Baseline Platelet Research Articles

A Phase 1 Study of Avapritinib in Combination with Decitabine in Patients with Systemic Mastocytosis with an Associated Hematologic Neoplasm

Background and Rationale: Systemic mastocytosis (SM) is a clonal hematologic neoplasm characterized by abnormal accumulation of mast cells which can lead to symptoms related to mast cell degranulation and/or, in the case of advanced systemic mastocytosis (AdvSM), organ dysfunction due to mast cell infiltration. AdvSM is a category of SM comprised of aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL), and SM with an associated hematologic neoplasm (SM-AHN). Among these, SM-AHN is the most common subtype, accounting for approximately 70% of AdvSM. A KIT D816V mutation found in up to 95% of SM cases is the primary oncogenic driver, making it a key therapeutic target. Avapritinib, a highly potent and selective inhibitor of D816V mutant KIT, has demonstrated high rates of rapid, deep, and durable responses in all AdvSM subtypes, including SM-AHN. However, a recent analysis of the EXPLORER study showed that avapritinib-treated patients were still at risk for progression of the AHN component, despite continued control of mast cell disease burden, indicating that combination therapy is likely to be required for optimal control of SM-AHN due to its inherent molecular complexity. Hypomethylating agents (HMA) form the backbone of therapy for advanced myelodysplastic syndrome (MDS) and myelodysplastic/myeloproliferative neoplasm (MDS/MPN), hematologic neoplasms most likely to co-occur with SM in patients (pts) with SM-AHN. To date, the combination of HMA and KIT inhibitors has not been clinically evaluated. In this study, we aim to assess the safety and tolerability of the combination of avapritinib and decitabine in patients with SM-AHN. Study design: The primary objective of the study is to establish the recommended dose (RP2D) of avapritinib in combination with decitabine based on dose-limiting toxicity, overall safety, and clinical activity data. A dose evaluation steering committee (DESC) comprised of participating investigators will review the totality of safety and efficacy data to determine RP2D. Secondary endpoints include SM overall response rate by the end of 6 cycles by the m-IWG consensus criteria and proposed ECNM-AIM criteria ( Gotlib et al., J Allergy Clin Immunol Pract, 2022), as well as incidence and frequency of adverse events. Exploratory endpoints will consist of patient reported outcomes, progression free survival, overall survival, and correlative biomarkers linked to mast cell disease or AHN. Adult pts with a diagnosis of SM-AHN by the WHO 2022 classification criteria will be eligible for inclusion. Eligible pts must have any of the following myeloid AHN per WHO 2022 criteria: MDS, chronic myelomonocytic leukemia, MDS/MPN with neutrophilia, MDS/MPN with SF3B1 mutation and thrombocytosis, or MDS/MPN- not otherwise specified. Patients with MDS must have intermediate, high- or very-high risk by IPSS-R. Patients with very-low or low-risk MDS by IPSS-R must be intolerant/refractory to ESA or have serum EPO > 200 U/L. A baseline platelet count of ≥ 75 x 10 9/L and ≥ 25 x 10 9/L will be required for inclusion in the dose-finding and the dose-expansion phases, respectively (Figure). Key exclusion criteria include a diagnosis of acute myeloid leukemia, history of intracranial hemorrhage or risk of major hemorrhage, prior treatment with avapritinib or decitabine with documented progression in SM or AHN component, respectively, or history of treatment with alternative KIT inhibitor or azacitidine within 4 weeks of study treatment initiation. In the dose finding part of the study, a Bayesian adaptive design will be employed to assess different doses of avapritinib (50 to 200 mg PO daily) in combination with fixed doses of decitabine (oral decitabine/cedazuridine: 35/100 mg/day or intravenous decitabine: 20 mg/m 2/day on days 1-5) in a 28-day treatment cycle. Close attention will be paid to treatment-emergent thrombocytopenia with protocol-driven treatment holds and dose modification strategies employed when platelet count drops below 50 x 10 9/L. After RP2D is determined, an additional 10 patients will be enrolled in the dose expansion phase. Patients with platelet count ≥ 25 x 10 9/L and < 75 x 10 9/L, will receive lead-in dosing with decitabine or decitabine/cedazuridine with the ability to add avapritinib if sufficient platelet thresholds are achieved. This study will open at 7 sites in the United States and is anticipated to open in January 2024.

Post-Transfusion Purpura: A Literature Review

Introduction: Post-transfusion purpura (PTP) is a rare and occasionally life-threatening transfusion reaction characterized by severe thrombocytopenia usually within two weeks of blood transfusion. It is associated with the development of alloantibodies to human platelet antigens (HPAs). Due to its rarity, our knowledge of PTP is mostly based on reported cases or small cohorts. Methods: This is a systematic literature review of English language articles published in 2 large medical databases (Embase and Pubmed) using the search terms “post-transfusion purpura”, “posttransfusion purpura”, and “post transfusion purpura” between the years 1985 and 2023. Only articles reporting on patients older than 18 years were included. 684 articles were identified, 590 of them were excluded since they represented a combination of case reports of other conditions, laboratory, and epidemiological reports. The 94 articles left, represented case reports and case series of PTP encompassing 149 patients. 21 patients were removed since they represented duplicate cases. 17 patients were excluded due to missing information. 11 patients were excluded due to the presence of confounding clinical conditions. Results: A total of 100 cases were included in the study. The mean age was 56.7 years. 85% were female, 14% were male, and 1 was missing gender data. 62% of cases reported a baseline platelet count, ranging between 78,000 - 600,000 cells/µL. 65% of cases presented after a procedure- or surgery-related transfusion, of these 22 were related to cardiovascular procedures, while 16, 10, and 9 cases were related to gynecological, abdominal, and orthopedic surgeries respectively. A history of prior transfusions was only documented in 24% of cases. A prior pregnancy was reported in 63% of the cases. Red blood cell, fresh frozen plasma, and platelet transfusions were associated to 64%, 11%, and 9% of cases, respectively. The most common HPA antibody detected was HPA-1a (81%). HPA-1b, HPA-5b, and HPA-3a were the next most common antibodies, identified in 7%, 5%, and 5% cases, respectively. The median time from the first transfusion to the development of thrombocytopenia was 8 days, reaching a platelet nadir in 9 days. The platelet nadir ranged between 0 - 50,000 cells/ µL. Clinical presentation included post-transfusion fever (15%), petechial rash, epistaxis, and oral bleeding (65%, 17%, and 12, respectively), and bleeding from the genitourinary system, gastrointestinal tract, surgical incisions, lower respiratory tract, and central nervous system (38%, 28%, 6%, 6%, and 2% of cases, respectively). Death was reported in 9% of cases. The median time from PTP diagnosis to initiation of first treatment was 1 day. 83% of cases achieved an adequate response, defined as a platelet count > 100,000 cells/µL, after a mean/median time of 14.2/11.5 days (available in 68% of cases). Corticosteroids, intravenous immunoglobulin, and plasmapheresis were administered in 68%, 63%, and 27%, of cases, respectively. 6 patients received HPA 1a negative platelet transfusions. Conclusions: The majority of reported PTP cases were females with a history of pregnancy or blood transfusions consistent with existing literature. Over 60% of cases were linked to a surgical procedure, with cardiovascular cases constituting the largest portion. Anti-HPA-1a represented the most commonly detected antibody, followed by HPA-1b, HPA-5b, and HPA-3a. The most common sites of bleeding were the gastrointestinal and genitourinary tracts. 9% died from PTP. The majority of patients (83%) achieved an adequate response, with the most common treatment modalities being corticosteroids, IV immunoglobulins, and plasmapheresis.

Prednisone Plus Ivig Compared with Prednisone for Immune Thrombocytopenia during Pregnancy

Introduction Immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by an isolated low platelet count and is the most common cause of thrombocytopenia during pregnancy, accounting for 1%-4% of thrombocytopenia in pregnant women. Women with ITP who have severe thrombocytopenia are at an increased risk for life-threatening obstetric complications. However, management of ITP during pregnancy can be challenging because treatment choices are limited. Corticosteroids or intravenous immunoglobulin (IVIg) are recommended as first-line treatments for pregnant women with ITP, but the response to initial treatment is approximately 39% and 38%, respectively, lower than that in nonpregnant patients with ITP. Therefore, in-depth studies investigating new solutions for the first-line treatment of ITP during pregnancy are urgently needed. Our previous retrospective study revealed an advantage of prednisone combined with IVIg compared to prednisone monotherapy for pregnant patients with ITP. Therefore, the aim of this prospective, randomized, open-label study was to further assess the efficacy and safety of prednisone plus IVIg compared to prednisone monotherapy in pregnant women with ITP. The study has been registered at clinicaltrials.gov. NCT05333744 Methods Eligible treatment-naive ITP patients during pregnancy with a platelet count < 30 × 10^9/L, accompanied by or without bleeding symptoms, were randomly assigned 1:1 to receive prednisone 20 mg per day for 4 weeks plus IVIg 400 mg/kg (total dose ≤20 g per day) for 5 days or prednisone 20 mg monotherapy per day for 4 weeks. Prednisone was gradually tapered to the maintenance dose of 5-10 mg per day until 6 weeks after delivery if there was a response to treatment; otherwise, prednisone was gradually tapered to withdrawal. The primary outcome was overall response (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 complete response (CR), time to response, platelet counts at delivery, platelet counts of newborns, and adverse events in parturients. CR was defined as platelet count ≥100×10^9/L measured on 2 occasions at least 7 days apart and the absence of bleeding. Results A total of 100 treatment-naive ITP patients during pregnancy were randomly assigned to either the prednisone plus IVIg (n=50) or prednisone monotherapy (n=50) groups. All the baseline characteristics were comparable between the two groups. The median ages of patients in the prednisone plus IVIg group and prednisone monotherapy group were 30.32 years (range, 22-43) and 30 years (range, 28-46), respectively. For patients in the combination and monotherapy groups, the mean estational ages at intervention start were 28.3 weeks and 30.9 weeks, respectively. All patients were followed up for more than 2 months. OR was observed in 23 (46.0%) patients in the combination group and 22 (44%) in the monotherapy group, and no significant difference was observed between the two groups (p=0.91). A significant difference was observed in the time to response between the prednisone plus IVIg group and prednisone monotherapy group (6.14 days vs. 9.84 days, p=0.001). However, the predelivery platelet transfusion of the prednisone plus IVIg group was greater than that of the prednisone monotherapy group. There were no significant differences in the delivery mode between the combined group and monotherapy group. No significant differences were found between the two groups in neonatal outcomes, particularly concerning the neonatal platelet counts. Conclusion Prednisone plus IVIg was an effective and safe treatment for ITP in pregnancy, and this therapy may be a new first-line treatment option for pregnant patients with ITP.

Anti-GPIb/IX Autoantibodies Are Associated with Poor Response to Dexamethasone Combined with Rituximab Therapy in Primary Immune Thrombocytopenia Patients

This retrospective study aimed to evaluate whether anti-glycoproteins (GPs) autoantibodies can be used as predictors of response to high-dose dexamethasone combined with rituximab (DXM-RTX) in the treatment of primary immune thrombocytopenia (ITP) patients. According to the screening criteria (Figure. 1), 126 ITP patients, including 85 (67.5 %) women and 41 (32.5 %) men, were included in the analyses, with a median age was 32 (10 - 80) years, the median duration of disease was 18 (0.1-228.0) months, and the median platelet count at baseline was 6.0 (0-28.0) × 10 9/L. As shown in Table 1, 56.4% (71/126) of patients responded to DXM-RTX at four weeks, including 43 CR and 28 partial responses. The median time to response (TTR) of 71 responded patients was seven days (range: 4-28 days). The OR rate of ITP patients with anti-GPIb/IX positivity was 47.6% (40/84), while that of anti-GPIb/IX autoantibody-negativity was 73.8% (31/42) (χ 2 = 7.808, P = 0.005). In line with the OR rate, a significant difference was found in the CR rate between ITP patients with anti-GPIb/IX positivity and anti-GPIb/IX autoantibody-negativity (26.2% vs. 50.0%, χ 2 = 7.061, P = 0.008). At six months of DXM-RTX therapy, 54.0% (68/126) of patients responded to DXM-RTX, with 39 (31.0%) of CR. The CR and OR rates of anti-GPIb/IX autoantibody-positive patients were also significantly lower than those of negative patients (CR: 45.2% vs. 71.4%, χ 2 = 7.731, P = 0.005; OR: 25.0% vs. 42.9%, χ 2 = 4.178, P = 0.041). No significant difference ( P > 0.05) was found in OR and CR rates between anti-GPIIb/IIIa autoantibody positive and negative patients at four weeks and six months of DXM-RTX therapy. At four weeks of DXM-RTX therapy, a significant difference in OR rate was found among the patients with anti-GPIb/IX single-positivity (37.5%), double-positivity (51.7%), double-negativity (68.4%), and anti-GPIIb/IIIa single-positivity (78.3%) (χ 2 = 9.617, P = 0.022) (Table 2). The further comparison revealed a higher resistance to DXM-RTX in patients with anti-GPIb/IX single-positivity than patients with anti-GPIIb/IIIa single-positivity (OR: 37.5% vs. 78.3%; P < 0.05). A similar trend was also found in the six-month OR rate (29.2% vs. 78.3%, P < 0.05). An analysis of the CR rate at four weeks of therapy showed a significant difference among the four groups (χ 2 = 8.523, P = 0.036) but no significant difference after Bonferroni's correction ( P > 0.05). No significant difference ( P = 0.119) was found in the CR rate among the four groups at six months of combined therapy. In addition, the NR rate of patients with anti-GPIb/IX single-positivity also increased significantly in comparison with the patients with anti-GPIIb/IIIa single-positivity at four weeks (62.5% vs.21.7%, P < 0.05) and six months (70.8% vs.21.7%, P < 0.05) of combined therapy. Multivariate logistic regression analyses revealed that age, sex, duration of disease, liver function, and baseline platelet count were not associated with patient response to DXM-RTX at 4 weeks and 6 months (Table 3). Anti-GPIb/IX autoantibodies and megakaryocytes of DXM-RTX therapy at both 4 weeks and 6 months were associated with the OR rate of patients, with an odds ratio of 0.194 ( P = 0.003, 95% CI: 0.065-0.575) at 4 weeks and 0.189 ( P = 0.003, 95% CI: 0.064-0.563) at 6 months by comparing patients with anti-GPIb/IX autoantibodies to those without anti-GPIb/IX autoantibodies. The factorial design analyses revealed no interaction effect between autoantibodies and showed anti-GPIb/IX autoantibodies at 4 weeks represented the only significant factor affecting OR rate with DXM-RTX therapy (F = 9.128, P = 0.003, Table 4). Therefore, platelet anti-GPIb/IX autoantibodies can predict poor response to DXM-RTX in ITP patients.

Population Pharmacokinetics (PopPK) and Exposure-Response (E-R) Analyses for Belantamab Mafodotin Monotherapy in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Enrolled in DREAMM-2 and DREAMM-3

Background: Belantamab mafodotin (belamaf) is a B-cell maturation antigen (BCMA)-targeting antibody-drug conjugate (ADC) with a humanized afucosylated anti-BCMA monoclonal antibody (mAb) conjugated to a cytotoxic payload (microtubule-disrupting agent monomethyl auristatin F [MMAF]) by a protease-resistant maleimidocaproyl (mc) linker. This ADC binds to BCMA and induces cell death by direct cell killing and immune-mediated mechanisms. The DREAMM-2 trial (NCT03525678) showed rapid, deep, and durable responses to single-agent belamaf in patients with RRMM. The Phase 3 DREAMM-3 trial (NCT04162210) evaluated single-agent belamaf vs. pomalidomide plus low-dose dexamethasone in patients with RRMM at second relapse or later (Weisel et al., J Clin Oncol 41, 2023 [suppl 16; abstr 8007]); DREAMM-3 did not meet its primary endpoint on superiority for progression free survival (PFS). The present analysis evaluated the PopPK of the ADC and cytotoxin cysteine-mcMMAF (cys-mcMMAF) as well as the E-R relationships for key efficacy and safety endpoints to contribute to further understanding of belamaf. Methods: Patients with RRMM were administered intravenous (IV) doses of belamaf 2.5 or 3.4 mg/kg Q3W in DREAMM-2 (n=218) and 2.5 mg/kg Q3W in DREAMM-3 (n=217). Previously built PopPK models of ADC and cys-mcMMAF were updated and used to predict individual Cycle 1 exposure measures for the E-R analyses performed on the DREAMM-3 belamaf arm only. Exposure-efficacy analyses evaluated the probability of response (PoR), PFS, and time to response (TTR). Exposure-safety analyses evaluated the probability of occurrence of adverse events of special interest such as changes in best corrected visual acuity (BCVA), grade ≥2 or ≥3 corneal events, grade ≥3 thrombocytopenia and infusion-related reactions (IRR). Logistic regression models were used to assess event probabilities, while Cox proportional-hazard models were used to assess time to event endpoints. Stepwise covariate analyses were performed. Results: The PopPK data were described well by two-compartment models with linear elimination. The ADC model included time-varying clearance and the cys-mcMMAF model included decreasing MMAF:mAb ratio after each dose. ADC clearance was reduced on average by 30% over the first 5 months on treatment. The PopPK of ADC and cys-mcMMAF were both influenced by disease-related factors (baseline concentrations of soluble BCMA [sBCMA], immunoglobulin G, and albumin), as well as body weight and to a lower extent body mass index. Mild to severe renal impairment, mild hepatic impairment, age, race (Black or Asian), or prior therapies were not found to impact the PopPK of belamaf. Cycle 1 ADC average concentrations (C avg) were inversely correlated with disease burden factors and highly correlated (r=0.97) with ADC trough concentration (C tau). In DREAMM-3, PoR and PFS were higher and longer with higher ADC exposure when evaluated independently of other covariates. In the final model, PoR and PFS were respectively lower and shorter with higher baseline sBCMA or prior anti-CD38 mAb treatment; PoR was also related to presence of extra medullary disease. TTR was not related to ADC exposure or other factors. Safety endpoints were associated with exposure. Higher ADC C avg was associated with higher probability of developing grade ≥2 or ≥3 corneal events and inversely associated with time to their onset. ADC C avg was similarly associated with changes in BCVA but with a lower intercept for BCVA-related endpoints. Baseline sBCMA was inversely associated with probability of grade ≥2 corneal events. Lower baseline platelet count (but not ADC exposure) was associated with increased probability of grade ≥3 thrombocytopenia. ADC C avg was inversely associated with probability of IRR. In addition, the observed incidence of post-treatment anti-belamaf antibodies was low (<1%) with no observed impact on PK, efficacy, or safety. Conclusion: PopPK and E-R analyses for DREAMM-3 demonstrated the impact of disease factors and patient characteristics on PK, efficacy, and safety endpoints following single-agent belamaf, consistent with prior results for later-line populations.

Prolonged Cytopenia Following CAR T-Cell Therapy in Relapsed/Refractory Multiple Myeloma: A Prospective Comprehensive Biomarker Study

Background Chimeric antigen receptor (CAR) modified T-cells are leading to a paradigm shift in the treatment of relapsed/refractory (RR) multiple myeloma (MM). A high proportion of patients treated with CAR T-cells, however, experience prolonged cytopenia, with the mechanism remaining poorly understood. Here, we aimed to explore potential biomarkers that might correlate with cytopenia following CAR T-cell therapy in RRMM. Methods We prospectively collected peripheral blood (PB) of RRMM patients treated with idecabtagen-vicleucel (ide-cel) at the following time points: prior to lymphodepleting chemotherapy (LDC) (baseline), after ide-cel on day 4, 7, 14 and 28, and monthly thereafter. Cytopenia was determined according to the CTCAE version 5.0. Flow cytometry was performed with the following markers: CD45, CD3, CD4, CD8, CD62L, CD45RA, CD19, CD14, CD138, CD38 and a BCMA-CAR-detection marker. Results We included 222 PB samples at different sampling time points from 35 RRMM patients, who were pretreated with a median of 5 therapy lines (range 2-10). All patients were triple-class exposed and, 34 (97%) and 9 (26%) patients underwent autologous and allogeneic stem cell transplant (SCT), respectively. First, we analyzed the relationship between baseline parameters and the duration of grade ≥3 cytopenia after ide-cel (n=35). Notably, patients who received allogeneic SCT or >4 lines of therapy did not develop longer lasting cytopenia than the remaining patients. We found a correlation between the baseline hemoglobin level and the duration of grade ≥3 anemia (r=-0.55, P<0.001). Similarly, low baseline platelet count indicated long duration of grade ≥3 thrombocytopenia (r=-0.48, P=0.003). Moreover, high baseline ferritin level correlated with long duration of grade ≥3 anemia (r=0.52, P<0.001) and thrombocytopenia (r=0.51, P=0.002). Furthermore, the maximum ferritin level after ide-cel was an indicator for long lasting grade ≥3 anemia (r=0.73, P<0.001) and thrombocytopenia (r=0.71, P<0.001). Interestingly, we found significant correlations between the duration of grade ≥3 lymphopenia and baseline CD4+ T-cell frequency (r=0.41, P=0.02), CD8+ T-cell frequency (r=-0.38, P=0.04) and CD4+/CD8+ ratio (r=0.4, P=0.03). Noteworthy, patients with β2-microglobulin level >3.5 mg/l displayed longer duration of grade ≥3 anemia (median: 9 vs 0 day, P=0.007) and neutropenia (median: 43 vs 12 days, P=0.02) compared with the remaining patients, suggesting that high tumor load might be a risk factor for prolonged cytopenia after ide-cel. Second, we divided the follow-up PB samples (n=187) into two groups: early (<d60) and prolonged (≥d60) cytopenia to account for direct toxic effects related to LDC. A high ferritin level was associated with low hemoglobin level (<d60: r=-0.45, P<0.001, ≥d60: r=-0.62, P<0.001) and low platelet count (<d60: r=-0.58, P<0.001, ≥d60: r=-0.81, P<0.001) in both groups. In prolonged cytopenia (≥d60), lymphocyte count correlated with the T-cell count (r=0.7, P<0.001), suggesting that prolonged lymphopenia was mainly attributed to the reduced T-cell count after ide-cel. Of note, the frequency of naïve CD4+ T-cells (CD3+CD4+CD62L+CD45RA+) positively correlated with neutrophil count (r=0.58, P<0.001), hemoglobin level (r=0.37, P=0.03) and white blood cell count (r=0.5, P=0.002) in the ≥d60 group, suggesting that delayed immune reconstruction with reduced naïve CD4+ T-cells might contribute to prolonged cytopenia after ide-cel. Moreover, in the ≥d60 group, lymphocyte count was related with the frequency of CAR+CD4+ (r=-0.58, P<0.001), CAR+CD8+ (r=0.58, P<0.001), CAR-CD4+ (r=-0.72, P<0.001), CAR-CD8+ (r=0.75, P<0.001) T-cells, as well as the ratios of CAR+CD8+/CAR+CD4+ (r=-0.6, P<0.001) and CAR-CD8+/CAR-CD4+ (r=-0.75, P<0.001). Conclusion Here, we present one of the first prospective studies investigating the factors associated with prolonged cytopenia after CAR T-cell therapy in RRMM. High tumor load, preexisting cytopenia and high ferritin level are related with prolonged cytopenia after ide-cel. Delayed immune reconstruction, characterized by reduced naïve CD4+ T-cell count, indicates prolonged cytopenia following ide-cel therapy. Patients with high CD4+/CD8+ ratio are at risk of prolonged lymphopenia (with reduced T-cell count), which may be a risk factor for infectious complications and an issue for subsequent T-cell based immunotherapies.

The Combination of Iguratimod and Danazol Versus Danazol As a Treatment of Corticosteroid-Resistant/Relapse Immune Thrombocytopenia: A Randomized, Controlled, Multicenter, Open-Label Trial

Introduction: The treatment of choice in corticosteroid-resistant or relapsed immune thrombocytopenia (ITP) is still controversial due to the unclear mechanism and unpredictable efficacy of available therapies. The small molecule compound iguratimod is widely used as a novel antirheumatic drug to treat several autoimmune diseases. According to studies involving ITP mice, iguratimod may represent a new approach for the prevention and treatment of anti-platelet antibody-mediated ITP by modulating T-cell differentiation. Since iguratimod and danazol share disparate mechanisms in treating ITP, a combination of iguratimod and danazol may work synergistically based on a “double-hit” mechanism targeting both platelet production and destruction. The aim of this study was to evaluate the efficacy and safety of iguratimod and danazol versus danazol alone in patients with corticosteroid-resistant or relapsed primary immune thrombocytopenia. Methods: Across seven tertiary medical centers in China, adult ITP patients from this randomized, controlled, multicenter, open-label trial participated. Eligible corticosteroid-resistant or relapsed ITP patients with a platelet count <30×10 9/L or bleeding symptoms at enrollment were randomlyallocated by masked statisticians in a 1:1 ratio to receive oral iguratimod at 25 mg twice daily plus oral danazol at 200 mg twice daily or oral danazol monotherapy at 200 mg twice daily for 12 weeks. The group assignment was not masked for clinicians or patients. Following the first eight weeks of treatment, patients were assessed every two weeks thereafter. The primary endpoint was a 6-month sustained response (SR), defined as a platelet count of 30×10 9/L or more and at least a doubling of the baseline platelet count (partial response) or a platelet count of 100×10 9/L or more (complete response) and the absence of bleeding without rescue medication. This trial was registered with ClinicalTrials.gov (NCT05281068). Results: From September 1, 2021, to December 31, 2022, a total of 106 patients were screened for eligibility; 35 were excluded, and 71 were randomly assigned: 37 to the iguratimod plus danazol group and 34 to the danazol group. The median age of the patients was 41 years, and 69.0% (49/71) of them were females. All patients enrolled failed to respond to the first-line treatment with corticosteroids, and 21 (29.6%) of all patients had received three or more therapies. The data cutoff for the analyses was July 1, 2023. The median follow-up was 14 months (IQR 11-15) in the iguratimod plus danazol group and 12.5 months (11-15) in the danazol group. Six-month follow-up results showed that iguratimod plus danazol was more likely to produce SR than danazol alone (20 [54.1%] of 37 vs. 9 [26.5%] of 34; odds ratio 1.82, 95% CI 1.22-2.70, p = 0.003). The combination group had 25 (67.6%) patients with at least one response (overall response), and 13 (35.1%) patients had a complete response by the end of the follow-up; whereas 15 (44.1%) of 34 patients in the monotherapy group had an overall response, and three (8.8%) had a complete response. A target platelet count of 30×10 9/L was achieved in 18 (48.6%) of 37 patients given iguratimod plus danazol after 4 weeks and five (14.7%) of 34 patients given danazol monotherapy, indicating that the combination therapy significantly increased the initial response rate ( p = 0.002). Both groups experienced similar serious adverse events (AEs), rescue treatment, and treatment side effects, and all patients tolerated the treatment well, without any grade 4 AEs or treatment-related deaths reported. Conclusions: Patients with corticosteroid-resistant or relapsed ITP responds well to iguratimod plus danazol. This regimen achieved a rapid and long-lasting response. It is necessary to conduct further studies to determine the optimal dosage and a variety of combination therapies using several immune-suppressing agents, including iguratimod, to achieve a sustained response in patients with corticosteroid-resistant or relapsed ITP.

Predictors of Response to Rituximab in Chronic Immune Thrombocytopenia: Do Race, Gender and ABO Blood Type Matter?

Introduction: Immune thrombocytopenia (ITP)is characterized by immune mediated destruction of platelets causing isolated thrombocytopenia with a peripheral blood platelet count <100,000/microL in the absence of other causes that may be associated with thrombocytopenia. It remains a diagnosis of exclusion. Corticosteroids are the first-line treatment for ITP and more than 75% of adults with ITP will respond to them. However, approximately 70-80% of adult patients with ITP will experience treatment failure with corticosteroids or become dependent on them and require second-line therapy. Various options in the second line setting include thrombopoietin receptor agonists, rituximab, and splenectomy. In one study rituximab was noted to result in an overall platelet count response in 62.5% of adults. However not all patients remain in remission and clinical factors that are predictive of response are lacking. Racial disparities are known to predict response to rituximab in other hematologic disorders such as immune mediated thrombotic thrombocytopenic purpura (Mezapa et al, 2022). Herein, we are examining the effect of race, gender and ABO blood type on response to rituximab in patients diagnosed with ITP. Methods: This retrospective cohort study included adult patients, aged 18 and above, with a diagnosis of ITP who had received single agent rituximab within a multihospital academic healthcare system between January 2015 and December 2022. Initially 196 patients were identified but only 127 of those were included in the study. We excluded patients with missing response data, and those with combined rituximab and other therapies (stable or decreasing doses of steroids were allowed). Our primary end point was any response to rituximab by day 180 after starting rituximab. Any response was defined as complete response or partial response. Complete response was defined as platelet count ≥ 100,000 /microL and absence of bleeding. Partial response was defined as platelet count of at least 30,000/microL after week 4 from rituximab administration or doubling of platelet count from baseline without administration of any platelet increasing therapy. Our secondary end point was relapse rate which was defined as platelet count below 100,000/microL if complete response had been attained or below 30,000/microL or less than 2 fold increase of baseline platelet count. We also investigated clinical and socioeconomic predictors of response. Exploratory analysis was performed. Summary statistics are presented as percentages for categorical data and median with interquartile range for quantitative data. Chi square test was used to compare percentages and t-test was used to compare means. Univariate and multivariate regression models were used to analyze the predictors of any response to rituximab. Kaplan-Meier method was used to calculate estimates of relapse-free survival, and log-rank test was used to compare these estimates. Result: We identified 127 patients diagnosed with ITP who received rituximab. The median age was 64 years (IQR 48-74), there were 46.5% females. The majority of the patients were Caucasians (95.3%), and rituximab was most commonly received as a second line therapy (73.2%). Median initial platelet count was 28,000/microL. Complete response was observed in 50% of African American patients compared with 43.0% in Caucasian patients (p-value 0.63). No predictors for any response on univariate or multivariate analyses were found. Race (OR 0.30, 95CI 0.03-3.25, p-value 0.32) and female gender (OR 0.76, 95CI 0.33-1.76, p-value 0.51) did not affect response to rituximab in our patient cohort. Relapse rate was 60% in African American patients versus 67.5% in Caucasians (p-value 0.72), and 68.7% in males versus 64.9% in females (p-value 0.71). ABO blood type also did not predict a response to Rituximab in our patient population (Table 1) Conclusion: In our study, race and gender did not affect response or relapse rates after rituximab treatment in chronic ITP. Patient's ABO blood type also did not predict a difference in response to Rituximab. However, our study was limited by a small sample size and further multi-institutional analysis is warranted to confirm the findings of our study.

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.

Use of Fibrinogen and D-Dimer to Predict Platelet Recovery in Heparin-Induced Thrombocytopenia

Introduction Heparin-induced thrombocytopenia (HIT) occurs in approximately 0.5-1.0% of patients treated with unfractionated heparin, though true incidence is hard to quantify due to difficulties in recognition and diagnosis. The mainstay of treatment is the initiation of non-heparin anticoagulants until platelet recovery and for one to three months thereafter. There is no available model to predict platelet recovery. A predictive model may help identify (1) patients who are improving even if not reflected in platelet count, particularly in refractory cases; and (2) those who may require adjunctive therapies for treatment. It has been previously proposed that in a distinct subset of HIT, termed “autoimmune HIT,” the fibrinogen and d-dimer may be helpful markers to assess treatment response. Anecdotally, in complex HIT cases at our institution, we have observed improvements in fibrinogen and d-dimer preceding the resolution of thrombocytopenia. In this study, our aim was to establish a correlation between the fibrinogen, d-dimer, and the platelet count. Fibrinogen and d-dimer assay accessibility make them alluring for widespread use, if informative. We hypothesized that the fibrinogen and d-dimer trends would correlate with improvements in platelets. Methods This study design was reviewed and approved by the Vanderbilt University Medical Center (VUMC) Institutional Review Board. All inpatients admitted to VUMC between August 2022 and March 2023 with a positive HIT immunoassay (ELISA) were identified. Venous blood aliquots in sodium citrate used for anticoagulation management were collected daily. Patients with confirmed HIT based on a positive serotonin release assay were included in the analysis. Samples were collected until resolution of HIT, discharge, and/or death. Fibrinogen and d-dimer were measured on stored samples and compared to the daily platelet counts for each patient. Statistical Analysis To determine how baseline platelet count, time, fibrinogen and d-dimer relate to longitudinal measurements of platelet counts (assessed between 1- and 22-days post-baseline) we used a generalized least squares model with an AR1 within-patient correlation pattern, determined using AIC and variograms assessing fit with the data. Results In total, samples from 10 patients with HIT were collected. Baseline characteristics are presented in Table 1. Longitudinal regression analysis presented in the ANOVA plot in Figure 1 suggested that d-dimer ( X2 3.72, p=0.71) and fibrinogen ( X2 9.29, p=0.16) had no statistically significant correlation with platelet recovery, and the only strong variable was time ( X2 30.46, p=0.0002), indicating non-flat trajectories. Baseline platelet count showed signal for positive effect ( X2 3.34, p=0.07). Other effects were assessed, but not significant. Discussion The results of our exploratory laboratory correlation study suggest that fibrinogen and d-dimer values were not reliably correlated with platelet counts in patients with HIT, despite anecdotal experience suggesting benefit in monitoring fibrinogen and d-dimer in difficult HIT cases. The best correlation and strongest association with the improvement in platelet counts was time. Our study has several limitations. First is our small patient sample size. In addition, 4 patients (40%) died due to unrelated complications, therefore limiting the number of data points available for interpretation. Lastly, mean and median fibrinogen values are within the normal range in our data set; d-dimer mean and median are only mildly abnormal. Future prospective studies should be considered to further explore the relationship between fibrinogen and d-dimer with platelet trajectory when markedly abnormal at time of HIT diagnosis, as we have observed in severe HIT cases.

Effect of Hetrombopag Combined with Rhtpo in Patients with Severe Immune Thrombocytopenia

Background: Severe Immune Thrombocytopenia (ITP) is a life-threatening acquired hemorrhagic disease with dramatically decreased platelet number and clinical bleeding symptoms. Some patients with severe ITP did not respond to first-line treatment including steroids and Intravenous Immunoglobulin (IVIG). It was critical for them to use effective treatments to promote platelet and reduce the risk of fatal bleeding. Clinical practice guidelines have recommended the use of thrombopoietin receptor agonist (TPO-RA) as a second-line treatment for ITP. Recombinant human thrombopoietin (rhTPO) and hetrombopag are two distinct TPO-RAs with different mechanisms. As reported, there remains no study assessing the efficacy and safety of hetrombopag combined with rhTPO in the treatment of ITP. Therefore, the present study aimed to investigate the efficacy of hetrombopag plus rhTPO in Chinese patients with severe ITP, focusing on the short rather than the long-term efficacy, such as quickly increasing platelet count and significantly reducing bleeding, which would be more meaningful for severe patients whose platelet count <10 × 10 9/L. Methods: This was a prospective, open-label, single-center study with a planned enrollment of 30 patients. The inclusion criteria were patients ≥ 18 years, diagnosed with primary immune thrombocytopenia, platelet count <10 × 10 9/L, or bleeding score ≥ 5. Patients receiving other ITP drugs as maintenance therapy were eligible if previous glucocorticoid therapy doses were stable, and rituximab was used for at least 2 months and other immunosuppressants were stable for at least 4 weeks. Patients who had received IVIG, avatrombopag, eltrombopag, or romiplostim within 2 weeks prior to enrollment were excluded. Histories of platelet transfusion one week before treatment were excluded. Hetrombopag was given at 5 mg/day for 28 days, while rhTPO was administered at 300 U/kg subcutaneously daily for 14 days. When PLT > 100 × 10 9/L, rhTPO should be discontinued. When PLT > 150 × 10 9/L, the dosage of hetrombopag was reduced to 2.5mg/day, and it would be discontinued if PLT > 250 × 10 9/L. The primary endpoints were proportion of subjects with platelet count ≥30×10 9/L and at least doubled the baseline platelet count within 28 days. Secondary endpoints included bleeding score, incidence of thrombotic events, and adverse events (AEs). Results: As to July 27, 2023, a total of 20 patients were included in this study, with a median age of 36 years and a male proportion of 50%. Among them, 70% (14 cases) were newly diagnosed ITP patients. 50% of patients have received ≥ 1 line of previous treatment, of which 2 patients have received IVIG treatment and both have achieved CR (PLT ≥ 100 × 10 9/L). The baseline median platelet count was 5 × 10 9/L, and 95% (19 cases) of patients had active bleeding with a bleeding score of ≥ 1 point. The median duration for hetrombopag at dose of 5mg is 8.0 days, and rhTPO is 6.5 days. After combined treatment, the median time for platelet counts reached 30, 50, and 100 × 10 9/L was 4.5 days, 6 days, and 7 days, respectively. Among them, the median platelet count reached 103 × 10 9/L after 7 days treatment and 214.5 × 10 9/L after 15 days. Within 15 days of combined treatment, 15% (3 cases) of patients achieved partial platelet reaction (PLT > 50 × 10 9/L, without bleeding), and 85% (17 cases) achieved complete platelet reaction (PLT > 100 × 10 9/L, without bleeding). In terms of safety, two patients experienced liver function abnormalities, both of which were grade 1-2. One was related to treatment drugs, and the other was associated with underlying autoimmune liver disease. No thrombotic events occurred in all patients. Conclusion: This study innovatively explores the efficacy and safety of combination therapy with hetrombopag and rhTPO in the treatment of severe ITP. It is preliminarily confirmed that this combination therapy can effectively and quickly improve the early platelet response of ITP patients, avoid bleeding damage, and is expected to become a new treatment choice for severe ITP patients. We also look forward to the overall efficacy evaluation results of all patients after completing treatment in the future.

Effectiveness and Safety of Hetrombopag in the Management of Radiotherapy-Induced Thrombocytopenia in Patients with Gynecological Malignancies

Background: Radiotherapy is a cornerstone of treatment strategies for gynecological malignancies, However, while effective against neoplastic cells, pelvic radiotherapy frequently incurs collateral damage to normal tissues, especially to the bone marrow. This unintended consequence often precipitates thrombocytopenia, a condition characterized by diminished platelet levels, thereby elevating the risk of bleeding and posing hurdles for the continuity of anticancer regimens. Addressing this clinical challenge, hetrombopag, an innovative, orally administered non-peptide thrombopoietin receptor agonist, presents promise. It works by kindling megakaryocyte proliferation and differentiation, thereby enhancing platelet production via the activation of thrombopoietin receptor dependent STAT and MAPK signaling pathways. Previous studies have documented its efficacy in expediting platelet recovery in patients with chemotherapy-induced thrombocytopenia, thereby curtailing the duration of the condition and ensuring the execution of planned chemotherapy cycles. This study aims to investigate the therapeutic effectiveness and safety profile of hetrombopag in the treatment of radiotherapy-induced thrombocytopenia within a real-world context. Methods: This retrospective study encompassed gynecological cancer patients who developed thrombocytopenia (platelet counts<100×10 9/L) following radiotherapy and subsequently underwent treatment with hetrombopag from January 2022 to June 2023. The key inclusion criteria included an age of ≥18 years, the development of thrombocytopenia after radiotherapy or a combination of radiotherapy and other anticancer interventions, the administration of hetrombopag as monotherapy or as part of a combined regimen with other platelet-boosting agents, and the availability of follow-up data. The primary efficacy outcome was the proportion of patients exhibiting a platelet response (an elevation in platelet counts to ≥75×10 9/L) within 14 days. Results: Our cohort consisted of 28 gynecological cancer patients, encompassing 21 (75.0%) cases of cervical cancer, 3 (10.7%) of endometrial cancer, 1 (3.6%) of ovarian cancer, and 3 (10.7%) of other gynecological malignancies. The patients' median age was 58 years (range: 29-76 years), with 50% in clinical stage III/IV. Among them, 19 had received radiotherapy, 8 had undergone concurrent chemoradiotherapy, and 1 had received radiotherapy plus targeted therapy and immunotherapy. The baseline platelet count prior to hetrombopag treatment was 54.1±16.5×10 9/L. Hetrombopag was administered at a dose of 2.5mg/day as monotherapy in 32.1% of patients and combined with recombinant human thrombopoietin or recombinant human interleukin 11 in 67.9% of patients. The observed platelet response rate was 53.6% within 7 days and increased to 75.0% by the 14-day mark. The median time to platelet response was 7 days (95% confidence interval: 5-14). Following the introduction of hetrombopag as monotherapy or part of a combination regimen, we noted a steady uptick in patients' platelet counts. The mean platelet counts on days 3, 5, 7, 9, 11, and 14 were 62.3, 74.9, 78.7, 88.3, 87.9, and 147.9 ×10 9/L, respectively (Figure). Throughout the treatment period, no adverse events related to hetrombopag were reported. Conclusion: In conclusion, our findings provide preliminary evidence for the effectiveness and safety of hetrombopag, administered either as monotherapy or in combination, for managing radiotherapy-induced thrombocytopenia. Given the retrospective design of this study, further corroboration is needed through large-scale, prospective, randomized, and controlled clinical trials.

Real-World Evidence of Hetrombopag for Cancer Therapy-Induced Thrombocytopenia Among Patients with Gynecologic Malignancies

Background: Despite the widespread use of platinum-based combination chemotherapy, particularly when complemented with taxanes, for the treatment of gynecologic malignancies, its administration often results in myelosuppression. This effect can be potentiated across cumulative chemotherapy cycles, thereby inducing a more persistent condition known as cancer therapy-induced thrombocytopenia (CTIT). Traditionally, preferred treatments for CTIT entail platelet transfusion or the use of recombinant human thrombopoietin (rhTPO), or recombinant human interleukin-11 (rhIL-11). However, the efficacy of platelet transfusion tends to decrease with repetitive administration, and it carries inherent risks of infectious diseases. Additionally, rhIL-11 may induce severe hypersensitivity reactions, necessitating permanent discontinuation of the drug. Emerging as an appealing alternative, thrombopoietin-receptor agonists (TPO-RAs) present a promising approach for CTIT treatment. Among these, hetrombopag, an orally administered small-molecule TPO-RA, has demonstrated notable platelet-boosting effects and a favorable safety profile not only in patients with immune thrombocytopenia and severe aplastic anemia but also in those suffering from persistent CTIT. This study aims to appraise the real-world effectiveness and safety of hetrombopag, administered either alone or in conjunction with other platelet-boosting agents, for the management of CTIT in patients diagnosed with gynecologic malignancies. Methods: In this retrospective study conducted from January 2022 to June 2023, we examined the role of hetrombopag in treating CTIT among patients with gynecologic malignancies. The patients, aged 18 years and above, had experienced thrombocytopenia (platelet counts<100×10 9/L) following platinum-based chemotherapy or other antitumor treatments and subsequently received hetrombopag either as monotherapy or in combination with other platelet-boosting agents, such as rhTPO or rhIL-11. The primary outcome was platelet response within 14 days, denoted by a recovery in platelet counts to ≥100×10 9/L or an increase of ≥50×10 9/L or at least double from the baseline. Results: This study comprised 38 patients, with 55.3% diagnosed with ovarian cancer, 36.8% with cervical cancer, 5.3% with endometrial cancer, and 2.6% with other types. The median age was 58 years, with the majority (73.7%) at clinical stages III/IV. As for the antitumor regimens, 89.5% incorporated platinum, 68.4% included taxanes, 26.3% used antiangiogenic agents, and 15.8% employed PD-1 inhibitors. Among the patients, 15.8% received hetrombopag 2.5 mg/day monotherapy, while the remainder received hetrombopag in combination with rhTPO or rhIL-11. Baseline platelet counts prior to hetrombopag therapy averaged 46.5±24.9×10 9/L. Encouragingly, the 14-day platelet response rate was 71.1%, with a median time to response of 10 days (95% confidence interval, 5-14). Following treatment with hetrombopag, patients exhibited a gradual increase in platelet levels, recording mean platelet counts of 48.7, 67.1, 95.5, 108.5, 146.5, and 131.9×10 9/L on days 3, 5, 7, 9, 11, and 14 respectively. Importantly, hetrombopag was well-tolerated, with no treatment-related adverse events observed during the treatment course. Conclusion: In conclusion, our findings suggest hetrombopag, either alone or in combination with other therapies, displays preliminary effectiveness and safety in treating CTIT. Given its convenient oral administration and promising platelet-boosting effects observed in this study, prospective investigations of hetrombopag monotherapy for CTIT in gynecologic malignancies are warranted.

Interim Analysis of Platelet Response in a Prospective Phase 4 Study in Adult Immune Thrombocytopenia (ITP) Subjects after Switching from Eltrombopag (ELT) or Romiplostim (ROMI) to Avatrombopag (AVA)

Background: Three thrombopoietin receptor agonists (TPO-RAs) [eltrombopag, romiplostim, and avatrombopag] are currently approved in the United States (US) and Europe for the treatment of ITP in adult patients. ROMI is administered via injection whereas ELT and AVA are oral medications. Polyvalent cations significantly limit the bioavailability of ELT; therefore, patients must follow rigid dietary restrictions. AVA is taken with meals and does not have food-type or timing restrictions, aligning with reported patient preferences for ITP treatments. 1 A recent retrospective study of heavily pre-treated ITP patients at 4 large US tertiary care medical centers demonstrated that 91% of AVA patients who switched from ELT and 94% who switched from ROMI achieved a platelet response (platelet count (PC) ≥50 x 10 9/L) regardless of the reason for switch. 2 This study required a < 30-day gap between ELT or ROMI discontinuation and initiation of AVA. Platelet count response to AVA following an immediate switch from another TPO-RA has not been previously reported in a prospective study. The current study aims to evaluate the safety and efficacy of immediately switching to AVA from other TPO-RAs as well as capture patient-reported outcomes of treatment satisfaction and convenience. Methods: This is an interim analysis of a prospective, multi-center, open-label Phase 4 study conducted in the US (NCT04638829). Subjects who have been receiving ELT or ROMI ≥90 days prior to study entry are enrolled and immediately switched to AVA. The main inclusion criteria: age ≥18 years; subjects have been undergoing treatment for primary ITP with ELT or ROMI for at least 90 days prior to the screening visit and have a desire to switch therapy; subjects have had a previous response to either ELT or ROMI, defined as at least 2 platelet counts ≥50×10 9/L. The primary endpoint is occurrence of adverse events and serious adverse events. Clinic Visits were mandated per protocol at Baseline (BL), Days 15 (D15), 30 (D30), 60 (D60), and 90/End of Study (D90/EOS), and PCs were obtained at each timepoint. The interim analyses reported here evaluate the PC response to AVA following the switch from either ELT or ROMI. Results: As of April 1, 2023, 51 patients were screened and 47 enrolled. 35 completed the study, 3 dropped out, and 6 are on-going. The mean age at enrollment was 58 years, the median (min,max) time since ITP diagnosis was 2.88 years (0.2,31.0), 28/47 (60%) were female, 34/47 (72%) were Caucasian, and 5/47 (11%) had a previous history of splenectomy. 62% of patients were switched to AVA from ELT (median prior treatment duration 42 weeks (range 12 - 442 weeks); median daily dose 50 mg) and 38% from ROMI (median prior treatment duration 81 weeks (range 12 - 468 weeks); median weekly dose ≤3 µg). Baseline platelet counts revealed that patients were generally well-controlled on prior TPO-RA therapies when switched with a mean platelet count of 152×10 9/L and median platelet count of 130×10 9/L in the overall study population. Safety results will be reported when the study is complete. PC values for the Entire Population, as well as the ELT- and ROMI-switching subpopulations are summarized in Table 1. Median PC values over time are represented in Figure 1 for the Entire Population. For the Entire Population, after switching to AVA 20mg daily, there was an initial early increase in median PC from baseline noted on day 15, with median PC remaining well above 50 x10 9/L at each subsequent time point with less variability compared with day 15. ROMI-switched patients had a higher BL median PC than ELT-switchers (170 vs 76 x10 9/L).; median PC in patients switching from ELT rose from BL, whereas those switched from ROMI maintained a similar median PC throughout, with the minimum PC observed being similar to the minimum BL value (27 vs 24×10 9/L). Summary/Conclusion: In a population of patients who were generally responding to TPO-RAs prior to a switch to AVA, mean/median PCs were either improved or maintained with AVA treatment over 90 days. Importantly, patient satisfaction was also higher across each domain of the TSQM-9 with AVA treatment (convenience, global satisfaction, safety, and effectiveness) than with the prior TPO-RA (results reported in related abstract submission) suggesting that some patients may experience sustained effectiveness paired with enhanced overall treatment satisfaction when switching from ELT or ROMI.

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.

Factors Associated with Refractoriness or Relapse after Varnimcabtagene Autoleucel (IMN-003A) in Patients with Relapsed Refractory B Cell Malignancies: Phase 2 First-in-India Industry (IMAGINE) Study

Background: Varnimcabtagene autoleucel (IMN-003A) is an anti-CD19 CAR-T cell immunotherapy for patients with relapsed refractory B cell malignancies (RR BCM) in the Phase 2 IMAGINE study. Some patients (pts) do not respond or relapse early after CD19 directed CAR-T cell therapy. This abstract reviews the factors associated with disease relapse to help improve patient outcomes and development of novel strategies. Methods: Patients (pts) aged 3 to 45 years (B-ALL) and ≥ 18 years (B-NHL) with RR BCM were eligible for IMAGINE study if they had measurable disease, as assessed by lymphoid blasts (B-ALL) or metabolic tumour bulk (B-NHL), received ≥1 prior regimen, refractory to the last line of treatment with good performance status (ECOG 0 to 1). Multiple characteristics for disease progression were reviewed (n=36) and risk stratified as: 1) Baseline parameters (age, lines of treatment, bridging therapy, cytogenetics, blasts, total metabolic tumour volume (TMTV), sum of perpendicular diameter (SPD), refractory, relapse within 6 months, laboratory parameters - haemoglobin, neutrophil count, lymphocyte count, platelet count, CRP, LDH, ferritin, baseline interleukin-6 (IL-6), baseline total T cells, CD4, and CD8 subsets in peripheral blood); 2) Apheresis parameters (total T cells, naïve / central memory in CD4 and CD8 subsets); 3) Final Product characteristics [total CAR+ cells, naïve / central memory in CD4 and CD8 subsets, CD8 (naïve & central memory subsets / tumour burden (TMTV and SPD), product doubling time] and 4) Post Infusion factors (CAR peak & persistence, B cell aplasia, hypogammaglobulinema, infections and intravenous immunoglobulin (IVIg) replacement). These parameters were analyzed using chi-square and appropriate multivariant odds ratio (OR) to examine the association with disease relapse. Results: At data cut-off, of 25 pts enrolled (median age 31 yrs, range 3 - 66) with RR BCM (n=13 B-ALL; n=12 B-NHL), 24 pts received var-cel (1 withdrawal). Median follow-up after IMN-003A administration was 205 days (range 12 - 434). Overall response rate (ORR) was 91.7% (22/24) at D+28 (B-ALL 91.7%; B-NHL 91.7%) and 80.9% (17/21) at D+90 (B-ALL 80%; B-NHL 81.8%). Median progression free survival (PFS, range 12-NR), duration of response (DOR, range 0-NR) and overall survival (OS) were not reached (range 12-NR). Treatment related mortality was 4.2% (n=1/24); 3 pts died of disease progression. Nine pts had relapsed disease (B-ALL 4; B-NHL 5; overall 37.5%; CD19+ 7 pts; CD19- 2 pts; B-ALL: CD20 variable; CD22+ n=4/4; B-NHL PDL1 n=1/5) with median PFS of 178 days (range 28-319). For relapsed pts, median duration of B cell aplasia after primary infusion was 270 days (range 70-NR); var-cel was detected in 1 pt (n=1/4) at relapse and hypogammaglobulinema (IgG <4g/L) was seen in 4 pts. For the 36 multiple parameters studied, age, high risk cytogenetics / genomic aberrations, refractoriness / early relapse <6m, blasts burden in B-ALL, absolute lymphocyte count, inflammatory markers (LDH, ferritin) and baseline T cell subsets did not show association with disease relapse. Ten variables showing some association with disease progression on univariant analysis were: SPD, baseline haemoglobin, platelets, CRP, Apheresis CD8+ T N+CM, Final Product doubling time, CAR-T dosage (B-NHL), CD8 CAR+ T N+CM (weight & dose adjusted), Post Infusion Cmax and IVIg replacement. Multivariant analysis of these parameters showed some statistical significance for following variables: Baseline Platelet count <200 x 10 9/L (overall); Final Product doubling time ≥1 day (B-ALL); baseline SPD ≥2000 mm 2, Hb <12 g/dL, Platelet count <200 x 10 9/L and post infusion IVIg replacement (B-NHL), Table1 & Figure 1. Of these variables, statistically significant association was seen with Final Product doubling time ≥1 day (B-ALL) and baseline SPD ≥2000 mm 2 with Hb <12 g/dL and Platelet count <200 x 10 9/L (B-NHL). The impact of IVIg replacement on efficacy needs further study. Conclusions: In the IMAGINE study, with ORR 80.9% at primary endpoint and median PFS not reached, relapse was seen in 37.5% pts with median PFS of 178 days. Multivariant analysis has identified factors which may predict disease relapse. Further research is needed to identify strategies such as reinfusion or CAR-T targeting a different antigen to achieve cure.

The Bengaluru Score - a Prognostic Predictive Score for Clinical Efficacy Outcomes Based on Discovery Cohort of Patients Treated with Varnimcabtagene Autoleucel (IMN-003A) in the Phase-2 (IMAGINE) Study

Background: Recurrence of disease is seen in some patients post CD19 targeted CAR-T cell therapy. There is a need to develop CAR-specific efficacy risk-classification systems as established parameters of disease relapse are not predictive. In the Phase-2 IMAGINE study, multiple variables that may predict clinical outcomes were studied and the relevant clinical, laboratory and translational information were integrated. This abstract reviews the development of the Bengaluru Score as a predictive prognostic score for clinical efficacy outcomes based on discovery cohort of patients treated with varnimcabtagene autoleucel (IMN-003A). Methods: Multiple characteristics for disease progression were reviewed (n=36) and risk stratified as: 1) Baseline parameters (age, lines of treatment, bridging therapy, cytogenetics, blasts, total metabolic tumour volume (TMTV), sum of perpendicular diameter (SPD), refractory, relapse within 6m, laboratory parameters - haemoglobin, neutrophil count, lymphocyte count, platelet count, CRP, LDH, ferritin, baseline interleukin-6 (IL-6), baseline total T cells, CD4, and CD8 subsets in peripheral blood); 2) Apheresis (total T cells, naïve / central memory in CD4 and CD8 subsets); 3) Final Product characteristics [total CAR+ cells, naïve / central memory in CD4 and CD8 subsets, CD8 (naïve & central memory subsets / tumour burden (TMTV and SPD), product doubling time] and 4) Post Infusion (CAR peak & persistence, B cell aplasia, hypogammaglobulinemia, infections and intravenous immunoglobulin (IVIg) replacement). These parameters were analyzed using chi-square and appropriate multivariant odds ratio (OR) to examine the association with disease progression. Independent risk factors were identified and weighted score allocated for OR ≥10 to obtain a multifactorial prediction model - The Bengaluru Score. The specificity and sensitivity of this model was then studied in the discovery cohort. Results: In the IMAGINE study, with ORR 80.9% at primary endpoint (n=17/21) and median PFS not reached (range 12 to NR), relapse was seen in 37.5% (n=9/24) pts with median PFS of 178 days (range 28 to 319). Multivariant analysis of these parameters showed some statistical significance for following variables: Baseline Platelet count <200 x 10 9/L (overall); Final Product doubling time ≥1 day (B-ALL); Baseline SPD ≥2000 mm 2, Hb <12 g/dL, Platelet count <200 x 10 9/L and post infusion IVIg replacement (B-NHL), Of these variables, statistically significant association was seen with Final Product doubling time ≥1 day (B-ALL) and Baseline SPD ≥2000 mm 2 with Hb <12 g/dL and Platelet count <200 x 10 9/L (B-NHL). The impact of IVIg replacement on efficacy needs further study. A multiple factor-based prognostic score system - The Bengaluru Score was developed classifying patients into B-ALL low-risk (1 point) and high-risk (3 points) and for B-NHL low risk (<5 points) and high-risk (≥5 points), Table 1. The Bengaluru Score when applied to discovery cohort in the IMAGINE study was able to risk stratify patients for disease progression with Sensitivity, Specificity, Positive Predictive Value and Accuracy of 100.00%, 66.67%, 60.00% and 77.78% respectively (for B-ALL) and 100.00%, 100.00%, 100.00% and 100.00% respectively (for B-NHL), Table 2. Conclusions: The Bengaluru Score is probably the first predictive prognostic score for clinical efficacy outcomes and is based on multivariant statistical analysis in the discovery cohort of patients in the IMAGINE study integrating clinical, laboratory and translational data with a very high sensitivity, specificity and accuracy. The score highlights the role of overall T cell expansion in the final product for B-ALL (but not the T N+CM subsets on its own) and for B-NHL, disease burden and haematological reserve. This suggests that earlier use of varnimcabtagene autoleucel may positively influence efficacy outcome but needs to be proven in the real-world setting. The Bengaluru Score can guide informed treatment decisions and evolve clinical strategies, such as reinfusion, CAR-T targeting a different antigen or allogeneic transplant (if applicable), to reduce the risk of relapse / disease progression in high-risk patients. The Bengaluru Score needs validation in a larger cohort of patients following treatment with varnimcabtagene autoleucel and other CD19 targeted CAR-T cell therapies.

384. Factors Potentiating the Risk of Linezolid-induced Thrombocytopenia in Patients without Haemato-oncologic Diseases: A Case-control Study

Abstract Background Thrombocytopenia is a major adverse effect of linezolid due to myelosuppression. Many studies assessed factors associated with this effect, but most included patients with haemato-oncologic diseases, which may confound the assessment of thrombocytopenia. Therefore, this study aimed to investigate risk factors for linezolid-induced thrombocytopenia in patients without haemato-oncologic diseases. Methods This was a multicenter retrospective case-control study of adults treated with linezolid 600 mg twice daily for ≥ 3 days. Cases were the patients who developed thrombocytopenia while controls are those who didn't develop it. Exclusion criteria were haemato-oncologic diseases, active COVID-19, active dengue fever, baseline platelet count < 100 × 103/mm3, concurrent therapy with trimethoprim/sulfamethoxazole or valproic acid, platelet transfusion within 7 days before linezolid therapy, and insufficient platelets data. Various factors were assessed for potential association with linezolid-induced thrombocytopenia (defined as drop in platelet count below 100 × 103/mm3). Results 142 patients were included, 31 cases and 111 controls. Patients in both groups had a median age of 62 years and received linezolid for a median of 8 days. Platelet counts significantly dropped in the cases (Figure 1). Figure 2 shows the trend of change in platelet count (the white square indicates the median duration to thrombocytopenia, 8 days). In the univariate analysis, serum creatinine, creatinine clearance, baseline hemoglobin, baseline platelet count, and bacteremia were significantly associated with thrombocytopenia. However, after adjusting for confounders in the multivariate analysis, only low baseline hemoglobin and bacteremia were associated with thrombocytopenia (adjOR = 0.71; 95% CI 0.53-0.95; P = 0.022 and adjOR = 17.02; 95% CI 1.15-251-71; P = 0.039, respectively). Among the cases, those who had a baseline platelet count of < 200 × 103/mm3 developed thrombocytopenia faster as early as 3 days (log-rank P = 0.002; figure 3). Figure 1 Rate of change in platelet count between the cases (thrombocytopenia) and controls (no thrombocytopenia) Figure 2 Trend of platelet counts over 14 days in the cases (thrombocytopenia) and controls (no thrombocytopenia) Figure 3 Kaplan-Meier curve for the development of thrombocytopenia depending on baseline platelet count Conclusion Patients without haemato-oncologic diseases are at risk of linezolid-induced thrombocytopenia. especially those with bacteremia and low hemoglobin level. Patients with low baseline platelet count should be monitored closely early in therapy. Disclosures All Authors: No reported disclosures

Characteristics and outcomes of COVID-19 in Chinese immune thrombocytopenia patients: A prospective cohort study.

The coronavirus disease 2019 (COVID-19) pandemic has a significant impact on the immune system. This is the first and largest study on pre-existing immune thrombocytopenia (ITP) patients infected with COVID-19 in China. We prospectively collected ITP patients infected with COVID-19 enrolled in the National Longitudinal Cohort of Hematological Diseases (NICHE, NCT04645199) and followed up for at least 1 month after infection. One thousand and one hundred forty-eight pre-existing ITP patients were included. Two hundred and twelve (18.5%) patients showed a decrease in the platelet (PLT) count after infection. Forty-seven (4.1%) patients were diagnosed with pneumonia. Risk factors for a decrease in the PLT count included baseline PLT count <50 × 109/L (OR, 1.76; 95% CI, 1.25-2.46; p = 0.001), maintenance therapy including thrombopoietin receptor agonists (TPO-RAs) (OR, 2.27; 95% CI, 1.60-3.21; p < 0.001) and previous splenectomy (OR, 1.98; 95% CI, 1.09-3.61; p = 0.03). Risk factors for pneumonia included age ≥40 years (OR, 2.45; 95% CI, 1.12-5.33; p = 0.02), ≥2 comorbidities (OR, 3.47; 95% CI, 1.63-7.64; p = 0.001), maintenance therapy including TPO-RAs (OR, 2.14; 95% CI, 1.17-3.91; p = 0.01) and immunosuppressants (OR, 3.05; 95% CI, 1.17-7.91; p = 0.02). In this cohort study, we described the characteristics of pre-existing ITP patients infected with COVID-19 and identified several factors associated with poor outcomes.