Myelofibrosis Patients Research Articles

Evaluation of gecacitinib vs hydroxyurea in patients with intermediate-2 or high-risk myelofibrosis: final analysis results from a randomized phase 3 study

To compare the efficacy and safety of gecacitinib (also known as jaktinib) with hydroxyurea (HU) in treating myelofibrosis (MF) patients. In this multicenter, randomized phase 3 trial (ZGJAK016), intermediate- or high-risk primarily JAK inhibitor naïve MF patients were assigned in a 2:1 ratio to receive either gecacitinib (100 mg twice a day, BID) or HU (500 mg BID). The primary endpoint was the proportion of patients with ≥35% reduction in spleen volume (SVR35) from baseline at week 24. Secondary endpoints included the best spleen response rate, the proportion of patients with a ≥50% reduction in total symptom score (TSS50), anemia improvement, and safety profile. At 24 weeks, the SVR35 was reached by 64.8% of patients on gecacitinib (46/71), compared to 26.5% on HU (9/34), P = 0.0002. The best spleen response rates were also superior for gecacitinib at 81.7%, vs 32.4% for HU, P < 0.0001. The TSS50 rates were 62.0% for gecacitinib- and 50% for HU-treated patients. Among non-transfusion-dependent patients with baseline hemoglobin (HGB) ≤ 100 g/L, 31.0% (13/42) in the gecacitinib group showed a ≥20 g/L increase in HGB, compared to 15.0% (3/20) in HU group. The common grade ≥ 3 treatment-emergent adverse events (TEAEs), including anemia (26.8% vs 44.1%), thrombocytopenia (15.5% vs 32.4%), leukopenia (2.8% vs 20.6%), and neutropenia (1.4% vs 20.6%), were less frequent with gecacitinib than HU. Treatment discontinuation due to TEAEs was lower in gecacitinib (7.0%) compared to HU (11.8%). Gecacitinib demonstrates superior efficacy and a more favorable safety profile compared to HU, making it a promising treatment option for managing MF, particularly in patients with anemia (This trial was registered with ClinicalTrials.gov, (NCT04617028)).

Clinical and Immune Effects of Peri-Transplantation JAK Inhibition for Myelofibrosis.

Despite the introduction of JAK inhibitors, allogeneic hematopoietic cell transplant remains the only potentially curative treatment for patients with myelofibrosis but has considerable treatment-related complications. Whether the incorporation of JAK inhibition into the transplant algorithm leads to improved outcomes is still unclear. Here, we analyzed different transplant platforms in myelofibrosis patients undergoing a first transplant, comparing immune profiles and outcomes of (1) 33 patients continuing JAK inhibition at start of conditioning until stable engraftment (PERI-group), (2) 38 patients receiving JAK inhibition prior to transplant until start of conditioning (PRE-group), and (3) 38 patients that had never received JAK inhibition (NON-group). Patients in the PERI-group showed significantly higher early B-cell recovery as well as significantly increased late recovery of gamma-delta T cells and NK cells. We observed excellent neutrophil and platelet engraftment (100% for both) in the PERI-group and no hematotoxic effects or increased rates of infections following peri-transplant JAK inhibition. Cumulative incidence of acute graft-versus-host disease (GvHD) grade II-IV at day 100 after transplant was 15% in the PERI-group versus 29% in the PRE-group versus 34% in the NON-group. Cumulative incidence of relapse at 1 year after transplant was 9% in the PERI-group compared with 16% in the PRE-group and 18% in the NON-group. In conclusion, peri-transplant JAK inhibition was feasible with promising engraftment and acute GvHD rates, though deserves further investigation.

Triple immunostaining demonstrates the possible existence of segregated-nucleus-containing atypical monocytes in human primary myelofibrosis bone marrow: a case report

BackgroundSegregated-nucleus-containing atypical monocytes have recently been identified in mice. Segregated-nucleus-containing atypical monocytes are thought to originate from the bone marrow and induce fibrosis in the drug-injured lung. The Lyc6c− murine monocyte subset is the counterpart to human CD14−CD16++ non-classical monocytes; however, the human counterpart to murine segregated-nucleus-containing atypical monocytes has not yet been identified. Primary myelofibrosis is a well-known disease of progressive marrow fibrosis, and atypical megakaryocytes are thought to be closely related to fibrosis in primary myelofibrosis bone marrow. However, recently, monocytes have been reported to play an important role in marrow fibrosis in primary myelofibrosis. We speculated that, if there is a human counterpart to murine segregated-nucleus-containing atypical monocytes, it would present the same markers as murine segregated-nucleus-containing atypical monocytes, such as CD14−CD16+ macrophage-1 antigen (CD11b/CD18 complex)+, MSR1+, and CEACAM1+, and it might exist in the bone marrow of patients with primary myelofibrosis.Case presentationA 74-year-old Japanese male visited our hospital for clinical follow-up after total prostatectomy for prostatic cancer. Anemia, thrombocytosis, and elevated lactate dehydrogenase were suddenly observed in a periodic examination. CALR mutation type 2 (p.K385fs*47) was observed. The histological features of the patient’s bone marrow were consistent with fibrotic primary myelofibrosis. We immunohistochemically studied the bone marrow in an attempt to identify a human counterpart to murine segregated-nucleus-containing atypical monocytes. We detected a few CD16+MSR1+CEACAM1+ cells, but not CD14+MSR1+CEACAM1+ cells, by triple immunostaining. The patient is in a good condition and does not require treatment for primary myelofibrosis.ConclusionThere is a possibility that human segregated-nucleus-containing atypical monocytes exist in the bone marrow of primary myelofibrosis patients and might be related to marrow fibrosis.

Navigating 'grey areas' and challenges during evaluation of transplant eligibility in specific myelofibrosis populations: a perspective on behalf of the Chronic Malignancies Working Party of the EBMT.

Significant efforts have been made to effectively select myelofibrosis (MF) patients who can benefit from allogeneic hematopoietic cell transplantation (allo-HCT), the only current cure for MF. The recent EBMT/ELN 2024 recommendations offer valuable guidance for hematologists and transplant physicians. However, several grey areas remain in day-to-day clinical practice regarding the feasibility and optimal preparation for transplantation in patients with this disease. Effective spleen size reduction, often achieved with JAK inhibitors, appears crucial for transplant success. For resistant cases, switching JAK inhibitors, splenectomy, or spleen irradiation may be considered, taking into account patient profiles, treatment availability and center preferences. Managing splanchnic vein thromboses, portal, and pulmonary hypertension is critical as these conditions may affect transplant outcomes. Cytopenias, particularly transfusion-dependent anemia and thrombocytopenia, complicate treatment and impact on outcomes, though new drugs show promise. Comorbidities play a significant role and tools like the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) and frailty assessments are useful for evaluating transplant risks while allowing the implementation of corrective measures. Especially in low- and medium-income countries where access to novel therapies may be challenging, allo-HCT still represents an attractive therapeutic option for MF. Future directions include integrating new therapeutics into the transplant algorithm and leveraging artificial intelligence for more informed risk assessment, highlighting the need for tailored approaches to improve allo-HCT outcomes in such a setting.

Synergistic effect of concurrent high molecular risk mutations and lower JAK2 mutant variant allele frequencies on prognosis in patients with myelofibrosis-insights from a multicenter study.

In addition to high-molecular risk (HMR) mutations (ASXL1, EZH2, SRSF2, IDH, and U2AF1Q157), lower JAK2V617F variant allele frequencies (VAF) have been demonstrated to be associated with poor prognosis of myelofibrosis (MF) patients. Nevertheless, the relationship between JAK2V617F VAF and HMR mutations remains inconclusive. To address this, we analyzed the mutation status of 54 myeloid neoplasm-relevant genes using targeted next-generation sequencing in 124 MF patients. Three cohorts from multiple international centers were analyzed for external validation. Among JAK2-mutated patients, the presence of HMR mutations drove poor prognosis in patients with lower JAK2V617F VAF but not in those with higher JAK2V617F VAF. Survival analyses showed consistent results across validation cohorts. In multivariable analysis, concurrent HMR and a lower JAK2V617F VAF was identified as an independent adverse prognostic factor for survival, irrespective of age, MIPSS70, MIPSS70 + v2, and GIPSS risk groups. Mutation co-occurrence tests revealed no shared mutational pattern over different cohorts, excluding potential confounding effect from other concurrent mutations. Importantly, the integration of HMR/JAK2V617F VAF (≤50%) status significantly enhanced existing prognostic models, as evidenced by higher c-indexes and time-dependent ROC analyses. Single-cell studies with sequential follow-ups are warranted to decipher the clonal evolution of MF and how it relates to JAK2V617F VAF dynamics.

The impact of starting dose on overall survival in myelofibrosis patients treated with ruxolitinib: A prospective real-world study on AIFA monitoring registries.

Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of myelofibrosis (MF)-related splenomegaly or symptoms. The recommended starting dose depends on platelet count, regardless of haemoglobin level at baseline. In the recent years, an overall survival (OS) advantage was reported in patients treated with ruxolitinib compared with best available therapy. We analysed a large Italian cohort of 3494 patients identified by Agenzia Italiana del Farmaco (AIFA) monitoring registries. Of them, 2337 (66.9%) started at reduced dose: these patients were older (median age 70 vs. 67), with increased incidence of large splenomegaly (longitudinal diameter 20 vs. 19.1 cm, median volume 1064 cm3 vs. 1016 cm3), with higher IPSS risk (30.9% vs. 26.1%), and worse ECOG score (more than 1 in 14.3% vs. 9.8%). After balancing for baseline characteristics, Kaplan-Meier analysis showed a median OS of 78.2 months (95% CI 65.9-89) for patients who started at full dose and 52.6 (95% CI 49-56.6) months for patients who started with reduced dose (p < 0.001). Group analysis also showed a substantial difference in patients with intermediate-2 and high IPSS risk. The majority of MF patients in real-world analysis started with a reduced dose of ruxolitinib, which is associated with less favourable outcomes.

Elevated levels of damage-associated molecular patterns HMGB1 and S100A8/A9 coupled with toll-like receptor-triggered monocyte activation are associated with inflammation in patients with myelofibrosis.

Inflammation plays a pivotal role in the pathogenesis of primary and post-essential thrombocythemia or post-polycythemia vera myelofibrosis (MF) in close cooperation with the underlying molecular drivers. This inflammatory state is induced by a dynamic spectrum of inflammatory cytokines, although recent evidence points to the participation of additional soluble inflammatory mediators. Damage-associated molecular patterns (DAMPs) represent endogenous signals released upon cell death or damage which trigger a potent innate immune response. We assessed the contribution of two prototypical DAMPs, HMGB1 and S100A8/A9, to MF inflammation. Circulating HMGB1 and S100A8/A9 were elevated in MF patients in parallel to the degree of systemic inflammation and levels increased progressively during advanced disease stages. Patients with elevated DAMPs had higher frequency of adverse clinical features, such as anemia, and inferior survival, suggesting their contribution to disease progression. Monocytes, which are key players in MF inflammation, were identified as a source of S100A8/A9 but not HMGB1 release, while both DAMPs correlated with cell death parameters, such as serum LDH and cell-free DNA, indicating that passive release is an additional mechanism leading to increased DAMPs. HMGB1 and S100A8/A9 promote inflammation through binding to Toll-like receptor (TLR) 4, whereas the former also binds TLR2. Monocytes from MF patients were shown to be hyperactivated at baseline, as reflected by higher CD11b and tissue factor exposure and increased expression levels of proinflammatory cytokines IL-1β and IL-6. Patient monocytes showed preserved TLR4 and TLR2 expression and were able to mount normal or even exacerbated functional responses and cytokine upregulation following stimulation of TLR4 and TLR2. Elevated levels of endogenous TLR ligands HMGB1 and S100A8/A9 coupled to the finding of preserved or hyperreactive TLR-triggered responses indicate that DAMPs may promote monocyte activation and cytokine production in MF, fueling inflammation. Plasma IL-1β and IL-6 were elevated in MF and correlated with DAMPs levels, raising the possibility that DAMPs could contribute to cytokine generation in vivo. In conclusion, this study highlights that, in cooperation with classic proinflammatory cytokines, DAMPs represent additional inflammatory mediators that may participate in the generation of MF inflammatory state, potentially providing novel biomarkers of disease progression and new therapeutic targets.

A Retrospective Analysis of Pacritinib Treatment Outcomes in Myelofibrosis Patients With and Without Monocytosis

A Retrospective Analysis of Pacritinib Treatment Outcomes in Myelofibrosis Patients With and Without Monocytosis

MPN-499 A Retrospective Analysis of Pacritinib Treatment Outcomes in Myelofibrosis Patients With and Without Monocytosis

MPN-499 A Retrospective Analysis of Pacritinib Treatment Outcomes in Myelofibrosis Patients With and Without Monocytosis

MPN-288 Genomic and Molecular Analysis of Myelofibrosis Patients who received Momelotinib and Pacritinib at Moffitt Cancer Center

MPN-288 Genomic and Molecular Analysis of Myelofibrosis Patients who received Momelotinib and Pacritinib at Moffitt Cancer Center

Genomic and Molecular Analysis of Myelofibrosis Patients Who Received Momelotinib and Pacritinib at Moffitt Cancer Center

Genomic and Molecular Analysis of Myelofibrosis Patients Who Received Momelotinib and Pacritinib at Moffitt Cancer Center

Hypomethylating Agents are Effective in Treatment for Relapsed Myelofibrosis After Allogeneic Hematopoietic Cell Transplantation

Myelofibrosis (MF) is a myeloproliferative neoplasm with a relapse rate of 10% to 30% after allogeneic transplantation (alloHCT). Current recommendations to treat relapse include withdrawal of immunosuppression, donor lymphocyte infusion, and potentially a second alloHCT. Hypomethylating agents (HMAs) have shown efficacy as salvage therapy by inducing an immune response and improving donor chimerism for myeloid neoplasm post-HCT. Data is limited on use of HMAs for MF post-alloHCT relapse. To determine the benefit of using HMAs for MF patients relapsing after alloHCT, we retrospectively analyzed 12 patients with MF post-alloHCT relapse who received HMA to determine response via restoration of donor chimerism and clearance of molecular mutation. The median age was 61 years (range 41-72) with 92% classified as intermediate-2/high-risk by the Dynamic International Prognostic Scoring System (DIPSS) and 83% as high/very high risk by the MIPSS70+ (Molecular International Prognostic Scoring System). The median time to relapse post-alloHCT was 282.5 days (range 96-2388) with median donor chimerism 57.82% (range 2.48-84.0) prior to starting an HMA. After two cycles of HMA, 58% experienced restoration of donor chimerism. Molecular clearance of pre-HCT driver mutations occurred in 50% of patients at the most recent follow-up. New chronic graft-vs.-host disease (cGVHD) occurred in 50% of patients, with most being mild to moderate that resolved after treatment. HMA was safe and effective in a high-risk population after post-alloHCT relapse and is an option for patients in the future.

Myelofibrosis and anemia: A German claims data analysis to describe epidemiology and current treatment.

There is limited data on the incidence, prevalence, and treatments for myelofibrosis (MF) in Germany. This retrospective study examined claims data from 3.3 million insured individuals, spanning from 2010 to 2021. Four sensitivity scenarios were explored to identify cases of MF. Point prevalence and cumulative incidence of MF were determined as of December 31, 2021, and within 2021, respectively. A cross-sectional analysis used the main scenario definition of MF to identify cases and evaluate the period prevalence of patients receiving treatment for symptoms and/or splenomegaly, including first-line (1L) Janus kinase inhibitor (JAKi), second-line, or further (2L+) MF-related treatment therapies during 2021. The prevalence of anemia treatment was also reported. The estimated standardized point prevalence of MF on December 31, 2021, was 9.9-12.4 cases per 100 000 persons, and cumulative incidence in 2021 was 1.2-1.8 cases per 100 000 persons. Standardized period prevalence in 2021 for MF patients receiving 1L JAKi and/or 2L+ MF-related treatment was 4.0 cases per 100 000. Among these patients, 47.1%-53.7% required treatment for anemia, resulting in a period prevalence of 1.9-2.2 cases per 100 000 individuals. The data reveal gaps in MF treatments and the need to improve patient quality of life.

Allogeneic Hematopoietic Cell Transplantation for Myelofibrosis Aged 70 Years or Older: A Study from the German Registry for Stem Cell Transplantation

Current consensus recommends hematopoietic cell transplantation (HCT) for patients with myelofibrosis with intermediate or high-risk disease and age of less than 70 years. However, a higher chronological age should not be prohibitive for the eligibility decision in general, acknowledging that current life expectancy for the general population aged 70 years is ∼15 years, and current numbers of patients transplanted at 70 years or older is steadily increasing. The following study aimed to evaluate characteristics and outcomes of HCT in 115 myelofibrosis patients aged 70 years or older. This is a retrospective multicenter study, using the German Registry for Stem Cell Transplantation and Cellular Therapy (DRST). Adult myelofibrosis patients were included who received HCT up until 2021. Patients with secondary leukemia were excluded. Main endpoints were HCT demographics over time and outcomes after HCT (including overall survival, relapse incidence, non-relapse mortality, and graft-versus-host disease/relapse-free survival). Numbers of HCT increased over the past decade, with a significant spike since 2019. Comorbidity status of transplanted patients improved over time, while reduced-intensity conditioning was the preferred HCT platform, especially in most recent years. The 3-year overall survival was 55% (95% confidence interval [CI], 44%-65%). The 1-year cumulative incidence of relapse was 7% (95% CI, 3%-13%) and the 1-year cumulative incidence of non-relapse mortality was 22% (95% CI, 14%-31%). The 3-year graft-versus-host disease and relapse-free survival was 37% (95% CI, 27%-47%). Driver mutation genotype (in particular, non-CALR/MPL genotype) appeared to be the only variable that was significantly and independently associated with better survival in multivariable analysis, whereas neither comorbidity index nor dose intensity of pre-transplant conditioning appeared to influence outcome. This study demonstrated feasibility of curative treatment with HCT for myelofibrosis aged 70 or older, with significant increases in HCT numbers and improved fitness of older adults over recent years.

Clinical outcomes of ruxolitinib treatment in 595 intermediate-1 risk patients with myelofibrosis: The RUX-MF Real-World Study.

Ruxolitinib (RUX) is a JAK1/2 inhibitor approved for the therapy of myelofibrosis (MF) based on clinical trials including only intermediate2-high risk (INT2/HIGH) patients. However, RUX is commonly used in intermediate-1 (INT1) patients, with scarce information on responses and outcome. The authors investigated the benefit of RUX in 1055 MF patients, included in the "RUX-MF" retrospective study. At baseline (BL), 595 (56.2%) patients were at INT1-risk according to DIPSS (PMF) or MYSEC-PM (SMF). The spleen was palpable at <5 cm, between 5 and 10 cm, and >10 cm below costal margin in 5.9%, 47.4%, and 39.7% of patients, respectively; 300 (54.1%) were highly symptomatic (total symptom score ≥20). High-molecular-risk (HMR) mutations (IDH1/2, ASXL-1, SRSF2, EZH2, U2AF1Q157) were detected in 77/167 patients. A total of 101 (19.2%) patients had ≥1 cytopenia (Hb<10 g/dL: n.36; PLT <100 x 109/L: n = 43; white blood cells <4 x 109/L: n = 40). After 6 months on RUX, IWG-MRT-defined spleen and symptoms response rates were 26.8% and 67.9%, respectively. In univariate analysis, predictors of SR at 6 months were no HMR mutations odds ratio [OR], 2.0, p=.05], no cytopenia (OR, 2.10; p=.01), and blasts <1% (OR, 1.91; p=.01). In multivariate analysis, absence of HMR maintained a significant association (OR, 2.1 [1.12-3.76]; p=.01). In INT1 patients, responses were more frequent and durable, whereas toxicity rates were lower compared to INT2/high-risk patients. Presence of HMR mutations, cytopenia, and peripheral blasts identified less-responsive INT1 patients, who may benefit for alternative therapeutic strategies.

MoReLife - real-life data support the potential of momelotinib as a safe and effective treatment option for cytopenic myelofibrosis patients.

Recurrent problems of patients with myelofibrosis (MF) are cytopenias, debiliating disease-related symptoms and splenomegaly. Whereas the latter are usually addressed by the JAK1/2 inhibitors ruxolitinib and fedratinib, cytopenias often remain critical. Momelotinib, a JAK1/2 inhibitor recently approved for the treatment of anemic MF patients, was shown to improve anemia via a direct inhibition of activin A receptor type I. In this German-wide, multicenter, retrospective analysis the safety and efficacy profile of momelotinib was evaluated in a real world setting within a cohort of 60 MF patients independent of pre-treatment. The median duration of treatment was 12 weeks. As a new, but manageable safety finding, creatinine increase (CTC°1-2) was detected in 10/60 patients (17%). Interestingly, not only hemoglobin levels increased in 84% of patients, but also platelet values (67%). In the cohort of transfusion-dependent individuals (n = 38), transfusion requirement improved in 15 patients (39%) with 8 reaching transfusion independency (21%). Transfusion independency was achieved within a median of 4 weeks (range 2-12). Spleen size decreased in 13/53 individuals (25%) with a median response time of 6 weeks. Thereof, 11 patients had been pre-treated with JAK inhibitor(s) (85%). Clinical improvement was detected in 24/51 symptomatic individuals (47%) with a median response time of 4 weeks. 5 patients stopped treatment due to side effects (8%), 6 patients due to a worsening of clinical symptoms (10%). Taken together, the MoReLife analysis identifies momelotinib as potent and safe therapeutic option also for heavily pre-treated cytopenic MF patients under real world conditions.

Liver and spleen shear-wave elastography in the diagnosis and severity staging of myeloproliferative diseases and myelofibrosis.

Spleen and liver stiffness, investigated by VCTE (Vibration-Controlled Transient Elastography), have been associated with marrow fibrosis in patients with myeloproliferative neoplasms (MPNs). Tissue stiffness can be assessed by shear wave point (pSWE) and bidimensional elastography (2DSWE). Spleen stiffness (SS)values were higher in Myelofibrosis (MF) and Polycythemia Vera (PV) compared to Essential Thrombocythemia (ET). We aimed to identify SWE differences between MPN patients and healthy volunteers; to evaluate specific SWE features in patients with MF, PV and ET; to establish a correlation with bone marrow fibrosis in patients with myeloproliferative disease. Patients with myeloproliferative disease and healthy volunteers performed evaluation of spleen and liver stiffness (LS)by pSWE and 2DSWE. A total of 218 subjects were included: 143 with myeloproliferative disease (64 MF, 29.4%, 33 PV, 15.1% and 46 ET, 21.1%), and 75 (34.4%) healthy volunteers. Compared to volunteers, MF patients had greater spleen (pSWE 40.9 vs. 26.3kPa, p < 0.001; 2DSWE 34.9 vs. 20.1kPa, p < 0.001), and liver stiffness (pSWE 7.72 vs. 5.52kPa, p < 0.001; 2DSWE 6.96 vs. 5.01kPa, p < 0.001). In low (0-1) (n = 81, 60.4%) versus high-grade bone marrow fibrosis (2-3) (n = 42, 39.6%), is evident a higher median stiffness in patients with higher grades of fibrosis both for liver (pSWE 5.2 vs. 6.65kPa; 2DSWE 5.1 vs. 6.05kPa) and spleen (pSWE 27.2 vs. 37.9kPa, 2DSWE 21.7 vs 30.75kPa-p < 0.001 in both). SWE evaluation distinguishes MF patients from HV and ET/PV and may help in MPN diagnosis. LS and SS values are associated with bone marrow fibrosis grade.

Socio-demographic determinants of myelofibrosis outcomes in an underserved center and the SEER national database

The influence of demographic characteristics and social determinants on cancer outcomes is widely recognized in various malignancies but remains understudied in myelofibrosis (MF). This study aims to investigate social and demographic variables associated with MF survival. We retrospectively reviewed data of biopsy-proven MF patients from the Surveillance, Epidemiology and End Results (SEER) database (2000–2021) and Montefiore Medical Center (2000–2023), an underserved inner-city hospital. The SEER cohort included 5,403 MF patients and was predominantly Non-Hispanic (NH) White (82%) with a median age of 69 years. The age-adjusted incidence rate of MF was 0.32 cases per 100,000 person-years, increasing annually by 1.3% from 2000 to 2021. Two- and five- year overall survival rates were 69% and 42%, respectively. Worse cause-specific survival was associated with older age, male sex, and diagnosis before 2011 (year of Ruxolitinib approval). NH-Black ethnicity, unmarried status and lower median income were independent predictors of worse overall survival. The single-center analysis included 84 cases, with a median age of 66 years. NH-White patients comprised 37% of the sample, followed by NH-Black (28.5%). Two- and five- year overall survival rates were 90% and 61%, respectively, with NH-Black patients exhibiting the lowest median survival, although the difference was not statistically significant. Age was a significant predictor of worse survival in this cohort. NH-Black and Hispanic patients lived in areas with higher socioeconomic and demographic stress compared to NH-White patients. Overall, this study highlights the association of social and demographic factors with MF survival and emphasizes the need for equitable healthcare and further exploration of social-demographic factors affecting MF survival.

Myeloproliferative Neoplasms Transcriptome Reveals Pro-Inflammatory Signature and Enrichment in Peripheral Blood Monocyte-Related Genes

Myeloproliferative neoplasms (MPN) are hematological diseases associated with genetic driver mutations in the JAK2, CALR, and MPL genes and exacerbated oncoinflammatory status. Analyzing public microarray data from polycythemia vera (n = 41), essential thrombocythemia (n = 21), and primary myelofibrosis (n = 9) patients’ peripheral blood by in silico approaches, we found that pro-inflammatory and monocyte-related genes were differentially expressed in MPN patients’ transcriptome. Genes related to cell activation, secretion of pro-inflammatory and pro-angiogenic mediators, activation of neutrophils and platelets, coagulation, and interferon pathway were upregulated in monocytes compared to controls. Together, our results suggest that molecular alterations in monocytes may contribute to oncoinflammation in MPN.

FRACTION: protocol of a phase II study of Fedratinib and Nivolumab combination in patients with myelofibrosis and resistance or suboptimal response to JAK-inhibitor treatment of the German MPN study group (GSG-MPN)

Development of Janus-kinase (JAK) inhibitors has revolutionized the therapeutic landscape for patients with myeloproliferative neoplasia (MPN). Following approval of the first JAK1/2-inhibitor Ruxolitinib, symptoms of this inflammatory disease, characterized by splenomegaly, release of inflammatory cytokines and appearance of thrombosis, could be effectively reduced for the first time. However, JAK-inhibitor treatment is limited in several aspects: 1) duration of response: 3 years after initiation of therapy more than 50% of patients have discontinued JAK-inhibitor treatment due to lack of efficacy or resistance; 2) reduction of disease burden: while effective in reducing inflammation and constitutional symptoms, JAK-inhibitors fail to reduce the malignant clone in the majority of patients and therefore lack long-term efficacy. Early clinical trials for patients with myelofibrosis (MF) have tried to address these issues for patients with suboptimal response to Ruxolitinib therapy while combination therapies with Fedratinib are rare. Recent reports provided first evidence on how the JAK2-V617F mutated myeloid cells may influence T-cell responses. JAK2-V617F promoted the synthesis of PD-L1 in MPN cells leading to limited anti-neoplastic T-cell responses, metabolic changes in T-cells and eventually JAK2-V617F-driven immune-escape of MPN cells. These findings may facilitate the use of immunotherapeutic approaches for JAK-mutated clones. Immune checkpoints refer to a variety of inhibitory pathways that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. The FRACTION study is a single arm, open label Phase II trial investigating the combination of Fedratinib with the PD-1 inhibitor Nivolumab in patients with myelofibrosis and suboptimal or lack of response to JAK-inhibitor therapy. Over a 12 months period the trial assesses longer term outcomes, particularly the effects on clinical outcomes, such as induction of clinical remissions, quality of life and improvement of anemia. No prospective clinical trial data exist for combinations of JAK- and immune-checkpoint-inhibitors in the planned MF study population and this study will provide new findings that may contribute to advancing the treatment landscape for MF patients with suboptimal responses and limited alternatives.