Eltrombopag and the Bcl-extra-large (xL) Pathway in Idiopathic Thrombocytopenic Purpura (ITP)
| Status: | Completed |
|---|---|
| Conditions: | Infectious Disease, Hematology |
| Therapuetic Areas: | Hematology, Immunology / Infectious Diseases |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 3/20/2019 |
| Start Date: | January 2009 |
| End Date: | September 7, 2015 |
The Effect of Eltrombopag on Platelet Survival: the Role of the B-cell L Extra Large (BcL-xL) Pathway
The purpose of this study is to further evaluate the effects that eltrombopag (and
romiplostim) have on platelets in subjects with chronic ITP. Eltrombopag is approved by the
Food and Drug Administration (FDA) for the treatment of low platelets in patients with
chronic ITP. It is being further studied by GlaxoSmithKline (now Novartis) in other
conditions associated with low platelets. This research study is being done because
eltrombopag has been shown to increase platelet counts in a different way than other
therapies for ITP. The investigators want to further study how eltrombopag and romiplostim
affect subjects and their platelets to determine how the study drug should best be used in
ITP treatment.
romiplostim) have on platelets in subjects with chronic ITP. Eltrombopag is approved by the
Food and Drug Administration (FDA) for the treatment of low platelets in patients with
chronic ITP. It is being further studied by GlaxoSmithKline (now Novartis) in other
conditions associated with low platelets. This research study is being done because
eltrombopag has been shown to increase platelet counts in a different way than other
therapies for ITP. The investigators want to further study how eltrombopag and romiplostim
affect subjects and their platelets to determine how the study drug should best be used in
ITP treatment.
The B-cell lymphoma extra large (Bcl-xL/Bak) balance has been identified as an intrinsic
mechanism that is critical in determining platelet lifespan (Mason, Cell 2007). There is
evidence that Bcl-xL protein expression in megakaryocytes is regulated by Thrombopoietin
(TPO) mediated activation of Akt pathways mediated by Jak2 and Stat 5 (possibly by Stat 3 as
well). (e.g., Kozuma et. al., Journal of Thrombosis and Haemostasis). Little is known about
the Bcl-xL / Bak axis in patients with ITP, or the effect of TPO-R stimulation on platelet
survival in patients with ITP. The TPO effect may be a result of stimulation of
thrombopoietin-receptor (TPO-R) signalling in megakaryocytes altering the packaging of Bcl-xl
into platelets, or be a direct effect of platelet TPO-R stimulation as described above.
mechanism that is critical in determining platelet lifespan (Mason, Cell 2007). There is
evidence that Bcl-xL protein expression in megakaryocytes is regulated by Thrombopoietin
(TPO) mediated activation of Akt pathways mediated by Jak2 and Stat 5 (possibly by Stat 3 as
well). (e.g., Kozuma et. al., Journal of Thrombosis and Haemostasis). Little is known about
the Bcl-xL / Bak axis in patients with ITP, or the effect of TPO-R stimulation on platelet
survival in patients with ITP. The TPO effect may be a result of stimulation of
thrombopoietin-receptor (TPO-R) signalling in megakaryocytes altering the packaging of Bcl-xl
into platelets, or be a direct effect of platelet TPO-R stimulation as described above.
Inclusion Criteria:
- Subject has signed and dated a written informed consent
- Male or female adults (≥18 years) diagnosed with either primary ITP according to the
American Society for Hematology or British Committee for Standards in Haematology
(ASH/BCSH) guidelines [Blood, 1996; British Journal of Haematology, 2003] for at least
three months prior to study entry or with ITP secondary to Evans syndrome, systemic
lupus erythematosus (SLE), or Common Variable Immunodeficiency (including
hypogammaglobulinemia).
- Subjects must have responded with a platelet count > 30,000/µL to a previous ITP
therapy including thrombopoietic agents.
- Platelet count < 30,000/µL
- Female subjects of childbearing potential are practicing an acceptable method of
contraception or are completely abstinent from intercourse.
Exclusion Criteria:
- Active infection
- Previously treated with thrombopoietic agents IF either no response at a therapeutic
dose (peak platelet count < 50k) OR treatment with the agent within the past 4 weeks
- Currently treated with concomitant ITP medication that has not been stable in dose for
at least 2 weeks - only prednisone, azathioprin, and danazol are allowed.
- Female subjects who are nursing or pregnant
- Thrombosis of any kind within past 6 months or on blood thinners because of
thrombosis.
- Intravenous Immunoglobulin (IVIG), IV anti-D, bolus corticosteroids or vinca alkaloids
within the past week
- Other cytotoxic or immunosuppressive ITP therapy within the past 8 weeks or rituximab
within the past 12 weeks
- Active non-dermatologic malignancy defined as presence of known tumor ie. visible by
radiography or evident on blood or bone marrow testing OR receiving chemotherapy
within past 2 months
- Hemoglobin < 10 gm/dl or white blood cell count < 2,500/ul
- Liver function tests (ALT, Aspartate Aminotransferase (AST), or total bilirubin) >
three times upper limit of normal (ULN)
- Creatinine > two times upper limit of normal (ULN)
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