Clinical trial NCT00001964: Combination Therapy of Severe Aplastic Anemia
Official title: Treatment of Severe Aplastic Anemia With Combined Immunosuppression: Antithymocyte Globulin (ATG) and Cyclosporine A (CSA), and Mycophenolate Mofetil (MMF)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Severe Aplastic Anemia
Keywords: Hematopoiesis
Bone Marrow Failure
Aplastic Anemia
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2000-01-19
Enrollment: 104
Sex: ALL
Minimum age (years): 1
Maximum age (years): 99
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study will test the safety and effectiveness of a combination of three drugs in treating severe aplastic anemia and preventing its recurrence. Two drugs used in this trial ATG and cyclosporine are standard combination therapy for aplastic anemia. This study will try to improve this therapy in three ways: 1) by altering the drug regimen to allow the drugs to work better; 2) by reducing the risk of kidney damage; and 3) by adding a third drug mycophenolate mofetil to try to prevent disease relapse.

Patients with severe aplastic anemia who do not have a suitable bone marrow donor or who decline bone marrow transplantation may participate in this study. Patients will have a skin test for ATG allergy, chest X-ray, blood test, and bone marrow aspiration before treatment begins. ATG will then be started, infused through a vein continuously for 4 days. Ten days after ATG is stopped, cyclosporine treatment will begin, taken twice a day by mouth in either liquid or capsule form and will continue for 6 months. Also, in the first 2 weeks of treatment, patients will be given a full dose of corticosteroid (prednisone) to prevent serum sickness that could develop as a side effect of ATG therapy. The dosage will be decreased after that. Mycophenolate will be started at the same time as ATG, in two daily doses by mouth, and will continue for 18 months.

Patients will be hospitalized at the beginning of the study. During this time, blood will be drawn at 3-week intervals and a bone marrow examination will be repeated 3 months after treatment has begun. Additional tests, including X-rays may be required. After hospital discharge, patients will be followed on an outpatient basis at 3-month intervals. The patients own physician will perform blood tests weekly and kidney and liver function tests every 2 weeks during cyclosporine therapy. Transfusions may be required initially.

Detailed description: Severe acquired aplastic anemia (SAA) has a poor prognosis if untreated. Bone marrow transplantation is available to only a minority of patients due to lack of a matched sibling donor, advanced age of the patient, or cost. Clinical studies at NIH and elsewhere have demonstrated excellent response rates and improved survival with immunosuppressive treatments. Laboratory data implicate underlying cytotoxic T-lymphocyte-mediated suppression of hematopoiesis as the likely proximal cause of disease in most patients. In earlier clinical protocols we treated SAA with cyclosporine A (CSA) (86-H-0007), antithymocyte globulin (ATG) (87-H-0124), and combined ATG and CSA (90-H-0146). While intensive immunosuppression is most effective, relapse is common and some patients also develop second hematologic complications like myelodysplasia. In this protocol, we modify our regimen by delaying the introduction of cyclosporine to promote ATG tolerizing effects and adding mycophenolate mofetil (MMF), a new agent that, like ATG may be relatively specific for activated lymphocytes, in an effort to reduce the high relapse rate.

Eligibility criteria: * INCLUSION CRITERIA:

Only patients with SAA will be admitted, defined as:

Bone marrow cellularity less than 30%.

At least two of the following blood count findings: absolute granulocyte count less than 500/mm(3); platelet count less than 20,000/mm(3); reticulocyte count less than 60,000/mm(3).

Age greater than or equal to 1 years.

Weight greater than 12 kg.

EXCLUSION CRITERIA:

Serum creatinine greater than 2 mg/dl or estimated creatinine clearance less than 40 ml/min.

Underlying carcinoma, recent history of radiation or chemotherapy.

Current pregnancy or unwillingness to be treated with oral contraceptives.

Inability to comprehend the investigational nature of the study.

Moribund status or concurrent hepatic, renal, cardiac, neurologic, or metabolic disease of such severity that death within 7 to 10 days is likely.

Evidence of other etiology than AA for bone marrow failure, including positive clastogenic stress cytogenetic assay for Fanconi anemia and marrow chromosome abnormalities typical of myelodysplasia.

Primary outcomes:
measure: reduction in 24-month relapse
timeFrame: 24 months
Secondary outcomes:
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Heart, Lung, and Blood Institute (NHLBI)
name: Neal S Young, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Young NS. Acquired aplastic anemia. JAMA. 1999 Jul 21;282(3):271-8. doi: 10.1001/jama.282.3.271. No abstract available.
citation: 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.
citation: Nimer SD, Ireland P, Meshkinpour A, Frane M. An increased HLA DR2 frequency is seen in aplastic anemia patients. Blood. 1994 Aug 1;84(3):923-7.
citation: Zaimoku Y, Patel BA, Adams SD, Shalhoub R, Groarke EM, Lee AAC, Kajigaya S, Feng X, Rios OJ, Eager H, Alemu L, Quinones Raffo D, Wu CO, Flegel WA, Young NS. HLA associations, somatic loss of HLA expression, and clinical outcomes in immune aplastic anemia. Blood. 2021 Dec 30;138(26):2799-2809. doi: 10.1182/blood.2021012895.