Baseline Platelet Count Research Articles

Grip strength affects the association between platelet count and disability-free survival: Evidence from the China Health and Retirement Longitudinal Study

Background and aimsPrevious studies found elevated platelet count (PLT), especially long-term persist high or increased PLT was associated with less likelihood disability-free survival (DFS). However, whether grip strength affects the relationship between them is still not elucidated. MethodsA total of 6252 participants were recruited in the analysis based on the China Health and Retirement Longitudinal Study. The primary outcome was DFS, evaluated by a composite endpoint based on the first occurrence of either disability (having difficulty in at least one of the 6 activities of daily living: namely, dressing, bathing, continence, eating, getting into or out of bed, and toileting) or all-cause mortality. ResultsThe association of PLT with primary outcome was significantly modified by grip strength (pinteraction = 0.022). The rates of primary outcome were significantly lower among participants with lower baseline PLT in participants with normal grip strength (multivariable odds ratio [OR], 0.67; 95% confidence interval [CI], 0.54–0.84; ptrend < 0.001), but not in those with low grip strength (multivariable OR, 1.70; 95% CI, 0.88–3.15; ptrend = 0.135), for the lowest quartile vs the highest quartile. Adding baseline PLT (quartiles or continuous) to a model containing conventional risk factors significantly improved risk reclassification for primary outcome among those with normal grip strength (most of p < 0.05). ConclusionAn inverse dose-response association of PLT with DFS was found among participants with normal grip strength, but not among those with low grip strength. Low grip strength might weaken the benefit of low PLT on DFS among middle-aged and older Chinese.

Long-term endoscopic surveillance in HBV compensated cirrhotic patients treated with Tenofovir or Entecavir for 11 years.

Long-term administration of TDF/ETV in patients with HBV-related compensated cirrhosis reduces HCC and decompensation events but the effect of this regimen on development/regression of oesophageal varices (EV) is currently unknown. To assess the risk of EV development/progression in this population. A total of 186 Caucasian HBV-monoinfected compensated cirrhotics were enrolled in a long-term cohort study from TDF/ETV introduction. Upper GI endoscopies were performed according to Baveno recommendations. Primary endpoint was development/progression of oesophageal/gastric varices over time. At TDF/ETV start, median age was 61 years, 80% males, 60% HBV-DNA undetectable, 63% NUCs previously exposed, 73% normal ALT, 40% platelets <150,000/mmc and 25 (13%) with low-risk varices (LRV). During 11 years of antiviral therapy and 666 endoscopies performed, 9 patients either developed or had a progression of oesophageal or gastric varices with an 11-year cumulative probability of 5.1% (95% CI 3-10%); no patient bled. Out of 161 patients without EV at baseline, the 11-year probably was 4.5% with all varices developing within the first six years of treatment. In 25 patients with LRV at baseline, the 11-year probability of progression or regression was 9.3% and 58%, respectively. Only baseline platelet count (HR 0.96, p=0.028) was associated with LRV development at multivariate analysis: platelet ≤90,000/mmc (AUROC 0.70) had 98.1% specificity, 42.9% sensitivity, 50% PPV for LRV onset. In compensated cirrhotic patients under long-term effective TDF/ETV treatment, the 11-year risk of developing/progressing EV is negligible, thus challenging the current endoscopic surveillance recommendations in patients without EV at baseline.

The association between long-term platelet count and disability-free survival among middle-aged and older Chinese: Evidence from the China Health and Retirement Longitudinal Study

Background and aimsWe aimed to assess the associations of baseline and long-term platelet count (PLT) with disability-free survival (DFS) among middle-aged and older Chinese. Methods and resultsA total of 7296 participants were recruited in the analysis. Updated mean PLT was defined as the mean of the two PLT measurements (4 years between wave 1–3). The long-term status of PLT was defined as persistent low, attenuated, increased and persistent high PLT according to the optimal cut points from the receiver operating characteristic curves of the two PLT measurements, respectively. The primary outcome was DFS, evaluated by the first occurrence of either disability or mortality. During 6-year visit, 1579 participants experienced disability or all-cause mortality. The rates of primary outcome were significantly higher among participants with elevated baseline PLT and updated mean PLT. Multivariable adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of primary outcome were 1.253 (1.049–1.496) for highest baseline PLT tertile and 1.532 (1.124–2.088) for highest updated mean PLT tertile, comparing to the lowest tertiles. Multivariable-adjusted spline regression models showed a linear association of baseline PLT (plinearity < 0.001) and updated mean PLT (plinearity = 0.005) with primary outcome. Moreover, participants with persistent high PLT and increased PLT had increased risk of primary outcome (ORs [95% CIs]: 1.825 [1.282–2.597] and 1.767 [1.046–2.985], respectively), compared with the reference of those with persistent low PLT. ConclusionThis study proved elevated baseline PLT, especially long-term persist high or increased PLT was associated with less likelihood of DFS among middle-aged and older Chinese.

LInezolid Monitoring to MInimise Toxicity (LIMMIT1): A multicentre retrospective review of patients receiving linezolid therapy and the impact of therapeutic drug monitoring

BackgroundLinezolid is a broad-spectrum antimicrobial with limited use due to toxicity. This study aimed to evaluate linezolid toxicity in a large multicentre cohort. Secondary objectives were to identify factors contributing to toxicity, including the impact of therapeutic drug monitoring (TDM). MethodsPatients administered linezolid between January 2017 and December 2019 were retrospectively reviewed. Data were collected on patient characteristics, linezolid therapy and outcomes. Descriptive statistics were performed on all patients, and statistical comparisons were undertaken between those who did and did not experience linezolid toxicity. A multivariable logistic regression model was constructed to identify any covariates that correlated with toxicity. ResultsLinezolid was administered to 1050 patients; of these, 381 did not meet the inclusion criteria and 47 were excluded as therapy ceased for non-toxicity reasons. There were 105 of 622 (16.9%) patients assessed to have linezolid toxicity. Patients who experienced toxicity displayed a higher baseline creatinine (96.5 µmol/L vs. 79 µmol/L; P = 0.025), lower baseline platelet count (225 × 109/L vs. 278.5 × 109/L; P = 0.002) and received a longer course (median 21 vs. 14 days; P < 0.001) than those who did not. Linezolid TDM was performed in 144 patients (23%). Multivariable logistic regression demonstrated that TDM-guided appropriate dose adjustment significantly reduced the odds of linezolid toxicity (aOR = 0.45; 95% CI 0.21–0.96; P = 0.038) and a treatment duration > 28 days was no longer significantly associated with toxicity. ConclusionsThis study confirmed that linezolid treatment-limiting toxicity remains a problem and suggests that TDM-guided dose optimisation may reduce the risk of toxicity and facilitate prolonged courses beyond 28 days.

The prediction value of platelet-derived growth factor for major adverse cardiovascular events in patients with acute non-ST-segment elevation myocardial infarction

Background The value of plasma Platelet-Derived Growth Factor (PDGF) as a biomarker in predicting major adverse cardiovascular events (MACEs) in patients with acute non-ST-segment elevation myocardial infarction (NSTEMI) remains unclear. Methods A total of 242 patients with NSTEMI were enrolled in this observational cohort study. The correlation between PDGF and MACEs was evaluated during a five-year follow-up. Kaplan–Meier survival analysis with Cox proportional-hazards regression was used to identify predictive values of PDGF. Results The mean follow-up of NSTEMI patients was 1334 days. It was found that as the PDGF level increased, a significant uptrend in the incidence of MACEs and all-cause death, including the MACEs of 30 days, 180 days, 1 year, 5 years and the death of 1 year and 5 years (All Log-rank p < .05). Subgroup analysis further showed that PDGF had better predictive value for patients with age >65 years, GRACE score ≥140 and platelet count (PLT) >200 × 109/L. Conclusion PDGF levels can predict short-term and long-term MACEs in NSTEMI patients after discharge, especially for patients with older age, higher GRACE score and baseline PLT > 200 × 109/L. Key messages PDGF is a risk factor for short- and long-term MACEs in patients with STEMI. PDGF has a better prognostic value in patients with older age and PLT > 200 × 109/L. Baseline plasma PDGF levels were positively correlated with GRACE score.

EFFECTS OF ISOTRETINOIN ON PLATELET COUNT AND MEAN PLATELET VOLUME DURING TREATMENT OF ACNE VULGARIS

The most effective systemic therapy for acne is Isotretinoin. However, Isotretinoin has many side effects, including known side effects like dryness, palmoplantar exfoliation, rash, teratogenicity, raised intraocular pressure, and deranged liver functions and lipid profile. Its lesser-known side effects include its effects on platelet count and mean platelet volume (M.P.V.). This Quasi-experimental case series was conducted to observe the change in platelet count and mean platelet volume in patients taking Isotretinoin for acne vulgaris, attending the dermatology outpatient department at Jinnah Hospital Lahore from May 10th 2016 to November 9th 2016. After ethical committee approval and informed consent, subjects of acne vulgaris with an indication for Isotretinoin were included in the study from O.P.D. Relevant demographic and clinical details were recorded in a standardized predesigned proforma. Citrated blood samples were taken under aseptic conditions. Baseline platelet counts and mean platelet volume were determined using an auto-analyzer in the pathology laboratory of Jinnah hospital Lahore. All the patients were advised to take daily Isotretinoin at a dose of 0.5 mg/kg for 12 weeks. Platelet counts and mean platelet volume were again measured after twelve weeks after the start of treatment. A total of 100 patients completed the study. The age of the patients ranged from 18 to 60 years with a mean + sd age of 27.26+5.88 years. Out of these 41%(n=41) were male and 59%(n=59) were females. The severity of acne was measured using Global Acne Grading System (G.A.G.S.). It was recorded that 62%(n=62) had moderate, 22%(n=22) had severe while 16%(n=16) had very severe acne vulgaris. The mean pre-treatment platelet count was 271273+9139 c/µL, while 259192+11717 c/µL was post-treatment. The mean difference was 12080+8140 c/µL, and the p-value was 0.001. The mean platelet volume was 10.63+1.01 fl as pre-treatment and 9.77+1.01 fl as post-treatment. The mean difference was 0.85+0.04 fl, and the p value was 0.001. We concluded that Isotretinoin decreases platelet count and means platelet volume in patients receiving isotretinoin treatment for acne vulgaris.

Prediction of hepatic decompensation and hepatocellular carcinoma after direct-acting antiviral therapy in patients with hepatitis C-related liver cirrhosis: a cohort study

AimThis study aimed to evaluate the rate of hepatic decompensation and de novo HCC and identify their independent factors in HCV genotype 4-infected patients with compensated liver cirrhosis following successful direct-acting antiviral (DAA) therapy.MethodsThis prospective cohort study included 1789 patients with HCV genotype 4-related compensated liver cirrhosis who achieved viral eradication after DAAs. Baseline and follow-up clinical, laboratory, albumin-bilirubin score (ALBI), and abdominal ultrasound were recorded to detect hepatic decompensation and de novo HCC. Logistic regression was performed to evaluate the variables associated with decompensation and HCC.ResultsDuring the 24-month period of follow-up, 184 (10.28%) patients developed hepatic decompensation. Ascites was the commonest presentation. Baseline serum albumin, bilirubin, and platelet count were the independent factors associated with hepatic decompensation (P-values 0.022, 0.03, and < 0.001, respectively). A formula was developed for the prediction of decompensation using these 3 factors (AUC: 0.641 at cutoff 0.1098969 with a sensitivity of 59.9% and specificity of 61.7%). Pre-treatment ALBI score could predict decompensation at cutoff value − 2.5184, AUC 0.609, sensitivity 58.3%, and specificity 59.7%. Post-treatment ALBI score could predict hepatic decompensation after DAA therapy at cutoff value − 2.9521, AUC 0.597, sensitivity 48.1%, and specificity 75.5%. Sixteen (0.9%) patients developed de novo HCC. Age (odds ratio: 1.061, 95%, confidence interval: 1–1.126) and male gender (OR 3.450, 95% CI 1.105–10.769) were the independent factors associated with the development of de novo HCC but not the ALBI score.ConclusionBaseline demographic and laboratory data could predict hepatic decompensation and HCC in patients with compensated liver cirrhosis after successful DAA therapy

Multicenter, retrospective, cohort study shows platelet counts predict hepatocellular carcinoma development in patients with nonalcoholic fatty liver disease.

Impacts of platelet counts at the time of liver biopsy on hepatocellular carcinoma (HCC) development in patients with nonalcoholic fatty liver disease (NAFLD) remain unknown. The aim of this study was to investigate the prognostic value of platelet counts in patients with biopsy-confirmed NAFLD using data from a multicenter study. One thousand three hundred ninety-eight patients were included in this subanalysis of the CLIONE (Clinical Outcome Nonalcoholic Fatty Liver Disease) in Asia study. Liver biopsy specimens were pathologically diagnosed, and histologically scored using the NASH Clinical Research Network system. Demographic, clinical, laboratory, and pathological data were collected. During a median follow-up period of 4.6years (range, 0.3-21.6years), which corresponds to 8874 person-years, 37 patients developed HCC. Using a cut-off baseline platelet count of 192×109/L, the lower platelet group had a higher HCC rate than the higher platelet group (6.7% vs. 0.4%; p<0.001). This cut-off value significantly stratified the event-free rate for HCC. Lower platelet counts were associated with an increased risk of HCC development. Relative to patients with platelet counts of 192×109/L, patients with platelet counts of 100×109/L had an unadjusted hazard ratio (HR) for HCC development of 7.37 (95% confidence interval [CI], 3.81-14.2) and an adjusted HR of 11.2 (95% CI, 3.81-32.7; p<0.001), adjusting for age, sex, NASH,anddiabetes. Baseline platelet counts of 192×109/L and lower are associated with a higher risk of developing HCC in patients with biopsy-confirmed NAFLD and require active surveillance.

Effect of platelet counts and activator in platelet-rich plasma on the treatment of androgenetic alopecia, split-head comparison: A randomised, double-blind study.

Background Androgenetic alopecia is a common, chronic, non-scarring alopecia. It is characterised by stepwise miniaturisation of the hair follicles, due to alteration in the hair cycle dynamics, leading to the transformation of terminal hair follicles into a vellus ones. Oral finasteride and topical minoxidil are the only approved drugs for treating this condition. Due to a limited number of effective therapies for androgenetic alopecia, platelet-rich plasma may be an effective alternative treatment. Aims To study the effect of activator in platelet-rich plasma and baseline platelet count in platelet-rich plasma on the treatment of androgenetic alopecia. Methods A randomised, double-blind split-head comparative study. The sample size was calculated and randomisation was done. Patients with androgenetic alopecia were allocated into two groups; in the first group, autologous activated platelet-rich plasma was injected in the right half of the affected scalp and autologous non-activated platelet-rich plasma was injected in the left half of the affected scalp and vice versa in the second group. Patients were also categorised on the basis of platelet counts in their platelet-rich plasma in three groups; group A (6-8 lakh/mm3), group B (8.1-10 lakh/mm3) and group C (>10 lakh/mm3). Interventions were done monthly for three months and followed up for the next three months. Effects of interventions were assessed by hair density, hair thickness, patient self-assessment and clinical photography. Results A total of 80 patients were included in the study. Activated platelet-rich plasma produced significant improvement of hair density after four months and hair thickness at 6 months. An increase in platelet count led to a significant increase in hair density and hair thickness after three and four months respectively and a highly significant increase in both parameters at the end of the study. Limitations Long-term follow-up of cases was not done and no measurement of vellus hair count was done. Conclusion There is a significant effect of activator and platelet count of the platelet-rich plasma on hair density as well as hair thickness.

Real-world safety and effectiveness of maintenance niraparib for platinum-sensitive recurrent ovarian cancer: A GEICO retrospective observational study within the Spanish expanded-access programme

AimTo describe patient characteristics, effectiveness and safety in a real-world population treated with niraparib in the Spanish expanded-access programme. Patients and methodsThis retrospective observational study included women with platinum-sensitive recurrent high-grade serous ovarian cancer who received maintenance niraparib within the Spanish niraparib expanded-access programme. Eligible patients had received ≥2 previous lines of platinum-containing therapy, remained platinum-sensitive after the penultimate line of platinum and had responded to the most recent platinum-containing therapy. Niraparib dosing was at the treating physician's discretion (300 mg/day fixed starting dose or individualised starting dose [ISD] according to baseline body weight and platelet count). Safety, impact of dose adjustments, patient characteristics and effectiveness were analysed using data extracted from medical records. ResultsAmong 316 eligible patients, 80% had BRCA wild-type tumours and 66% received an ISD. Median niraparib duration was 7.8 months. The most common adverse events typically occurred within 3 months of starting niraparib. Median progression-free survival was 8.6 (95% confidence interval [CI] 7.6–10.0) months. One- and 2-year overall survival rates were 86% (95% CI 81–89%) and 65% (95% CI 59–70%), respectively. Dose interruptions, dose reductions, haematological toxicities and asthenia/fatigue were less common with ISD than fixed starting dose niraparib, but progression-free survival was similar irrespective of dosing strategy. Subsequent therapy included platinum in 71% of patients who received further treatment. ConclusionOutcomes in this large real-world dataset of niraparib-treated patients are consistent with phase III trials, providing reassuring evidence of the tolerability and activity of niraparib maintenance therapy for platinum-sensitive recurrent ovarian cancer. ClinicalTrials.gov registrationNCT04546373.

633: LABORATORY MONITORING DURING THE FIRST 24 HOURS OF PEDIATRIC EXTRACORPOREAL MEMBRANE OXYGENATION

Introduction: Pediatric extracorporeal membrane oxygenation (ECMO) is a potentially lifesaving intervention for cardiopulmonary failure. Anticoagulation protocols are necessary to prevent complications. Limited data exist on how traditional coagulation tests correlate with early bleeding complications in this population. This study evaluates pre-and-post cannulation coagulation parameters during the first 24 hours of ECMO initiation in pediatric patients. Methods: This is an IRB approved retrospective cohort study. Included are 116 children that received ECMO at our academic institution from January 2017 to March 2022. Children with no hematologic events and acute bleeding events were compared. Routine pre-and-post-cannulation coagulation profiles in the initial 24-hours of ECMO were evaluated. Data was analyzed between groups using Mann Whitney U test with SPSS Statistics version 10.0. Results: Patients were grouped into “no event” (N=88) and “bleed event” (N=28). Average age was 43.3 months. Children with major bleeding events in the first 24 hours of ECMO had a longer time until target ACT was reached, 5 vs 3.5 hours (p=0.003). These patients also had more prolonged post-cannulation prothrombin time (PT), 19.2 vs 16.1 seconds (p=0.002), and international normalized ratio (INR), 1.9 vs 1.6 (p=0.002). Also, bleeding patients had lower pre-and-post-cannulation fibrinogen levels, 135 vs 229 (p=0.008) and 106.5 vs 181 (p=< 0.001), respectively, and lower post-cannulation platelet counts, 82.5 vs 109.5 (p=0.035). No differences were seen for the initial ACT, heparin dose, baseline platelet count, or pre-and-post hemoglobin and activated partial thromboplastin time. Conclusions: Major bleeding events occurred within 24 hours in approximately 24% of our cohort. Identifying risk factors for bleeding may aid in reducing morbidity and mortality. Our data shows that consideration of fibrinogen levels, platelet count, PT and ACT may help to identify pediatric patients at risk of early bleeding during ECMO. Attention to these baseline and immediate post-cannulation laboratory values may be important to determine initial bolus dosing and adjustment of anticoagulation in these patients. Continued multi-center collaboration and incorporation of other coagulation studies, like anti-FXa and thromboelastography, is needed.

Recombinant human thrombopoietin treatment in patients with chronic liver disease-related thrombocytopenia undergoing invasive procedures: A retrospective study.

Chronic liver disease (CLD) related thrombocytopenia increases the risk of bleeding and poor prognosis. Many liver disease patients require invasive procedures or surgeries, such as liver biopsy or endoscopic variceal ligation, and most of them have lower platelet counts, which could aggravate the risk of bleeding due to liver dysfunction and coagulation disorders. Unfortunately, there is no defined treatment modality for CLD-induced thrombocytopenia. Recombinant human thrombopoietin (rhTPO) is commonly used to treat primary immune thrombocytopenic purpura and thrombocytopenia caused by solid tumor chemotherapy; however, there are few reports on the use of rhTPO in the treatment of CLD-related thrombocytopenia. To evaluate the efficacy of rhTPO in the treatment of patients with CLD-associated thrombocytopenia undergoing invasive procedures. All analyses were based on the retrospective collection of clinical data of patients with CLD who were treated in the Department of Infectious Diseases at The First Affiliated Hospital of Soochow University between June 2020 and December 2021. Fifty-nine male and 41 female patients with liver disease were enrolled in this study to assess the changes in platelet counts and parameters before and after the use of rhTPO for thrombocytopenia. Adverse events related to treatment, such as bleeding, thrombosis, and disseminated intravascular coagulation, were also investigated. Among the enrolled patients, 78 (78%) showed a platelet count increase after rhTPO use, while 22 (22%) showed no significant change in platelet count. The mean platelet count after rhTPO treatment in all patients was 101.53 ± 81.81 × 109/L, which was significantly improved compared to that at baseline (42.88 ± 16.72 × 109/L), and this difference was statistically significant (P < 0.001). In addition, patients were further divided into three subgroups according to their baseline platelet counts (< 30 × 109/L, 30-50 × 109/L, > 50 × 109/L). Subgroup analyses showed that the median platelet counts after treatment were significantly higher (P < 0.001, all). Ninety (90%) patients did not require platelet transfusion partially due to an increase in platelet count after treatment with rhTPO. No serious adverse events related to rhTPO treatment were observed. Overall, rhTPO demonstrated good clinical efficacy for treating CLD-associated thrombocytopenia. rhTPO can improve platelet count, reduce the risk of bleeding, and decrease the platelet transfusion rate, which may promote the safety of invasive procedures and improve overall survival of patients with CLD.

Platelet to albumin ratio is an independent indicator for disease activity in ankylosing spondylitis.

The objective of this study is to characterize the association between platelet to albumin ratio (PAR) and disease activity in patients with ankylosing spondylitis (AS) and axial psoriatic arthritis (axPsA). Baseline platelet count, albumin, PAR, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), Bath ankylosing spondylitis disease index (BASDAI), Bath ankylosing spondylitis functional index (BASFI), and ankylosing spondylitis disease activity score (ASDAS) were collected from patients with a definitive diagnosis of AS or axPsA. Spearman's correlation analysis, quantile regression, and receiver operating characteristic (ROC) curves were performed. Four hundred forty-six patients with AS and 68 patients with axPsA were included. AS patients had higher CRP, ASDAS-CRP, and ASDAS-ESR than axPsA patients (median: CRP, 6.8 vs. 3.5mg/L, p = 0.02; ASDAS-CRP, 2.32 vs.1.93, p = 0.001; ASDAS-ESR, 2.57 vs.1.97, p = 0.007; respectively). Platelet count, albumin, PAR, ESR, BASDAI, and BASFI did not significantly differ between the two populations (all p > 0.05). In AS patients, PAR was positively correlated with BASDAI (r = 0.204, p < 0.01), BASFI (r = 0.24, p < 0.01), ASDAS-CRP (r = 0.475, p < 0.01), and ASDAS-ESR (r = 0.483, p < 0.01), while these coefficients were not significant in axPsA patients. The quantile regression further confirmed that, in AS patients, PAR was independently associated with BASDAI, BASFI, ASDAS-CRP, and ASDAS-ESR at their individual quantiles (all p < 0.01). However, in axPsA patients, PAR was not significantly associated with these disease activities. The optimal cut-off value of PAR for AS disease activity was 5.87, with an AUC of 0.745, a sensitivity of 72.4%, and a specificity of 71%. PAR could serve as an alternative indicator for AS disease activity. Key Points • Platelet to albumin ratio is independently associated with ankylosing spondylitis disease activity. • Platelet to albumin ratio could serve as an alternative indicator for ankylosing spondylitis disease activity.

The Combination of Navitoclax and Ruxolitinib in JAK Inhibitor-Naïve Patients with Myelofibrosis Mediates Responses Suggestive of Disease Modification

Background: Myelofibrosis (MF) is a myeloproliferative neoplasm associated with splenomegaly, high symptom burden, bone marrow fibrosis (BMF), and poor prognosis. The Janus kinase inhibitor (JAKi) ruxolitinib is the current standard of care for patients with MF. It improves splenomegaly and disease symptoms with limited impact on disease biology, highlighting an unmet medical need in MF. Driver mutations of JAK2, CALR, and MPL are key to the pathogenesis of MF. Reduction in variant allele frequency (VAF) of driver mutations and reversal of BMF are suggestive of disease modification (Pemmaraju, Cancer, 2022). Additionally, mutations in ASXL1, EZH2, SRSF2, IDH1/2, and U2AF1 p.Q157 are classified as high molecular risk (HMR) mutations associated with a worse prognosis (Arber et al., Blood, 2016). We previously demonstrated evidence of disease modification independent of HMR mutations by adding navitoclax to ruxolitinib in patients with suboptimal responses to ruxolitinib monotherapy (Pemmaraju, Lancet Oncology, 2022). Herein, we investigated whether the type of MF and risk (e.g., age, Dynamic International Prognostic Scoring System [DIPSS], and HMR) correlated with clinical outcomes and responses suggestive of disease modification (e.g., VAF reduction and improvement in BMF) among JAKi treatment-naïve patients with MF treated with the combination of navitoclax and ruxolitinib. Methods: Cohort-3 of the phase-2 multicenter REFINE study (NCT03222609) enrolled JAKi treatment-naïve patients with MF. Enrolled patients had primary or secondary MF with splenomegaly (DIPSS ≥ Intermediate-1) and did not receive prior JAK-2 therapy or bromodomain and extra terminal motif (BET) inhibitors. Patients initiated navitoclax at 100 mg QD or 200 mg QD if baseline platelet count was ≤ 150 × 109/L or > 150 × 109/L, respectively. Ruxolitinib was given BID with starting dose based on baseline platelet count per local label. The primary endpoint was spleen volume reduction of ≥ 35% (SVR35) from baseline at week 24, assessed by MRI conducted by central review. Key secondary and exploratory endpoints evaluated in this analysis were a reduction in BMF obtained from BM biopsies by local evaluation and a reduction in VAF for the driver gene mutations (JAK2V617, CALR, or MPL), respectively. Driver gene VAF and HMR mutations were determined in whole blood with the 50-gene Focus Myeloid next-generation sequencing panel (Interspace Pharma Solutions, Morrisville, NC, USA). Results: As of Feb 07, 2022, all enrolled patients (N = 32) treated with navitoclax and ruxolitinib were evaluable for biomarker analysis. The median duration of follow-up was 6.1 months (range, 1.9 – 18.6); median age was 69 years (range, 44 – 83), and median spleen volume was 1889.08 cm3 (range, 645.6 – 7339.6). At baseline, 22 (69%) patients had JAK2, 6 (19%) had CALR, and 3 (9%) had MPL mutations. One (3%) patient was triple negative. Nineteen (59%) patients had HMR mutations. SVR35 at week 24 was observed in all subgroups known to confer poor prognosis, including age (≥75 years, 50% [n = 4/8]), high DIPSS score (Intermediate-2, 63% [n = 12/19]; high, 33% [n = 1/3]), and HMR mutations (47% [n = 9/19]; Figure). BMF grade improvement was evaluable in 26/32 (81%) patients, of which 9/26 (35%) achieved ≥ 1-grade improvement at any time during treatment with a median time-to-improvement of 12.3 weeks (range, 12.1 – 24.1). Complete resolution of BMF was observed in 2/9 (22%) patients. The baseline BMF grades of these patients were 2 and 3. BMF ≥ 1-grade improvement was achieved by 7/13 (54%) patients with HMR mutations and 2/13 (15%) without HMR mutations. Reduction in driver gene JAK2V617 mutation VAF > 20% from baseline at week 12 or 24 was observed in 14/28 (50%) patients, and 5/14 (36%) patients achieved > 50% VAF reduction from baseline. There were no differences in > 20% VAF reductions from baseline to week 12 or 24 between those with or without HMR mutations (7/15 [47%] versus 7/13 [54%], respectively). Conclusions: Among JAKi treatment-naïve patients with MF, the combination of navitoclax and ruxolitinib reduced splenomegaly in several high-risk groups known to confer poor prognosis. Reductions in BMF and VAF were independent of HMR mutations. The reduction in BMF and VAF for the driver mutation JAK2V617 is encouraging and suggestive of evidence of disease modification with the combination of navitoclax and ruxolitinib. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Fostamatinib for the Treatment of Japanese Patients with Primary Immune Thrombocytopenia: 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 the US, Canada, and Europe. We conducted a phase 3, multi-center study to evaluate the efficacy and safety of fostamatinib in Japanese patients with ITP. The study was composed of 3 treatment periods and 1 non-dosing period: a placebo-controlled, double-blind study of fostamatinib for 24 weeks, an open-label study of fostamatinib for 28 weeks, a non-dosing period of up to 4 weeks, and the voluntary open-label study of fostamatinib until official approval. Here we report the results of the 24-week, placebo-controlled, double-blind, parallel-group study. Methods The study enrolled Japanese patients, ≥20 years old, with ITP for ≥6 months, and who had failed or not tolerated ≥1 prior ITP treatment. The mean of 3 screening and baseline platelet counts had to be <30,000/μL, with a platelet count at each visit < 35,000/μL. Patients were randomised 2:1 to fostamatinib or placebo for 24 weeks, stratified by baseline platelet count (< or ≥ 15,000/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). Results The study included 34 patients, fostamatinib (n=22) or placebo (n=12). See Table 1 for baseline characteristics. Stable responses (platelets ≥50,000/μL at ≥4 of 6 visit, weeks 14-24) were observed in 8 (36%) patients on fostamatinib and 0 patients on placebo (P=0.030) (Figure 1). Overall responses (platelets ≥50,000/μL at ≥1 visit, weeks 2-12) were seen in 10 (45%) patients on fostamatinib and 0 patients on placebo (P=0.006). The median platelet counts of stable responders were higher than those of non-responders and patients on placebo throughout weeks 2 to 24. The median platelet counts of responders on fostamatinib increased ≥50,000/μL from the early stage of fostamatinib administration and stayed at around 100,000/μL from weeks 14 to 24, whereas non-responders on fostamatinib and patients on placebo remained below 30,000/μL most of the time. No platelet overshoot (> 400,000/μL) was observed. Rescue medication was required less often with fostamatinib, and fewer bleeding symptoms occurred with fostamatinib than with placebo. Adverse events in ≥10% of patients on fostamatinib were diarrhoea, hypertension, and decreased neutrophil count. Most adverse events were mild or moderate and manageable. There was no difference in the incidence of infection between the fostamatinib and placebo group; no patients developed a severe infection. No thromboembolic events were reported. The safety profile was consistent with prior studies of fostamatinib. Conclusions This study demonstrated the efficacy and safety of fostamatinib in Japanese patients with ITP, including those who had failed or were intolerant to other approved ITP therapies. No new safety signals were identified in Japanese patients with ITP. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Immune Thrombocytopenia Purpura Relapse in Patients Who Received mRNA COVID-19 Vaccines

Background: Immune thrombocytopenic purpura (ITP) is a syndrome in which platelets become coated with autoantibodies to platelet membrane antigens. The mononuclear macrophage system of the spleen is responsible for removing platelets in ITP. This leads to a decrease in circulating platelet count and propensity for bleeding. Patients usually present with bruising and mucosal bleeding, with a minority of cases developing major bleeding complications such as intracranial hemorrhage. Cases of ITP and ITP relapse have been reported in people who received the mRNA SARS-CoV-2 vaccine, most reported cases present with bruising and mucosal bleeding in the first few weeks after receiving the vaccine, nevertheless, the causal relationship is not yet proved. Objectives: This study aims to prove the causal relationship betweenITP relapse in known ITP patients and the mRNA covid vaccine. And to evaluate the long-term effect of the vaccine on ITP patients > 6 months after receiving the second dose. Methods a retrospective study was conducted to check platelet count in 67 patients known for immune thrombocytopenia purpura, who are >18-year- old, and not known for any other causes of thrombocytopenia (including congenital thrombocytopenia, malignancy, SLE, anti-phospholipid syndrome). The platelet count was identified at baseline before receiving the vaccine and within 3 months, 6 months, and after 6 months after receiving the vaccine. Results: The results showed that 6% of ITP patients had ITP relapse within the first 3 months after the mRNA covid vaccine, 10% of patients had a relapse within the first 6 months and another 8% had a relapse more than 6 months after receiving the vaccine. on follow-up for the patient who didn't have a frank relapse, within the first 6 months after receiving the vaccine 8% of patients had more than 50% reduction from their baseline platelet count and 6% had a 25-50% reduction in the platelets count. on follow-up more than 6 months after the vaccine,4% of patients had more than 50% reduction in platelet count and 3% had a 25-50% reduction from their baseline platelet count. There was no statically significant difference between Moderna and Pfizer vaccine on ITP relapse rate or platelet count reduction. Conclusion mRNA covid vaccine increases the risk of ITP relapse and leads to a reduction in platelets count compared to the baseline count before receiving the vaccine, with no statically significant difference between Pfizer and Moderna vaccines. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Safety and Efficacy of Fostamatinib in Patients with Chronic Immune Thrombocytopenic Purpura Treated in a Real-World Community Hematology Setting

Background: Chronic immune thrombocytopenia (ITP) in adults is a serious autoimmune disease in which platelets are prematurely destroyed, leaving the patient vulnerable to bruising and bleeding. Initial treatment with corticosteroids is intended to suppress the immune response and is effective in many patients but not sustainable. Fostamatinib is an approved therapy for adult patients with ITP who have had an insufficient response to a prior treatment. It is an oral small molecule that targets spleen tyrosine kinase (SYK), which has important roles in cellular proliferation, differentiation, and immune regulation. By blocking SYK, fostamatinib reduces the immune system's destruction of platelets, which allows the platelet (PLT) count to rise, thereby reducing the risk of bleeding in ITP patients. Two placebo-controlled randomized trials demonstrated that fostamatinib was well tolerated and able to induce meaningful platelet responses in heavily pretreated patients, as well as in earlier lines of therapy. The use of fostamatinib in a community hematology setting has not been evaluated. In this study, the real-world utilization and treatment patterns of fostamatinib in patients treated within the QCCA, a network of 17 community hematology clinics across the United States, is presented. Methods: The QCCA network real world database was reviewed for ITP patients who had received fostamatinib over the past 3 years. Data collection consisted of patient demographics, disease characteristics, duration of ITP, existing comorbidities, number and type of prior ITP treatments and PLT count at baseline prior to the start of fostamatinib. All of the information was collected via a standardized data collection form. From the first day until the end of treatment, data were collected on hemoglobin, white blood cells, absolute neutrophil counts, PLT counts, concomitant ITP therapies and the use of rescue IVIG. A meaningful increase in PLTs was defined as achievement of platelet counts ≥ 30 and ≥ 50 x 103/μL over the course of therapy. Results: The medical records of the 46 ITP patients who met the inclusion criteria and received fostamatinib were evaluated. Patients had a median age of 58 years, 65% were female and 35% had a splenectomy. All patients had prior exposure to corticosteroids and the median number of therapies before stating fostamatinib was two. In addition, 65% had received thrombopoietin receptor agonists and rituximab. All patients started therapy at a dose of 100 mg twice daily for a median duration of 2 months (interquartile range [IQR] = 1 to 15) and a mean duration of 6.7 months (95%CI: 3.5 to 9.9). When fostamatinib was started, the median PLT count was 19 x 103/μL (IQR = 3 to 70). From the start of therapy, the maximum increase in the median PLT count was 78 x 103/μL (IQR = 13 to 231), which was achieved after a median of 1.8 months. Over the course of therapy, 31 (67.4%) and 26 (56.5%) of 46 patients achieved or maintained PLT levels ≥ 30 and ≥ 50 x 103/μL respectively. Of note, prior to the start of fostamatinib, 9 and 7 patients respectively, already had PLT levels ≥ 30 and ≥50 x 103/μL. The percent of patients with at least a doubling of their baseline PLT count was 47.8% (95%CI: 32.9 to 63.0%). There were no serious bleeding events reported, and only one patient required the discontinuation of fostamatinib because of adverse events. Among the 46 patients, 16 received concomitant IVIG to increase PLT counts. Conclusions: In this real-world setting, the findings suggest that fostamatinib is safe and effective in patients with chronic ITP who had relapsed or had not responded to one or more prior treatments.

Real-World Safety and Health Care Resource Utilization Analysis of Venetoclax and Hypomethylating-Agent Treatment for AML in an Academic-Affiliated Urban Community Oncology Network

Introduction Acute Myeloid Leukemia (AML) is a disease that affects predominantly older patients with a median age at diagnosis of 68 years. Elderly patients often have medical comorbidities and are ineligible for intensive induction chemotherapy. Recently, the FDA approved the combination of HMA/venetoclax for patients with newly diagnosed AML who are 75 years or older, or who have comorbidities precluding intensive induction chemotherapy. Through this retrospective analysis of patients treated at a metropolitan academic leukemia center and academic-affiliated community oncology practice network, our goal was to evaluate the safety and health care resource utilization of HMA/venetoclax treatment in a real-world experience. Methods We performed a retrospective analysis of patients treated for AML with HMA/venetoclax as standard-of-care at UCLA from 2018 to 2021. Patients treated with first-line HMA/venetoclax at UCLA community clinics (CC) and at UCLA main campus (academic centers, AC) and had a treatment record available in the electronic medical system were included. We specifically sought to collect safety parameters. Short-term efficacy outcomes were secondary endpoints. Results Thirty-three patients were eligible for analysis: eleven patients who received care in CC and 22 patients who were treated at AC. Baseline characteristics and treatment information are presented in Table 1. The average age was 76 years old for CC and 71 years old for AC. The proportion of patients older than 60 years old is 100% in CC, and 82% at AC. ECOG performance status was predominantly 0 and 1, irrespective of treatment location. Both groups have predominantly a secondary AML diagnosis (CC 64%, AC 59%). According to ELN 2017 criteria, 36.4% of CC had adverse risk disease, compared to 72% of AC patients. CC patients had median of 30% bone marrow blasts at diagnosis and AC had 59% blasts. Forty percent of CC patients and 64% of AC patients had baseline platelet counts <50x103/uL. Regarding treatment, eight out of 11 CC patients had consultation with a physician from the academic leukemia group. Twenty-seven percent of CC patients and 82% of AC patients were treated inpatient for cycle 1. Eighteen percent of CC patients and 66.6% AC patients received venetoclax at a starting dose lower than 400mg daily. Eighty-six percent of the dose reductions were due to concurrent azoles use. Finally, prophylactic antibiotics were used in 45% of CC patients compared to 64% of AC patients, and antifungal prophylaxis was used in 27% of CC patients compared to 64% of AC patients. Safety data, health care resource utilization, and clinical outcome information are reported in Table 2. The percentage of patients with grade 4 neutropenia duration >30 days after cycle 1 was 50% in CC vs. 43% at AC. There were no deaths before 30 days at CC and there were 2 deaths (10%) in AC. Thirty- to sixty-day mortality was zero in both groups. Thirty-six percent of CC patients and 59% of AC required hospitalization (infectious related: 43% CC, 52% AC; cytopenia: 29% CC, 10% AC). The median number of hospital days was 3 (range, 0-17) in CC, and 27 (range, 6-81) in AC; and 0% of CC vs. 18% of AC patients required an ICU stay. Regarding clinical response, bone marrow biopsy was done after cycle 1 in 91% of CC vs. 41% of AC patients. Of these patients, CR/CRi rate was 80% in CC patients vs. 56% in AC patients. Discussion Our study suggests that AML treatment with HMA/venetoclax can be administered safely in real-world community setting. The high number of CC patients that had consultation with AC group reflects the integrative collaborative practice model at our urban academic affiliated oncology community practice. Patients treated in CC tend to be older, with more favorable AML, and better BM function reserve at baseline. The CR rate for patients treated in CC is comparable to previously published data. The high number of patients treated inpatient for cycle one at AC likely indicates AC carries a more acutely ill AML patient population compared to CC, which likely resulted in more health care resource utilization. It is interesting to observe that in the CC group, 29% of the complications leading to hospitalization are from cytopenia, suggesting that health care resource utilization could be further optimized with pre-emptive transfusion scheduling. Limitations of this analysis include that this is a small, single center, retrospective analysis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Eltrombopag Plus Diacerein Versus Eltrombopag in Adult Primary Immune Thrombocytopenia: Interim Analysis of a Multicenter, Randomized, Controlled, Phase 2 Trial

Background: Primary immune thrombocytopenia (ITP) is an autoimmune bleeding disorder. Eltrombopag is a preferred second-line treatment of ITP, but many patients still have no response or relapse due to unknown reasons. Our preclinical data indicate that rhein, the active metabolite of diacerein, can enhance megakaryocyte sensitivity to thrombopoietin receptor agonists, and promote megakaryocyte polyploidization and platelet formation in ITP. Thus, a prospective randomized controlled trial was conducted to compare the efficacy and safety of eltrombopag plus diacerein versus eltrombopag alone in adult ITP. Here we report the interim analysis of this study. Methods: This multicenter, open-label, randomized, phase 2 trial screened eltrombopag-inefficient or relapsed ITP patients from five tertiary medical hospitals in China. Eligible participants were randomly assigned into the combination arm (eltrombopag orally at an initial dose of 75 mg daily for 14 days, plus diacerein orally at an initial dose of 50 mg bid for 14 days) or the monotherapy arm (eltrombopag orally at an initial dose of 75 mg daily for 14 days) by masked statisticians. To maintain participants’ platelet counts at a safe range, individualized dosages were allowed to be adjusted by physicians according to the protocol. The primary outcome was initial response at day 15. Complete response was defined as a platelet count at or above 100×109/L and an absence of bleeding. Partial response was defined as a platelet count at or above 30×109/L but less than 100×109/L and at least a doubling of the baseline platelet count and an absence of bleeding. No response was defined as a platelet count of less than 30×109 cells per L, or less than two-times increase from baseline platelet count, or bleeding. Key secondary enpoints included response at day 28, time to response (TTR), duration of response, bleeding scores, health-related quality of life assessment and adverse events (AEs). This trial was registered with ClinicalTrials.gov (NCT04917679). Results: From September 2020 to December 2021, 90 patients were screened for eligibility, of whom 24 were ineligible, 66 were randomly assigned to receive either eltrombopag plus diacerein (n=32) or eltrombopag alone (n=34). Four patients did not receive allocated intervention and they were excluded from the analysis. Baseline characteristics were balanced between the two arms. The total population (female accounted for 51.6%) had a mean age of 42.6 years and a mean platelet count of 8.6 ×109/L. At day 15, a significantly higher proportion of participants in the eltrombopag plus diacerein arm (13 [43.3%] of 30) than in the eltrombopag monotherapy arm (5 [15.6%] of 32) had an initial response (p=0.0247). At day 28, the response rate in the combination arm was higher than that in the eltrombopag arm even though it did not reach statistical significance (10 [33.3%] of 30 vs 4 [12.5%] of 32, p=0.0699). There was no significant difference in median TTR between the two arms (p>0.05). During the follow-up period, the duration of response was longer in the eltrombopag plus diacerein arm than in the eltrombopag arm by the Kaplan Meier analysis (Hazard ratio 0.57, 95% CI 0.34-0.96, p=0.0178). Eltrombopag plus diacerein exhibited lower bleeding scores and better health-related quality of life scores than eltrombopag. Incidence of AEs was similar between the two arms. Most of AEs were mild and resolved spontaneously after treatment was completed. The incidence of gastrointestinal reactions in the combination arm was slightly higher, but no significant difference was observed. There were no grade 4 or 5 AEs. No treatment-related deaths occurred. Conclusions: In conclusion, our findings suggest that the addition of diacerein as a sensitizer to eltrombopag has improved initial response than eltrombopag alone for eltrombopag-inefficient or relapsed ITP patients. This oral combination therapy warrants further exploration. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes of Older Patients with Aplastic Anemia Treated with Frontline Anti-Thymocyte Globulin (ATG)-Based Immunosuppressive Therapy

Background: Advances in the treatment of aplastic anemia (AA), such as the addition of eltrombopag (EPaG) to immunosuppressive therapy (IST) and the expanded use of unrelated and haploidentical stem cell transplant (SCT) have steadily improved outcomes. However, little is known about the characteristics and outcomes of patients (pts) ≥ 60 years (yrs) of age with newly diagnosed AA who have been treated with an ATG-based regimen. Presumed low bone marrow (BM) reserves, higher frequency of underlying clonal hematopoiesis, intolerance to therapy, comorbidities, and challenges in proceeding to salvage SCT have led to the speculation that response and survival of these pts to IST may be inferior than their younger counterparts. Methods: We retrospectively analyzed the characteristics and outcomes of pts ≥ 60 yrs of age (OLDER) at the time of diagnosis of AA treated with frontline (F/L) ATG based therapy at our center and compared them to pts < 60 yrs of age (YOUNG) treated with F/L ATG over the same time period. We captured their clinical characteristics, cytogenetic abnormalities, mutations in DNMT3A (D), ASXL1 (A) and TET2 (T), exposure to EPaG, response, time to response (TTR) and survival. Overall response included complete and partial response per the standard definitions. Relapse free survival (RFS) was tabulated from the time of best response to loss of response, 2nd ATG infusion, salvage SCT or death (whichever was earlier) and overall survival was tabulated from the time of response to death from any cause. Results: From Jan 2011-May 2012, 43 OLDER pts were treated as F/L for AA of whom 41 (95%) received ATG based therapy; 68 YOUNG pts were treated as F/L for AA over the same time period of whom 62 (91%) received ATG based regimen. Four YOUNG pts vs. no pts in the OLDER group received upfront SCT, and 2 pts in each group were treated with non ATG based therapy: single agent CSA, EPaG, or alemtuzumab. Comparative baseline characteristics are depicted in Table 1. There were no differences in the baseline WBC, peripheral blood lymphocyte percentage and platelet counts between the ATG treated OLDER and YOUNG groups. Both groups had similar frequencies of cytogenetic abnormalities and PNH clones, though OLDER pts had mutations in D-A-T genes compared to the YOUNG group (62% vs. 38%, p=0.05). Both groups had equal concurrent exposure to EPaG with ATG. Cumulatively 23/41 (56%) pts in the OLDER group had an overall response (OR) compared to 43/62 (70%) pts in the YOUNG group (p=0.1); 11/23 (48%) and 23/43 (53%) responders in each group attained CR respectively. There were no differences in OR rates in both groups based on concurrent EPaG exposure: 61% vs. 46% with and without EPaG, respectively, in the OLDER group (p=0.5) and 74% vs 60%, respectively, (p=0.38) in the YOUNG group. On logistic regression analysis using baseline platelet counts, PB lymphocyte (%), D-A-T mutations, karyotype, and EPaG use as covariates, none affected the odds of OR in the 2 groups. The median TTR was 111 days (range, 10-323 days) and 177 days (51-410) in YOUNG AND OLDER groups, respectively; and this was not affected by EPaG use in either group. At a median follow of 38 months (mos) from ATG initiation (53 mos for the OLDER group and 32 mos for the YOUNG group), the median RFS was 49 mos and 39 mos (p=0.6) and median OS 55 vs. not reached (NR) (p <0.0001) in OLDER and YOUNG groups respectively (Fig.1). Significantly more pts in the YOUNG group underwent a subsequent SCT (19% vs. 5%) due to loss of response/ no response, possibly accounting for the higher OS rates. Rates of transformation to MDS or AML was 5% in both groups. Conclusion: Frontline ATG based IST in older pts with AA is a feasible and safe treatment option with promising response rates of 56% and median RFS more than 4 years; figures which are comparable to younger pts with AA treated with IST. The overall risks of transformation to MDS/AML on long term follow-up remain low (≈5%). Further studies assessing the response of the ATG+EPaG combination in these pts and the possibilities of clonal evolution with time needs to be conducted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal