CXCL8 and its cognate receptors CXCR1/CXCR2 in primary myelofibrosis.

BCR::ABL1 negative myeloproliferative neoplasms (MPN) form a distinct group of hematologic malignancies characterized by sustained proliferation of cells from multiple myeloid lineages. With a median survival of 16-35 months in patients with high-risk disease, primary myelofibrosis (PMF) is considered the most aggressive entity amongst all BCR::ABL1 MPN. Additionally, for a significant subset of patients, MPN evolve into secondary acute myeloid leukemia (AML), which has an even poorer prognosis compared to de novo AML. As the exact mechanisms of disease development and progression remain to be elucidated, current therapeutic approaches fail to prevent disease progression or transformation into secondary AML. As each MPN entity is characterized by sustained activation of various immune cells and raised cytokine concentrations within bone marrow (BM) and peripheral blood (PB), MPN may be considered to be typical inflammation-related malignancies. However, the exact role and consequences of increased cytokine concentrations within BM and PB plasma has still not been completely established. Up-regulated cytokines can stimulate cellular proliferation, or contribute to the development of an inflammation-related BM niche resulting in genotoxicity and thereby supporting mutagenesis. The neutrophil chemoattractant CXCL8 is of specific interest as its concentration is increased within PB and BM plasma of patients with PMF. Increased concentration of CXCL8 negatively correlates with overall survival. Furthermore, blockage of the CXCR1/2 axis appears to be able to reduce BM fibrosis and megakaryocyte dysmorphia in murine models. In this review, we summarize available evidence on the role of the CXCL8-CXCR1/2 axis within the pathogenesis of PMF, and discuss potential therapeutic modalities targeting either CXCL8 or its cognate receptors CXCR1/2.

Prognostic Impact of Bone Marrow Fibrosis and Effects of Tyrosine Kinase Inhibitors on Bone Marrow Fibrosis in Chronic Myeloid Leukemia.

BACKGROUND: Myelofibrosis is reported in around 40% of newly diagnosed chronic myeloid leukemia (CML) patients and have an important role in the pathobiology and prognosis of CML. This retrospective study aimed to evaluate the effects of bone marrow (BM) fibrosis on disease prognosis and the effects of specific tyrosine-kinase inhibitors (TKIs) on BM fibrosis in CML patients. METHODS: The study included 96 patients (>18 years) diagnosed with chronic phase (CP) CML. The clinical and demographic information were collected from the medical files. Post-treatment BM aspirate and core biopsy samples were analyzed for the presence of fibrosis and dysplasia. RESULTS: The mean age of the study patients was 52.69 years; 47.9% of the patients were female. At the onset, 53 (63.1%) patients had BM fibrosis. The difference in the overall survival of the patients with respect to BM fibrosis grades was significant (p = .001). Within the BM fibrosis grade groups, there were significant differences between grade 0 vs. grade 2, grade 0 vs. grade 3, and grade 1 vs. grade 3 (p = .005, p = .002, and p = .003 respectively) There was no significant association between the presence of BM fibrosis at the onset and not responding to first-line therapy (p = .724). Moreover, no significant association was found between the presence of BM fibrosis at the onset and molecular (p = .623) or cytogenetic response (p = .535) to first-line therapy. Additionally, the association between the type of second-line and third-line therapy and molecular response (p = .773 and p = .424, respectively) or cytogenetic response (p = .298 and p = .641) was not significant. CONCLUSION: Although BM fibrosis seems to be a crucial complication of CML with a poor prognosis, it can be reversed via TKI treatment which may result in improved survival. It might be considered to check the BM for this complication on a regular basis during therapies to test its prognostic influence in CML patients in prospective controlled trials. Further studies focused on this issue are required to utilize BM fibrosis as a candidate prognostic factor.

Real-world clinical characteristics of post-essential thrombocythemia and post-polycythemia vera myelofibrosis.

There are few prospective studies on patients with post-essential thrombocythemia myelofibrosis (PET-MF) and post-polycythemia vera myelofibrosis (PPV-MF). Therefore, we conducted a nationwide longitudinal prospective survey to clarify the clinical characteristics of these diseases. A total of 197 PET-MF and 117 PPV-MF patients diagnosed between 2012 and 2021 were analyzed. The median age at diagnosis was 70.0 years for both diseases. The time from diagnosis of ET or PV to that of MF was 9.6 and 10.4 years, respectively, with no significant difference. Patients with PPV-MF had higher hemoglobin levels and white blood cell counts than those with PET-MF, whereas those with PET-MF had higher platelet counts than those with PPV-MF. Although splenomegaly was more frequent in patients with PPV-MF at diagnosis, there was no difference in the frequency of constitutional symptoms. Ruxolitinib was the most common treatment administered to 74.6% and 83.8% of patients with PET-MF and PPV-MF, respectively. Patients with PET-MF and PPV-MF had similar prognoses, with 3-year overall survival (OS) of 0.742 in PET-MF and 0.768 in PPV-MF patients. In both diseases, leukemic transformation was the leading cause of death, followed by infection. The 3-year OS for patients with PET/PPV-MF and primary MF diagnosed during the same period was 0.754 and 0.626, respectively, with no significant difference. This survey provides real-world clinical features and prognostic data on secondary myelofibrosis in the ruxolitinib era.

[Research status and challenges of advanced myeloproliferative neoplasms].

Classical myeloproliferative neoplasms (MPN), also known as Ph-MPN, includes polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Secondary myelofibrosis (sMF) and secondary acute myeloid leukemia (sAML) are important disease progressions of MPN. After MPN disease progression, hematopoietic stem cells undergo new clonal evolution, leading to drug resistance, poor treatment effect and poor survival of patients. In recent years, the exploration of the mechanism of disease progression and the precise diagnosis and treatment of MPN have attracted much attention. This article summarizes the research status of MPN disease progression, including the pathogenesis, risk stratification, and precision treatment, in order to provide reference for exploring new diagnosis and treatment methods of MPN disease progression.

Fibrosis and bone marrow: understanding causation and pathobiology.

Bone marrow fibrosis represents an important structural change in the marrow that interferes with some of its normal functions. The aetiopathogenesis of fibrosis is not well established except in its primary form. The present review consolidates current understanding of marrow fibrosis. We searched PubMed without time restriction using key words: bone marrow and fibrosis as the main stem against the terms: growth factors, cytokines and chemokines, morphology, megakaryocytes and platelets, myeloproliferative disorders, myelodysplastic syndrome, collagen biosynthesis, mesenchymal stem cells, vitamins and minerals and hormones, and mechanism of tissue fibrosis. Tissue marrow fibrosis-related papers were short listed and analysed for the review. It emerged that bone marrow fibrosis is the outcome of complex interactions between growth factors, cytokines, chemokines and hormones together with their facilitators and inhibitors. Fibrogenesis is initiated by mobilisation of special immunophenotypic subsets of mesenchymal stem cells in the marrow that transform into fibroblasts. Fibrogenic stimuli may arise from neoplastic haemopoietic or non-hematopoietic cells, as well as immune cells involved in infections and inflammatory conditions. Autoimmunity is involved in a small subset of patients with marrow fibrosis. Megakaryocytes and platelets are either directly involved or are important intermediaries in stimulating mesenchymal stem cells. MMPs, TIMPs, TGF-ß, PDGRF, and basic FGF and CRCXL4 chemokines are involved in these processes. Genetic and epigenetic changes underlie many of these conditions.

Successful Outcome in Patients with Myelofibrosis Undergoing Allogeneic Donor Hematopoietic Cell Transplantation Using Reduced Doses of Post-Transplantation Cyclophosphamide: Challenges and Review of the Literature.

Engraftment and nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation (allo-HCT) depend greatly on the transplantation platform in patients with myelofibrosis (MF). We report outcomes of 14 consecutive MF patients who received reduced doses of post-transplantation cyclophosphamide (PTCy; 60 mg/kg total dose) and tacrolimus as graft-versus-host disease (GVHD) prophylaxis as part of a new standardized allo-HCT protocol. The median patient age at allo-HCT was 59 years (range, 41 to 67 years), and the median interval from diagnosis to HCT was 19 months (range, 2 to 114 months). All patients received ruxolitinib before HCT, and 71% had no response. Most patients (78%) had symptomatic splenomegaly at HCT. Eighty-six percent received reduced-intensity conditioning, and 64% underwent allo-HCT from an unrelated donor. There were no graft failures, and neutrophil and platelet recovery occurred at a median of 21 days and 31 days, respectively. The cumulative incidence of grade II-IV acute GVHD was 28.6%, and that of grade III-IV acute GVHD was 7%. The 2-year incidence of overall and moderate-severe chronic GVHD was 36% and 14%, respectively. Only 1 patient relapsed after transplantation, and NRM was 7% at 100 days and 14% at 2 years. The GVHD-free/relapse-free and immunosuppression-free incidence at 1 year was 41%. With a median follow-up for survivors of 28 months (range, 8 to 55 months), the 2-year overall survival and progression-free survival were 86% and 69%, respectively. Reduced doses of PTCy as GVHD prophylaxis for high-risk MF patients showed promising results by reducing the incidence of GVHD without any cases of graft failure.

Comparison of Pretransplantation Prediction Models for Nonrelapse Mortality in Patients with Myelofibrosis Undergoing Allogeneic Stem Cell Transplantation.

Allogeneic stem cell transplantation (alloSCT) is the only known curative treatment for myelofibrosis (MF). Risk assessment remains important for patient counseling and predicting survival outcomes for relapse and nonrelapse mortality (NRM). Outcome-prediction tools can guide decision-making. Their use in MF has relied on their extrapolation from other malignancies. The primary objective of this study was to assess the performance of the Hematopoietic cell Transplantation Comorbidity Index (HCT-CI), the augmented HCT-CI (aHCT-CI), and the Endothelial Activation and Stress Index (EASIX) in predicting NRM in patients with MF undergoing alloSCT. We retrospectively reviewed patients with MF undergoing alloSCT between 2012 and 2020 at the Mayo Clinic. Data were abstracted from the electronic medical record. EASIX score was calculated before starting conditioning therapy and analyzed based on log2- transformed values. We evaluated the log2-EASIX scores by quartiles to assess the effect of increasing values on NRM. NRM was evaluated using competing risk analyses. We used the Kaplan-Meier and log-rank methods to evaluate OS. The Fine-Gray model was used to determine risk factors for NRM. The performance of HCT-CI and aHCT-CI was compared by evaluation of model concordance given the high correlation between HCT-CI and aHCT-CI (r = .75). A total of 87 patients were evaluated. The median duration of follow-up after alloSCT was 5 years (95% confidence interval [CI], 4.4 to 6.31 years). Patients with a high HCT-CI score had significantly increased cumulative incidence of NRM at 3 years (35.5% versus 11.6%; P = .011) after alloSCT. A progressively increasing 3-year NRM was observed with increasing aHCT-CI risk category, and patients with a high or very high aHCT-CI score had significantly higher 3-year NRM compared to those with intermediate-risk or low-risk aHCT-CI scores at 3 years post-alloSCT (31.9% versus 6.52%; P = .004). An increasing log2-EASIX score quartile was not associated with 3-year NRM (19.0% versus 10.1% versus 25% versus 14.3%; P = .59), and the EASIX score was not found to be a predictor of post-transplantation NRM. A high HCT-CI was associated with significantly worse 3-year overall survival (OS) (hazard ratio [HR], 4.41; 95% CI, 1.97 to 9.87; P < .001). A high or very high aHCT-CI was significantly associated with poor 3-year OS (HR, 3.99; 95% CI, 1.56 to 10.22; P = .004). An increasing log2-EASIX score quartile group was not associated with 3-year OS (3-year OS rate, 66.7% versus 80.4% versus 64.6% versus 76.2%; P = .57). The EASIX score should not be used routinely in patients with MF. Both the HCT-CI and the aHCT-CI are accurate in predicting long-term survival outcomes in this patient population. Further studies are important to validate our findings of the role of EASIX in predicting NRM in patients with MF or other myeloproliferative neoplasms undergoing alloSCT. © 2023 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

New Treatments for Myelofibrosis.

OPINION STATEMENT: Currently approved therapies for myelofibrosis (MF) consist of JAK inhibitors, which produce meaningful improvements in spleen size and symptom burden but do not significantly impact leukemic progression. In addition, many patients develop resistance or intolerance to existing therapies and are left without meaningful therapeutic options. There has been recent rapid development of agents in MF that may be able to fill these unmet needs. Importantly, most treatments currently in clinical development have targets outside the JAK-STAT pathway, including BET, BCL-2/BCL-xL, PI3k, HDM2, PIM-1, SINE, telomerase, LSD1, and CD123. These therapies are being tested in combination with JAK inhibitors in the front-line setting and in patients with a suboptimal response, as well as a single agent after JAK inhibitor failure. This next generation of agents is likely to produce a paradigm shift in MF treatment with a focus on combination treatment targeting multiple areas of MF pathophysiology.

Transplantation algorithm for myelofibrosis in 2022 and beyond.

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm with a very heterogenous clinical course. Median survival of patients with overt MF is close to 6 years, but with great individual variability. Allogeneic hematopoietic cell transplantation (allo-HCT) constitutes the only curative treatment, yet the advanced age of MF patients, together with significant transplant-related mortality, limit the applicability of this procedure in clinical practice to less than 10% of patients. In this article, we review the current indications for allo-HCT in MF and factors that should be considered when selecting candidates for the procedure. To this end, we describe the prognostic tools that have been developed to predict survival in MF patients managed with conventional pharmacological therapies and allo-HCT. We then summarize the main results of allo-HCT, review practical aspects of the procedure, and discuss optimal timing, particularly in relation to JAK inhibitor treatment.

Contemporary and future strategies in polycythemia vera.

Polycythemia vera (PV) is characterized by clonal proliferation of a hematopoietic stem cell leading to erythrocytosis. Patients with PV have significantly higher morbidity and mortality compared to the general population due to increased risk of thrombosis, hemorrhage, and well-characterized microvascular and constitutional symptoms. There is also a propensity to transform to myelofibrosis and to an aggressive form of acute leukemia, further increasing morbidity and mortality. Current management is aimed at reducing the risk of thromboembolic events and improving symptom burden; however, none of the existing therapies have proven the ability to deplete the underlying malignant clone, or definitively reduce the risk of disease, progression leaving a large area of unmet need. In this review, we highlight the pathophysiology of PV, current management and limitations therein. We propose highly debated clinical practices that require further investigation. We conclude by discussing therapies in development and how these may fill unmet needs and be incorporated into the future PV treatment paradigm.

Prediction of thrombosis in post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a study on 1258 patients.

Patients with Philadelphia-negative myeloproliferative neoplasms are at high risk of thrombotic events (TEs). Predisposing factors have been identified in essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (primary MF, PMF), while yet not recognized in post PV/ET-MF (known as secondary MF, SMF). Within the 1258 SMF of the MYSEC (MYelofibrosis SECondary to PV and ET) dataset, 135 (10.7%) developed a TE at a median follow-up of 3.5 years (range, 1-21.4), with an incidence of 2.3% patients per year. Venous events accounted for two-thirds of the total. Cox multivariable analysis, supported by Fine-Gray models with death as competitive risk, showed that being on cytoreductive therapy at time of SMF evolution is associated with an absolute risk reduction of thrombosis equal to 3.3% within 3 years. Considering individually cytoreductive therapies, univariate regression model found that both conventional cytoreduction, mainly hydroxyurea, (HR 0.41, 95% CI: 0.26-0.65, p = 0.0001) and JAK inhibitors, mostly ruxolitinib, (HR 0.50, 95% CI: 0.24-1.02, p = 0.05) were associated with fewer thrombosis. Our study informs treating physicians of a non-low incidence of TEs in post PV/ET-MF and of the potential protective role of cytoreductive therapy in terms of thrombotic events.

Eltrombopag may induce bone marrow fibrosis in allogeneic hematopoietic stem cell transplant recipients with prolonged thrombocytopenia.

Poor graft function (PGF) and secondary failure of platelet recovery (SFPR) are significant causes of transplant related morbidity and mortality. Although thrombopoietin receptor agonists (TPO-RA), particularly Eltrombopag (EPAG), have been reported to be efficacious in the treatment of prolonged thrombocytopenia, potential long term adverse effects remain to be elucidated. This retrospective study was performed to determine the efficacy and toxicity profile of TPO-RAs in allogeneic hematopoietic stem cell transplant (alloHCT) recipients. Medical records of 27 patients [median age: 55(21-73) years; male/female: 15/12] who received posttransplant EPAG for SFPR or PGF were analysed. Eltrombopag was started on day 110(33-670) after transplant. Median initial dose was 25(25-50) mg/day which was properly escalated to a maximum dose of 75(50-100) mg/day. Duration of the treatment was median 120(31-377) days. Overall response rate (ORR) was 59.3% in the study population. Time-to-treatment response was 42(3-170) days. Mild-to-moderate bone marrow fibrosis was detected in the posttreatment biopsies of 12/22 patients (54.5%), 9 of whom did not represent any grade of myelofibrosis in their inital biopsies. The grade of posttreatment fibrosis was significantly increased when time-to-treatment response was longer (p = 0.008). Long term use of TPO-RAs may be considered as a potential cause of myelofibrosis in alloHCT recipients.

Presence of bone marrow fibrosis in multiple myeloma may predict extramedullary disease.

We analyzed the incidence of bone marrow fibrosis in 91 newly diagnosed Japanese multiple myeloma (MM) patients and evaluated the impact of fibrosis on clinical characteristics and therapeutic outcomes. Thirty-four (37%) patients had greater than grade 1 bone marrow fibrosis. The presence of bone marrow fibrosis did not affect laboratory data, the percentage of plasma cells in bone marrow or cytogenetic findings. It also had no significant effect on response to initial treatment, engraftment after autologous hematopoietic stem cell transplantation or overall survival. Interestingly, the incidence of extramedullary disease at diagnosis was significantly higher in patients with bone marrow fibrosis (p = 0.006). Analysis of biological characteristics of MM cells revealed that expression of CD49e, an alpha5/beta1 integrin, was downregulated in MM cells derived from patients with bone marrow fibrosis (p = 0.026). When seven of the original 34 patients were re-evaluated for fibrosis grading after treatment, five (71%) showed a reduction in fibrosis. Our present findings suggest that the presence of bone marrow fibrosis may predict development of extramedullary disease in MM.

The odyssey of pacritinib in myelofibrosis.

Myelofibrosis (MF) can present with symptomatic splenomegaly and/or cytopenias including thrombocytopenia. Disease-related thrombocytopenia is a poor prognostic factor with a median overall survival of less than 2 years. Currently approved JAK1/2 inhibitors have not been evaluated in patients with platelets ≤ 50 × 109/L and in fact could potentiate thrombocytopenia because of their combined JAK1/2 inhibitory activity. Pacritinib (PAC), a selective JAK2, fms-like tyrosine kinase 3, interleukin-1 receptor-associated kinase 1 multikinase inhibitor was developed to meet this unmet need. PAC was evaluated in 2 randomized phase 3 trials in the frontline setting (PERSIST-1, PAC 400 mg daily vs best available therapy) and second-line setting in patients with MF with platelets ≤ 100 × 109/L (PERSIST-2, PAC 400 mg daily or 200 mg twice daily vs best available therapy). PERSIST-1 met its primary end point; however, the development of PAC hit a brief pause because of a US Food and Drug Administration-mandated clinical hold for excess of bleeding and cardiac events in the PAC 400 mg daily arm in the PERSIST-1 study. Although the PERSIST-2 study was terminated abruptly because of this clinical hold, it met its splenic response end point and demonstrated a trend toward symptom improvement. Subsequent, diligent review of the PERSIST-1 and PERSIST-2 studies did not confirm an excess of severe bleeding or cardiac events on the PAC arm. Additionally, the dose finding PAC203 study endorsed the safety and efficacy of 200 mg twice daily, leading to the approval of PAC for the treatment of patients with MF with platelets ≤ 50 × 109/L.

Ruxolitinib combined with prednisone, thalidomide and danazol in patients with myelofibrosis: Results of a pilot study.

Ruxolitinib is a safe and effective therapy of myeloproliferative neoplasm-associated (MPN) myelofibrosis. However, often there are dose reductions and/or therapy interruptions because of therapy-related adverse events (AEs), especially anemia and thrombocytopenia. We previously reported combined therapy with prednisone, thalidomide and danazol (PTD) reversed anemia and thrombocytopenia in people with MPN-associated myelofibrosis. We wondered whether adding PTD to ruxolitinib might mitigate the hematologic AEs and thereby avoid the dose reduction of ruxolitinib and improve the efficacy. To test this hypothesis, we conducted a baseline hemoglobin and platelet concentration assignment prospective observational study in 72 patients comparing 3-month dose adjustment and efficacy of ruxolitinib with (N = 53, the study group) or without (N = 19, the control group) PTD. According to the platelet counts, the median daily ruxolitinib doses in the study group increased from 30 to 40 mg by week 12, whereas in the control group it remained at 30 mg (p = 0.019). In the study group 35 patients had a hemoglobin increase ≥10 g/L compared with no patient receiving ruxolitinib only (p < 0.001). Platelet increases >100 × 10E+9/L were seen in 56.6% and 5.3% of patients in the two groups, respectively (p < 0.001). In patients with anemia and thrombocytopenia, 18 patients in the study group had an anemia response at week 12 and 12 had a platelet increase of ≥50 × 10E+9/L. No patient in the control group achieved either response (p < 0.001 and p = 0.078). The study group had a more spleen response than the control group (p = 0.046). Peripheral edema and transaminase elevation were the main nonhematologic AEs of PTD. These AEs can be alleviated by adjusting the danazol dose. In conclusion, adding PTD to ruxolitinib improved ruxolitinib-associated anemia and thrombocytopenia, and resulted in a higher ruxolitinib dose.

Updated recommendations on the use of ruxolitinib for the treatment of myelofibrosis.

OBJECTIVES: Myelofibrosis is a rare bone marrow disorder associated with a high symptom burden, poor prognosis, and shortened survival. While allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for myelofibrosis, the only approved and reimbursed pharmacotherapy for non-HSCT candidates in Belgium is ruxolitinib. METHODS: These updated recommendations are based on a consensus reached during two meetings and provide guidance for ruxolitinib administration in myelofibrosis patients considering the particularities of Belgian reimbursement criteria. RESULTS AND DISCUSSION: In Belgium, ruxolitinib is indicated and reimbursed for transplant-ineligible myelofibrosis patients from intermediate-2- and high-risk groups and from the intermediate-1-risk group with splenomegaly. Our recommendation is to also make ruxolitinib available in the pre-transplant setting for myelofibrosis patients with splenomegaly or heavy symptom burden. Before ruxolitinib initiation, complete blood cell counts are recommended, and the decision on the optimal dosage should be based on platelet count and clinical parameters. In anemic patients, we recommend starting doses of ruxolitinib of 10 mg twice daily for 12 weeks and we propose the use of erythropoiesis-stimulating agents in patients with endogenous erythropoietin levels ≤500 mU/mL. Increased vigilance for opportunistic infections and second primary malignancies is needed in ruxolitinib-treated myelofibrosis patients. Ruxolitinib treatment should be continued as long as there is clinical benefit (reduced splenomegaly or symptoms), and we recommend progressive dose tapering when stopping ruxolitinib. CONCLUSION: Based on new data and clinical experience, the panel of experts discussed ruxolitinib treatment in Belgian myelofibrosis patients with a focus on dose optimization/monitoring, adverse events, and interruption/rechallenge management.

Novel therapeutics and targets in myelofibrosis.

Myelofibrosis is a myeloproliferative neoplasm characterized by clonal proliferation of myeloid cells, bone marrow fibrosis and cytopenias, extramedullary hematopoiesis and hepatosplenomegaly, increased pro-inflammatory cytokine production, and systemic symptoms. Patients with MF also have a propensity toward leukemic transformation. Allogeneic hematopoietic stem cell transplantation (aHCT) is the only curative therapy for patients with MF; however, transplant-related morbidity and mortality precludes this option for the majority of patients. In the last decade, two targeted therapies have been approved for the treatment of MF, both JAK2 inhibitors, ruxolitinib and fedratinib. Despite the clinical efficacy of these two compounds in terms of splenomegaly and symptom burden reduction, there remain many areas of unmet need in the treatment of myelofibrosis. In this review, we discuss the limitations of currently approved treatment options and novel therapeutic targets with drug candidates in late-stage (phase II or III) clinical development for the treatment of MF. We delve into the mechanism of action and scientific rational of each candidate agent as well as the available clinical data, and ongoing trials that could lead to the approval of some of these novel therapies.