High-risk Polycythemia Vera Research Articles

Comparison of the crystal structures of the JAK1/2 inhibitor ruxolitinib and its hydrate and phosphate.

Ruxolitinib {RUX; systematic name: (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, C17H18N6} is an orally bioavailable JAK1/2 inhibitor approved for treating intermediate- or high-risk myelofibrosis (MF) and high-risk polycythemia vera (PV). Recent patents claim that RUX can exist in many different forms, information for which is important for the clinical utilization of RUX, especially for the formulation and bioavailability of the drug. But there has been no detailed study on its forms so far. Herein crystals of RUX and its dihydrate (RUX-2H; C17H18N6·2H2O) and phosphate (RUX-P; systematic name: 4-{1-[(1R)-2-cyano-1-cyclopentylethyl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-3-ium dihydrogen phosphate, C17H19N6+·H2PO4-) were prepared successfully and their structures studied in detail for the first time. Our study shows that the three crystals of RUX differ in the orientation of the pyrimidine ring relative to the pyrazole ring of the RUX molecule, and in their hydrogen-bond interactions. The water molecules in RUX-2H and the dihydrogen phosphate anion in RUX-P enrich the hydrogen-bond networks in these forms. The expected proton transfer occurs in RUX phosphate and the protonated N atom is engaged in a charge-assisted hydrogen bond with the counter-anion. Hydrogen-bonding interactions dominate in the crystal packing of the three forms. The detailed conformations and packing of the three forms were compared through the calculation of both Hirshfeld surfaces and fingerprint plots.

Spinal extramedullary hematopoiesis mimicking an epidural tumor in a patient with high-risk polycythemia vera: illustrative case.

Here the authors present the case of a 43-year-old male with a history of T-cell lymphoma, which was treated with azacitidine plus cyclophosphamide, doxorubicin, vincristine, and prednisone and autologous hematopoietic cell transplant, and high-risk polycythemia vera (PCV) presenting with severe lower-back pain radiating to the bilateral legs with associated lower-extremity weakness and splenomegaly. T2-weighted magnetic resonance imaging revealed multilevel epidural lesions involving T1-10 and S1-2. Because of severe spinal canal stenosis, the patient underwent surgical decompression of T5-7, with immediate postoperative alleviation of the lower-extremity pain and complete resolution of the lower-leg weakness. Biopsy results revealed extramedullary hematopoiesis (EMH) mimicking a spinal epidural tumor. EMH is radiosensitive and displays a rapid response to low dosages, so the patient was further treated with palliative radiation therapy for residual tumors and symptom alleviation, as well as hydroxyurea and corticosteroids as indicated for cytoreduction. EMH associated with PCV or myeloproliferative conditions occurring within the spine is a rare phenomenon without a standard treatment approach. https://thejns.org/doi/10.3171/CASE23659.

Association between elevated white blood cell counts and thrombotic events in polycythemia vera: analysis from REVEAL

AbstractPolycythemia vera (PV) is a myeloproliferative neoplasm characterized by clonal proliferation of hematopoietic progenitor cells and is associated with an increased risk of thrombotic events (TEs). Established risk factors for TEs in patients with PV include advanced age, TE history, and elevated hematocrit. Although an association of TE with elevated white blood cell (WBC) counts has been suggested by retrospective studies, this relationship needs further validation. The prospective observational study of patients with polycythemia vera in US clinical practices (REVEAL) study collected prospective clinical data from 2510 patients with PV with a median follow-up of 44.7 months (range, 2-59 months) from enrollment. Using time-dependent covariate Cox proportional hazards models, blood counts were individually modeled with sex, age, disease duration, TE history at enrollment (baseline covariates), and treatment (time-dependent covariate). Analysis of 2271 participants identified 142 TEs in 106 patients. Significant associations with initial TE occurrence during the study period were observed for hematocrit level >45% (hazard ratio [HR], 1.84; 95% confidence interval [95% CI], 1.234-2.749; P = .0028) and WBCs >11 × 109/L (HR, 2.35; 95% CI, 1.598-3.465; P < .0001). Elevated WBC count was significantly associated with initial TE occurrence in both low-risk and high-risk PV. When hematocrit was controlled at ≤45%, WBC count >12 × 109/L was significantly associated with TE occurrence (HR, 1.95; 95% CI, 1.066-3.554; P = .0300). The results support incorporation of WBC count into PV risk stratification and studies of treatment strategies, and indicate the importance of controlling both hematocrit and WBC count in disease management. This trial was registered at www.clinicaltrials.gov as #NCT02252159.

Real-World Analysis of Thromboembolic Event Rates in Patients in the United States with Polycythemia Vera

Background:Polycythemia vera (PV) is a myeloproliferative neoplasm associated with an increased risk of thromboembolic events (TEs). PV patients are characterized based on their risk for TEs as low-risk (age &amp;lt;60 without prior history of TE) or high-risk (age ≥60 and/or prior history of TE). Observational studies have shown higher rates of TEs in PV patients compared to matched controls (14.3 vs 4.9/1000 patient years, or PY), with rates as high as 40% in patients with PV (Goyal et al., Blood. 2014;124:4840; Griesshammer et al., Ann Hematol. 2019;98:1071-82; Pemmaraju et al., Leuk Res. 2022;115:106809). We assessed the rate of arterial and venous TEs in a large cohort of low- and high-risk PV patients. Methods:We conducted a real-world, retrospective cohort study using Optum's de-identified Market Clarity Data, which includes electronic health records (EHR) on 105 million US patients between 2007-2019. Eligible patients were ≥18 years [yrs] old and required ≥2 PV diagnosis codes with ≥60 days between the first and last diagnosis code in the data period. Patients were indexed at the first diagnosis code of PV preceded by ≥1 year of EHR data (“index”) and required ≥1 year of post-index data or death prior to data period end (12/31/2019). Patients with a pre-index diagnosis of secondary polycythemia, leukemia, myelodysplastic syndrome, myelofibrosis, or stem cell transplant were excluded. Patients were stratified into three groups based on risk status at index: low-risk (age &amp;lt;60 without prior history of TE), age-based high-risk (age &amp;gt;60 without prior history of TE) and event-based high-risk (prior history of TE). As outcomes, TEs were identified at the first occurrence of a diagnosis code for a TE in EHR during the post-index period. Descriptive statistics were used to characterize the proportion of patients with TEs and event rates per 1000 PY. Kaplan-Meier analysis was used to evaluate the probability of TE-free survival among patients in the three risk groups at various time points. Patients were censored at death or last engagement date. Results:The total study cohort included 20,089 PV patients (mean age, 63.0 yrs; 57.8% male; 88.6% Caucasian). Approximately one-third (34.4%; 6909 patients) were low-risk, 49.4% (9924 patients) were age-based high-risk, and 16.2% (3256 patients) were event-based high-risk. Among 17,402 patients with pre-index medication data, 16.0% (n=2777) received hydroxyurea (HU) pre-index. HU usage was highest in age-based high-risk patients (21.8%) followed by event-based high-risk (20.0%) and low-risk patients (5.8%). Median follow-up period was 4.3 yrs (IQR, 2.4-5.9). Incidence of TEs was assessed within patient groups (Table 1). Overall, 25.1% (5035/20,089) of patients with PV experienced at least one TE during the post-index period. Incidence of TEs was highest among event-based high-risk patients (50.2%; 1634/3256), followed by age-based high-risk (25.0%; 2480/9924) and low-risk patients (13.3%; 921/6909). The rate of post-index TEs was more than triple for event-based high-risk patients vs. age-based high-risk patients (206 vs. 68/1000 PY) and nearly 7 times higher vs. low-risk patients (206 vs. 31/1000 PY). The rate of TEs was more than double for age-based high-risk patients vs. low-risk patients (68 vs. 31/1000 PY). Incidence of arterial and venous TEs was assessed across the total cohort (Table 1). The most common arterial events were stroke (7.1%) and MI/ACS (6.4%). The most common venous events were DVT/deep thrombophlebitis (8.1%) and pulmonary embolism (4.5%). Kaplan-Meier analysis indicated that at ≈2.5 yrs (1000 days) post-index, TE-free survival was ≈90% for low-risk, ≈80% for age-based high-risk, and ≈55% for event-based high-risk patients (Figure 1). At ≈5.5 yrs (2000 days) post-index, TE-free survival had fallen to ≈85% for low-risk, ≈70% for age-based high-risk, and ≈40% for event-based high-risk patients. The downward trend continued until the end of the data period. Conclusion: Findings from this real-world analysis indicate that PV patients experience high rates of arterial and venous TEs. Event-based high-risk patients have a substantially lower probability of TE-free survival compared with age-based high-risk and low-risk patients. While patients with a prior history of TE have the highest thromboembolic risk, all patients with PV are at high risk of TE, indicating an unmet need for reduction of thromboembolic risks.

Age-Adjusted Charlson Comorbidity Index Is a Significant Factor for Predicting Thrombosis Development and Survival in Polycythemia Vera

Background: The worldwide-recognized prognostic role of age and previous thrombosis as part of standard risk score in polycythemia vera (PV) deserves some deeper insight . Aimof our study was to identify prediction factors for thrombosis development and overall survival (OS) in PV patients. Methods: Study included 816 PV patients diagnosed according to WHO classification and treated between 2005-2022 at University center. The analysis included: demographic, clinical and laboratory parameters with neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), thrombosis data, age-adjusted Charlson comorbidity index (ACCI) and presence of cardiovascular (CV) risk factors (arterial hypertension, diabetes, smoking, hyperlipidaemia). JAK2 positivity had 97.8% of patients. During follow up 29.8% of patients died. Results: Mean age was 62 years (range 18-87), 51.7% male and 61.3% older &amp;gt;60 years. According to standard risk score, 26.5% of patients belonged to low-risk group while 73.5% to high-risk group. According to ACCI: 11.8% were without comorbidities, mild grade had 34.4%, moderate 36% and severe 17.8% of patients. Distribution according to CV risk factor presence: without 25.6%, one 38.8%, two 27.5%, three 7.5%, four 0.6% of patients with highest incidence of arterial hypertension&amp;gt;smoking&amp;gt;diabetes &amp;gt;hyperlipidaemia. Previous thrombosis was reported in 182 patients (22.3%) with 222 thrombosis (160 arterial, 62 venous). During follow up 111 patients (13.6%) had 120 thrombosis (82 arterial, 38 venous). Previous thrombosis (p=0.029), ACCI groups (p&amp;lt;0.001), presence of CV factor ≥1 (p=0.001) or secondary malignancy (p&amp;lt;0.001) predicted venous thrombosis development. In comparison, previous thrombosis (p = 0.03), male gender (p=0.006) standard risk score (p=0.001), ACCI (p&amp;lt;0.001), CV factor ≥1 (p&amp;lt;0.001), NLR ≥5 (p=0.008) and PLR ≥500 (p&amp;lt;0.001), were predictors of arterial thrombosis development. In multivariate analysis, risk of venous thrombosis development was independently associated with only ACCI (HR 3.75; p&amp;lt;0.001) while arterial thrombosis with ACCI (HR2 2.12; p&amp;lt;0.01) and PLR ≥500 (HR 1.886, p=0.028). Patients with thrombosis during the follow-up had significantly shorter survival (p=0.048). Patients in low risk standard group had median survival of 221 months v.s high risk group patients with 119months (p&amp;lt;0.001). Median survival of patients according ACCI groups: without comorbidities 233 months; mild grade 171 months; moderate grade 120 months and severe grade 84 months (p&amp;lt;0.001). Univariate analysis identified factors associated with shorter OS: age ≥65y(p&amp;lt;0.001), Le ≥15x10 9/L (p&amp;lt;0.001), ANC ≥10x10 9/L (p&amp;lt;0.001), Plt ≥1000x10 9/L (p=0.027), presence of secondary malignancy (p&amp;lt;0.001), previous thrombosis (p=0.03), development of arterial (p&amp;lt;0.001) and venous (p&amp;lt;0.001) thrombosis during follow up. Of CV factors only presence of arterial hypertension showed negative survival effect (p=0.003). Multivariate Cox regression model revealed age ≥65y (HR=3.3; p&amp;lt;0.001), ACCI group (HR=1.7; p&amp;lt;0.001) and ANC ≥10x10 9/L (HR=1.6; p=0.001) as most important survival predictors. Patients with ACCI score ≥4 significantly received hydroxyurea (p&amp;lt;0.001). The mean OS was 12.5 years while 5-years and 10-years OS was 81% and 62% respectively. The cause of death was as the follows: heart failure (37%), second malignancy (15.2%), thrombosis (14.8%), progression of disease (8.6%), COVID infection (4.2%) and unknown cause in 20.2% of patients. Conclusion: Age-adjusted CCI was found to be the most reliable predictor of thrombosis development in PV. The application of ACCI allows better PV survival assessment by delineating ACCI moderate grade as intermediate risk survival group and improves identification of high-risk PV patients incorporating ACCI severe grade group with survival less than 7 years.

Firstline Treatment with Ruxolitinib Versus Best Available Therapy in Patients with Polycythemia Vera: Pre-Specified Interim Analysis of the Randomized Phase 2b Ruxobeat Clinical Trial of the German Study Group for Myeloproliferative Neoplasms (GSG-MPN)

Introduction: Polycythemia vera (PV) is characterized by trilineage blood cell expansion, PV-associated symptoms, and the risk of thromboembolic complications, progression to post-PV myelofibrosis, and acute leukemia. Cytoreductive treatment with hydroxyurea (HU) or ropeginterferon-alpha is approved in EU for the treatment of high-risk patients (pts) with PV. In addition, ruxolitinib (RUX) is approved for HU-intolerant/-resistant PV. However, RUX vs. best available therapy (BAT) has not been investigated as first-line treatment of pts with untreated PV. We hypothesized that RUX may have higher efficacy in such early-line PV pts. Methods: The clinical trial entitled “Ruxolitinib versus Best Available Therapy in pts with high-risk PV or high-risk ET” (RuxoBEAT; NCT02577926) is a multicenter, open-label, two-arm phase-IIb trial with a target population of 190 pts in each stratum. Crossover from BAT to RUX is possible in eligible pts after 6 months. Pts with PV in the RUX arm received a starting dose of 10 mg BID and may increase their dose up to 20 mg BID. The primary endpoint is the clinicohematologic complete response (CR) rate at month 6, as defined by Barosi et al (Blood 2009), using a strict score of zero for the four symptoms by patient-reported outcome measures (PROM, Table 2) and an adjusted level alpha = 0.005 at a power of 80%. Secondary endpoints include overall response rate (CR+PR), freedom from phlebotomy, changes in blood counts, spleen size, and PROM, using p values descriptively. The interim trial data were recently reviewed by the DMC, and, due to the low likelihood of reaching the primary endpoint (CR rate improvement), the DMC has recommended that the trial should continue without recruitment of new pts. Therefore, this pre-specified interim analysis was performed after 78 (instead of 95) PV pts were randomized 1:1 to RUX vs. BAT. A maximum of 6 weeks of previous PV-directed therapy was allowed. Differences between RUX and BAT at month 6 and between baseline and end of month 6 data for each treatment were calculated using Fisher´s exact test/ McNemar Test (for unpaired/ paired binary variables) or the Mann-Whitney-U test/ Wilcoxon signed-rank test (for unpaired/ paired ordered or continuous variables). Results: 78 first-line pts (33% were pre-treated for a median of 22 days [range 1-42]) were included in the intention-to-treat set (n=44 vs 34 randomized to RUX vs. BAT, resp.) and analyzed at the 6-month time point. Baseline characteristics are listed in Table 1. In pts on RUX or BAT, CR rates at 6 months were comparable (2.3% and 2.9%, p=1.0), while overall response (CR+PR) rates were 77.3% with RUX and 55.9% with BAT (p=0.054). Also, at month 6 (Table 2), pts on RUX showed significantly lower hematocrit (40.8% vs 42.1%, p=0.046), and PROM symptom points for pruritus (1 vs 4, p=0.001) and fatigue (2.5 vs 5, p=0.031), and a trend towards less headache, abdominal discomfort, and weight loss, while the number of platelets was lower with BAT vs. RUX (254/nl vs 386/nl, p=0.013). There was no difference between RUX and BAT in the number of white blood cells (WBC), spleen size, or other symptoms at this time point. When each treatment arm was analyzed separately for changes between baseline and month 6, RUX treatment significantly reduced platelet counts, WBC, hemoglobin and hematocrit, phlebotomy rates, spleen size and fraction of pts with splenomegaly (Table 2), and significantly improved PROMs for pruritus, early satiety, and quality of life. During the same time period, BAT significantly reduced platelet counts, WBC, hematocrit, and phlebotomy rates, but failed to impact on hemoglobin, spleen size, fraction of pts with splenomegaly, or any of the symptoms (Table 2). Safety analysis revealed 301 adverse events (AE) in both assigned treatment groups, including 153 AE in the RUX and 148 AE in the BAT group (11.8% and 8.1% grade ≥3, resp.). There was no significant difference in the percentage of grade ≥3 AE between both groups (p=0.358), and there were no consistent patterns of grade ≥3 AE in either of the two arms. Conclusion: In this interim analysis, first-line treatment with ruxolitinib for 6 months in high-risk pts with PV led to clinically meaningful improvements in overall response, hemoglobin and hematocrit, phlebotomy rates, splenomegaly, and patient-reported pruritus and fatigue severity, while BAT only improved platelet counts, WBC, hematocrit, and phlebotomy rates, without having an impact on symptoms.

Efficacy and safety of ruxolitinib in patients with newly-diagnosed polycythemia vera: futility analysis of the RuxoBEAT clinical trial of the GSG-MPN study group

Patients (pts) with polycythemia vera (PV) suffer from pruritus, night sweats, and other symptoms, as well as from thromboembolic complications and progression to post-PV myelofibrosis. Ruxolitinib (RUX) is approved for second-line therapy in high-risk PV pts with hydroxyurea intolerance or resistance. The RuxoBEAT trial (NCT02577926, registered on October 1, 2015, at clinicaltrials.gov) is a multicenter, open-label, two-arm phase-IIb trial with a target population of 380 pts with PV or ET, randomized to receive RUX or best available therapy. This pre-specified futility analysis assesses the early clinical benefit and tolerability of RUX in previously untreated PV pts (6-week cytoreduction was allowed). Twenty-eight patients were randomly assigned to receive RUX. Compared to baseline, after 6 months of treatment, there was a significant reduction of median hematocrit (46 to 41%), the median number of phlebotomies per year (4.0 to 0), and median patient-reported pruritus scores (2 to 1), and a trend for reduced night sweat scores (1.5 to 0). JAK2V617F allele burden, as part of the scientific research program, also significantly decreased. One hundred nine adverse events (AEs) occurred in 24/28 patients (all grade 1 to 3), and no pt permanently discontinued treatment because of AEs. Thus, treatment with ruxolitinib in untreated PV pts is feasible, well-tolerated, and efficient regarding the above-mentioned endpoints.

Characteristics, Blood Counts, Treatments, and Clinical Outcomes of 5871 Patients with Polycythemia Vera Treated in US Community Practices

Background: Cytoreduction with hydroxyurea (HU) is the recommended first-line (1L) treatment for high-risk polycythemia vera (PV) (age ≥60 years or history of thrombosis), but many patients (pts) have suboptimal response to HU. This study describes characteristics, blood counts, treatments, and clinical outcomes among pts with PV, including those with suboptimal response to HU, in 2 large networks of US community oncology practices. Methods: This was a retrospective observational study of adult pts with a documented new diagnosis of PV in the iKnowMed electronic health record database (01Jan2008-31Jan2020), which is implemented in The US Oncology Network and non-Network practices. Pts with ≥2 postdiagnosis visits during the study observation period (01Jan2008-31Jan2021) were included in the analysis. Suboptimal response to HU was defined as meeting ≥1 of the following criteria after ≥3 months of treatment: (1) white blood cell (WBC) count >10 × 109/L, (2) platelet count >400 × 109/L, and/or (3) hematocrit (HCT) >45%. Data on demographic/clinical characteristics and prior treatment were summarized with descriptive statistics. Duration of therapy and overall survival were assessed via the Kaplan-Meier method, which censored pts without subsequent treatment discontinuation/death records at the end of the study observation period. Results: 5871 pts (The US Oncology Network, n=3022; non-Network, n=2849) met all eligibility criteria and were included in the analysis. Mean (SD) age at diagnosis was 66.1 (13.6) years (70% ≥60 years), 44% of pts were female, 87% were White, and 49% were current or former tobacco users. At diagnosis, 6% of pts had a history of thrombotic event, and 71% had high-risk PV; 38% (1535/4021), 34% (1361/4014), and 67% (2696/4010) of evaluable pts had elevated WBC (>10 × 109/L), platelets (>400 × 109/L), and HCT (>45%), respectively. Over half of pts with high-risk PV (55%; 2303/4185) received a cytoreductive agent as 1L treatment (90% HU), and 45% did not receive cytoreductive therapy. Among those with low-risk PV, 32% (540/1686) received a cytoreductive agent as 1L treatment (89% HU), and 68% did not receive cytoreductive therapy. Five-year survival probability was 82% among all pts, 79% for pts with high-risk PV (age ≥60 years or history of thrombosis), and 96% for those with low-risk PV. Overall, 56% of patients had a suboptimal response for blood count control after 3 months of treatment; this remained roughly the same at 6 months (Table). Among pts who received 1L HU, median (Q1, Q3) time from diagnosis to HU initiation was 29.0 (0.0, 252.5) days for those with high-risk PV and 103.0 (0.0, 683.5) days for those with low-risk PV; median (Q1, Q3) duration of HU was 26.7 (8.1, 54.6) and 35.6 (9.3, 68.5) months, respectively. Among pts treated with 1L HU who had evaluable blood counts, 42% (1078/2548) had a suboptimal response at 3 months, 64% of whom (691/1078) continued to have a suboptimal response at 6 months (WBC >10 × 109/L and/or platelets >400 × 109/L, 50%; HCT >45%, 36%). Median duration of 1L HU treatment for pts with suboptimal response was 26.6 (95% CI: 24.0, 29.3) months. Among pts with suboptimal response to 1L HU, 5-year survival probability was 82% overall (high risk, 78%; low risk, 99%). Pts with suboptimal response appeared to have a lower 5-year survival probability than pts with optimal response (81.5% [95% CI: 77.7%, 85.5%] vs 84.3% [95% CI: 81.2%, 87.4%]). This difference between pts with suboptimal vs optimal response was statistically significant in non-Network (74.5% [95% CI: 67.7%, 82.0%] vs 85.1% [95% CI: 81.1%, 89.3%]; P=0.008) but not in The US Oncology Network practices (86.7% [95% CI: 82.3%, 91.2%] vs 83.6% [95% CI: 79.1%, 88.3%]; P=0.109). Besides this difference observed in the 5-year survival probability, pt characteristics and outcomes were similar between the 2 networks, although additional data (eg, pt/disease characteristics; phlebotomy use, supportive care) are needed to better understand differences between networks. Conclusions: The prevalence of elevated blood counts at diagnosis and follow-up while on HU treatment is consistent with previous real-world evidence. About 1 in 6 pts with a suboptimal response to HU died within 5 years, and there was a trend toward shorter survival among those with suboptimal response compared with pts with blood count control. HU dose adjustments or alternative treatments may be needed for pts with suboptimal response to HU. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Long-Term Ropeginterferon Alfa-2b Treatment in Patients with Low-Risk and High-Risk Polycythemia Vera (PV)

Introduction: Patients with "low-risk” (LR) PV are managed conservatively despite higher risk of vascular events and impaired quality of life compared to a population without PV. Acknowledging new evidence (LOW-PV study, Barbui et al 2021), recent treatment guidelines (European LeukemiaNet [ELN] 2021) recommend ropeginterferon alfa-2b (BESREMi®) as a cytoreductive treatment in LR PV patients meeting specific criteria as well as in high-risk (HR) PV patients. Final data from the phase 3 PROUD-PV and CONTINUATION-PV trials (NCT01949805; NCT02218047) demonstrated the long-term efficacy and safety of ropeginterferon alfa-2b compared with hydroxyurea/best available treatment (HU/BAT); here we report results in the ropeginterferon alfa-2b arm by risk stratum. Methods: PV patients were randomized 1:1 and received ropeginterferon alfa-2b or HU/BAT for ≥6 years. In the ropeginterferon alfa-2b arm, subgroup analyses were performed post-hoc by risk stratum (LR: age ≤60 years and no history of thrombosis; all others HR). Complete hematologic response (CHemR) and molecular response defined by modified ELN criteria were assessed in the full analysis set for CONTINUATION-PV (N=95); safety analyses included all data regardless of roll-over (N=127). Results: CONTINUATION-PV enrolled 46 LR and 49 HR patients in the ropeginterferon alfa-2b arm. At baseline, mean age was 50.7 vs 63.7 years respectively, and median duration since PV diagnosis was 1.9 months vs 1.5 months. HR patients had higher platelet and leukocyte counts at baseline and more frequently presented with clinically significant splenomegaly or PV-related symptoms. Median JAK2V617F allele burden was similar for LR and HR patients (37.0% vs 39.4%), however LR patients were less likely to harbor additional non-driver mutations (11.4% vs 24.4%). The median 4-weekly ropeginterferon alfa-2b dose was comparable in LR and HR patients throughout the study (in the 6th year, 499 µg and 489µg respectively) as was the use of an extended 3-4 weekly dose regimen (6th year: 59.5% vs 65.4%). LR patients achieved a significantly higher CHemR rate than HR patients during long-term treatment (Month 72: 73.2% vs 38.3% in LR and HR respectively [RR: 2.41; 95% CI: 1.50 to 3.90; p=0.0003]). Higher CHemR among LR patients was confirmed in a sensitivity analysis including discontinued patients (last observation carried forward [LOCF]; 80.4% in LR vs 65.3% in HR patients at Month 72) indicating that in the HR group, more patients discontinued despite CHemR. In general, discontinued patients were older than those who completed the study (mean age 62.8 years vs 55.2 years) but did not have a longer duration of PV or markedly greater symptom burden at baseline. Importantly, regardless of risk stratum, most patients receiving ropeginterferon alfa-2b did not require any phlebotomy for the entire 6th year (85.7% of LR patients and 75.0% of HR patients entering the 6th year [p=0.3]). LR patients had a higher molecular response rate than HR patients (LOCF at Month 72: 84.4% vs 49.0% respectively, RR: 2.15 [95% CI: 1.37 to 3.37]; p=0.0009) and achieved molecular response more rapidly (median time to first response: 12 months [95% CI: 12 to 18] vs 18 months [95% CI: 12 to 24]; Log-rank test p=0.03). The median JAK2V617F allele burden was 5.6% for LR and 17.9% for HR patients at Month 72 (p<0.0001). During the entire PROUD-PV/CONTINUATION-PV studies (≥6 years exposure), adverse drug reactions (ADRs) to ropeginterferon alfa-2b led to withdrawal of treatment in 1 (1.8%) LR patient (due to sarcoidosis), and in 13 (18.3%) HR patients (due to thrombocytopenia [n=1], elevated transaminases [n=1], psychiatric disorders [n=2], autoimmune disorders [n=6], hypothyroidism [n=2] and dyspnea/pneumonitis [n=1]). LR patients were also less likely than HR patients to experience ADRS of grade ≥3 severity (5.4% vs 23.9%). Conclusion: These results demonstrate the benefit of ropeginterferon alfa-2b therapy in both HR and LR patient populations. LR patients may have a greater potential benefit: higher hematologic and molecular response rates can be safely achieved, and the patients are more likely to remain on long-term treatment. These data provide further evidence for an early treatment start as recently outlined by the updated ELN guidelines.

The Second Generation Type II JAK2 Inhibitor, AJ1-10502, Demonstrates Enhanced Selectivity, Improved Therapeutic Efficacy and Reduced Mutant Cell Fraction Compared to Type I JAK2 Inhibitors in Models of Myeloproliferative Neoplasms (MPNs)

Type I JAK inhibition (JAKi) represents a mainstay therapy for myelofibrosis and hydroxyurea-resistant high-risk polycythemia vera. Current type I JAKi, including ruxolitinib (RUX) and fedratinib, improve symptoms and outcomes in MPNs; however, JAK2VF allele burden remains essentially unchanged, and efficacy wanes over time. Sustained JAK/STAT signaling plays a critical role in MPN cell persistence in the setting of type I inhibition. CHZ868, a type II JAKi that binds the inactive conformation of the kinase domain, overcomes RUX persistence in vitro and reduces Jak2VF allele fraction in vivo suggesting improved JAK2 targeting might enhance clinical efficacy. However, current type II JAKi, including CHZ868, are limited by lack of kinome specificity and off-target toxicity. We therefore sought to develop novel type II JAK2i with improved potency and selectivity. Computational free energy perturbation and structure-activity relationship-based methods were used to identify lead type II inhibitor compounds. This work, followed by Absorption, Distribution, Metabolism and Excretion modeling, led to the development of AJ1-10502. Kinome selectivity profiling of AJ1-10502 revealed potent JAK2 selectivity with minimal kinase cross-reactivity compared to CHZ868, including among other JAK family tyrosine kinases (Figure 1A). Assessment of in vitro efficacy of AJ1-10502 in SET2 inhibitor naïve and SET2 RUX persistence (RUXper) cells revealed concentration-dependent inhibition of proliferation of RUXper cells comparable to that of CHZ868. The IC50 for AJ1-10502 in RUXper cells was similar to the IC50 observed in inhibitor naïve cells. We next evaluated AJ1-10502 in vivo using a novel dual Dre/Cre-recombinase Jak2VF knock-in/knock-out model allowing for the comparison of JAKi to Jak2VF genetic deletion. AJ1-10502 demonstrated reductions in leukocytosis comparable to that of RUX (K/uL: VEH 18.7 vs. RUX 10.1 vs. AJ1-10502 9.3) but dose-dependent improvements in hematocrit, platelet levels, and spleen weights superior to RUX, with reductions in spleen weights on par to that of Jak2VF deletion (mg: VEH 480 vs. RUX 255 vs. AJ1-10502 145 vs. del 107, p<0.05). A greater degree of restoration of splenic architecture was also observed with AJ1-10502 compared to type I JAKi. Critically, we observed reductions in peripheral blood (PB) and bone marrow (BM) mutant allele fraction with AJ1-10502 not observed with RUX, including within Mac1+Gr1+ myeloid cell fractions (VEH 94% vs. RUX 92% vs. AJ1-10502 78.5%, p<0.05), consistent with a mutant-biased reduction in myeloid output. In a separate series of competitive transplants using a Cre-inducible human JAK2VF transgenic mouse line, we validated the phenotypic changes in regard to leukocytosis, hematocrit, and spleen weight reduction seen with the DreCre model. Most importantly, we confirmed significant reductions in mutant cell fraction within the hematopoietic stem (HSC) compartment of BM and spleen, including among granulocytic-monocytic progenitor (GMP) and long-term HSC (LT-HSC) populations (Figure 1B). Finally, a separate study comparing AJ1-10502 to CHZ868 revealed no significant weight loss with AJ1-10502 (-0.5g) compared to CHZ868 (-2.2g, p<0.05) despite similar reductions in Jak2VF allele fraction suggesting comparable efficacy without systemic toxicity. In sum, AJ1-10502 is a potent, selective type II JAK2i with improved efficacy compared to RUX and an enhanced safety profile compared to previous non-selective type II JAKi. Most importantly, AJ1-10502 results in superior reductions in PB and BM mutant cell fraction in vivo not observed with type I JAKi. These data demonstrate the preclinical utility of type II JAKi with AJ1-10502 and inform a path to clinical development of type II JAKi for MPN patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

MPN-077 Characteristics, Blood Counts, Treatments, and Clinical Outcomes of 3022 Patients With Polycythemia Vera (PV) Treated in US Community Practices.

Cytoreduction with hydroxyurea (HU) is the recommended first-line (1L) treatment for high-risk PV (age ≥60 years; history of thrombosis), but many patients have a suboptimal response. To describe characteristics, blood counts, treatments, and clinical outcomes among patients with PV. Retrospective observational study of adults in The US Oncology Network iKnowMed electronic health record database with ≥2 post-PV diagnosis visits during the study (01JAN2008-31JAN2021). Suboptimal response was defined as meeting ≥1 of the following criteria after ≥3 months of HU treatment: (1) white blood cell (WBC) count >10×109/L, (2) platelet count >400×109/L, and/or (3) hematocrit (HCT) >45%. Duration of therapy and overall survival were assessed via Kaplan-Meier method. Overall, 3022 patients with PV were included (mean age at diagnosis, 65.8 years [69% ≥60 years]; female, 46%; White, 85%; current/former tobacco users, 49%). At diagnosis, 7% of patients had a history of thrombosis, and 71% had high-risk PV; 37% (886/2413), 32% (778/2411), and 67% (1617/2418) had elevated WBC (>10×109/L), platelets (>400×109/L), and HCT (>45%), respectively. Cytoreductive therapy as 1L treatment was received by 48% of patients (44% HU); phlebotomy data were unavailable. Five-year survival probability was 84% among all patients (low-risk [age <60 years; no history of thrombosis], 97%; high-risk, 81%). Among patients who received 1L HU (n=1317), median (Q1, Q3) time from diagnosis to HU initiation was 19 (0, 189) days; median (Q1, Q3) duration of HU was 30 (9.5, 64.4) months, and 29.5 (9.5, 58.5) and 35.0 (9.5, 77.0) months for high- and low-risk patients, respectively. Among patients on 1L HU with evaluable blood counts, 55% (584/1053) had a suboptimal response (WBC >10×109/L, 26%; platelets >400×109/L, 26%; HCT >45%, 36%) at 3 months; similar findings were seen at 6 months. Among patients with suboptimal response to 1L HU, 5-year survival probability was 87% (low risk, 100%; high risk, 84%). The prevalence of elevated blood counts at diagnosis and follow-up while on HU treatment is consistent with previous real-world experience. About 1 in 8 patients with a suboptimal response to HU died within 5 years.

The Predictive Value of Neutrophil-Lymphocyte Ratio in Patients with Polycythemia Vera at the Time of Initial Diagnosis for Thrombotic Events.

Objective To investigate and discuss the predictive value of the neutrophil-to-lymphocyte ratio (NLR) in patients with polycythemia vera (PV) at the time of initial diagnosis, as well as its clinical significance in predicting the occurrence of thrombotic events and the progression of future thrombotic events during follow-ups, with the goal of providing a reference for the early identification of high-risk PV patients and the early intervention necessary to improve the prognosis of PV patients. Method A total of 170 patients diagnosed with PV for the first time were enrolled in this study. The risk factors affecting the occurrence and development of thrombotic events in these patients were statistically analyzed. Results NLR (P = 0.030), WBC count (P = 0.045), and history of previous thrombosis (P < 0.001) were independent risk factors for thrombotic events at the time of initial diagnosis. Age ≥ 60 years (P = 0.004), NLR (P = 0.025), history of previous thrombosis (P < 0.001), and fibrinogen (P = 0.042) were independent risk factors for the progression of future thrombotic events during follow-ups. The receiver operating characteristic curve (ROC curves) showed that NLR was more effective in predicting the progression of future thrombotic events than age ≥ 60 years, history of previous thrombosis, and fibrinogen. Kaplan-Meier survival analysis showed progression-free survival time of thrombotic events in the high NLR value group (NLR ≥ 4.713) (median survival time 22.033 months, 95% CI: 4.226-35.840), which was significantly lower compared to the low NLR value group (NLR < 4.713) (median overall survival time 66.000 months, 95% CI: 50.670-81.330); the observed difference was statistically significant (P < 0.001). The 60-month progression-free survival in the low NLR value group was 58.8%, while it was 32.8% in the high NLR value group. Conclusion Peripheral blood NLR levels in patients with PV resulted as an independent risk factor for the occurrence of thrombotic events at the time of initial diagnosis and for the progression of future thrombotic events during follow-ups. Peripheral blood NLR levels at the time of initial diagnosis and treatment had better diagnostic and predictive value for the progression of future thrombotic events in patients with PV than age ≥ 60 years, history of previous thrombosis, and fibrinogen.

PB2053: PRIMARY ARTERIAL HYPERTENSION IN MYELOPROLIFERATIVE NEOPLASMS: A SYSTEMATIC REVIEW

Background: Patients diagnosed with myeloproliferative neoplasms (MPNs) are prone to experience thrombotic events and often experience a high burden of cardiovascular comorbidities. Primary arterial hypertension (HTN) remains one of the most common comorbidities in the elderly. However, the impact of HTN on MPNs is unclear. Aims: Report on the occurrence of HTN in MPNs. Describe its epidemiology, influence on development of thrombosis, HTN treatment strategies. Methods: Systematic search in PubMed/Medline, Web of Science and SCOPUS, from the inception of these databases to retrieve relevant English-written articles. Eligibility criteria: 1. Confirmed MPNs diagnosis, 2. Confirmed HTN diagnosis, 3. Studies reported on the epidemiology of HTN in MPNs, impact of HTN on the development of thrombosis or on the therapeutic options used to treat HTN in MPNs. We excluded studies investigating secondary HTN, e.g., drug-induced HTN. Results: The systematic search resulted in 590 potentially relevant manuscripts. After removal of duplicates and screening of abstracts/titles (n=503), 87 manuscripts were selected for full-text review. After applying the eligibility criteria and full-text evaluation, 25 articles were excluded and the remaining 62 were entered into the qualitative/quantitative analysis. HTN emerged as the most common comorbidity in MPNs, affecting 41-63% of primary myelofibrosis (PMF), 40-64% of essential thrombocythemia (ET), 46-90% of polycythemia vera (PV) cases. In PV, the presence of HTN was associated with decreased serum free epinephrine and aldosterone levels, reduced retinal microperfusion, elevated kidney arteries resistance, JAK2-V617F mutation and high-risk PV. In PMF, it was linked with high uric acid concentrations and elevated risk of thrombosis (OR=1.96). PV subjects with HTN were non-dippers, suffered from systolic/diastolic dysfunction as assessed by cardiac ultrasound, displayed elevated cell-free hemoglobin and nitrite/nitrate ratio, and an increased risk of thrombosis (HR=1.77). HTN in ET was associated with overall thrombosis, especially arterial thrombosis (HR=1.91-3.8). The cardio-IPSET score was superior in predicting thrombosis in ET patients with HTN. Individuals with MPNs and HTN exhibited signs of carotid artery injury, end-organ damage, increased albumin-to-creatinine ratio, P-selectin concentrations and were prone to develop kidney dysfunction. Moreover, stroke was more common in MPNs with concomitant HTN (HR=4.24) and HTN was a predictor of ischemic stroke recurrence in MPNs. The risk of thrombosis in MPNs was higher if HTN was also associated with other cardiovascular risk factors, i.e., dyslipidemia, diabetes or smoking. The risk of cerebral venous sinus thrombosis was lower in MPNs with co-occurring HTN. In terms of treatment options for patients with HTN and MPNs, angiotensin-converting enzyme inhibitors (ACEI), e.g., lisinopril, and calcium-channel blockers (CCB - nifedipine for hypertensive emergencies) have been successfully used. The recommendation to avoid the use of diuretics in patients with elevated blood viscosity, e.g., PV, remains unaltered. Summary/Conclusion: Our findings suggest that HTN is the most common comorbidity in MPNs and is associated with development of thrombosis, end-organ damage, i.e., retinal and kidney dysfunction. Integration of HTN in the current scores employed to predict the development of thrombosis and stratify MPNs subjects in warranted. Screening for HTN in MPNs is urgently needed. Accurate management strategies based on the use ACEI and CCB need further exploration in MPNs with associated HTN.

Anagrelide for platelet-directed cytoreduction in polycythemia vera: Insights into utility and safety outcomes from a large multi-center database

Anagrelide (ANA) is a platelet-specific cytoreductive agent utilized in the guideline-directed management of high-risk essential thrombocythemia. In the context of polycythemia vera (PV), ANA is occasionally employed in clinical practice, although data has not consistently demonstrated a benefit to targeting a platelet goal as a therapeutic endpoint. The aim of the current study was to delineate the patterns of ANA use in PV, and to describe outcomes and toxicities. Within a multi-center cohort of 527 patients with PV, 48 received ANA (9 excluded for absent data). 27 (69.2%) had high-risk PV, 10 (25.6%) had prior thrombosis, and none had extreme thrombocytosis, acquired von Willebrand disease, and/or documented resistance to hydroxyurea. While ANA effectively lowered median platelet count, 43.5% of patients had an unresolved thrombocytosis at time of ANA discontinuation. Treatment-emergent adverse events—including headaches, cardiac palpitations and arrhythmias, nausea, vomiting and/or diarrhea—led to ANA discontinuation in 76.9% of patients. Further, three patients experienced arterial thromboses during a median duration of 27.5 months of ANA therapy. In conclusion, this study highlights ANA’s restrictive tolerability profile which, compounded by the absence of clear advantage to strict platelet control in PV, suggests the use of ANA should be limited in this setting.

Characteristics, blood counts, treatments, and clinical outcomes of 3,022 patients (Pts) with polycythemia vera (PV) treated in U.S. community practices.

e19076 Background: Cytoreduction with hydroxyurea (HU) is the recommended first-line (1L) treatment for high-risk PV (age ≥60 y or history of thrombosis), but many pts have a suboptimal response on HU. The objective of this study was to describe characteristics, blood counts, treatments, and clinical outcomes among pts with PV, including those with suboptimal response to HU, in a large network of US community oncology practices. Methods: This was a retrospective observational study of adult pts with a documented diagnosis of PV in The US Oncology Network iKnowMed electronic health record database. Pts with ≥2 post-diagnosis visits during the study observation period (01JAN2008–31JAN2021) were included in the analysis. Suboptimal response to HU was defined as meeting ≥1 of the following criteria after ≥3 months of treatment: (1) white blood cell (WBC) count &gt; 10 × 109/L, (2) platelet count &gt; 400 × 109/L, and/or (3) hematocrit (HCT) &gt; 45%. Data on demographic and clinical characteristics and prior treatment were collected and summarized using descriptive statistics. Duration of therapy and overall survival were assessed via Kaplan-Meier method; pts without subsequent treatment discontinuation/death records were censored. Results: Overall, 3022 pts with PV were included in the analysis; mean age at diagnosis was 65.8 years (69% ≥60 y), 46% of pts were female, 85% were White, and 49% were current/former tobacco users. At diagnosis, 7% of pts had a history of thrombotic event, and 71% had high-risk PV; 37% (886/2413), 32% (778/2411), and 67% (1617/2418) of evaluable pts had elevated WBC (&gt; 10 × 109/L), platelets (&gt; 400 × 109/L), and HCT (&gt; 45%), respectively. Nearly half of pts (48%) received a cytoreductive agent as 1L treatment (44% HU), and 52% did not receive cytoreductive therapy; phlebotomy data were unavailable. Five-year survival probability was 84% among all pts, 97% for low-risk pts (age &lt; 60 y; no history of thrombosis), and 81% for high-risk pts. Among pts who received 1L HU (n = 1317), median (Q1, Q3) time from diagnosis to HU initiation was 19 (0, 189) days; median (Q1, Q3) duration of HU was 30 (9.5, 64.4) months overall, and 29.5 (9.5, 58.5) and 35.0 (9.5, 77.0) months for high- and low-risk pts, respectively. Among pts on 1L HU with evaluable blood counts, 55% (584/1053) had a suboptimal response (WBC &gt; 10 × 109/L, 26%; platelets &gt; 400 × 109/L, 26%; HCT &gt; 45%, 36%) at 3 months; similar findings were seen at 6 months. Among pts with suboptimal response to 1L HU, 5-year survival probability was 87% overall (low risk, 100%; high risk, 84%). Conclusions: The prevalence of elevated blood counts at diagnosis and follow-up while on HU treatment is consistent with previous real-world experience. About 1 in 8 pts with a suboptimal response to HU died within 5 years. HU dose adjustments or alternative treatments may be needed for pts with suboptimal response to HU.

Hydralazine Associated With Reduced Therapeutic Phlebotomy Frequency in a Nationwide Cohort Study: Real-World Effectiveness for Drug Repurposing.

Background: Therapeutic phlebotomy, known as scheduled bloodletting, has been the main method for managing erythrocytosis symptoms and thrombocytosis-associated complications in various blood disorders. One of the major indications for phlebotomy is polycythemia vera (PV). The main goal of current treatment strategies for patients who require phlebotomy is to prevent thrombohemorrhagic complications rather than to prolong survival or lessen the risk of myelofibrotic or leukemic progression. Additional cytoreductive therapy is recommended for high-risk PV, for which the common first-line drug is hydroxyurea. However, recent evidence suggests that phlebotomy may not reduce the risk of thrombosis in patients with PV. Further evidence suggests that patients with PV treated with hydroxyurea who require three or more phlebotomy procedures per year have a higher risk of thrombotic complications. Methods: We hypothesized that a drug-repurposing strategy of utilizing antineoplastic drugs for patients who require phlebotomy would result in greater benefits than would phlebotomy. The antihypertensive hydralazine and the anticonvulsant valproate, which have both been reported to have antineoplastic activity that mimics cytoreductive agents, were selected as candidates for the drug-repositioning strategy in a retrospective cohort study. We measured the hazard ratios (HR) and the frequencies of phlebotomy in patients with prescriptions for hydralazine or valproate or the two drugs in combination by using data from Taiwan’s National Health Insurance Research Database from 2000 to 2015 (n = 1,936,512). Results: The HRs of undergoing phlebotomy in groups with hydralazine, valproate, and combination hydralazine–valproate prescriptions were reduced to 0.729 (p = 0.047), 0.887 (p = 0.196), and 0.621 (p = 0.022), respectively. The frequency of undergoing phlebotomy decreased from 2.27 to 1.99, 2.01, and 1.86 per person-year (p = 0.015), respectively. However, no significant differences were observed for the hydralazine group or the hydralazine–valproate combination group. Conclusion: Whether a repurposed drug can serve as a cytoreductive agent for patients who require phlebotomy depends on its risk–benefit balance. We suggest that hydralazine, instead of the hydralazine–valproate combination, is a reasonable alternative for patients who require regular phlebotomy.

Role of JAK inhibitors in myeloproliferative neoplasms: current point of view and perspectives.

Classic Philadelphia-negative myeloproliferative neoplasms (MPN) include polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), classified as primary (PMF), or secondary to PV or ET. All MPN, regardless of the underlying driver mutation in JAK2/CALR/MPL, are invariably associated with dysregulation of JAK/STAT pathway. The discovery of JAK2V617F point mutation prompted the development of small molecules inhibitors of JAK tyrosine kinases (JAK inhibitors-JAKi). To date, among JAKi, ruxolitinib (RUX) and fedratinib (FEDR) are approved for intermediate and high-risk MF, and RUX is also an option for high-risk PV patients inadequately controlled by or intolerant to hydroxyurea. While not yet registered, pacritinib (PAC) and momelotinib (MMB), proved to be effective particularly in thrombocytopenic and anemic MF patients, respectively. In most cases, JAKi are effective in reducing splenomegaly and alleviating disease-related symptoms. However, almost 50% lose response by three years and dose-dependent toxicities may lead to suboptimal dosing or treatment discontinuation. To date, although not being disease-modifying agents, JAKi represent the therapeutic backbone particularly in MF patient. To optimize therapeutic strategies, many trials with drug combinations of JAKi with novel molecules are ongoing. This review critically discusses the role of JAKi in the modern management of patients with MPN.

What's new in myeloproliferative neoplasia?

Treatment of myeloproliferative neoplasia (MPN) is based on patients' individual risk-stratification and includes cytoreductive agents for high-risk essential thrombocythemia (ET), polycythemia vera (PV) and Myelofibrosis (MF). Classical cytoreductive drugs largely fail to modify the basic clonal composition of the disease. In contrast, in PV for example treatment with Ropeg-Interferon not only results in higher hematological response rates compared to hydroxyurea but in addition significantly reduces JAK2 allele-burden in high-risk PV patients as well as it depletes concurrent cytogenetic and molecular abnormalities. Treatment with Ropeg-Interferon so far is only approved for high-risk PV. A very recent trial however also demonstrated this disease-modifying effect also in low-risk PV patients in addition to an increased rate of transfusion independence. Thus, Ropeg-Interferon is the current standard for first line treatment of high-risk PV and we assume that the data in low-risk PV will lead also to a broader clinical use of Ropeg-Interferon this particular patient group, as it may decrease transformation to MF or even MPN-blast crisis.Myelofibrosis management has been extended by novel JAKi. Fedratinib is the first second generation JAK-inhibitor approved for Ruxolitinib-intolerant or refractory patients. Fedratinib reduces both spleen volume as well as symptom burden. Two other second generation JAK-inhibitors are in clinical development for MPN treatment. Pacritinib has demonstrated efficacy in reducing both spleen volume and symptom score in MF including a cohort of Ruxolitinib-pretreated patients and Momelotinib is the only JAK-inhibitor which has been shown to alleviate anemia in addition to its effect on improving spleen volume and symptom. So far, neither Pacritinib nor Momelotinib are currently EMA-approved for MPN treatment.Finally, it has recently been acknowledged that inflammation is a key driver of MPN pathogenesis. Both, mutated as well as non-clonal inflammatory and other stromal cells produce significant amounts of local cytokines. Also the initiation of the neoplastic process itself seems to depend on inflammatory cytokines. Recent scRNASeq data revealed components of the alarmin complex (S100A8 und S100A9) drive this local sterile inflammation process, which also represents a potential therapeutic target, as the S100A8 and A9 inhibitor Tasquinimod reduced fibrosis in a pre-clinical animal model.

Thrombotic events and mortality risk in patients with newly diagnosed polycythemia vera or essential thrombocythemia

Patients with polycythemia vera (PV) and essential thrombocythemia (ET) have increased thrombotic risk. This retrospective, real-world analysis of Medicare patients (age ≥ 65 years) newly diagnosed with high-risk PV or intermediate-/high-risk ET compared mortality risk among those with versus without thrombotic events during the study period. Patients diagnosed with PV or ET with ≥ 1 inpatient or ≥ 2 outpatient claims (January 1, 2010–December 31, 2017; index was date of first qualifying claim) were included. The study included 50,405 Medicare beneficiaries with PV and 124,569 with ET. During follow-up (median [range]: PV, 34.5 [0–97.3] months; ET, 25.5 [0–97.4] months), 14,334 patients (28.4%) with PV and 30,478 (24.5%) with ET experienced thrombotic events (most commonly ischemic stroke [PV, 46.0%; ET, 42.5%]. Mortality risk was increased for patients with versus without post-index thrombosis for both PV (adjusted hazard ratio [aHR; 95% CI], 18.6 [16.1–21.6]; P < 0.001) and ET (aHR [95% CI], 25.2 [23.1–27.5]; P < 0.001). Median survival was shorter for patients who experienced a thrombotic event ≤ 1 year post-index versus those who did not (PV, 5.1 years vs not reached; ET, 3.7 vs 6.7 years; both P < 0.001). These findings highlight the importance of thrombosis risk mitigation in PV and ET management.

Atorvastan, Apsirin and Hydorxyurea for an Effective and Low-Cost Treatment in High-Risk Polycythemia Vera

Introduction: Polycythemia vera (PV) treatment focuses on preventing thrombotic events and delaying transformation to myelofibrosis or leukaemia. According to risk stratification, low-risk patients require therapeutic phlebotomy combined with acetylsalicylic acid, whilst the treatment of high-risk patients with PV relies on cytoreductive therapies, employing hydroxyurea (HU), ruxolitinib, or interferons. However, in low- and middle-income countries, the availability and cost of these drugs poses a challenge in treating high-risk patients, so optimising existing resources is required. Method: A prospective longitudinal study aimed to investigate the combination of atorvastatin (ATV), aspirin, and low-dose HU as a therapeutic strategy to treat PV in high-risk patients. The study evaluated the effect of statins on erythroid colony proliferation in vitro, as well as the applicability of ATV (20 mg/day), acetylsalicylic acid (100 mg/day), and hydroxiurea (500 mg/day) in high-risk patients with PV from La Paz, Bolivia, residing at 3,600 metres above sea level. Results: Simvastatin (3.5 μm) inhibited UKE-1 cell (JAK2V617F mutated) proliferation at 33%, and burstforming unit-erythroid colonies from patients with PV at 61%. Patients receiving ATV, aspirin, and low-dose HU displayed a good response and adequate tolerance to treatment (13-years follow-up). No patients experienced myelofibrosis or transformation to leukaemia, and no severe adverse events were observed. Conclusions: This accessible, effective, and low-cost therapeutic strategy could improve adherence to treatment and the overall survival of high-risk patients with PV in resource-limited countries.