Rabbit Antithymocyte Globulin Versus Campath-1H for Treating Severe Aplastic Anemia

NCT00065260 | Completed Phase 2 Results DMC

• 2 other identifiers: 03024903-H-0249
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 1

Brief Summary

Severe aplastic anemia, characterized by pancytopenia and a hypocellular bone marrow, is effectively treated by immunosuppressive therapy, usually a combination of antithymocyte globulin (ATG) and cyclosporine (CsA). Survival rates following this regimen are equivalent to those achieved with allogeneic stem cells transplantation. However, approximately 1/3 of patients will not show blood count improvement after ATG/CsA. General experience and small pilot studies have suggested that such patients may benefit from further immunosuppression. Furthermore, analysis of our own clinical data suggest that patients with poor blood count responses to a single course of ATG, even when transfusion-independence is achieved, have a markedly worse prognosis than patients with robust hematologic improvement. The management of such cases is uncertain. This study will enroll patients who are either refractory to h-ATG (continued severe pancytopenia) or who have only modest improvement in blood counts (weak hematologic responders) to receive a further immunosuppressive therapy, delivered either as rabbit ATG (Thymoglobulin, r-ATG) or a humanized monoclonal antibody to T-cells, alemtuzumab (Campath-1H ). Primary endpoint will be response rate at 3 months defined as no longer meeting criteria for severe aplastic anemia. Relapse, robustness of hematopoietic recovery at 3 months, survival and clonal evolution to paroxysmal nocturnal hemoglobinuria (PNH), myelodysplasia and acute leukemia will be the secondary endpoints.

Conditions

Aplastic Anemia

Keywords

Alemtuzumab (Campath-1H); Rabbit ATG; Severe Aplastic Anemia; Cyclosporine; Thrombocytopenia; Leukopenia; Neutropenia; Autoimmunity; Relapse; Anemia

Outcome Measures

Primary Outcomes (1)

• Participants no Longer Meeting Criteria for Severe Aplastic Anemia.

  Number of participants no longer meeting the criteria for severe aplastic anemia as measured by response to treatment at 6 months

  6 months

Secondary Outcomes (4)

• Number of Participants With Robust Hematologic Recovery With Reticulocyte or Platelet Count

  6 months

• Percentage of Cumulative Incidence of Relapse in Participants

  3 year

• Percentage of Cumulative Incidence of Clonal Evolution in Participants

  3 years

• Percentage of Participants no Longer Meeting Criteria for Severe Aplastic Anemia.

  3 months and 6 months

Study Arms (2)

r-ATG /cyclosporine

EXPERIMENTAL

A randomized trial of rabbit anti-thymocyte globulin (r-ATG)/ cyclosporine (CsA) versus Campath-1H in aplastic anemia patients with refractory pancytopenia or suboptimal hematological response after horse ATG treatment. Subjects who receive rabbit ATG/ CsA will be given rabbit ATG 3.5mg/kg/day for 5 days and CsA 10mg/kg/day orally twice daily for 6 months (15mg/kg/day for children under 12 yrs. Subjects who receive Campath-1H will receive an intravenous infusion for 10 days. Adult subjects will receive 10mg/day (children:0.2mg/kg/day).

Drug: r-ATG; Drug: CsA

Alemtuzumab (Campath-1H)

EXPERIMENTAL

A randomized trial of rabbit anti-thymocyte globulin (ATG)/ cyclosporine (CsA) versus Campath-1H in aplastic anemia patients with refractory pancytopenia or suboptimal hematological response after horse ATG treatment. Subjects who receive rabbit ATG/ CsA will be given rabbit ATG 3.5mg/kg/day for 5 days and CsA 10mg/kg/day orally twice daily for 6 months (15mg/kg/day for children under 12 yrs. Subjects who receive Campath-1H will receive an intravenous infusion for 10 days. Adult subjects will receive 10mg/day (children:0.2mg/kg/day).

Drug: Campath-1H

Interventions

Campath-1H DRUG

Campath-1H IV 10 days. Adults:10mg/day (children:0.2mg/kg/day).

Also known as: Alemtuzumab

Alemtuzumab (Campath-1H)

r-ATG DRUG

Rabbit ATG 3.5mg/kg/day for consecutive 5 days

Also known as: Rabbit Anti-Thymoglobulin

r-ATG /cyclosporine

CsA DRUG

CsA 10mg/kg/day orally twice daily for 6 months (15mg/kg/day for children under 12 yrs.

Also known as: Cyclosporine

r-ATG /cyclosporine

Eligibility Criteria

• Age: 2 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Severe aplastic anemia confirmed at NIH by:
• Bone marrow cellularity less than 30% (excluding lymphocytes)
• At least two of the following:
• Absolute neutrophil count less than 500/microL;
• Platelet count less than 20,000/ microL;
• Reticulocyte count less than 60,000/ microL.
• Severe aplastic anemia refractory to prior course(s) of h-ATG/CsA defined after 3 months from treatment with less or equal to 4 years from receiving h-ATG.
• Suboptimal response to initial immunosuppression with h-ATG/CsA as defined by platelet and reticulocyte count less than 50,000 /microL at 3 months.
• Age greater than or equal to 2 years of age

You may not qualify if:

• Diagnosis of Fanconi anemia.
• Evidence of a clonal disorder on cytogenetics. Patients with super severe neutropenia (ANC less than 200/microL) will not be excluded initially if results of cytogenetics are not available or pending. If evidence of a clonal disorder is later identified, the subject will go off study.
• Prior treatment courses with rabbit ATG or high dose cyclophosphamide (200 mg/kg or equivalent).
• Infection not adequately responding to appropriate therapy.
• Underlying immunodeficiency state including seropositivity for HIV.
• Failure to discontinue the herbal supplements Echinacea purpurea or Usnea barbata (Old Man's Beard) within two weeks of enrollment.
• Previous hypersensitivity to Campath-1H or its components.
• Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the patient s ability to tolerate protocol therapy or that death within 7-10 days is likely.
• Potential subjects with cancer who are on active chemotherapeutic treatment or who take drugs with hematological effects will not be eligible.
• Serum creatinine greater than 2.5 mg/dL.
• Current pregnancy or lactation or unwillingness to take contraceptives.
• Inability to understand the investigational nature of the study or give informed consent.

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• 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.

  PMID: 9134878 BACKGROUND

• Mathe G, Amiel JL, Schwarzenberg L, Choay J, Trolard P, Schneider M, Hayat M, Schlumberger JR, Jasmin C. Bone marrow graft in man after conditioning by antilymphocytic serum. Br Med J. 1970 Apr 18;2(5702):131-6. doi: 10.1136/bmj.2.5702.131.

  PMID: 4909449 BACKGROUND

• Stein RS, Means RT Jr, Krantz SB, Flexner JM, Greer JP. Treatment of aplastic anemia with an investigational antilymphocyte serum prepared in rabbits. Am J Med Sci. 1994 Dec;308(6):338-43. doi: 10.1097/00000441-199412000-00005.

  PMID: 7985721 BACKGROUND

• Scheinberg P, Nunez O, Weinstein B, Scheinberg P, Wu CO, Young NS. Activity of alemtuzumab monotherapy in treatment-naive, relapsed, and refractory severe acquired aplastic anemia. Blood. 2012 Jan 12;119(2):345-54. doi: 10.1182/blood-2011-05-352328. Epub 2011 Nov 8.

  PMID: 22067384 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Anemia, Aplastic; Thrombocytopenia; Leukopenia; Neutropenia; Autoimmune Diseases; Recurrence; Anemia

Interventions

Alemtuzumab; Cyclosporine

Condition Hierarchy (Ancestors)

Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Failure Disorders; Bone Marrow Diseases; Blood Platelet Disorders; Cytopenia; Leukocyte Disorders; Agranulocytosis; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides

Results Point of Contact

• Title: Dr. Bhavisha Patel
• Organization: NIH NHLBI

bhavisha.patel@nih.gov

301.402.3477

Study Officials

• Danielle M Townsley, M.D.

  National Heart, Lung, and Blood Institute (NHLBI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 18, 2003
• First Posted: July 21, 2003
• Study Start: November 6, 2003
• Primary Completion: December 29, 2010
• Study Completion: February 5, 2016
• Last Updated: July 21, 2021
• Results First Posted: March 3, 2016

Record last verified: 2021-06

Locations

US (1)