Median Baseline Platelet Count Research Articles

A Phase 3 Study of Eltrombopag Vs. Standard First-Line Management for Newly Diagnosed Immune Thrombocytopenia in Children: Trial in Progress Update

Background: Immune thrombocytopenia (ITP) causes low platelet counts, variable bleeding symptoms, and reductions in health-related quality of life (HRQoL). Despite this, novel therapies for newly diagnosed ITP have not been introduced in over 30 years. Eltrombopag, a thrombopoietin receptor agonist (TPO-RA), was FDA approved for children with chronic ITP in 2015. The use of eltrombopag for adults with newly diagnosed ITP has been described in two small single-center trials (Tripathi et al, Int J Hematol, 2014; Gόmez-Almaguer et al, Blood, 2014), and pediatric hematologists do use TPO-RAs off-label in some cases of newly diagnosed ITP (Neunert et al, Pediatr Blood Cancer, 2016). TPO-RAs may be an efficacious and more durable first-line therapy for children with newly diagnosed ITP who require treatment. This abstract provides a 4-year interval update on the Pediatric ITP Newly diagnosed patients Eltrombopag vs Standard therapy (PINES) trial in progress. Study Design and Methods: The PINES trial, NCT03939637, is an investigator-initiated prospective, open label, randomized, multi-center trial sponsored by the ITP Consortium of North America (ICON) and funded by Novartis. The primary objective is to determine if the proportion of patients with a platelet response, defined as ≥3 of 4 platelet counts >50 x10 9/L during weeks 6-12 without rescue treatment, is significantly greater in patients with newly diagnosed ITP treated with eltrombopag compared to those treated with standard first-line therapy. Patients (n=162) from 30 ICON centers (Figure) are randomized 2:1, stratified by age and treatment status, to receive the experimental treatment, eltrombopag, or investigator's choice of 3 standard first-line therapies: prednisone, intravenous immune globulin or anti-D globulin at standardized doses. Eligible patients are ages 1 to <18 with primary ITP, within 3 months of diagnosis, with platelet count <30 x10 9/L who require pharmacologic treatment from the perspective of the treating clinician. Baseline treatment status is 1) upfront treatment, or patients within 10 days of ITP diagnosis with no prior treatment, and 2) treatment failure, or patients previously managed with observation or a first-line standard agent. Patients are ineligible if they can be observed without medication or have severe bleeding. A one-sided z-test, at alpha=0.025, will be used to compare the proportion of patients who have a platelet response between the two treatment arms. All randomized patients will be analyzed in the intention-to-treat analysis. Secondary objectives include treatment arm comparison of bleeding scores (WHO Bleeding Scale and Modified Buchanan Score), changes in HRQoL (measured by the Kids ITP Tool, Hockenberry Fatigue Scale, PROMIS, and Global Change Scale), and changes in percentage of CD4 +25 +Foxp3 + regulatory T (Treg) cells. Due to challenges related to recruitment and the logistics and safety of obtaining frequent assessments during the COVID-19 pandemic, the primary endpoint was re-defined in 2021 to what is considered a clinically equivalent definition of response, from ≥6 of 8 weekly to ≥3 of 4 biweekly platelet counts >50 x10 9/L during weeks 6-12. Baseline Characteristics: Since first site activation in 2019, 100 patients have been enrolled (Table). Subjects include 42 patients aged 1-<6 years, 34 patients aged 6-<12 years, and 24 patients aged 12-<18 years. Thirty-six patients received upfront treatment and 64 patients had treatment failure prior to enrollment. Median baseline platelet count at enrollment was 5 x10 9/L (range 1 - 28 x10 9/L). Median WHO Bleeding Scale at enrollment was 1 (range 0 - 3) and median modified Buchanan Overall Score was 3 (range 0 - 3). Baseline HRQoL surveys have been obtained for >80% of eligible subjects. Treg samples have been obtained for 95% of subjects, and 74% of subjects have consented to optional biology studies. Conclusion: Despite historical difficulty completing interventional trials in pediatric ITP and pandemic-related enrollment challenges, PINES trial enrollment is progressing successfully and will ultimately provide definitive data regarding the efficacy of eltrombopag in children with newly diagnosed ITP. There are no current data supporting the use of TPO-RAs for newly diagnosed ITP in children, or as monotherapy for newly diagnosed ITP in adults. Results from this trial therefore carry the potential to change management practices in ITP.

Initial Report of Part B Phase 1/2 Efficacy and Safety Results for Bruton Tyrosine Kinase Inhibitor Rilzabrutinib in Patients with Relapsed Immune Thrombocytopenia

Introduction: Rilzabrutinib is a potent oral, reversible Bruton tyrosine kinase inhibitor that can treat hematological autoimmune diseases through multiple putative mechanisms of action: (1) inhibition of B-cell activation, (2) interruption of antibody-coated cell phagocytosis by FcϒR in spleen and liver, and (3) induce sustained anti-inflammatory effects (Langrish J Immunol 2021). Preliminary evidence showed that rilzabrutinib treatment resulted in rapid and durable platelet responses with a favorable safety profile in previously treated patients with immune thrombocytopenia (ITP) as studied in part A of a phase 1/2 clinical study (LUNA 2; Kuter N Engl J Med 2022). This abstract summarizes the results of part B that focused on the durability of response with rilzabrutinib in relapsed ITP patients. Methods: Part B of the multicenter, open-label, phase 1/2 study evaluated the efficacy and safety of rilzabrutinib 400 mg bid in patients with relapsed ITP (NCT03395210). Adult patients aged 18-80 y were eligible with ≥2 baseline platelet counts <30x10 9/L no less than 7 days apart in the 15 days before the first dose. Eligible patients were required to have a past response (achievement of platelet count ≥50x10 9/L) to intravenous immunoglobulin (IVIg)/anti-D or corticosteroid (CS) that was not sustained and failed ≥1 other ITP therapy (that was not IVIg or CS). Stable doses of concomitant CS/thrombopoietin receptor agonists (TPO-RA) were allowed with rilzabrutinib. The primary endpoints for part B were safety and durable platelet response defined as platelet counts ≥50x10 9/L on ≥8 of the last 12 weeks of rilzabrutinib without rescue medication. Patients completing 24 weeks of rilzabrutinib with platelet counts ≥50x10 9/L or ≥30x10 9/L and doubling from baseline in ≥4 of the last 8 weeks of treatment without rescue medication could continue rilzabrutinib in the long-term extension (LTE) period. Results: At baseline, 26 enrolled patients had a median age of 57 y (range, 20-75), 62% were female, and median baseline platelet count was 13x10 9/L (range, 2-24x10 9/L). Patients had a median duration of ITP of 10.3 y (range, 0.7-48.2) and had received a median of 6 prior unique ITP therapies (range, 3-19; 46% splenectomy). Seventeen patients (65%) received concomitant non-rescue CS and/or TPO-RA. Nine patients (35%; 95% CI, 17%-56%) achieved the primary endpoint of durable platelet response. Approximately 25% of patients achieved platelet counts ≥50x10 9/L by day 15 of rilzabrutinib treatment (Figure 1A). In 16 patients who achieved platelet counts ≥50x10 9/L, median time to first platelet count ≥50x10 9/L was 15 days (range, 7-134). Median platelet counts for all patients (responders and non-responders) increased over time, exceeding the platelet count thresholds of 30x10 9/L at day 57 and 50x10 9/L at day 120 (Figure 1B). The mean number of weeks with platelet counts ≥50x10 9/L and/or ≥30x10 9/L and doubling from baseline was both 9.3 weeks (SD, 10.1). Three patients (12%) received rescue medication in the main treatment period. Fifteen patients (58%) completed 24 weeks of rilzabrutinib and 11 (42%) entered the LTE. Over the main treatment period, the median duration of treatment was 167 days (range, 7-169). Sixteen patients (62%) had ≥1 related treatment-emergent adverse event (AE), including 35% diarrhea, 23% headache, and 15% nausea. Most AEs were grade 1 or 2; there was 1 treatment-related AE of grade 3 blood creatinine phosphokinase increase. There was no treatment-related grade ≥2 bleeding/thrombotic events or infections, serious AEs, or deaths. Conclusion: Part B study results were consistent with part A. Rilzabrutinib demonstrated rapid, stable, and durable platelet responses in patients with relapsed ITP, with a favorable safety profile in part B.

Treatment with Hetrombopag for Poor Platelet Engraftment after Allo-HSCT-a Single Center Retrospective, Observational Study

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a common and important treatment for most hematopoietic diseases. Some patients may experience poor platelet engraftment after allo-HSCT, which may lead to transplant failure and is also an important influencing factor for post-HSCT complications such as graft versus host disease (GVHD) and non-relapse mortality (NRM). Thus, exploring methods to improve platelet engraftment is very important. Hetrombopag is a small-molecule thrombopoietin-receptor agonist (TPO-RA) produced in China, stimulates the proliferation and differentiation of megakaryocytes and promotes platelet production through binding to thrombopoietin receptor to stimulate multiple intracellular signaling pathways. It has been reported that hetrombopag was effective in promoting platelet engraftment and decreasing platelet transfusion after allo-HSCT. Here, we studied the efficacy and safety of hetrombopag for poor platelet engraftment after allo-HSCT, of whom did not respond to rhTPO treatment. Aims: To evaluate the efficacy of hetrombopag in patients with poor platelet engraftment after allogeneic hematopoietic stem cell transplantation. Methods: In this retrospective study, data from patients with poor platelet engraftment after allo-HSCT who had been treated firstly with rhTPO and then with hetrombopag at Henan Cancer Hospital from July 1, 2021 to July 1, 2023 were collected. Patients should meet the following criteria to enroll in the study: experienced poor platelet engraftment who had been treated with rhTPO from day +4 post-HSCT. Here we defined poor platelet engraftment as platelet count (PLT) < 20 × 10 9/L beyond day +28 post-HSCT. We analyzed 57 patients mentioned above and divided them into two groups in a ratio of 1:2, 19 of them were given hetrombopag until their PLT exceeded 50 × 10 9/L and maintained for more than 7 days without platelet transfusion (hetrombopag group), another 38 patients were treated without hetrombopag (control group). The initial dose of hetrombopag was 5, or 7.5 mg/d according to the patient's conditions and characteristics (e.g., age, PLT, and bleeding risk). After allo-HSCT, patients administered rhTPO at a dose of 300U/kg·d from day +4. We defined rhTPO as ineffective when PLT was still below 20×10 9/L beyond +21 days post-HSCT after rhTPO administration. At this time, rhTPO was replaced with hetrombopag, or IL-11, decitabine, platelet transfusion, etc. Results: The median ages of the two groups of patients were 38 years (hetrombopag group) and 41 years (control group), respectively. The median baseline platelet count in both groups were 20 × 10 9/L. The proportion of patients with PLT recovery to 50×10 9/L was significantly higher in the hetrombopag group than in the control group (47.3% vs 7.9%, χ2=26.03, P<0.0001). The median time to PLT recovery to 50×10 9/L was 10 (7-48) days in the hetrombopag group and 33 (21-94) days in the control group ( P=0.004). The mean units of platelet transfusion in the hetrombopag group was significantly lower than that in the control group (2.7 vs 6.3 U, P=0.001), and no thrombotic events occurred. There was no statistical difference in the incidence of aGVHD (42.0% vs 44.7%, P=0.850) and NRM (5.2% vs 7.9%, P=0.714) between the two groups, suggesting that hetrombopag had no significant effect on aGVHD and NRM. Conclusion: For allo-HSCT patients who experienced poor platelet engraftment after rhTPO treatment, hetrombopag can rapidly promote PLT recovery, reduce the units of platelet transfusion, and have no risk of the increase of aGVHD and NRM. These results still need further validation in a larger sample prospective confirmatory study in the future.

Long-Term Treatment with Fostamatinib in Japanese Patients with Primary Immune Thrombocytopenia: An Open-Label Extension Study Following a Phase 3 Placebo-Controlled, Double-Blind, Parallel-Group Study

Background Fostamatinib, a spleen tyrosine kinase inhibitor, has been approved for the treatment of chronic immune thrombocytopenia (ITP) in adults in the US, Canada, Europe, Israel, and Japan. We evaluated the long-term efficacy and safety of fostamatinib treatment and the off-therapy platelet count in Japanese patients with primary ITP in a phase 3 clinical trial with a 24-week double-blind period, a 28-week open-label extension period, and a pre-defined washout period. Methods The trial enrolled Japanese patients who had failed to respond or did not tolerate ≥1 prior ITP treatment, who had a mean platelet count <30,000/μL (based on 3 screening and baseline platelet measurements), and had a platelet count at each visit <35,000/μL. Dosing was at 100 mg bid for 4 weeks and then 150 mg bid if needed and tolerated. One concomitant treatment was allowed (corticosteroids, azathioprine or danazol). The dosage of the concomitant treatment was to remain the same during the 24-week double-blind period but could be reduced or discontinued during the open-label period. Efficacy endpoints were platelet response rate (i.e., the percentage of patients who achieved a platelet count of ≥ 50 × 10 3/μL at 2 consecutive visits at least 28 days apart). The platelet count of the responders during the study period were evaluated. Results A total of 33 patients who were either treated with fostamatinib in the 24-week double-blind period (Fostamatinib-Fostamatinib group, n=22) or treated with placebo in the double-blind period and then treated with fostamatinib in the 28-week open-label extension period (Placebo-Fostamatinib group, n=11) were analyzed. Of those, 79% (26/33) were women, the median age was 62, the median baseline platelet count was 19 x 10 3/μL, and 58% (19/33) had two or more previous treatments. The platelet response rate was 36% (8/22) in the Fostamatinib-Fostamatinib group and 27% (3/11) in the Placebo-Fostamatinib group. The platelet count of the responders in the Fostamatinib-Fostamatinib group increased to ≥50 × 10 3/μL shortly after initiating fostamatinib and remained around 100 × 10 3/μL between Week 14 and Week 52, whereas the platelet count of the responders in the Placebo-Fostamatinib group remained low while receiving placebo but increased after receiving fostamatinib ( Figure 1). Among 14 patients with concomitant glucocorticoids treatments at the beginning of the open-label period, 43% (6/14) reduced or discontinued glucocorticoids while receiving fostamatinib without disease relapse. In the washout period of up to 4 weeks, all 12 patients experienced a mild decrease in platelet count, but none developed bleeding events ( Figure 2). Three of four patients who completed the 4-week washout period had a slight increase in platelet counts from Week 2 to Week 4. In the double-blind and open-label periods, adverse events were reported in 96% (21/22) of the Fostamatinib-Fostamatinib group and 100% (11/11) of the Placebo-Fostamatinib group, and treatment-related adverse events in 77% (17/22) and 46% (5/11), respectively. In the washout period, adverse events were reported in 50% (6/12) of patients, and treatment-related adverse events in 0% (0/12). We found no new safety risk or late-onset adverse events specific to Japanese patients. Conclusions The long-term efficacy and safety of fostamatinib were observed in Japanese patients with primary ITP, along with the feasibility of glucocorticoid reduction/discontinuation during fostamatinib treatment, and a lack of bleeding events after abrupt discontinuation of fostamatinib. The findings obtained from this study will help position fostamatinib as a second-line treatment in patients with primary ITP.

CM313, a Novel Anti-CD38 Antibody, As a Potential Treatment for Primary Immune Thrombocytopenia: A Phase II Trial

Background: Primary immune thrombocytopenia (ITP) is an autoimmune disease characterized by autoantibody-mediated platelet destruction. Antiplatelet-specific plasma cells (PCs) have been identified in ITP patients, making PCs depletion a potential treatment for ITP. CM313, a novel anti-CD38 monoclonal antibody currently under investigation in a phase I trial for multiple myeloma, has demonstrated targeted depletion of CD38-positive cells, including PCs. This phase II trial (NCT05694767) was designed to assess the safety and efficacy of CM313 in ITP patients. Methods: The open-label phase II trial consisted of a 4-week screening period, an 8-week treatment period, and a 16-week follow-up period. The main inclusion criteria were patients (age ≥18 years) with ITP and a platelet count <30×10 9/L, who did not response to or relapsed after glucocorticoid therapy and at least one second-line therapy (including rituximab and/or thrombopoietin receptor agonists [TPO-RAs]). Eligible patients received CM313 intravenously at a dose of 16 mg/kg weekly for a total of 8 weeks. The participants were requested to maintain the stable doses of glucocorticoids or TPO-RAs for 4 weeks prior to receiving the first dose without dose escalation during the study. Prophylactic medication, including glucocorticoids, antihistamines, and acetaminophen, was administered to all patients before and after the infusion. The primary endpoints were the percentage of patients with a platelet count ≥50×10 9/L within 8 weeks after the first dose (platelet count must be consecutive on at least 2 occasions with an interval of at least 1 day) and the incidence/severity of adverse events during the study period. Results： As of June 30, 2023, a total of 21 patients had been enrolled in the study and 7 subjects had completed 8 doses of the treatment with at least 8 weeks of follow-up. The 7 subjects consisted of 2 males and 5 females, with a median age of 40 years (range 18-56), a median weight of 62 kg (range 52-93), a median duration of ITP of 30 months (range 12-200) and a median baseline platelet count of 8×10 9/L (range 2-24). Of the 7 patients, 100.0% (7/7) achieved a platelet count ≥50×10 9/L within 8 weeks after the first dose, with a median time to response of 1 week (range 1-3). Furthermore, 4 out of 7 patients (57.1%) maintained a platelet count of ≥50×10 9/L until week 16, while 2 patients experienced a relapse at week 6 and 1 patient had a relapse at week 13. Platelet count (expressed as the median with the interquartile range) of the 7 patients from baseline to week 23 are shown in Figure 1. Of all 21 patients, 6 (6/21, 28.6%) had an infusion-related reaction (IRR) at the first dose but none at subsequent doses. The severity of IRR was grade 1 or 2 (according to CTCAE version 5.0). Conclusion: CM313, a novel anti-CD38 monoclonal antibody, has demonstrated tolerable safety and preliminary efficacy in refractory/relapsed ITP patients. Figure 1: Platelet count in 7 patients.

Switching from Eltrombopag to Hetrombopag in Patients with Primary Immune Thrombocytopenia (ITP): Post-Hoc Analysis of a Multicenter, Randomized Phase III Trial

Introduction: Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by a low platelet count resulting from platelet destruction and impaired platelet production. In the last decades, thrombopoietin receptor agonists (TPO-RAs) demonstrated a high rate of response in ITP and are licensed for use in persistent or chronic patients who have had an insufficient response to first line treatment with corticosteroids or Intravenous Immunoglobulin (IVIG). Some evidence suggests that switching to the alternate TPO-RA can be an appealing treatment option in patients with ITP for efficacy or safety issues; however, much of the evidence is retrospective and only a few prospective studies investigating alternate use of TPO-RAs. Hetrombopag is the first small molecule, nonpeptide oral TPO-RA developed in China and its efficacy has been demonstrated in a multicenter phase III trial (NCT03222843). Here we conducted a post hoc analysis of this phase III trial to assess the response in patients who switched from eltrombopag to hetrombopag. Methods：A multicenter phase III study included a randomized, double-blind, placebo-controlled, 10-week treatment period (hetrombopag or placebo), sequentially followed by an open-label 14-week treatment period, during which patients who received placebo switched to eltrombopag with an initial dosage of 25 mg once daily and can be adjusted to a maximum of 75 mg once daily. Patients who completed eltrombopag 14-week treatment could directly continue additional 24-week hetrombopag treatment initiated at 2.5, 3.75, 5, or 7.5 mg once daily at the discretion of the investigator. Patients were assessed for efficacy and safety at every scheduled visit. In this post-hoc analysis, we investigated the response switching from eltrombopag to hetrombopag in ITP patients. Results: All 63 (74.1%) patients who completed the initial 24-week treatment (10-week placebo and 14-week eltrombopag) entered a prespecified additional 24-week hetrombopag treatment period. At enrollment, the median age was 43 years (range 18-70) and 47 (74.6%) patients were female, the duration of ITP was three years or longer in 40(63.5%) patients. The median baseline platelet count before switching to hetrombopag was 69.0×109/L (range 6.0-278.0×109/L ) and one third patients had not achieved a sustained response (platelet count≥50×109/L) after eltrombopag treatment. The median dose of the prior eltrombopag at the time of switching was 50 mg daily. As of data cutoff on November 19, 2020, 58 (92%) patients completed the hetrombopag treatment period, the median exposure to hetrombopag was 169.0 days (range, 53.0-176.0); 28 (44.4%) patients received the maximum dose of 7.5 mg once daily and the final dose of the other 16 (25.4 %) patients was 5 mg once daily. Overall, 56/63 (88.9%) achieved a platelet response (platelet count≥50×109/L) after switching from eltrombopag to hetrombopag. Among 12 patients with prior platelet count lower than 30×109/L, eight patients (66.7%) achieved response. For nine patients with prior platelet count between 30×109/L and 50×109/L, eight patients (88.9%) achieved response (Table 1). The median platelet count was 70 ×109/L after 2 weeks of switching and ranged between 62.5 ×109/L and 110 ×109/L across every scheduled visit during 24-week treatment with hetrombopag, highlighting that consistent platelet response could be maintained after switching from eltrombopag to hetrombopag. (Figure 1). The median maximum continuous duration of response was 78 days (range 8-165) and the median total duration of response was 104 days (range, 8-165) after switching to hetrombopag. In addition, 5(7.9%) patients received protocol-defined rescue therapy and 3(4.8%) patients had bleeding symptoms (All were grade 1 according to WHO bleeding scale) during hetrombopag treatment. Conclusion：In this one of the largest evaluations of switching between different TPO-RAs. Hetrombopag was effective following prior eltrombopag treatment, with high response rates even in patients with inadequate response to the prior therapy. Our results confirm the reported efficacy of TPO-RA switch in ITP patients and the lack of cross-resistance between the two available TPO-RAs. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Avatrombopag Treatment Response in Patients with Immune Thrombocytopenia: A Real-World Evidence Study

Introduction: Thrombopoietin-receptor agonists (TPO-RAs) are used in the treatment of chronic immune thrombocytopenia (ITP), a disorder characterized by prolonged low platelet counts (PCs) that pose a risk of serious bleeding episodes. The TPO-RAs eltrombopag (ELT) and romiplostim (ROMI) have been available for over 10 years. ELT is an oral medication with food restrictions and carries a boxed warning for hepatoxicity; additionally, ELT requires hepatic monitoring and has a potential need for statin dosing adjustment. ROMI, an injectable, is typically administered in a health care practitioner's office on a weekly basis without food restrictions. Avatrombopag (AVA), an oral medication taken with food, is the most recently approved TPO-RA for the treatment of chronic ITP (2019 by FDA and 2021 by EMA). AVA does not require hepatic monitoring or potential statin dose adjustment. A high proportion of patients (~90%) responded to AVA in clinical trials, and treatment was well-tolerated; however, limited real-world effectiveness data have been reported to date. This study is the first to use administrative claims linked to lab data to evaluate treatment response following the initiation of AVA in patients with ITP in the US. Methods: This retrospective study used administrative claims data from the Komodo Healthcare Map (02/01/2017-02/28/2022) linked with platelet count (PC) laboratory data from Quest Diagnostics. Patients with >1 diagnosis of ITP (ICD-9-CM: 287.31; ICD-10-CM: D69.3) followed by ≥1 paid prescription for AVA (first such prescription was defined as the index date) and ≥1 PC during the twelve-month period following the index date (study observation period) were selected. The percentages of patients achieving clinically meaningful PC thresholds (≥30 x 109/L, ≥50 x 109/L, ≥75 x 109/L, and ≥100 x 109/L) were assessed at any time within 1 year of AVA initiation. Additionally, median and mean PCs were assessed at baseline (PC closest to and within 3 months before the index date), and within each 3-month period after AVA initiation, among the subgroups of patients with available PC data in each subsequent 3-month period. Results: A total of 46 patients met all eligibility criteria. On average, patients were 56.1 (±16.7) years of age, and 52.2% were female. Of the 46 patients, 32 (69.6%) had a baseline PC; among them, median baseline PC was 40.5 x 109/L. Across the full sample of 46 patients, 89.1%, 78.3%, 67.4%, and 50.0% of patients achieved thresholds of ≥30 x 109/L, ≥50 x 109/L, ≥75 x 109/L, and ≥100 x 109/L, respectively, during the 12-month period following AVA initiation (Table 1). Median PCs were 68.0 x 109/L during months 1-3 post initiation, 67.7 x 109/L between months 4-6, 80.5 x 109/L between months 7-9, and 58.0 x 109/L between months 10-12 (Table 2). Mean PCs were notably higher, reflecting the wide variability in the platelet counts data. Conclusions: The majority of patients with ITP in this real-world study achieved clinically meaningful platelet counts following AVA initiation. Throughout the 12-month study observation period, mean and median PC values obtained were above a clinically meaningful threshold of 50 x 109/L. While this study was limited by the availability of PC data, the results are consistent with those from the pivotal clinical trials of AVA. Additional real-world studies are warranted to confirm these findings. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comparative Effectiveness of Fedratinib and Pacritinib for the Treatment of Myelofibrosis in Patients with Low Platelet Counts: A Simulated Treatment Comparison Study

Introduction: Myelofibrosis (MF) is a Philadelphia chromosome-negative myeloproliferative neoplasm with an estimated prevalence of 4-6/100,000 persons in the USA. Patients with MF experience aberrant hematopoiesis, bone marrow fibrosis, splenomegaly, and cytopenias, including thrombocytopenia, as well as diminished survival ranging from months to years, depending on risk status. Symptoms progressively worsen, underscoring the need for effective treatments across heterogeneous risk statuses and patient dispositions. Among intermediate- to high-risk patients, Janus kinase 2 (JAK2) inhibitors are the primary treatment for MF. Fedratinib was approved by the US Food and Drug Administration (FDA) based on the results of the JAKARTA trials (NCT01437787; NCT01523171), and a new drug application for pacritinib has been submitted to the FDA for the treatment of MF in patients with severe thrombocytopenia. A head-to-head trial of fedratinib and pacritinib for the treatment of MF has not been conducted. Moreover, there is a paucity of evidence evaluating these agents in patients with MF and thrombocytopenia (platelets < 100 × 10 9/L). Therefore, indirect treatment comparisons (ITCs) are required to assess the comparative efficacy of fedratinib and pacritinib in this population.Methods: A systematic literature review (SLR) was conducted to identify all clinical evidence in patients with MF and thrombocytopenia. Based on the SLR results, the JAKARTA, JAKARTA-2, and PERSIST-2 (NCT01773187) trials were identified as the studies to form the basis of the ITC. A pooled analysis data set was developed based on individual patient-level data from the fedratinib 400-mg arms of the JAKARTA and JAKARTA-2 trials including patients with platelets < 100 × 10 9/L. Published summary data from the pacritinib 200-mg arm of the PERSIST-2 trial served as the comparator. Simulated treatment comparisons (STCs) were used to compare spleen volume reduction (SVR) ≥ 35% while adjusting for mutually reported baseline patient characteristics such as age, sex, Dynamic International Prognostic Scoring System, Eastern Cooperative Oncology Group (ECOG) performance status (PS), JAK2 V617F mutation status, prior ruxolitinib exposure, and laboratory tests. Final adjustment models were selected based on fit statistics and the literature review. Indirect relative risk (RR) was estimated with 95% confidence intervals (CIs) using unanchored naive ITC (unadjusted) and STC (adjusted) methodologies.The PERSIST-2 trial included patients with baseline platelets < 50 × 10 9/L, but did not report median baseline counts. Therefore, a sensitivity analysis was conducted to evaluate the impact of differential median baseline platelet counts. In the sensitivity analysis, an outcome model was generated in the full pooled JAKARTA trial population irrespective of platelet count, and platelet count was forced into the multivariable adjustment model. Outcomes were simulated at 3 median baseline platelet counts (25, 50, and 75 × 10 9/L) and compared using similar methodology to the main analysis.Results: The main analysis suggests that fedratinib is associated with a greater proportion of SVR ≥ 35% than pacritinib (Table, A). According to the naive ITC, fedratinib was numerically favored over pacritinib in terms of SVR ≥ 35% (RR, 1.67 [95% CI, 0.94-2.97]). After adjustment for ECOG PS, JAK2 V6127F mutation status, and prior ruxolitinib exposure, fedratinib was statistically favored relative to pacritinib for SVR ≥ 35% (RR, 1.76 [95% CI, 1.00-3.10]).Results of the platelet-count-adjusted sensitivity analysis showed that a significant difference was observed in favor of fedratinib with respect to SVR ≥ 35% (Table, B). The resulting indirect RRs were similar regardless of simulated median baseline platelet count, which suggest that differential baseline platelet count has a minimal impact on the ITC results.Conclusion: This analysis used a population-adjusted ITC to assess the comparative efficacy of pacritinib and fedratinib in patients with MF and thrombocytopenia. Following population adjustment, fedratinib was associated with a greater proportion of patients achieving SVR ≥ 35% than pacritinib. In lieu of a head-to-head clinical trial, further real-world evidence studies should be conducted to assess the effectiveness of these treatments in the clinical setting. [Display omitted] DisclosuresDaniele: BMS/Celgene: Consultancy; Purple Squirrel Economics: Current Employment. Abraham: Bristol Myers Squibb: Current Employment. Kee: Bristol Myers Squibb: Current Employment. Tremblay: Cytel: Consultancy; Purple Squirrel Economics: Current Employment. Rose: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. McBride: BMS: Current Employment.

Evidence of NF-ΚB Pathway Activation in Patients with Advanced, High Molecular Risk Myelofibrosis

Evidence of NF-ΚB Pathway Activation in Patients with Advanced, High Molecular Risk Myelofibrosis

All-Trans Retinoic Acid Plus Low-Dose Rituximab Vs Low-Dose Rituximab in Corticosteroid-Resistant or Relapsed ITP

IntroductionApproximately one-third of immune thrombocytopenia (ITP) patients fail to achieve a response with first-line treatments, and most patients who respond to first-line treatment relapse and require further second-line therapies. Rituximab (RTX) has been frequently used in ITP treatment, and proposed schedules include the standard dose (SD) and low dose (LD). Previous studies on LD-RTX in ITP revealed a comparable overall response (OR) and reduced incidences of short- and long-term complications (e.g., infections) compared with SD-RTX (Blood, 2012; Platelets, 2019). However, LD-RTX does not achieve a rapid and long-lasting response in the treatment of ITP. Our preliminary studies demonstrated the efficacy of all-trans retinoic acid (ATRA) in the ITP model due to its effects on inducing megakaryocyte maturation and its immunomodulatory effects (Stem Cells Dev, 2017; J Thromb Haemost, 2017; Br J Haematol, 2018; Haematologica, 2019). Since RTX and ATRA share disparate mechanisms in treating ITP, a combination of RTX and ATRA may work synergistically based on a “double-hit” mechanism targeting both platelet production and destruction, which may overcome the long TTR and improve the SR rate of LD-RTX. Therefore, our study aimed to determine the efficacy and safety of ATRA plus LD-RTX compared to LD-RTX monotherapy in patients with corticosteroid-resistant or relapsed ITP (NCT03304288).MethodsEligible corticosteroid-resistant or relapsed ITP patients with a platelet count < 30 × 10 9/L or bleeding symptoms at enrolment were randomly allocated in a 2:1 ratio to receive 100 mg of RTX weekly for 6 weeks plus ATRA orally at 20 mg/m 2 daily for 12 weeks or 100 mg of RTX weekly for 6 weeks. Stable doses of concomitant corticosteroids, danazol, and cyclosporin were permitted. Treatment was discontinued if platelet counts in two consecutive tests at least 2 weeks apart were more than 300 × 10 9/L and resumed when the platelet count fell to less than 150 × 10 9/L. Assessments were performed at baseline, weekly during the first 4 weeks, every 2 weeks until week 24, and every 4 weeks thereafter. The primary outcome was OR, defined as a platelet count ≥ 30 × 10 9/L, a doubling of the baseline platelet count and the absence of bleeding. Secondary endpoints included sustained response (SR), initial response, complete response, time to response, duration of response and adverse events. SR was defined as maintenance of a platelet count > 30 × 10 9/L, the absence of bleeding, and no requirement for other ITP-specific treatment for 6 consecutive months.ResultsOne hundred sixty-eight patients from 7 tertiary medical centres in China were included between 2017 and 2020, 112 patients received combination treatment of LD-RTX and ATRA, and 56 patients received LD-RTX monotherapy. All the baseline characteristics were comparable between the two groups. The median ages of patients in the LD-RTX plus ATRA group and LD-RTX monotherapy group were 46.0 years and 44.5 years, respectively. For patients in the combination and monotherapy groups, the median number of previous therapies was 2.0. The median baseline platelet count was 17.0 × 10 9/L in the combination group and 19.0 × 10 9/L in the monotherapy group. All the patients were followed up for more than 11 months. OR was observed in 90 (80.4%) patients in the combination group and 33 (58.9%) in the LD-RTX monotherapy group (between-group difference, 0.22; 95% CI, 0.07 to 0.36), indicating that the combination treatment increased the response rate. SR was achieved by 68 (60.7%) patients in the combination group and 23 (41.1%) patients in the monotherapy group at the 6-month follow-up (between-group difference, 0.20; 95% CI, 0.04 to 0.35). Additionally, 56 (50%) subjects in the combination group and 19 (34%) in the monotherapy group were still in sustained remission at 12 months (between-group difference: 0.16; 95% CI, -0.01 to 0.33). No significant difference was found between the 2 treatment groups in terms of the time to a response. The severity of AEs was primarily of grade 1-2. The 2 most common AEs for the combination group were dry skin and headache or dizziness, with incidences of 40.2% (45/112) and 18.8% (21/112), respectively.ConclusionsIn conclusion, ATRA plus LD-RTX significantly increased the overall and sustained response, indicating a novel promising treatment option for corticosteroid-resistant or relapsed adult ITP patients. DisclosuresNo relevant conflicts of interest to declare.

TPO versus TPO: the good, the bad, and the to be determined.

TPO versus TPO: the good, the bad, and the to be determined.

Final results of a phase 2 clinical trial of LCL161, an oral SMAC mimetic for patients with myelofibrosis

AbstractOutcomes in patients with high-risk and treatment-resistant myelofibrosis (MF) post-JAK inhibitor therapy remain poor, with no approved drug therapies beyond the JAK inhibitor class. In certain clinical situations, such as severe thrombocytopenia, administration of most JAK inhibitors are contraindicated. Thus, there is an unmet medical need for the development of novel agents for patients with MF. SMAC mimetics [or inhibitor of apoptosis (IAP) antagonists] induce apoptosis in cancer cells. Because these agents are hypothesized to have increased activity in a tumor necrosis factor-α cytokine-rich microenvironment, as is the case with MF, we conducted a single-center, investigator-initiated phase 2 clinical trial, with a monovalent SMAC mimetic LCL161 (oral, starting dose, 1500 mg per week) in patients with intermediate to high-risk MF. In an older group, 66% with ≥2 prior therapies and a median baseline platelet count of 52 × 103/μL and 28% with ASXL1 mutations, we observed a 30% objective response by Revised International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) 2013 criteria. Notably, 6 responding patients achieved clinical improvement of anemia: 4, hemoglobin response; 2, transfusion independence. Median OS was 34 months (range, 2.2-60.1+). Reductions of cIAPs were observed in all responders. The most common toxicity was nausea/vomiting (N/V) in 64% (mostly grade 1/2); fatigue in 46%; and dizziness/vertigo in 30%. There were 4 grade 3/4 adverse events (2, syncope; 1, N/V; 1, skin eruption/pruritis). There were 2 deaths during the study period, both unrelated to the study drug. SMAC mimetics may represent an option for older patients with thrombocytopenia or for those in whom prior JAK inhibitors has failed. This trial was registered at www.clinicaltrials.gov as #NCT02098161.

A Single-Arm, Open-Label, Long-Term Efficacy and Safety Study of Subcutaneous (SC) Romiplostim in Children with Immune Thrombocytopenia (ITP)

A Single-Arm, Open-Label, Long-Term Efficacy and Safety Study of Subcutaneous (SC) Romiplostim in Children with Immune Thrombocytopenia (ITP)

Final Safety and Efficacy Data of Long-Term Open-Label Dosing of Subcutaneous (SC) Romiplostim in Children with Immune Thrombocytopenia (ITP)

Final Safety and Efficacy Data of Long-Term Open-Label Dosing of Subcutaneous (SC) Romiplostim in Children with Immune Thrombocytopenia (ITP)

A Molecular-Based Response Prediction Model to Romiplostim in Patients with Lower-Risk Myelodysplastic Syndrome and Severe Thrombocytopenia

A Molecular-Based Response Prediction Model to Romiplostim in Patients with Lower-Risk Myelodysplastic Syndrome and Severe Thrombocytopenia

Oral Rilzabrutinib, a Bruton Tyrosine Kinase Inhibitor, Showed Clinically Active and Durable Platelet Responses and Was Well-Tolerated in Patients with Heavily Pretreated Immune Thrombocytopenia

Oral Rilzabrutinib, a Bruton Tyrosine Kinase Inhibitor, Showed Clinically Active and Durable Platelet Responses and Was Well-Tolerated in Patients with Heavily Pretreated Immune Thrombocytopenia

Safety and efficacy of self-administered romiplostim in patients with immune thrombocytopenia: Results of an integrated database of five clinical trials.

Romiplostim self‐administration by patients or caregivers may offer time/cost savings to healthcare professionals (HCPs) and convenience for patients who avoid weekly clinic visits. We performed an integrated analysis of five clinical trials to evaluate the efficacy and safety of romiplostim self‐administration. Data were analyzed from adults with immune thrombocytopenia (ITP) who received weekly romiplostim via self‐administration or from an HCP. Patients who achieved a stable romiplostim dose for ≥3 weeks (HCP group ≥5 weeks to provide an appropriate index date to enable comparisons with the self‐administration group) with platelet counts ≥50 × 109/L were eligible. In the self‐administration (n = 621) vs HCP (n = 133) groups, respectively, median age was 53 vs 58 years, median time since primary ITP diagnosis was 3.7 vs 2.5 years, and median baseline platelet count at ITP diagnosis was 19.0 vs 20.0 × 109/L. In the self‐administration and HCP‐dosed groups, median romiplostim treatment duration was 89 vs 52 weeks and median total number of doses was 81 vs 50, respectively. In the self‐administration and HCP groups, respectively: 95.0% and 100.0% of patients achieved ≥1 platelet response (defined as weekly platelet count ≥50 × 109/L without rescue medication in previous 4 weeks); the median percentage of weeks with a response was 94.5% and 95.9%; and rescue medication was used in 36.7% and 39.8% of patients. Self‐administration did not adversely affect safety; duration‐adjusted rates for all treatment‐emergent adverse events (TEAEs) and bleeding TEAEs were numerically lower with self‐administration. Romiplostim self‐administration appears effective and well tolerated in eligible patients with ITP.

Transcriptomic analysis of patients with immune thrombocytopenia treated with eltrombopag

In the last years, the use of thrombopoietin receptor agonists (TPO-RA), eltrombopag and romiplostim, has improved the management of immune thrombocytopenia (ITP). Moreover, eltrombopag is also active in patients with aplastic anemia and myelodysplastic syndrome. However, their mechanisms of action and signaling pathways still remain controversial. In order to gain insight into the mechanisms underlying eltrombopag therapy, a gene expression profile (GEP) analysis in patients treated with this drug was carried out. Fourteen patients with chronic ITP were studied by means of microarrays before and during eltrombopag treatment. Median age was 78 years (range, 35–87 years); median baseline platelet count was 14 × 109/L (range, 2–68 × 109/L). Ten patients responded to the therapy, two cases relapsed after an initial response and the remaining two were refractory to the therapy. Eltrombopag induced relevant changes in the hematopoiesis, platelet activation and degranulation, as well as in megakaryocyte differentiation, with overexpression of some transcription factors and the genes PPBP, ITGB3, ITGA2B, F13A1, F13A1, MYL9 and ITGA2B. In addition, GP1BA, PF4, ITGA2B, MYL9, HIST1H4H and HIST1H2BH, genes regulated by RUNX1 were also significantly enriched after eltrombopag therapy. Furthermore, in non-responder patients, an overexpression of Bcl-X gene and genes involved in erythropoiesis, such as SLC4A1 and SLC25A39, was also observed. To conclude, overexpression in genes involved in megakaryopoiesis, platelet adhesion, degranulation and aggregation was observed in patients treated with eltrombopag. Moreover, an important role regarding heme metabolism was also present in non-responder patients.

Molecular Analysis in the Pacritinib Dose-Finding PAC203 Study in Patients with Myelofibrosis Refractory or Intolerant to Ruxolitinib

PAC203 is a global multicenter dose-finding study of pacritinib (PAC), an oral JAK2/IRAK1 inhibitor in patients with primary or secondary myelofibrosis refractory or intolerant to ruxolitinib, including patients with severe thrombocytopenia. Patients were randomized 1:1:1 (PAC 100mg QD, 100mg BID or 200mg BID) and stratified by baseline platelet count. The mutational landscape of this patient group is not well characterised, and the impact of mutation status on disease response and hematologic parameters is unknown. We carried out baseline mutational analysis on 105 (of total 164 recruited; 161 treated) patients using an ISO accredited Illumina TruSeq Custom Amplicon Panel, including 32 gene mutation hotspots and exons (~36,000 bp, 287 amplicons). CALR mutation screening was carried out independently. Accepted coverage was achievement of a depth of ≥100 reads per base in ≥95% of targeted bases. Median follow-up time for this cohort was 163 (28-476) days. 57% of patients had a diagnosis of primary myelofibrosis (PMF), whereas 27% and 15% had post-polycythemia vera MF (PPV-MF) and post-essential thrombocythemia MF (PET-MF), respectively. The median baseline platelet count was 64.5 x109/L, with &lt;50 x109/L in 38.3% of patients and baseline Hb &lt;10g/dL in 67.8% of patients. The median age was 67.5 (37-87) years. The majority of patients were JAK2 V617F-mutated (77%), followed by MPL-mutated (8.6%), with a notably low incidence of CALR-mutated (8.6%; type 1 CALR n=6, type 2 CALR n=3) and "triple-negative" (4.8%) cases. Non-myeloproliferative neoplasm driver mutations (NDM) were present in 77.1% (n=81) with ≥3 NDMs in 18.1% of patients. Similar to previous reports, the most prevalent NDMs were TET2 and ASXL1 (n=27 and n=25 respectively). Splicing factor (SF) mutations were mutually exclusive and detected in 32.3% of patients: SF3B1 [13], U2AF1 [14], SRSF2 [6], ZRSR2 [1]. RAS pathway mutations (KRAS/NRAS) were found at a higher frequency than previously in MF cohorts; 16.2% (n=17). SF mutations were present in more PMF (45.6%) than PPV-MF (3.7%, n=1/27) or PET-MF patients (33.3%, n=5/15), P=.002. SF3B1-mutated patients had higher trial entry platelet counts (66.7% platelets ≥100x109/L, P=.014). Baseline red cell transfusion dependency was more often associated with U2AF1 mutations 24.1% (n=7/29) as compared with red cell transfusion independence, 4.5% (n=2/44), P=.047 and U2AF1-mutated patients had lower baseline hemoglobin &lt;10g/dL (n=11/12), P=.015. Overall, 41 (39%) of patients had a high molecular risk mutation (HMR; IDH1/2, SRSF2, ASXL1, SRSF2, U2AF1Q157), and 8 patients had TP53 mutations. In those with molecular analysis available, the highest rates of ≥35% SVR were observed in the 200mg BID arm: 11.1% (n=4/36) followed by 3.2% (n=1/32) in 100mg BID arm and 0% (n=0/30) in 100mg QD arm). Rates of TSS reduction ≥50% were similar across arms. There were no significant correlations between mutations and SVR or TSS response. More grade 3/4 anemia occurred in TET2-mutated patients (OR 5.7, 95% CI 1.6-20.4, P=.007). RAS pathway mutations were associated with grade 3/4 thrombocytopenia (OR 4.4, 95% CI 1.3-14.8, P=0.016). Treatment discontinuation was not influenced by mutation status. In summary, the PAC203 cohort is molecularly high risk, with a high incidence of HMR and low incidence of CALR mutations. We identified novel associations between mutation profiles and hematologic events in this population with advanced MF. Disclosures Taylor: Baxalta: Research Funding; CTI BioPharma: Employment, Equity Ownership. Gerds:Roche: Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy; CTI Biopharma: Consultancy, Research Funding; Imago Biosciences: Research Funding; Sierra Oncology: Research Funding; Celgene Corporation: Consultancy, Research Funding. Buckley:CTI BioPharma: Employment, Equity Ownership. Harrison:Incyte: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Promedior: Honoraria; Celgene: Honoraria, Speakers Bureau; AOP: Honoraria; Sierra Oncology: Honoraria; Janssen: Speakers Bureau; Gilead: Speakers Bureau; Roche: Honoraria; CTI: Speakers Bureau; Shire: Speakers Bureau. Oh:Novartis: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees. Mead:CTI: Honoraria, Research Funding; Bristol Myers-Squibb: Consultancy; Novartis: Consultancy, Honoraria, Other: Travel/accommodation expenses, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Pfizer: Consultancy.

Final Results of Phase 2 Clinical Trial of LCL161, a Novel Oral SMAC Mimetic/IAP Antagonist, for Patients with Intermediate to High Risk Myelofibrosis

Final Results of Phase 2 Clinical Trial of LCL161, a Novel Oral SMAC Mimetic/IAP Antagonist, for Patients with Intermediate to High Risk Myelofibrosis