What is aplastic anemia?
Aplastic anemia (AA) is a rare hematologic disorder characterized by pancytopenia and bone marrow cytopenia. Patients are usually symptomatic at presentation, but some are discovered incidentally when unexpected cytopenias are found in routine blood counts. Diagnosis of severe aplastic anemia in the setting of myelocytopenia when 2 of the 3 blood counts were met: absolute neutrophil count < 500/μL, reticulocyte absolute count < 60 000/μL, platelet count < 20 000/μL and exclude myelodysplastic syndrome. Patients with aplastic aplastic are eager to find a more effective and long-lasting treatment.
Rationale for thrombopoietin stimulation in aplastic aplasia
The control of TPO levels and TPO production is complex and involves sensing of c-mpl receptor occupancy, where TPO levels are inversely proportional to megakaryocyte mass rather than peripheral platelet count. TPO levels are higher in bone marrow failure syndromes such as myelodysplastic syndromes and SAA, while TPO levels are low to normal in chronic ITP. Hematopoietic cytokines such as erythropoietin and granulocyte-stimulating growth factor (G-CSF) have historically played a very limited role in the treatment of patients with SAA.
Eltrombopag: The Rise of New Therapeutics
Eltrombopag, an oral, small molecule drug, has made its mark in the field of aplastic therapy in recent years. It improves symptoms such as anemia, bleeding, and infection in patients by stimulating hematopoietic stem cells in the bone marrow and promoting the production of red blood cells, white blood cells, and platelets. Compared with traditional treatments, eltrombopag has the advantages of definite efficacy, ease of use, and few side effects.
Eltrombopag (Riverland)
Clinical Study of Eltrombopag in the Treatment of Aplastic Disorders
1. Rationale for the use of eltrombopag in AA
AA is characterized by reduced HSC reserves, primarily due to immune-mediated bone marrow destruction. Several preclinical studies have confirmed that TPO and TPO receptors have beneficial effects on the expansion of HSCs and hematopoietic progenitor cells, so TPO receptor agonists appear to be ideal therapeutic agents for AA.
The TPO receptor agonist eltrombopag is a synthetic, non-peptide TPO mimetic that selectively binds to c-mpl in the transmembrane and proximal membrane domains of the TPO receptor, at sites distinct from the TPO binding site. Therefore, eltrombopag does not compete with endogenous cytokines for binding. Considering the effects of TPO on megakaryocyte production, eltrombopag was first successfully studied for the treatment of ITP. However, TPO agonists are also thought to enhance bone marrow function in AA based on their positive effects on HSC proliferation and maintenance (Figure 1). High serum TPO levels measured in AA are thought to hinder the action of TPO agonists, and the National Institutes of Health (NIH) has demonstrated through dose-escalation studies that elevated endogenous TPO serum levels can be overcome by using a high dose of the oral TPO agonist eltrombopag. This landmark study achieved compelling results in hematologic response, sparking further research into AA.
Figure 1: Pseudomemetic mechanism of action of eltrombopag in the treatment of aplastic anemia
Results from a non-randomized phase 2 study conducted by the National Institutes of Health in SAA using eltrombopag16. Forty-three patients with SAA were enrolled who were resistant to at least one course of IST started at least 6 months ago and had a platelet count less than 30x10 3/ul. Subjects were treated with a dose-escalation regimen starting at 50 mg with 25 mg increasing every 2 weeks to a maximum dose of 150 mg. The primary endpoint is hematologic response at 3-4 months. If patients respond, they will be allowed to enter the expansion phase of the study, and they can continue the medication indefinitely or until the decision to stop is made. Enrolled patients received a significant amount of prior treatment with an average of 2 prior courses of IST. Nearly all patients were dependent on red blood cell and platelet transfusions, and 6 of them met criteria for very severe aplastic anemia (SAA) and had a neutrophil count of < 200/ul. 17 of the 43 patients (40%) had a hematologic response to eltrombopag. Several multi-lineage reactions (Figure 2) were observed and blood counts continued to improve in most patients who continued to take eltrombopag at the time of response assessment, as well as improvements in other lineages in some single-lineage responders.
Figure 2: Response to the eltrombopag spectrum in patients with IST-refractory SAA.
Seven patients eventually exhibited a trilineage response. Only the baseline reticulocyte count is a predictor of pre-treatment response and may reflect the number of residual HSCs, as previously demonstrated by IST 36. Eltrombopag was well tolerated with no dose-limiting toxicities except for rare reversible aminotransferitis, similar to the larger safety and efficacy studies in ITP. All patients had bone marrow biopsies performed at baseline and during medication and did not show an increase in reticular protein staining, which was a concern in a recent ITP study. An increase in the number of bone marrow cells was observed in some responders (Figure 3).
Figure 3: Bone marrow cell structure of two patients who responded to eltromboppa.
The figure on the left shows the cellular structure of these strong responders at baseline. The figure in the middle shows the cellular structure before eltrombopag was discontinued. The figure on the right shows that for patients 1 and 2, the bone marrow is still cellular.
Another single-center phase II trial at MD Anderson Cancer Center could not confirm the benefit of adding eltrombopag to a standard IST containing G-CSF. Initially, the trial was designed to investigate the separate combination of IST with G-CSF, but after encouraging results from previous NIH trials, the investigators decided to add eltrombopag. This resulted in a slight increase in the overall response rate (from 71% to 76%), but was not statistically significant. Assi et al. noted that it was difficult to compare the two studies because of the large differences in trial design. Initiation of eltrombopag at a later time point, continuation of eltrombopag for more than 6 months, and short-term administration of CSA for at least 6 months. Finally, response rates were assessed during a full follow-up period of a median of 21 months, while the NIH investigated response rates after 6 months. Finally, a common drawback of the current eltrombopag trials is that they use very different response definitions and response assessment time points. Previous and ongoing landmark trials evaluating eltrombopag as a monotherapy or in combination with SAAs and MAAs as first- or second-line therapy are shown in the table below:
Conclusions: Comparing these results to historical data (66% overall hematologic response and 10% complete response), response rates were improved by the addition of eltrombopag to the standard IST. In addition to the increased hematologic response rate, quality of life was also improved, and an increase in bone marrow progenitor cells was observed.
summary
Eltrombopag brings new hope to patients with aplasia. We believe that with the continuous advancement of medicine, more and more patients will be able to overcome their diseases and regain their health. Let's look forward to more miracles from eltrombopag in the field of aplastic therapy!
Tips: The medical content involved in this article is a general application suggestion, which is for learning and reference only, and the final opinion is subject to the diagnosis of the clinician.