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Introduction: Myelodysplastic syndromes/neoplasms (MDS) are a heterogeneous group of hematologic malignancies that are stratified into high-risk (HR-MDS) and low-risk (LR-MDS) categories. Until recently, LR-MDS has been typically managed by supportive measures and erythropoiesis-stimulating agents (ESAs); whereas management of HR-MDS typically included hypomethylating agents and allogeneic hematopoietic stem cell transplant. However, the limited rates and durations of response observed with these interventions prompted the search for targeted therapies to improve the outcomes among patients with MDS., Areas Covered: Here, we review the current landscape of targeted therapies in MDS. These include pyruvate kinase and hypoxia-inducible factor (HIF) activators; TGF-beta, telomerase, BCL2 and isocitrate dehydrogenase (IDH) inhibitors; as well as novel approaches targeting inflammation, pyroptosis, immune evasion, and RNA splicing machinery., Expert Opinion: This review highlights the progress and challenges in MDS treatment. Despite some promising results, many therapies remain in early development or have faced setbacks, emphasizing the need for a more comprehensive understanding of the disease's pathobiology. Continued research into targeted therapies, homogenous clinical trial designs, as well as increased incorporation of molecular prognostic tools and artificial intelligence into trial design are essential for developing effective treatments for MDS and improving patient outcomes.

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-β 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.

Myelodysplastic syndromes (MDS) are broadly categorized as lower- and higher-risk with lower-risk dominated by cytopenias and higher-risk plagued by the risk of transformation to acute myeloid leukemia (AML). The management of MDS utilize a risk-adapted approach aimed at ameliorating cytopenias in lower-risk MDS (LR-MDS) and preventing AML transformation in higher-risk MDS. Hematopoietic stem cell transplantation is a potentially curative intent therapy in higher-risk MDS; however, it is not routinely recommended in LR-MDS in view of unfavorable risk/benefit ratio. Therefore, the goal of treatment in LR-MDS is aimed at improving the transfusion burden and health related quality of life. Currently, erythropoiesis stimulating agents (recombinant erythropoietin), erythroid maturation agents (luspatercept), disease modifying agents (lenalidomide) and hypomethylating agents are the agents of choice in the treatment of LR-MDS. This review will discuss the current treatment standards, meaningful clinical outcomes, and emerging therapies in LR-MDS.

Given its rarity, multi-faceted clinical presentation and the relative paucity of approved therapies, the management of myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF) can be challenging. Janus kinase (JAK) inhibitors, the only approved agents at present, have brought many clinical benefits to patients, with prolongation of survival also demonstrated for ruxolitinib. However, these agents have clear limitations. Optimal management of anemia in MF remains a major unmet need. Neither ruxolitinib nor fedratinib is recommended for use in patients with severe thrombocytopenia, i.e. platelets <50 × 10 9 /L, who have a particularly poor prognosis. The search for the optimal partner for JAK inhibitors to address some of the shortcomings of these agents (e.g. limited ability to improve bone marrow fibrosis, cytopenias and induce molecular responses) and achieve meaningful 'disease modification' continues. This has led to the development of a number of rational, preclinically synergistic combinations for use either upfront or in the setting of sub-optimal response to JAK inhibition. Finally, the outlook for patients whose disease progresses on JAK inhibitor therapy continues to be grim, and agents with alternative mechanisms of action may be needed in this setting. In this article, we use a case-based approach to illustrate challenges commonly encountered in clinical practice and our management of the same. Fortunately, there has been enormous growth in drug development efforts in the MF space in the last few years, some of which appear poised to bear fruit in the very near future.

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.

Introduction: Essential thrombocythemia (ET) and polycythemia vera (PV) belong to the BCR-ABL1-negative myeloproliferative neoplasms and are characterized by the clonal proliferation of hematopoietic stem and progenitor cells. The contribution of aberrant immune regulation within the bone marrow microenvironment to ET and PV pathogenesis as well as the underlying molecular landscape is becoming increasingly understood., Areas Covered: Authors searched PubMed and conference abstracts in August 2020 for preclinical and clinical studies to provide an overview of the immune pathobiology in ET and PV and the rationale for several novel agents. A discussion of recent clinical trials on interferon and ruxolitinib in ET and PV patients is provided followed by an outline of the future challenges in the field particularly for novel therapeutics and an increasingly individualized, molecularly driven approach to treatment selection. Several novel agents are currently being actively evaluated and are reviewed herein as well., Expert Opinion: While hydroxyurea remains the first-line treatment for cytoreduction in most high-risk ET and PV patients, the disease-modifying potential of IFN is promising and could make it a preferred option for selected patients. Advances in molecular testing will enable a more individualized approach to prognostication and treatment selection.

Introduction: Despite the dramatic progress made in the treatment of patients with myelofibrosis since the introduction of the JAK1/2 inhibitor ruxolitinib, a therapeutic option that can modify the natural history of the disease and prevent evolution to blast-phase is still lacking. Recent investigational treatments including immunomodulatory drugs and histone deacetylase inhibitors benefit some patients but these effects have proven modest at best. Several novel agents do show promising activity in preclinical studies and early-phase clinical trials. We will illustrate a snapshot view of where the management of myelofibrosis is evolving, in an era of personalized medicine and advanced molecular diagnostics. Areas covered: A literature search using MEDLINE and recent meeting abstracts was performed using the keywords below. It focused on therapies in active phases of development based on their scientific and preclinical rationale with the intent to highlight agents that have novel biological effects. Expert commentary: The most mature advances in treatment of myelofibrosis are the development of second-generation JAK1/2 inhibitors and improvements in expanding access to donors for transplantation. In addition, there are efforts to identify drugs that target pathways other than JAK/STAT signaling that might improve the survival of myelofibrosis patients, and limit the need for stem-cell transplantation.

The unsatisfactory outcomes for osteosarcoma necessitate novel therapeutic strategies. This study evaluated the effect of the telomerase inhibitor imetelstat in pre-clinical models of human osteosarcoma. Because the chaperone molecule HSP90 facilitates the assembly of telomerase protein, the ability of the HSP90 inhibitor alvespimycin to potentiate the effect of the telomerase inhibitor was assessed. The effect of single or combined treatment with imetelstat and alvespimycin on long-term growth was assessed in osteosarcoma cell lines (143B, HOS and MG-63) and xenografts derived from 143B cells. Results indicated that imetelstat as a single agent inhibited telomerase activity, induced telomere shortening, and inhibited growth in all 3 osteosarcoma cell lines, though the bulk cell cultures did not undergo growth arrest. Combined treatment with imetelstat and alvespimycin resulted in diminished telomerase activity and shorter telomeres compared to either agent alone as well as higher levels of γH2AX and cleaved caspase-3, indicative of increased DNA damage and apoptosis. With dual telomerase and HSP90 inhibition, complete growth arrest of bulk cell cultures was achieved. In xenograft models, all 3 treatment groups significantly inhibited tumor growth compared with the placebo-treated control group, with the greatest effect seen in the combined treatment group (imetelstat, p = 0.045, alvespimycin, p = 0.034; combined treatment, p = 0.004). In conclusion, HSP90 inhibition enhanced the effect of telomerase inhibition in pre-clinical models of osteosarcoma. Dual targeting of telomerase and HSP90 warrants further investigation as a therapeutic strategy.