Pacritinib and concurrent azole antifungal therapy is deliverable in patients with hematologic malignancies.

OBJECTIVE: Pacritinib is a novel kinase inhibitor approved for the treatment of adults with intermediate or high-risk primary or secondary myelofibrosis. Strong and moderate CYP3A4 inhibitors, such as some azole antifungals, are contraindicated or recommended to be avoided in combination with pacritinib, respectively. We aim to report our experience in patients who received pacritinib with concurrent azole antifungal therapy. DATA SOURCES: We queried for patients with hematologic malignancies in the electronic medical record who received concurrent pacritinib and azole antifungal therapy. DATA SUMMARY: There were five cases of concurrent pacritinib and azole antifungal therapy in which none of the patients experienced grade 3 or higher non-hematologic toxicities. Some patients required dose modifications and/or interruptions in pacritinib therapy. CONCLUSION: This is the first clinical experience describing concurrent pacritinib and azole antifungals. Our experience shows that in the setting where this interaction cannot be avoided, concurrent administration is feasible with close monitoring and possible empiric dose reductions in select patients.

IRAK1 inhibition blocks the HIV-1 RNA mediated pro-inflammatory cytokine response from microglia.

Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) are a common source of morbidity in people living with HIV (PLWH). Although antiretroviral therapy (ART) has lessened the severity of neurocognitive disorders, cognitive impairment still occurs in PLWH receiving ART. The pathogenesis of HAND is likely multifaceted, but common factors include the persistence of HIV transcription within the central nervous system, higher levels of pro-inflammatory cytokines in the cerebrospinal fluid, and the presence of activated microglia. Toll-like receptor (TLR) 7 and TLR8 are innate pathogen recognition receptors located in microglia and other immune and non-immune cells that can recognise HIV RNA and trigger pro-inflammatory responses. IL-1 receptor-associated kinase (IRAK) 1 is key to these signalling pathways. Here, we show that IRAK1 inhibition inhibits the TLR7 and TLR8-dependent pro-inflammatory response to HIV RNA. Using genetic and pharmacological inhibition, we demonstrate that inhibition of IRAK1 prevents IRAK1 phosphorylation and ubiquitination, and the subsequent recruitment of TRAF6 and the TAK1 complex to IRAK1, resulting in the inhibition of downstream signalling and the suppression of pro-inflammatory cytokine and chemokine release.

Properties of FDA-approved small molecule protein kinase inhibitors: A 2023 update.

Owing to the dysregulation of protein kinase activity in many diseases including cancer, this enzyme family has become one of the most important drug targets in the 21st century. There are 72 FDA-approved therapeutic agents that target about two dozen different protein kinases and three of these drugs were approved in 2022. Of the approved drugs, twelve target protein-serine/threonine protein kinases, four are directed against dual specificity protein kinases (MEK1/2), sixteen block nonreceptor protein-tyrosine kinases, and 40 target receptor protein-tyrosine kinases. The data indicate that 62 of these drugs are prescribed for the treatment of neoplasms (57 against solid tumors including breast, lung, and colon, ten against nonsolid tumors such as leukemia, and four against both solid and nonsolid tumors: acalabrutinib, ibrutinib, imatinib, and midostaurin). Four drugs (abrocitinib, baricitinib, tofacitinib, upadacitinib) are used for the treatment of inflammatory diseases (atopic dermatitis, psoriatic arthritis, rheumatoid arthritis, Crohn disease, and ulcerative colitis). Of the 72 approved drugs, eighteen are used in the treatment of multiple diseases. The following three drugs received FDA approval in 2022 for the treatment of these specified diseases: abrocitinib (atopic dermatitis), futibatinib (cholangiocarcinomas), pacritinib (myelofibrosis). All of the FDA-approved drugs are orally effective with the exception of netarsudil, temsirolimus, and trilaciclib. This review summarizes the physicochemical properties of all 72 FDA-approved small molecule protein kinase inhibitors including lipophilic efficiency and ligand efficiency.

Deucravacitinib is an allosteric TYK2 protein kinase inhibitor FDA-approved for the treatment of psoriasis.

Psoriasis is a heterogeneous, inflammatory, autoimmune skin disease that affects up to 2% of the world's population. There are many treatment modalities including topical medicines, ultraviolet light therapy, monoclonal antibodies, and several oral medications. Cytokines play a central role in the pathogenesis of this disorder including TNF-α, (tumor necrosis factor-α) IL-17A (interleukin-17A), IL-17F, IL-22, and IL-23. Cytokine signaling involves transduction mediated by the JAK-STAT pathway. There are four JAKS (JAK1/2/3 and TYK2) and six STATS (signal transducer and activators of transcription). Janus kinases contain an inactive JH2 domain that is aminoterminal to the active JH1 domain. Under basal conditions, the JH2 domain inhibits the activity of the JH1 domain. Deucravacitinib is an orally effective N-trideuteromethyl-pyridazine derivative that targets and stabilizes the TYK2 JH2 domain and thereby blocks TYK2 JH1 activity. Seven other JAK inhibitors, which target the JAK family JH1 domain, are prescribed for the treatment of neoplastic and other inflammatory diseases. The use of deuterium in the trimethylamide decreases the rate of demethylation and slows the production of a metabolite that is active against a variety of targets in addition to TYK2. A second unique aspect in the development of deucravacitinib is the targeting of a pseudokinase domain. Deucravacitinib is rather specific for TYK2 and its toxic effects are much less than those of the other FDA-approved JAK inhibitors. The successful development of deucravacitinib may stimulate the development of additional pseudokinase ligands for the JAK family and for other kinase families as well.

Janus kinase (JAK) inhibitors in the treatment of neoplastic and inflammatory disorders.

The Janus kinase (JAK) family of nonreceptor protein-tyrosine kinases consists of JAK1, JAK2, JAK3, and TYK2 (Tyrosine Kinase 2). Each of these proteins contains a JAK homology pseudokinase (JH2) domain that interacts with and regulates the activity of the adjacent protein kinase domain (JH1). The Janus kinase family is regulated by numerous cytokines including interferons, interleukins, and hormones such as erythropoietin and thrombopoietin. Ligand binding to cytokine receptors leads to the activation of associated Janus kinases, which then catalyze the phosphorylation of the receptors. The SH2 domain of signal transducers and activators of transcription (STAT) binds to the cytokine receptor phosphotyrosines thereby promoting STAT phosphorylation and activation by the Janus kinases. STAT dimers are then translocated into the nucleus where they participate in the regulation and expression of dozens of proteins. JAK1/3 signaling participates in the pathogenesis of inflammatory disorders while JAK1/2 signaling contributes to the development of myeloproliferative neoplasms as well as several malignancies including leukemias and lymphomas. An activating JAK2 V617F mutation occurs in 95% of people with polycythemia vera and about 50% of cases of myelofibrosis and essential thrombocythemia. Abrocitinib, ruxolitinib, and upadacitinib are JAK inhibitors that are FDA-approved for the treatment of atopic dermatitis. Baricitinib is used for the treatment of rheumatoid arthritis and covid 19. Tofacitinib and upadacitinib are JAK antagonists that are used for the treatment of rheumatoid arthritis and ulcerative colitis. Additionally, ruxolitinib is approved for the treatment of polycythemia vera while fedratinib, pacritinib, and ruxolitinib are approved for the treatment of myelofibrosis.

Imetelstat in intermediate-2 or high-risk myelofibrosis refractory to JAK inhibitor: IMpactMF phase III study design.

Imetelstat, a first-in-class telomerase inhibitor, demonstrated meaningful clinical benefit including a robust symptom response rate and potential overall survival benefit in IMbark, a phase II study in intermediate-2 or high-risk myelofibrosis (MF) patients who have relapsed after or are refractory to JAK inhibitors. We describe the rationale and design for the phase III trial, IMpactMF (NCT04576156), an open-label evaluation of imetelstat versus best available therapy, excluding JAK inhibitors, in MF patients refractory to JAK inhibitor. Imetelstat 9.4 mg/kg is administered as an intravenous infusion every 21 days. Primary objective is to assess overall survival. Secondary objectives include symptom and spleen responses, progression-free survival, clinical response assessment, bone marrow fibrosis reduction, safety and pharmacokinetics. Biomarker, cytogenetics and mutation analyses will be performed.

Imetelstat is a new type of treatment being studied in patients with myelofibrosis (MF). Encouraging clinical benefits were seen in a phase II clinical trial of imetelstat in higher risk MF. This article discusses the ongoing phase III trial, called IMpactMF. IMpactMF is comparing imetelstat to best available therapy (BAT) in MF patients not responding to a specific type of treatment, a JAK inhibitor. Imetelstat is an intravenous infusion, given every 21 days. This study will determine if patients who receive imetelstat live longer than patients who are given BAT. It will also collect information on additional outcomes, including safety. Trial Registration Number: NCT04576156 (ClinicalTrials.gov).

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.

Preclinical activity and a pilot phase I study of pacritinib, an oral JAK2/FLT3 inhibitor, and chemotherapy in FLT3-ITD-positive AML.

Activating FLT3 internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) associate with inferior outcomes. We determined that pacritinib, a JAK2/FLT3 inhibitor, has in vitro activity against FLT3-ITD and tyrosine kinase domain (TKD) mutations. Therefore, we conducted a phase I study of pacritinib in combination with chemotherapy in AML patients with FLT3 mutations to determine the pharmacokinetics and preliminary toxicity and clinical activity. Pacritinib was administered at a dose of 100 mg or 200 mg twice daily following a 3 + 3 dose-escalation in combination with cytarabine and daunorubicin (cohort A) or with decitabine induction (cohort B). A total of thirteen patients were enrolled (five in cohort A; eight in cohort B). Dose limiting toxicities include hemolytic anemia and grade 3 QTc prolongation in two patients who received 100 mg. Complete remission was achieved in two patients in cohort A, one of whom had a minor D835Y clone at baseline. One patient in cohort B achieved morphologic leukemia free state. Seven patients (two in cohort A; five in cohort B) had stable disease. In conclusion, pacritinib, an inhibitor of FLT3-ITD and resistant-conferring TKD mutations, was well tolerated and demonstrated preliminary anti-leukemic activity in combination with chemotherapy in patients with FLT3 mutations.

Management of myelofibrosis after ruxolitinib failure.

Myelofibrosis is a BCR-ABL1-negative myeloproliferative neoplasm characterized by anemia, progressive splenomegaly, extramedullary hematopoiesis, bone marrow fibrosis, constitutional symptoms, leukemic progression, and shortened survival. Constitutive activation of the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway, and other cellular pathways downstream, leads to myeloproliferation, proinflammatory cytokine expression, and bone marrow remodeling. Transplant is the only curative option for myelofibrosis, but high rates of morbidity and mortality limit eligibility. Several prognostic models have been developed to facilitate treatment decisions. Until the recent approval of fedratinib, a JAK2 inhibitor, ruxolitinib was the only available JAK inhibitor for treatment of intermediate- or high-risk myelofibrosis. Ruxolitinib reduces splenomegaly to some degree in almost all treated patients; however, many patients cannot tolerate ruxolitinib due to dose-dependent drug-related cytopenias, and even patients with a good initial response often develop resistance to ruxolitinib after 2-3 years of therapy. Currently, there is no consensus definition of ruxolitinib failure. Until fedratinib approval, strategies to overcome ruxolitinib resistance or intolerance were mainly different approaches to continued ruxolitinib therapy, including dosing modifications and ruxolitinib rechallenge. Fedratinib and two other JAK2 inhibitors in later stages of clinical development, pacritinib and momelotinib, have been shown to induce clinical responses and improve symptoms in patients previously treated with ruxolitinib. Fedratinib induces robust spleen responses, and pacritinib and momelotinib may have preferential activity in patients with severe cytopenias. Reviewed here are strategies to ameliorate ruxolitinib resistance or intolerance, and outcomes of clinical trials in patients with myelofibrosis receiving second-line JAK inhibitors after ruxolitinib treatment.

Management of Myelofibrosis: from Diagnosis to New Target Therapies.

OPINION STATEMENT: Myelofibrosis (MF) is a clonal disorder of the pluripotent hematopoietic stem cell, whose clinical manifestations can be extremely heterogeneous, including cytopenias, organomegaly, constitutional symptoms, and cachexia. Median survival ranges from approximately 3.5 to 5.5 years; while the most frequent cause of death is the evolution to acute myeloid leukemia, also other conditions such as progression without transformation, complications due to cytopenias including infections or bleeding, and cardiovascular events may be fatal. Myelofibrosis is still orphan of curative treatments: allogeneic hematopoietic stem cell transplant (HSCT), the only therapeutic approach that has clearly demonstrated an impact on disease progression, is associated with relevant morbidity and mortality and only a minority of patients is eligible for such an intensive procedure. While the discovery of the crucial role of JAK2 mutations and the consequent clinical use of JAK inhibitors has led to a dramatic improvement of symptoms control and quality of life, yet these drugs do not significantly modify the natural history of the disease. A better understanding of the molecular pathogenesis will hopefully foster the development of new targeted therapies aimed at improving MF prognosis. Herein, we review the most recent advances about JAK inhibitors and other molecules which are under investigation.

Outcomes of patients with myelofibrosis treated with compassionate use pacritinib: a sponsor-independent international study.

Myelofibrosis (MF) is a chronic yet progressive myeloid neoplasm in which only a minority of patients undergo curative therapy, hematopoietic stem cell transplantation. Ruxolitinib, a JAK1/2 inhibitor, is the lone therapy approved for MF, offering a clear symptom and spleen benefit at the expense of treatment-related cytopenias. Pacritinib (PAC), a multi-kinase inhibitor with specificity for JAK2, FLT3, and IRAK1 but sparing JAK1, has demonstrated clinical activity in MF with minimal myelosuppression. Due to an FDA-mandated full clinical hold, the randomized phase 3 PERSIST trials were abruptly stopped and PAC was immediately discontinued for all patients. Thirty-three patients benefitting from PAC on clinical trial prior to the hold were allowed to resume therapy on an individual, compassionate-use basis. This study reports the detailed outcomes of 19 of these PAC retreatment patients with a median follow-up of 8 months. Despite a median platelet count of 49 × 109/L at restart of PAC, no significant change in hematologic profile was observed. Grade 3/4 adverse events of epistaxis (n = 1), asymptomatic QT prolongation (n = 1), and bradycardia (n = 1) occurred in three patients within the first 3 months of retreatment. One death due to catheter-associated sepsis occurred. The median time to discontinuation of PAC therapy on compassionate use for all 33 patients was 12.2 (95% CI 8.3-NR) months. PAC retreatment was associated with modest improvement in splenomegaly without progressive myelosuppression and supports the continued development of this agent for the treatment of MF second line to ruxolitinib or in the setting of treatment-limiting thrombocytopenia.

Pacritinib and its use in the treatment of patients with myelofibrosis who have thrombocytopenia.

The treatment landscape for myelofibrosis (MF) has reached the molecular era by targeting different pathways that are implied in this myeloproliferative neoplasm. A few years ago, the first-in-class JAK1/JAK2 inhibitor ruxolitinib, demonstrated reductions in both constitutional symptoms and splenomegaly, leading to the US FDA approval. The development or worsening of cytopenias in patients receiving ruxolitinib uncovered an unmet need that has been addressed by alternative approaches. Pacritinib, a dual JAK2 and FLT3 inhibitor which also inhibits IRAK1, has demonstrated the ability to favorably impact MF-associated splenomegaly and symptom burden, while having limited myelosuppression with manageable gastrointestinal toxicity. Herein, we provide an overview of pacritinib, from early preclinical studies to the latest and ongoing PAC203 trial, as an emerging therapy for MF.

Synergistic effect of pacritinib with erlotinib on JAK2-mediated resistance in epidermal gowth factor receptor mutation-positive non-small cell lung Cancer.

The combination effect of pacritinib, a novel JAK2/FLT3 inhibitor, with erlotinib, the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), on non-small cell lung cancer cells with EGFR activating mutations was investigated. The combination showed synergistic effects on JAK2-mediated EGFR TKI-resistant PC-9/ER3 cells in some cases. The combination markedly suppressed pAKT and pERK although pSTAT3 expression was similar regardless of treatment with the pacritinib, pacritinib + erlotinib, or control in PC-9/ER3 cells. Receptor tyrosine kinase array profiling demonstrated that pacritinib suppressed MET in the PC-9/ER3 cells. The combined treatment of pacritinib and erlotinib in PC-9/ER3 xenografts showed more tumor shrinkage compared with each drug as monotherapy. Western blotting revealed that pMET in tumor samples was inhibited. These results suggest MET suppression by pacritinib may play a role in overcoming the EGFR-TKI resistance mediated by JAK2 in the PC-9/ER3 cells. In conclusion, pacritinib combined with EGFR-TKI might be a potent strategy against JAK2-mediated EGFR-TKI resistance.

A comprehensive review of pacritinib in myelofibrosis.

The first-in-class JAK1/JAK2 inhibitor ruxolitinib inhibits JAK/STAT signaling, inducing durable reductions in splenomegaly and constitutional symptoms in patients with myelofibrosis. However, the association of ruxolitinib therapy with myelosuppression indicates the continued need for optimal treatment choices in myelofibrosis. Pacritinib, a dual JAK2 and FLT3 inhibitor, improves disease-related symptoms and signs with manageable gastrointestinal toxicity in patients with myelofibrosis with splenomegaly and high-risk features, without causing overt myelosuppression, and therefore may provide an important treatment option for a range of patients with myelofibrosis. This article examines the role of JAK2 and FLT3 signaling in myelofibrosis and provides an overview of the clinical development of pacritinib as a new therapy for myelofibrosis.

Enhanced synergy of pacritinib with temsirolimus and sunitinib in preclinical renal cell carcinoma model by targeting JAK2/STAT pathway.

Pacritinib is an oral medication that inhibits several kinases including JAK2, FLT3, IRAK and STAT3. It has been recently approved to treat patients with thrombocytopenia and myelofibrosis. Studies are currently exploring the potential use of pacritinib in treating other types of cancer such as leukaemia, breast cancer and prostate cancer. Our study aimed to investigate the effects of pacritinib alone and its combination with standard of care in renal cell carcinoma (RCC). We showed that pacritinib dose-dependently decreased viability of RCC cells, with IC50 at nanomolar or low micromolar concentration rage. Pacritinib inhibited cell proliferation, decreased colony formation, and increased apoptosis. Interestingly, pacritinib exhibited synergistic effects when combined with temsirolimus and sunitinib, but antagonistic effects when combined with doxorubicin, in a panel of RCC cell lines. We also confirmed that the combination of pacritinib with temsirolimus and sunitinib resulted in synergistic effects in RCC mouse models, with complete inhibition of tumour growth throughout the treatment period. Mechanistic studies indicated that the inhibition of JAK2, but not IRAK, was the main contributor to the anti-RCC activity of pacritinib. Our study is the first to demonstrate that pacritinib shows promise as a treatment option for RCC and underscores the therapeutic potential of targeting the JAK2/STAT signalling pathway in RCC.

Development and validation of an LC-MSMS method for the quantitation of pacritinib; application of kinetics in rabbits.

BACKGROUND: Accurate and selective LC/ESI-MSMS method development and validation for the quantitation of pacritinib is the primary goal of this study to perform kinetic studies in the healthy rabbit. METHODS: Chromatographic resolution was accomplished with a hypersil/ODS (50 mm × 4.6 mm, 3 µ) analytical C18 column and a mobile phase composition of 0.1% formic acid and ACN in the proportion of 25:75 with a 0.6 ml/min flow of the mobile phasic system from the analytical column. The method was employed by monitoring the established ionic transitions of m/z-473.25/98.09 for Pacritinib and 506.18/57.12 for the internal standard (Amprenavir) in multiple reaction monitoring. RESULTS: The calibration plot regression line was y = 0.0002× + 0.007, with a correction coefficient (r2) of 0.9989. The CV outcomes for the matrix effect at low-QC and high-QC levels were 4.79% and 4.91%, respectively. The percentage average recoveries for Pacritinib in High-QC (12.70 µg/ml), MQC (8.50 µg/ml), and Low-QC (1.19 µg/ml) were 95.87%, 103.64%, and 94.32%, respectively. The obtained values were found between 2.98 and 5.07% for the QC (1.19, 8.50, and 12.70 µg/ml) samples. The established procedure was subjected to kinetics study of Pacritinib after oral administration in rabbits. Cmax, Tmax, and T1/2, of the Pacritinib tablets were 247.25 ± 3.32 ng/ml, 6.0 ± 0.03 h, and 12.24 ± 0.53 h, respectively. AUC0-∞ infinity for Pacritinib tablets was 1691.74 ± 3.67 ng h/ml. CONCLUSION: After oral administration of Pacritinib to healthy rabbits, pharmacokinetic characteristics were presented, and the established technique was effectively verified.

Advances with janus kinase inhibitors for the treatment of myeloproliferative neoplasms: an update of the literature.

INTRODUCTION: The hallmark discovery of hyperactivation of the janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway was a sentinel moment in the history of myeloproliferative neoplasms (MPNs). This finding paved the way for the development of JAK inhibitors, which now represent the foundation of myelofibrosis therapy. With four JAK inhibitors now approved for myelofibrosis, awareness of their clinical efficacy and safety data and recognition of their unique pharmacologic attributes are of critical importance. Additionally, ruxolitinib represents an integral part of the therapeutic arsenal for polycythemia vera. AREAS COVERED: This review provides a broad overview of the published literature supporting JAK inhibitor therapy for MPNs. Primarily focusing on myelofibrosis, each of the four available JAK inhibitors is reviewed in detail, including pharmacology, efficacy, and safety data. Failure of JAK inhibitors and future directions in JAK inhibitor therapy are also discussed. EXPERT OPINION: JAK inhibitors revolutionized the treatment of MPNs and have dramatically improved patient outcomes. However, data informing selection between currently available JAK inhibitors is limited. These agents are not curative and eventually fail most patients with myelofibrosis. Combining JAK inhibitors with novel targeted agents appears to be the most promising path to further improve outcomes.

Current therapies for classic myeloproliferative neoplasms: A focus on pathophysiology and supportive care.

PURPOSE: This article concisely evaluates current therapies that have received regulatory approval for the treatment of classic myeloproliferative neoplasms (MPNs). Pertinent pathophysiology and supportive care are discussed. Emerging therapies are also briefly described. SUMMARY: MPNs are a heterogeneous group of diseases characterized by acquired abnormalities of hematopoietic stem cells (HSCs), resulting in the generation of transformed myeloid progenitor cells that overproduce mature and immature cells within the myeloid lineage. Mutations in JAK2 and other driver oncogenes are central to the genetic variability of these diseases. Cytoreductive therapies such as hydroxyurea, anagrelide, interferon, and therapeutic phlebotomy aim to lower the risk of thrombotic events without exposing patients to an increased risk of leukemic transformation. However, no comparisons can be made between these therapies, as reduction of thrombotic risk has not been used as an endpoint. On the other hand, Janus kinase (JAK) inhibitors such as ruxolitinib, fedratinib, pacritinib, and momelotinib (an investigational agent at the time of writing) directly target the constitutively activated JAK-signal transducer and activator of transcription (JAK-STAT) pathway of HSCs in the bone marrow. Mutations of genes in the JAK-STAT signaling pathway provide a unifying understanding of MPNs, spur therapeutic innovations, and represent opportunities for pharmacists to optimize mitigation strategies for both disease-related and treatment-related adverse effects. CONCLUSION: Treatment options for MPNs span a wide range of disease mechanisms. The growth of targeted therapies holds promise for expanding the treatment arsenal for these rare, yet complex diseases and creates opportunities to optimize supportive care for affected patients.

Cytopenic myelofibrosis: prevalence, relevance, and treatment.

INTRODUCTION: Cytopenic myelofibrosis is increasingly recognized as a phenotype of myelofibrosis presenting with low blood counts, lower driver mutation allele burden, increased likelihood of arising de novo, i.e. primary myelofibrosis, greater genomic complexity, worse survival, and higher rates of leukemic transformation compared to the more traditional 'myeloproliferative' phenotype. Both anemia and thrombocytopenia are very common, often coexist, and can be worsened by treatment. Several JAK inhibitors with different kinome profiles are now available for routine clinical use. Additionally, ancillary therapies can also provide some, albeit non-durable, benefit. AREAS COVERED: In this review, we discuss the prevalence and clinical significance of cytopenias in myelofibrosis. We then discuss the various Janus kinase (JAK) inhibitors and ancillary therapies available with a special focus on their use in cytopenic populations, ability to improve cytopenias, and notable adverse events. Articles included were selected through literature searches using the PubMed database. EXPERT OPINION: Pacritinib and momelotinib are new treatment options for patients with cytopenic myelofibrosis. These JAK inhibitors are less myelosuppressive and allow for cytopenia stabilization or improvement while providing additional benefits. It is likely that their use will expand and these newer JAK inhibitors will become backbones for future combinations with novel, 'disease modifying' agents.

An evaluation of fedratinib for adult patients with newly diagnosed and previously treated myelofibrosis.

INTRODUCTION: Myelofibrosis (MF) is a life-shortening myeloproliferative neoplasm that has multiple features such as clonal proliferation, fibrosis and splenomegaly. Until recently, ruxolitinib, a Janus Kinase (JAK) 1/2 inhibitor was the only targeted therapy approved for transplant-ineligible patients with MF and who require treatment for symptoms and/or splenomegaly. However, the discontinuation rate with ruxolitinib at 3 to 5 years is high and mostly due to loss of response or toxicity, and these patients had no subsequent treatment. AREAS COVERED: Fedratinib, a selective JAK2 inhibitor, was approved by the Food and Drug Administration (FDA) in August 2019 for the treatment of intermediate-2 or high-risk primary or secondary MF, regardless of prior JAK inhibitor treatment for the management of symptoms and splenomegaly. We discuss herein the development of fedratinib and its pharmacology and pharmacokinetics as well as the clinical development and the future directions. We used PubMed for the search of articles related to fedratinib and myelofibrosis. EXPERT OPINION: Fedratinib provided a second-line treatment for patients with MF who failed or discontinued ruxolitinib. New combinations of JAK inhibitors with other targeted therapies are a must in order to improve the management of MF.