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Current evidence and the emerging role of eltrombopag in severe aplastic anemia.

ABSTRACT: Acquired aplastic anemia (AA) is characterized by a reduced stem cell reserve. Several preclinical studies have confirmed the beneficial effect of thrombopoietin (TPO) on the expansion and maintenance of hematopoietic stem cells (HSCs). Thus, TPO receptor agonists seem to be an ideal therapeutic agent for AA to augment marrow function. First studies with eltrombopag as a single agent at 150 mg/day showed an overall response rate of 40-50% in patients with refractory severe AA (rSAA). Subsequent studies examined the first-line use of eltrombopag together with horse antithymocyte globulin and cyclosporine, reaching response rates up to 94%. Although used at high doses, known adverse events in the form of skin, gastrointestinal, or hepatic impairment are feasible in AA, however first data show a relatively high rate of clonal evolution in the form of karyotypic aberrations in patients with rAA. Nonetheless, there is a strong rationale that eltrombopag can contribute to restoring hematopoiesis in SAA by stimulating HSCs. Further studies are needed to decide if eltrombopag is clearly superior to current established treatments and to determine optimal treatment duration, dosage, and long-term effects.

SUBMITTER: Drexler B

PROVIDER: S-EPMC7940771 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Current evidence and the emerging role of eltrombopag in severe aplastic anemia.

Drexler Beatrice B Passweg Jakob J

Therapeutic advances in hematology 20210303

Acquired aplastic anemia (AA) is characterized by a reduced stem cell reserve. Several preclinical studies have confirmed the beneficial effect of thrombopoietin (TPO) on the expansion and maintenance of hematopoietic stem cells (HSCs). Thus, TPO receptor agonists seem to be an ideal therapeutic agent for AA to augment marrow function. First studies with eltrombopag as a single agent at 150 mg/day showed an overall response rate of 40-50% in patients with refractory severe AA (rSAA). Subsequent ...[more]

PMID: 33747425

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Project description:BackgroundAcquired aplastic anemia results from immune-mediated destruction of bone marrow. Immunosuppressive therapies are effective, but reduced numbers of residual stem cells may limit their efficacy. In patients with aplastic anemia that was refractory to immunosuppression, eltrombopag, a synthetic thrombopoietin-receptor agonist, led to clinically significant increases in blood counts in almost half the patients. We combined standard immunosuppressive therapy with eltrombopag in previously untreated patients with severe aplastic anemia.MethodsWe enrolled 92 consecutive patients in a prospective phase 1-2 study of immunosuppressive therapy plus eltrombopag. The three consecutively enrolled cohorts differed with regard to the timing of initiation and the duration of the eltrombopag regimen (cohort 1 received eltrombopag from day 14 to 6 months, cohort 2 from day 14 to 3 months, and cohort 3 from day 1 to 6 months). The cohorts were analyzed separately. The primary outcome was complete hematologic response at 6 months. Secondary end points included overall response, survival, relapse, and clonal evolution to myeloid cancer.ResultsThe rate of complete response at 6 months was 33% in cohort 1, 26% in cohort 2, and 58% in cohort 3. The overall response rates at 6 months were 80%, 87%, and 94%, respectively. The complete and overall response rates in the combined cohorts were higher than in our historical cohort, in which the rate of complete response was 10% and the overall response rate was 66%. At a median follow-up of 2 years, the survival rate was 97%; one patient died during the study from a nonhematologic cause. Marked increases in bone marrow cellularity, CD34+ cell number, and frequency of early hematopoietic progenitors were noted. Rates of relapse and clonal evolution were similar to our historical experience. Severe rashes occurred in two patients, resulting in the early discontinuation of eltrombopag.ConclusionsThe addition of eltrombopag to immunosuppressive therapy was associated with markedly higher rates of hematologic response among patients with severe aplastic anemia than in a historical cohort. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT01623167 .).

Project description:Thrombopoietin (TPO) is the most potent cytokine stimulating thrombopoiesis. Therapy with exogenous TPO is limited by the formation of antibodies cross-reacting with endogenous TPO. Mimetics of TPO are compounds with no antigenic similarity to TPO. Eltrombopag is an orally-active nonpeptide small molecule that binds to the transmembrane portion of the TPO receptor MPL. Initial trials of eltrombopag have centered on immune thrombocytopenia (ITP), which is due to both increased destruction and decreased production of platelets. Eltrombopag at 25-75 mg/day has been shown to be highly effective in raising the platelet count in ITP with suboptimal response to immunosuppression and splenectomy. These successful results led to the exploration of eltrombopag in other thrombocytopenic disorders. In hepatitis C viral infection, eltrombopag raises the platelet count sufficiently enough to allow treatment with ribavirin and pegylated interferon. Because MPL is expressed on hematopoietic cells, eltrombopag use in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) might enhance leukemic proliferation. Clinical trials of eltrombopag in MDS and AML, however, have shown amelioration of thrombocytopenia without promoting disease progression. In severe aplastic anemia (SAA) not responding to immunosuppression with anti-thymocyte globulin (ATG) and cyclosporine, eltrombopag as a single agent at 150-300 mg/day results in an overall response rate of 40-70%. At high doses, adverse effects including pigmentation, gastrointestinal upset and hepatic derangement have become evident. Current studies have examined the first-line use of eltrombopag in combination with ATG in SAA. In a recent study, eltrombopag used at 150 mg/day with horse ATG resulted in an overall response rate of 90% in newly diagnosed SAA patients, with a complete response rate of about 50%. Clonal karyotypic aberrations are, however, found in 10-20% of SAA patients treated with eltrombopag. The safety and efficacy of eltrombopag in SAA require further evaluation, particularly when it is used with less intensive immunosuppression.

Project description:Few therapeutic options are available for patients with aplastic anemia who are ineligible for transplantation or refractory to immunosuppressive therapy. Eltrombopag was recently shown to produce trilineage responses in refractory patients. However, the effects of real-life use of this drug remain unknown. This retrospective study (2012-2016) was conducted by the French Reference Center for Aplastic Anemia on patients with relapsed/refractory aplastic anemia, and patients ineligible for antithymocyte globulin or transplantation, who received eltrombopag for at least 2 months. Forty-six patients with aplastic anemia were given eltrombopag without prior antithymocyte globulin treatment (n=11) or after antithymocyte globulin administration (n=35) in a relapsed/refractory setting. Eltrombopag (median daily dose 150 mg) was introduced 17 months (range, 8-50) after the diagnosis of aplastic anemia. At last followup, 49% were still receiving treatment, 9% had stopped due to a robust response, 2% due to toxicity and 40% due to eltrombopag failure. Before eltrombopag treatment, all patients received regular transfusions. The overall rates of red blood cell and platelet transfusion independence were 7%, 33%, 46% and 46% at 1, 3, 6 months and last follow-up. Responses were slower to develop in antithymocyte treatment-naïve patients. In patients achieving transfusion independence, hemoglobin concentration and platelet counts improved by 3 g/dL (interquartile range, 1.4-4.5) and 42×109/L (interquartile range, 11-100), respectively. Response in at least one lineage (according to National Institutes of Health criteria) was observed in 64% of antithymocyte treatment-naïve and 74% of relapsed/refractory patients, while trilineage improvement was observed in 27% and 34%, respectively. We found high rates of hematologic improvement and transfusion independence in refractory aplastic anemia patients but also in patients ineligible for antithymocyte globulin receiving first-line treatment. In conclusion, elderly patients unfit for antithymocyte globulin therapy may benefit from eltrombopag.

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Current evidence and the emerging role of eltrombopag in severe aplastic anemia.

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Current evidence and the emerging role of eltrombopag in severe aplastic anemia.

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