Platelets are particles found along with red and white blood cells in the blood that play a
role in the process of blood clotting. Disorders affecting the platelets can lower the
amount of platelets in the blood and put patients at risk of bleeding. The condition of low
platelets is referred to as thrombocytopenia.
Thrombocytopenia can be associated with a variety of diseases including cancer, leukemia,
tuberculosis, or as a result of an autoimmune reaction. Autoimmune reactions are disorders
in which the normal immune system begins attacking itself. Autoimmune thrombocytopenia
(AITP) is a disorder of low blood platelet counts in which platelets are destroyed by
antibodies produced by the immune system.
Unfortunately, many patients with AITP do not respond to standard treatments for
thrombocytopenia. Cyclophosphamide is a drug that works to suppress the activity of the
immune system. Researchers believe that combining this drug with transplanted rescued blood
stem cells may provide effective treatment for AITP.
The purpose of this study is to explore the affordability and safety of this therapy for the
treatment of AITP. The effectiveness of the therapy will be measured by the number of
patients whose platelet levels rise greater than 100,000/m3.
If this treatment approach appears affordable, this study will form the basis for a larger
study to compare alternate treatment approaches.
Autoimmune Thrombocytopenia (AITP) is a disorder of low blood platelet counts in which
platelet destruction is caused by antiplatelet autoantibodies. A large proportion of
patients with chronic AITP are refractory to standard therapies including corticosteroids,
immune globulin and splenectomy. Cyclophosphamide is a cytotoxic immunosuppressive agent
which may induce durable remissions of refractory autoimmune diseases. High-dose
cyclophosphamide with peripheral blood stem cell (PBPC) rescue has been proposed as a
potential definitive therapy for AITP; however, the infusion of autoreactive lymphocytes
could result in relapse. The use of PBPC depleted of T-lymphocytes could circumvent this
The purpose of this phase I/II study is to explore the feasibility and safety of this
approach, and to seek preliminary evidence of effectiveness, of using high-dose
cyclophosphamide (50 mg/kg/day x 4) followed by infusion of autologous PBPC enriched for
CD34+ cells (concomitantly depleted of CD3+ cells) for the treatment of patients with
refractory AITP. Safety/feasibility parameters to be examined will include the ability to
mobilize, harvest and purify sufficient PBPC to yield greater than 2 x 10(6) CD34+ cells/kg;
symptomatic acceptability and hematologic toxicities of the mobilization regimen (filgrastim
10 micrograms/kg/day IV); tolerability of the leukapheresis procedure, including the central
line placement and maintenance; depth and duration of blood cell nadirs following
chemotherapy; peritransplant bleeding episodes and transfusion requirements; episodes of
febrile neutropenia, culture-proven infections and antibiotic usage. Effectiveness will be
gauged by the rapidity and number of patients to achieve complete remission (platelet count
greater than 100,000/mm(3) and partial remission (platelet count greater than 50,000/mm(3)
or doubling of the platelet count with resolution of bleeding episodes). Ancillary evidence
of therapeutic effect will be sought by examining changes in titers of platelet surface
glycoprotein antibodies. In addition, alterations in T-lymphocyte subsets will be examined
by flow cytometry. If this treatment approach appears feasible, this study will form the
basis for a larger trial to compare alternate treatment approaches.
- INCLUSION CRITERIA:
Male or female, ages 18-65 years old.
Refractory severe chronic autoimmune thrombocytopenia, with or without autoimmune
hemolytic anemia (Evan's syndrome), with all the following:
1. Platelet count frequently below 20,000/mm(3) despite active
treatment for a period of greater than 6 months.
2. Normal or increased megakaryocytes on bone marrow
3. No plausible alternative etiology such as drug-mediated
thrombocytopenia, marrow failure syndrome or thrombocytopenia
related to viral or bacterial infection.
4. Failure of treatment with:
i. conventional-dose steroids (e.g., prednisone or dosage of 40
mg/day or equivalent, followed by dosage taper) for at least 3
ii. intravenous immunoglobulin.
e. Episodic bleeding requiring transfusions or ecchymoses interfering
with ordinary daily activities.
ECOG performance status greater than 1.
Cardiopulmonary disease including:
1. History of coronary artery disease, angina pectoris or congestive heart failure.
2. LV ejection fraction less than 40 percent by 2D echocardiogram.
Renal disease, serum creatinine greater than 2.5 mg/dL or creatinine clearance less than
Significant hepatic dysfunction, bilirubin greater than 2 mg/dL or transaminases greater
than 2 times UNL.
Bone marrow aplasia (cellularity less than 10 percent), single or multilineage
hematopoietic failure, myelodysplastic syndrome, or extensive marrow fibrosis.
History or active diagnosis of malignancy (except treated non-melanoma skin cancer or
cevical carcinoma in situ).
Pregnancy or lactation, unwillingness to practice adequate birth control in the
Psychiatric illness or mental incapacity to understand and give informed consent.
Other medical illness or condition which, in the opinion of the Investigators, may
contraindicate participation in this study due to patients' risk or compromise of study