Three Immunosuppressive Treatment Regimens for Severe Aplastic Anemia

NCT00260689 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 06003406-H-0034
• Study Type: interventional
• Target: 136
• Locations: 1 country
• Sites: 1

Brief Summary

Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder characterized by pancytopenia and a hypocellular bone marrow. Allogeneic bone marrow transplantation offers the opportunity for cure in 70% of patients, but most patients are not suitable candidates for hematopoietic stem cell transplantation (HSCT) due to advanced age or lack of a histocompatible donor. For these patients, comparable long term survival is attainable with immunosuppressive treatment with anti-thymocyte globulin (ATG) and cyclosporine (CsA). However, of those patients treated with horse ATG(h-ATG)/CsA, one quarter to one third will not respond, and about 50% of responders relapse. Auto-reactive T cells may be resistant to the effect of ATG/CsA (non-responders), while in others residual auto-reactive T cells expand post-treatment, leading to hematopoietic stem cell destruction and recurrent pancytopenia (relapse). As long term survival is correlated to response rates and robustness of hematopoietic recovery, novel immunosuppressive regimens that can achieve hematologic response and decrease relapse rates are needed. This trial will compare the effectiveness of three immunosuppressive regimens as first line therapies in patients with SAA with early hematologic response as the primary endpoint, as well as assess the role of extended CsA treatment after h-ATG in reducing numbers of late events of relapse and clonal evolution. Randomization is employed to obtain an equal distribution of subject to each arm; comparisons of early hematologic responses will be made among the rates observed among the three concurrent arms (rabbit-ATG \[r-ATG\] versus standard h-ATG; alemtuzumab vs standard h-ATG). For long course CSA, comparison of primary end points will be to well established historic relapse rate of 38% at 2-3 years and a cumulative rate of clonal evolution of 15%.

Conditions

Immunosuppresion; Thrombocytopenia; Pancytopenia; Neutropenia

Keywords

Immunosuppression; T-cells; Hematopoiesis; Autoimmunity; Thrombocytopenia; Severe Aplastic Anemia; SAA

Outcome Measures

Primary Outcomes (3)

• Hematologic Response

  Hematologic response is defined as subjects having blood counts no longer meeting the standard ("Camitta") criteria for severe pancytopenia in Severe Aplastic Anemia, equivalent to 2 of the following values obtained on 2 serial blood count measurements at least one week apart at landmark time points (3, 6 and 12 months) * Absolute neutrophil count \> 500/ μL * Platelet count \> 20,000/ μL * Reticulocyte count \> 60,000/ μL Improvement in counts that are dependent upon exogenously administered growth factors or transfusion will not be considered as fulfilling response criteria.

  3 months

• Hematologic Response

  Hematologic response is defined as subjects having blood counts no longer meeting the standard ("Camitta") criteria for severe pancytopenia in Severe Aplastic Anemia, equivalent to 2 of the following values obtained on 2 serial blood count measurements at least one week apart at landmark time points (3, 6 and 12 months) * Absolute neutrophil count \> 500/ μL * Platelet count \> 20,000/ μL * Reticulocyte count \> 60,000/ μL Improvement in counts that are dependent upon exogenously administered growth factors or transfusion will not be considered as fulfilling response criteria.

  6 months

• Hematologic Response

  Hematologic response is defined as subjects having blood counts no longer meeting the standard ("Camitta") criteria for severe pancytopenia in Severe Aplastic Anemia, equivalent to 2 of the following values obtained on 2 serial blood count measurements at least one week apart at landmark time points (3, 6 and 12 months) * Absolute neutrophil count \> 500/ μL * Platelet count \> 20,000/ μL * Reticulocyte count \> 60,000/ μL Improvement in counts that are dependent upon exogenously administered growth factors or transfusion will not be considered as fulfilling response criteria.

  12 months

Study Arms (3)

Horse ATG/CsA taper

EXPERIMENTAL

h-ATG (Anti-thymocyte globulin (horse)) + 6 months CsA (Cyclosporine) followed by an 18 month CsA taper

Biological: Anti-thymocyte globulin (horse); Drug: Cyclosporine

Rabbit ATG/CsA

EXPERIMENTAL

r-ATG (Anti-thymocyte globulin (rabbit)) + 6 months CsA (Cyclosporine)

Biological: Anti-thymocyte globulin (rabbit); Drug: Cyclosporine

Alemtuzumab

EXPERIMENTAL

Alemtuzumab administered for 10 days

Drug: Alemtuzumab

Interventions

Anti-thymocyte globulin (rabbit) BIOLOGICAL

Rabbit ATG/CsA

Anti-thymocyte globulin (horse) BIOLOGICAL

Horse ATG/CsA taper

Cyclosporine DRUG

Horse ATG/CsA taper; Rabbit ATG/CsA

Alemtuzumab DRUG

Also known as: Campath

Alemtuzumab

Eligibility Criteria

• Age: 2 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Severe aplastic anemia characterized by bone marrow cellularity less than 30% (excluding lymphocytes) and at least two of the following:
• Absolute neutrophil count less than 500/microliter
• Platelet count less than 20,000/microliter
• Absolute reticulocyte count less than 60,000/microliter
• Age greater than or equal to 2 years old
• Weight greater than 12 kg

You may not qualify if:

• Diagnosis of Fanconi's anemia
• Evidence of a clonal disorder on cytogenetics. Patients with super severe neutropenia (ANC less than 200/microliter) will not be excluded initially if cytogenetics are not available or pending. If evidence of a clonal disorder is later identified, the patient will go off study.
• Prior immunosuppressive therapy with ATG, ALG, alemtuzumab, or high dose cyclophosphamide.
• Infection not adequately responding to appropriate therapy.
• Serologic evidence of HIV infection.
• Failure to discontinue the herbal supplements Echinacea purpurea or Usnea barbata (Old Man's Beard) within 2 weeks of enrollment.
• 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.
• Current pregnancy, or unwillingness to take oral contraceptives or refrain from pregnancy if of childbearing potential.
• Not able to understand the investigational nature of the study or give informed consent.

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (11)

• Young NS, Barrett AJ. The treatment of severe acquired aplastic anemia. Blood. 1995 Jun 15;85(12):3367-77. No abstract available.

  PMID: 7780125 BACKGROUND

• 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.

  PMID: 9134878 BACKGROUND

• Zoumbos NC, Gascon P, Djeu JY, Trost SR, Young NS. Circulating activated suppressor T lymphocytes in aplastic anemia. N Engl J Med. 1985 Jan 31;312(5):257-65. doi: 10.1056/NEJM198501313120501.

  PMID: 2981406 BACKGROUND

• Feng X, Scheinberg P, Biancotto A, Rios O, Donaldson S, Wu C, Zheng H, Sato K, Townsley DM, McCoy JP, Young NS. In vivo effects of horse and rabbit antithymocyte globulin in patients with severe aplastic anemia. Haematologica. 2014 Sep;99(9):1433-40. doi: 10.3324/haematol.2014.106542. Epub 2014 Jun 6.

  PMID: 24907357 BACKGROUND

• Scheinberg P, Townsley D, Dumitriu B, Scheinberg P, Weinstein B, Rios O, Wu CO, Young NS. Horse antithymocyte globulin as salvage therapy after rabbit antithymocyte globulin for severe aplastic anemia. Am J Hematol. 2014 May;89(5):467-9. doi: 10.1002/ajh.23669. Epub 2014 Mar 7.

  PMID: 24415649 BACKGROUND

• Scheinberg P, Nunez O, Weinstein B, Scheinberg P, Wu CO, Young NS. Activity of alemtuzumab monotherapy in treatment-naive, relapsed, and refractory severe acquired aplastic anemia. Blood. 2012 Jan 12;119(2):345-54. doi: 10.1182/blood-2011-05-352328. Epub 2011 Nov 8.

  PMID: 22067384 BACKGROUND

• Scheinberg P, Nunez O, Weinstein B, Scheinberg P, Biancotto A, Wu CO, Young NS. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med. 2011 Aug 4;365(5):430-8. doi: 10.1056/NEJMoa1103975.

  PMID: 21812672 BACKGROUND

• 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.

  PMID: 34724566 DERIVED

• Giudice V, Wu Z, Kajigaya S, Fernandez Ibanez MDP, Rios O, Cheung F, Ito S, Young NS. Circulating S100A8 and S100A9 protein levels in plasma of patients with acquired aplastic anemia and myelodysplastic syndromes. Cytokine. 2019 Jan;113:462-465. doi: 10.1016/j.cyto.2018.06.025. Epub 2018 Jun 27.

  PMID: 29958797 DERIVED

• Giudice V, Banaszak LG, Gutierrez-Rodrigues F, Kajigaya S, Panjwani R, Ibanez MDPF, Rios O, Bleck CK, Stempinski ES, Raffo DQ, Townsley DM, Young NS. Circulating exosomal microRNAs in acquired aplastic anemia and myelodysplastic syndromes. Haematologica. 2018 Jul;103(7):1150-1159. doi: 10.3324/haematol.2017.182824. Epub 2018 Apr 19.

  PMID: 29674506 DERIVED

• Hosokawa K, Kajigaya S, Feng X, Desierto MJ, Fernandez Ibanez MD, Rios O, Weinstein B, Scheinberg P, Townsley DM, Young NS. A plasma microRNA signature as a biomarker for acquired aplastic anemia. Haematologica. 2017 Jan;102(1):69-78. doi: 10.3324/haematol.2016.151076. Epub 2016 Sep 22.

  PMID: 27658437 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Thrombocytopenia; Pancytopenia; Neutropenia; Autoimmune Diseases; Anemia, Aplastic

Interventions

Antilymphocyte Serum; Cyclosporine; Alemtuzumab

Condition Hierarchy (Ancestors)

Blood Platelet Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Cytopenia; Agranulocytosis; Leukopenia; Leukocyte Disorders; Immune System Diseases; Anemia; Bone Marrow Failure Disorders; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Immune Sera; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Biological Products; Complex Mixtures; Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal

Limitations and Caveats

Originally, there were 3 regimens: h-ATG/CsA ; r-ATG/CsA; alemtuzumab. Subjects not responding to r-ATG will cross over to alemtuzumab, and subjects failing alemtuzumab will cross over to r-ATG. Subjects not responding to h-ATG/CsA will go off study.

Results Point of Contact

• Title: Danielle Townsley MD
• Organization: NHLBI, NIH

townsleydm@nhlbi.nih.gov

301-402-3477

Study Officials

• Danielle M Townsley, M.D.

  National Heart, Lung, and Blood Institute (NHLBI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 1, 2005
• First Posted: December 1, 2005
• Study Start: November 28, 2005
• Primary Completion: May 4, 2016
• Study Completion: May 4, 2016
• Last Updated: June 8, 2017
• Results First Posted: June 8, 2017

Record last verified: 2017-05-15

Data Sharing

• IPD Sharing: Will share

Locations

US (1)