Treatment of myelofibrosis with refractory anemia with luspatercept: a multicenter Chinese study.

Myelofibrosis is a rare and often fatal hematological neoplasm, and the treatment of myelofibrosis-associated anemia remains suboptimal, with no improved therapies. Luspatercept was shown to display some efficacy in a phase 2 clinical trial for Myelofibrosis with anemia, yet relevant research are limited. Threrfore, data from patients diagnosed with refractory anemic primary or post-essential thrombocythemia/polycythemia vera myelofibrosis, who were treated with luspatercept for at least 9 weeks, were retrospectively collected. Eighteen patients with myelofibrosis treated with luspatercept were enrolled. Median age was 68 years (range, 44-80 years), and 27.8% were males. Ten (55.6%) were transfusion-dependent. Ten (55.6%) were Dynamic International Prognostic Scoring System intermediate-1, and eight (44.4%) were intermediate-2. The median follow-up was 7 (4-16) months. Erythroid response occurred in eight patients (44.4%) at week 12, four patients (30.8%) at week 24, and nine (50%) at the end of follow-up. Patients who were transfusion-dependent and not transfusion-dependent had similar HI-E responses, at different time points (P > 0.05). Patients had a significantly higher hemoglobin level at 12 weeks, 24 weeks, and at the end of follow-up, than at baseline (P = 0.001, P = 0.021, and P = 0.005, respectively). Treatment-related adverse events occurred in five (16.7%) patients, with no serious adverse events. Two (11.1%) patients relapsed at weeks 15 and 31. One patient progressed to acute myeloid leukemia. No patients had died by the end of follow-up. Luspatercept induced a good response in patients with anemic myelofibrosis, with a low relapse rate and good tolerance.

Management of luspatercept therapy in patients with transfusion-dependent ß-thalassaemia.

Patients with transfusion-dependent ß-thalassaemia require lifelong, regular red blood cell transfusions for survival; however, frequent blood transfusions are associated with an increased risk of iron overload, transfusion-transmitted disease and alloimmunization, as well as reduced quality of life. Luspatercept, an erythroid maturation agent that promotes late-stage erythroid maturation independently of erythropoietin, has demonstrated efficacy in reducing transfusion burden in patients with transfusion-dependent ß-thalassaemia. In this review, we discuss treatment initiation, ongoing evaluation, dose adjustment and management of adverse events in transfusion-dependent patients with ß-thalassaemia receiving luspatercept, and we provide guidance on how to determine whether patients are deriving clinical benefit.

Myelodysplastic syndromes with ring sideroblasts.

Myelodysplastic syndromes (MDS) are acquired bone marrow malignant disorders characterized by ineffective hematopoiesis, resulting from a complex interaction between genetic and epigenetic mutations, alterations of the marrow microenvironment, and the immune system. In 2001, the World Health Organization (WHO) proposed a classification that integrates morphologic and genetic information, considering the MDS with ring sideroblasts (MDS-RS) as a distinct entity. Considering the strong association between MDS-RS and SF3B1 mutation and its importance in the development of MDS, the last WHO classification replaced the prior entity of MDS-RS with MDS with SF3B1 mutation. Several studies were performed to explore this genotype-phenotype correlation. Mutant SF3B1 protein deregulates the expression of genes implicated in developing hematopoietic stem and progenitor cells. Of paramount importance are PPOX and ABCB7 involved in iron metabolism. Another essential role in hemopoiesis is played by the transforming growth factor-beta (TGF-ß) receptor. This gene exerts its effects on SMAD pathways, regulating hematopoiesis through effects on balancing proliferation and apoptosis cell inactivity, differentiation, and migration. Luspatercept (ACE-536) is a soluble fusion protein that inhibits molecules in the TGF-ß superfamily. Since its structure resembles the TGF-ß family receptor, it catches TGF-ß superfamily ligands before binding to the receptor, resulting in reduced activation of SMAD signaling, thus enabling erythroid maturation. Luspatercept was investigated in the phase III trial MEDALIST, showing promising efficacy in treating anemia compared to placebo. Nowadays, further studies are needed to explore the real potential of luspatercept, investigating the biological features likely associated with treatment response, the potential use in combination treatments, and its role in the treatment of naïve MDS.

Treatment of refractory or relapsed myelodysplastic neoplasms with luspatercept: a multicenter Chinese study.

Few effective therapies are available to treat patients with relapsed/refractory myelodysplastic neoplasms (MDS). Luspatercept was shown to display good efficacy in a phase 3 clinical trial for lower-risk MDS (LR-MDS) patients, yet real-world data are limited, especially in China. Therefore, data from patients diagnosed as having MDS with low blasts and SF3B1 mutation (MDS-SF3B1) and MDS with SF3B1 mutation and thrombocytosis were retrospectively analyzed. Of the 23 enrolled patients, 17 (73.9%) were males (median age 67 years: range 29 to 80 years). Previously, a total of 22 (95.7%) patients had received recombinant human erythropoietin (rhEPO), 9 (39.1%) roxadustat, 7 (30.4%) lenalidomide and 3 (13.0%) hypomethylating agents (HMA). The median treatment time was 22.9 weeks (9.0-32.4). At week 12, 60.9% (14/23) of the patients achieved a hematologic improvement-erythroid (HI-E) response. Red blood cell transfusion independence (RBC-TI) for ≥ 8 weeks was found in 57.1% (8/14) of transfusion-dependent patients. The median hemoglobin concentration was 84 g/L, and patients had significantly higher hemoglobin concentrations after 12 weeks of treatment (P < 0.001). It is noteworthy that responders had a greater reduction in serum ferritin (P = 0.021). Those with serum EPO < 500 IU/L at baseline tended to have a higher HI-E rate (P = 0.081), but only patients in non-transfusion and low transfusion burden (LTB) subgroups had statistical differences (P = 0.024). The most commonly occurring adverse events were blood bilirubin increase (17.4%), fatigue (13.0%) and dizziness (13.0%). Luspatercept was effective and tolerated well in refractory LR-MDS-SF3B1 patients. In particular, baseline non-transfusion and LTB patients exhibited a greater response rate to treatment.

Improved benefit of continuing luspatercept therapy: sub-analysis of patients with lower-risk MDS in the MEDALIST study.

Red blood cell transfusion independence (RBC-TI) is an important goal in treating lower-risk myelodysplastic syndromes with ring sideroblasts. In the phase 3 MEDALIST study, RBC-TI of ≥ 8 weeks was achieved by significantly more luspatercept- versus placebo-treated patients in the first 24 weeks of treatment. In this post hoc analysis, we evaluated RBC transfusion units and visits based on patients' baseline transfusion burden level and the clinical benefit of luspatercept treatment beyond week 25 in initial luspatercept nonresponders (patients who did not achieve RBC-TI ≥ 8 weeks by week 25) but continued luspatercept up to 144 weeks. RBC transfusion burden, erythroid response, serum ferritin levels, and hemoglobin levels relative to baseline were evaluated. Through week 25, fewer RBC transfusion units and visits were observed in luspatercept-treated patients versus placebo, regardless of baseline transfusion burden. This continued through 144 weeks of luspatercept treatment, particularly in patients with low baseline transfusion burden. Sixty-eight patients were initial nonresponders at week 25 but continued treatment; most (81%) received the maximum dose of luspatercept (1.75 mg/kg). Sixteen percent achieved RBC-TI for ≥ 8 weeks during weeks 25-48, 26% had reduced RBC transfusion burden, 10% achieved an erythroid response, 44% had reduced serum ferritin, and hemoglobin levels increased an average of 1.3 g/dL from baseline. These data have implications for clinical practice, as transfusion units and visits are less in luspatercept-treated patients through week 25 regardless of baseline transfusion burden, and continuing luspatercept beyond week 25 can potentially provide additional clinical benefits for initial nonresponders. Trial registration: NCT02631070.

Luspatercept in combination with recombinant erythropoietin in patients with myelodysplastic syndrome with ring sideroblasts: Stimulating early and late-stage erythropoiesis.

Patients with myelodysplastic syndromes and ring sideroblasts (MDS RS) are clinically characterized by severe anemia and transfusion need. Erythropoiesis-stimulating agents (ESAs), which stimulate hemoglobin production and early maturation of erythroid precursors, are effective only in a portion of patients and for limited time. Luspatercept, an inhibitor of the TGF-beta pathway, is beneficial in unblocking late-stage erythropoiesis and has been approved for MDS RS patients failing or not-candidate to ESAs. ESAs and/or luspatercept failure represents an unmet clinical need and most patients become life-long transfusion dependent. Here, we describe the clinical combination of luspatercept with ESAs (subcutaneous epoetin alpha 40-80 000 IU/week) in seven MDS RS patients. Two patients had ESAs as pre-existing therapy, while five were re-challenged with ESAs as add-on treatment due to luspatercept failure. Three patients achieved hematologic improvement, and one became transfusion independent. No adverse events were noted. This is the first clinical evidence that stimulating both early and late-stage erythropoiesis may offer a further option for this challenging patient population.

Current Therapeutic Landscape in Lower Risk Myelodysplastic Syndromes.

OPINION STATEMENT: Lower risk myelodysplastic syndromes are typically characterized by an indolent disease course with a relatively low risk of transformation into acute myeloid leukemia. These patients are classically identified using the revised International Prognostic Scoring System and most likely its molecular version in the near future which may change the paradigm of treatment. The overall goals of care are symptomatic control to reduce transfusion requirements and improve quality of life. Symptomatic anemia is the most common indication to initiate disease-specific therapies after the optimization of supportive measures. Currently, erythropoiesis-stimulating agents remain the standard upfront therapy for anemia, and patients with del(5q) cytogenetic changes can benefit from lenalidomide monotherapy. Other therapeutic options after failure of upfront treatment include luspatercept, hypomethylating agents, and immunosuppressive therapies after taking into account of individualized disease features. Allogeneic hematopoietic stem cell transplant is the only potentially curative option and is usually reserved for medically fit patients with severe symptomatic cytopenias who failed all standard options and/or the disease is progressing toward higher risk categories. Fortunately, novel investigational therapies are rapidly emerging by targeting different biological processes contributing to MDS pathogenesis, and eligible patients should be managed in clinical trials if available.

Therapeutic perspective for children and young adults living with thalassemia and sickle cell disease.

Hemoglobinopathies, including thalassemias and sickle cell disease, are the most common monogenic diseases worldwide, with estimated annual births of more than 330,000 affected infants. Hemoglobin disorders account for about 3.4% of deaths in children under 5 years of age. The distribution of these diseases is historically linked to current or previously malaria-endemic regions; however, immigration has led to a worldwide distribution of these diseases, making them a global health problem. During the last decade, new treatment approaches and novel therapies have been proposed, some of which have the potential to change the natural history of these disorders. Indeed, the first erythroid maturation agent, luspatercept, and gene therapy have been approved for beta-thalassemia adult patients. For sickle cell disease, molecules targeting vaso-occlusion and hemoglobin S polymerization include crizanlizumab, which has been approved for patients ≥ 16 years, voxelotor approved for patients ≥ 12 years, and L-glutamine for patients older than 5 years.    Conclusion: We herein present the most recent advances and future perspectives in thalassemia and sickle cell disease treatment, including new drugs, gene therapy, and gene editing, and the current clinical trial status in the pediatric populations. What is Known: • Red blood cell transfusions, iron chelation therapy and hematopoietic stem cell transplantation have been the mainstay of treatment of thalassemia patients for decades. • For sickle cell disease, until 2005, treatment strategies were mostly the same as those for thalassemia, with the option of simple transfusion or exchange transfusion. In 2007, hydroxyurea was approved for patients ≥ 2 years old. What is New: • In 2019, gene therapy with betibeglogene autotemcel (LentiGlobin BB305) was approved for TDT patients ≥ 12 years old non ß0/ß0 without matched sibling donor. • Starting from 2017 several new drugs, such as L-glutamine (approved only by FDA), crizanlizumab (approved by FDA and EMA for patients ≥ 16 years), and lastly voxelotor (approved by FDA and EMA for patients ≥ 12 years old).

Real world practices of luspatercept at an academic medical center.

Introduction: Luspatercept is approved for patients with very low-to intermediate-risk myelodysplastic syndrome (MDS). Dosing is based on pre-dose hemoglobin levels and transfusion requirements. This study aims to evaluate if a site with a pharmacist prospectively reviewing luspatercept doses achieves dose optimization, compared to a site that does not have a pharmacist prospectively reviewing doses. Methods: We performed a retrospective chart review involving patients age ≥18 years or older with MDS at a major academic medical center main campus, which does not have a pharmacist prospectively review luspatercept doses, and a satellite campus infusion center, which has a pharmacist prospectively reviewing doses. Patients included received at least one dose of luspatercept between January 1, 2017 through August 31, 2022. The primary endpoint is the percentage of off-label luspatercept doses not consistent with prescribing information (PI) recommended dose adjustments. Results: The study included 17 patients. Of the 162 doses evaluated, 37 (23%) were off-label. Off-label dosing at the main campus was more common than at a satellite location (29.6% vs. 2.4%; p < 0.003). More patients achieved transfusion independence at the satellite compared to the main campus (83.3% vs. 27.3% p < 0.39). Conclusions: There was a higher percentage of off-label dosing at a center without a pharmacist's prospective review vs. a center with a pharmacist's prospective review. On-label dose optimization may lead to a higher percentage of patients achieving transfusion independence. Enhancements in the current ordering and review process can be improved with the involvement of a pharmacist's prospective involvement at both centers.

Luspatercept (RAP-536) modulates oxidative stress without affecting mutation burden in myelodysplastic syndromes.

In low-risk myelodysplastic syndrome (LR-MDS), erythropoietin (EPO) is widely used for the treatment of chronic anemia. However, initial response to EPO has time-limited effects. Luspatercept reduces red blood cell transfusion dependence in LR-MDS patients. Here, we investigated the molecular action of luspatercept (RAP-536) in an in vitro model of erythroid differentiation of MDS, and also in a in vivo PDX murine model with primary samples of MDS patients carrying or not SF3B1 mutation. In our in vitro model, RAP-536 promotes erythroid proliferation by increasing the number of cycling cells without any impact on apoptosis rates. RAP-536 promoted late erythroid precursor maturation while decreasing intracellular reactive oxygen species level. RNA sequencing of erythroid progenitors obtained under RAP-536 treatment showed an enrichment of genes implicated in positive regulation of response to oxidative stress and erythroid differentiation. In our PDX model, RAP-536 induces a higher hemoglobin level. RAP-536 did not modify variant allele frequencies in vitro and did not have any effect against leukemic burden in our PDX model. These results suggest that RAP-536 promotes in vivo and in vitro erythroid cell differentiation by decreasing ROS level without any remarkable impact on iron homeostasis and on mutated allele burden.

Luspatercept, a two-edged sword in beta-thalassemia-associated paravertebral extramedullary hematopoietic masses (EHMs).

Paravertebral extramedullary hematopoietic masses (EHMs) account for up to 15% of extramedullary pseudotumors in beta-thalassemia (BT) and are most likely related to compensatory hematopoiesis. In most cases, pseudotumors are incidentally detected, as the majority of patients are asymptomatic. Since June 2020, luspatercept is approved for the treatment of patients with BT who require regular red blood cell transfusions. Data addressing the safety and efficacy of luspatercept in patients with BT-associated EHMs are pending. To date (May 2022), paravertebral EHMs were observed in two asymptomatic patients out of currently 43 adult patients with BT registered at the Adult Hemoglobinopathy Outpatient Unit of the University Hospital Essen, Germany. In one of them, a paravertebral EHM was diagnosed more than 10 years prior to referral. Throughout observation time, treatment with luspatercept was associated with a clinically significant reduction in transfusion burden while allowing to maintain a baseline hemoglobin concentration of ≥10 g/dL aiming to suppress endogenous (ineffective) erythropoiesis associated with BT. Considering the rarity of paravertebral EHMs in BT, luspatercept might potentially represent a novel therapeutic option for these often-serious disease-associated complications. However, appropriate follow-up investigations are recommended to detect (early) treatment failures secondary to an undesired luspatercept-associated erythroid expansion.

Emerging drugs for the treatment of myelofibrosis: phase II & III clinical trials.

INTRODUCTION: Myelofibrosis is a clonal hematologic malignancy with clinical manifestations that include cytopenias, debilitating constitutional symptoms, splenomegaly, bone marrow fibrosis and a propensity toward leukemic progression. While allogeneic hematopoietic stem cell transplantation can be curative, this therapy is not available for the majority of patients. Ruxolitinib and fedratinib are approved JAK2 inhibitors that have produced meaningful benefits in terms of spleen reduction and symptom improvement, but there remain several unmet needs. AREAS COVERED: We discuss novel therapies based upon published data from phase II or III clinical trials. Specifically, we cover novel JAK inhibitors (momelotinib and pacritinib), and agents that target bromodomain and extra-terminal domain (pelabresib), the antiapoptotic proteins BCL-2/BCL-xL (navitoclax), MDM2 (navtemadlin), phosphatidylinositol 3-kinase (parsaclisib), or telomerase (imetelstat). EXPERT OPINION: Patients with disease related cytopenias are ineligible for currently approved JAK2 inhibitors. However, momelotinib and pacritinib may be able to fill this void. Novel therapies are being evaluated in the upfront setting to improve the depth and duration of responses with ruxolitinib. Future evaluation of agents must be judged on their potential to modify disease progression, which current JAK2 inhibitors lack. Combination therapy, possibly with an immunotherapeutic agent might serve as key components of future myelofibrosis treatment options.

Luspatercept in the treatment of lower-risk myelodysplastic syndromes.

Transforming growth factor beta (TGF-ß) signaling pathway is key to hematopoiesis regulation. Increased activation of this pathway contributes to ineffective terminal erythroid differentiation in myelodysplastic syndromes (MDS). Luspatercept is a novel fusion protein that traps TGF-ß ligands preventing them from binding to Type II TGF-ß receptors, thereby decreasing phosphorylated SMAD2/3 resulting in the downstream effect of promoting erythropoiesis. Seminal clinical trials using luspatercept, PACE-MD and MEDALIST, demonstrated impressive efficacy in the treatment of transfusion-dependent anemia in intermediate risk or lower MDS had led to the US FDA approval for this indication. This review summarizes luspatercept mechanisms of action, efficacy/safety data supporting its use and ongoing clinical trials in MDS.

Novel agents for myelodysplastic syndromes.

REVIEW OBJECTIVE: There have been several advances in the field of myelodysplastic syndromes over the past year, yielding two new US Food and Drug Administration drug approvals. The pharmacology, pharmacokinetics, clinical trials, therapeutic use, adverse effects, clinical use controversies, product description, and upcoming trials for myelodysplastic syndromes novel agents luspatercept-aamt and decitabine/cedazuridine are reviewed. DATA SOURCES: This review article utilized primary information obtained from both the published studies involved in the approval of luspatercept-aamt and decitabine/cedazuridine and package inserts for the respective medications. This review article utilized secondary information obtained from National Comprehensive Cancer Network guidelines using filters and keywords to sustain information relevancy as well as key studies using the keywords, "luspatercept-aamt, myelodysplastic syndromes, decitabine, cedazuridine, hypomethylating agent, ASTX727" from scholarly journal database PubMed. DATA SUMMARY: Myelodysplastic syndromes consist of myeloid clonal hemopathies with a diverse range of presentation. Until recently, there have been relatively few new therapies in the myelodysplastic syndromes treatment landscape. On April 3, 2020 the US Food and Drug Administration approved Reblozyl®(luspatercept-aamt), then on July 7, 2020, the US Food and Drug Administration approved INQOVI® (decitabine and cedazuridine). Luspatercept-aamt acts as a erythroid maturation agent through differentiation of late-stage erythroid precursors. The safety and efficacy of luspatercept-aamt was demonstrated in the MEDALIST trial, a phase III trial in patients with very low-intermediate risk refractory myelodysplastic syndromes and ring sideroblasts. Luspatercept-aamt met both primary and secondary endpoints of transfusion independence of 8 weeks or longer and transfusion independence of 12 weeks or longer, respectively. Decitabine/cedazuridine has a unique mechanism of action in which decitabine acts as a nucleoside metabolic inhibitor promoting DNA hypomethylation and cedazuridine then prevents degradation of decitabine. The safety and efficacy of decitabine/cedazuridine was shown in the ASCERTAIN study, a phase III trial in patients with intermediate or high risk myelodysplastic syndromes or chronic myelomonocytic leukemia. The primary outcome evaluated was 5-day cumulative area under the curve between decitabine/cedazuridine and IV decitabine as well as additional outcomes including safety. Decitabine/cedazuridine met primary outcome and had a similar safety profile to IV decitabine. CONCLUSION: The novel myelodysplastic syndromes agents luspatercept-aamt and decitabine/cedazuridine provide a clinical benefit in the studied populations.

[Thalassemia in Japan].

Thalassemia is caused by a reduced production of one globin chain due to a quantitative imbalance between the α-globin and non-α-globin chains that make up the hemoglobin. It is classified into α- and ß-thalassemia and characterized by microcytosis with polycythemia, and a Mentzer index of ≤13 aids in the diagnosis. In the genetic analysis of α-thalassemia, the Southeast Asian type was found to be the most common genetic subtype among Japanese and non-Japanese without a substantial difference. Conversely, the genetic analysis of ß-thalassemia revealed differences in the types and frequencies of mutations between Japanese individuals and foreigners living in Japan, with Japanese-specific mutations such as -31 A→G (TATA box). Acquired α-thalassemia exists in exceptional cases, and cases of myelodysplastic syndrome with acquired Hemoglobin H disease have been reported as α-thalassemia myelodysplastic syndrome. Recent trials using a novel therapeutic agent, luspatercept, for transfusion-dependent ß-thalassemia revealed that luspatercept safely and significantly reduces the transfusion volume.

Illuminating novel biological aspects and potential new therapeutic approaches for chronic myeloproliferative malignancies.

This review reflects the presentations and discussion at the 14th post-American Society of Hematology (ASH) International Workshop on Chronic Myeloproliferative Malignancies, which took place on the December 10 and 11, 2019, immediately after the 61st ASH Annual Meeting in Orlando, Florida. Rather than present a resume of the proceedings, we address some of the topical translational science research and clinically relevant topics in detail. We consider how recent studies using single-cell genomics and other molecular methods reveal novel aspects of hematopoiesis which in turn raise the possibility of new therapeutic approaches for patients with myeloproliferative neoplasms (MPNs). We discuss how alternative therapies could benefit patients with chronic myeloid leukemia who develop BCR-ABL1 mutant subclones following ABL1-tyrosine kinase inhibitor therapy. In MPNs, we focus on efforts beyond JAK-STAT and the merits of integrating activin receptor ligand traps, interferon-α, and allografting in the current treatment algorithm for patients with myelofibrosis.

Evolving therapies for lower-risk myelodysplastic syndromes.

The development in the therapeutic landscape of myelodysplastic syndromes (MDS) has substantially lagged behind other hematologic malignancies with no new drug approvals for MDS for 13 years since the approval of decitabine in the United States in 2006. While therapeutic concepts for MDS patients continue to be primarily defined by clinical-pathologic risk stratification tools such as the International Prognostic Scoring System (IPSS) and its revised version IPSS-R, our understanding of the genetic landscape and the molecular pathogenesis of MDS has greatly evolved over the last decade. It is expected that the therapeutic approach to MDS patients will become increasingly individualized based on prognostic and predictive genetic features and other biomarkers. Herein, we review the current treatment of lower-risk MDS patients and discuss promising agents in advanced clinical testing for the treatment of symptomatic anemia in lower-risk MDS patients such as luspatercept and imetelstat. Lastly, we review the clinical development of new agents and the implications of the wider availability of mutational analysis for the management of individual MDS patients.

Emerging therapies in ß-thalassemia: toward a new era in management.

INTRODUCTION: The thalassemias are among the most  common inherited monogenic diseases worldwide, characterized by autosomal recessive inherited defects in the production of hemoglobin. Currently available conventional therapies have many challenges and limitations. Advances in understanding the underlying pathophysiology of ß-thalassemia enabled clinicians and researchers to move toward the development of novel therapeutic modalities. These can be classified into three categories based on their efforts to address different features of the underlying pathophysiology of ß-thalassemia: correction of the globin chain imbalance, addressing ineffective erythropoiesis, and improving iron overload. AREAS COVERED: In this review, we will provide an overview of the novel therapeutic approaches that are currently in development for ß-thalassemia. EXPERT OPINION: A thorough understanding of the pathophysiology and overall disease burden of ß-thalassemia has aided clinicians and scientists to optimize disease management approaches and construct a plan for the development of novel therapies, with ultimate goals of prolonging longevity, reducing symptom burden, improving compliance and adherence for a better quality of life.

Treatment of anemia in myelofibrosis: focusing on novel therapeutic options.

INTRODUCTION: Myelofibrosis is a clonal myeloproliferative neoplasm associated with the proliferation of hematopoietic stem cells, increased bone marrow fibrosis, extramedullary hematopoiesis, hepatosplenomegaly, abnormal cytokine production, and constitutional symptoms. These and many other factors contribute to the development of anemia in myelofibrosis patients. AREAS COVERED: This review summarizes novel and promising treatments for anemia in myelofibrosis including transforming growth factor-ß inhibitors luspatercept and KER-050, JAK inhibitors momelotinib, pacritinib, and jaktinib, BET inhibitors pelabresib and ABBV-744, antifibrotic PRM-151, BCL2/BCL-XL inhibitor navitoclax, and telomerase inhibitor imetelstat. EXPERT OPINION: Standard approaches to treat myelofibrosis-related anemia have limited efficacy and are associated with toxicity. New drugs have shown positive results in myelofibrosis-associated anemia when used alone or in combination.