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

Sponsored by:	National Heart, Lung, and Blood Institute (NHLBI)
Information provided by:	National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:	NCT00065260

Purpose

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® (Registered Trademark)). 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.

Condition	Intervention	Phase
Aplastic Anemia	Drug: Alemtuzumab (Campath-1H) Drug: Thymoglobulin (r-ATG) Drug: Cyclosporine (CsA)	Phase II

MedlinePlus related topics: Anemia Leukemia, Adult Acute Leukemia, Adult Chronic Leukemia, Childhood

Drug Information available for: Cyclosporin Cyclosporine Alemtuzumab Campath

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Open Label, Uncontrolled, Parallel Assignment, Safety/Efficacy Study
Official Title:	A Randomized Trial of Immunosupression in Aplastic Anemia Patients With Refractory Pancytopenia or Suboptimal Hematologic Response After h-ATG/CsA Treatment

Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:

No longer meeting criteria for severe aplastic anemia. [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Secondary endpoints will include: a) relapse; b) robustness of hematologic recovery w/ANC or platelet count greater than or equal to 50000/uL at 3 months; c) 6-month response rate; d) clonal evoluation to MDS, PNH or acute leukemia; and e) survival. [ Time Frame: months/years ] [ Designated as safety issue: No ]

Estimated Enrollment:	120
Study Start Date:	July 2003

Intervention Details:

N/A

Detailed Description:

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® (Registered Trademark), r-ATG) or a humanized monoclonal antibody to T-cells, alemtuzumab (Campath-1H® (Registered Trademark)). 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.

Eligibility

Ages Eligible for Study:	2 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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/uL;

Platelet count less than 20,000/ uL;

Reticulocyte count less than 60,000/ uL.

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 /uL 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.

Moribound status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the patients 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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00065260

Contacts

Contact: Patient Recruitment and Public Liaison Office	(800) 411-1222	prpl@mail.cc.nih.gov
Contact: TTY	1-866-411-1010

Locations

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

Sponsors and Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

More Information

NIH Clinical Center Detailed Web Page This link exits the ClinicalTrials.gov site

Publications:

Young NS, Maciejewski J. The pathophysiology of acquired aplastic anemia. N Engl J Med. 1997 May 8;336(19):1365-72. Review. No abstract available.

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(702):131-6. No abstract available.

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.

Responsible Party:	National Institutes of Health ( Neal S. Young, M.D./National Heart, Lung, and Blood Institute )
Study ID Numbers:	030249, 03-H-0249
Study First Received:	July 18, 2003
Last Updated:	November 1, 2008
ClinicalTrials.gov Identifier:	NCT00065260
Health Authority:	United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):

Alemtuzumab (Campath-1H)
Rabbit ATG
Severe Aplastic Anemia
Cyclosporine
Thrombocytopenia
Leukopenia

Neutropenia
Autoimmunity
Relapse
Anemia
Severe Aplastic Anemia

Study placed in the following topic categories:

Cyclosporine
Clotrimazole
Hematologic Diseases
Miconazole
Tioconazole
Anemia
Pancytopenia
Cyclosporins

Antilymphocyte Serum
Neutropenia
Thrombocytopenia
Alemtuzumab
Anemia, Aplastic
Leukopenia
Bone Marrow Diseases
Aplastic anemia

Additional relevant MeSH terms:

Anti-Infective Agents
Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Antineoplastic Agents
Therapeutic Uses
Antifungal Agents

Physiological Effects of Drugs
Enzyme Inhibitors
Antirheumatic Agents
Dermatologic Agents
Immunosuppressive Agents
Pharmacologic Actions

ClinicalTrials.gov processed this record on January 13, 2009