Table 1 - uploaded by Lan-Ping Xu
Content may be subject to copyright.
Source publication
Prolonged thrombocytopenia is a frequent complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT); however, its pathogenesis has remained obscure. In the present study, we used flow cytometry to determine the frequency of bone marrow megakaryocytes (MKs) and MK ploidy distributions in allo-HSCT recipients with or without pr...
Contexts in source publication
Context 1
... demographic and clinical characteristics of the allo-HSCT recipients with and without prolonged thrombocytopenia are summarized in Table 1. All char- acteristics except the transplanted CD34 1 cell dose, platelet engraftment time, and history of CMV reactiva- tion were nearly equally represented in the study and control groups. ...
Context 2
... char- acteristics except the transplanted CD34 1 cell dose, platelet engraftment time, and history of CMV reactiva- tion were nearly equally represented in the study and control groups. As shown in Table 1, the observed differ- ences in platelet engraftment time for the 2 groups were significant (P 5 .002), and allo-HSCT patients with prolonged thrombocytopenia exhibited slower platelet engraftment times. ...
Citations
... 9 of platelet maturation. 3,20,21 In the past, a method of evaluating the risk of SFPR in β-TM patients has not been reported. This study was the first to construct a model to predict the risk of SFPR in β-TM patients after HSCT. ...
Background
Secondary failure of platelet recovery (SFPR) is a common complication that influences survival and quality of life of patients with β-thalassemia major (β-TM) after hematopoietic stem cell transplantation (HSCT).
Objectives
A model to predict the risk of SFPR in β-TM patients after HSCT was developed.
Design
A retrospective study was used to develop the prediction model.
Methods
The clinical data for 218 β-TM patients who received HSCT comprised the training set, and those for another 89 patients represented the validation set. The least absolute shrinkage and selection operator regression algorithm was used to identify the critical clinical factors with nonzero coefficients for constructing the nomogram. Calibration curve, C-index, and receiver operating characteristic curve assessments and decision curve analysis (DCA) were used to evaluate the calibration, discrimination, accuracy, and clinical usefulness of the nomogram. Internal and external validation were used to test and verify the predictive model.
Results
The nomogram based on pretransplant serum ferritin, hepatomegaly, mycophenolate mofetil use, and posttransplant serum albumin could be conveniently used to predict the SFPR risk of thalassemia patients after HSCT. The calibration curve of the nomogram revealed good concordance between the training and validation sets. The nomogram showed good discrimination with a C-index of 0.780 (95% CI: 70.3–85.7) and 0.868 (95% CI: 78.5–95.1) and AUCs of 0.780 and 0.868 in the training and validation sets, respectively. A high C-index value of 0.766 was reached in the interval validation assessment. DCA confirmed that the nomogram was clinically useful when intervention was decided at the possibility threshold ranging from 3% to 83%.
Conclusion
We constructed a nomogram model to predict the risk of SFPR in patients with β-TM after HSCT. The nomogram has a good predictive ability and may be used by clinicians to identify SFPR patients early and recommend effective preventive measures.
... Thrombopoietin (TPO) is a key cytokine that can induce megakaryocyte (MK) proliferation and differentiation and promote thrombopoiesis [8][9][10]. Our previous study showed that endogenous TPO was relatively insufficient in PT patients [11] and that reducing the ploidy of MKs and increasing the proportion of immature MKs may be the potential mechanism of PT after allo-HSCT [12]. Therefore, enhancing thrombopoiesis through the TPO pathway may be a rational therapeutic approach for PT patients after allo-HSCT. ...
Persistent thrombocytopenia (PT) has an unsatisfactory response to therapy after haploidentical haematopoietic stem cell transplantation (haplo-HSCT). We retrospectively evaluated the safety and efficacy of avatrombopag treatment in 69 patients with PT following haplo-HSCT and assessed whether baseline thrombopoietin (TPO) levels could predict treatment response. Overall response (OR) and complete response (CR) were defined as increased platelet levels to over 20 × 10⁹/L or 50 × 10⁹/L independent of platelet transfusion during or within 7 days of the end of avatrombopag treatment, respectively. The incidences of OR and CR were 72.5% and 58.0%, with a median of 11 and 29 days to OR and CR, respectively. ROC analysis suggested that the optimally discriminant baseline TPO level threshold for both OR and CR to avatrombopag was ≤ 1714 pg/mL. In multivariate analysis, a lower baseline TPO level (P = 0.005) was a significant independent factor of response to avatrombopag. For patients resistant to other TPO receptor agonists (TPO-RAs), 9/16 (56.3%) exhibited a response after switching to avatrombopag. Avatrombopag was well tolerated, and responders achieved improved overall survival (79.0% vs. 91.1%, P = 0.001). In conclusion, avatrombopag is a potential safe and effective treatment for PT after haplo-HSCT, and lower baseline TPO levels predicted a better response.
... Additionally, some recipients of successful haematopoietic cells allotransplants have impaired platelet recovery despite otherwise normal bone marrow function and complete haematopoietic chimerism. Diverse reasons for impaired platelet recovery are reviewed elsewhere [11][12][13] . ...
Background Aplastic anaemia has diverse aetiologies. Distinguishing between these is, in part, testable by analyzing results of haematopoietic cells transplants between genetically-identical twins one of whom has aplastic anaemia.
Objective Describe outcomes of genetically-identical twin transplants for aplastic anaemia with and without pretransplant conditioning.
Methods We interrogated data from an observational database of 59 consecutive recipients of genetically-identical twin transplants for aplastic anaemia reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) 2000-2019.
Results 38 subjects were male. Median age was 18 years (Interquartile Range [IQR], 11-32 years). Median interval from diagnosis to transplant was 2 months (IQR 1-3 months). 11 subjects received a 1st transplant without pretransplant conditioning. 2 of recovered normal bone marrow function. The other 9 received a 2nd transplant with pretransplant conditioning 7 of whom recovered. 48 subjects received pretransplant conditioning before a 1st or 2nd transplant all of whom recovered.
Conclusion Only some genetically-identical twins with aplastic anaemia recover normal bone marrow function after a 1st haematopoietic cell transplant without pretransplant conditioning whereas most subjects recover when a transplant is preceded by pretransplant conditioning. These data are consistent with an immune-mediated aetiology of aplastic anaemia in most cases.
... Yamazaki et al. reported that PIT was associated both with thrombocyte production impairment and increased turnover of platelets, 9 whereas Zhang et al. 10 Before choosing the ideal donor for a patient, transplant teams must evaluate donor candidates in many aspects. Post-transplant cytopaenias may result from undiagnosed clonal haematopoiesis of indeterminate potential (CHIPs) engrafted from the donor. ...
Background:
Eltrombopag has an off-label indication for haematopoietic cell transplantation in patients experiencing delayed thrombocyte recovery and/or thrombocytopaenia.
Aims:
To present our centre's experience of using this agent not only for post- haematopoietic cell transplantation thrombocytopaenia but also for poor graft functioning in the post-haematopoietic cell transplantation setting.
Study design:
Retrospective cross-sectional study.
Methods:
Thirty-nine patients who had persistent cytopaenia following haematopoietic cell transplantation and treated with eltrombopag at our centre between October 2011 and December 2021 were retrospectively identified. During this period, 9 (23.1%) and 30 (76.9%) patients who underwent allogeneic transplantations, respectively, received eltrombopag.
Results:
The female-to-male ratio was 12:27, and the median transplant age was 49 (18-70) years. Eight (20.5%) patients had isolated thrombocytopaenia, 19 (49.4%) had bi-lineage cytopaenia and 12 (30.1%) had pancytopaenia. Patients received a median of 50 mg/day (25-150 mg/day) of eltrombopagfor a median duration of 82 (24-386) days. Nine (23.1%) patients had autologous haematopoietic cell transplantation, and 30 (76.9%) had allogeneic haematopoietic cell transplantation (14 unrelated, 9 sibling and 7 haploidentical). The median donor age was 32 (20-67) years. The median follow-up was 16.4 (1.8-84.3) months. The median pre-treatment platelet count was 11x109/l (1-23), which increased to 41x109/l (6-150). The median platelet count increment was 29.5x109/l (p = 0.001). The pre-treatment median neutrophil count was 1.19x109/l (0.39-5.1), which increased to 2.35 x109/l (0.1-5.33) (p = 0.05), and the pre-treatment median haemoglobin was 8.3 (6.2-14) g/dl, which increased to 10 (6.2-14) g/dl (p = 0.001) with eltrombopag. No eltrombopag-related hepatotoxicity occurred; however, 1 (2.6%) patient failed to continue treatment because of two consecutive episodes of deep venous thrombosis. Six (15.4%) patients were unresponsive to eltrombopag and dependent on blood product transfusions. After a median time of 82 days, 61.5% of the patients discontinued eltrombopag successfully.
Conclusion:
The results confirmed that eltrombopag could provide a rapid, sustained response in patients with poor graft functioning after haematopoietic cell transplantation. This finding is essential given the high rate of non-relapse mortality caused by poor graft functioning after haematopoietic cell transplantation.
... Platelet graft failure is a frequent and serious complication after allo-HSCT, and prolonged thrombocytopenia after transplantation is major type which could affect the long-term survival of patients. Thrombocytopenia after HSCT could be divided into 2 categories: prolonged or prolonged isolated thrombocytopenia (PT/PIT)all blood cells in the peripheral blood except platelets (PLT) recover to normal levels after HSCT, and PLT counts are lower than 20×10^9/L for longer than 3 months, without relapse and clear cause (4); and secondary failure of platelet recovery (SFPR) -PLT≥50×10^9/L for 7 consecutive days after HSCT without blood transfusion support, then PLT ≤ 20×10^9/L occurred for more than 7 consecutive days after primary PLT recovery or PLT transfusion required (5). The risk factors for thrombocytopenia after HSCT include graft versus host disease (GVHD), number of HSCs, anti-HLA antibodies (donor-specific antibodies) (6), previous alloimmunization and strength of the pretreatment regimen, cytomegalovirus (CMV), graft source, low PLT before pretreatment, iron overload, etc. (7). ...
Platelet graft failure (PGF) is a frequent and serious complication after Allogeneic hematopoietic stem cell transplantation (allo-HSCT) and lacks effective treatment strategies, which could affect the prognosis of patients and even cause death. The exact underlying mechanism of PGF remains unclear, and lacks standard treatment. Here, we conduct a retrospective study to evaluate the efficacy and safety of avatrombopag combined with mesenchymal stem cells (MSCs) in 16 patients with thrombocytopenia after allo-HSCT. Patients were administered the following treatment regimen: 20 mg/d avatrombopag; if the PLT count was less than 50×10^9/L for at least 2 weeks, the dose was increased to 40 mg/d; if the PLT count was 200-400×10^9/L, the dose was reduced; and if the PLT count was greater than 400×10^9/L, avatrombopag was terminated. Umbilical cord MSCs (1×10^6 cells/kg) infusion was performed every week for 4-6 weeks. Among the 16 patients, 13 patients (81.3%) achieved a complete response (CR), 2 patients (12.5%) got a partial response (PR), and 1 patient (6.3%) had no response (NR). The median time to obtain CR was 32 (7-426) days after treatment with avatrombopag combined with umbilical cord MSCs. The time to reach 20×10^9/L≤ PLT <50×10^9/L in the 2 patients with PR was 52 and 230 days after treatment, respectively. One patient had a severe pulmonary infection and died of cytomegalovirus pneumonia. Overall, our results indicated that combination of avatrombopag with MSCs can promote platelet recovery after transplantation, thereby improving the survival rate of patients and improving the quality of life of patients after transplantation, and providing a new method and strategy for the treatment of thrombocytopenia after allo-HSCT.
... 2 Furthermore, unfortunately, patients may also experience secondary failure of platelet recovery after achieving primary platelet recovery following allogeneic HSCT. 1 Severe thrombocytopenia requires platelet transfusion for the prevention and management of bleeding, and it is highly related to the therapeutic effects and prognosis of transplantation. 3 Patients presenting hematologic diseases may receive chemotherapy, radiotherapy, and HSCT. Chemotherapy and the conditioning regimens for HSCT affect oral tissues in several different ways, according to both the nature of medication and dosage. ...
Introduction: Thrombocytopenia is usually seen after allogeneic hematopoietic stem cell transplantation (HSCT) and may favor the development of oral bleeding, infections, and ulcerations.
Case Report: A patient with chronic myelomonocytic leukemia had been submitted to allogeneic HSCT. Within a few days, she developed severe thrombocytopenia and an extensive ulcerative area comprising both lips, which bled spontaneously, as well as smaller ulcers on the tongue mucosa. The lesions were managed using a combination of phototherapies (photobiomodulation and antimicrobial photodynamic therapies), totalizing 4 laser sessions. After 4 days, there was an important reduction in the severity of the lesions, with spontaneous disappearance of the crusts and reepithelization.
Conclusion: The proposed combination of phototherapies would be a suitable therapeutic modality for the management of oral lesions related to platelet disorders induced by oncologic treatments.
... In a recent prospective case-control study [9], the authors demonstrated that BM T-cell response was abnormal, with high proportions in the BM microenvironment of Th17, Th1 and Tc1 cells; and high levels of Th17 and Th1-associated cytokines (IL-6, IL-17, IL-21 and IFN-y,) in plasma. Zhang et al. [10] demonstrated an increase in immature megakaryocytes in allo-SCT patients with PT with low ploidy, which was related to the recruitment of CD8 T-cells, suggesting the role of the BM immune microenvironment. ...
Thrombocytopenia following allogeneic hematopoietic stem cell transplantation is a usual complication and can lead to high morbidity and mortality. New strategies, such as the use of another graft versus host-disease prophylaxis, alternative donors, and management of infections, have improved the survival of these patients. The mechanisms are unknown; therefore, the identification of new strategies to manage this potentially serious problem is needed. Thrombopoietin receptor agonists are currently available to stimulate platelet production. Some small retrospective studies have reported their potential efficacy in an allogeneic stem cell transplant setting, confirming good tolerability. Recent studies with higher numbers of patients also support their safety and efficacy in this setting, hence establishing the use of these drugs as a promising strategy for this post-transplant complication. However, prospective trials are needed to confirm these results.
... Alvarado et al. [11] stated that PT after allo-HSCT is partly due to immune-mediated bone marrow failure or inflammation, such as AA. Zhang et al. [21] described that PT and slow platelet engraftment may be resulted from a low ploidy and immaturation of MKs. Based on this understanding, platelet transfusion, corticosteroid, and intravenous immunoglobulin were once successfully prescribed for the treatment of ITP or AA for PT after haplo-HSCT, but were less effective in boosting platelet counts and had more adverse events. ...
Persistent thrombocytopenia (PT) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with an increased risk of bleeding and poor survival. The exact pathogenesis underlying PT remains unclear, and its management is difficult. Here we conducted a retrospective study to evaluate the efficacy and safety of eltrombopag (EPAG) in 34 patients with PT after allo-HSCT. Seven patients suffered from prolonged isolated thrombocytopenia (PIT), and 27 had secondary failure of platelet recovery (SFPR). For most patients, the initial dose was 25 mg or 50 mg daily, then adjusted to the maximum dose of 50–100 mg per day according to the response of platelet recovery and toleration of patients. The cumulative incidence (CI) of platelet recovery to at least 20 × 10⁹/L and 50 × 10⁹/L without transfusion support for at least 7 days was 72.1% and 60.7%, respectively. Nineteen (86.4%) of 22 responders were able to taper off the medication; furthermore, the platelet counts remained stable 1 month after withdrawal of EPAG. Although two patients discontinued EPAG during treatment due to headache and nausea, no patients developed grade 3 or 4 toxicities. Hypoplasia of bone marrow and decreased megakaryocytes (MKs) were found to be risk factors for overall response (OR) and complete response (CR) in multivariate analysis, respectively. Overall, our results indicated that EPAG can be used in the treatment of PT and that continuous exposure to EPAG may not be necessary.
... Patients with PIT/SFPR have been shown to have both decreased platelet production and increased platelet destruction with a decrease in the ploidy and maturity of bone marrow megakaryocytes [22,23]. The mechanism of eltrombopag in thrombocytopenia and poor graft function after Allo HCT is not entirely clear [3,24]. ...
Eltrombopag has shown efficacy in the treatment of thrombocytopenia and poor graft function (PGF) after allogeneic hematopoietic cell transplantation (HCT) in retrospective observational studies, but is not approved for this indication. The cost of this drug is also a major concern in publicly funded health care systems. We collected data about patients who received eltrombopag for thrombocytopenia or PGF after HCT. Post-HCT thrombocytopenia, PGF, and eltrombopag response were defined as per previously published criteria. Primary outcome was treatment efficacy and secondary outcome was cost comparison between estimated treatment cost prior to and after initiation of eltrombopag. Seventeen patients (males 70.6%; median age = 58) received eltrombopag. Isolated thrombocytopenia was present in 11.8% (n = 2) patients while PGF was present in 88.2% (n = 15) of patients. After 8 weeks of treatment at the maximum dose of 150 mg orally daily, overall response rate (ORR) was seen in 76.5% (13/17) of patients: complete response (CR) in 10/13 patients and partial response (PR) in 3/13 patients. The use of eltrombopag was associated with an overall decrease in the total weekly care costs (5021 vs 2,524 CA$; P = 0.04). Thus, Eltrombopag is an efficacious and possibly cost-effective therapy for thrombocytopenia and PGF after allogeneic HCT.
... The underlying mechanism of prolonged thrombocytopenia after alloSCT is complex and may include both impaired thrombopoiesis and increased platelet turnover [23]. Several studies suggest reduced differentiation of megakaryocytes from stem cells and defects in megakaryocytic maturation rather than peripheral destruction of platelets to account for prolonged thrombocytopenia after alloSCT [24,25]. Recently, direct damaging effects of inflammation-associated cytokines on ex vivo megakaryocytic and hematopoietic stem cell function have been demonstrated [26]. ...
Simple Summary
We have previously shown that high pre-conditioning levels of Interleukin-18 were associated with worse survival after allogeneic stem cell transplantation due to increased non-relapse mortality. While no correlations with acute graft-versus-host disease were observed, interleukin-18-related excess mortality was mainly driven by fatal infectious complications. In multiple studies, delayed hematopoietic recovery and poor graft function following allogeneic stem cell transplantation has been demonstrated as a powerful predictor of non-relapse mortality. The present study links high interleukin-18 to delayed platelet recovery in allografted patients. Given the functions of interleukin-18 in regulating the quiescence of hematopoietic stem/progenitor cells, our findings may be explained by Interferon gamma-independent inhibitory effects of interleukin-18 on stem cell proliferation and hematopoietic reconstitution in allografted patients. Importantly, considering recent successful interleukin-18-neutralizing approaches in autoimmune disorders, our results provide a rationale to explore modulation of interleukin-18 for improving hematopoietic recovery and outcomes in allogeneic stem cell transplantation recipients.
Abstract
Interleukin-18 (IL-18) is an immunoregulatory cytokine and a context-dependent regulator of hematopoietic stem/progenitor cell (HSPC) quiescence in murine models. In a previous study, high pre-conditioning levels of IL-18 were associated with increased non-relapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). To investigate the clinical impact of IL-18 status on hematopoietic function, the associations of pre-conditioning and day 0–3 cytokine levels with platelet and neutrophil recovery were analyzed in a training cohort of 714 allografted patients. In adjusted logistic regression analyses, both increasing pre-conditioning and day 0–3 IL-18 levels had a significantly higher adjusted odds ratio (aOR) of delayed platelet and neutrophil recovery on day +28 post-transplant (aOR per two-fold increase: 1.6–2.0). The adverse impact of high pre-conditioning IL-18 on day +28 platelet recovery was verified in an independent cohort of 673 allografted patients (aOR per two-fold increase: 1.8 and 1.7 for total and free IL-18, respectively). In both cohorts, a platelet count ≤20/nL on day +28 was associated with a significantly increased hazard of NRM (hazard ratio 2.13 and 2.94, respectively). Our findings support the hypothesis that elevated peritransplant IL-18 levels affect post-transplant HSPC function and may provide a rationale to explore modulation of IL-18 for improving alloSCT outcomes.
