Secondary Failure Of Platelet Recovery Research Articles

Development of a nomogram to predict the risk of secondary failure of platelet recovery in patients with β-thalassemia major after hematopoietic stem cell transplantation: a retrospective study.

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). A model to predict the risk of SFPR in β-TM patients after HSCT was developed. A retrospective study was used to develop the prediction model. 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. 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%. 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.

Efficacy and Safety of Herombopag for the Treatment of Secondary Failure of Platelet Recovery after Allogeneic Hematopoietic Stem Cell Transplantation: The Single Center Prospective Study from China

Background Thrombocytopenia is a frequent and serious complication after Allogeneic hematopoietic stem cell transplantation (allo-HSCT). It often has a multifactorial etiology, including poor graft function, GVHD, drugs, infections, and microangiopathy. Prolonged thrombocytopenia after HSCT, which is an independent adverse prognostic factor for transplant-related mortality (TRM) and overall survival, has not yet been systematically investigated. Among then, secondary failure of platelet recovery (SFPR) is the most common type of thrombocytopenia after allo-HSCT. SFPR refers to thrombocytopenia that develops after initial platelet engraftment and is not due to graft rejection or relapse. It defined as a decline in platelet count of < 20×10 9/L for 7 consecutive days or requiring transfusion support after achieving a sustained platelet count > 50×10 9/L without transfusion for 7 consecutive days after HSCT. Methods Here, we conduct a retrospective study to the efficacy and safety of herombopag in 81 patients with SFPR after allo-HSCT. Patients were administered the following treatment regimen: 5 mg/d herombopag; if the PLT count was less than 50×10^9/L for at least 2 weeks, the dose was increased to 7.5 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, herombopag was terminated. Results Baseline platelet count of patients before treatment is 12 (2-20)×10 9/L. The initial time of treatment is 5 (3-14) months after allo-HSCT, and the median duration of treatment is 103 (45-276) days. Among the 81 patients, 51 patients (62.9%) had complete response (CR, defined as PLT≥50×10 9/L without PLT transfusion for 7 continuous days), 9 patients (11.1%) had a partial response (PR, defined as PLT of [20-50] ×10 9/L without PLT transfusion for 7 continuous days), and 21 patient (26.0%) had no response (NR, defined as the application of the maximum tolerated dose for 8 weeks and PLT<20×10 9/L or the need for PLT transfusion). The median time to obtain CR was 49 (18-229) days after treatment. The time to reach 20×10 9/L<PLT<50×10 9/L in the 9 patients with PR was 74 (52-276) days after treatment, respectively. One patient died of intracranial hemorrhage and two patients died of severe infection. Conclusion Our results indicated that herombopag can promote platelet recovery for patients with SFPR after allo-HSCT, 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.

Thrombopoietin receptor agonists for refractory thrombocytopenia in patients after autologous hematopoietic stem cell transplantation

ObjectiveAutologous hematopoietic stem cell (ASC) transplantation (ASCT) is an effective treatment method for patients with hematological disorders and malignant diseases. The patient's ASCs are harvested prior to radiotherapy/chemotherapy, cryopreserved and then transfused back after the high-dose radiotherapy/chemotherapy conditioning treatment. Since some patients develop thrombocytopenia after receiving ASCT, it is difficult for them to bear simultaneously the management of their original disease and thrombocytopenia. The present study aimed to evaluate the efficacy and safety of thrombocytopenia therapy with thrombopoietin receptor agonists (TPORAs) after ASCT. MethodsWe retrospectively analyzed the clinical safety and efficacy of TPORA treatment for the enrolled 20 patients who developed thrombocytopenia after ASCT. The measured parameters were prolonged isolated thrombocytopenia (PIT), secondary failure of platelet recovery (SFPR) and other calculated response index. Patients with platelet count (PC) ≤ 50×109/L were treated with TPORA, namely with either eltrombopag (Elt), hetrombopag (Het), or avatrobopag (Ava). ResultsThe group of 20 patients, who received TPORA administration for their thrombocytopenia after ASCT, had a median age of 50 years (ranging between 17 and 60 years). The median administration time of TPORA application was 48 days (ranging from 7 to 451 days); an overall response rate (ORR) was 85% with no response in 15% of patients, while with complete response (CR) in 70% of patients and partial response (PR) in 15% of patients. The median platelet count was 19 × 109/L before TPORA treatment and increased to 87×109)/L after the treatment. The TPORA treatment was safe as only 4 patients (20%) displayed a mild transaminase elevation. No other reported side effects occurred, such as thrombosis, joint pain, diarrhea, and myelofibrosis. It was demonstrated that the short response time to TPORA treatment correlated to the fast platelet recovery, when the number of megakaryocytes in the bone marrow smear exceeded 35/4.5 cm2 under a low magnification of 100 times (p = 0.015). ConclusionTPORA therapy for thrombocytopenia occurring after the radiotherapy/ chemotherapy-conditioned ASCT was well tolerated and effective for platelets recovery.

Efficacy and Safety of Avatrombopag in the Treatment of Thrombocytopenia after Umbilical Cord Blood Transplantation

Background: Delayed platelet engraftment is a common complication after umbilical cord blood transplantation (UCBT), and it has no standard therapy. Avatromboapg is a second generation thrombopoietin receptor agonist (TPO-RA) and showed efficacy in immune thrombocytopenia (ITP). However, few reports focused on its efficacy in patients diagnosed with thrombocytopenia after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: We conducted a retrospective study to evaluate the efficacy of avatrombopag in 69 patients after UCBT as the first-line thrombopoietin receptor agonist (TPO-RA) treatment. Results: Sixty-one patients were given avatrombopag to promote platelet engraftment, the other 8 for secondary failure of platelet recovery (SFPR). For the majority of patients (44/69, 63.8%), the initial dose was 40 mg daily. Among the 61 patients given avatrombopag for platelet engraftment, 40 achieved an overall response (OR) (65.6%), and the cumulative incidence of OR was 76.2% (95% CI, 61.3-86.0), at a median time of 23 days (range, 3-131 days). Thirty-eight of 61 (62.3%) patients achieved complete remission (CR), and the cumulative incidence of CR was 76.2% (95% CI, 61.1-86.1). Patients suffering from SFPR had a better cumulative incidence of OR [100% (95% CI, NA), P = 0.005]. Giving avatrombopag before 37 days post-UCBT was beneficial for OR in multivariate analysis. Conclusion: In summary, our results indicate that avatrombopag could be used to promote platelet engraftment, especially in the early period (< 37 days after UCBT). Patients with SFPR may have a better response to avatrombopag therapy. Keywords: Avatrombopag; umbilical cord blood transplantation; thrombopoietin receptor agonist; secondary failure of platelet recovery Conflict-of-interest disclosure: The authors declare that they have no competing interests.

Efficacy and safety of avatrombopag for thrombocytopenia following allogeneic hematopoietic stem cell transplantation: A real-world data evaluation on 14 cases.

Thrombocytopenia following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a common and serious complication that leads to an increased risk of bleeding and poor prognosis. Traditional strategies consist of platelet transfusion, glucocorticoid therapy, intravenous human immunoglobulin, recombinant human thrombopoietin injection, and CD34+-selected hematopoietic stem cell transplantation, but the effects of these treatments are not satisfactory and the treatment continues to be challenged. This study aims to determine the treating efficacy of avatrombopag, a novel thrombopoietin receptor agonist, on thrombocytopenia after allo-HSCT, and to increase the evidence-based medical evidence for the clinical use of this drug. Fourteen patients with thrombocytopenia after allo-HSCT underwent avatrom-bopag treatment from September 2020 to September 2021 were retrospectively studied. Of these patients, 8 patients had delayed platelet engraftment (DPE) and 6 cases had secondary failure of platelet recovery (SFPR). The efficacy and safety of the treatment and the survival of the patients were assessed. The median treatment time of avatrombopag was 34 days, and no patients stopped treatment due to adverse reactions or drug intolerance. Compared with the treatment before, the levels of platelet count, megakaryocytes, and hemoglobin in patients were significantly increased (P=0.000 1, P=0.001 0, and P=0.001 7, respectively). The optimal platelet count of 13 patients reached the complete response standard after drug withdrawal. The median follow-up time of 14 patients was 371 days, and the 2-year overall survival rate was 78.6%. Avatrombopag is effective on increasing platelet counts in patients with thrombocytopenia after allo-HSCT, with a good safety profile. It is a suitable therapeutic option for thrombocytopenia after allo-HSCT.

Avatrombopag for the treatment of thrombocytopenia in children's patients following allogeneic hematopoietic stem-cell transplantation: A pilot study.

Thrombocytopenia following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a common and life-threatening complication. Thus, new prevention and treatment strategies for post-HSCT thrombocytopenia are urgently required. In recent studies, thrombopoietin receptor agonists (TPO-RA) for treating post-HSCT thrombocytopenia indicated efficiency and safety. The improved effect of post-HSCT thrombocytopenia in adults was found in the administration of avatrombopag which was a new TPO-RA. However, there was no relevant study in the children's cohort. Herein, we retrospectively analyzed the effect of avatrombopag in post-HSCT thrombocytopenia in children. As a result, the overall response rate (ORR) and complete response rate (CRR) were 91% and 78%, respectively. Furthermore, both cumulative ORR and CRR were significantly lower in the poor graft function (PGF)/secondary failure of platelet recovery (SFPR) group compared to the engraftment-promotion group (86.7% vs. 100%, p = 0.002 and 65.0% vs. 100%, p < 0.001, respectively). Achieving OR required a median of 16 days in the PGF/SFPR group while 7 days in the engraftment-promotion group (p = 0.003). Grade III-IV acute graft vs. host disease and inadequate megakaryocytes were identified as risk factors of CRR only in univariate analysis (p = 0.03 and p = 0.01, respectively). No severe adverse events were documented. Conclusively, avatrombopag is an alternatively efficient and safe agent for treating post-HSCT thrombocytopenia in children.

Evaluation of Platelet Parameters in Patients With Secondary Failure of Platelet Recovery and Cytomegalovirus Infection After Hematopoietic Stem Cell Transplantation.

To investigate the clinical significance of changes in platelet parameters in patients with secondary failure of platelet recovery (SFPR) and cytomegalovirus (CMV) infection after hematopoietic stem cell transplantation (HSCT). In this retrospective study, 79 patients who had undergone allogeneic HSCT (allo-HSCT), including 40 patients with SFPR and 39 patients without SFPR, were recruited. The evaluated parameters were platelet count (PLT), plateletcrit (PCT), platelet-large cell ratio (P-LCR), mean platelet volume (MPV), platelet distribution width (PDW), the incidence of CMV infection after allo-HSCT, and the correlation of SFPR and CMV infection in patients who had undergone allo-HSCT. The control group included 107 healthy donors. The SFPR group had significantly lower megakaryocyte counts, PLT, and PCT and significantly higher P-LCR, MPV, and PDW than the healthy donor and non-SFPR groups. The incidence of CMV infection was higher in SFPR patients than in non-SFPR patients. Among the patients with SFPR, P-LCR, MPV, and PDW were lower in those with CMV DNA >8000 copies/mL than in those with CMV DNA <8000 copies/mL (P < .05 for all); the CMV viral load was slightly negatively correlated with MPV (P = .0297) and P-LCR (P = .0280). We demonstrate for the first time that the level of platelet activation in SFPR patients, which was closely related to CMV infection, was higher than that in that in non-SFPR patients, and higher CMV load was associated with the inhibition of platelet activation.

Thrombopoietin Levels Predict the Response to Avatrombopag Treatment in Patients with Persistent Thrombocytopenia after Haploidentical Hematopoietic Stem Cell Transplantation

Introduction: Persistent thrombocytopenia (PT) is a common and severe complication after haploidentical allogeneic hematopoietic stem cell transplantation (haplo-HSCT), and there are currently no effective treatment strategies. Avatrombopag has shown promising results in the treatment of several thrombocytopenia disorders. However, no studies have examined the efficacy and safety of avatrombopag in the treatment of PT after haplo-HSCT, and predicting clinical response to avatrombopag before initiation is not possible. Thrombopoietin (TPO) is the chief cytokine that regulates megakaryocyte production and maturation, and endogenous TPO may be a biomarker of avatrombopag response. Methods: This study evaluated outcomes in patients who received the treatment of avatrombopag for persistent severe thrombocytopenia after haplo-HSCT between October 2019 and March 2022. On starting avatrombopag treatment, all included patients were with platelet counts ≤20×109/L and/or with platelet transfusion-dependence. Efficacy was assessed based on the platelet counts. Response was defined as platelet recovery to independence from platelet transfusion during or within 7 days after avatrombopag treatment, and complete response (CR) was defined as platelet recovery to ≥ 50×109/L for 7 consecutive days without platelet transfusion support. Endogenous TPO levels were measured by ELISA. Results: We report a cohort of 69 patients with PT after haplo-HSCT who were treated with avatrombopag. The 69 patients included 43 (62.3%) males and 26 (37.7%) females. The median age was 37 (11-60) years. Before starting avatrombopag therapy, the median platelet count was 15×109/L (range, 2-20×109/L). Forty patients (58.0%) had delayed platelet engraftment, and 29 patients (42.0%) had secondary failure of platelet recovery. Sixteen (23.2%) of the 69 patients had a history of using other TPO-RA (rhTPO or eltrombopag) for at least one round. Avatrombopag was initiated on a median of 59 (range 16-824) days after haplo-HSCT. Both the median starting and maximum doses were 40 mg daily. The rate of platelet recovery to transfusion independence was 72.5%, and the rate of platelet recovery to ≥ 50 ×109/L without transfusion support was 56.5%. Forty-seven (94.0%) of the 50 responders were able to taper off avatrombopag. The median duration of treatment was 40 (range 15-195) days. In addition, we present a novel clinical investigation of the use of TPO levels to predict the response to avatrombopag in patients with PT after haplo-HSCT. Logistic regression models demonstrated a significant predictive relation between TPO levels and probability of response. The TPO levels were inversely correlated with response (r = −0.998, P =0.011).(Figure) ROC analysis identified TPO levels ≤1714 pg/mL as the optimal threshold for discriminating responders and nonresponders. Based on univariate analysis, the presence of megakaryocytes in bone marrow before initiation (P=0.016), lower endogenous TPO levels (P =0.024) and no prior history of TPO-RA treatment (P =0.021) were independent factors that influenced the efficacy of avatrombopag. In the multivariate analysis, lower endogenous TPO levels (P =0.021) and no prior history of TPO-RA treatment (P=0.018) were independent factors that influenced the efficacy of avatrombopag. Avatrombopag was well tolerated in all patients, and patients responding to avatrombopag achieved improved overall survival (77.3% vs. 96.6%, P=0.008). Conclusions: Avatrombopag is a safe and effective therapy for severe PT after haplo-HSCT, and endogenous TPO levels prior to treatment could predict the response to avatrombopag. Key words: Avatrombopag, Persistent thrombocytopenia, Allogeneic hematopoietic stem cell transplantation, Haploidentical Figure legends：Multiple logistic regression models for the probability of response to avatrombopag based on endogenous TPO levels. The shaded area represents the 95% CI. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Eltrombopag may induce bone marrow fibrosis in allogeneic hematopoietic stem cell transplant recipients with prolonged thrombocytopenia

Poor graft function (PGF) and secondary failure of platelet recovery (SFPR) are significant causes of transplant related morbidity and mortality. Although thrombopoietin receptor agonists (TPO-RA), particularly Eltrombopag (EPAG), have been reported to be efficacious in the treatment of prolonged thrombocytopenia, potential long term adverse effects remain to be elucidated. This retrospective study was performed to determine the efficacy and toxicity profile of TPO-RAs in allogeneic hematopoietic stem cell transplant (alloHCT) recipients. Medical records of 27 patients [median age: 55(21−73) years; male/female: 15/12] who received posttransplant EPAG for SFPR or PGF were analysed. Eltrombopag was started on day 110(33−670) after transplant. Median initial dose was 25(25−50) mg/day which was properly escalated to a maximum dose of 75(50−100) mg/day. Duration of the treatment was median 120(31−377) days. Overall response rate (ORR) was 59.3% in the study population. Time-to-treatment response was 42(3−170) days. Mild-to-moderate bone marrow fibrosis was detected in the posttreatment biopsies of 12/22 patients (54.5%), 9 of whom did not represent any grade of myelofibrosis in their inital biopsies. The grade of posttreatment fibrosis was significantly increased when time-to-treatment response was longer (p = 0.008). Long term use of TPO-RAs may be considered as a potential cause of myelofibrosis in alloHCT recipients.

Eltrombopag for Treatment of Thrombocytopenia Following Hematopoietic Stem Cell Transplantation

Objective:This study aimed to evaluate the efficacy and safety of eltrombopag (ELT) in the treatment of thrombocytopenia following hematopoietic stem cell transplantation (HSCT).Materials and Methods:Forty-eight patients treated with ELT for thrombocytopenia after allogeneic or autologous transplantation at the Erciyes University Bone Marrow Transplantation Center between July 2017 and July 2021 were evaluated retrospectively.Results:Forty-eight HSCT recipients were included in this study. Thirty (62.5%) patients were evaluated as having experienced delayed platelet recovery (DPR) and 18 (37.5%) patients as having experienced secondary failure of platelet recovery (SFPR). The median platelet count before ELT treatment was 13x109/L (range: 3-20x109/L). Twenty-three patients responded to treatment and the cumulative incidence of successful platelet recovery was 48%. Patients with both DPR and SFPR responded, but patients with DPR had a higher response rate (50% vs. 44%). The median platelet count of the 23 responding patients was 12x109/L (5-19x109/L) before treatment and 68x109/L (52-266x109/L) after treatment (p<0.0001). While the number of bone marrow megakaryocytes before treatment was adequate in 22 (46%) cases, it was decreased in 26 (54%) cases. Patients with adequate bone marrow megakaryocytes had a better response rate than those without (77% vs. 23%, p<0.0001). The group with adequate megakaryocytes responded to treatment at a median of 33 days (range: 9-174 days). Patients with decreased megakaryocytes responded at a median of 55 days (30-164 days) (p=0.002). No drug-related side effects were observed in any patients.Conclusion:This real-life experience demonstrates that ELT is an effective and safe treatment option for thrombocytopenia after HSCT. The adequacy of bone marrow megakaryocytes before ELT treatment was an important factor affecting response to treatment.

Efficacy of Recombinant Human Thrombopoietin for the Treatment of Secondary Failure of Platelet Recovery After Allogeneic HSCT.

Secondary failure of platelet recovery (SFPR) is a life-threatening complication that may affect up to 20% of patients after allogeneic hematopoietic stem cell transplantation (HSCT). In this study, to evaluate the efficacy of recombinant human thrombopoietin (rhTPO), we retrospectively analyzed 29 patients who received continuous rhTPO for the treatment of SFPR. Overall response and complete response were observed in 24 (82.8%) patients and 10 (34.5%) patients, at a median time of 21.5 days (range, 3-41 days) and 39.5 days (range, 7-53 days) after initiation of rhTPO treatment, respectively. Among the responders, the probability of keeping overall response and complete response at 1 year after response was 77.3% and 80.0%, respectively. In multivariate analysis, higher CD34+ cells (≥3 × 106/kg) infused during HSCT (HR: 7.22, 95% CI: 1.53-34.04, P = 0.01) and decreased ferritin after rhTPO treatment (HR: 6.16, 95% CI: 1.18-32.15, P = 0.03) were indicated to associate with complete response to rhTPO. Importantly, rhTPO was well tolerated in all patients without side effects urging withdrawal and clinical intervention. The results of this study suggest that rhTPO may be a safe and effective treatment for SFPR.

Efficacy of eltrombopag in thrombocytopenia after hematopoietic stem celltransplantation.

Thrombocytopenia is a common complication following hematopoietic stem cell transplantation (HSCT). Eltrombopag has been used in thrombocytopenia treatment after HSCT in recent years. Herein, we present our experience of 25 patients treated with eltrombopag for post-HSCT thrombocytopenia. Fifteen autologous hematopoietic stem cell transplantation (AHSCT) and 10 allogenic hematopoietic stem cell transplantation (allo-HSCT) recipients treated with eltrombopag for treatment of prolonged isolated thrombocytopenia (PIT) or secondary failure of platelet recovery (SFPR) in the stem cell transplantation unit of Hacettepe University Hematology Department between 2017 and 2021 were included in the study. The primary endpoint of this study is eltrombopag response in patients diagnosed with PIT or SFPR. Platelet count above 50,000/mm3 for five consecutive days without platelet transfusion was considered as eltrombopag response. Overall survival (OS) analyses were calculated based on the time between HSCT and death from any cause. The patients who were alive at the last follow-up were censored at this time for calculation of OS analyses. AHSCT (66.7% (10/15)) and allo-HSCT (50% (5/10)) recipients responded to eltrombopag for the treatment of post-HSCT thrombocytopenia. There was no excess toxicity related to the eltrombopag use. The median response duration of allo-HSCT recipients and AHSCT recipients were 41 (13-104) days and 50 (7-342) days, respectively. There was a statistically significant OS duration difference between the responders and nonresponders in allo-HSCT and AHSCT recipients with p values of 0.005 and 0.02, respectively. Eltrombopag is promising for the treatment of thrombocytopenia after AHSCT and allo-HSCT in terms of efficacy and safety.

Eltrombopag in the treatment of patients with persistent thrombocytopenia after haploidentical peripheral blood stem cell transplantation: a single-center experience.

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 25mg or 50mg daily, then adjusted to the maximum dose of 50-100mg 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 7days 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 1month 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.

Usefulness of Thrombopoietin Receptor Agonists for Thrombocytopenia after Allogeneic Stem Cell Transplantation. An Eight-Year Single Center Experience

IntroductionProlonged isolated thrombocytopenia (PT) and secondary failure of platelet recovery (SFPR) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are well known complications that could lead to a potentially lethal bleeding. To date, there are not specific guidelines for the treatment of post allo-HSCT thrombocytopenia, being platelet transfusion the mainstay of the management. Thrombopoietin receptor agonists (TRA), e.g. Eltrombopag (ETP) and Romiplostim have been approved for the treatment of primary immune thrombocytopenia and thrombocytopenia in other conditions (e.g. aplastic anemia) but information on their role in the allo-HSCT is scarce. The aims of our study were a) to analyze the effectiveness, in terms of platelet recovery and length of the response, and b) the safety profile of TRA for the treatment of thrombocytopenia after allo-HSCT in our Institution.MethodsWe performed a retrospective study on 467 patients who underwent to allo-HSCT from 2010 to 2017 in our center, of which a total of 17 patients were treated with TRA as compassionate use for thrombocytopenia after peripheral blood allo-HSCT. In order to be subsidiary to receive a TRA, patients had to be in complete remission with complete chimerism. Patients with thrombocytopenia related to cytomegalovirus and/or thrombotic microangiopathy were excluded. PT was defined as the engraftment of all peripheral blood cell lines but with a platelet (PLT) count <20,000/μL or dependence on PLT transfusions for more than 60 days after allo-HSCT. SFPR was defined as a decline in PLT count <20,000/μL for 7 consecutive days, or requirement of transfusion support after achievement of sustained PLT count ≥50,000/μL without transfusions for 7 consecutive days post-HSCT. The effectiveness or response consisted on achieving platelet recovery (≥20,000/μL) and transfusion independence of at least 7 days.ResultsPatient characteristics are detailed in table 1. One patient was excluded due to short course of treatment that was not evaluable. Platelet recovery and transfusion independence was achieved in 9 out of 16 patients (56%) with a median of 71 days (range: 8-176 days). Three of these responder-patients (R-patients) were switched to an alternative TRA in order to achieve response. Most of the R-patients had SFPR (n=7; 78%). Four patients (44%) were previously treated with mesenchymal stromal cells (MSC; n=2), immunoglobulins (n=3) and/or rituximab (n=1). The median of treatment duration was 181 days (21-350) and all R-patients (n=9) discontinued TRA. At the last follow-up, with a median of 282 days (67-1617), 7 out 9 patients (78%) maintained the response [P=152,000/μL (11,000-358,000)] and 6 (67%) are alive.Among NR-patients (n=7; 43.7%), the median duration of TRA treatment was 14 days (8-82) and 3 patients (43%) were previously treated (MSC and/or immunoglobulins). The main characteristics of NR-patients related to poor response were: active acute graft-versus host disease (GVHD) (n=2; p=0,038), active chronic GVHD (n=1; p=0,025), decreased number of bone marrow megakaryocytes (<++) (n=6; p>0,05), 5 (71%) required platelet transfusion frequency >2 times per week (p>0,05) and all NR-patients received packed red blood cell transfusions (p=0,09). In this group, at the last follow-up, with a median of 86 days (9-144), all except one patient died due to infection (n=5; 83%) or relapse disease (n=1). Finally, no adverse events were related to TRA.ConclusionsTreatment of thrombocytopenia after allo-HSCT with TRA is feasible. Further prospective studies are necessary to determine if these treatments may be considered as a potentially therapeutic alternative. [Display omitted] DisclosuresSanchez-Guijo:Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding.

Eltrombopag for treatment of thrombocytopenia after allogeneic hematopoietic cell transplantation in children: Single-centre experience.

Delayed recovery of thrombocytopenia is a well-known complication after allogeneic HSCT. Eltrombopag (ELT), a thrombopoietin receptor agonist (TRAs), induces platelet maturation and release. Mostly conducted in adults, some of the previous studies have shown that ELT seems to enhance platelet recovery for post-allogeneic HSCT thrombocytopenia, appears efficacious, and offers transfusion independence. To evaluate the safety and efficacy of ELT in pediatric patients with prolonged isolated thrombocytopenia (PIT) or secondary failure of platelet recovery (SFPR) after alloHSCT. Retrospective analysis of childhood patients who received treatment with ELT for persistent thrombocytopenia after alloHSCT between May 2016 and August 2019. We evaluated the safety and efficacy of ELT in 18 childhood patients with PIT or SFPR after alloHSCT. Eltrombopag (50mg/d) treatment was started in all patients, above 6years of age and 20kg weight, who had thrombocytopenia despite neutrophil engraftment on the 30th day of HSCT. Our objective was to decrease the need for platelet transfusion and have a platelet count of more than 50000/µL. The overall response rate was 77.7%. The median time to achieve a platelet level above 30000/µL and 50000/µL was 21 and 44days, respectively. In four patients, platelet count never reached 30000/mm3 . In two patients, the treatment was discontinued due to grade 3 hepatotoxicity. Our study supports the efficacy and relative safety of ELT use for the treatment of PIT and SFPR seen after alloHSCT in children.

Secondary failure of platelet recovery in patients treated with high-dose thiotepa and busulfan followed by autologous stem cell transplantation.

Autologous stem cell transplantation (ASCT) with high-dose thiotepa and busulfan is a treatment option for patients with central nervous system (CNS) lymphoma. We report here the occurrence of secondary failure of platelet recovery (SFPR) in three out of 24 patients who received high-dose thiotepa and busulfan followed by ASCT. Although there was no obvious abnormality in the primary platelet engraftment as well as the recovery of other blood cells, they developed SFPR with a median time to onset of day 38, and the platelets gradually recovered over several months with steroid therapy. During the same period, there was no development of SFPR among 50 patients who received ASCT with a conditioning regimen of MEAM (ranimustine, etoposide, cytarabine, and melphalan) or high-dose melphalan. However, one of the two patients who received a conditioning regimen of busulfan and melphalan developed SFPR, suggesting that the use of a busulfan-based conditioning regimen may be one of the risk factors for SFPR. It is important to be aware of this possible adverse effect of ASCT with high-dose thiotepa and busulfan to ensure timely diagnosis and prevention of subsequent serious complications.

Suppression of Hematopoietic Primitive Cells in Patients with Secondary Failure of Platelet Recovery after Acute Graft-versus-Host Disease.

Secondary failure of platelet recovery (SFPR) can occur after allogeneic hematopoietic stem cell transplantation (alloHSCT), and 20% of cases are related to acute graft-versus-host disease (aGVHD). The underlying mechanisms of this association are unclear, however. The aim of the present study was to investigate the potential mechanisms of SFPR secondary to aGVHD, which may provide a new therapeutic strategy for these patients. A total of 468 patients with malignant hematologic disease who underwent alloHSCT were included. Sixty-six patients developed SFPR after alloHSCT, and in 45 of these 66 patients (68.2%), SFPR was secondary to grade II-IV aGVHD (SFPR/aGVHD). Compared with patients with good graft function (GGF), patients with SFPR had poor overall survival (20.72% versus 88.01%; P < .0001). Grade II-IV aGVHD was identified as an independent risk factor for SFPR in multivariate analysis (hazard ratio, 9.512; P < .0001). We observed reduced erythroid and megakaryocyte colony formation in bone marrow (BM) samples isolated from SFPR/aGVHD patients, consistent with the lower frequency of megakaryocyte and erythrocyte progenitors in BM. Levels of the inflammatory cytokines IL-2R and TNF-R1 were significantly higher in the SFPR/aGVHD group compared with the GGF group (P=.002 and .001, respectively), as were the frequencies of proinflammatory T helper subsets. Furthermore, the pathways that regulate hematopoiesis and immune responses were universally underexpressed in CD34+ cells isolated from SFPR/aGVHD patients. Differentially expressed genes were significantly enriched in the hematopoietic cell lineage pathway and other pathways involved in both immune responses and megakaryopoiesis. In summary, we found that both the immune microenvironment and compromised proliferation of hematopoietic primitive cells contribute to the development of SFPR secondary to aGVHD, and our data provide new insight into the mechanisms of SFPR in the context of aGVHD.

Eltrombopag treatment promotes platelet recovery and reduces platelet transfusion for patients with post-transplantation thrombocytopenia.

Post-transplantation thrombocytopenia (PT) is a common and severe complication which usually leads to poor prognosis. Eltrombopag (EPAG), a novel oral thrombopoietin (TPO) receptor agonist, has shown promising effects in thrombocytopenia due to immune thrombocytopenic purpura (ITP) and refractory severe aplastic anemia (rSAA), while the effectiveness of EPAG for PT patients still needs to be evaluated. A total of 32 PT patients receiving EPAG were retrospectively analyzed between September 2017 and July 2019, including 15 patients with poor graft function (PGF) and 17 patients with secondary failure of platelet recovery (SFPR). To date, 21 (65.6%) patients achieved overall recovery (OR) and 14 (43.8%) patients achieved complete recovery (CR). Among responders, 18 (85.7%) patients discontinued or tapered the drug and 16 (76.2%) patients successfully maintained their best response. During the EPAG treatment, responders received much lower median platelet transfusion units than non-responders (11 vs. 95, P < 0.001). After a median follow-up time of 364 days (range, 24-842), the overall survival in these patients was 78.1% (100% for responders and 36.4% for non-responders, P < 0.001). In the univariate and multivariate analysis, PGF was identified as the independent risk factor for OR (P = 0.041, HR = 5.333). Megakaryocyte (Megk) amounts (P = 0.025, HR = 14.638) and splenomegaly (P = 0.042, HR = 11.278) were identified as independent risk factors for CR. Besides, PGF patients tended to take a longer time to achieve PR and CR than SFPR patients. In conclusion, our data suggest that EPAG can promote platelet recovery and reduce platelet transfusion in PT patients.

Use of Thrombopoietin Receptor Agonists in Prolonged Thrombocytopenia after Hematopoietic Stem Cell Transplantation.

Prolonged thrombocytopenia after hematopoietic stem cell transplantation (HSCT) is a strong risk factor for transplantation-related morbidity and mortality, and no standard treatment guideline exists. Thrombopoietin receptor agonists (TPO-RAs), eltrombopag and romiplostim, increases the platelet production, and are being increasingly used in various conditions with thrombocytopenia. In this review, we present an overview of these TPO-RAs and review their efficacy and safety in prolonged post-HSCT thrombocytopenia. Through a systematic literature search, we identified 25 reports describing their use for this indication. Thirteen reports (8 case series and 5 case reports) described the use of eltrombopag in 78 patients with prolonged isolated thrombocytopenia (PIT) and 43 patients with secondary failure of platelet recovery (SFPR). A consistent and durable response with a rise in platelet counts >50×10 9/L for 7 consecutive days without platelet transfusion was seen in 85 of 121 patients (overall response rate [ORR], 70%). The responders included 56 patients with PIT (ORR for PIT, 72%) and 29 patients with SFPR (ORR for SFPR, 67%). No serious grade 3 or 4 adverse effects were reported. Similarly, 12 reports (6 case series and 6 case reports) described the use of romiplostim in prolonged post-HSCT thrombocytopenia (in 17 patients with PIT and 32 patients with SFPR). Response with the increment of platelet count was described in 40 out of 49 patients (ORR, 82%). Among the responders, 10 patients had PIT (ORR for PIT, 59%) and 30 patients had SFPR (ORR for SFPR, 94%). Our data show that TPO-RAs have an overall favorable response rate for both PIT and SFPR with a reasonable safety profile. However, given the lack of control groups, study heterogeneity, and the potential publication bias, these results should be interpreted with caution.

Eltrombopag Treatment for Patients with Thrombocytopenia Post-Transplantation Showed a Good Chance of Platelet Recovery

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) dramatically improves the outcomes of patients with hematologic disorders. However, thrombocytopenia post-transplantation is a common and severe complication, which not only diminishes the quality of life but also leads to fatal bleeding events. Blood transfusion could not be a permanent solution and it seldom achieves satisfactory results. Eltrombopag (EPAG), a novel oral thrombopoietin receptor agonist (TPO-RA), has been shown promising effects in thrombocytopenia caused by immune thrombocytopenic purpura (ITP) and severe aplastic anemia (SAA). Yet, the effectiveness of EPAG for patients with thrombocytopenia post-transplantation still needs to be discovered. From September 2017 to April 2019, twenty-two patients were diagnosed as thrombocytopenia post-transplantation in our center, including 10 patients with poor graft function (PGF) and 12 patients with secondary failure of platelet recovery (SFPR). Since insensitive to traditional treatment such as thrombopoietin and intravenous immunoglobin, all these patients received the EPAG treatment. So far, 16 (72.7%) patients achieved hematopoietic overall recovery (OR) and 11(50.0%) patients were complete recovery (CR). 12(75.0%) of the responded patients discontinued or tapered the drug and 9 patients (56.3%) successfully maintained their best response. Among 16 responded patients, the median time to achieve PR status was 33 (range, 7-105) days and the median time of CR was 67 (range, 40-175) days. Interestingly, 11 (91.7%) patients from SFPR subgroup achieved OR, while only 5 (50%) patients from PGF subgroup achieved OR. Besides, patients with normal spleen size (n=16) experience a higher CR rate than splenomegaly patients (n=8) (10 vs 1, 71.4% vs 12.5%). On univariate and multivariate analysis, PGF was identified as the independent risk factor of OR (P=0.050) and splenomegaly was identified as the independent risk factor of CR (P=0.019). Interestingly, 3 patients with enlarged spleen received ruxolitinib to minimize the spleen size during the EPAG treatment. Accompanied by the reduction in spleen size, the platelet counts increased gradually and all these 3 patients achieved OR. In contrast, only 2 of the other 5 splenomegaly patients who without ruxolitinib achieved OR. In conclusion, EPAG treatment for patients with thrombocytopenia post-transplantation showed a good chance of platelet recovery. Disclosures No relevant conflicts of interest to declare.