A Study to Determine Whether Therapy With Daclizumab Will Benefit Patients With Bone Marrow Failure

A Pilot Study of Recombinant Humanized Anti-Interleukin (IL-2) Receptor Antibody (Daclizumab) in Patients With Moderate Aplastic Anemia, Pure Red Cell Aplasia, or Diamond Blackfan Anemia

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.

Study Overview

• Status: Terminated
• Conditions: Aplastic Anemia; Pure Red Cell Aplasia; Diamond Blackfan Anemia
• Intervention / Treatment: Drug: Daclizumab

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 Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 months and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

-INCLUSION CRITERIA:

1. 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)

2. Age greater than or equal to 2 years old
3. Weight greater than 12 kg
4. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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: Zenapax

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Hematologic Response Following Daclizumab in Patients With Moderate Aplastic Anemia (MAA) and Pure Red Cell Aplasia (PRCA).	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.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants That no Longer Required Blood Transfusion	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.	5 years
Overall Survival	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.	5 years

Collaborators and Investigators

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Neal Young, MD, NIH National Heart, Lung and Blood Institute

Publications and helpful links

General Publications

• Young NS, Maciejewski J. The pathophysiology of acquired aplastic anemia. N Engl J Med. 1997 May 8;336(19):1365-72. doi: 10.1056/NEJM199705083361906. No abstract available.
• Young NS, Barrett AJ. The treatment of severe acquired aplastic anemia. Blood. 1995 Jun 15;85(12):3367-77. No abstract available.
• 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.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start: November 1, 1999
• Primary Completion (Actual): August 1, 2009
• Study Completion (Actual): September 1, 2010

Study Registration Dates

• First Submitted: January 18, 2000
• First Submitted That Met QC Criteria: January 18, 2000
• First Posted (Estimate): January 19, 2000

Study Record Updates

• Last Update Posted (Actual): July 9, 2021
• Last Update Submitted That Met QC Criteria: June 15, 2021
• Last Verified: April 1, 2015

More Information

Terms related to this study

• Keywords: Immunosuppression; T-cells; Hematopoiesis; Immunosuppressive Therapy; Monoclonal Antibody Therapy; Aplastic Anemia
• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Anemia, Hypoplastic, Congenital; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Anemia; Anemia, Aplastic; Red-Cell Aplasia, Pure; Anemia, Diamond-Blackfan; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Daclizumab
• Other Study ID Numbers: 000029; 00-H-0029 (Other Identifier: NIH NHLBI)