Persistent thrombocytopenia after stem cell transplantation (SCT) can lead to increased morbidity and mortality.1 The underlying causes are often multifactorial in this patient population, with complexities such as engraftment deficits, medication effects, graft-versus-host disease (GVHD), and other immunologic processes potentially influencing platelet counts.2 Eltrombopag is an orally available nonpeptide thrombopoietin receptor agonist that interacts with the transmembrane domain of the receptor on bone marrow megakaryocytes and upstream progenitor cells. It has been studied in patients with thrombocytopenia from chronic idiopathic thrombocytopenic purpura, hepatitis C infection, and marrow failure disorders such as aplastic anemia and myelodysplastic syndrome.3-5 The use of eltrombopag as an effective agent to elevate platelet counts post-SCT to levels that eliminate the need for platelet transfusions would be extremely useful in this patient population. Small series have emerged recently to explore this possibility. This Diffusion reviews two manuscripts from 2019.
Dr. Serena Marotta and colleagues describe utilizing eltrombopag specifically for persistent cytopenia and poor graft function in 12 patients at a single European center in this retrospective series. The treatment was started at a dose of 50 mg/d and uptitrated to 150 mg to increase response rates. Eltrombopag was started at a median time post-SCT of 79 days (range, 42-367 days) and given for a median of 107 days (range, 28-155 days). No patient required discontinuation of eltrombopag owing to adverse effects, including no liver abnormalities. Hematologic responses were observed in seven patients, with six complete responses; these included patients with thrombocytopenia presumably caused by immune factors and medication. Once robust hematologic response was achieved with platelet counts of 80,000/µL or greater, the treatment was tapered (by 50%) and eventually discontinued. The authors called for future prospective studies given these early promising results.
Dr. Cai Yuan and colleagues also published a U.S. experience of 13 patients treated with eltrombopag for poor platelet engraftment (without evidence of relapse) at the time of initiation, including six patients with primary platelet engraftment failure and seven with secondary platelet engraftment failure. Eltrombopag was started at an initial dose of 25 or 50 mg/d, and dose adjustments were made to gain platelets counts of 50,000/μL or higher without the need for transfusions for several weeks. Of the six patients with primary isolated platelet failure, three (50%) responded, and of the seven patients with secondary platelet failure, five (71%) responded. The median time to response was 33 days (range, 11-68 days). No patients discontinued treatment as a result of adverse events in this cohort. Given that most of this cohort relapsed and died, the authors concluded that while there is a relatively good response rate (without toxicity) to eltrombopag for post-SCT thrombocytopenia, ultimately, inadequate platelet engraftment is a harbinger of poor outcomes overall.
These two articles highlight a small but real-world clinical experience with eltrombopag for thrombocytopenia post-SCT. This is a therapeutic approach that is becoming more prominent in practice but does require further investigation, given there is currently a paucity of prospective data. The exception is one preliminary abstract of phase II placebo-controlled randomized trial with early results in 60 patients statistically inconclusive6 ; thus, case series like the ones discussed here are useful to gain experience. These two studies show safety and reasonable response rates but likely do not fully support eltrombopag’s mainstream use post-SCT to improve blood counts. Nonetheless, the rationale for using eltrombopag in this fashion is sound. It is known early post-SCT that there is impairment of the stem cell compartment due to reduction of hematopoietic progenitors as the graft is developing in the recipient. Given the activity of eltrombopag in aplastic anemia,3 another disease of limited hematopoietic progenitor function, it is reasonable to hope that eltrombopag can also stimulate the stem cell pool post-SCT. Additionally, there are complicated immune mechanisms2 post-SCT that contribute to the graft function and recently, also in abstract form, it has been shown that eltrombopag could improve cytopenias through heterodimerization between interferon-γ and thrombopoietin to disable the immune-inhibitory effect of interferon-γ on stem cells.7 Additional familiarity with eltrombopag in clinical practice post-SCT will allow us to further understand its utility as well as benefits and toxicities. We look forward to additional prospective studies. Future developments in this arena may show hematologists additional ways to use this oral thrombopoietin receptor agonist for our patients.
Dr. DeZern indicated no relevant conflicts of interest.