Three Immunosuppressive Treatment Regimens for Severe Aplastic Anemia

• ClinicalTrials.gov Identifier: NCT00260689
• Recruitment Status: Completed
• First Posted: December 1, 2005
• Results First Posted: June 8, 2017
• Last Update Posted: June 8, 2017
• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

Tracking Information

• First Submitted Date: December 1, 2005
• First Posted Date: December 1, 2005
• Results First Submitted Date: May 16, 2017
• Results First Posted Date: June 8, 2017
• Last Update Posted Date: June 8, 2017
• Study Start Date: November 28, 2005
• Actual Primary Completion Date: May 4, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 16, 2017)

• Hematologic Response [ Time Frame: 3 months ]
  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.
• Hematologic Response [ Time Frame: 6 months ]
  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.
• Hematologic Response [ Time Frame: 12 months ]
  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.

• Original Primary Outcome Measures: Not Provided
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Three Immunosuppressive Treatment Regimens for Severe Aplastic Anemia
• Official Title: A Randomized Study of Three Immunosuppressive Regimens in Treatment Naive Patients With Severe Aplastic Anemia: Horse ATG/CsA Taper vs Rabbit-ATG/CsA vs Alemtuzumab

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%.

Detailed Description

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%.

In the original design subjects were randomized to one of three different regimens: h-ATG + 6 months CsA followed by an 18 month CsA taper; r-ATG + 6 months CsA; or alemtuzumab (Campath). Subjects failing to respond to r-ATG will be crossed over to alemtuzumab (Campath), and subjects failing alemtuzumab (Campath) will be crossed over to r-ATG. Subjects failing to respond to h-ATG + CsA taper will go off study and be evaluated for eligibility for a second course of immunosuppression on companion protocol 03-H-0249, which similarly randomizes subjects between r-ATG and alemtuzumab (Campath) as salvage therapy.

The Campath arm was closed to new accrual for lack of efficacy on 4/10/2008. Subsequently, new accruals will be randomized to h-ATG + 6 months CsA followed by an 18 month CsA taper or r-ATG + 6 months CsA. Subjects failing to respond to h-ATG + CsA taper will go off study and be evaluated for eligibility for a second course of immunosuppression on companion protocol 03-H-0249, which similarly randomizes subjects between r-ATG and alemtuzumab (Campath ) as salvage therapy. Subjects who fail to respond to r-ATG + 6 months CsA will be offered treatment with h-ATG as salvage therapy or will go off-study to alternative treatments or stem cell transplant (from sibling or unrelated donor).

The primary endpoint will be hematologic response, defined as no longer meeting criteria for SAA, at 6 months. Secondary endpoints are relapse, robustness of hematologic recovery at 6 months, response at 3 and 12 months, survival, clonal evolution to PNH, myelodysplasia and acute leukemia. Long-course CSA will be assessed separately for its efficacy in reducing late events of relapse and evolution by comparison to historical control data.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Immunosuppresion
• Thrombocytopenia
• Pancytopenia
• Neutropenia

Intervention

• Biological: Anti-thymocyte globulin (rabbit)
• Biological: Anti-thymocyte globulin (horse)
• Drug: Cyclosporine
• Drug: Alemtuzumab
  Other Name: Campath

Study Arms

• Experimental: Horse ATG/CsA taper
  h-ATG (Anti-thymocyte globulin (horse)) + 6 months CsA (Cyclosporine) followed by an 18 month CsA taper
  Interventions:

  • Biological: Anti-thymocyte globulin (horse)
  • Drug: Cyclosporine
• Experimental: Rabbit ATG/CsA
  r-ATG (Anti-thymocyte globulin (rabbit)) + 6 months CsA (Cyclosporine)
  Interventions:

  • Biological: Anti-thymocyte globulin (rabbit)
  • Drug: Cyclosporine
• Experimental: Alemtuzumab
  Alemtuzumab administered for 10 days
  Intervention: Drug: Alemtuzumab

Publications *

• Young NS, Barrett AJ. The treatment of severe acquired aplastic anemia. Blood. 1995 Jun 15;85(12):3367-77. Review.
• Young NS, Maciejewski J. The pathophysiology of acquired aplastic anemia. N Engl J Med. 1997 May 8;336(19):1365-72. Review.
• Zoumbos NC, Gascón 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.
• 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.
• 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.
• 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.
• 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. Erratum in: N Engl J Med. 2018 Jun 13;:null.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 19, 2008): 136
• Original Enrollment (submitted: November 30, 2005): 180
• Actual Study Completion Date: May 4, 2016
• Actual Primary Completion Date: May 4, 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

-INCLUSION CRITERIA:

1. 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
2. Age greater than or equal to 2 years old
3. Weight greater than 12 kg

EXCLUSION CRITERIA:

1. Diagnosis of Fanconi's anemia
2. 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.
3. Prior immunosuppressive therapy with ATG, ALG, alemtuzumab, or high dose cyclophosphamide.
4. Infection not adequately responding to appropriate therapy.
5. Serologic evidence of HIV infection.
6. Failure to discontinue the herbal supplements Echinacea purpurea or Usnea barbata (Old Man's Beard) within 2 weeks of enrollment.
7. 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.
8. Potential subjects with cancer who are on active chemotherapeutic treatment or who take drugs with hematological effects will not be eligible.
9. Current pregnancy, or unwillingness to take oral contraceptives or refrain from pregnancy if of childbearing potential.
10. Not able to understand the investigational nature of the study or give informed consent.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 2 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00260689
• Other Study ID Numbers: 060034; 06-H-0034 ( Other Identifier: NIH )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: NIH Biomedical Translational Research Information System (BTRIS)

• Responsible Party: National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
• Study Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Collaborators: Not Provided

Investigators

• Principal Investigator: Danielle M Townsley, M.D.; National Heart, Lung, and Blood Institute (NHLBI)

• PRS Account: National Institutes of Health Clinical Center (CC)
• Verification Date: May 15, 2017