Alefacept in Patients With Relapsed/Refractory Aplastic Anemia

• Status: Terminated
• Trial end date: 2013-04-16
• Target enrollment: 0
• Participant gender: All

Summary

Aplastic Anemia (AA) is an autoimmune hematologic stem cell disease mediated by activated T-lymphocytes that leads to pancytopenia. The disease related morbidity and mortality if left untreated can approach 90%. For over 30 years, anti-thymocyte globulin (ATG) in combination with cyclosporine (CsA) remains the standard therapy. However, the treatment response with ATG is at best between 50-60% with a sizeable number of partial responses. Treatment with ATG is also associated with significant toxicity and high relapse rate that can be as high as 45%. Since the prognosis in refractory and relapsed AA remains poor, there is a need for less toxic novel immunosuppressive agents that can improve response rates and remission duration in refractory and relapsed AA.

Alefacept is a human recombinant dimeric fusion protein composed of the terminal portion of leukocyte functioning antigen-3 (LFA3/CD58) and the Fc portion of human IgG1. It prevents co-stimulatory signals between antigen presenting cells and memory T cells by competitive inhibition of CD2 in T cells, induces selective apoptosis of CD4+ and CD8+ memory effector T cells by interaction between the Fc portion of IgG1 and the FcyIII in NK cells, and possibly direct ligation of CD2 molecules on T cells that subsequently result in the alteration in T cell agonist signaling. It has been used successfully in the treatment of other T cell mediated disorders particularly psoriasis and steroid refractory graft versus host disease (GVHD) with minimal side effects. In a case of liver transplant associated AA (similar to transfusion associated AA) which is fatal in most patients, Alefacept induced remission after patient did not respond to ATG and other immunosuppressants. The investigators hypothesize that the LFA3-CD2 co-stimulatory pathway play an important role in the immune pathogenesis of AA and treatment with Alefacept can help treat refractory/relapsed cases of AA.

• Phase: Phase 1
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: The Cleveland Clinic
• Collaborator: Astellas Pharma US, Inc.
• Treatments: Alefacept

Criteria

Inclusion Criteria:

1. Fulfilled criteria for diagnosis of either moderate (mAA) or severe aplastic anemia (sAA) at the time of initial diagnosis defined per protocol.

2. Patient with a history sAA must have had an incomplete response at least 3 months following treatment with ATG/CsA, or they must have relapsed following an initial response to treatment.

3. Patient must not be receiving any cyclosporine or any other T cell immunosuppressive agents within 4 weeks of study entry.

4. Patients must have organ function as defined below:

• total bilirubin within normal institutional limits (NV: 0.0-1.5 mg/dL)

• AST(SGOT)/ALT(SGPT) <2.5 X institutional upper limit of normal AST (NV: 7-40 U/L); ALT (NV: Male 5-50 U/L; Female 0-45 U/L)

• creatinine within normal institutional limits (NV: Age 18 0.4-1.3 mg/dL; 19-99 years old 0.7-1.4 mg/dL) OR

• creatinine clearance >60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.

5. Peripheral blood counts at the time of enrollment must include at least one of the following: Hgb <9 g/dL or red blood cell (RBC) transfusion dependence, ANC <1000/µl, or platelet count of <60,000/µL.

6. Women of child-bearing potential and men must agree to use adequate contraception defined per protocol.

7. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Patients may not be receiving any other investigational agents (other than hematopoietic growth factors) within 4 weeks of study entry.

2. History of allergic reactions attributed to compounds of similar chemical or biologic composition to Alefacept.

3. Current diagnosis of acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), Fanconi's anemia, Dyskeratosis Congenita (DC) or other hereditary forms of AA.

4. Psychiatric, addictive or any other disorder that compromises ability to give a truly informed consent.

5. Age <18 years.

6. ECOG performance status >2 (Karnofsky <60%, see Appendix A).

7. Malignancy other than non-melanoma skin cancer within the last 2 years.

8. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (defined as uncontrolled infection requiring IV antibiotics, invasive fungal infection and progressive CMV viremia), symptomatic congestive heart failure (NYH class III and IV), unstable angina pectoris, or cardiac arrhythmia.

9. Pregnant or breastfeeding women.

10. HIV-positive patients on combination antiretroviral therapy.

11. Patients who have previously received systemic chemotherapy and/ or radiation therapy.

12. Patients who previously underwent allogeneic hematopoietic stem cell transplant.