Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for
many hematological diseases. Thrombocytopenia is a common complication of allo-HSCT.
Incidence ranged from 5% to 37%. In order to promote the transplantation of donor stem cells
and reduce the incidence of graft versus host disease (GVHD) and disease recurrence,
high-dose chemotherapy, radiotherapy and other pretreatment schemes are usually used before
operation to induce immune tolerance and eliminate tumor cells to the greatest extent. At the
same time, the recipient's bone marrow was in an "empty" state before the donor's stem cell
engraftment. At this time, the hematopoietic function of the bone marrow was severely
inhibited, and the blood cell count was very low. Generally, the platelet count was less than
20 × 10^9/L within 13-54 days. Patients whose time to platelet recovery ≥ 50 × 10^9/L was
greater than 60 days had a significant increase in transplant-related mortality rate and a
significant decrease in long-term survival. Therefore, it is very important to prevent and
treat thrombocytopenia after hematopoietic stem cell transplantation.
To date, no standard treatment has been proposed for thrombocytopenia after allo-HSCT. In
order to prevent bleeding, patients often need multiple platelet transfusions for a long
time, which increases the economic burden, and platelet transfusion may also lead to many
adverse reactions, such as anaphylactic shock, acute lung injury, heart failure, viral
infection, etc. Some patients may also have ineffective platelet transfusion. In addition,
prolonged blood transfusion consumes a lot of hospital resources and costs, and reduces the
quality of life of patients. The 2021 edition of the Chinese Expert Consensus on the
Management of Hemorrhagic Complications after Hematopoietic Stem Cell Transplantation
suggests that patients with thrombocytopenia after transplantation should actively control
the inducing factors. In addition to platelet transfusion, recombinant human thrombopoietin
(rhTPO) 300 U/kg/d subcutaneous injection can be used, and TPO receptor agonists can also be
tried. Platelet counts > 50 × 109/L1 were maintained.
Thrombopoietin (TPO) is the most important cytokine that promotes platelet production in
humans. TPO promotes platelet production by binding to the TPO receptor (TPO-R) on the cell
surface. TPO receptor agonist (TPO-RA) activates downstream STAT/MAPK signaling pathway by
binding and activating TPO receptor, which effectively stimulates platelet production,
increases platelet count and reduces the occurrence of bleeding events. At present, TPO-RA in
clinical application includes recombinant human thrombopoietin (rhTPO), peptide TPO-RA
(Romiplostim), non-peptide TPO RA (Hetrombopag, Eltrombopag, Avatrombopag, etc.), which is
widely used in various thrombocytopenia, including primary immune thrombocytopenia (ITP).
Aplastic anemia (AA), chemotherapy-induced thrombocytopenia (CIT) and perioperative
thrombocytopenia in patients with liver diseases have good efficacy and safety. Han et al.
conducted a prospective randomized controlled study to explore the role of rhTPO in promoting
platelet engraftment after haplo-HSCT. The rhTPO group was given rhTPO 15000U subcutaneously
once a day from the first day after transplantation. Discontinue when platelet count ≥ 50 ×
109/L for more than 3 days; The incidence of platelet engraftment was significantly higher in
the rhTPO group than in the control group on day + 60 after transplantation (91.7 ± 3.8% vs.
74.5 ± 5.8%, p = 0.041), and the number of platelet transfusions during + 14d to + 60d was
significantly reduced (4 ± 5 vs. 7 ± 9, p = 0.018), suggesting that routine use of
thrombopoiesis drugs after transplantation can effectively promote platelet engraftment and
reduce the need for platelet transfusion therapy, which is a safe and effective treatment.
Other TPO receptor agonists have been reported to be effective in the treatment of
thrombocytopenia after hematopoietic stem cell transplantation, but there is no consensus on
the optimal timing and dosage. With the continuous progress of transplantation technology in
China, the indications of HSCT have been further broadened, the number of cases has continued
to grow, and more clinical evidence is needed.
Hetrombopag is a new generation of oral small molecule non-peptide TPO-RA independently
developed by Jiangsu Hengrui Pharmaceutical Co., Ltd. In June 2021, it was approved by NMPA
for the treatment of adult chronic ITP patients who did not respond well to glucocorticoid,
immunoglobulin and other treatments, as well as adult SAA patients who did not respond well
to immunosuppressive therapy. Pharmacological studies at the protein level showed that the
phosphorylation of various signaling proteins was significantly stronger at the same dose
than that of eltrombopag. Compared with rhTPO, it has a more lasting and stable effect on the
phosphorylation level of downstream signals. There is great potential for the clinical
application of hetrombopag in hematopoietic stem cell transplantation, but the efficacy and
safety of hetrombopag in promoting platelet engraftment after transplantation need to be
further verified.
Thus,this investigator-initiated, prospective, multicenter, open-label, randomized,
controlled clinical study is designed to evaluate the clinical efficacy and safety of
hetrombopag for promoting platelet engraftment after allo-HSCT in patients with hematological
disease.
After signing the informed consent form, the patients will enter the screening period (up to
14 days), and the qualified patients will be randomly selected into the experimental group
and the control group according to the ratio of 1:1.
Experimental group: After hematopoietic stem cell reinfusion, the patients begin to take
hetrombopag orally 7.5mg/d, until the patients reach complete platelet response (CR, platelet
count ≥ 50×10^9/L for 3 consecutive days without platelet transfusions for 7 consecutive
days). The treatment will stop when patients accept 21 consecutive days of treatment or reach
the discontinuation criteria.
Control group: After hematopoietic stem cell transfusion, the patients will be only observed,
and the observation during the treatment period will be ended after 30 days.
Patients will continue to enter the follow-up period (+ 100 days after transplantation) and
the survival follow-up period (1 year after transplantation) after the end of the treatment
period.