Patients with inherited thrombocytopenias often require platelet transfusions to raise their platelet count before surgery or other invasive procedures; moreover, subjects with clinically significant spontaneous bleeding may benefit from an enduring improvement of thrombocytopenia. The hypothesis that thrombopoietin-mimetics can increase platelet count in inherited thrombocytopenias is appealing, but evidence is scarce. We conducted a prospective, phase II clinical trial to investigate the efficacy of the oral thrombopoietin-mimetic eltrombopag in different forms of inherited thrombocytopenia. We enrolled 24 patients affected by MYH9-related disease, ANKRD26-related thrombocytopenia, X-linked thrombocytopenia/ Wiskott-Aldrich syndrome, monoallelic Bernard-Soulier syndrome, or ITGB3-related thrombocytopenia. The average pre-treatment platelet count was 40.4 ×109/L. Patients received a 3- to 6-week course of eltrombopag in a dose-escalated manner. Of 23 patients evaluable for response, 11 (47.8%) achieved a major response (platelet count >100 ×109/L), ten (43.5%) had a minor response (platelet count at least twice the baseline value), and two patients (8.7%) did not respond. The average increase of platelet count compared to baseline was 64.5 ×109/L (P<0.001). Four patients with clinically significant spontaneous bleeding entered a program of long-term eltrombopag administration (16 additional weeks): all of them obtained remission of mucosal hemorrhages, with the remission persisting throughout the treatment period. Treatment was globally well tolerated: five patients reported mild adverse events and one patient a moderate adverse event. In conclusion, eltrombopag was safe and effective in increasing platelet count and reducing bleeding symptoms in different forms of inherited thrombocytopenia. Despite these encouraging results, caution is recommended when using thrombopoietinmimetics in inherited thrombocytopenias predisposing to leukemia. ClinicalTrials.gov identifier: NCT02422394.

This will be a double-blind, placebo-control, randomized clinical trial conducted in the Department of Hematology, DMCH for one year. This study will help to establish the role of eltrombopag as a first-line therapy in newly diagnosed ITP. Newly diagnosed ITP patients will be selected after meeting inclusion and exclusion criteria, they will be thoroughly informed about the study, used drugs, randomization, risks, benefits, and follow-up. If they agree to participate, their consent will be taken and they will be enrolled in the study. A detailed history and clinical exam will be done. Primary investigation will be - CBC PBF, RBS, ANA, TSH, Anti H. pyloriIgG, Anti-HCV, APTT, and BMS (if indicated). The main outcome variable will be platelet count and number of spontaneous bleeding. Total sample size would be 100 (50 in each group). Enrolled patients would be divided into two groups (1:1) by block randomization. One group will get Eltrombopag\& Prednisolone and other group will get Eltrombopag\& Placebo. Researchers or any one related to the study in DMCH, patients \& their attendants, no one will know which patient will get placebo or eltrombopag. Only a respectable third party will know the information. A patient would be followed up on 1st, 2nd and 4th week of starting therapy. Patients would be evaluated in every follow up by history, physical examination and investigation. History of any spontaneous bleeding event, any discomfort or new symptoms science last follow up will be noted. General examination will be performed in every follow-up. CBC, RBS, ALT, AST, creatinine will be done in every follow-up. Data will be collected on a pre-designed case record form and will be collected through face-to-face interviews, physical examination, and laboratory reports. After data collection data will be edited, cleaned, and prepared for analysis at the end of the study. The statistical analysis will be conducted using SPSS version 25 statistical software. The results of the study will be published in national and international journals.

Thrombopoietin receptor analogs (TPO-RAs) are indicated for splenectomized immune thrombocytopenia refractory to corticosteroids or immunoglobulins, intravenous, or as second-line therapy when splenectomy is contraindicated. Herein, we report a case of left transverse and superior sagittal sinus thrombophlebitis in a 49-year-old woman with chronic immune thrombocytopenia who received 10 days of eltrombopag treatment. Etiologic assessment ruled out acquired thrombophilia and antiphospholipid syndrome. Pharmacovigilance investigation confirmed causality between eltrombopag and the cerebral events, necessitating the definitive discontinuation of the drug. The patient was treated with anticoagulants and anticonvulsants. This evolution was marked by clinical recovery and significant radiological improvement of the thrombotic event. Cerebral venous thrombophlebitis within TPO-RA treatment remains rare, and without codified recommendations, a strict assessment of patients at risk of thrombotic events remains necessary prior to TPO-RA initiation.

Background: Eltrombopag is a thrombopoietin receptor agonist (TPO-RA) approved for treating chronic primary ITP patients. Nevertheless, due to the non-existence of clinical trials there are no clear efficacy and safety data of eltrombopag in secondary ITP. Aims: To evaluate the efficacy and safety results using eltrombopag for treating secondary ITP patients in routine clinical practice in Spain. Methods: 33 secondary ITP patients from 23 Spanish centers who had been treated with eltrombopag and included in the Spanish Eltrombopag ITP Registry were retrospectively evaluated. However, 5 patients were excluded from the final analysis because three of them were aplastic anaemias, one was an amegakaryocytic thrombocytopenia and another one was a acute myeloid leukemia related thrombocytopenia. Results: Our secondary ITP case series included nine hepatitis C virus-ITP, five lymphoproliferative disorders, four systemic lupus erythematosus (SLE), three HIV-ITP, two synchronous HCV-HIV-ITP, two psoriatic arthritis, one Evans Syndrome, one common variable immunodeficiency and one Sjögren syndrome. The median age of our cohort was 54 (IQR, 35-66) years. There were 17 women and 11 men. 25% of patients had a Charlson Comorbidity Index score of 2 or more at diagnosis. The median time from secondary ITP diagnosis to eltrombopag initiation was 36 (IQR, 1-76) months. The median number of therapies before starting eltrombopag was 2 (IQR, 1-4), including rituximab (28%), romiplostim (17%) and splenectomy (10%). At the time of treatment start, 15 of 28 patients (53%) patients were receiving concomitant treatment for secondary ITP, mainly including corticosteroids (31%) or immunoglobulins (21%). 7 of 28 (25%) patients had bleeding symptomatology during the month preceeding the starting eltrombopag. At eltrombopag initiation the median platelet count was 9x109/L (IQR, 6-15x109/L). 25 of 28 (89%) patients responded to eltrombopag treatment. 23 patients (82%) achieved a complete response (CR; platelet count >100x109/L). To point out that 2 patients needed concomitant treatment with low prednisone doses to achieve or maintain the response. It was a slight difference between men and women regarding the response and complete response rates obtained: men achieved 82% and 73% respectively meanwhile women achieved 94% and 83%. The proportion of patients achieving platelet response was quite similar regardless the other studied parameters: age (87% and 92% for patients <65 years-old and ≥65 years-old, respectively), use of concomitant ITP medication at baseline (87% and 93% for patients with and without concomitant baseline ITP medication use) and bleeding at starting eltrombopag (100% and 87% for patients with and without bleeding, respectively). Three patients achieved complete response after only one month of tretament without relapsing afterwards. In five patients splenectomy was made few months after eltrombopag treatment (3 patients were in CR). Only two patients failed to achieve response with eltrombopag treatment: common variable immunodeficiency and one HIV patients. After a 9 months median follow-up, 15 patients maintain the response. Only 3 patients relapsed from their disease. Only two adverse events were reported: a grade 2-3 cephalea in a SLE patient and a death caused by respiratory insufficiency in a HIV patient with a CR ITP at that moment. Summary and Conclusions: Our case series describe the great efficacy and safety results observed with the use of eltrombopag in our secondary ITP patients. Our data suggest some diseases may not benefit from the use of eltrombopag. However more studies are needed to confirm the possible usefulness of TPO-RAs in this variety of secondary ITP cases.

BACKGROUND:

While chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment outcomes of relapsed/refractory hematological malignancies, this therapy is associated with post-treatment cytopenias, which can pose a challenge to its safe administration. This study describes the management of post-CAR T cytopenias using the thrombopoietin mimetic eltrombopag.

METHODS:

This retrospective analysis included adult patients with lymphoma or myeloma who received CAR T-cell therapy at two academic medical centers. Eltrombopag was initiated for patients who had persistent high-grade leukopenia and/or thrombocytopenia beyond 21 days post-CAR T infusion. Risk factors and outcomes were assessed and compared for patients who did or did not receive eltrombopag.

RESULTS:

Among the 185 patients analyzed, a majority (88%) experienced thrombocytopenia or leukopenia at day +30 post-CAR T infusion. A total of 42 patients met the criteria for eltrombopag treatment and initiated therapy. Patients who received eltrombopag were more likely to have pre-existing cytopenias at lymphodepletion, receive bridging therapy, experience an infection, or require intensive care. Recovery from cytopenias occurred within 180 days for a majority (94%) of patients.

CONCLUSIONS:

The use of eltrombopag for post-CAR T leukopenia and thrombocytopenia was considered safe without any significant toxicities. The use of eltrombopag for post-CAR T cytopenias might be effective in a high-risk patient population but requires further study.

Background: Thrombopoietin receptor (TPO) agonists are licensed for immune thrombocytopenia purpura ITP). Potential for use in other thrombocytopenic conditions is being explored. Aims: Our aim was to demonstrate the efficacy of eltrombopag in ITP -whether for severe disease or bridging therapy for surgery or chemotherapy. We also examined the use of eltrombopag in malignancy-associated thrombocytopenia, whether from disease or chemotherapy. Methods: We retrospectively identified all patients who had received eltrombopag from a single institution. Patients were identified who had received eltrombopag as part of standard treatment pathways, as well as those for whom special consideration was sought (ie refractory thrombocytopenia in advanced malignancy). Eltrombopag was commenced from between March 2012 (as the first documented prescription time point) to January 2016. For ITP, we included those deemed to have a 'severe' phenotype according to the international consensus guidelines. All patients fulfilled these criteria, warranting second-line treatment beyond steroids and IVIg. Many had failed multiple previous lines or had comorbidities limiting options. For non-ITP thrombocytopenic patients, indication for eltrombopag was examined on a case-by-case basis, according to benefit versus risk, since prescription was off-label. The primary indication was to enable chemotherapy, based on oncology requirements for platelet counts >100x109/L. Results: Our total cohort of 62 patients (36 males and 26 females) was treated over 8 years. This included 50 ITP patients requiring treatment for severe/refractory disease (n= 36), or bridging therapy (n=14). In the refractory group, 25 patients had primary ITP and 11 secondary ITP; including HIV (n=5), viral (n=2) malignancy (n=1) and other autoimmune aetiologies (n=3). Follow up was 1 to 85 months (median 12.5 months), with median 4 previous lines of therapy. Median time between ITP diagnosis and eltrombopag commencement was 24 months in the refractory ITP group. The delay was partially due to eltrombopag availability. In the overall ITP cohort (n=50), complete response (CR) was achieved in 28 patients (56%), partial response (PR) in 19 (38%) and no response (NR) in 3 patients (6%). Median time to response was 3 weeks (1 to 44 weeks). At follow up, 17 patients were in CR (34%) and 29 patients in PR (58%). Eltrombopag dose ranged from 25 to 100mg daily, with a median of 25mg (n=12). The difference in response at follow up was due to dose reduction, whilst maintaining haemostatic platelet counts. The malignancy-associated group included 12 patients. Eltrombopag use achieved CR in 6 patients (50%), PR in 3 (25%) and NR in 3 (25%). Summary/Conclusions: In conclusion, eltrombopag use in the severe ITP setting achieved a response in 94% cases. For severe or refractory disease, dose reduction was possible once response achieved. Although not CR by strict definition, a safe platelet count could be maintained- typically >50x109/Lwithout bleeding sequelae. In the bridging cohort, eltrombopag proved a reliable means of improving platelet counts for intervention, without the problems associated with steroids or IVIg. Beyond ITP, eltrombopag may be of practical benefit during chemotherapy and other myelosuppressive treatment, to ensure optimal dosing of these therapies via platelet count support. Although our non-ITP cohort was small, CR was achieved in half of these patients. Further trials are needed to demonstrate which patients may benefit from eltrombopag during treatment for malignancy-associated thrombocytopenia.

This open-label, repeat dosing study, TRA108057, will evaluate the efficacy, safety and tolerability of eltrombopag, when administered in a repeat, cyclic dosing schedule. The study will describe the effect of repeated (3 cycles), intermittent dosing of eltrombopag on the pharmacodynamics and durability of eltrombopag response as measured by the peripheral platelet counts.

For more information or to see if you qualify, please visit: http://www.itpstudy.com/gov

Pretreatment blood counts, particularly an absolute reticulocyte count ≥25×109/L, correlate with response to immunosuppressive therapy in severe aplastic anemia. In recent trials, eltrombopag combined with standard immunosuppressive therapy yielded superior responses than those to immunosuppressive therapy alone. Our single institution retrospective study aimed to elucidate whether historical predictors of response to immunosuppressive therapy alone were also associated with response to immunosuppressive therapy plus eltrombopag. We sought correlations of blood counts, thrombopoietin levels and the presence of paroxysmal nocturnal hemoglobinuria clones with both overall and complete responses in 416 patients with severe aplastic anemia, aged 2-82 years (median, 30 years), initially treated with immunosuppressive therapy plus eltrombopag between 2012 and 2019 (n=176) or with immunosuppressive therapy alone between 1999 and 2010 (n=240). Compared to non-responders, patients in the group of overall responders to immunosuppressive therapy plus eltrombopag had significantly higher pretreatment absolute reticulocyte counts, higher neutrophil counts and reduced thrombopoietin levels, as also observed for the group treated with immunosuppressive therapy alone. Addition of eltrombopag markedly improved the overall response in subjects with an absolute reticulocyte count between 10-30×109/L from 60% (54 of 90) to 91% (62 of 68). Absolute lymphocyte count correlated with complete response in the groups treated with immunosuppressive therapy with or without eltrombopag, especially in adolescents aged ≥10 years and adults, but the correlation was reversed in younger children. Platelet count and the presence of a paroxysmal nocturnal hemoglobinuria clone did not correlate with responses to immunosuppressive therapy. Blood counts remain the best predictors of response to nontransplant therapies in severe aplastic anemia. Addition of eltrombopag to immunosuppressive therapy shifted patients with a lower absolute reticulocyte count into a better prognostic category.

We monitored platelet activation by means of P-selectin and platelet monocyte aggregates (PMA) and platelet function by whole blood multiple electrode aggregometry and platelet adhesion under high shear in chronic immune thrombocytopenia patients to define changes in platelet activation during treatment with eltrombopag. Overall, platelet activation and function normalized with increasing platelet counts. However, P-selectin, which was already elevated before treatment, and PMA increased further transiently during the first weeks. The increases in P-selectin and in PMA indicate ongoing platelet activation during the early period of treatment.

Chronic immune thrombocytopenia (ITP) is an autoimmune disease that results in chronically low platelet counts. Treatment guidelines recommend a platelet count of at least 50,000/µl before minor surgery and at least 80,000/µl before major surgery. This retrospective analysis explored invasive non-dental procedures associated with the risk of bleeding (hemostatic challenges) among patients with chronic ITP in five phase 2/phase 3 studies of the thrombopoietin-receptor agonist, eltrombopag. Data collection for patients who underwent hemostatic challenges included demographics, study medication, timing of the procedure, platelet counts at last assessment before and first assessment after the procedure, supplemental ITP treatment, and bleeding events. Among 494 patients who participated in the studies, 87 hemostatic challenges were recorded. Median platelet counts before 44 major procedures in 32 patients were 100,000/µl and 18,500/µl among patients who received eltrombopag and placebo, respectively; before 43 minor procedures in 38 patients, median platelet counts were 82,000/µl and 20,000/µl among patients who received eltrombopag and placebo, respectively. A minority of patients required supplemental ITP treatment. Only 2 of 87 hemostatic challenges were associated with bleeding events; both patients received eltrombopag and pre-procedural platelet counts were 83,000/µl and 2000/µl. Although the number of patients who did not undergo procedures due to thrombocytopenia was not captured, these data suggest a majority of patients with chronic ITP who receive eltrombopag and experience increases in platelet counts meet current pre-procedural platelet count recommendations. The potential role of eltrombopag in supporting preparation of chronic ITP patients for surgical procedures still needs to be clinically established.