ABSTRACT:Secondary myelofibrosis (SMF) represents a late stage of polycythemia vera (PV) and essential thrombocythemia (ET), with overall survival (OS) currently defined by the myelofibrosis secondary to PV and ET prognostic model (MYSEC-PM). To identify additional myeloid neoplasm-associated cancer gene variants (CGVs) associated with SMF outcome, we evaluated next-generation sequencing panel testing in 644 patients within the MYSEC cohort. Overall, 429 (66.6%) patients reported at least 1 CGV, with ASXL1, TET2, and DNMT3A being the most frequently involved. Specific molecular profiles affected OS (P< .001): U2AF1, TP53, or SRSF2 variants (UTS; 9.3%; median OS, 4.1 years) and ASXL1 without UTS (25.3%; median OS, 8.4 years). By integrating these genetic signatures within the MYSEC-PM through penalized Cox regressions, we identified the following independent predictors (P< .0001 to .02): hemoglobin level <11 g/dL (1 point), circulating blasts ≥3% (2 points), platelet count <150 × 109/L (2 points), age (0.21 points/y), ASXL1 without UTS mutations (1 point), and any UTS mutations (3 points). Finally, we developed the MYSEC-molecular prognostic model (MYSEC-mPM) allocating 582 patients with SMF into 4 categories with different OS (P < .001): low (median OS, 18.0 years; score <14), intermediate-1 (8.8. years; score, 14-16), intermediate-2 (4.6 years; score, 17-18), and high risk (1.9 years; score ≥19). Additionally, in 381 patients with SMF and available cytogenetics, the MYSEC-mPM was implemented with complex/monosomal karyotype, generating the karyotype-enhanced MYSEC-kmPM. Our study shows that genomic and cytogenetic profiling improves survival prediction in SMF, outperforming the MYSEC-PM.

Neutrophils are the first key effector innate immune cells recruited toward inflammatory sites. Through the release of neutrophilic extracellular traps (NETs), the production of reactive oxygen species (ROS), degranulation and phagocytosis, neutrophils play a central role in the rapid elimination of invading pathogens. Recently, increasing attention has been given to the role of neutrophils in chronic inflammation, challenging the dichotomy between innate and adaptive immune responses. In chronic inflammatory conditions, neutrophils generally display a hyperinflammatory phenotype via dysregulated pathogen defense mechanisms. Excessive neutrophil activation may result in aberrant cell death, uncontrolled oxidative burst or NET formation and sustained release of inflammatory mediators such as proteases and inflammatory cytokines. Therefore, neutrophils contribute to the development of a sustained inflammatory environment and cause collateral tissue damage. In addition to their direct inflammatory effects, neutrophils further orchestrate inflammation and tissue remodeling by actively engaging in crosstalk with other cells within the immune microenvironment, such as endothelial cells, monocytes, platelets, and T and B cells. This review summarizes the current knowledge of the emerging role of neutrophils in the context of chronic inflammation. The key characteristics of neutrophils and their interactions with distinct cell types are discussed within the initial part of the review, whereas the second part focuses on their contributions to the pathophysiology of immune-driven diseases, including rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, systemic lupus erythematosus, chronic obstructive pulmonary disease, and fibrotic disorders. Increasing knowledge on neutrophil behavior in the context of chronic inflammation may offer novel insights into disease pathology and, potentially, the identification of novel therapeutic targets.

INTRODUCTION:Improvements in splenomegaly, anemia, and overall survival (OS) are key considerations in the management of patients with myelofibrosis. In the phase III SIMPLIFY-1 trial (NCT01969838), momelotinib was noninferior to ruxolitinib for spleen volume reduction ≥ 35% (SVR35) and nominally superior for transfusion independence (TI) at week 24 in Janus kinase (JAK) inhibitor-naive patients. However, the relative impact of these endpoints on OS in anemic patients has not been described. MATERIALS AND METHODS:The present post hoc analysis evaluated week 24 SVR35, TI, and dual responses (SVR35 + TI) in patients with baseline hemoglobin < 10 g/dL. RESULTS:SVR35 rates were similar overall with momelotinib versus ruxolitinib (27/86 [31%] vs. 31/94 [33%]), but higher with momelotinib in the baseline platelets < 200 × 109/L subgroup (19/49 [39%] vs. 8/47 [17%]) and with ruxolitinib in the baseline platelets ≥ 200 × 109/L subgroup (8/37 [22%] vs. 23/47 [49%]). Week 24 SVR35 + TI was also more common with momelotinib (23/86 [27%]) than with ruxolitinib (7/94 [7%]). Subsequent OS analysis focused on the momelotinib arm only, as the crossover trial design precluded analysis of long-term OS with ruxolitinib. OS was longer in patients who were transfusion independent and/or achieved SVR35 at week 24 versus those who met neither endpoint (TI alone: n = 17, hazard ratio [HR], 0.25 [95% CI, 0.09-0.70]; SVR35 + TI: n = 23, HR, 0.40 [95% CI, 0.18-0.87]). CONCLUSION:These results highlight that both spleen- and anemia-related benefits of momelotinib correlate with improved OS, supporting prioritization of TI in anemic patients for optimal long-term outcomes, and suggest that momelotinib may be the preferred JAK inhibitor in anemic patients with platelets < 200 × 109/L.

This systematic review aimed to identify clinical practice guidelines (CPGs) for platelet transfusion in non-surgical and non-traumatic care settings, and appraise their methodological quality. We searched three databases and eight grey literature sources for CPGs published between 2015 and 2025. Methodological characteristics of the literature review and guideline development process were charted. Data on the targeted population, transfusion indication, and the direction and strength of the recommendations were extracted. CPG methodological quality was assessed using the AGREE II Rigour of Development domain. We identified 30 CPGs, including 89 recommendations. Platelet transfusion recommendations were summarized in interactive evidence maps. These tools can aid clinicians seeking evidence-based guidance to support clinical decision making, and highlight priorities for future research. AGREE II assessment indicated good to poor methodological quality of the included CPGs. This work underscores the importance of applying a rigorous and transparent methodology to ensure the development of reliable CPGs.

Autosomal-dominant STAT1 gain-of-function (GOF) is an inborn error of immunity characterized by chronic mucocutaneous candidiasis and variable autoimmune manifestations. Janus kinase (JAK) inhibitors are a promising treatment, but their efficacy remains variable and incompletely understood. We evaluated the impact of JAK inhibitors by studying two STAT1 GOF patients (harboring R321S and T385M mutations) longitudinally using Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq), flow cytometry, and cytokine analysis in peripheral blood mononuclear cells and serum. Rapid, yet incomplete, immune reconstitution was observed after 1 week. T cells rebalanced from effector to naïve T cells, and T cell receptor diversity and abundance increased. Monocytes showed the most pronounced transcriptional dysregulation compared to healthy references, which markedly improved upon JAK-inhibitor treatment. Serum cytokine, cell–cell communication, and pathway analysis pointed toward an inflammatory phenotype in all cell types caused by monocytes and improved upon treatment. JAK inhibitors provided clinical and immunological benefit in STAT1 GOF but did not fully restore immune homeostasis, highlighting both its therapeutic potential and limitations.

The Phase 3 TRANSFORM-1 study (NCT04472598) evaluated ruxolitinib (RUX) in combination with navitoclax (NAV) or placebo (PBO) in Janus-kinase-inhibitor-naïve adults with intermediate-2 or high-risk myelofibrosis and Eastern Cooperative Oncology Group performance status ≤2. Patients were randomized 1:1 to NAV (200 mg/day starting dose or 100 mg escalated to 200 mg/day) or PBO, with RUX dosed per label. The primary endpoint was ≥35% spleen volume reduction (SVR) at Week 24 (SVR35W24). Secondary endpoints included change from baseline in Total Symptom Score (TSS) at Week 24 and SVR35 at any time. A total of 252 patients (NAV+RUX, n=125; PBO+RUX, n=127; median follow-up 20.3 months) were randomized; >80% had intermediate-2 risk and nearly 50% were high-molecular risk (HMR). SVR35W24 was achieved by 63.2% with NAV+RUX versus 31.5% with PBO+RUX (P<0.0001). Mean change in TSS at Week 24 was not significantly different between NAV+RUX and PBO+RUX (-10.2 vs -11.6; P=0.2852). SVR35 at any time was achieved in 76.8% with NAV+RUX versus 44.1% with PBO+RUX (nominal P<0.0001). A ≥20% variant allele frequency reduction (exploratory endpoint) occurred in 58.5% (95% CI: 49.0-67.5) with NAV+RUX and 45.5% (95% CI: 36.4-54.8) with PBO+RUX. NAV+RUX showed higher hematologic toxicity versus PBO+RUX (Grade 3/4 thrombocytopenia: 54.0% vs 19.2%; Grade 3/4 neutropenia: 40.3% vs 8.8%); diarrhea (any grade: 41.9% vs 16.8%) was also more common. Cytopenias were generally manageable and reversible with dose adjustments.

Introduction: Myelofibrosis (MF) is a progressive, life-limiting hematologic malignancy characterized by splenomegaly, anemia, and constitutional symptoms. Improvements in both anemia and splenomegaly have been linked to improved overall survival (OS) in MF; although spleen volume reduction ≥35% (SVR35) is the benchmark for spleen response and has been accepted as an endpoint for drug approval, its validity as the optimal indicator for survival remains uncertain. In a previous analysis of JAK inhibitor (JAKi)–naive patients with MF and baseline hemoglobin <10 g/dL in the phase 3 SIMPLIFY-1 trial (Palandri F, et al. EHA 2025. Poster P1829), transfusion independence (TI) at week 24 was associated with longer OS with the JAK1/JAK2/ACVR1 inhibitor momelotinib, with (hazard ratio [HR], 0.40; 95% CI, 0.18-0.89) or without (HR, 0.19; 95% CI, 0.06-0.65) achievement of SVR35. To better understand the impact of dual SVR and TI on OS in JAKi-naive and -experienced patients with MF, these post hoc analyses further explores the relationship between TI, different SVR thresholds, and OS in the SIMPLIFY-1 and MOMENTUM trials. Methods: SIMPLIFY-1 (NCT01969838) and MOMENTUM (NCT04173494) were randomized, double-blind, phase 3 trials in JAKi-naive and -experienced patients, respectively. In these post hoc analyses of the overall safety population randomized to momelotinib in each trial (SIMPLIFY-1, n=214; MOMENTUM, n=130), OS was compared between dual SVR+TI responders at week 24 vs nonresponders across various SVR thresholds (≥35%, ≥25%, ≥15%, and ≥10%). OS was analyzed using the Kaplan-Meier method, with median OS, HRs, and nominal log-rank P values reported. As all patients in both trials received open-label momelotinib after week 24, this crossover design precludes evaluation of outcomes beyond week 24 in the comparator arms. Results: In SIMPLIFY-1, JAKi-naive patients who had TI and achieved SVR35 at week 24 with momelotinib regardless of baseline anemia status had longer OS, which is consistent with the previous analysis in baseline anemic patients. Median OS was not estimable (NE) in both dual responders (n=53; 95% CI, NE-NE) and nonresponders (n=161; 95% CI, 44.09 mo-NE), but the difference in favor of responders was nominally significant (HR, 0.51; 95% CI, 0.27-0.99; P=.0425). Nominally significant OS benefits of dual TI and SVR response were observed with all other SVR thresholds evaluated: (1) SVR25+TI responders (n=77) vs nonresponders (n=137): median, NE (95% CI, NE-NE) vs 46.2 mo (95% CI, 41.53 mo-NE); HR, 0.46 (95% CI, 0.26-0.82; P=.0068); (2) SVR15+TI responders (n=103) vs nonresponders (n=111): median, NE (95% CI, NE-NE) vs 44.1 mo (95% CI, 35.5 mo-NE); HR, 0.33 (95% CI, 0.19-0.57; P< .001); and (3) SVR10+TI responders (n=113) vs nonresponders (n=101): median, NE (95% CI, NE-NE) vs 41.5 mo (95% CI, 30.6 mo-NE); HR, 0.28 (95% CI, 0.16-0.47; P< .001). In JAKi-experienced patients in MOMENTUM, there were no deaths among dual SVR+TI responders at any evaluated threshold at week 24; thus, OS HRs vs nonresponders could not be derived, and differences refer to comparisons of the survival distributions between responders and nonresponders. Median OS was NE in dual SVR35+TI responders (n=15; 95% CI, NE-NE) vs nonresponders (n=115; 95% CI, 12.5 mo-NE), a difference that did not reach significance (P=.0543). However, OS was significantly longer in dual SVR and TI responders vs nonresponders at all other SVR thresholds: (1) SVR25+TI responders (n=23) vs nonresponders (n=107): median, NE in both groups (95% CI, NE-NE vs 12.5 mo-NE; P=.0109); (2) SVR15+TI responders (n=31) vs nonresponders (n=99): median, NE in both groups (95% CI, NE-NE vs 11.3 mo-NE; P=.0014); and (3) SVR10+TI responders (n=33) vs nonresponders (n=97): median, NE in both groups (95% CI, NE-NE vs 11.3 mo-NE; P=.0009). Conclusions:In both JAKi-naive and -experienced patients, dual TI and SVR response at week 24 was associated with longer OS at all SVR thresholds evaluated; curve separation was more pronounced at lower SVR thresholds (≥10% and ≥20%), suggesting that OS benefits can be achieved with more modest SVRs in patients who are also TI. Overall, these analyses highlight the ability of momelotinib to comprehensively address both splenomegaly and anemia in MF, benefits that may translate into meaningful OS improvements.

Background: Janus Kinase (JAK) inhibitors are the current standard of care for patients (pts) with myelofibrosis (MF). However, many pts may not achieve spleen volume reduction (SVR) or total symptom score (TSS) response after frontline treatment, and most pts with relapsed/refractory (R/R) MF lack adequate responses. Momelotinib (MMB), a recently approved JAK/ACVR1 inhibitor for MF pts with anemia, showed symptom and spleen responses in about 25% pts in R/R setting. Combination strategies of JAK inhibitor and agent with unique mechanism of action and minimal overlapping toxicities (e.g. cytopenias) are needed to improve response rates in MF. PIM1 expression is upregulated in MF CD34 cells. In preclinical models, PIM1 knockout (KO) was shown to prevent MF progression without affecting PLT counts, whereas pan-PIM KO caused thrombocytopenia (TCP). Nuvisertib (NUVI, TP-3654), an oral investigational highly selective PIM1 kinase inhibitor, alone and in combination with ruxolitinib (RUX) showed spleen size reduction and bone marrow (BM) fibrosis improvement in JAK2V617F and MPLW515L MF mouse models. Preliminary data from the ongoing Phase 1/2 study in R/R MF pts with PLT count ≥25 x 109/L showed that NUVI monotherapy was well tolerated with limited myelosuppression, and clinical activity including SVR and TSS responses strongly correlating with cytokines modulation, and hemoglobin (Hgb), PLT, and BM improvement. Preclinical and monotherapy clinical data support the development of NUVI + MMB combo in MF. Methods: The global Phase 1/2 study evaluates the safety and efficacy of NUVI + MMB combo in pts with MF (NCT04176198, Arm 3). Key eligibility criteria include primary or secondary MF, previously treated with JAK inhibitor, DIPSS intermediate or high-risk MF, Hgb <10 g/dL, PLT ≥50 x 109/L, splenomegaly (≥450 cm3 by imaging), and ≥2 measurable symptoms with each score ≥3 or a total average score of ≥10 per MFSAF v4. The study aims to identify the RP2D of NUVI when given with MMB, and to assess the safety, clinical activity (SVR, TSS improvement), and PK and PD markers (cytokine, BM fibrosis etc.). Results: Here we present the first ever combination data of MMB in MF. As of 29 May 2025, total 18 pts enrolled in 4 dose levels of NUVI BID at 240 mg (n=4), 360 mg (n=8), 480 mg (n=5) and 720 mg (N=1) + MMB 200 mg QD using the BLRM dose escalation. At baseline, median age 75 years (range 51, 82); TSS 29 (9, 37); spleen volume 1370 cm3 (614, 4250); Hgb 9.1 g/dL (7.9, 10.1; 50% pts required transfusion); and PLT 196 x 109/L (81, 601). All pts received prior JAK inhibitor, and 53% pts had high molecular risk mutation. Median treatment duration of NUVI + MMB combo was 21 weeks (1, 30), and 13 of 18 (72%) pts were on treatment. One DLT of Grade 4 TCP without any bleeding occurred in NUVI 360 mg BID + MMB 200 mg QD dose. Treatment-related adverse events (TRAEs) occurring in ≥20% of pts were diarrhea, nausea, and TCP. Grade ≥3 TRAE occurring in ≥2 pts included TCP (n=2; 1 pt had baseline TCP). Mean Hgb and PLT remained stable throughout the 24-week treatment. Emerging NUVI + MMB combo safety data was generally consistent with NUVI monotherapy data. 5 pts in the NUVI 360 mg BID + MMB 200 mg QD dose completed ≥24 weeks of treatment and were considered efficacy evaluable. TSS improvement at WK24 was observed in all 5 patients (median change -65%, range -38% to -72%); 3 of 5 (60%) pts showed ≥50% TSS reduction. In addition, absolute reduction was observed in all 7 symptom parameters, including >50% reduction in mean fatigue score at WK24. 2 of 5 (40%) pts showed ≥25% SVR at WK24. Decreased EN-RAGE and increased adiponectin were observed in all 5 pts, consistent with NUVI monotherapy findings where modulation of these cytokines strongly correlated with TSS50, individual symptoms and SVR25 responses. Anemia improvement was observed in 2 of 5 (40%) pts during 24 weeks of treatment: 1 pt showed Hgb response (defined as mean ≥1.0 g/dL increase for ≥12 weeks without transfusion), and 1 pt achieved a >50% reduction in transfusions. Dose escalation is ongoing, and updated data will be presented.Conclusions: NUVI + MMB combo appeared to be well tolerated. Preliminary data showed early clinical activity including 60% TSS50 response and absolute symptom improvement, 40% SVR25 response, cytokine modulation and anemia improvement in R/R MF pts with anemia. Preliminary data supports further development of NUVI + MMB combo for pts with MF.

Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic cell transplantation (allo-HCT) that is caused by donor immune cells attacking and damaging host tissues. Immune suppressive small molecule and protein-based therapeutics targeting donor anti-host immune cells are currently used for GVHD prophylaxis and treatment. Even with these therapies, aGVHD progresses to life-threatening steroid-refractory aGVHD (SR-aGVHD) in up to 50% of cases and is a risk factor for the subsequent development of debilitating chronic GVHD. To improve aGVHD-related outcomes, donor graft engineering techniques and adoptive transfer of immune modulatory cells have been explored. Highly rigorous donor graft T-cell depletion approaches have revealed that mitigation of aGVHD can be accompanied by slow immune recovery post-allo-HCT and reduction in anti-microbial and anti-leukemia responses resulting in increased relapse and infection rates, respectively. Recent T-cell separation techniques allowing for precision graft engineering by selectively eliminating aGVHD-causing T-cells (eg, naïve T-cells) without loss of T-cells with beneficial functions and retaining and/or enriching immune regulatory populations (eg, regulatory T-cells (Tregs) or myeloid-derived suppressor cells) have been tested and will continue to improve. Clinical cell-based regulatory therapies have been employed for targeting SR-aGVHD, particularly mesenchymal stem cells (MSCs) and more recently, Tregs. In this review, we summarize aGVHD pathophysiology, highlight newly discovered aGVHD mechanisms, and discuss current and emerging cellular and graft manipulation approaches for aGVHD prevention and treatment.

Essential thrombocythemia (ET) and polycythemia vera (PV) are rare in adolescent and young adult (AYA). These conditions, similar to those in older patients, are linked with thrombotic complications and the potential progression to secondary myelofibrosis (sMF). This retrospective study of ET and PV patients diagnosed before age 25 evaluated complication rates and impact of cytoreductive drugs on outcomes. Among 348 patients (278 ET, 70 PV) with a median age of 20 years, the of thrombotic events was 1.9 per 100 patient-years. Risk factors for thrombosis included elevated white blood cell count (>11 × 109/L) (HR: 2.7, p = 0.012) and absence of splenomegaly at diagnosis (HR: 5.7, p = 0.026), while cytoreductive drugs did not reduce this risk. The incidence of sMF was 0.7 per 100 patient-years. CALR mutation (HR: 6.0, p < 0.001) and a history of thrombosis (HR: 3.8, p = 0.015) were associated with sMF risk. Interferon as a first-line treatment significantly improved myelofibrosis-free survival compared to other treatments or the absence of cytoreduction (p = 0.046). Although cytoreduction did not affect thrombotic event, early interferon use reduced sMF risk. These findings support interferon use to mitigate sMF risk in AYA ET and PV patients.

Introduction: Current EBMT/ELN-guidelines recommend pre-transplant spleen-directed management with JAK-inhibitors in symptomatic myelofibrosis (MF) patients, but emphasize the unmet need for data on the use of newer generation JAK-inhibitors in this setting. Transplant-eligible patients are typically excluded from registration trials in MF. The HOVON-134 trial aimed to answer this question: Is the use of the selective JAK2/IRAK1/ACVR1 inhibitor pacritinib (PAC) feasible in transplant-eligible MF-patients, particularly with regards to spleen and symptom responses, safety and ability to proceed toward intended allogeneic stem cell transplantation (alloHSCT)? Methods: HOVON-134 was a prospective, single-arm, phase 2 study for MF-patients with DIPSS Plus intermediate-2 and high-risk disease with intent-to-transplant, WHO performance status 0-2 and platelet count ≥25x109/L. Prior treatment with ruxolitinib (RUX) was allowed if tapered and discontinued before inclusion. PAC was given orally at a dose of 200 mg twice daily in 3 to 4 cycles of 28 days (depending on donor availability) and stopped one day before start of conditioning. Per protocol alloHSCT was done with a matched related donor (MRD) or 10/10 matched unrelated donor (MUD) and a standardized reduced-intensity conditioning protocol: intravenous busulfan 3.2 mg/kg adjusted ideal body weight (days -7 to -6) and 1.6 mg/kg adjusted ideal body weight (day -5), fludarabine 30 mg/m2 (days -7 to -2) and anti-T lymphocyte globulin 10 mg/kg (days -3 to -1) for MRD and 20 mg/kg (days -3 to -1) for MUD. Prophylaxis for graft-versus-host disease (GVHD) consisted of mycophenolate mofetil (days 0 to 28) and cyclosporine A (days -3 to 100, followed by tapering). This strategy was deemed feasible if at least 80% of included patients successfully reached their intended alloHSCT. Symptom response on PAC was defined as ≥50% reduction in the MPN symptom assessment form total symptom score; spleen response was defined as ≥50% reduction in palpable spleen size below the lower costal margin. Transplant outcomes are shown for per and off protocol treated patients. Results: Between 11 July 2018 and 16 February 2022, 61 patients were registered. Among them, 64% were JAK2V617F-mutated, 75% had DIPSS Plus intermediate-2 risk disease and 38% had prior RUX exposure. Median follow-up from registration was 55.8 months (IQR, 50.6-67.4). 36% and 43% of evaluable patients showed symptom and spleen responses respectively. In the group of patients with prior RUX exposure, 22% achieved symptom response and 18% achieved spleen response on PAC. 44% of patients had at least one treatment-emergent CTCAE grade 3 or 4 adverse event during PAC, mainly gastro-intestinal (8% CTCAE grade 3, no grade 4-5, PAC dose-modification in 3%). No patients were disqualified for alloHSCT for cardiac reasons. 58 patients (95%) proceeded to alloHSCT: 38 per protocol treatment, 20 off protocol (including use of alternative donors). Reasons for going off protocol were mainly related to study design (strict donor criteria and timeline for alloHSCT). Three patients did not proceed to alloHSCT because of disease progression in one and two deaths (triventricular hydrocephalus during PAC, possibly due to extramedullary hematopoiesis, and undetermined neurological event during conditioning). From registration, overall survival at 1 and 5 years was 80% (95% CI, 68-88) and 57% (95% CI, 43-70). Cumulative incidence of non-relapse mortality at 5 years post-transplant (on and off protocol) was 25%. For patients transplanted on protocol, one-year progression-free survival was 79% (95% CI, 62-89) and GVHD-free relapse-free survival was 42% (95% CI, 26-57). At 12 months post-transplant on protocol, grade 3-4 acute GVHD was observed in 3% of patients and severe chronic GVHD was observed in 26% of patients.In this group, no primary graft failure occurred, and a cumulative incidence of secondary graft failure of 5% was observed. Six patients received a CD34-selected stem cell boost for poor graft function (n=5) or graft failure (n=1) and seven patients received donor lymphocyte infusion for loss of chimerism (n=5) or hematological relapse (n=2).Conclusion: PAC is a feasible and effective symptomatic treatment in transplant-eligible MF-patients and its pre-transplant use does not limit higher-risk patients in proceeding to their intended alloHSCT. Ours is one of few studies in MF showing outcome of alloHSCT by intent-to-transplant.

BCR::ABL1 negative myeloproliferative neoplasms (MPNs) are a heterogenous group of disorders characterized by clonal proliferation of hematopoietic stem and progenitor cells (HSPCs) within the bone marrow. Although the identification of somatic key driver mutations significantly increased both understanding and diagnostic accuracy of MPNs, many questions about the exact pathophysiology remain unanswered. Increased neutrophil count at diagnosis is a well-recognized predictor of worse disease evolution and survival, nonetheless the exact role of neutrophilic granulocytes within MPN pathophysiology is almost unexplored. As the majority of these cells are residing within the bone marrow, they represent a non-negligible entity within the bone marrow niche and its homeostasis. This review describes how neutrophils might contribute to the development of the inflammatory bone marrow niche, and hereby also fibrosis, associated with MPNs. The versatile functions and effects in different contexts emphasize the necessity for future research oriented to bone marrow in addition to peripheral blood.

Background:Cytoreductive therapies have been the standard treatment for patients with high-risk polycythemia vera (PV) for decades. However, approximately 24% of patients treated with hydroxyurea will eventually develop resistance or intolerance to hydroxyurea and need second-line (2L) therapy. Objective:This study compared clinical outcomes of patients with high-risk PV who switched to ruxolitinib as 2L therapy (switchers) versus those who continued first-line (1L) therapy (nonswitchers) after suboptimal response. Design:This was a retrospective, multicenter, noninterventional study. Methods:The primary outcome was event-free survival (EFS), defined as the time between the index date and the earliest event of thrombosis, major bleeding, disease progression, or death. Key secondary outcomes included overall survival (OS), time to and rate of disease progression, rate of thrombosis, and change in spleen size. Results:Overall, 225 patients were included (switchers: 69; nonswitchers: 156). At baseline, >50% of switchers had a prior history of thrombosis (p = 0.006) and PV-related symptoms (p = 0.037) versus nonswitchers. Switchers had a numerically greater reduction in spleen size at 3 years than nonswitchers (-14.4% vs +15.9%; p = 0.107). Compared with nonswitchers, switchers were more likely to experience persistence or presence of new PV-related symptoms as suboptimal response before switching to ruxolitinib (p < 0.001). A greater proportion of nonswitchers required ⩾3 phlebotomies to maintain hematocrit <45% within 1 year (p < 0.001). No significant differences were observed between switchers and nonswitchers in terms of EFS, OS, time to disease progression, and rate of thrombosis. However, switchers had a significantly higher rate of disease progression to myelofibrosis than nonswitchers (p = 0.016). Conclusion:These data demonstrate the heterogeneity in patient characteristics and type of suboptimal responses between switchers and nonswitchers. The results suggest that patients who switched to ruxolitinib had more severe disease or rapid disease progression and that ruxolitinib may provide some clinical benefit in terms of spleen size reduction and hematocrit control.

BACKGROUND:Ponatinib is a third-generation tyrosine kinase inhibitor (TKI) for treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in patients who fail or are intolerant to a second generation TKI or who carry the T315I mutation. METHOD:This is the final analysis of the Belgian ponatinib registry evaluating use of ponatinib in clinical practice, with data available for up to 6 years after reimbursement. RESULT:Forty-eight percent of 54 CML and 28% of 29 Ph+ ALL patients had received ≥3 previous TKIs. Before ponatinib, most patients had already achieved a response, including at least a major molecular response (MMR), in 19% of CML and 17% of Ph+ ALL patients. Ponatinib was initiated due to intolerance to previous TKIs in 50% of CML and 41% of Ph+ ALL patients. Median follow-up was 545 and 258 days for CML and Ph+ ALL patients, respectively. Best response to ponatinib was at least an MMR in 65% of CML and 55% of Ph+ ALL patients. Overall and progression-free survival were 85.8% and 83.8% in CML patients after 48 months of treatment, and 82.5% and 54.2% in Ph+ ALL patients after 30 months of treatment. Adverse reactions were reported by 85% of CML and 76% of Ph+ ALL patients, with 33% of CML and 24% of Ph+ ALL patients experiencing cardiovascular events. CONCLUSION:In line with previously published trials, these real-world data support use of ponatinib in CML and Ph+ ALL patients with resistance or intolerance to previous TKIs or carrying the T315I mutation.Trial registration: ClinicalTrials.gov identifier: NCT03678454; September 19, 2018.

Abstract Background and Aims In the human kidney, nephron structures derive from a population of SIX2 positive kidney stem/progenitor cells. These cells are only present during kidney development, which is reported to terminate at approximately 36 weeks of gestation. We have previously described a non-invasive strategy to isolate the native SIX2 positive kidney stem/progenitor cells from the urine of neonates born before 36 weeks of gestation, named the neonatal kidney/stem progenitor cells (nKSPC) [1]. In preterm neonates, nephrogenesis is still ongoing at the time of birth and continues postnatally, enabling isolation of kidney stem/progenitor cells from the voided urine. In this study, we aimed to determine the efficiency of nKSPC isolation from the urine of neonates and which gestational age (GA) results in the highest yield of nKSPC. We hypothesized that the lower the gestational age, the higher the probability of isolating nKSPC. Method 37 fresh urine samples were obtained from 36 neonates (9 female, 27 male) at day 1 after birth at the Neonatology department of University Hospitals Leuven. Five urine samples were collected from extreme preterm (&lt; 28 weeks GA), 6 samples from very preterm (28–32 weeks GA), 18 samples from moderate to late preterm (32-37 weeks GA) and 8 samples from term neonates (&gt;37 weeks). When a sample yielded cell growth, cell colonies were subcultured to achieve clonal expansion. Cell lines were characterized for the SIX2 stem cell marker using RT-qPCR and immunofluorescence (IF) staining. SIX2 positive cell lines were further evaluated for their potential to differentiate into kidney epithelial cells (i.e. proximal tubular epithelial cells (PTEC) and podocytes) in 2D cultures using our previously established protocols [1]. Results From the 37 urine samples collected, 28 samples yielded cell growth (76%). After subcloning, 147 cell lines were characterized for the expression of SIX2, of which 42 were SIX2 positive. Four SIX2 positive cell lines were derived from extreme preterm, 12 from very preterm, 13 from moderate to late preterm and 13 from term neonates. SIX2 positive cell lines isolated from term neonates exhibited similar cells growth and differentiation potential compared to those isolated from extreme preterm neonates. Additionally, we observed a dose-response effect with regard to expression levels of SIX2 and the differentiation potential: cell lines with higher levels of SIX2 maintained their undifferentiated, uninduced state while lower levels of SIX2 enabled successful differentiation to PTEC and/or podocytes. Conclusion This study demonstrates that SIX2 positive nKSPC can be isolated from the urine of neonates, independently of their GA at birth. This could indicate that nephrogenesis persists longer than what has previously been reported (i.e. 36 weeks). Furthermore, the nKSPC exhibit a dose-response effect with regard to levels of SIX2 and induction of differentiation. This effect has previously been observed in an in vivo mice model [2]. To further investigate the timing of nephrogenesis cessation, we aim to perform a SIX2 staining on human fetal kidney tissue across different GA. Furthermore, we aim to further characterize in detail the isolated nKSPC using single cell RNA sequencing.

Background Hydroxyurea (HU) is a commonly used first-line treatment in patients with polycythemia vera (PV). However, approximately 15%-24% of PV patients report intolerance and resistance to HU.Methods This phase IV, European, real-world, observational study assessed the efficacy and safety of ruxolitinib in PV patients who were resistant and/or intolerant to HU, with a 24-month follow-up. The primary objective was to describe the profile and disease burden of PV patients.Results In the 350 enrolled patients, 70% were >60 years old. Most patients (59.4%) had received >= 1 phlebotomy in the 12 months prior to the first dose of ruxolitinib. Overall, 68.2% of patients achieved hematocrit control with 92.3% patients having hematocrit <45% and 35.4% achieved hematologic remission at month 24. 85.1% of patients had no phlebotomies during the study. Treatment-related adverse events were reported in 54.3% of patients and the most common event was anemia (22.6%). Of the 10 reported deaths, two were suspected to be study drug-related.Conclusion This study demonstrates that ruxolitinib treatment in PV maintains durable hematocrit control with a decrease in the number of phlebotomies in the majority of patients and was generally well tolerated.