Clinical Outcomes in Patients with Myelofibrosis Treated with Ruxolitinib and Anemia-Supporting Medications

Patients with myelofibrosis (MF) often present with anemia, and dose-dependent anemia is a known consequence of treatment with the Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib. Current guidelines recommend erythropoiesis-stimulating agents (ESAs) and danazol as options to manage anemia in this population. However, data are lacking regarding the clinical outcomes of patients with MF treated with ruxolitinib and these agents. This post hoc analysis, carried out by Dr. Pankit Vachhani et al,, of the phase 3 JUMP trial, the largest ruxolitinib trial to date, evaluated treatment patterns and clinical outcomes of ruxolitinib-treated patients with anemia at study enrollment who initiated treatment with ESAs or danazol.

The large (N=2233), single-arm, phase 3b, expanded-access JUMP trial evaluated safety and efficacy of ruxolitinib treatment for patients with MF in a setting similar to routine clinical practice. The study included patients ≥18 years old with primary or secondary MF and baseline (BL) platelets ≥50×109/L. Ruxolitinib was administered at a starting dose of 5–20 mg twice daily based on BL platelet count. This post hoc analysis included patients with BL anemia (hemoglobin [Hb] <12.0 g/dL or Hb <10.0 g/dL) who were not receiving supportive care for anemia at enrollment but initiated an ESA or danazol within 3 months of enrollment and remained on that therapy for ≥3 months. Clinical outcomes evaluated were spleen length response (SLR; ≥50% reduction from BL) and symptom response (≥6.5-point increase in Functional Assessment of Cancer Therapy–Lymphoma total score [FACT-Lym TS] from BL).

Of the 1384 patients with Hb<12.0 g/dL (755 with Hb<10.0 g/dL) who were not receiving supportive care for anemia at enrollment, 101 (7.3%) initiated an ESA (n=98) or danazol (n=3) within 3 months of enrollment (52 [6.9%] with Hb<10.0 g/dL) and were included in this analysis. For the Hb<12.0 g/dL cohort, median (range) age was 70 (45–86) years, 54% were male, median (range) MF duration since initial diagnosis was 19 (0.3–312) months, 91% had a palpable spleen, and median (range) time from enrollment to first dose of an ESA or danazol was 43.0 (2–91) days. For the Hb<10.0 g/dL subgroup, median (range) age was 72 (45–85) years, 52% were male, median (range) MF duration since initial diagnosis was 13 (0.3–158) months, 89% had a palpable spleen, and median (range) time from enrollment to first dose of ESA or danazol was 34 (2–90) days.

SLR at Week 12 was achieved by 42 (42%) patients with Hb<12.0 g/dL and 22 (42%) with Hb<10.0 g/dL. SLR at Week 24 was achieved by 34 (34%) patients with Hb<12.0 g/dL and 15 (29%) with Hb<10.0 g/dL. Symptom response at Week 24 was achieved by 26 (26%) patients with Hb<12.0 g/dL and by 12 (23%) with Hb<10.0 g/dL. These rates were similar to those previously reported for the entire JUMP population.
For the Hb<12.0 g/dL cohort, mean (SD) Hb was 9.9 (1.1) g/dL at BL, reached a nadir at Week 4 (8.9 [1.3] g/dL), and steadily increased thereafter to Week 48 (9.9 [1.5] g/dL; mean 1.5% change from BL). A similar trend was observed for the Hb<10.0 g/dL cohort, with mean (SD) Hb 9.1 (0.8) g/dL at BL, a nadir of 8.3 (1.2) g/dL at Week 4, and 9.5 (1.7) g/dL at Week 48 (mean 6.5% change from BL). Evaluable patients with Hb<12.0 g/dL required a mean (SD) 0.8 (0.9) transfusions in the 8 weeks before BL (n=101), 1.3 (1.6) in Weeks 17–24 (n=63), and 0.5 (1.1) in Weeks 41–48 (n=46). Among evaluable patients with Hb<10.0 g/dL, transfusion requirement was mean (SD) 1.0 (1.0) in the 8 weeks before BL (n=52), 1.7 (1.9) in Weeks 17–24 (n=33), and 0.6 (1.3) in Weeks 41–48 (n=25). Mean (SD) ruxolitinib total daily dose was 35 (9) mg at BL for the Hb<12.0 g/dL cohort (34 [9] for the Hb<10.0 g/dL cohort) and for both cohorts decreased to 25 (11) mg through Weeks 45–48.

For patients with anemia at MF diagnosis who received ESA or danazol in combination with ruxolitinib, spleen and symptom responses were similar to those reported in the entire JUMP study population. In addition, most patients tolerated doses of ruxolitinib >25 mg daily and post-enrollment maintained an Hb level within 1.0 g/dL of BL throughout the study period. These results reinforce the use of supportive care for anemia with an ESA or danazol combined with ruxolitinib and may allow for maintenance of ruxolitinib dose intensity in MF patients with anemia.

Clinical and Molecular Characterization of Disease Progression in Patients (Pts) with Low-Risk Myelofibrosis (MF) Enrolled in the MOST Study

Patients with low-risk MF have a relatively good prognosis; however, few data exist to identify pts likely to experience disease progression. The Myelofibrosis and Essential Thrombocythemia Observational Study (MOST; NCT02953704) is a prospective observational study that enrolled pts with low-risk MF defined by DIPSS criteria. Dr Abdulraheem Yacoub et al identify here clinical and molecular characteristics of pts who progressed from low-risk to intermediate-/high-risk disease.

MOST enrollment criteria (confirmed locally and centrally) included a physician-reported MF diagnosis (primary MF, post-polycythemia vera, or post-essential thrombocythemia) and low-risk status by DIPSS (except age >65 y). Biospecimens were optionally collected every 12 months. Of 232 pts with MF enrolled, 158 met these criteria by central review, had available biospecimens, and were included in this analysis. MF progression was defined by meeting ≥1 of the following criteria during the study: hemoglobin <10 g/dL, presence of constitutional symptoms (weight loss, fever, fatigue, or sweats), platelets <100×109/L, new/worsening splenomegaly, blasts >1%, white blood cell (WBC) count >25×109/L, death due to disease progression, >1 red blood cell transfusion, or leukemic transformation. Uni- and multivariate logistic regressions were performed to assess risk factors of progression. RNA sequencing (RNA-seq) was performed on samples from 107 pts with available RNA specimens (42 pts with and 65 pts without progression) using Illumina NovaSeq™ X Plus (100 paired-end [PE] base reads with >50 M PE reads per sample). RNA-seq data were analyzed using differential gene expression analysis (DESeq2), fast gene set enrichment analysis (FGSEA), and cell type-specific enrichment analysis (CSEA). Driver mutation genotyping was performed on DNA if RNA was unavailable.

During the study, 97/158 pts (61.4%) had evidence of MF progression from low-risk to intermediate- or high-risk disease. Baseline demographics were similar between pts with vs without disease progression. Enrollment duration was similar in pts with and without progression (median [range], 53.6 months [42-68] vs 50.7 months [42-62]). Driver mutation genotyping identified 111 pts with JAK2 V617F, 24 with CALR, 9 with MPL, and 14 triple-negative pts; of whom, 61.3%, 54.2%, 77.8%, and 64.3% had evidence of MF progression.

Univariate analysis of baseline covariates, including driver mutations, identified only WBC >11×109/L at enrollment as significantly associated with increased progression risk (OR [95% CI], 2.98 [1.31-6.78]; P=0.009). All other covariates assessed (age, body mass index, time from MF diagnosis to enrollment, sex, race, driver mutation, hematocrit >0.45 L/L, and platelets >400×109/L at enrollment) were not significant predictors (all P>0.05). WBC >11×109/L remained significant in multivariate analyses (OR [95% CI], 2.88 [1.15-7.23]; P=0.024).

RNA-seq identified 104 upregulated and 20 downregulated genes in pts with and without progression, respectively. Of note, CD34 and MMP8 were upregulated in pts with progression. CD34 is a marker of myeloid stem/progenitor cells with a function in stem cell activity. MMP8, a collagenase largely secreted by neutrophils and monocytes, is considered an important mediator of microenvironment remodeling.

FGSEA identified 18 significantly upregulated pathways in pts with MF progression, including interferon-α and interferon-γ response (P<0.05). Using the results from differential gene expression analysis, CSEA identified spleen hematopoietic stem cells and spleen intermediate monocytes as the most differentially expressed markers at the cellular tissue level, while hematopoietic stem cells and intermediate monocytes were identified as the most differentially expressed cell types (P<0.05).

This analysis of prospective data from MOST found the majority of pts with low-risk MF experienced disease progression over a median ~54 months of follow-up. Multivariate regression analysis identified WBC >11×109L as a significant risk factor of progression. RNA-seq analysis demonstrated differences in gene expression patterns of relevant cell types in pts with vs without MF progression. Several key genes were identified, including overexpression of CD34 and MMP8, that may provide predictive biomarker signatures of progressive disease and inform therapeutic targeting.

Molecular Predictors of Disease Progression to Myelofibrosis (MF) in Patients (Pts) with Polycythemia Vera (PV) Enrolled in Reveal

Progression of PV to MF represents a major cause of morbidity and mortality; however, predictors of progression remain unclear. The Prospective Observational Study of Patients With Polycythemia Vera in US Clinical Practices Trial (REVEAL; NCT02252159) followed pts for a median of ~4 years, with optional biospecimen collection every 12 months. This analysis, carried out by Dr. Stephen T. Oh et al, investigated the clonal architecture and molecular mechanisms that predict transformation to MF in pts with PV.

Of 2510 pts enrolled in REVEAL, 1880 had an available biospecimen and a confirmed JAK2 mutation by ddPCR. Of these pts, 114 had MF transformation during the study period based on modified World Health Organization criteria. Whole exome sequencing was performed on enrollment biospecimens (pretransformation) from the 114 pts, as well as a control cohort of 340 pts without transformation, matched (1:3) by propensity score based on age, sex, duration of PV, body mass index, and history of thrombosis. Sequencing was performed using the Illumina (paired-end) platform at an average depth of 300× and processed using Genome Analysis Toolkit best practices. Variants were filtered (VarSeq) according to the following criteria: ≥60 reads coverage, ≥3 reads support, >1% variant allele frequency (VAF), and <1% (or missing) minor allele frequency in the Genome Aggregation Database. Variants were annotated via tiers based on predicted pathogenicity using multiple algorithms. Data were analyzed using fast gene set enrichment analysis (FGSEA) and cell type-specific enrichment analysis (CSEA).

There were no significant differences in clinical characteristics at enrollment between the transformed and nontransformed groups. Median (range) enrollment duration was 18.2 (0-30.0) and 19.1 months (0-32.5) in the transformed and nontransformed groups. A wide JAK2 V617F VAF distribution was observed in both cohorts; however, median (range) VAF was significantly higher in the transformed vs nontransformed group (84.21 [0.02-97.99] vs 57.45 [0.05-98.65]; P<0.0001). For both transformed and nontransformed pts, prevalence of commonly mutated genes was consistent with observations in other myeloid malignancies. A higher number of combined Tier I/II mutations in myeloid-related genes was observed per pt in the transformed vs nontransformed group (mean [range], 5.6 [2-14] vs 4.8 [1-12]; P<0.05). In particular, SF3B1, IDH1/2, EZH2, and TP53 mutations were enriched in the transformed group, with VAFs that trended higher compared with the nontransformed group. In addition, the presence of multiple clones was suggested by a difference in VAF between JAK2 V617F and co-occurring somatic variants.

To identify novel genes potentially contributing to PV transformation, genes with Tier I variants significantly associated with transformation (P<0.05) and an odds ratio >2 were prioritized. 83 genes were identified, including the tumor suppressor gene PTPN2, which has a known role in regulation of inflammation. Copy number variant (CNV) analysis identified 25 genes with gains and 28 with losses in the transformed vs nontransformed group. More pts in the transformed group had a CNV gain in TYRO3, which has been linked to myeloid leukemia cell growth. Pathways with the highest enrichment scores via FGSEA comparison of the transformed vs nontransformed group included Wnt/β-catenin signaling, inflammatory response, and DNA repair, whereas CSEA indicated a strong signal in bone marrow granulocytes and blood monocytes. Analysis of Tier II variants further identified markers of upregulated interferon-α response, notch signaling, and IL-6 and JAK-STAT3 signaling. Together, these data suggest a potential signature of inflammation in PV transformation to MF.

Although clinical characteristics were similar at enrollment for all pts in this analysis, JAK2 V617F VAF was significantly higher in pts with PV who transformed to MF. In addition, the VAF of nondriver somatic mutations trended higher in multiple genes with a known role in myeloid malignancy. Ongoing analyses of novel genes suggest a role of inflammatory pathways in PV transformation and may uncover additional pathways that contribute to this process. Further investigation will include analysis of clonal evolution via intra-pt longitudinal biospecimens and development of a machine learning approach to predict pts at increased risk of transformation.

Revised ELN Criteria in Polycythemia Vera Identify an Increased Risk Phenotype for Thrombotic Events Beyond Conventional Risk Stratification. a Multicenter Cooperative Study

The European LeukemiaNet (ELN) criteria for initiating cytoreductive therapy aim to manage this risk, primarily using hydroxyurea (HU) (Marchetti M et al, Lancet Haematol 2022). However, the impact of ELN criteria for therapy start (CTS) on thrombotic risk, particularly among low-risk (LR, age <60 yrs & no previous thromboses) and high-risk (HR: HR-AGE, age >60 yrs; HR-THRO: previous thrombosis regardless of age) patients, needs further exploration.

This study, carried out by Francesca Palandri et al, evaluates the incidence of thrombosis among PV pts undergoing HU treatment across different risk categories and the impact of CTS on thrombotic risk.

The PV-ARC study (NCT06134102) is a multicenter, retrospective study of 1162 WHO2022 PV patients.

Among these, 739 pts treated with HU were evaluated for CTS, which were revised to apply real-world practice as follows: 1) persistent/progressive leucocytosis: 100% increase if white blood cells (WBC) <10 x109/L or 50% increase if WBC>10 or WBC>15 at diagnosis and HU start; 2) extreme persistent thrombocytosis: platelet (PLT) >1000 x10 9/L at diagnosis and HU start; 3) progressive splenomegaly: >5 cm below costal margin (BCM) from diagnosis; 4) inadequate hematocrit (HCT) control: 5) >6 phlebotomies (PHL)/yr or HCT >53% at diagnosis and HU start or PHL intolerance; 6) uncontrolled cardiovascular risk factors; 7) severe itching (score ≥5/10).

Incidence rate ratios (IRR) were calculated per 100 patient-years (%p-y). Thrombosis-free survival (TFS) was assessed using Kaplan-Meier analysis from HU start, and multivariate Cox regression analysis was used to identify factors independently associated with thrombotic risk.

Among the 739 HU-treated pts, 137 (18.5%) were LR and 602 (81.5%) HR (HR-AGE: 70.4%; HR-THRO: 29.6%). Revised CTS were identified in 445 (60.3%) pts: 95 (69.3%) LR, 242 (57.1%) HR-AGE, and 109 (61.2%) HR-THRO, with a significant difference between LR and HR pts. More than one CTS was present in 152 (34.1%) pts, mainly in LR pts (43.2% LR vs. 31.6% HR, p=0.02).

Additional reasons to start HU (spleen palpable at 2-5 cm BCM, mild leucocytosis/thrombocytosis, microvascular disturbances, PHL requirement <6/yr) were present in 100% LR and in 71.3% HR pts without CTS.

Median HU starting dose was 0.5 g/die (34.2% received ≥1 g/d). Over time, maximum HU dose was ≥1 g/d more frequently in LR (70.3%), compared to HR-THRO pts (48.7%, p=0.05) and HR-AGE (41.9%, p=0.005) pts.

Antiplatelets and/or anticoagulants were used in 94.5% of pts, comparably across risk categories.

The IRR of thrombosis during HU was 1.7 %p-y. It was similar in LR and HR-AGE pts (1.1 vs 1.3 %p-y, p=0.68) but significantly higher (3.0 %p-y) in HR-THRO pts (p=0.006 vs LR and p=0.002 vs HR-AGE). The IRR of arterial thrombosis was significantly higher in HR-THRO pts (1.1 %p-y) compared to LR (0.4 %p-y, p=0.05) and comparable to HR-AGE (0.6 %p-y, p=0.10). The IRR of venous thrombosis was significantly higher in HR-THRO pts (1.3 %p-y) compared to both LR (0.5 %p-y, p=0.05) and HR-AGE (0.6 %p-y, p=0.02).

CTS were associated with a significantly increased IRR of thrombosis in the total cohort (2.2 vs 0.7 %p-y, p<0.001) and across all risk categories: LR pts (1.6 vs 0 %p-y, p=0.05), HR-AGE pts (2.0 vs 0.5 %p-y, p=0.001), and HR-THRO pts (4.0 vs 1.7 %p-y, p=0.04).

During HU treatment, TFS at 5 years was 88.7% in pts with CTS compared to 96.1% in those without CTS (p<0.001). Across all the risk categories, best TFS at 5 yrs was observed in LR and HR-AGE (LR with no CTS, 100%; HR-AGE with no CTS: 97.8%). LR/HR-AGE pts with CTS and HR-THRO pts with no CTS had comparable TFS (86.4%, 91.4% and 88.1%, respectively). HR-THRO pts with CTS had the worse TFS (79.5%).
Multivariate Cox analysis considering CTS, age>60 yrs and previous thrombosis, confirmed that CTS (HR: 3.1, p<0.001) and previous thrombosis (HR: 3.2, p<0.001) were independent predictors of thrombotic risk.

This study demonstrates that ELN criteria for therapy start effectively identify PV pts at increased thrombotic risk, regardless of their conventional risk category. These findings highlight the need for incorporating CTS into existing prognostic models to improve risk stratification and therapeutic decision-making in PV. Additionally, the data suggest that most LR pts require HU due to CTS, emphasizing the necessity for tailored management strategies and further research into the long-term impact of HU therapy in younger pts.

Real-World Treatment Patterns and Blood Count Control in Patients with Polycythemia Vera Who Switched from Hydroxyurea to Ruxolitinib

Polycythemia vera (PV) is a myeloproliferative neoplasm that typically presents with elevated hemoglobin and/or hematocrit (Hct) levels. Current National Comprehensive Cancer Network guidelines recommend maintaining Hct <45% with phlebotomy or cytoreductive treatment, such as hydroxyurea (HU), in all patients. This analysis, carried out by Dr.Naveen Pemmaraju et al, describes treatment patterns, blood count control, and use of phlebotomy in patients with PV who switched from HU to ruxolitinib at community practices in the United States.

This retrospective study included adults with a new PV diagnosis and ≥2 postdiagnosis visits during the study period of January 2014 to May 2023 in the Integra Precision Q electronic health record database. Patients who switched from HU to ruxolitinib, either as line of treatment (LOT) 1 to LOT2 or from LOT2 to LOT3, were characterized in this analysis. Elevated blood counts were defined as Hct ≥45%, white blood cell (WBC) count ≥11×109/L, or platelet (PLT) count >400, aligning with European LeukemiaNet response criteria and findings from the CYTO-PV study. Treatment duration and time between treatments were based on date of prescription refills.

Of 10,112 patients who met eligibility criteria in the full study, 443 patients switched from HU to ruxolitinib (LOT2: n=317; LOT3: n=126) and were included in this analysis; 47/443 (10.6%) received ruxolitinib as combination therapy, either in combination with HU (46/47; 97.9%) or with pegylated-interferon (1/47; 2.1%). Mean (SD) age at HU initiation was 68.6 (10.4) years (79.7% ≥60 years); 49% were female, and 62% were White. Mean (SD) time from PV diagnosis to HU initiation was 9.3 (14.9) months and from PV diagnosis to ruxolitinib initiation was 31.0 (23.8) months (LOT2: 27.5 [23.6]; LOT3: 39.8 [22.0]).

Median (IQR) duration of HU treatment was 9.7 (3.6–27.5) months as LOT1 and 9.2 (3.9–25.0) months as LOT2. Mean (SD) time between end date of HU and start date of ruxolitinib was 4.3 (11.3) months for LOT1 to LOT2 and 3.1 (7.4) months for LOT2 to LOT3. Median (IQR) duration of ruxolitinib treatment was 10.5 (4.1–28.7) months for LOT2 and 12.2 (5.0–29.4) months for LOT3. Median (IQR) time from ruxolitinib initiation to the end of the study period was 20.4 (9.1–39.5) months. At that time, 170 (38.4%) patients continued on ruxolitinib (LOT2: 37.2%; LOT3: 41.3%).

Of the patients who switched to ruxolitinib, 178 had Hct data available at all 4 time points, of which 74 (41.6%) had elevated Hct (ie, ≥45%) following HU treatment and before ruxolitinib initiation; elevated Hct was observed in 40/178 (22.5%), 32/178 (18.0%), and 26/178 (14.6%) patients at 3, 6, and 12 months from ruxolitinib initiation, respectively. Of 192 patients with available WBC data, 105 (54.7%) had elevated WBC (ie, ≥11×109/L) following HU and before ruxolitinib; elevated WBC was seen in 78/192 (40.6%), 89/192 (46.4%), and 88/192 (45.8%) at 3, 6, and 12 months from ruxolitinib initiation. Additionally, of 200 patients with available PLT data, 85 (42.5%) had elevated PLT (ie, >400) following HU and before ruxolitinib treatment; elevated PLT was seen in 92/200 (46.0%), 93/200 (46.5%), and 85/200 (42.5%) at 3, 6, and 12 months from ruxolitinib initiation. The differences in percentages of patients meeting treatment goals for Hct control compared with WBC and PLT may reflect current treatment guidelines in PV.

Among patients who initiated ruxolitinib as LOT2, mean (SD) phlebotomies per patient per year (PPPY) were 7.2 (9.5) during HU treatment (start date through end date HU) vs 3.8 (3.3) during ruxolitinib treatment (start date through end date ruxolitinib). Among patients who initiated ruxolitinib as LOT3, mean (SD) phlebotomies PPPY were 5.0 (4.2) during HU treatment vs 3.6 (5.3) during ruxolitinib treatment.

Patients switching from HU to ruxolitinib treatment had improved Hct and WBC count control. Additionally, frequency of phlebotomy was numerically lower during ruxolitinib treatment vs during HU treatment. Taken together, these data suggest clinical benefits for patients switching to ruxolitinib following inadequate disease control with HU treatment.

Thrombosis Risk Assessment in Polycythemia Vera (TRAP): A 4,636-Patient-Year Analysis of Arterial and Venous Thrombosis in Low-Risk Patients

Conventional thrombosis risk stratification in polycythemia vera (PV) considers age > 60 years and thrombosis history for assignment to low (no risk factor) or high (at least 1 risk factor) risk category (J Clin Oncol 2011;29(6):761-70). The current study, carried out by Dr. Naseema Gangat, et al, exclusively focused on low-risk PV with the following objectives: i) estimate the incidence of arterial and venous thrombosis; ii) examine the prognostic relevance of clinical and genetic risk factors for thrombosis; and iii) assess the impact of treatment on thrombosis risk.

Patients were retrospectively recruited from the Mayo Clinic, USA, and University of Florence, Italy, PV databases. Diagnosis was according to the International Consensus Classification criteria (Blood 2022;140:1200). Only first major arterial (AT) and unprovoked venous thrombosis (VT) were considered. Conventional statistical methods were applied (JMP Pro 17.0.0, SAS Institute, Cary, NC, USA).

Mayo Clinic cohort: A total of 346 patients with low-risk PV were considered: median age 49 years; males 54%; median hemoglobin 17.7 g/dl; median leukocyte count 10.9 x 109/L; leukocyte count >11 x 109/L 49%; median platelet count 471 x 109/L; cardiovascular (CV) risk factors 47%; hypertension 29%; hyperlipidemia 20%; smoking history 12%; diabetes mellitus 5%. Most frequent mutations, other than JAK2, were ASXL1 (13%) and TET2 (13%). Median follow-up was 13.4 years (1-52) (4,636 patient-years) during which 25 (7%) AT and 20 (6%) VT were documented. The corresponding incidence rates were 5.4 and 4.3 per 1,000 patient-years.

In multivariable logistic regression analysis, baseline hemoglobin >17.5 g/dl in women or >20 g/dl in men (15% vs 4%; OR 5.1; p<0.01) and absence of leukocytosis >11 x 109/L (10% vs 4%; OR 2.9; p=0.02) were associated with increased risk of AT; in addition, diabetes mellitus (19% vs 7%; OR 3.9; p=0.06), showed borderline significance; overall incidence of AT was 20% in the presence of ≥2 risk factors (n=61), 7% in the presence of one risk factor (n=177), and 1% in the absence of all three risk factors (n=108; p<0.01). Multivariable analysis for arterial thrombosis-free survival (TFS) confirmed the predictive performance of these risk factors: hemoglobin thresholds (HR 4.4; p<0.01); absence of leukocytosis >11 x 109/L (HR 2.7; p=0.03); and diabetes (HR 2.8; p=0.09); 20-year cumulative incidence of AT was 32% in the presence of ≥2 risk factors and 7% otherwise (p<0.01).

In multivariable analysis, smoking history was found to be surprisingly protective against VT (0% vs. 7%; p=0.02) while female gender was associated with a borderline higher risk (8% vs 4%; OR 2.2; p=0.09); VT incidence rates were 9% in the presence of both risk factors (n=144), 4% with one risk factor (n=172), and 0% in the absence of both risk factors (n=40; p=0.02); 20-year cumulative incidence of VT was 10% in the presence of both risk factors and 3% otherwise (p=0.03). ASXL1 and TET2 mutations did not appear to modify the risk of either VT (p=0.59) or AT (p=0.66). Treatment at diagnosis included aspirin and cytoreductive therapy in 63% and 24% of patients, respectively. Aspirin but not cytoreductive therapy was associated with a lower incidence of AT (5% vs 11%; 2.3 vs 3.0 per 1,000 patient-years; p=0.04) and VT (4% vs 10%; 1.9 vs 2.8 per 1,000 patient-years; p=0.03). Thrombosis-free survival was not influenced by documented treatment at diagnosis or at the time of event (p>0.1).

University of Florence cohort: A total of 284 low-risk PV patients were followed for a median of 9.1 years (1-38) with 19 (7%) AT and 24 (8%) VT events recorded; the corresponding incidence rates were 7.4 and 9.3 per 1,000 patient-years. In this Florence cohort, risk factors for AT were diabetes mellitus (HR 3.9), hyperlipidemia (HR 3.8) and advanced age, with only age remaining significant during multivariable analysis (p=0.03). Predictors of VT included hyperlipidemia (HR 4.2) and hypertension (HR 2.1). Treatment with aspirin or cytoreductive therapy did not impact thrombosis-free survival (p>0.1).

The current study confirms the infrequent occurrence of AT and VT in low-risk PV but also exposes the challenges in identifying risk factors that are reproducible in different but otherwise well-characterized patient cohorts. Discrepancies were also apparent in retrospective comparison of treatment effects on thrombosis, which reinforces the need for prospective studies.

Updated Results from the Phase 3 Manifest-2 Study of Pelabresib in Combination with Ruxolitinib for Janus Kinase Inhibitor–Naïve Patients with Myelofibrosis

Myelofibrosis (MF) is characterized by splenomegaly, MF-associated symptoms, cytopenias (eg, anemia), and impairment of the bone marrow (BM) microenvironment (including fibrosis). Pelabresib (CPI-0610; PELA) is an investigational, oral, small molecule drug that inhibits BET proteins and subsequent BET-mediated gene expression involved in MF pathogenesis. The Phase 3 MANIFEST-2 study (NCT04603495) met its primary endpoint, showing a statistically significant higher proportion of patients (pts) with ≥35% reduction in spleen volume (SVR35) from baseline (BL) at Week (Wk) 24 with PELA+ruxolitinib (RUX) vs placebo (PBO)+RUX (p<0.001) in Janus kinase inhibitor–naïve pts with MF. PELA+RUX also showed a trend toward improved total symptom score (TSS) from BL at Wk 24, as well as improvements in multiple measures of anemia (eg, hemoglobin [Hb] response) and in the BM microenvironment, vs PBO+RUX (Rampal R, et al. Presented at ASH 2023 [Oral 628]).

The aim of this study, carried out by Dr John O. Mascarenhas et al, is to present follow-up efficacy and safety outcomes at Wk 48 from the Phase 3 MANIFEST-2 study.

Eligible patients had a DIPSS ≥intermediate-1 risk, platelet count ≥100 × 109/L, spleen volume ≥450 cm3, ≥2 symptoms with an average score ≥3 or TSS ≥10 by MF Symptom Assessment Form v4.0, peripheral blast count <5%, and ECOG PS ≤2. Pts were randomized 1:1. PELA or PBO was administered once daily for 14 consecutive days of 21-day cycles in combination with RUX, which was administered twice daily for 21-day cycles. Primary endpoint was SVR35 at Wk 24. Key secondary endpoints were absolute change in TSS and ≥50% reduction in TSS from BL (TSS50) at Wk 24. Other prespecified endpoints included SVR35 at Wk 48, absolute change in TSS and TSS50 at Wk 48, Hb response (≥1.5 g/dL mean increase from BL without transfusions in the prior 12 wks), BM fibrosis (BMF), and safety. Mutation profiles were assessed by next-generation sequencing. Informed consent was obtained from all pts.

As of March 29, 2024, all pts assessed had been followed for ≥48 wks; 58.9% (126/214) and 62.0% (134/216) of pts continued on double-blind treatment in the PELA+RUX and PBO+RUX arms, respectively. Preliminary data are presented here; analyses are ongoing and data points are subject to change. At Wk 48, 56.5% (121/214) vs 37.5% (81/216) of pts had SVR35 responses in the PELA+RUX vs PBO+RUX arms, showing sustained benefit beyond Wk 24. SVR35 responders at any time were 82.2% (176/214) vs 58.3% (126/216) in the PELA+RUX vs PBO+RUX arm; loss of SVR35 response was observed in 13.1% (23/176) vs 19.8% (25/126) of pts in the PELA+RUX vs PBO+RUX arm. At Wk 48, least squares mean (standard error) absolute change in TSS was −16.24 (1.133) vs −14.11 (1.085) in the PELA+RUX vs PBO+RUX arms, with a greater difference in absolute TSS observed between treatment arms at Wk 24 and Wk 48 for pts with higher symptom burden at BL. TSS50 response at Wk 48 was 45.3% (97/214) vs 39.4% (85/216) with PELA+RUX vs PBO+RUX. Dual SVR35 and TSS50 response was observed in 36.0% (77/214) vs 19.0% (41/216) of pts in the PELA+RUX vs PBO+RUX arms at Wk 48. Hb response was observed in 12.6% (27/214; 95% confidence interval [CI], 8.17–17.07) vs 6.9% (15/216; 95% CI, 3.55–10.33) of pts in the PELA+RUX vs PBO+RUX arms, with differences between arms in mean Hb levels maintained at Wk 48; in pts with anemia (Hb BL <10 g/dL), Hb response was observed in 17.9% (12/67; 95% CI, 8.73–27.09) vs 14.1% (10/71; 95% CI, 5.99–22.18) of pts. The trend of higher rate of BMF improvement of ≥1 grade in the PELA+RUX arm vs the PBO+RUX arm continued to be observed at Wk 48. Of 426 pts evaluated for safety, ≥1 treatment-emergent adverse event (TEAE) was reported in 97.6% vs 96.7% of pts in the PELA+RUX vs PBO+RUX arms; Grade ≥3 events were reported in 56.6% vs 62.1% of pts. Rates of the most common TEAEs (≥10%) at Wk 48 in the PELA+RUX vs PBO+RUX arms were similar to rates at Wk 24. Updated efficacy and safety results, including data on BMF, mutational profile, and leukemic transformation, will be presented.

At Wk 48, PELA+RUX continued to show improvements in spleen volume, TSS, multiple measures of anemia, and the BM microenvironment vs PBO+RUX, impacting the four hallmarks of MF. These data suggest that PELA+RUX could lead to more profound and sustained responses in pts with MF vs PBO+RUX.

Treatment of Myeloproliferative Neoplasms with Janus Kinase Inhibitors: A Meta-Analysis of Cardiovascular Safety

Myeloproliferative neoplasms (MPN) are characterized by excess proliferation of hematopoietic cells, and include entities such as myelofibrosis (MF), polycythemia vera (PV) and essential thrombocythemia (ET). Thrombosis is a significant cause of mortality and morbidity for MPN patients. Janus kinase (JAK) inhibitors have transformed the treatment of MF and PV over the last decade. However, they are known to increase weight and cholesterol, and have been shown to increase major adverse cardiovascular events (MACE) in the context of rheumatoid arthritis. Dr. Edouard Long et al, here conducted a first-of-a-kind narrative review and meta-analysis of cardiovascular events in MPN patients treated with JAK inhibitors.

A systematic search was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) using medical subject headings and key terms for MPNs, JAK inhibitors and cardiovascular disease. The search was performed on the following databases: Pubmed, Ovid Embase, Ovid Medline, Cochrane Library and Clinicaltrials.gov from inception to January 2024. The title, abstract and full-text report were screened by two researchers independently, and any conflicts were resolved by consensus. Clinical trials and retrospective studies were eligible for inclusion provided they had a control group which did not include a JAK inhibitor.

MACE was defined as a composite of myocardial infarction, cerebrovascular events, heart failure and cardiovascular death. Hypertension was included as an adverse event due to its proven association with cardiovascular disease. MACE, hypertension, and thrombosis were recorded as rate per 100 patient-years in tabular format. Incidence rate ratios (IRR) were calculated for each study. IRRs were pooled using a random effects model, to account for the different JAK inhibitors and MPN subtypes within the meta-analysis. Heterogeneity across studies was assessed using Cochran Q and I2 indices: low heterogeneity (I2<30%), moderate heterogeneity (I2=30-60%), high heterogeneity (I2>60%). The ‘meta’ package on R was employed to perform all analyses (version 2024.04.2). Data concerning MACE, hypertension and thrombosis was available for 10, 6 and 9 studies, respectively.

The criteria for inclusion were met by 23 publications including 11 studies, 9 clinical trials and 2 retrospective analyses. Studies included patients with MF (n=6), PV (n=4) and ET (n=1). The analysis of MACE included ruxolitinib (n=8) and pacritinib (n=2); the analysis of hypertension included ruxolitinib (n=4), momelotinib (n=1), and pacritinib (n=1); and the analysis of thrombosis included ruxolitinib (n=8) and momelotinib (n=1). Median follow-up for the control group was between 17.3 to 122 weeks and 20 to 260 weeks for the JAK inhibitor group. Study heterogeneity was low in all analyses.

In the analysis of thrombosis, the pooled IRR was 0.52 (95% CI: 0.28-0.98, p=0.04) (I2 = 53.9%) suggesting a significant reduction in thrombotic events with JAK inhibitor treatment. This finding was primarily driven by studies investigating the use of ruxolitinib in MF and PV (n=7). When a subgroup analysis of ruxolitinib in MF and PV was performed, an even more significant reduction was found (IRR 0.378, 95%CI: 0.22-0.66, p=0.0006) (I2=27.4%). Collectively, JAK inhibitor treatment did not significantly increase the risk of MACE (IRR 0.97, 95% CI: 0.52-1.82, p=0.93) (I2 = 8.8%), or hypertension (IRR 0.81, 95%CI: 0.48-1.35, p=0.42) (I2= 11.3%).

These findings suggest that ruxolitinib significantly reduces the risk of thrombosis in patients with PV and MF and may show a similar effect in ET alongside momelotinib in MF. As thrombosis is a major cause of mortality in MPNs, a reduction in thromboembolic events should be considered an additional clinical benefit of JAK inhibitors. Moreover, our analysis suggests that the use of JAK inhibitors in the treatment of MPNs is not associated with an increase in MACE, adding to the existing body of evidence which demonstrates the safety of JAK inhibitors in the treatment of MPNs. Further prospective clinical trials are warranted to explore the potential thrombosis risk reduction with other JAK inhibitors and in other types of MPNs.

Outcomes Are Similar for Combination Interferon and Ruxolitinib Versus Ruxolitinib in Myelofibrosis: A Propensity-Score Matched Study

Combining interferon (rIFNα), namely peginterferon alpha-2a, with ruxolitinib (rIFNα-RUX) in the treatment (Rx) of myelofibrosis (MF) is thought to enhance clinical benefit and deplete malignant clones. High response rates were observed in two single-arm rIFNα-RUX trials in both rIFNα-refractory and rIFNα-RUX-naïve patients1,2. However, it is not known if the combination improves longer-term outcomes, including progression-free survival (PFS) and overall survival (OS). Dr. Katie Erdos et al conducted this single-center, retrospective, propensity-score matched study to compare clinical response, PFS/OS outcomes and adverse events (AEs) between rIFNα-RUX and RUX in pts with MF.

Medical records of pts with MF treated with rIFNα-RUX were identified and matched to a control group of RUX monotherapy pts using propensity-scores based on the Dynamic International Prognostic Scoring System Plus (DIPSS+) variables of age, hemoglobin (HGB), white blood count (WBC), platelets (PLT) and peripheral blasts (PB) at Rx initiation, as well as sex and MF type (primary vs secondary). Clinical and lab data were collected as previously described3. MF diagnoses met WHO & ICC 2022 criteria4,5 and clinical response was assessed using the IWG-MRT response criteria5. Spleen response (SR) by physical exam, molecular response (MR) in driver mutation allele frequency, and serial bone marrow response (BMR) was assessed as available. OS and PFS were compared using the Kaplan-Meier method. Fisher’s test was used to compare response rates, AEs and discontinuation rates.

31 MF pts treated with rIFNα-RUX were matched 1:1 to 31 RUX monotherapy pts (total 62). Groups were similar in age (both median of 67 years (yr)), sex, race, HGB, WBC, PLT or PB at the start of Rx, MF type, driver mutation (JAK2 in 77% rIFNα-RUX vs 74% RUX), and DIPSS+ risk (majority intermediate-1: 65% rIFNα-RUX vs 58% RUX). Median follow-up (5.9 yr rIFNα-RUX vs. 6.6 yr RUX, p=0.08) and times from diagnosis to Rx were similar (median 0.9 yr rIFNα-RUX vs 0.9 yr RUX). Of the rIFNα-RUX pts, 16 received rIFNα first to which RUX was added, 13 received RUX first and 2 initiated both simultaneously. rIFNα-RUX was initiated to improve clinical response (n=20), for hypothesized disease-modifying benefit (n=8) or both (n=3). Median RUX doses and durations were comparable (median 1.6 yr rIFNα-RUX vs 1.7 yr RUX). Discontinuation rates were not significantly different (68% rIFNα-RUX vs 58% RUX). The most common reasons for discontinuation were Rx-related AEs (8 vs 9 pts) and lack of response/progression (4 vs 5).

Median PFS was not reached in either cohort, and there was no significant difference in PFS (p=0.78). Median OS was 9.7 yrs, with no significant advantage for combination Rx (p=0.75). Clinical response rates by IWG-MRT response were comparable between groups at all timepoints. Eleven pts (35%) in each group had clinical benefit (clinical improvement, partial or complete response).

There were no significant differences in SR, MR or BMR between groups. Median SR was 33% for rIFNα-RUX (n=21) vs 29% for RUX (n=20). Best MR was similar between Rx groups for the 26 pts with serial molecular testing. There was no significant difference in reticulin grade reduction in the 28 pts with serial marrow biopsies during Rx.

rIFNα-RUX was well tolerated, with no significant differences in AEs compared to RUX. The most common Rx-emergent AEs were constitutional symptoms (55%), anemia (31%) and thrombocytopenia (32%).

This matched, retrospective analysis of 62 MF pts identified no significant differences in OS or PFS between pts treated with rIFNα-RUX compared to RUX. Despite high clinical responses in earlier single-arm studies, our analysis did not find the combination improved clinical response rates at the doses used. AEs and discontinuation rates were comparable, indicating similar efficacy and tolerability. These results suggest that while rIFNα-RUX is safe, its clinical and survival outcomes compared to RUX do not yet justify the financial burden of combination drug costs. Randomized trials are needed to define any advantages of rIFNα-RUX to monotherapy. Until then, the combination should be reserved for carefully selected pts.

References:

1. Sørensen et al. Haematologica, 2020.
2. Kiladjian et al. Blood, 2022.
3. Abu-Zeinah et al. Leukemia, 2021.
4. Khoury et al. Leukemia, 2022.
5. Arber et al. Blood, 2022
6. Tefferi et al. Blood, 2013.

A Predictive Model for Progression to Overt Primary Myelofibrosis in Early/Prefibrotic Primary Myelofibrosis Patients

The 2016 WHO reclassified myelofibrosis into two distinct entities: early/prefibrotic primary myelofibrosis (pre-PMF) and overt primary myelofibrosis (overt-PMF). Approximately 15% of pre-PMF patients progress to overt-PMF during the disease course. Currently, there is limited research on the risk factors for fibrotic progression, and no models to predict the progression of pre-PMF to overt-PMF. This study, carried out by Dr. Shiwei Hu et al, aimed to establish a nomogram model to predict the overt-PMF free survival probability in pre-PMF patients, assisting clinical practitioners in early disease monitoring and timely implementation of appropriate therapy.

Data from 2,275 patients diagnosed with ET, pre-PMF and overt-PMF were collected from 19 hematology centers from January 2010 to May 2024. After re-evaluation of bone marrow biopsy specimens, 338 pre-PMF patients were included. The authors randomly assigned 218 patients to the training group and 120 patients to the validation group. Least absolute shrinkage and selection operator (LASSO) regression was used to screen out potential prognostic factors. These factors were further analyzed by multivariate Cox regression analysis. And a nomogram model was constructed based on the weight of these independent risk factors. Receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA) were employed to assess the performance of the nomogram.

A total of 338 pre-PMF patients were included, with 167 (49.4%) males. During a median follow-up of 52 months (range: 1–335 months), 44 (13.0%) patients progressed to overt-PMF. There were no statistically differences in all variables included between the two groups. The Lasso regression selected a model with excellent performance but minimum variables when the λ value was 0.063. The variables included gender, MF grade, constitutional symptoms, splenomegaly, platelet count (PLT), lactate dehydrogenase (LDH), and peripheral blood blasts. These factors were subsequently included in the multivariate Cox regression analysis. Male (P=0.008, HR=3.185, 95% CI 1.355-7.488), MF grade 1 (P=0.008, HR=16.700, 95% CI 2.083-133.863), PLT (P=0.037, HR=0.999, 95% CI 0.998-1.000), LDH (P=0.016, HR=1.002, 95% CI 1.000-1.003) and peripheral blood blasts (P<0.0001, HR=5.235, 95% CI 2.071-13.237) were found to be independent risk factors for the progression of overt-PMF in pre-PMF patients. Nomogram was constructed according to these risk factors. The C-indices of the training and validation cohorts were 0.888 and 0.736, respectively. ROC analysis showed the AUC values at 3, 5, and 10 years were 0.899 (95% CI 0.823-0.975), 0.938 (95% CI 0.888-0.9788), and 0.899 (95% CI 0.802-0.997) for the training cohort and 0.761 (95% CI 0.570-0.951), 0.754 (95% CI 0.606-0.902), and 0.902 (95% CI 0.794-1.010) for the validation cohort. The calibration plots and DCA analysis showed that the model had good early fibrotic progression prediction and clinical application value in both training and validation cohorts. Furthermore, we divided the patients into low-risk (≤245) and high-risk (>245) groups. In the training and validation cohorts, the Kaplan-Meier curve showed a significant difference between the high-risk and low-risk groups (P<0.0001, P<0.0001). The 3-, 5-, and 10-year overt-PMF free survival probability for the low-risk group were 98.1% (95% CI 96.5%-99.8%), 96.4% (95% CI 93.9%-99.0%), and 89.1% (95% CI 82.9%-95.6%), respectively, while for the high-risk group, 3-, 5-, and 10-year overt-PMF free survival probability were 68.7% (95% CI 56.2%-84.0%), 49.4% (95% CI 36.0%-67.9%), and 23.9% (95% CI 12.0%-47.7%), respectively.

The authors developed a nomogram capable of predicting the overt-PMF free survival probability at 3 year, 5 years and 10 years in pre-PMF patients. This tool helps doctors identify high-risk patients for overt-PMF transformation, enabling close monitoring to improve patient prognosis.

Understanding the Lived Experience of Fatigue in Adolescents and Young Adults with Myeloproliferative Neoplasms: A Mixed Methods Study

Fatigue is a debilitating symptom of myeloproliferative neoplasms (MPN), profoundly affecting quality of life (QoL) and outcomes. While fatigue is pervasive across all age groups of MPN patients, our previous research indicated that adolescents and young adults (AYA) experience higher levels of fatigue compared to older adults (Poullet, 2023). This study, carried out by Dr. Steve Dagenais-Bellefeuille et al, aimed to explore the lived experience of fatigue in AYA using a mixed-methods approach in a large, real-world, population. Specifically, we sought to: i) identify age-related differences in fatigue; ii) delineate how fatigue manifests and impacts AYA patients; and iii) explore effective management strategies.

Quantitative analysis: the authors analyzed patient-reported outcomes per MPN-Symptom Assessment Form Total Symptom Score (MPN-SAF TSS), a validated questionnaire grading 10 MPN symptoms (0-10), including fatigue (JCO, 2012). Recruitment: Quebec MPN Research Group registry (>20 centers). Eligibility: i) diagnosis of polycythemia vera (PV), essential thrombocytosis (ET), or myelofibrosis (MF) per WHO; ii) completion of 1+ MPN-SAF TSS (2013-2023). Patients were risk-stratified according to MPN specific risk score. Conventional statistics were used (JMP® Pro 14.1.0 software; SAS Institute, NC, USA).

Qualitative analysis: In-depth individual interviews (n=12) were conducted with AYA (range 18-40 years) with MPN, using a semi-structured questionnaire. Interviews were transcribed and underwent iterative content analysis using QDA Miner 6.0.16 (Provalis Research, Montreal, Qc, Canada).
Age-associated differences: Analysis included 399 MPN-SAF TSS from 74 AYA patients (15 PV, 56 ET, 3 MF) and for comparison, 3706 MPN-SAF TSS from 710 older patients (non-AYA) (270 PV, 366 ET, 74 MF). AYA patients had a median age at diagnosis of 34 years (range 18-40); 68% female, and completed a median of 5 questionnaires per patient (range 1-16).

High fatigue scores (>4) were reported by 57% of AYA patients (n=41) compared to 43% of non-AYA (n=302) (p=0.03). In both groups, high fatigue correlated with a clinically significant mean aggregate MPN-SAF TSS score (>20) (p=0.001-p<0.001). In AYA patients, high fatigue was independent of gender, whereas females predominantly reported higher fatigue among older patients (p<0.001). High fatigue levels in AYA did not correlate with MPN disease-specific risk score, while this association was observed in non-AYA cohorts (p=0.02). Interestingly, high fatigue in AYA clustered with specific MPN-SAF TSS subitems: early satiety (p=0.04), inactivity (p=0.04), and pruritus (p=0.02). Conversely, in older patients, high fatigue showed universal correlation with all other MPN-SAF TSS subitems (p=0.01-p<0.0001), with no discriminatory patterns.

Expression of fatigue and impact: Fatigue emerged as the primary symptom impacting QoL among interviewed AYA patients. Participants often struggled to distinguish whether their fatigue stemmed from their disease or other aspects of life such as work, family, or aging. Dimensions of fatigue conveyed by participants included physical lethargy, weakness, concentration issues, and motivation loss, often with non-restorative sleep. The most significant impact reported was on work productivity, sometimes requiring career adjustments.

Management: Interviewed AYA MPN patients found that pharmacological treatments aimed at controlling MPN-related biomarkers did not effectively alleviate their fatigue. Initial strategies such as coffee consumption, provided temporary relief. Regular physical activity was the most effective fatigue management strategy, with additional benefits from naps, healthy diet, and sleep routines.

This mixed-methods study provides a comprehensive understanding of fatigue in AYA patients with MPN, highlighting several key findings. Fatigue is the predominant symptom driving MPN-SAF-TSS scores in AYA patients and clusters specifically with early satiety, inactivity and pruritus, exposing a unique pattern compared to older patients. Moreover, fatigue in AYA is independent of overall risk score, indicating potential undertreatment in this subgroup. Expression of fatigue is multidimensional and significantly impacts AYA patients’ ability to work. Targeting fatigue with non-pharmacological interventions, particularly physical activity, could enhance QoL for AYA patients with MPN.

Prognostic Implications of Pulmonary Hypertension in Myeloproliferative Neoplasms and Predictors of Hematologic Progression

Myeloproliferative neoplasms (MPNs), which include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are a group of disorders of clonal hematopoiesis associated with increased risk of cardiovascular disease (CVD), including pulmonary hypertension (PH). In a prior study of patients with MPN and established CVD, PH was associated with increased risk of hematologic progression to secondary MF or acute leukemia and major adverse cardiovascular events (MACE). However, the prognostic implication of PH among patients with MPN regardless of prior CVD status is unclear. Furthermore, transthoracic echocardiographic (TTE) characterization of risk of hematologic progression among those with PH has not been well studied.

This was a multicenter retrospective cohort study, carried out by Dr. Orly Leiva et al, of MPN patients with ≥ 1 TTE after diagnosis of MPN at New York University Langone Health and Massachusetts General Hospital from 2010 to 2023. PH was defined as estimated pulmonary artery systolic pressure (PASP) ≥ 40 mmHg on first TTE after MPN diagnosis. The primary outcome was a composite hematologic outcome of progression to secondary MF, acute leukemia, or death from MPN. Secondary outcome was MACE, a composite of arterial or venous thrombosis, heart failure (HF) hospitalization, or CV death. Given the competing risk of death, multivariable Fine-Gray competing-risk regression was used to estimate subhazard ratio (SHR) of the primary and secondary outcomes, and were adjusted for age at first TTE, MPN type, driver mutation, any non-driver mutation status, time from MPN to TTE, hemoglobin and WBC concentration, and spleen size. The association between PH and MACE was further adjusted for treatment for the MPN, left ventricular ejection fraction (LVEF), prior CVD, indication/setting of TTE, diastolic dysfunction, anti-thrombotic use, statin use, and creatinine. Hemodynamic predictors of the composite hematologic outcome among patients with PH was assessed using univariate competing-risk regression. Variables that were significantly different between groups (p < 0.05) were adjusted for age, time from MPN to TTE, driver and non-driver mutations, and spleen size.

Of the 555 patients included, 42.7% had PV, 41.1% ET, and 16.2% had MF at time of TTE, 48.5% were male and 86.8% were White race. PH was diagnosed in 195 patients (35.1%). The median time from MPN diagnosis to TTE was 39 months. Patients with PH were older (median age 71 vs 66 years, p <0.001), more likely to have MF (25.6% vs 11.1%, p <0.001), and higher VAF of driver MPN mutation (median 50% vs 40%, p = 0.002) and larger spleen sizes at time of TTE (median 13.7 vs 12.0 cm, p <0.001). Patients with PH had a higher rate of prior HF (15.4% vs 3.3%, p <0.001), hypertension (69.7% vs 56.7%, p= 0.003), and AF (29.7% vs 15.6%, p <0.001). After a median follow-up of 51 months, the composite hematologic outcome (23.6% vs 10.3%, p <0.001) and MACE (41.5% vs 19.2%, p <0.001) were more common among patients with PH. After multivariable competing-risk regression, PH was associated with increased risk of hematologic outcome (aSHR 1.79, 95% CI 1.10–2.92) and MACE (aSHR 1.67, 95% CI 1.10–2.56). Among patients with PH, 46 (23.6%) had hematologic outcome. After adjustment, atrial enlargement (aSHR 0.42, 95% CI 0.20–0.90) and valvular regurgitation (aSHR 0.30, 95% CI 0.16–0.57) were associated with decreased risk of hematologic outcome. Tricuspid annular plane systolic excursion (TAPSE, aSHR 2.44, 95% CI 1.27–4.69), a marker of right ventricular (RV) function, and estimated cardiac output (CO, aSHR 1.33, 95% CI 1.40–1.70) were associated with increased risk of hematologic outcome.

Among patients with MPN, PH was associated with increased risk of hematologic progression and MACE. Our study also sheds some light on the pathophysiology behind PH and MPN progression given the association between preserved RV function and higher CO and MPN progression. MPN progression may lead to increased catabolic demand and cell turnover that may increase CO and may in part explain the association of preserved RV function and increased CO among patients with PH and MPN progression. However, further studies are needed to better understand the physiology of PH in MPN, characterize PH phenotypes and their associations with outcomes, and to assess the utility of TTE for screening for PH and surveillance of MPN progression.