Herombopag for Enhancement of Platelet Engraftment in Patients Undergoing Hematopoietic Stem Cell Transplantation

Abstract

Abstract Background Hematopoietic stem cell transplantation (HSCT) is the only curative treatment option for many patients suffering from hematological malignancies. However, thrombocytopenia is a common and potentially severe complication of HSCT. A recent study found that the median time to platelet engraftment, defined as the first of 7 consecutive days of an unsupported platelet count of at least 20,000/μl, was more than 54 days. It was also reported that the incidence of mortality was significantly higher in patients with post-HSCT thrombocytopenia. We developed a clinical trial to facilitate platelet engraftment after HSCT using herombopag, an oral nonpeptide thrombopoietin receptor agonist. Herombopag is CFDA-approved for the treatment of chronic immune thrombocytopenia, and patients with severe aplastic anemia who do not respond well to immunosuppressive therapy in June 2021. From the pharmacological point of view, it functions by phosphorylating multiple downstream signaling proteins and has stronger effects than eltrombopag when used at the same dosages. Here we present the results of this prospective clinical trial. Methods: This is a phase I/II clinical trial. Eligible patients had: a platelet count before conditioning regimen≥ 50,000/μl, >18 years of age, ECOG ≤ 2, ALT ≤ 3 ULN (upper limit of normal), AST ≤ 3 ULN, total bilirubin ⩽ 1.5 ULN, creatinine ⩽ 1.5 ULN, the first HSCT and an expected survival period ≥ 3 months. The primary objective was to evaluate the safety and efficacy of herombopag for platelet engraftment after HSCT. After transplantation, oral herombopag (7.5 mg) was administered until platelet counts reached 50,000/μL for 7 consecutive days without platelet transfusions. The primary endpoints of this trial were the 21-day incidence of partial platelet engraftment (A platelet count exceeding 20,000/μl for 7 consecutive days without transfusion), and 50-day cumulative incidence of complete platelet engraftment (A platelet count exceeding 50,000/μl for 7 consecutive days without transfusion) after HSCT. We used Propensity Score Matching (PSM) to select matching subjects among other eligible subjects. Differences between groups were analyzed using Chi-squared tests. Results: Between February 2022 and June 2022, 17 patients with acute leukemia were enrolled (Table1). For partial and complete engraftment, the median time was 13 (range, 8-24) days, and 20 (range, 14-61) days. The median time to neutrophil engraftment was 11 (range, 9-19) days. We performed a comparison of engraftment data between our study cohort and a historical cohort comprised of 17 individuals. The 2 cohorts were matched in sex, age, ABO match, and transplantation type using the propensity score matching method (PSM). The incidence of partial and complete platelet engraftment was significantly higher in the study group (partial, 89% versus 59%, p=0.05; complete, 94% versus 65%, p=0.03). The median follow-up duration was 3 (range, 1-5) months. The median number of platelet transfusions required within 30 days after HSCT was 3 (range 1-9) U. The overall survival (OS) was 94%, and 1（6%）patient suffered from molecular recurrence. 1（6%）patient developed grade III aGVHD and died 3.4 months after transplantation. 5 (29%) developed grade I-II aGVHD and no grade IV aGVHD occurred. 3（18%）patients suffered cytomegalovirus (CMV) viremia. According to acute WHO side effects, 7 (41%) patients suffered grade I-II AEs of the digestive tract, and 1 (6%) patient suffered grade III. 3 (18%) patients suffered grade I-II AEs of fever, and no grade IV adverse events occurred. The AEs of the digestive tract included nausea (3/17, 18%), vomiting (2/17, 12%), oral ulcer (7/17, 41%), and diarrhea (3/17, 18%). Conclusions: Herombopag has a significant contribution to platelet engraftment in patients undergoing HSCT and the drug is very well-characterized and safe. While Further investigations for a longer period and more cases would be necessary next. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal