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

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

54 participants

Study Classification

INTERVENTIONAL

Study Start Date

2003-11-06

Study Completion Date

2016-02-05

Brief Summary

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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.

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Detailed Description

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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 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 6 months defined as no longer meeting criteria for severe aplastic anemia. Relapse, robustness of hematopoietic recovery at 6 months, survival and clonal evolution to paroxysmal nocturnal hemoglobinuria (PNH), myelodysplasia and acute leukemia will be the secondary endpoints.

Conditions

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Aplastic Anemia

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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r-ATG /cyclosporine

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).

Group Type EXPERIMENTAL

r-ATG

Intervention Type DRUG

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

CsA

Intervention Type DRUG

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

Alemtuzumab (Campath-1H)

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).

Group Type EXPERIMENTAL

Campath-1H

Intervention Type DRUG

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

Interventions

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Campath-1H

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

Intervention Type DRUG

r-ATG

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

Intervention Type DRUG

CsA

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

Intervention Type DRUG

Other Intervention Names

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Alemtuzumab Rabbit Anti-Thymoglobulin Cyclosporine

Eligibility Criteria

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Inclusion Criteria

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.

OR

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

Exclusion Criteria

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.

Minimum Eligible Age

2 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No