Polycythemia Vera Pts Research Articles

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.

ELN Criteria for Cytoreduction Start Identify Patients with Polycythemia Vera at Higher Thrombotic Risk

Introduction Recently, the European Leukemia Net (ELN) recommended cytoreduction in patients (pts) with Polycythemia Vera (PV) at low risk (LR) (age <60 yrs & no previous thromboses) but carrying additional criteria for therapy start (CTS) ( Marchetti M et al, Lancet Haematol 2022). Little is known about: 1] efficacy of hydroxyurea (HU) in LR pts, high risk due to age >60 yrs (HR-AGE) or high risk due to previous thrombosis regardless of age (HR-THRO); 2] impact of CTS on thrombotic risk. Aims In a large cohort of HU-treated PV pts, we investigated if thrombotic risk was influenced by: 1] conventional risk factors for thrombosis; 2] ELN-defined complete response (CR) at 12 mos; 3] presence of CTS. Methods After IRB approval, data of 961 WHO2016-defined PV pts were retrospectively collected by 21 Hematology Centers. In April 2023, an update was performed in 10 participating Centers with specific focus on CTS at diagnosis and HU start; 504 HU-treated pts resulted eligible for this analysis. Therapy was at discretion of the treating hematologist. Pts were followed until death or data cut-off date. CTS evaluated for association with thrombosis included: persistent/progressive leukocytosis (100% increase if white blood cells (WBC) <10 x10 9/L or 50% increase if WBC>10 or WBC>15 at diagnosis and HU start); extreme persistent thrombocytosis (>1000 x10 9/L platelets (PLT) at diagnosis and HU start); progressive splenomegaly (increase of >5 cm from diagnosis); inadequate hematocrit (Hct) control (>6 PHL/yr; HCT >53% at diagnosis and HU start; PHL intolerance); uncontrolled cardiovascular risk factors (CVRF). Symptoms were present as the only ELN criterion in 40 patients, of whom none had thrombosis; therefore, they were not included in the analysis. Results 504 pts received HU: 81 pts were at LR and 423 (83.9%) were at HR (HR-AGE, no. 290, 57.5%; HR-THRO, no. 133, 26.4%). Median time on HU was 11.6 yrs (0.1-23.1). During HU, 53 pts had 69 thromboses (35 arterial) for an incidence rate of thrombosis (IR-thro) of 1.5 %p-y, comparably in LR and HR ( Table 1). Notably, IR-thro was equal in LR and HR-AGE (p=0.94), but significantly higher in HR-THRO pts (p=0.005 vs LR and p=0.009 vs HR-AGE). At 12 months, CR was achieved by 8.2%, 23% and 25% of LR, HR-AGE and HR-THRO pts, respectively (LR vs HR-AGE and HR-THRO, p<0.001 and p=0.003). Thrombosis-free survival (TFS) by landmark analysis at 12 months was significantly better in CR pts (p=0.01). Specifically, best TFS was observed in LR and HR-AGE pts with CR, while HR-THRO pts without CR had the worst TFR (p=0.009). CTS were observed in 255 (50.6%) pts: 48 LR (59.3%), 139 HR-AGE (47.9%) and 68 HR-THRO (51.1%). In the remaining LR pts, HU was triggered by mild thrombocytosis (<1000 x10 9/L) and/or mild leukocytosis (<15 x10 9/L) and/or mild splenomegaly (<5 cm from costal margin) and/or persistent systemic symptoms. CTS were associated to significantly increased of IR-thro in the overall cohort (p<0.001), in LR pts (p=0.04), in HR-AGE pts (p=0.02) and in HR-THRO pts (p=0.03) ( Table 1) . The impact of CTS was confirmed in the overall cohort both for arterial (1.30 vs 0.44 %p-y, p=0.01) and venous thrombosis (1.37 vs 0.44 %p-y, p=0.007). TFS at 5 yrs was 87% and 95% in pts with or without CTS (p<0.001) ( Fig.1a). In presence of CTS, TFS of LR and HR-AGE pts were comparable to HR-THRO pts without CTS ( Fig. 1b). In multivariate Cox analysis considering age>60 yrs, previous thrombosis, CTS, and CR to HU at 12 months, CTS and previous thrombosis remained associated with thrombotic risk (HR: 2.7, 95% CI: 1.4-5, p =0.002; HR: 2.4, 95% CI: 1.4-4.2, p =0.001). Finally, in 59 additional LR pts untreated with HU, IR-thro was 0.78 in absence of CTS, and 1.57 %p-y in presence of such criteria. Conclusions Albeit retrospective, this study shows for the first time that ELN criteria for therapy start including splenomegaly, leukocytosis, thrombocytosis, uncontrolled Hct and CVRF, identified an increased risk phenotype either in LR and HR pts treated with HU. This was confirmed also in HU-untreated pts. Also, lack of CR at 12 months was detrimental on TFS particularly in HR-THRO pts, and less significantly than CTS. These findings, that complement data from the Majic-PV trial ( Harrison CN et al, J Clin Oncol 2023), dictate better management of HU therapy, and call for greater attention to CTS and their integration into prognostic models that go beyond the two categories related only to age and thrombotic history.

Using Machine Learning to Predict Near-Term Thrombosis Risk in Patients with Polycythemia Vera

Introduction: Thrombosis (arterial and venous) remains the leading cause of morbidity/mortality for patients (pts) with polycythemia vera (PV) [1-2]. With appropriate therapy, thrombosis risk can be reduced to 1-5% per year (yr) [3]. Yet some seemingly well-controlled pts still suffer thrombotic events. This rate means that a well-powered clinical trial testing anti-thrombotic strategies in PV to improve thrombosis-free survival is prohibited by the large number of pts and study duration required. For example, the high-end annual incidence of thrombosis in ELN high-risk pts is <5%/yr, so a 2yr study hoping to demonstrate a 50% thrombosis reduction (α=5%, 1-ß=80%) requires 1104 pts. This study would be vastly more efficient if we could enroll only pts with high near-term thrombotic risk but we cannot accurately identify these pts. To address this, we developed a machine learning (ML) approach to dynamically predict this risk. Methods: After obtaining institutional approval, 526 pts with manually verified PV diagnoses were identified by querying electronic health records and our research database repository. The dataset (4M data elements,14K hematology clinic visits) includes lab measures, molecular/pathology studies, medications, and pt history. Data completeness varied with >90% availability in 200+ features. To assess the error introduced by imputation, we computed the Euclidean distance/Jaccard index between masked pre-imputed data and imputed data over 8K iterations. We found that features with <50% missingness could be imputed without dataset corruption. ML classification models (random forest (RF), boosted models, and support vector machines) were evaluated using AutoGluon. RF emerged as the top performer. Feature engineering, guided by Gini feature importance and clinical feedback, identified 21 training features. A parallelized pipeline optimized 1.6M model combinations (# of trees, node splitting features, max depth, thresholding) via grid search. Several optimization strategies were assessed. Of 470 pts with clinic visits through Mar 31, 2020, 75% were used for model training (Training Cohort) and 25% for model evaluation (Testing Cohort). Cohort details were previously reported [4]. A prospective Validation Cohort included clinic visits after Apr 1, 2020 and was unseen by trained models. A risk calculator designed in RShiny applied models corresponding to user-entered clinical data and computed 1yr thrombosis risk. User-entered data are not stored to protect data privacy. Results: Training/Testing pts had median age of 54, and 64 (14%) had a prior thrombosis at dx (8% venous, 7% arterial). Over a median followup of 10 yrs, 159 thromboses occurred in 115 pts (88 venous, 71 arterial). Annual incidence rates (IR) of thrombosis were higher shortly after dx (IR: 4% vs 1%, 2yr cutoff) and following a thrombotic event (IR: 10% vs 2%, 2yr cutoff). The full model performed very well (F1=0.91, AUC=0.84) when compared with ELN (F1=0.1, AUC=0.39) (Figure 1). High-performing simplified models (>90% testing/validation sensitivity) were applied to the Validation Cohort. The full 21-feature model and high-performing models (Figure 2) showed clear separation for 1yr thrombosis risk prediction. Features of importance included blood counts, body mass index (BMI), and time since dx were frequently represented in these models. Discussion: Over 1M models were trained on high-volume clinical data to predict near-term thrombosis risk in PV pts, considering intrinsic factors (age, blood type), disease events (time since dx/thrombosis), and short-term changes (BMI) to tailor risk mitigation strategies. Prospective validation demonstrates model generalizability. External validation using REVEAL study [1] and the Danish Registry data is ongoing. Our tool's ability to identify high-risk pt populations can be applied as an inclusion criterion for prospective clinical trials, reducing the time and pt numbers needed for a well-powered study. Whereas using ELN-defined high risk would require 1K pts to demonstrate a 50% reduction in thrombosis rates, our prospective ML model-defined high near-term risk would only require ~80 pts, making such a study very feasible.

Effect of durable hematocrit control and minimal thrombotic risk in real-world polycythemia vera patients treated with ruxolitinib.

e19080 Background: Polycythemia Vera (PV) is a myeloproliferative neoplasm characterized by unregulated red blood cell production. Most patients (pts) harbor a JAK2 mutation and must have erythrocytosis or elevated red cell mass for diagnosis (DX). Pts are at increased risk of thrombosis. Current treatments include aspirin, therapeutic phlebotomy (TP), and cytoreductive therapy such as hydroxyurea (HU). In 2014, based on the RESPONSE study, ruxolitinib (rux), a selective JAK inhibitor, was approved for second line treatment after intolerance or inadequate response to HU. A recent real-world analysis of rux in PV showed durable hematocrit (HCT) control and decreased need for TP (Coltoff 2020). Despite emerging clinical reports, real-world data on HCT control, dose adjustment, and thrombotic risk with rux are extremely limited. Methods: A retrospective chart review from three centers was performed to evaluate PV pts treated with rux between Dec 2014 and Dec 2019. Pts age <18 at rux start, who received rux through investigational studies, and/or who had myelofibrosis were excluded. Data cutoff was May 30, 2022. Results: 69 patients were identified. Median time from PV DX to rux start was 4.4 yrs (range 0.1 to 40.2), and median follow-up from start of rux was 3.3 yrs (range 0.1 to 6.3). Pt characteristics: 37 (54%) Male, 59 pts (86%) White, 4 (6%) Black, and 64 (93%) Non-Hispanic. The most common reasons for starting rux were HU intolerance (46%), uncontrolled platelet count (28%), and symptom burden (19%). Median time on rux was 2.4 yrs (range 0.1 to 6.3); 43 pts (62%) remained on rux at data cutoff. A total of 6 pts (9%) received less than 3 months of rux before discontinuation, 8 pts (12%) received less than 6 months of rux. 41% pts (27/66), did not have HCT control (HCT <45%) within 1 month prior to rux start. Of evaluable pts, HCT control rates at 3 and 6 months were 88% (52/59) and 89% (47/53) respectively. Phlebotomy frequency in the 3-month periods before and after rux start were known for 48 pts; 21 (44%) experienced a decrease in phlebotomies within 3 months after initiation of rux, 20 (42%) remained stable, and 7 (16%) saw an increase (ranging from +1 to +3). Twelve pts (17%) required dose reductions/suspensions due to cytopenias. One pt experienced an acute pulmonary embolism while on rux (4.4 yrs after rux initiation). The pt was diagnosed with T cell lymphoma while on rux and the thrombotic event was attributed to lymphoma. This pt achieved HCT control on rux at 3 and 6 months. No arterial thromboses were observed. Conclusions: In this real-world analysis, rux was highly effective in controlling HCT in the vast majority of PV pts by 3 and 6 months. PV pts treated with rux rarely developed thrombosis. Rux was well tolerated, and few patients required dose reduction or discontinuation. [Table: see text]

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.

Measuring the Incidence of Distress and Supportive Oncology Utilization Among Patients with Myeloproliferative Neoplasms: A Single Center Experience

INTRODUCTION Cancer related distress is an experience comprised of physical, psychological, social, and religious/spiritual factors that impact how a patient (pt) copes with illness. High levels of distress have been associated with increased healthcare utilization. NCCN guidelines recommend pts with significant distress be referred to supportive services (SS) within 6 months of screening. Pts with myeloproliferative neoplasms (MPNs) experience a substantial symptom burden that decreases their quality of life. Little is known about the prevalence of distress and the utilization of SS in pts with myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET). Hence, we designed and present results of a single center study evaluating levels of distress, SS evaluations, and frequency of hospitalizations in pts with MF, PV, and ET. METHODS Adult pts (age≥18) diagnosed with MF, PV, or ET followed at Levine Cancer Institute (LCI) in Charlotte, NC between 1/1/2017-6/30/21 were included. All included pts were established with a LCI clinician (>1 visit) and had completed an electronic distress survey (EDS), which contained sociodemographic questions and patient-reported outcomes (PROs): distress level, physical symptoms, screening for depression (PHQ-2) and anxiety (GAD-2), daily function, social support, and emotional/spiritual concerns. Pts diagnosed with another hematologic or solid tumor malignancy at the time of survey were excluded. EDS responses, mutations, disease risk assessments, SS visits, ED visits, and hospitalizations were collected retrospectively. Primary objective was to measure the proportion of pts who reported significant distress (score ≥4, based on NCCN guidelines) and were evaluated by ≥1 SS (psychiatry, social work, psychology, chaplaincy, palliative care, and integrative oncology) within 6 months of screening; the proportions with automated referrals based on system triggers (distress score ≥7, GAD-2 ≥5, or PHQ-3 ≥3), unplanned hospitalizations, and ED encounters were also measured. Disease characteristics and PROs were compared between distress groups (score ≥4, 4-6, ≥7) with Fisher's Exact test. Statistical analysis was performed in SAS v9.4; P<0.05 was considered statistically significant. This study was approved by the institutional IRB. RESULTS Pt characteristics and demographics are presented in Table 1. One hundred forty-one pts were included: PV 44 (31%), ET 49 (35%), MF 48 (34%). Median age was 63 years, and 62% were female. Seventy-five (53%) pts reported significant distress, of which 44 (59%) were ≤3 months of diagnosis. Sixty-four percent of PV pts and 60% of MF pts reported significant distress versus 37% of ET pts (P=0.016). SS and healthcare utilization is presented in table 2. The proportion of pts expressing significant distress and being evaluated by SS within 6 months of screening was 33% (n=25). Of 38 (27%) pts who met criteria for an automated referral, 15 (39%) were evaluated by SS within 6 months. Distressed pts (DPTS) had more ED visits (15% vs. 0%, P<0.001) and unplanned hospitalizations (16% vs. 6%, P=0.11). DISCUSSION Despite consensus recommendations, most DPTS were not evaluated by SS. Among DPTS evaluated by SS, social work was most frequently utilized. PV and MF pts were more likely to report distress compared to ET. Limitations to this analysis include lack of data of SS utilization outside of our system, barriers to accessing SS within our system, treatment characteristics, and impact on outcomes. Future work should identify ways to better use patient-reported outcomes to promote early intervention and access to SS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Unbiased Identification of Thrombosis Risk Factors in Polycythemia Vera (PV) Using Machine Learning and Rich Data from Automated Extraction of Medical Records Generates Dynamic Models Highly Predictive for Thrombosis in PV

Background: Thrombosis is a leading cause of early morbidity and mortality in patients (pts) with polycythemia vera (PV)1. Thrombosis risk informs treatment decisions in PV but current risk stratification relies upon two non-modifiable factors - Age(</≥ 60) and thrombosis history (hx)2 - thereby offering no potential to monitor changes in risk. We used a rich dataset and machine learning (ML) methods to identify clinically available data useful for dynamic prediction of individualized thrombosis risk in PV. Methods: Under Weill Cornell Medicine (WCM) institutional board approval, we identified in our research repository (RDR) 470 eligible pts with PV diagnosis (Dx) and annotated thrombosis outcomes, as previously described3. We queried electronic medical records using our RDR, Observational Medical Outcomes Partnership, Structured Query Language, and novel workflows implemented in R and Python, to automate extraction of all available clinical data for pts at every clinical visit. Over 2100 clinical parameters were available for ~8400 hematology clinic visits yielding ~1.4 million data elements. These data included all laboratory measures, molecular studies, pathology reports, vitals, medications and clinical hx. Data completeness varied across data types with 283 parameters available in >90% of visits for all pts. In total, 292 parameters with over 50% availability were assessed while others were excluded from analysis. Multivariate imputation by chained equations (MICE) was used to impute missing data. To address potential artifacts from imputation, all analyses were performed on 10 separately imputed datasets and results were aggregated. AutoGluon infrastructure was used to identify the best performing ML algorithms. We then used our dataset to train random forest (RF) ML models that classify, at each clinic visit, the likelihood of thrombosis within a year. Parameters were ranked by Gini feature importance to identify a practical clinical model comprised of a few core parameters (eg 3-7) and interrogated the performance of >2x105 of these models (every combination of top 20 parameters in groups of 3-7) compared to the full model. Model performance was evaluated using the F1 score, which is considered highly predictive when >0.8. Results: Of 470 PV pts, Dx at median age of 54 (range 20-94), 64 (14%) had a thrombosis hx at Dx (8.1% venous, 6.6% arterial). Over a median follow-up of 10 years (yr), 159 thromboses occurred in 115 pts (88 venous, 71 arterial). Cumulative incidence of thrombosis was non-linear, as previously appreciated1. Annual incidence rate (IR) of thrombosis was higher shortly after diagnosis (IR of 4.4% vs 1%, 2yr cutoff), and following a thrombotic event (IR of 9.7% vs 1.8%, 2 yr cutoff). Consistent with this observation, ML models identified time from Dx, and time from prior thrombosis among the top 20 most predictive parameters as assessed by Gini feature importance (Figure 1). Most predictive parameters also included risk factors previously implicated in PV thrombosis (age, blood counts, JAK2 allele burden) as well as known thrombosis risk factors under-recognized in PV (blood type4, BMI, creatinine), and parameters not previously thought to contribute to thrombosis risk (MCV, uric acid, LDH). The full ML model was highly predictive of thrombosis with an F1 of 0.82 (Figure 2). We then identified simplified models (combinations of 4-5 variables) that performed similarly to the full model with an F1 > 0.8. One example combines age, time since Dx, time since prior thrombosis, and BMI. These models are being validated against external datasets and an online risk calculator will be developed. Discussion: We used ML and deep datasets for unbiased identification of the clinical parameters most predictive of near-term thrombosis risk in PV pts. These models address dynamic changes to patient risk due to intrinsic factors (e.g. age, blood type), life events (e.g. time since Dx/thrombosis) and clinical changes (e.g. ANC, BMI) that can be used to tailor risk mitigation strategies. Validation of models with at least core variables of age, time since Dx, time since prior thrombosis, and BMI against external datasets would likely establish a universal model to dynamically predict individualized risk of thrombosis in PV pts. References 1 Hultcrantz. et al. Ann Intern Med. 2018 2 Barbui T, et al.Leukemia 2018 3 Abu-Zeinah G, et al. Leukemia 2021 4 Groot H, et al. Arterioscler Thromb Vasc Biol 2020 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Safety of Cytoreductive Therapy in Younger Patients with Polycythemia Vera: A Systematic Review and Meta-Analysis

Background: Treatment recommendations for polycythemia vera (PV) are age-based and reserve cytoreductive agents for patients (pts) older than 60, with some exceptions such as thrombosis history (Marchetti M, et al. Lancet Haematol 2022; Ali H, et al. NCCN Guidelines Version 2.2022). Effective, potentially life-prolonging cytoreductive treatment such as interferon-alpha (IFN) and hydroxyurea (HU) is often deferred in younger pts due to a presumption that treatment toxicity exceeds its potential benefit (Abu-Zeinah G, et al. Leuk 2021). In this systematic review, we examine the safety of cytoreductive agents in PV pts younger than 60, and discuss the implications of our findings to the clinical care of younger PV pts. Methods: We used the databases PubMed, Scopus, Web of Science and Embase to identify relevant articles with search terms "polycythemia vera" and one of: hydroxyurea, hydroxycarbamide, interferon, ruxolitinib, cytoreductive. Inclusion criteria were predefined as: prospective studies including clinical trials, and retrospective studies including case series with at least 20 pts; pts with a diagnosis of PV; median age 18-60 years (yr) at enrollment; and the use of IFN, HU, or ruxolitinib (RUX). Data on treatment discontinuation for toxicity (DCT), frequency of grade 3-4 adverse events (AEs), and duration of follow-up were collected. Toxicity data were pooled using random-effects models with weights assigned based on study size and duration (patient-years). The derived annual DCT rate assumes linear correlation of toxicity with treatment time, and the pooled analysis assumes Poisson distribution of DCT probability. Results: The search resulted in 691 articles. Titles and abstracts were independently screened by two reviewers with 91% concordance and 102 articles were ultimately selected for full-text review. Of those, 18 met inclusion criteria and were selected for data extraction. JBI quality scores were calculated and ranged between 0.6 and 1. The median age of PV patients in these studies was between 47 and 59 yr. On IFN (n= 760, 12 studies), the reported DCT ranged from 4.6-37% over median durations of 0.4-6.3 yr (Table 1). The pooled DCT was 13% (95% CI 2.7-23%) and annual DCT rate for IFN was 3.2% (95% CI 0-6.4%). Of note, there was significant heterogeneity in reported DCT between studies (Cochran's Q = 29, p<0.001, and I2 = 70%), perhaps related to differences in dosing. Commonly reported causes for IFN DCT include fatigue, flu-like symptoms, and pneumonia. On HU (n= 1169, 6 studies), the reported DCT ranged from 2.6-17% over median durations of 2-14 yr (Table 1). The pooled DCT for HU was 15% (95% CI 6.9-24%) and annual DCT rate was 3% (95% CI 1-5%). There was no significant heterogeneity in reported HU DCT between studies (Q = 6.4, p=0.3, and I2 = 27%). Commonly reported causes for HU DCT included gastrointestinal symptoms and skin ulcers. Only one study was available for RUX and reported a DCT of 23.5% over 2.9 yr. Discussion: PV-related complications and mortality is higher than expected in younger pts (Abu-Zeinah K, et al. Leuk Lymphoma 2022; Abu-Zeinah G, et al. Leuk 2021), but cytoreductive treatment is often deferred - until patients are older or experience symptoms, thrombosis, or progression - because of toxicity concerns. In this systematic review focused on younger PV cohorts, we found the annual rate of DCT with IFN or HU to be relatively low at 3-3.2%. Additional long-term data is required because most patients in these studies were treated for less than 10 yr. Nevertheless, given the excess risks of thrombosis, progression and death in PV patients compared to age-matched controls; and the potential for IFN or HU to safely reduce those risks, we continue to advocate for earlier intervention in young PV pts. Treatment recommendations should account for these findings, particularly as PV is being diagnosed more frequently at a younger age. Acknowledgements: Mr. Sa'ad Laws for library and systematic review support. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Characteristics and Clinical Outcomes in Patients (Pts) With Polycythemia Vera (PV) Receiving Ruxolitinib (RUX) After Hydroxyurea (HU): A Longitudinal Analysis From REVEAL

Background: Resistance or intolerance to first-line HU occurs in ~24% of pts with PV; RUX is a recommended second-line treatment (tx). In the large, real-world, multicenter, prospective Observational Study of pts with Polycythemia Vera in US Clinical Practices (REVEAL; NCT02252159), demographics, disease burden, clinical management, and pt-reported outcomes data of pts with PV were collected from 227 community or academic centers between 2014 and 2019. This analysis describes the characteristics and clinical outcomes of pts with PV who switched to RUX after HU tx. Methods: This analysis included pts (≥18 y) with a clinical diagnosis of PV who were treated with HU at least 3 mo prior to study enrollment and did not switch to an alternative therapy during the observation period (index: study enrollment date) or who switched to RUX after previous HU tx (index: RUX initiation date). Descriptive statistics were used to describe demographics, disease characteristics, and tx patterns. Blood count, Myeloproliferative Neoplasm-Symptom Assessment Form total symptom score (MPN-SAF TSS), and spleen length measurements were analyzed at index and at 3 and 12 mo post index for pts who switched to RUX. Results:Characteristics of pts who switched to RUX vs who were treated with HU Out of 2510 pts enrolled in REVEAL,1053 were eligible for this analysis and comprised of 906 pts treated with HU and 147 who switched to RUX (Table 1). Median age for both groups at index was similar (RUX, 67 y; HU, 70 y); 44.2% and 51.8% were women in the RUX and HU groups, respectively. In RUX vs HU, median (range) time to index date from PV diagnosis was 6.9 (0.3-36.3) vs 4.8 (0.1-36.5) y. The median (range) duration of HU tx prior to index date was 27.6 (0.1-221.0) mo in the RUX and 26.7 (3.0-435.7) mo in the HU group. Main reasons for HU discontinuation prior to RUX tx were lack of efficacy (n=53, 36.1%), adverse events (n=47, 32.0%), and disease progression (n=10, 6.8%). Pts who switched to RUX vs HU had higher mean (SD) MPN-SAF TSS (27.5 [17.7] vs 17.3 [15.1]) and higher percentage of pts (n=40, 27.2% vs n=84, 9.3%) with a palpable spleen. At index, 26 (18.1%) vs 65 (7.8%) pts who switched to RUX vs HU had an elevated white blood cell (WBC) count, with mean (SD) of 16.1 (16.3) vs 9.2 (6.2) ×109/L, respectively. Mean (SD) number of phlebotomies (PHL) 6 mo prior to index date was 1.3 (2.3) in the RUX and 0.7 (1.45) in the HU groups. In RUX vs HU, 27.2% vs 19.3% had a thrombotic event (TE) history prior to index date. Tx patterns and clinical outcomes in pts who switched to RUX (n=147) Ninety-two pts (62.6%) received the recommended initial dose of RUX (10 mg BID); additional initial doses were 5 mg BID (n=19), 20 mg BID (n=16), 15 mg BID (n=10), and other (n=10). Seventy-two (49.0%) required a dose modification. The median (range) RUX tx duration was 22.6 (3.0-54.5) mo; most pts (89.1%) received RUX for ≥6 mo. At the end of study, 118 pts (80.3%) were still on RUX. Compared with index, MPN-SAF TSS, proportion of pts with palpable spleen, and spleen length decreased at 3- and 12-mo follow-up (Table 2). The number of pts with hematocrit >0.45 L/L decreased from 49 at index to 19 and 16 at 3 and 12 mo, respectively (Table 2). The number of pts with WBC counts >10×109/L decreased from 87 at index to 66 and 48 at 3 and 12 mo, respectively (Table 2). Pts with no blood count test at 3- or 12-mo follow-up more likely had controlled hematocrit/WBC at index. Mean (SD) number of PHL decreased from 1.3 (2.3) at index (6 mo prior) to 0.5 (1.3) after 6 mo; 110 pts (74.8%) no longer required PHL 12 mo after index date. The TE rate after index date was numerically lower in RUX vs HU (2.7% vs 4.2%) after a median follow-up of 26 and 44 mo, respectively. Conclusion: This analysis of REVEAL, the largest real-world cohort of PV pts to date, demonstrated that pts who switched from HU to RUX had more severe disease burden vs those who were treated with HU. RUX tx resulted in significant improvements in PV-related symptoms, correlating with reduction in spleen size and sustained improvement in hematologic parameters. This resulted in a reduction of PHL within 6 mo, with most pts becoming PHL-free at 12 mo. There was also a trend towards lower rates of TEs with RUX. This longitudinal analysis validates the efficacy of RUX for the tx of PV after HU exposure in the real-world and suggests monitoring of PV pts on HU to identify those who are likely to benefit from transition to RUX in order to meet tx goals and become PHL-free. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Polycythemia Vera Molecular Response and Its Correlation with Disease Progression: A Systematic Review and Meta-Analysis

Background: Polycythemia vera (PV) is a chronic myeloproliferative neoplasm (MPN) driven primarily by JAK2V617F and is associated with an excess risk of thrombosis and progression to myelofibrosis (MF) and acute leukemia (AML). Advances in treatment of PV and earlier diagnosis has reduced fatal thrombotic events, but with longer thrombosis-free survival, the natural progression to MF is an increasingly common cause of morbidity. More than 50% of PV patients (pts) have MF after 30 years from diagnosis, independent of age, making this a particularly important issue for young pts1. Because of disease chronicity, short-term monitoring biomarkers are needed to dynamically predict risk of disease progression on the long-term and allow appropriate implementation and modification of therapy. Whole blood (WB) JAK2V617F allele frequency (MAF) is frequently measured in clinical trials to assess molecular response to treatment, yet no study has established whether serial changes in MAF are predictive of progression. Despite limitations of WB MAF monitoring 2, the readily accessible WB samples and feasibility of testing, along with the need for a clinical biomarker in PV, merits a study to determine whether MAF change correlates with disease progression. Objective & Methods: We conducted a systematic review and meta-analysis to examine the correlation of molecular response with thrombosis or progression to MF and AML in PV pts. We searched the main scholarly engines: Pubmed, Scopus and Embase for "Polycythemia vera" and terms including "JAK2V617F" and "molecular response". Title and abstracts were screened by 2 reviewers independently based on predefined criteria and selected for full-text review if criteria are met or further information was required. Studies were included if they reported serial MAF measurements in PV patients, and excluded for other JAK2V617F MPNs or lack of serial MAF assessment. Pearson correlation analysis was conducted on the subset of studies that reported rates of thrombosis, MF and or AML to determine the correlation of MAF reduction with clinical outcomes. Results: The search resulted in 563 abstracts to screen. A total of 59 studies were selected for full-text review and ultimately only 20 studies met inclusion criteria where MAF was serially assessed in PV patients. In all studies, MAF was monitored on cytoreductive therapy, and these included 12 on interferon (IFN), 8 on hydroxyurea (HU), and 2 on ruxolitinib (RUX). The median follow-up times were between 16-116 months. In most studies (n=18, 90%), there was an overall decrease in MAF on cytoreductive treatment (Figure 1). There was a poor correlation between molecular response rates and hematological response rates (n=11 studies, r2=0.20). Of the 20 studies, only 7 reported clinical outcomes of thrombosis and/or progression: 2 were prospective and 5 were retrospective. In our analysis, MAF reduction correlated with decreased rates of MF (n = 7 studies, r2=0.69) (Figure 2), irrespective of treatment (IFN: r2 =0.83, HU: r2 =0.72), but results were not statistically significant (p=0.08). On the other hand, there was no correlation between MAF reduction and progression to AML (n= 3 studies, r2=0.17), or the incidence of thrombotic events (n = 6 studies, r2=0.15), but fewer studies reported these outcomes. Discussion: This systematic review highlights the lack of high-level evidence available to determine if molecular response in PV is associated with reduced risk of progression. The correlation observed between MAF reduction and MF rates requires validation in larger, ideally prospective studies. Until then, reduction in WB MAF should not be the determinant of a treatment's long-term likelihood of success. Alternative biomarkers are needed to capture the biology of malignant MPN stem cells and better predict the long-term outcomes of patients with PV.

Gaps in the Assessment and Monitoring of Cardiovascular Risk and Psychological Burden in Polycythemia Vera: Landmark 2.0, a Worldwide Health Survey

INTRODUCTION: Patients (pts) with polycythemia vera (PV) have a significantly higher risk of thrombosis than the general population, and cardiovascular (CV) events are the main cause of death. Pts with PV also report reduced quality of life (QoL) due to high symptom and psychological burden. This analysis of the LANDMARK 2.0 survey examines patterns related to assessments of CV risk and PV-related psychological burden in pts with PV. METHODS: LANDMARK 2.0 is an online survey of MPN pts and treating physicians that was conducted in 11 countries between April 2021-May 2022. This analysis included pts with PV aged 18-89 years (yrs), and physicians who were actively managing PV pts within 12 months (mos) prior to the survey. Pts were stratified into 3 therapy (tx) stages: currently receiving first-line cytoreductive tx for ≤1 yr (PV-C), currently receiving second-line tx for ≤1 yr (PV-I), or currently receiving any line of tx for >1 yr (PV-M). RESULTS: Overall, 133 physicians and 274 pts with PV (PV-C, n=86; PV-I, n=26; PV-M, n=162) completed the survey. At survey completion, the median age of pts was 63, 59, and 64 yrs in the PV-C, PV-I, and PV-M groups, respectively, and the median time since PV diagnosis was 10.8, 39, and 91 mos, respectively. Most common treatments across all tx stages were hydroxyurea and ruxolitinib. Phlebotomies were received by 53%, 31%, and 29% pts in PV-C, PV-I, and PV-M stages, respectively, with a mean number of 4.2, 3.4, and 4.6 phlebotomies, respectively, in the past 12 mos. During routine visits, basic CV assessment (e.g. blood pressure and cholesterol) was ever performed by 53% of physicians treating PV-M pts, 77% physicians treating PV-C pts, and 62% physicians treating PV-I pts, and comprehensive CV assessment (i.e. electrocardiogram and/or echocardiogram) was ever performed by 32%, 60%, and 47% of physicians, respectively (Fig 1). Among physicians who never conducted basic (n=21) or comprehensive (n=40) CV assessments, 38% and 43%, respectively, considered the assessment unnecessary, 38% and 15%, respectively, cited insufficient time as reason, and 36% and 19%, respectively, cited insufficient resources. Among all physicians, 68% and 63%, respectively, did not think that basic or comprehensive CV tests could be used more effectively in pt management. In contrast to physicians' responses, only 55% of pts across tx stages reported having ever received basic CV tests during routine visits. Fewer pts in PV-M received advice on reducing CV risk (45% in the last 12 mos) vs pts in PV-C and PV-I (73% and 69%, respectively, in the last 6 mos). When asked about the burden of PV on QoL on a scale of 1 (no impact) to 5 (significant impact), a large proportion of pts reported an impact of 3-5 on emotional well-being and mental health, in particular those in PV-C (66%) and PV-I (80%). Overall, 38% of pts rated the impact of phlebotomy on QoL as 3-5, but only around a third of physicians (PV-C, 33%; PV-I, 28%; PV-M, 36%) reported ever having assessed the emotional burden of phlebotomy. Among respondents who had ever carried out/received a psychosocial burden assessment during routine visits, there was a discordance in the perceived frequency of these tests, with fewer pts than physicians reporting the assessment being performed 'always' or 'often' (discordance of -32%, -75% and -23% in the PV-C, PV-I, and PV-M groups, respectively; Fig 2). With respect to the support received for PV-related psychological burden, only 52% of pts reported being 'somewhat' or 'very' satisfied. More pts vs physicians reported a lack of communication on self-help strategies in PV-I (36% vs 12%) or on the rationale for having performed specific tests in PV-I (20% vs 8%) and PV-C (24% vs 9%). CONCLUSIONS: Whilst international recommendations recognize the need to control CV risk factors, there is no standard recommendation on how to monitor CV risk in PV, highlighting an unmet need. These results show that CV-risk testing and education on CV-risk minimization are not routinely performed throughout the treatment continuum, in particular in pts who are stabilized on long-term maintenance tx. Additionally, our findings indicate a discordance between pts and physicians in the perceived importance of PV-related QoL assessments. Pt care may be enhanced with regular assessments throughout treatment and increased communication between pts and physicians. Study funding: Novartis Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

JAK2V617F variant allele frequency, non-driver mutations, single-nucleotide variants and polycythemia vera outcome

IntroductionDespite comparatively favourable prognosis in polycythemia vera (PV) patients (pts), the overall survival is shorter compared to the age-matched general population. The aim of the study was to evaluate the impact of chosen laboratory and genetic factors on the individual disease outcome, i.e. risk of thrombosis, myelofibrosis/blastic transformation and death.Materials and methodsThe study group consisted of 151 pts and 57 healthy donors (HD).ResultsJAK2V617F mutation was found in 96.7% (146/151) of the studied pts. JAK2 exon 12 mutations were identified in 2 individuals. The coexistence of JAK2V617F and JAK2 exon 12 mutation was confirmed in 2 other pts. In one case, neither JAK2V617F nor JAK2 exon 12 mutation was found. The presence of ten different non-driver mutations (ASXL1, SRSF2, U2AF1, IDH2) in eight of the analyzed pts (5.3%) was confirmed. The overall frequency of thrombotic events (TE) in the studied PV group was 23.8% (36/151). In patients with TE, median platelet count was lower than in pts without TE. Thrombotic risk did not depend on JAK2 rs12343867, TERT rs2736100, OBFC1 rs9420907 SNV, however, we found a novel strong tendency towards statistical significance between the CC genotype miR-146a rs2431697 and thrombosis. The disease progression to fibrotic phase was confirmed in 9% of the pts. Fibrotic transformation in PV pts was affected mainly by JAK2V617F variant allele frequency (VAF) and the presence of coexisting non-driver variants. The high JAK2V617F VAF and elevated white blood cell (WBC) count at the time of diagnosis were associated with an increased risk of death.ConclusionTherefore, in our opinion, complex, laboratory and genetic PV pts evaluation at the time of diagnosis should be incorporated into a new prognostic scoring system to more precisely define the PV prognosis and to optimize the therapeutic decision-making process.

P1011: PREDICTORS OF COVID-19 DISEASE AND SURVIVAL TO COVID-19 IN MPN PATIENTS TREATED WITH RUXOLITINIB

Background: Ruxolitinib (RUX) use and discontinuation are risk factors for severe COVID-19 and death in MPN patients (pts). In pts on RUX therapy, predictors for COVID-19 disease and survival (OS) to COVID-19 are unknown. Aims: The aims of this study were to distinguish RUX-treated pts at higher risk of COVID-19 and to assess prognostic factors for OS. Methods: We performed a sub-analysis of the RUX-MF and the PV-ARC observational studies that include consecutive adult pts with myelofibrosis (MF) and polycythemia vera (PV), respectively. Overall, 815 MF and 172 PV pts treated with RUX outside clinical trials have been registered. At pandemic start, 494 pts (359 MF and 135 PV) on RUX were included in this analysis. Results: Among 66 (13.6%) pts (PV n=11, MF n=55) with COVID-19 from Feb 2020 to Jan 2022, 1 (1.5%), 14 (21.2%), 9 (13.6%), 17 (25.8%), 4 (6.1%) and 21 (31.8%) pts had an asymptomatic, mild, moderate, severe, critical, and fatal infection, respectively; 42 (63.7%) were hospitalized. Overall, 14, 38 and 14 infections were observed during the 1st (Feb-Jun 2020), 2nd (Jul 2020-Jun2021) and 3rd (Jul 2021-Jan 2022) wave of the pandemic, with an overall incidence rate of 10.2 per 100 pt-yrs. Incidence rates in the 3 waves were 8, 10.2 and 7 per 100 pt-yrs respectively. Hospitalized cases were significantly less frequent during the 3rd wave (35.7% vs 64.3%/73.7% in the 1st/2nd wave, p=0.04). Overall, 283/390 evaluable pts (72.6%) received ≥1 dose of Comirnaty vaccine (19/66 COVID-19 pts; 5, 7 and 7 pts had received 1, 2 or 3 vaccine doses, respectively). At COVID-19 diagnosis, RUX was reduced in 10 (15.1%) pts and discontinued in 9 (13.6%) pts, comparably in MF and PV. In the total cohort, COVID-19 infection was more frequent in pts with MF (15.3% vs. 8.2% PV pts, p=0.04), with ≥1 comorbidity (15% vs. 8.7%, p=0.04). Also, COVID-19 infections after vaccine availability were more frequent in unvaccinated pts (37.4 vs. 6.3%, p<0.001). COVID-19 requiring hospitalization was more frequently observed in pts ≥70 yrs (12.2% vs. 6.8% in pts <70 yrs, p=0.04), and without COVID-19 vaccine (32.4% vs. 2.9%, p<0.001). No additional predictors for COVID-19 were noted analyzing MF and PV separately. In COVID-19 pts, hospitalized cases had a significantly lower median platelet count (275 vs. 168 x109/L, p=0.02), were receiving lower RUX doses (33.3% <10 mg BID vs. 8.3%, p=0.02) and more frequently presented comorbidities (40.5% vs. 13.6%, p=0.03) compared to outpatients. MF vs. PV, median hemoglobin levels, age≥70 yrs and sex were not associated with hospitalization. MF pts who were not in spleen response at COVID-19 infection had higher risk of hospitalization (73% vs. 44.4% in responders, p=0.04). After multivariable Cox analysis including previous anti-SARS-Cov-2 vaccine, need for hospitalization, age≥70 and male sex, OS to COVID-19 was significantly improved in pts who had previously received anti-SARS-Cov-2 vaccine (HR=0.10, p=0.02) (Fig.1), in pts with COVID-19 not requiring hospitalization (HR=0.19, p=0.03) and in patients <70 yrs (HR=0.38, p=0.03). The COVID-19 wave did not impact OS (p=0.53). Image:Summary/Conclusion: Among RUX-treated pts, lower RUX doses, comorbidities and no spleen response are significant predictors of hospitalization. Vaccine was the most protective factor against COVID-19 disease, hospitalization, and mortality. RUX-treated pts, regardless of MPN type, should be sensitized to adherence to the vaccine program and prioritized for antiviral therapy in case of infection.

P1062: A REAL-WORLD EVALUATION OF THE ASSOCIATION BETWEEN ELEVATED BLOOD COUNTS AND THROMBOTIC EVENTS IN POLYCYTHEMIA VERA: AN ANALYSIS OF DATA FROM THE REVEAL STUDY

Background: Polycythemia vera (PV) is characterized by clonal hematopoiesis leading to elevated peripheral blood counts and an increased risk of thrombotic events (TEs). Advanced age and TE history form the conventional risk model used to determine TE risk/treatment strategy. Associations between TEs and elevated hematocrit (HCT) levels exist, but associations with white blood cell (WBC) or platelet (PLT) counts have not been assessed consistently. The large, real-world, prospective Observational Study of Pts with Polycythemia Vera in US Clinical Practices (REVEAL; NCT02252159) followed pts with PV treated in community or academic centers. Aims: This analysis evaluated associations between elevated blood counts and TEs in pts with PV using data from REVEAL. Methods: Eligible pts had ≥3 lab values (blood counts) post-enrollment; pts with a post-enrollment TE but no lab value <6 mo before that TE were excluded. The association between blood counts and TEs was assessed using a time-dependent covariate Cox proportional hazards model. Time to first post-enrollment TE was modeled with time censored at last known visit for pts with no TE. Each lab parameter was modeled with sex, age, disease duration, and TE history at enrollment as baseline covariates and treatment as a time-dependent covariate. Blood counts were included as binary time–dependent covariates using the following thresholds: HCT >45%, WBC >11×109/L, PLT >400×109/L. Linear interpolation was used to determine lab values between observed lab values. Alternative thresholds for WBC (<7, ≥7 to <8.5; ≥8.5 to <11, and ≥11×109/L, and >12×109/L with HCT controlled at ≤45%) and PLT counts (>600×109/L) were evaluated. Statistical significance was considered at P<0.05. Results: 2271/2510 pts were eligible (median age, 66 y [range, 22–95]; male, 54.1%). Median disease duration was 4.1 y (range, 0–56.3), 456 (20.1%) had TE history; 52.6% of pts received hydroxyurea. Of 106 pts who had TEs, 30 had arterial TEs (most commonly, transient ischemic attack [n=15]) and 76 had venous TEs (most commonly, deep vein thrombosis [n=37]). Elevated HCT levels (>45%, hazard ratio [HR]=1.84 [95% CI, 1.234–2.749], P=0.0028), WBC (>11×109/L, HR=2.35 [1.598–3.465], P<0.0001), and PLT counts (>400×109/L, HR=1.60 [1.088–2.359], P=0.0170) were each associated with increased TE risk (Table 1). WBC count ≥11×109/L is associated with the highest TE risk compared with WBC count <7×109/L (HR=2.61 [95% CI, 1.594–4.262], P<0.0001). Elevated WBC >12×109/L was significantly associated with increased risk of TE with HCT controlled at ≤45%. PLT count (>600×109/L) increased TE risk (HR=1.37 [95% CI, 0.763–2.468]) compared with PLT count ≤600×109/L, but this was not statistically significant (P>0.05). In all models, advanced age, female sex, and TE history were associated with increased TE risk. Image:Summary/Conclusion: This analysis of REVEAL, the largest real-world cohort of PV pts to date, demonstrated that elevated HCT levels (>45%), WBC (>11×109/L), and PLT counts (>400×109/L) were associated with increased TE risk. An association of elevated WBC >12×109/L with increased risk of TE was also observed when HCT was controlled, indicating that TE risk may be reduced by controlling WBC as well as HCT. These data support the need to incorporate blood count into risk stratification and treatment strategies for pts with PV in clinical practice and to move beyond the conventional risk model. Further studies to understand the causal relationship between elevated blood counts and TEs are warranted.

Excess Mortality in Young Patients with Myeloproliferative Neoplasms

▪Introduction: Myeloproliferative neoplasms (MPNs) - essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) - are associated with significant morbidity and shortened survival, irrespective of age (Srour et al. Br J Hematol. 2016). Despite shortened survival, young MPN patients (pts) are often classified as “low-risk” and managed with aspirin alone, phlebotomy-only (PHL), or observation instead of potentially life-prolonging cytoreductive and/or disease-modifying treatment. Age-biased risk assessment and treatment practices deprive young pts from early intervention and access to clinical trials. Our goal is to highlight the unmet need for identifying and implementing life-prolonging treatment in young MPN pts. Here, we determine and compare the excess mortality from MPNs in young (<60 years) to older pts (≥60 years) in the United States (US).Methods: In this population-based study, demographic (age, sex, race), survival, and cause-of-death data were collected for MPN pts from the US Survey, Epidemiology, and End Results (SEER) registry between 2001-2017; and for the general US population from the Centers for Disease Control and Prevention Wide-ranging OnLine Data for Epidemiologic Research (CDC WONDER) database. SEER reports cancers classified by International Classification of Diseases for Oncology, version 3 (ICD-O-3), which evolved with the WHO classification of myeloid neoplasms in 2001 for ET, PV and PMF. Cause-of-death is reported by ICD-10 codes, which we categorized into cardiovascular (CVE), second cancers (CA), acute leukemia (AL), and others. Excess, or relative mortality was determined by the ratio of observed mortality in MPN pts (Kaplan-Meier estimate) over the expected mortality of the US population matched by age, sex, race, and birth-year (actuarial estimate). A one-sided log-rank test was used. Excess mortality of young compared to older pts was determined from a random-effects model using restricted maximum-likelihood estimator method. All analyses were performed using RStudio software v 1.4.1106.Results: The SEER query identified 40,333 MPN pts (ET: 17,420 (43%), PV: 18,027 (45%), PMF: 4,886 (12%)) diagnosed at a median age of 66 years (ET: 67, PV: 65, PMF: 69) of whom 20,470 (51%) were females (ET: 10,709 (61%), PV: 7,768 (43%), PMF: 1,993 (41%)). The 10-year mortality for ET, PV, and PMF pts <60 was 13%, 18%, and 49% respectively (versus 6% for controls); and ≥60 was 59%, 59%, and 87% respectively (versus 35% for controls) (Figure 1A). Excess all-cause mortality was higher in pts <60 compared to ≥60 with ET (2.75 versus 1.82, p<0.001), PV (3.16 versus 1.92, p<0.001), and PMF (10.6 versus 5.73, p<0.001) (Figure 1B). Excess CVE mortality was higher in PV<60 compared to PV≥60 (3.36 versus 2.55, p=0.036) but not in ET or PMF. Excess CA mortality was higher in PV<60 than PV≥60 (2.36 versus 1.53, p=0.002) but not in ET or PMF. Excess AL mortality was high for all pts, particularly PMF, and was not significantly different in pts <60 compared to ≥60Discussion: Excess or relative mortality emphasizes the burden of MPN-related death with current treatment. In this population-based study, we found excess mortality in young MPN pts (<60), greater than in older pts (≥60). This difference may result from age-biased risk assessment and treatment recommendations that recommend lower intensity therapy for young pts. It may be time to revisit these recommendations since accruing evidence demonstrates long-term safety, efficacy and potential survival benefit of available cytoreductive agents. Certain treatments such as interferon-alpha (IFN) may improve survival in PV (Abu-Zeinah et al. Leukemia. 2021), and a recent randomized clinical trial established superiority of IFN over standard of care PHL in young PV pts (Barbui et al. Lancet Hematol. 2021). These data advocate for early intervention with potentially disease-modifying treatment for all pts regardless of age. These data also call into question age-biased exclusions of many young pts from participation in clinical trials of established or promising drugs.Conclusion: Excess mortality of young MPN pts (<60) is unacceptably high and greater than that of older pts (≥60). Clinical trials testing early intervention with potentially life-prolonging treatments are required. [Display omitted] DisclosuresSilver: Abbvie: Consultancy; PharamEssentia: Consultancy, Speakers Bureau. Scandura: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Constellation: Research Funding; MPN-RF (Foundation): Research Funding; CR&T (Foudation): Research Funding; European Leukemia net: Honoraria, Other: travel fees . Abu-Zeinah: PharmaEssentia: Consultancy.

Normal Life Expectancy for Polycythemia Vera Patients Is Possible

▪Introduction: Polycythemia vera (PV), a chronic myeloproliferative neoplasm, is characterized by shortened overall survival (OS) due to potentially fatal thrombosis, progression to myelofibrosis (MF), and acute leukemia. Treatment with aspirin, attentive phlebotomy (PHL) and cytoreductive agents can prevent thrombosis; but it is unknown whether available treatments can achieve a normal life-span for PV patients (pts). Our objective was to assess the extent by which PV alters OS of pts receiving available treatment at our center and in the community.Methods: We obtained demographics and survival data of adult PV pts from our Weill Cornell Medicine (WCM) Research Database Repository (PV-WCM) diagnosed from 1974-2020 as previously described (Abu-Zeinah et al. Leukemia 2021); and from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) Program, 2001-2017. PV-WCM thrombosis and MF progression data were available. WCM institutional review board approval and SEER data use agreement were in place. OS of PV pts was estimated using Kaplan-Meier (KM) analysis. Propensity Score Matching was used to identify a subgroup of SEER pts (PV-SEER) with similar age, sex, and race demographics to PV-WCM for comparison of OS. Cox proportional hazards was used for multivariable analysis (MVA) of survival. Actuarial survival of the US population matched by age, sex, race, and year-of-birth was obtained from US Census. Observed OS was compared to actuarial OS using one-sided log-rank test.Results: We identified 470 PV-WCM and 16,492 PV pts from SEER. The median OS of the PV-WCM cohort and the SEER population was 26.6 and 12.8 years, respectively, but the groups differed by age and sex (Fig 1A). PV-WCM and matched PV-SEER, however, were well balanced by age, sex, and race (standardized mean difference <0.1). The median OS of PV-WCM was 10.8 years longer than PV-SEER (p<0.001, Fig 1B). MVA confirmed 65% lower mortality in the PV-WCM group relative to the PV-SEER population (p<0.001, Fig 1C). PV-SEER OS was shorter than actuarial OS of the US population (mortality HR 2.47, p<0.001), whereas PV-WCM OS was not significantly different than expected (mortality HR 1.15, p=0.136). Excess late mortality was observed in PV-WCM after 17 years, potentially due to increased incidence of MF progression, affecting almost 50% of PV pts after 25 years (Fig 1D).Discussion: These data point to the success of attentive management with aspirin, targeted PHL, and cytoreductive therapy at a specialty center in reducing the mortality of PV, owing in part, to ELN and NCCN treatment recommendations for preventing fatal thrombosis. Although excess thrombosis was not eliminated in PV-WCM pts, the incidence rate was low after the first two years (Fig 1D). In contrast, the incidence of MF progression increased, potentially contributing to excess late mortality. Current PV risk stratification and treatment recommendations neither predict nor aim to mitigate progression to MF, and do not satisfy the needs of younger, low-risk pts who are often symptomatic and harbor a lifetime threat of progression (Fig 1E). The recent Low-PV study showed that low-risk pts may also benefit from cytoreductive therapy with an agent such as interferon-alpha (rIFNα) over PHL alone (Barbui et al. Lancet Hematol 2021). PV-WCM pts treated with rIFNα (n=137), previously shown to have improved MF-free survival and OS (Abu-Zeinah et al. Leukemia 2021), had an OS similar to the matched US population (p=0.33, Fig 1F); whereas pts not treated with rIFNα had modestly shortened OS (HR 1.26, p=0.03). Because PV progression is among the leading causes of late morbidity and mortality, and available therapy can mitigate this, it may be time to reconsider and improve upon PV risk stratification and treatment.Conclusion: This large population-based and single center study shows that although PV survival remains shortened, normal life expectancy for PV pts is possible with available care. The discrepancy between survival in the community and at a specialized center highlights the need for greater community outreach, health equity, and education regarding treatment standards for PV. Hopefully, this study motivates development of new PV risk stratification and treatment recommendations that focus not only on hematologic control and thrombosis prevention, but also on preventing MF progression, improving OS, and restoring normal life expectancy. [Display omitted] DisclosuresAbu-Zeinah: PharmaEssentia: Membership on an entity's Board of Directors or advisory committees. Silver: Abbvie: Consultancy; PharamEssentia: Consultancy, Speakers Bureau. Scandura: CR&T (Foudation): Research Funding; European Leukemia net: Honoraria, Other: travel fees ; MPN-RF (Foundation): Research Funding; Constellation: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure:Interferon-alpha is used off label in the treatment of polycythemia vera.

Efficacy and Safety of Ruxolitinib in the Treatment of Elderly Patients with Policythemia Vera Resistant/Intolerant to Hydroxyurea

▪Introduction: Ruxolitinib (Rux) has been recently approved as second-line therapy in patients (pts) with Polycythemia Vera (PV) resistant/intolerant to hydroxyurea (HU). Median age of PV pts enrolled in the pivotal Response trials was around 60 yrs; at present, no data is reported on the use of Rux in elderly pts.Aims: In a real-world cohort of PV pts treated with Rux, we investigated whether the efficacy and safety of Rux were comparable in pts who initiated therapy when aged ≥75 years compared with younger pts.Methods: After IRB approval, clinical/laboratory data of 934 WHO2016-defined PV pts followed in 29 Hematology Centers were retrospectively collected. Of them, 168 (17.9%) were considered resistant/intolerant to HU at any time during follow-up by responsible physician and shifted to Rux as second-line therapy.Results: Among the 168 pts treated with Rux, 42 (25%, median age 78.2 years) were aged ≥75 yrs at Rux start, 74 (44%, median age 67.7) were aged 60-74 and 52 (31%, median age 53) were <60 at Rux start.No significant differences were observed between the 3 groups, apart from a lower need for phlebotomies in pts aged ≥75 yrs and lower presence of palpable spleen in older pts (age ≥60), that more frequently switched to Rux due to HU intolerance (Table 1).Median duration of HU treatment was 41.0 months (IQR 14.6 - 85.8), with a trend for a longer median treatment duration in pts aged ≥75 [61.0 months (IQR 21.5 - 89.6) vs 35.9 months (IQR 13.4 - 79.6), p=0.04]. Rux starting dose was similar across age groups; however, more elderly pts underwent Rux dose reductions during follow-up (45.2% in pts aged ≥75 vs 28.6% in younger pts, p=0.04).Responses during Rux therapy are reported in Table 2, with no significant differences between the 3 groups at any time. In the overall cohort, response on PV-related symptoms at 6 and 12 months was significantly higher in pts who switched to Rux because of HU intolerance; however, this difference was not observed in pts aged ≥75 yrs.As to the most common hematologic Rux-related toxicities, grade 3-4 anemia and thrombocytopenia were observed in only 2 (1.2%) and 5 (3%) pts, with no difference across age groups (p=0.45 and p=0.18). However, any grade anemia and thrombocytopenia during Rux were more frequently observed in pts aged ≥75 (68.3% vs 51.7% of anemia, p=0.06 and 12.2% vs 3.5% of thrombocytopenia in younger pts, p=0.04). Nineteen and 4 pts experienced infectious and thrombotic complications during Rux with incidence rates of 0.59 and 0.12 per 100 patient-months, respectively, comparably in younger and older (≥75) pts (p=0.75 and p=0.29, respectively). Notably, 6 infections were herpes simplex/zoster virus, comparably distributed between the 3 groups (p=0.60).Permanent Rux discontinuation was needed in 14 pts (8.3%) after a median Rux exposure of 7.8 months (IQR 4.6 - 17.6) (incidence: 0.41 per 100 pts/months). Discontinuation was comparable between age groups, with Rux stop in 4 pts aged ≥75 yrs and 10 younger pts (2.4% vs 5.2% at 8 months, log-rank p=0.75). At last follow-up, 2 pts had died (1 from 2 nd neoplasia after 19.1 months from Rux start and 1 from acute leukemia after 3.3 years), both pts aged 60-74 yrs.Conclusions. In this real-world analysis, use of Rux in HU resistant/intolerant elderly PV pts was effective and safe despite the more frequent need for dose reductions. Older age should not discourage Rux therapy, but stricter hematological monitoring may be suggested. [Display omitted] DisclosuresLatagliata: BMS Cellgene: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Breccia: Pfizer: Honoraria; Incyte: Honoraria; Bristol Myers Squibb/Celgene: Honoraria; Abbvie: Honoraria; Novartis: Honoraria. Bonifacio: Amgen: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Cavo: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Palandri: AOP: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

A JAK2V617F Variant Allele Frequency Greater Than 50% Identifies Patients with Polycythemia Vera at High Risk for Venous Thrombosis

▪Background: Thrombosis is the main cause of morbidity and mortality in pts with Polycythemia Vera (PV). Current risk stratification is based on 2 variables: age >60y and history of thrombosis. Additional thrombotic risk factors in PV are generic cardiovascular risk factors and leukocytosis. JAK2V617F (JAK2VF) variant allele frequency (VAF) at diagnosis is highly heterogeneous. A VAF>75% was associated with higher rate of all thrombosis after diagnosis (Vannucchi AM et al, Leukemia 2007), and a VAF ≥ 60% correlated with increased rate of venous thrombosis (VT) in high-risk pts (Guglielmelli P et al, ASH 2018); however, predictive role of JAK2VF VAF is still debated.Aim: To evaluate the impact of JAK2VF VAF on rate of arterial and venous thrombosis in PV pts.Patients and methods: A cohort of 576 strictly 2016 WHO-defined PV pts followed at Univ. of Florence (1981-2020) were included. All pts were annotated for JAK2VF VAF, determined <3 years from diagnosis, and thrombosis at diagnosis and follow-up (FU). Arterial thromboses (AT) included stroke, transient ischemic attacks, retinal artery occlusion, coronary artery disease, and peripheral arterial disease; VT included cerebral venous thrombosis, deep vein thrombosis, pulmonary embolism. Splanchnic vein thromboses (SVT) were excluded. Only first occurring event was considered. Cox proportional hazard regression model was used for univariate and multivariable analysis. Kaplan-Meier (KM) analysis was used for time-to-event assessment, compared by log-rank test.Results: Median age was 61.4 y (range, 16.2-91.8), 58.2% were male; 62% were high-risk based on current classification. Median JAK2VF VAF was 41.5% (range, 0.3-100). A total of 76 (13.2%) pts had an AT event before/at PV diagnosis and 49 (8.5%) pts had an AT during FU. As regards VT, 64 (11.1%) and 39 (6.8%) pts had a VT before/at or after PV diagnosis, respectively. We found that JAK2 VAF as a continue variable was correlated with the risk of VT in FU (p=0.003) but not with AT (p=0.8). ROC analysis to determine the best cut-off level for JAK2 VAF predicting VT had an AUC of 0.72 and a best cut-off value of VAF=50%. VT at FU were significantly enriched in pts with VAF >50%: 14.5% versus 2.4%, p=<0.0001. VT -free survival (VT-FS) by KM was significantly shorter in the presence of a JAK2 VAF >50% (HR 4, CI 1.9-8.6, p<0.0001) (Figure 1A), whereas no difference was found for AT (HR 0.9). In addition to JAK2VF VAF>50%, univariate analysis for VT-FS identified history of VT (HR 2.9; CI 1.4-6.1, p=0.006), leukocytosis ≥11x10 9/L (HR 1.9; CI 1.1-3.4, p=0.02) and palpable splenomegaly (HR 1.9, CI 1-3.6; p=0.04) as risk factors. Multivariable analysis confirmed VAF>50% (HR 3.8, CI 1.8-8.1, p=0.0006) and previous VT (HR 2.4, CI 1.1-5.1; p=0.02) as independent risk factors for future VT. In contrast, univariate analysis for AT-free survival (AT-FS) identified history of AT (HR 2.5; CI 1.3-4.9, p=0.007), diabetes (HR 3.3; CI 1.6-6.5, p=0.0007), hyperlipidemia (HR 3.1; CI 1.7-5.6, p=0.0003) and hypertension (HR 2, CI 1.1-3.8; p=0.03) as predictors of future AT; age >60y showed only a trend (p=0.08). Multivariable analysis for AT-FS identified diabetes (HR 2.4, CI 1.2-5; p=0.02), hyperlipidemia (HR 2.3; CI 1.2-4.3, p=0.01) and previous AT (HR 2.1, CI 1-4.2; p=0.04) as independent predictors of future AT.Validation: Our findings were validated in an independent cohort of 315 2016-WHO defined PV pts from Policlinico Gemelli, Catholic Univ., Rome. After exclusion of 26 pts with SVT, analysis was conducted on 289 pts, 38 of them with thrombosis as heralding event (21 AT and 17 VT). Multivariable analysis confirmed JAK2VF VAF >50% (HR 2.3, CI 1.03-5.0, p=0.04) and previous VT (HR 4.5, CI 2.0-10.1; p=0.0003) as independent risk factors for future VT. In pts with VAF >50%, the rate of VT at FU was 19.9% vs 7.7%, P=0.005. KM curve showed that VT-FS was significantly shorter in pts with a JAK2VF VAF >50% (HR 2.2, CI 1.2-4.2; p=0.01) (Figure 1B). Of note, impact of JAK2 VAF>50% on VT at FU was statistically significant particularly in conventionally low-risk pts, accounting for an HR of 9.4 (CI 1.2-72) and HR 3.6 (CI 1.3-10) in Florence and Rome cohorts, respectively.Conclusions: These data support JAK2VF VAF as a strong independent predictor for future venous thrombosis in PV, in association with history of prior venous events, reinforcing that AT and VT are associated with unique risk factors in pts with PV.Supported by AIRC, Project Mynerva n.21267 [Display omitted] DisclosuresVannucchi: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

Characteristics of High-Risk Polycythemia Vera Patients with Suboptimal Response to First-Line Therapy Who Switched to Ruxolitinib Vs Those Who Did Not Switch: Findings from PV-Switch, a Multinational, Retrospective Chart Review Study

Characteristics of High-Risk Polycythemia Vera Patients with Suboptimal Response to First-Line Therapy Who Switched to Ruxolitinib Vs Those Who Did Not Switch: Findings from PV-Switch, a Multinational, Retrospective Chart Review Study

Critical Evaluation of Who 2016 Criteria for the Diagnosis of Polycythemia Vera: Distinction from JAK2V617+ Essential Thrombocythemia

IntroductionThe JAK2V617F and exon 12 mutations are critical for the diagnosis of polycythemia vera (PV) and JAK2V617F is the molecular marker of 50-60% of patients (pts) with essential thrombocythemia (ET) [Arber, DA et al. Blood. 2016;127:2391-2405]. Distinguishing these illnesses in their early stage remains a clinical problem because of this shared mutation and phenotypic characteristics [Silver, RT et al. Blood. 2013;122:1881-1886][Ancochea, A et al. Br J Haematol. 2014;167:411-417]. When the hematocrit (HCT), red blood cell (RBC) count, or hemoglobin (HGB) are increased, we distinguish PV from JAK2V617F -mutated(JAK2V617F +) ET using chromium-51 (Cr-51) labeled RBC to measure red cell mass (RCM) and iodine-135 (I135) to determine plasma volume. To define polycythemia, the World Health Organization (WHO) 2016 criteria used HCT and HGB values derived from a retrospective study which have never been confirmed [Arber].Materials and MethodsWe diagnosed PV by establishing JAK2V617F positivity, a Cr-51 measured RCM>125% of expected volume, and a marrow biopsy consistent with PV [Silver]. Utilizing a receiver operating characteristic (ROC) analysis [IBM SPSS, 23.0], we determined threshold values for HCT, HGB, and RBC to distinguish 69 PV pts from 31 JAK2V617F + ET pts who presented with “high-normal” HCT or HGB values.Results:Relevant demographic and hematologic data are shown in Table 1. The Cr-51 determined RCM of all 69 PV pts was >125%, establishing polycythemia [Silver], and was measured in 28/31 JAK2V617F + ET pts; it was normal in all (mean=95.6 ±13.1%).ROC analyses were performed to determine threshold HCT, HGB, and RBC values to distinguish PV from JAK2 V617F + ET pts. For men and women, respectively, the HCT threshold values were 49.3 and 45.8%, for HGB 16.8 and 15.2 g/dL, and for RBC 5.79 and 5.125 x106/uL . These values and those proposed by WHO 2016 are shown in Table 2. The area under the curve (AUC) for the Cr-51 RCM was 1, indicating 100.0% diagnostic specificity (spec) and sensitivity (sens) for distinguishing PV from JAK2 V617F + ET (AUC measures how well groups are distinguished and can range from 0 to 1, with 1 representing a perfect test). Figure 1 shows ROC curves representing the spec and sens of using HCT to distinguish PV from JAK2V617F+ ET. For men, the AUC for HCT was 0.846 (spec=100.0%, sens=64.9%), for HGB 0.753 (spec=100.0%, sens=55.6%), and for RBC 0.761 (spec=100.0%, sens=77.4%). For women, the AUC for HCT was 0.974 (spec=95.7%, sens=78.1%), for HGB 0.875 (spec=95.5%, sens=77.4%), and for RBC 0.924 (spec=90.9%, sens=88.0%). Blood values were less sensitive in men than in women, whereas the specificities were consistent (Table 2). Distribution curves plotted for HCT, HGB, and RBC values are shown in Figure 2. For pts with PV or JAK2V617F+ ET, the HCT values overlap in 40.8% of men and 18.3% of women. The HGB values overlap in 49.0% of men and 53.6% of women, and the RBC values overlap in 53.3% of men and 50.0% of women.Discussion:The Cr-51 RCM was 100% specific and sensitive for distinguishing PV from JAK2V617F+ ET. Our HCT and HGB values derived at the time of the diagnostic Cr-51 RCM from PV pts are concordant with those of WHO 2016 for diagnosing PV [Arber]. However, there is substantial overlap in HCT values occurring in 40.8% of men and 18.3% of women, and in HGB values occurring in 49.0% of men and 53.6% of women, which indicates low sensitivity for distinguishing PV from JAK2V617F+ ET. In the absence of performing a Cr-51 RCM, a marrow biopsy is mandatory for distinguishing them. It has been suggested that JAK2V617F + ET pts are at higher risk for thrombosis than calreticulin-mutated ET [Rumi, E et al. Blood. 123;10:1544-1551]. Since median HCT values were not reported and since neither isotope studies nor systematic marrow biopsies were performed, some alleged JAK2V617F+ ET pts who had a higher risk of thrombotic events may actually have had PV.Conclusion:Of importance, this is the first confirmation of WHO 2016 values for the diagnosis of PV. However, these values do not provide unequivocal separation of PV from JAK2V617F+ ET. In these cases, in the absence of a Cr-51 RCM, a marrow biopsy is mandatory because its distinction has serious prognostic and therapeutic implications. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.