Difficult-to-treat primary immune thrombocytopenia in adults: Prevalence and burden. Results from the CARMEN-France registry.

The aim of this study was to assess the prevalence and the burden of difficult-to-treat primary ITP (pITP), defined by the need for another ITP treatment after romiplostim and eltrombopag. Adult patients were selected in the prospective, real-world CARMEN-France registry up to December 2021. Out of 821 adult patients with pITP, 29 had difficult-to-treat ITP (3.5%; 95% confidence interval [CI]: 2.3%-4.8% in total; 7.6%; 95% CI: 4.9%-10.2% of patients needing ≥2nd line treatment). The 3-year cumulative incidence of bleeding, infection and thrombosis was 100%, 24.1% and 13.8% respectively. The median cumulative duration of hospital stays was 31 days (median follow-up: 30.3 months).

Safety of selinexor as the only exportin 1 (XPO1) inhibitor so far: a post-marketing study based on the world Health Organization pharmacovigilance database (Vigibase).

BACKGROUND: Exportin 1 (XPO1) inhibitors are being developed as a new agent for anti-cancer therapies. This study aimed to broadly portray the adverse event (AE) profile of selinexor, an XPO1 inhibitor, in actual clinical practice. RESEARCH DESIGN AND METHODS: Disproportionality analyses were conducted by calculating the information component and reporting odds ratio in VigiBase over different reporting periods. All selinexor-related AEs were classified by system organ class (SOC) and preferred term (PT) according to the Medical Dictionary for Regulatory Activities. RESULTS: A total of 116,443 AEs were identified in 2,608 patients that received selinexor. Patients with cardiac disorders had a higher propensity for death. Thirteen SOCs and 125 PTs were identified as having a potential connection with selinexor. Notably, 29 suspected signals detected in our study were defined as significant AEs by the European Medicines Agency, including febrile neutropenia, pancytopenia, and acute kidney injury. Attention should be paid to these AEs, despite most toxicities being manageable and reversible. CONCLUSIONS: This study highlights a number of AEs associated with selinexor. Most toxicities are reversible but require careful management. The benefit of selinexor still outweighs the potential risks, indicating XPO1 inhibitors as promising agents.

Sustained response off-treatment in eltrombopag-treated adult patients with ITP who are refractory or relapsed after first-line steroids: Primary, final, and ad-hoc analyses of the Phase II TAPER trial.

Immune thrombocytopenia (ITP) is characterized by reduced platelet count due to increased destruction and is categorized according to the time following diagnosis (newly diagnosed, persistent, chronic). First-line corticosteroid therapy is associated with transient response, high relapse rates, and considerable toxicity. TAPER (NCT03524612) is a Phase II, prospective, single-arm trial investigating whether eltrombopag can induce a sustained response off-treatment (SRoT) in adult patients with ITP after first-line corticosteroid failure. This study defines SRoT as an off-treatment period wherein platelet count remains above 30 × 109 /L in the absence of bleeding or rescue therapy. The primary endpoint was the proportion of patients who achieved SRoT until Month 12, which was 30.5% (n = 32/105; p < .0001 testing hypothesis H1: proportion >15%) following eltrombopag tapering and discontinuation, and median SRoT duration was ~8 months until Month 12. Median platelet count increased within 1 month of treatment and remained elevated until Month 12. Quality of life improved within 3 months and was maintained. Headache (21%) was the most common adverse event. None of the 4 deaths reported were considered treatment-related. In summary, ~one-third of patients achieved SRoT until Month 12 following eltrombopag tapering and discontinuation. An ad-hoc early-use analysis, stratified by ITP duration at baseline, assessed initial hematologic responses and safety. Results suggest that eltrombopag has similar efficacy in newly diagnosed and later stages of ITP. In follow-up until Month 24, a median SRoT duration of ~22 months was observed (n = 20). The safety profile was comparable across analyses and ITP duration groups and aligned with its well-established safety profile.

Efficacy and safety of thrombopoietin receptor agonists in solid tumors with chemotherapy-induced thrombocytopenia: a meta-analysis.

OBJECTIVE: To evaluate the efficacy and safety of thrombopoietin receptor agonists (TPO-RAs) in solid tumors with chemotherapy-induced thrombocytopenia (CIT). METHODS: We conducted a comprehensive search of PubMed, FMRS, Cochrane Library, Web of Science, EMBASE, and ClinicalTrials.gov for randomized controlled trials (RCTs) reporting the efficacy and safety of TPO-RAs in solid tumors with CIT. The search was limited to articles published before April 30, 2022. Primary outcomes included chemotherapy dose reduction or delays, platelet transfusion, the incidence of grade 3 or 4 thrombocytopenia, and bleeding events. Secondary outcomes encompassed the incidence of platelet count > 400 × 109/L, adverse events (AEs), serious AEs, thrombosis, and mortality. RESULTS: Our analysis encompassed six studies: five rigorous RCTs and one unique study comparing romiplostim to an observation group, involving a total of 489 patients. For primary outcomes, TPO-RAs significantly reduced the incidence of grade 3 or 4 thrombocytopenia (RR = 0.69, 95% CI: 0.52-0.91). After applying the Bonferroni correction for multiple comparisons, the significance of the reduction in grade 3 or 4 thrombocytopenia incidence persisted (P = 0.008). TPO-RAs showed no significant impact on chemotherapy dose reduction or delays (RR = 0.81, 95% CI: 0.65-1.01), platelet transfusion (RR = 1.04, 95% CI: 0.48-2.27), or bleeding events (RR = 0.50, 95% CI: 0.23-1.10). In terms of safety, there were no significant difference in the incidence of any AEs (RR = 0.98, 95% CI:0.92-1.04), serious AEs (RR = 0.79, 95% CI:0.45-1.40), thrombotic events (RR = 1.20, 95% CI:0.51-2.84) and mortality (RR = 1.15, 95% CI:0.55-2.41). CONCLUSIONS: This meta-analysis suggests that TPO-RAs are generally well-tolerated. However, their efficacy in solid tumors with CIT appears limited, as they only demonstrate a reduction in the incidence of grade 3 or 4 thrombocytopenia.

Romiplostim use for thrombocytopenia following allogeneic hematopoietic stem cell transplantation: a case series from a single center in Qatar.

Thrombocytopenia is a common and serious complication that can occur following hematopoietic stem cell transplantation (HSCT), and it contributes to increased morbidity and mortality. The mechanisms of post-HSCT thrombocytopenia are multifactorial and complex. There are no clear consensus and guidelines for managing thrombocytopenia post-HSCT. Recently, there has been promising use of thrombopoietin receptor agonists (TPO-RAs), particularly eltrombopag and romiplostim, as treatments for post-HSCT thrombocytopenia. Notably, that this indication is considered off-label, and data in this use are limited. Based on the existing body of evidence, romiplostim emerges as a safe and effective option for individuals with transfusion-dependent thrombocytopenia after HSCT. In this context, we present a summary of our experience at a single center, where romiplostim was used in the management of post-HSCT thrombocytopenia due to poor graft function. Notably, all four cases responded positively to romiplostim treatment, and no significant adverse events were observed.

Multicenter evaluation of the addition of eltrombopag to immunosuppressive therapy for adults with severe aplastic anemia.

Eltrombopag has been shown to improve response rates when added to standard therapy in adults with severe aplastic anemia in controlled trial settings. However, outcomes in real-world populations have mostly been examined in small retrospective studies. This robust, multicenter, retrospective cohort study across six academic health systems compared outcomes in patients who received immunosuppressive therapy with or without eltrombopag. The study included 82 patients who received front-line therapy from January 2014 to August 2021. Overall response rates at 6 months did not differ significantly for patients receiving eltrombopag versus immunosuppressive therapy alone (58% v. 65%, p = 0.56). However, complete response rates at 6 and 12 months were over two times higher in the eltrombopag arm (29% v. 12%, p = 0.06 and 48% v. 18%, p = 0.005). Rates of hepatotoxicity were similar across both arms. Eltrombopag addition did not impact overall survival (median not reached in either arm at 2 years, p = 0.86) or disease-free survival (median not reached v. 13.3 months at 2 years, p = 0.20). Eltrombopag may not produce as large of a benefit in real-world settings compared to controlled trial settings but may offer patients deeper responses with similar rates of toxicity to immunosuppressive therapy alone.

Treatment of immune thrombocytopenia during pregnancy with thrombopoietin receptor agonists.

The introduction of thrombopoietin receptor agonists (TPO-RAs) led to a paradigm shift in the management of immune thrombocytopenia (ITP). However, TPO-RAs are not approved for use during pregnancy due to the absence of evidence and concerns for possible effects on the fetus due to their expected transplacental transfer. This comprehensive review examines the safety and efficacy of TPO-RA in 45 pregnancies of women with ITP (romiplostim n = 22; eltrombopag n = 21; both in the same pregnancy n = 2). Mothers experienced failure of the median of three treatment lines during pregnancy prior to TPO-RA administration. A platelet response (>30 × 109 /L) was seen in 86.7% of cases (including a complete response >100 × 109 /L in 66.7%) and was similar between eltrombopag and romiplostim (87.0% and 83.3%, p = 0.99). The maternal safety profile was favourable, with no thromboembolic events encountered. Neonatal thrombocytopenia was noted in one third of cases, with one case of ICH grade 3, and neonatal thrombocytosis was observed in three cases. No other neonatal adverse events attributable to TPO-RAs were seen. This review suggests that the use of TPO-RA during pregnancy is associated with a high response rate and appears safe. Nevertheless, TPO-RA should not be routinely used in pregnancy and should be avoided in the first trimester until further evidence is accumulated.

Selinexor for the treatment of recurrent or metastatic salivary gland tumors: Results from the GEMS-001 clinical trial.

OBJECTIVES: We aimed to evaluate the activity of selinexor, an oral selective inhibitor of nuclear export, in patients with recurrent or metastatic salivary gland tumors (SGT). METHODS: GEMS-001 is an open-label Phase 2 study for patients with recurrent or metastatic SGT with two parts. In Part 1 of the protocol, patients had tumor samples profiled with targeted next generation sequencing as well as immunohistochemistry for androgen receptor, HER-2 and ALK. For Part 2, patients with no targeted therapies available were eligible to receive selinexor 60 mg given twice weekly every 28 days. The primary endpoint was objective response rate. Secondary endpoints included progression-free survival (PFS) and prevalence of druggable alterations across SGT. RESULTS: One hundred patients were enrolled in GEMS-001 and underwent genomic and immunohistochemistry profiling. A total of 21 patients who lacked available matched therapies were treated with selinexor. SGT subtypes (WHO classification) included adenoid cystic carcinoma (n = 10), salivary duct carcinoma (n = 3), acinic cell carcinoma (n = 2), myoepithelial carcinoma (n = 2), carcinoma ex pleomorphic adenoma (n = 2) and other (n = 2). Of 18 evaluable patients, stable disease (SD) was observed in 17 patients (94%) (SD ≥6 months in 7 patients (39%)). However, no objective responses were observed. The median PFS was 4.9 months (95% confidence interval, 3.4-10). The most common treatment-related Grade 1-2 adverse events were nausea [17 patients (81%)], fatigue [16 patients (76%)], and dysgeusia [12 patients (57%)]. Most common treatment-related Grade 3-4 adverse events were hyponatremia [3 patients (14%)], neutrophil count decrease [3 patients (14%)] and cataracts [2 patients (10%)]. No treatment-related deaths were observed. CONCLUSIONS: Although tumor reduction was observed across participants, single agent selinexor anti-tumor activity was limited.

Oral Selinexor as Maintenance Therapy After First-Line Chemotherapy for Advanced or Recurrent Endometrial Cancer.

PURPOSE: Selinexor inhibits exportin-1 (XPO1) resulting in nuclear accumulation of tumor suppressor proteins including p53 and has clinical activity in endometrial cancer (EC). The primary end point was to assess progression-free survival (PFS) with once-weekly oral selinexor in patients with advanced or recurrent EC. PATIENTS AND METHODS: ENGOT-EN5/GOG-3055/SIENDO was a randomized, prospective, multicenter, double-blind, placebo-controlled, phase III study at 107 sites in 10 countries. Patients 18 years or older with histologically confirmed EC were enrolled. All had completed a single line of at least 12 weeks of taxane-platinum combination chemotherapy and achieved partial or complete response. Patients were assigned to receive 80 mg oral selinexor once weekly or placebo with 2:1 random assignment (ClinicalTrials.gov identifier: NCT03555422). RESULTS: Between January 2018 and December 2021, 263 patients were randomly assigned, with 174 allocated to selinexor and 89 to placebo. The median PFS was 5.7 months (95% CI, 3.81 to 9.20) with selinexor versus 3.8 months (95% CI, 3.68 to 7.39) with placebo (hazard ratio [HR], 0.76 [95% CI, 0.54 to 1.08]; two-sided P = .126), which did not meet the criteria for statistical significance in the intent-to-treat population. Incorrect chemotherapy response stratification data for 7 (2.7%) patients were identified. In a prespecified exploratory analysis of PFS in audited stratification data, PFS for selinexor met the threshold for statistical significance (HR, 0.71; 95% CI, 0.499 to 0.996; two-sided P = .049). Furthermore, patients with the TP53 wild-type (wt) EC had a median PFS of 13.7 and 3.7 months with selinexor and placebo. The most common grade 3 treatment-related adverse events were nausea (9%), neutropenia (9%), and thrombocytopenia (7%). CONCLUSION: The significance level for PFS was only met in the audited analysis. However, a preliminary analysis of a prespecified exploratory subgroup of patients with TP53wt EC showed promising results with selinexor maintenance therapy.

Eltrombopag for Low-Risk Myelodysplastic Syndromes With Thrombocytopenia: Interim Results of a Phase II, Randomized, Placebo-Controlled Clinical Trial (EQOL-MDS).

PURPOSE: In myelodysplastic syndromes (MDS), severe thrombocytopenia is associated with poor prognosis. This multicenter trial presents the second-part long-term efficacy and safety results of eltrombopag in patients with low-risk MDS and severe thrombocytopenia. METHODS: In this single-blind, randomized, placebo-controlled, phase-II trial of adult patients with International Prognostic Scoring System low- or intermediate-1-risk MDS, patients with a stable platelet (PLT) count (<30 × 103/mm3) received eltrombopag or placebo until disease progression. Primary end points were duration of PLT response (PLT-R; calculated from the time of PLT-R to date of loss of PLT-R, defined as bleeding/PLT count <30 × 103/mm3 or last date in observation) and long-term safety and tolerability. Secondary end points included incidence and severity of bleeding, PLT transfusions, quality of life, leukemia-free survival, progression-free survival, overall survival and pharmacokinetics. RESULTS: From 2011 to 2021, of 325 patients screened, 169 patients were randomly assigned oral eltrombopag (N = 112) or placebo (N = 57) at a starting dose of 50 mg once daily to maximum of 300 mg. PLT-R, with 25-week follow-up (IQR, 14-68) occurred in 47/111 (42.3%) eltrombopag patients versus 6/54 (11.1%) in placebo (odds ratio, 5.9; 95% CI, 2.3 to 14.9; P < .001). In eltrombopag patients, 12/47 (25.5%) lost the PLT-R, with cumulative thrombocytopenia relapse-free survival at 60 months of 63.6% (95% CI, 46.0 to 81.2). Clinically significant bleeding (WHO bleeding score ≥ 2) occurred less frequently in the eltrombopag arm than in the placebo group (incidence rate ratio, 0.54; 95% CI, 0.38 to 0.75; P = .0002). Although no difference in the frequency of grade 1-2 adverse events (AEs) was observed, a higher proportion of eltrombopag patients experienced grade 3-4 AEs (χ2 = 9.5, P = .002). AML evolution and/or disease progression occurred in 17% (for both) of eltrombopag and placebo patients with no difference in survival times. CONCLUSION: Eltrombopag was effective and relatively safe in low-risk MDS with severe thrombocytopenia. This trial is registered with ClinicalTrials.gov identifier: NCT02912208 and EU Clinical Trials Register: EudraCT No. 2010-022890-33.

Pediatric immune thrombocytopenia: a focus on eltrombopag as second-line therapy.

BACKGROUND: Immune thrombocytopenia (ITP) is the most common acquired bleeding disorder. In both children and adults, the primary goal of any therapeutic approach consists of cessation of bleeding and its prevention. Several options are currently available for first-line therapy in Europe, including corticosteroids and intravenous immunoglobulin (IVIg) infusion, which has a similar efficacy and safety profile in both the pediatric and adult populations. When second-line therapy is needed in the pediatric setting, current guidelines recommend eltrombopag as the drug of choice. PROCEDURE: The aim of this article is to summarize the available evidence and present real-life experience on eltrombopag as second-line therapy in pediatric patients with ITP, with a focus on dosing and response to therapy as well as its tapering and discontinuation. RESULTS: In our setting, eltrombopag is associated with good safety profile as well as promising efficacy; dose de-escalation was feasible in 94% of cases and often reached very low pro/kg dosage, with full discontinuation in 15% of cases. In daily practice, a standardized approach for discontinuation of eltrombopag in pediatric patients with ITP is still lacking. Herein, an easy-to-use scheme for tapering and discontinuation in candidate pediatric patients is proposed that proposes 25% dose reduction every four weeks. CONCLUSIONS: In future management of pediatric ITP patients, it will be crucial to assess if thrombopoietin receptor agonists might be more effective in earlier phases of the disease and can modify the course of the disease.

Combining thrombopoietin receptor agonists with immunosuppressive drugs in adult patients with multirefractory immune thrombocytopenia, an update on the French experience.

Combining drugs could be an effective option for treating multirefractory ITP, that is, patients not responding to rituximab, thrombopoietin receptor agonists (TPO-RA) and splenectomy. We conducted a retrospective, multicenter, observational study including multirefractory ITP patients who received a combination of a TPO-RA and an immunosuppressive drug. We included 39 patients (67% women, median age 59 years [range 21-96]), with a median ITP duration of 57 months [3-393] and a median platelet count at initiation of 10 × 109 /L [1-35]. The combination regimen was given for a median duration of 12 months [1-103] and included eltrombopag (51%) or romiplostim (49%), associated with mycophenolate mofetil (54%), azathioprine (36%), cyclophosphamide (5%), cyclosporin (3%) or everolimus (3%). Overall, 30 patients (77%) achieved at least a response (platelet count ≥30 × 109 /L and at least doubling baseline during at least 3 months), including 24 complete responses (platelet count >100 × 109 /L during at least 3 months) with a median time to response of 30 days [7-270] and a median duration of response of 15 months [4-63]. Severe adverse event related to ITP treatment was observed in 31%. In conclusion, this study confirms that some patients with multirefractory ITP can achieve long lasting response with this combination.

Long-Term Safety and Efficacy of Eltrombopag for Advanced Myelodysplastic Syndromes or Acute Myeloid Leukemia and Severe Thrombocytopenia: Results of the ASPIRE Extension Study.

ASPIRE, a three-part, international, phase 2 trial (ClinicalTrials.gov identifier: NCT01440374), investigated eltrombopag efficacy and safety in patients with advanced myelodysplastic syndrome or acute myeloid leukemia and grade 4 thrombocytopenia (<25 × 109 platelets/L). Approximately 30-65% of patients in this open-label extension phase experienced clinically relevant thrombocytopenic events; no conclusions could be made regarding long-term efficacy (non-randomized design, no placebo control), and survival rates may simply reflect advanced disease. Long-term safety was consistent with the double-blind phase and contrasted with earlier SUPPORT study findings in higher-risk patients, suggesting that eltrombopag may have a role in treating thrombocytopenia in patients with low-/intermediate-risk myelodysplastic syndrome.

Efficacy and safety of thrombopoietin receptor agonists in children and adults with persistent and chronic immune thrombocytopenia: a meta-analysis.

INTRODUCTION: In this paper, we systematically review the efficacy and safety of thrombopoietin receptor agonists (TPORAs) for treatment of persistent and chronic immune thrombocytopenia (ITP) in children and adults. METHODS: We searched PubMed, MEDLINE, ScienceDirect, Scopus, EMbase and the Cochrane Library to collect randomized controlled trials (RCTs) of TPO-RAs which including avatrombopag hetrombopag eltrombopag and romiplostim treated persistent and chronic ITP from their earliest records to February 2022. RESULTS: We included 15 RCTs with a total of 1563 patients. There were ten trials of adults and five trials of children. The results of meta-analysis showed that in adult patients, patients treated with TPO-RAs had longer duration of platelet response, higher platelet response rate, lower use of rescue therapy, and lower incidence of bleeding events, and similar incidence of adverse events compared with placebo. Except for the incidence of any bleeding, the results in children were consistent with those in adults. The network meta-analysis of data on overall platelet response rates in adults showed that avatrombopag was more effective than eltrombopag and hetrombopag. CONCLUSIONS: TPO-RAs has better efficacy and higher safety in the treatment of ITP. And the overall response rate of avatrombopag in adults was higher than that in eltrombopag and hetrombopag.

Evaluation of the procoagulant state in chronic immune thrombocytopenia before and after eltrombopag treatment-a prospective cohort study.

BACKGROUND: Thrombopoietin receptor agonists are frequently used in treating immune thrombocytopenia (ITP) owing to high response rates and good tolerability. ITP is associated with an increased risk of thrombosis. Whether treatment with eltrombopag further increases this risk is controversial. The mechanisms behind the thrombotic risk in ITP are unclear. OBJECTIVES: To assess platelet function and hypercoagulability in patients with ITP and the effect of eltrombopag thereon. METHODS: This prospective multicenter study assessed adult primary patients with ITP who were starting eltrombopag treatment. Platelet (re)activity and hypercoagulability were measured in whole blood or plasma before start and after 2 to 3 weeks of eltrombopag treatment and compared with those of controls. Change over time was assessed by mixed-effects models, and the results were corrected for multiple testing. RESULTS: We included 16 patients and 33 controls. At baseline, patients with ITP exhibited lower expression of glycoprotein VI, more activated platelets, and lower reactivity toward agonists compared with controls. ß-Thromboglobulin levels reduced and thrombin generation peak height increased compared with those of controls. In line with this finding, patients with ITP showed high factor VIII (median, 217%; IQR, 174%-272%) and von Willebrand factor levels (median, 167%; IQR, 109%-198%). Eltrombopag treatment increased thrombin generation potential: lag time decreased and peak height and endogeneous thrombin potential increased. The latter changes were not significant after correction for multiple testing. CONCLUSION: Patients with ITP in this study were in a hypercoagulable state, with preactivated platelets, increased thrombin generation potential, and increased levels of factor VIII and von Willebrand factor. Eltrombopag treatment further increased plasma thrombin generation potential but no other hemostatic parameters.