receive daclizumab once every other week for a total of 5 doses. Patients relapsing after response to initial treatment may be treated with 2 additional courses of daclizumab. In November 2005, the relapsed and refractory severe aplastic anemia arms were closed by the Data and Safety Monitoring Board (DSMB) for lack of efficacy. In October 2008, the moderate aplastic anemia arm was closed by the DSMB when the data was determined sufficient for making statistical inferences regarding the original hypotheses. In October 2008, accrual to the Diamond Blackfan anemia arm was closed by the DSMB for lack of accrual.
The Primary endpoint is hematologic response at 3 months. Secondary endpoints include transfusion dependence, overall survival, life threatening toxicity, transformation-free survival, and response duration.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Daclizumab in participants with a bone marrow failure syndrome daclizumab, 1 mg/kg, will be given for a total of 5 intravenous infusions. These subjects may be diagnosed with moderate aplastic anemia, pure red cell aplasia, Diamond Blackfan anemia, relapse and refractory severe aplastic anemia will receive treatment. The subjects will be seen and receive the daclizumab infusion biweekly during the treatment period. |
Drug: Daclizumab
Daclizumab, 1mg/kg, every 2 weeks for a total of 5 infusions.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Number of Participants With Hematologic Response Following Daclizumab in Patients With Moderate Aplastic Anemia (MAA) and Pure Red Cell Aplasia (PRCA). [3 months]
Number of participants with hematologic response at 3 months following Daclizumab, 1 mg/kg, will be given for a total of 5 intravenous infusions to subjects diagnosed with moderate aplastic anemia (MAA), pure red cell aplasia (PRCA), Diamond Blackfan anemia (DBA), relapse and refractory severe aplastic anemia (SAA) will receive treatment. A complete hematologic response will be considered an achievement of normal blood counts. A partial response was defined as any response less than a complete response. The primary endpoint was a hematologic response in at least one affected peripheral blood count parameter, as determined by 3 separate measurements in the first 12 weeks after completion of the infusion.
Secondary Outcome Measures
- Number of Participants That no Longer Required Blood Transfusion [5 years]
Number of participants that no longer required blood transfusion after receiving Daclizumab, 1 mg/kg, for a total of 5 intravenous infusions to subjects diagnosed with moderate aplastic anemia (MAA), pure red cell aplasia (PRCA), Diamond Blackfan anemia (DBA), relapse and refractory severe aplastic anemia (SAA) will receive treatment.
- Overall Survival [5 years]
Overall Survival at end of study after receiving Daclizumab, 1 mg/kg, for a total of 5 intravenous infusions to subjects diagnosed with moderate aplastic anemia (MAA), pure red cell aplasia (PRCA), Diamond Blackfan anemia (DBA), relapse and refractory severe aplastic anemia (SAA) will receive treatment.
Eligibility Criteria
Criteria
-INCLUSION CRITERIA:
- Acquired pure red cell aplasia requiring red blood cell (RBC) transfusions defined by
-
anemia,
-
reticulocytopenia (reticulocyte count less than or equal to 50,000/mm(3))
-
and absent or decreased marrow erythroid precursors
Acquired aplastic anemia of moderate severity (In October 2008, this arm was closed by the DSMB when the data was determined sufficient for making statistical inferences regarding the original hypotheses.
Diamond Blackfan Anemia (DBA) (In October 2008, accrual of DBAs was closed by the DSMB for lack of accrual)
Relapsed patients with severe aplastic anemia (In November 2005 this arm was closed by the DSMB for lack of efficacy)
Refractory disease not responding to both horse and rabbit ATG/CsA (In November 2005 this arm was closed for lack of efficacy)
-
Age greater than or equal to 2 years old
-
Weight greater than 12 kg
-
Patients or their parent(s)/responsible guardian(s) must be able to comprehend and be willing to sign an informed consent.
EXCLUSION CRITERIA:
Current diagnosis or past history of myelodysplastic syndrome or Fanconi's anemia.
Known allergy to E.coli-derived products.
Persistent B19 parvovirus infection.
Evidence of uncontrolled infection.
Chronic or current clinically significant infection, including HIV positivity or hepatitis B and C virus infection.
Significant other diseases, congestive heart failure (greater than New York Class II), poorly controlled diabetes mellitus, uncontrolled cardiac arrhythmias.
Subjects with cancer who are on active chemotherapeutic treatment or who take drugs with hematological effects will not be eligible
A moribund status or concurrent hepatic, renal, cardiac, metabolic disease of such severity that death within 1-4 weeks from initiation of therapy is likely.
Recent major surgery.
Treatment with an investigational agent other than hematopoietic growth factors within 4 weeks of study entry.
Psychiatric, affective, or other disorder that may compromise the ability to give informed consent or to cooperate in a research study.
Pregnancy or lactation.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda | Maryland | United States | 20892 |
Sponsors and Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
Investigators
- Principal Investigator: Neal Young, MD, NIH National Heart, Lung and Blood Institute
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
- Maciejewski JP, Hibbs JR, Anderson S, Katevas P, Young NS. Bone marrow and peripheral blood lymphocyte phenotype in patients with bone marrow failure. Exp Hematol. 1994 Oct;22(11):1102-10.
- Young NS, Barrett AJ. The treatment of severe acquired aplastic anemia. Blood. 1995 Jun 15;85(12):3367-77. Review.
- Young NS, Maciejewski J. The pathophysiology of acquired aplastic anemia. N Engl J Med. 1997 May 8;336(19):1365-72. Review.
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Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Daclizumab in Bone Marrow Failure Syndromes |
|---|---|
| Arm/Group Description | Daclizumab, 1 mg/kg, will be given for a total of 5 intravenous infusions in participants with a bone marrow failure syndrome. These subjects may be diagnosed with moderate aplastic anemia, pure red cell aplasia, Diamond Blackfan anemia, relapse and refractory severe aplastic anemia will receive treatment. The subjects will be seen and receive the daclizumab infusion biweekly during the treatment period. |
| Period Title: Overall Study | |
| STARTED | 100 |
| COMPLETED | 72 |
| NOT COMPLETED | 28 |
Baseline Characteristics
| Arm/Group Title | Daclizumab in Bone Marrow Failure Syndromes |
|---|---|
| Arm/Group Description | Daclizumab, 1 mg/kg, will be given for a total of 5 intravenous infusions in participants with a bone marrow failure syndrome. These subjects may be diagnosed with moderate aplastic anemia, pure red cell aplasia, Diamond Blackfan anemia, relapse and refractory severe aplastic anemia will receive treatment. The subjects will be seen and receive the daclizumab infusion biweekly during the treatment period. |
| Overall Participants | 100 |
| Age (Count of Participants) | |
| <=18 years |
27
27%
|
| Between 18 and 65 years |
57
57%
|
| >=65 years |
16
16%
|
| Sex: Female, Male (Count of Participants) | |
| Female |
49
49%
|
| Male |
51
51%
|
Outcome Measures
| Title | Number of Participants With Hematologic Response Following Daclizumab in Patients With Moderate Aplastic Anemia (MAA) and Pure Red Cell Aplasia (PRCA). |
|---|---|
| Description | Number of participants with hematologic response at 3 months following Daclizumab, 1 mg/kg, will be given for a total of 5 intravenous infusions to subjects diagnosed with moderate aplastic anemia (MAA), pure red cell aplasia (PRCA), Diamond Blackfan anemia (DBA), relapse and refractory severe aplastic anemia (SAA) will receive treatment. A complete hematologic response will be considered an achievement of normal blood counts. A partial response was defined as any response less than a complete response. The primary endpoint was a hematologic response in at least one affected peripheral blood count parameter, as determined by 3 separate measurements in the first 12 weeks after completion of the infusion. |
| Time Frame | 3 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| The daclizumab hematologic response was evaluated for subjects diagnosed with moderate aplastic anemia (MAA) and pure red cell aplasia (PRCA). The Diamond Blackfan arm was closed due to lack of accrual. Relapse and Refractory Severe Aplastic Anemia (SAA) was closed to lack of efficacy. |
| Arm/Group Title | Daclizumab in Participants With a Bone Marrow Failure Syndrome |
|---|---|
| Arm/Group Description | Daclizumab, 1 mg/kg, will be given for a total of 5 intravenous infusions in participants with a bone marrow failure syndrome. These subjects may be diagnosed with moderate aplastic anemia, pure red cell aplasia, Diamond Blackfan anemia, relapse and refractory severe aplastic anemia will receive treatment. The subjects will be seen and receive the daclizumab infusion biweekly during the treatment period. |
| Measure Participants | 72 |
| MAA Complete response |
6
6%
|
| MAA Partial response |
13
13%
|
| MAA No response |
26
26%
|
| PRCA Complete response |
6
6%
|
| PRCA Partial response |
4
4%
|
| PRCA No response |
17
17%
|
| Title | Number of Participants That no Longer Required Blood Transfusion |
|---|---|
| Description | Number of participants that no longer required blood transfusion after receiving Daclizumab, 1 mg/kg, for a total of 5 intravenous infusions to subjects diagnosed with moderate aplastic anemia (MAA), pure red cell aplasia (PRCA), Diamond Blackfan anemia (DBA), relapse and refractory severe aplastic anemia (SAA) will receive treatment. |
| Time Frame | 5 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| This was evaluated for subjects diagnosed with moderate aplastic anemia (MAA) and pure red cell aplasia (PRCA). The Diamond Blackfan anemia arm was closed due to the lack of accrual. The Relapse and Refractory Severe Aplastic Anemia (SAA) was closed due to lack of efficacy. |
| Arm/Group Title | Daclizumab in Participants With a Bone Marrow Failure Syndrome |
|---|---|
| Arm/Group Description | Daclizumab, 1 mg/kg, will be given for a total of 5 intravenous infusions in participants with a bone marrow failure syndrome. These subjects may be diagnosed with moderate aplastic anemia, pure red cell aplasia, Diamond Blackfan anemia, relapse and refractory severe aplastic anemia will receive treatment. The subjects will be seen and receive the daclizumab infusion biweekly during the treatment period. |
| Measure Participants | 72 |
| MAA |
7
7%
|
| PRCA |
28
28%
|
| Title | Overall Survival |
|---|---|
| Description | Overall Survival at end of study after receiving Daclizumab, 1 mg/kg, for a total of 5 intravenous infusions to subjects diagnosed with moderate aplastic anemia (MAA), pure red cell aplasia (PRCA), Diamond Blackfan anemia (DBA), relapse and refractory severe aplastic anemia (SAA) will receive treatment. |
| Time Frame | 5 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| This was evaluated for subjects diagnosed with moderate aplastic anemia (MAA) and pure red cell aplasia (PRCA). The Diamond Blackfan anemia arm was closed due to the lack of accrual. The Relapse and Refractory Severe Aplastic Anemia (SAA) was closed due to lack of efficacy. |
| Arm/Group Title | Daclizumab in Participants With a Bone Marrow Failure Syndrome |
|---|---|
| Arm/Group Description | Daclizumab, 1 mg/kg, will be given for a total of 5 intravenous infusions in participants with a bone marrow failure syndrome. These subjects may be diagnosed with moderate aplastic anemia, pure red cell aplasia, Diamond Blackfan anemia, relapse and refractory severe aplastic anemia will receive treatment. The subjects will be seen and receive the daclizumab infusion biweekly during the treatment period. |
| Measure Participants | 72 |
| Deaths |
7
7%
|
| Alive |
65
65%
|
Adverse Events
| Time Frame | 5 years | |
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Daclizumab in Participants With a Bone Marrow Failure Syndrome | |
| Arm/Group Description | Daclizumab, 1 mg/kg, will be given for a total of 5 intravenous infusions in participants with a bone marrow failure syndrome. These subjects may be diagnosed with moderate aplastic anemia, pure red cell aplasia, Diamond Blackfan anemia, relapse and refractory severe aplastic anemia will receive treatment. The subjects will be seen and receive the daclizumab infusion biweekly during the treatment period. | |
All Cause Mortality |
||
| Daclizumab in Participants With a Bone Marrow Failure Syndrome | ||
| Affected / at Risk (%) | # Events | |
| Total | 7/100 (7%) | |
Serious Adverse Events |
||
| Daclizumab in Participants With a Bone Marrow Failure Syndrome | ||
| Affected / at Risk (%) | # Events | |
| Total | 9/100 (9%) | |
| Blood and lymphatic system disorders | ||
| polycythemia | 1/100 (1%) | 1 |
| Cardiac disorders | ||
| angina | 1/100 (1%) | 1 |
| Hepatobiliary disorders | ||
| elevated liver function tests | 1/100 (1%) | 1 |
| Immune system disorders | ||
| infection | 2/100 (2%) | 2 |
| Infections and infestations | ||
| sinusitis | 1/100 (1%) | 1 |
| gastroenteritis | 1/100 (1%) | 1 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||
| hepatocellular carcinoma | 1/100 (1%) | 1 |
| myeloma | 1/100 (1%) | 1 |
| Renal and urinary disorders | ||
| renal failure | 1/100 (1%) | 1 |
Other (Not Including Serious) Adverse Events |
||
| Daclizumab in Participants With a Bone Marrow Failure Syndrome | ||
| Affected / at Risk (%) | # Events | |
| Total | 40/100 (40%) | |
| Blood and lymphatic system disorders | ||
| gum bleeding | 9/100 (9%) | 9 |
| petechiae | 13/100 (13%) | 13 |
| elevated hemoglobin | 2/100 (2%) | 2 |
| hemolysis | 1/100 (1%) | 1 |
| ear bleeding | 1/100 (1%) | 1 |
| trauma bleeding | 1/100 (1%) | 1 |
| vaginal bleeding | 2/100 (2%) | 2 |
| blood blisters | 1/100 (1%) | 1 |
| blood in stool | 3/100 (3%) | 3 |
| bruising | 9/100 (9%) | 9 |
| epistaxis | 6/100 (6%) | 6 |
| heavy menses | 2/100 (2%) | 2 |
| retinal hemorrhage | 1/100 (1%) | 1 |
| subconjunctival hemorrhage | 1/100 (1%) | 1 |
| Cardiac disorders | ||
| edema | 14/100 (14%) | 14 |
| palpitations | 2/100 (2%) | 2 |
| lower extremity edema | 1/100 (1%) | 1 |
| peripheral vascular disease | 1/100 (1%) | 1 |
| Ear and labyrinth disorders | ||
| hearing loss | 1/100 (1%) | 1 |
| earache | 2/100 (2%) | 2 |
| Endocrine disorders | ||
| gynecomastia | 1/100 (1%) | 1 |
| hyperparathyroid | 1/100 (1%) | 1 |
| hypothyroidism | 1/100 (1%) | 1 |
| Eye disorders | ||
| blurred vision | 3/100 (3%) | 3 |
| Gastrointestinal disorders | ||
| diarrhea | 7/100 (7%) | 7 |
| abdominal pain | 2/100 (2%) | 2 |
| nausea | 11/100 (11%) | 11 |
| mouth sores | 7/100 (7%) | 7 |
| constipation | 5/100 (5%) | 5 |
| anorexia | 1/100 (1%) | 1 |
| esophageal stricture | 1/100 (1%) | 1 |
| abdominal discomfort | 3/100 (3%) | 3 |
| duodenal ulcer | 1/100 (1%) | 1 |
| gingival hyperplasia | 1/100 (1%) | 1 |
| heartburn | 1/100 (1%) | 1 |
| General disorders | ||
| headache | 11/100 (11%) | 12 |
| fatigue | 5/100 (5%) | 5 |
| fever | 4/100 (4%) | 4 |
| pallor | 4/100 (4%) | 4 |
| back pain | 6/100 (6%) | 6 |
| knee pain | 3/100 (3%) | 3 |
| hepatic pain | 3/100 (3%) | 3 |
| myalgia | 6/100 (6%) | 6 |
| dizziness | 3/100 (3%) | 3 |
| weight gain | 3/100 (3%) | 3 |
| diaphoresis | 1/100 (1%) | 1 |
| bone pain | 4/100 (4%) | 4 |
| joint pain | 1/100 (1%) | 2 |
| leg pain | 3/100 (3%) | 3 |
| Hepatobiliary disorders | ||
| elevated liver function tests | 3/100 (3%) | 3 |
| Immune system disorders | ||
| allergic reaction | 7/100 (7%) | 7 |
| post nasal drip | 1/100 (1%) | 1 |
| Infections and infestations | ||
| shortness of breath | 9/100 (9%) | 9 |
| upper respiratory tract infection | 40/100 (40%) | 48 |
| urinary tract infection | 6/100 (6%) | 6 |
| viral infection | 1/100 (1%) | 1 |
| strept throat | 1/100 (1%) | 2 |
| catheter related sepsis | 1/100 (1%) | 2 |
| gastritis | 1/100 (1%) | 1 |
| localized infection | 4/100 (4%) | 4 |
| strep throat | 1/100 (1%) | 2 |
| localized infection | 1/100 (1%) | 1 |
| Metabolism and nutrition disorders | ||
| decreased potassium | 1/100 (1%) | 1 |
| Musculoskeletal and connective tissue disorders | ||
| pain | 6/100 (6%) | 6 |
| tendonitis | 1/100 (1%) | 1 |
| arthritis | 2/100 (2%) | 2 |
| cramps | 4/100 (4%) | 4 |
| neck stiffness | 1/100 (1%) | 1 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||
| endometrial benign polyp | 1/100 (1%) | 1 |
| prostate malignancy | 1/100 (1%) | 1 |
| Nervous system disorders | ||
| lightheadness | 4/100 (4%) | 4 |
| depression | 1/100 (1%) | 1 |
| anxiety | 1/100 (1%) | 1 |
| insomnia | 2/100 (2%) | 2 |
| sensory neuropathy | 1/100 (1%) | 1 |
| vertigo | 1/100 (1%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||
| cough | 2/100 (2%) | 4 |
| Skin and subcutaneous tissue disorders | ||
| dry skin | 1/100 (1%) | 1 |
| eczema | 1/100 (1%) | 1 |
| alopecia | 1/100 (1%) | 1 |
| rash | 14/100 (14%) | 15 |
| sclerodactyly | 1/100 (1%) | 1 |
| rosacea | 1/100 (1%) | 1 |
| acne | 1/100 (1%) | 1 |
| furuncle | 1/100 (1%) | 1 |
| nail changes | 1/100 (1%) | 1 |
| skin lesions | 3/100 (3%) | 3 |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Neal Young MD |
|---|---|
| Organization | NIH National Heart, Lung and Blood Institute |
| Phone | 301-496-5093 |
| youngns@nhlbi.nih.gov |
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