Citations

Objective Vacuoles, E1 enzyme, X‐linked, autoinflammatory, somatic syndrome (VEXAS) syndrome is characterized by a complex spectrum of inflammatory and hematologic manifestations. Clinical research to identify effective therapies is urgently needed but is hindered by the lack of validated outcome measures. A VEXAS‐specific disease activity index (DAI) is an essential tool for reliably capturing changes in disease activity over time, thereby supporting clinical research and informing patient care in this emerging disease. This study aimed to develop a comprehensive DAI to assess disease‐related inflammation across affected organ systems in patients with VEXAS syndrome. Methods Inflammatory manifestations of VEXAS were previously identified through a systematic literature review and expert input. A multinational expert advisory committee developed the VEXAS‐DAI using modified Delphi methodology until consensus (defined as ≥75% concurrence) was reached. Item grading was adapted from the Common Terminology Criteria for Adverse Events. Scoring criteria were developed based on 158 test cases using the Physician Global Assessment of Inflammation. Results Consensus on the VEXAS‐DAI was achieved after four Delphi rounds. The index assesses inflammatory activity at the time of evaluation across 12 domains: inflammatory rash, chondritis, periorbital, ophthalmologic, joint, pulmonary, cardiovascular, genitourinary, neurologic, oral and gastrointestinal, renal, and constitutional symptoms. The total score ranges from 0 to 40. Conclusion The VEXAS‐DAI is a novel instrument designed to quantify active inflammation over time in patients with VEXAS. Prospective validation within a clinical trial setting is ongoing. image

VEXAS (Vacuoles, E1 ubiquitin-activating enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a systemic disorder characterized by an overlap of hematologic and inflammatory features. Most patients require chronic use of moderate-to-high doses of glucocorticoids (GCs) to maintain disease control. Data on GC-sparing therapies is limited, and there have been no prospective pharmacotherapeutic trials in VEXAS syndrome published to date. Pacritinib, an oral inhibitor of IRAK1, JAK2, and ACVR1, has emerged as a promising therapeutic option for VEXAS syndrome. The PAXIS trial is the first prospective, randomized pharmacotherapeutic study conducted in this rare and severe disease. Utilizing a novel study design and disease-specific endpoints, the trial will evaluate the efficacy and safety of two dose levels of pacritinib compared with placebo in patients with VEXAS syndrome (NCT06782373, EUCTR: 2024-516347-41-00).

Abstract Background and Significance: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy with overlapping dysplastic and proliferative features, a high risk of leukemic transformation, and no disease-modifying therapies. Patients with proliferative CMML often present with symptomatic monocytosis, leukocytosis, splenomegaly, and systemic inflammation, which contribute to shortened survival and impaired quality of life. Hydroxyurea (HU), the standard cytoreductive agent, provides transient control of leukocytosis but has no known disease modifying properties. In the phase 3 DACOTA trial (Itzykson et al., JCO 2022), decitabine modestly delayed leukemic transformation compared to HU but did not improve event-free or overall survival and was associated with increased early mortality. HU achieved a clinical benefit rate (CBR) of approximately 15% (excluding stable disease), highlighting the urgent need for safer and more effective therapies. Pacritinib is a potent and selective multikinase inhibitor with a kinome profile that targets key mediators of clonal proliferation and inflammatory signaling relevant to CMML. It inhibits JAK2 (IC₅₀ = 6 nM) and IRAK1 (IC₅₀ = 13.6 nM)—critical drivers of cytokine-mediated growth and monocytic skewing—while sparing JAK1, potentially reducing myelosuppressive toxicity. Pacritinib also inhibits CSF1R (IC₅₀= 39.5 nM) which is involved in monocytic differentiation. Preclinical models demonstrate that dual inhibition of JAK2 and IRAK1 suppresses CMML colony formation and prolongs survival in xenografts. Furthermore, CSF1R inhibition may reduce monocyte-lineage bias in leukemic clones. Clinically, pacritinib is FDA-approved for intermediate- or high-risk myelofibrosis with severe thrombocytopenia (platelets <50 × 10⁹/L) based on evidence of significant spleen volume and symptom reduction with limited hematologic toxicity. These mechanistic and clinical data provide a strong rationale for evaluating pacritinib in advanced proliferative CMML, a setting characterized by both cytokine-driven proliferation and treatment-limiting cytopenias. Study Design and Methods PROSPERA (NCT07033598) is a collaborative multicenter, open-label, randomized phase 2 trial. Sixty-six patients with WHO-defined CMML-1 or CMML-2 will be enrolled. Eligible patients must have proliferative features (WBC ≥13 × 10⁹/L) and advanced disease as defined by ≥5 cm palpable splenomegaly, symptom burden (Myeloproliferative Neoplasm-Symptom Assessment Form Total Symptom Score MPNSAF-TSS ≥20), or thrombocytopenia (platelets <100 × 10⁹/L). Prior JAK inhibitor therapy is not allowed. The trial will be conducted at approximately six sites across the United States and United Kingdom, with enrollment anticipated to begin by the end of 2025. Participants will be randomized 2:1 to receive either pacritinib (200 mg orally twice daily) or HU (dosed as per investigator discretion) for 48 weeks. Patients in the HU arm may cross over to pacritinib at Week 24 if, in the opinion of the treating physician, they are not deriving clinical benefit (after assessment of the primary endpoint). Randomization will be stratified by prior cytoreductive therapy (none vs. prior HU or hypomethylating agents). The primary endpoint is CBR at Week 24, defined by modified IWG MDS/MPN criteria incorporating hematologic improvement, spleen volume reduction, and symptom response. Secondary endpoints include CBR at any time, duration of response, event-free survival, leukemia-free survival, and overall survival. Correlative studies will assess treatment-related changes in clonal dynamics, cytokine signaling, and hematopoietic composition using longitudinal peripheral blood and bone marrow sampling. Single-cell transcriptomic and immunophenotypic profiling will be employed to characterize pacritinib's impact on both the malignant clone and the surrounding immune microenvironment.

Abstract Objective VEXAS syndrome is a severe systemic haemato-inflammatory disease with heterogeneous clinical presentations. Most patients experience recurrent inflammatory flares despite anti-inflammatory therapy. The lack of accepted definitions of flare in these patients is preventing development of disease activity tools that are essential for conducting clinical trials. We aimed to develop a consensus definition of a VEXAS flare for use in clinical trials. Methods A nine-member international expert advisory committee established a consensus definition of VEXAS flare using modified Delphi methodology. Clinical inflammatory manifestations of VEXAS syndrome were identified through a systematic literature review. Committee members developed a conceptual framework for flare definition, proposed revisions and voted on changes until consensus (≥75% concurrence) was reached. Results Consensus defined VEXAS flare as active inflammatory manifestation(s) of VEXAS syndrome requiring escalation in glucocorticoid therapy. Three flare categories were established: (i) recurrence of a prior documented VEXAS manifestation; (ii) development of a new VEXAS-defining inflammatory manifestation; or (iii) emergence of a new inflammatory manifestation not meeting criteria for A or B. The panel endorsed an independent adjudication committee to assess Category C flares in clinical trials. Conclusions This study proposes a standardized definition of VEXAS flare, providing uniform criteria for identifying VEXAS disease activity. Future research will evaluate its performance in clinical trials.

ABSTRACTSpleen volume reduction (SVR) is a key endpoint in inhibitors of Janus kinase (JAK) inhibitor studies. Retrospective analyses have demonstrated an association between SVR and improved overall survival (OS) among patients treated with ruxolitinib with a platelet count > 100 × 109/L. Whether this association occurs in patients with thrombocytopenia is unclear. Pacritinib, a JAK2/IRAK1/ACVR1 inhibitor, demonstrated improved SVR versus best available therapy (BAT [best available therapy]; including ruxolitinib) in patients with myelofibrosis and platelet counts ≤ 100 × 109/L in the PERSIST‐2 study. Patients on study at the start of the 12‐week SVR window on pacritinib 200 mg twice daily or BAT were included. OS was evaluated among SVR responders versus non‐responders using different SVR thresholds (≥ 35%, ≥ 20%, ≥ 10%, and > 0%). Among patients on pacritinib (n = 89), SVR ≥ 10% demonstrated the greatest separation in OS curves between responders and non‐responders (HR, 0.00; 95% CI, 0.00–0.14; p < 0.01), though SVR ≥ 0% and SVR ≥ 20% were also associated with improved OS. No SVR threshold conferred OS benefit on BAT (n = 84), including ruxolitinib (n = 39). In patients with myelofibrosis and platelets ≤ 100 × 109/L, achieving SVR on pacritinib, but not BAT (including ruxolitinib), was associated with significant OS benefit, suggesting that pacritinib may offer a unique survival advantage in patients with myelofibrosis and thrombocytopenia who achieve any SVR. Trial Registration: ClinicalTrials.gov number: NCT02055781

Background: Pacritinib is a JAK1-sparing inhibitor of JAK2/IRAK1/ACVR1 that demonstrated symptom benefit measured by TSS (v2.0, excluding tiredness) vs best available therapy (BAT) in PERSIST-2, which enrolled cytopenic myelofibrosis patients with platelets ≤100×10 9/L. Recent datashowed that in patients with cytopenic MF, a ≥10% reduction in spleen volume at 12 weeks is associated with improved survival in patients treated with pacritinib ( Ajufo H, et al., J Clin Oncol;2023:14(16):Suppl). Surprisingly, this association was not confirmed in patients treated with BAT (82% of whom were on ruxolitinib). The association between other important measures of clinical benefit such as symptom burden reduction and anemia improvement on survival in patients treated with pacritinib has not previously been described. Methods: Patients randomized to pacritinib 200 mg BID and to BAT on PERSIST-2 were included if they were alive and on study at the start of the week 12 efficacy assessment period. Survival was assessed by Total Symptom Score (TSS; v2.0 excluding tiredness) reduction at various thresholds (≥50%, ≥20%, ≥10%, &gt;0%) and transfusion independence (TI) response. TI was assessed among patients who required red blood cell (RBC) transfusion at baseline (within 90 days) and was defined, for the purposes of a landmark survival analysis, as the absence of RBC transfusions over any 12-week period from first dose through week 14 (allowing for a ±2-week window around week 12). Overall survival (OS) was estimated via the K-M method following the landmark approach; survival in responders vs non-responders was compared using the log-rank test. Results: Of the 59 patients treated with pacritinib who had a reduction of TSS≥10%, the median age was 67 years, 25% had a baseline high-risk DIPSS, median platelet count was 61 x10 9/L, median hemoglobin was 9.7 g/dL, and baseline TSS was 19.1. Reduction of TSS≥10% was associated with improved OS, with 1 death among 59 responders vs 4 deaths among 30 non-responders (hazard ratio [HR]=0.12, 95% confidence interval [CI]: 0.01, 0.79] P=0.021, Fig 1a). Similar to spleen volume reduction, the association between TSS response and OS weakened at more stringent TSS response thresholds (Fig 1c, e), with the BAT arm not showing an association between TSS response and OS at any threshold. (Fig 1b, d, f). In order to assess the relationship of specific TSS domains and survival , a landmark OS analysis was performed based on ≥20% reduction in physical function scores (sum of ‘tiredness’ and 'inactivity'), spleen-related symptom scores (sum of 'abdominal discomfort', ‘early satiety’, and 'left rib pain'), and cytokine-related symptom scores (sum of 'itching', ‘night sweats’, and ‘bone pain‘). For cytokine-related symptoms, the number of deaths in PAC responders was significantly different compared to non-responders, with 0 deaths among 35 responders vs 2 among 15 non-responders ( P=0.0325). Conversely the deaths among responders (2/22) vs non-responders (2/20) were not significantly different in the BAT arm. For the physical function and spleen-related symptom subscales, no significant differences between PAC responders and non-responders was observed (HR=0.60; 95% CI [0.05, 6.74] P=0.679) and (HR=0.26; 95% CI 0.02, 2.93, P=0.2435) respectively. Among 36 patients on PAC who received RBC transfusions at baseline, 7 achieved TI over at least a 12-week period up to the time of the landmark analysis. There were no deaths among TI responders compared to 2 (6.9%) among TI non-responders. There were too few TI responders on BAT (only 2 out of 38) to assess the impact on survival. Conclusion: In cytopenic myelofibrosis patients enrolled in PERSIST-2, having a reduction of TSS≥10% on full-dose PAC was associated with OS benefit - a finding that has not been noted with other JAK inhibitors to date. By contrast, this association was not found with BAT, (82% of these patients received ruxolitinib). Thus, reductions in TSS in patients treated with PAC were associated with an OS benefit. It is possible that pacritinib, with its distinctive mechanism of action, may offer a unique survival advantage for MF patients with moderate or severe thrombocytopenia, and further studies are required to understand the potential mechanisms of these distinct clinical observations. Study funded by CTI BioPharma Corp., a Sobi company.

7018 Background: MF is a life-limiting malignancy characterized by marrow fibrosis, splenomegaly, and progressive cytopenias. JAK2 inhibitors can reduce spleen volume, which is considered a surrogate for disease response. For example, ≥10% SVR on ruxolitinib (RUX) is associated with improved OS among patients with platelet (PLT) counts ≥100×109/L. RUX cannot be administered at full dose in patients with lower PLTs, and it is not known whether the association between SVR and OS persists in such patients. PAC is a JAK1-sparing inhibitor of JAK2/IRAK1/ACVR1 that demonstrated SVR benefit vs BAT (including RUX) in PERSIST-2, which enrolled MF patients with PLTs ≤100×109/L. Here we present a retrospective landmark OS analysis of the relationship between SVR and OS on PERSIST-2. Methods: This analysis includes PERSIST-2 patients who were alive and on study at the start of the 12-week SVR window (study week 10) on PAC 200 mg BID or BAT. Spleen volume was assessed radiographically (MRI or CT). OS was evaluated among SVR responders vs non-responders within each treatment arm using different SVR thresholds (≥35%, ≥20%, ≥10%, > 0%) and a landmark analysis methodology. OS was compared using the log-rank test. Results: Among patients on PAC (n = 89), any SVR ( > 0%) at 12 weeks was significantly associated with improved survival (HR = 0.08 [95% CI: 0.01, 0.51], P = 0.0007). Among all SVR response thresholds, SVR ≥10% demonstrated the greatest separation in OS curves between responders vs. non-responders on PAC, with no deaths on study among 65 responders compared to 5 deaths among 24 non-responders (HR = 0.0 [95% CI: 0.0, 0.14], P < 0.0001). By contrast, SVR did not predict OS benefit on BAT (n = 84), including RUX (n = 39). For example, 11% (3/28) of patients on BAT who achieved SVR ≥10% died compared to a similar number (14%, 8/56) of non-responders (HR = 0.63 [95% CI: 0.17, 2.37], P = 0.49). Of the 28 patients on BAT who achieved SVR ≥10%, 23 (82%) were treated with RUX. Among these 23 patients, most patients were receiving low-dose RUX at the time of the landmark: 78% were on ≤10 mg BID and 43% were on £5 mg BID. By contrast, the median relative dose intensity on PAC was 100% (200 mg BID) through week 12 among both SVR ≥10% responders and non-responders. Conclusions: In MF patients with PLTs ≤100×109/L, achieving SVR on full-dose PAC was associated with significant OS benefit. By contrast, this association was not found with BAT, even though most responders were on RUX, albeit at low doses. As PAC can be given at full dose regardless of PLT count, it is possible that PAC may offer a unique survival advantage for MF patients with moderate or severe thrombocytopenia who achieve spleen reduction. Clinical trial information: NCT02055781 .