NCT00061360

Improving Immunosuppressive Treatment for Patients With Severe Aplastic Anemia

Completed Phase 2 Last updated 30 June 2021

What this trial tests

Phase 2 trial testing ATG+Rapamune+cyclosporine in Severe Aplastic Anemia in 77 participants. Completed in 8 September 2015.

Timeline

26 June 2003

Primary endpoint
15 February 2006

8 September 2015

Quick facts

Lead sponsor	National Heart, Lung, and Blood Institute (NHLBI)
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	77
Start date	26 June 2003
Primary completion	15 February 2006
Estimated completion	8 September 2015
Sites	1 location across United States

Drugs / interventions tested

• ATG+Rapamune+cyclosporine — full drug profile →
• ATG+cyclosporine — full drug profile →

Conditions studied

• Severe Aplastic Anemia — all drugs for Severe Aplastic Anemia →

Sponsor

National Heart, Lung, and Blood Institute (NHLBI)

Who can join

Adults 2 to 110, any sex, with Severe Aplastic Anemia. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own 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 and immunosuppressive treatment with anti-thymocyte globulin (ATG) and cyclosporine (CsA) have dramatically changed the natural course of this illness, with 5 year survival of 75% in patients undergoing either treatment. Since most patients are not suitable candidates for hematopoietic stem cell transplantation (HSCT) due to advanced age or lack of a histocompatible sibling, efforts at NHLBI have focused on improving immunosuppression treatment in order to improve response rates, survival, and to decrease relapse.

In our experience of 122 patients treated at NHLBI with the combination of ATG and cyclosporine, one quarter to one third did not respond; about 50% of responders relapsed; and 5 year survival was correlated with the robustness in blood cell count improvement at 3 months (reticulocyte or platelet count greater than or equal to 50,000 /uL). Why some patients do not respond initially while others relapse is unclear. Autoreactive T cells may be resistant to the effect of ATG/CsA (nonresponders), while in others residual autoreactive T cells expand post-treatment leading to hematopoietic stem cell destruction and recurrent pancytopenia (relapse). Therefore, novel immunosuppressive regimens to increase response rates and hematologic recovery at 3 months and to decrease relapse rates are needed. An ongoing NHLBI trial, which is close to completing accrual, has added mycophenolate mofetil (MMF) for a total of 18 months to standard ATG + CsA in an attempt to reduce the relapse rate after cyclosporine is discontinued. Preliminary results have been disappointing, with no marked reduction in relapse among patients who received MMF.

Sirolimus (rapamycin, Rapamune , RAPA) is a novel immunosuppressive agent, which acts synergistically with cyclosporine by blocking T cell activation through CsA-resistant pathways. The potentiation of the combination of CsA-RAPA has been established in vitro and in the clinical setting, mainly in islet cell and solid organ transplantation. The significant increase in response rate seen with the addition of CsA to ATG indicated that an inhibitory effect on T lymphocytes is important in blocking autoreactive T cells in aplastic anemia. The combination of CsA-RAPA may further block activated autoreactive T cells and therefore lead to improved response rates (and survival) and decreased relapse rates.

This prospective randomized phase II study will investigate two different immunosuppressive regimens in patients with severe aplastic anemia who have not received prior immunosuppressive therapy. One arm will receive ATG + CsA in addition to sirolimus for 6 months, and the second arm will receive standard ATG + CsA for 6 months followed by a slow taper of CsA with a 25% dose reduction every 3 months for the subsequent 18 months. This trial will determine the effectiveness of sirolimus in patients with aplastic anemia as well as the role of a cyclosporine taper in preventing relapses. Primary endpoint will be no longer meeting criteria for severe aplastic anemia while secondary endpoints are relapse, robustness of hematologic recovery at 3 months, survival, clonal evolution to PNH, myelodysplasia and acute leukemia.

10/11/2005. The Sirolimus (Rapamune) arm of the trial was stopped for lack of efficacy. The study will continue as a single arm study to establish if slow taper of CsA prevents relapse rates after initial standard treatment with ATG followed by CsA for six months.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Treatment of severe aplastic anemia with a combination of horse antithymocyte globulin and cyclosporine, with or without sirolimus: a prospective randomized study.
   Scheinberg P, Wu CO, Nunez O, Scheinberg P, et al · · 2009 · cited 132× · PMID 19181786 · DOI 10.3324/haematol.13829
2. Long-term outcomes in patients with severe aplastic anemia treated with immunosuppression and eltrombopag: a phase 2 study.
   Patel BA, Groarke EM, Lotter J, Shalhoub R, et al · · 2022 · cited 97× · PMID 34525188 · DOI 10.1182/blood.2021012130
3. Short telomeres result in chromosomal instability in hematopoietic cells and precede malignant evolution in human aplastic anemia.
   Calado RT, Cooper JN, Padilla-Nash HM, Sloand EM, et al · · 2012 · cited 76× · PMID 22005790 · DOI 10.1038/leu.2011.272
4. Eltrombopag added to immunosuppression for children with treatment-naïve severe aplastic anaemia.
   Groarke EM, Patel BA, Gutierrez-Rodrigues F, Rios O, et al · · 2021 · cited 50× · PMID 33410523 · DOI 10.1111/bjh.17232
5. Predicting response of severe aplastic anemia to immunosuppression combined with eltrombopag.
   Zaimoku Y, Patel BA, Shalhoub R, Groarke EM, et al · · 2022 · cited 44× · PMID 33910334 · DOI 10.3324/haematol.2021.278413
6. Predictors of clonal evolution and myeloid neoplasia following immunosuppressive therapy in severe aplastic anemia.
   Groarke EM, Patel BA, Shalhoub R, Gutierrez-Rodrigues F, et al · · 2022 · cited 43× · PMID 35896822 · DOI 10.1038/s41375-022-01636-8
7. HLA associations, somatic loss of HLA expression, and clinical outcomes in immune aplastic anemia.
   Zaimoku Y, Patel BA, Adams SD, Shalhoub R, et al · · 2021 · cited 42× · PMID 34724566 · DOI 10.1182/blood.2021012895
8. Prolonged cyclosporine administration after antithymocyte globulin delays but does not prevent relapse in severe aplastic anemia.
   Scheinberg P, Rios O, Scheinberg P, Weinstein B, et al · · 2014 · cited 31× · PMID 24971433 · DOI 10.1002/ajh.23692