SOHO State of the Art Updates and Next Questions: Identifying and Treating “Progression” in Myelofibrosis

Over the last decade, the Janus kinase (JAK) 1/2 inhibitor ruxolitinib has become widely established as the cornerstone of pharmacologic therapy for most patients with myelofibrosis (MF), providing dramatic and durable benefits in terms of splenomegaly and symptoms, and prolonging survival. Ruxolitinib does not address all aspects of the disease, however; notably cytopenias, and its ability to modify the underlying biology of the disease remains in question. Furthermore, patients eventually lose response to ruxolitinib. Multiple groups have reported the median overall survival of MF patients after ruxolitinib discontinuation to be 13 to 14 months. While consensus criteria only recognize splenic and blast progression as “progressive disease” in patients with MF, disease progression can occur in a variety of ways. Besides increasing splenomegaly and progression to accelerated phase/leukemic transformation, patients may develop worsening disease-related symptoms, cytopenias, progressive leukocytosis, extramedullary hematopoiesis, etc. As in the frontline setting, treatment needs to be tailored to the clinical needs of the patient. Current treatment options for patients with MF who fail ruxolitinib remain unsatisfactory, and this continues to represent an area of major unmet medical need. The regulatory approval of fedratinib has introduced an important option in the postruxolitinib setting. Fortunately, a plethora of novel agents, both new JAK inhibitors and drugs from other classes, eg, bromodomain and extraterminal (BET), murine double minute 2 (MDM2) and telomerase inhibitors, activin receptor ligand traps, BH3-mimetics and more, are poised to greatly expand the therapeutic armamentarium for patients with MF if successful in pivotal trials.     

SOHO State of the Art Updates and Next Questions: Novel Therapies in Development for Myelofibrosis

Myeloproliferative neoplasms research has entered a dynamic and exciting era as we witness exponential growth of novel agents in advanced/early phase clinical trials for myelofibrosis (MF). Building on the success and pivotal role of ruxolitinib, many novel agents, spanning a wide range of mechanisms/targets (epigenetic regulation, apoptotic/intracellular signaling pathways, telomerase, bone marrow fibrosis) are in clinical development; several are studied in registrational trials and hold great potential to expand the therapeutic arsenal/shift the treatment paradigm if regulatory approval is granted. Insight into MF pathogenesis and its molecular underpinnings, preclinical studies demonstrating synergism of ruxolitinib with investigational agents, urgent unmet clinical needs (cytopenias, loss of response to JAK inhibitors); and progressive disease fueled the rapid rise of innovative therapeutics. New strategies include pairing ruxolitinib with erythroid maturation agents to manage anemia (luspatercept), designing rational combinations with ruxolitinib to boost responses in both the frontline and suboptimal response settings (pelabresib, navitoclax, parsaclisib), treatment with non-JAK inhibitor monotherapy in the second-line setting (navtemadlin, imetelstat), novel JAK inhibitors tailored to subgroups with challenging unmet needs (momelotinib and pacritinib for anemia and thrombocytopenia, respectively); and agents potentially enhancing longevity (imetelstat).Beyond typical endpoints evaluated in MF clinical trials (spleen volume reduction ≥ 35%, total symptom score reduction ≥ 50%) thus far, emerging endpoints include overall survival, progression-free survival, transfusion independence, anemia benefits, bone marrow fibrosis and driver mutation allele burden reduction. Novel biomarkers and additional clinical features are being sought to assess new agents and tailor emerging therapies to appropriate patients. New strategies are needed to optimize the design of clinical trials comparing novel combinations to standard agent monotherapy.     

SOHO State of the Art Updates and Next Questions: Novel Therapeutic Strategies in Development for Myelofibrosis

Development of myelofibrosis (MF) therapeutics has reached fruition as the transformative impact of JAK2 inhibitors in the MPN landscape is complemented/expanded by a profusion of novel monotherapies and rational combinations in the frontline and second line settings. Agents in advanced clinical development span various mechanisms of action (eg, epigenetic or apoptotic regulation), may address urgent unmet clinical needs (cytopenias), increase the depth/duration of spleen and symptom responses elicited by ruxolitinib, improve other aspects of the disease besides splenomegaly/constitutional symptoms (eg, resistance to ruxolitinib, bone marrow fibrosis or disease course), provide personalized strategies, and extend overall survival (OS). Ruxolitinib had a dramatic impact on the quality of life and OS of MF patients. Recently, pacritinib received regulatory approval for severely thrombocytopenic MF patients. Momelotinib is advantageously poised among JAK inhibitors given its differentiated mode of action (suppression of hepcidin expression). Momelotinib demonstrated significant improvements in anemia measures, spleen responses, and MF-associated symptoms in MF patients with anemia; and will likely receive regulatory approval in 2023. An array of other novel agents combined with ruxolitinib, such as pelabresib, navitoclax, parsaclisib, or as monotherapies (navtemadlin) are evaluated in pivotal phase 3 trials. Imetelstat (telomerase inhibitor) is currently evaluated in the second line setting; OS was set as the primary endpoint, marking an unprecedented goal in MF trials, wherein SVR35 and TSS50 at 24 weeks have been typical endpoints heretofore. Transfusion independence may be considered another clinically meaningful endpoint in MF trials given its correlation with OS. Overall, therapeutics are at the cusp of an exponential expansion and advancements that will likely lead to the golden era in treatment of MF.     

Ruxolitinib for Myelofibrosis–An Update of Its Clinical Effects

Myelofibrosis (MF), a Philadelphia chromosome-negative myeloproliferative neoplasm, is characterized by progressive bone marrow fibrosis and ineffective hematopoiesis. Clinical hallmarks include splenomegaly, anemia, and debilitating symptoms. In 2 randomized phase III studies, the Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib significantly improved splenomegaly and disease-related symptoms compared with placebo (Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment [COMFORT-I]) or best available therapy (COMFORT-II) in patients with intermediate-2 or high-risk MF. Although ruxolitinib therapy was associated with dose-dependent anemia and thrombocytopenia, these adverse events rarely led to treatment discontinuation. This update of the clinical effects of ruxolitinib in patients with MF was based on original articles and meeting abstracts published after the primary publication of the COMFORT trials in March 2012. Long-term follow-up data from the COMFORT trials and clinical experience with ruxolitinib in unselected patient populations suggest that improvement of splenomegaly and symptoms is durable. Patients benefit from ruxolitinib therapy across subgroups defined by age, MF type, risk category, performance status, JAK2 V617F mutation status, extent of splenomegaly, or presence of cytopenias. In COMFORT-I, platelet counts stabilized with dose adjustments, and hemoglobin levels gradually recovered to slightly below baseline after the first 8 to 12 weeks of therapy. After initial increases, the need for red blood cell transfusions decreased to a level similar to that found in the placebo group. The 2-year follow-up data from the COMFORT trials suggest that patients with intermediate-2 or high-risk MF receiving ruxolitinib therapy may have improved survival compared with those receiving no (placebo) or traditional therapy.     

Bcl-2 antisense therapy in B-cell malignant proliferative disorders

Opinion statement Overexpression of Bcl-2 oncogene has been clinically associated with an aggressive clinical course, chemotherapy and radiotherapy resistance, and poor survival in patients with malignant B-cell disorders. Patients with relapsed or refractory chronic lymphocytic leukemia, multiple myeloma, or non-Hodgkin’s lymphoma have limited therapeutic options. Preclinical and early clinical data have shown that Bcl-2 oncoprotein can be decreased by Bcl-2 antisense therapy. Also, downregulation of Bcl-2 protein can result in reversal of chemotherapy resistance and improved antitumor activity of biologic agents. Various clinical trials are evaluating the role of targeting Bcl-2 as a mechanism to enhance the antitumor potential of chemotherapy and immunotherapy. Early results from these clinical studies are encouraging and confirm the proof of principle for antisense therapy. As current data mature, these trials will hopefully validate preliminary results and establish Bcl-2 antisense as an important addition to the current armamentarium used in the treatment of patients with B-cell neoplasms.v     

ruxolitinib在血液肿瘤中的临床应用进展

随着JAK/STAT通路异常在骨髓增生性肿瘤（myeloproliterative neoplasms，MPN）、急性白血病（acute leukemia，AL）、多发性骨髓瘤（multiple myeloma，MM）、噬血细胞综合征（hemophagocytic syndrome，HPS）等多种血液系统疾病中被发现，一系列针对JAK/STAT途径的靶向药物被研发，其中一种JAK1/JAK2抑制剂芦可替尼（ruxolitinib）已被美国食品药品监督管理局（FDA）批准用于治疗骨髓纤维化（myelofibrosis，MF）和真性红细胞增多症（polycythemia vera，PV）。ruxolitinib治疗其他血液系统疾病，如AL、MM和HPS均取得了较好的疗效，为血液病患者带来新的希望。本文将就ruxolitinib在上述疾病中的作用机制和临床研究结果予以综述。      

Therapy with JAK 1/2 inhibitors for myelofibrosis

Purpose

Myelofibrosis (MF) is currently the myeloproliferative disorder with the most severe prognosis. A mutation of the JAK2 (V617F) enzyme is present in about 65?% of patients. Inhibition of JAK-kinases was therefore a proposed treatment for the disease. The purpose of this article is to give an updated overview about the recent developments in the therapy of MF with JAK-inhibitors.

Materials and methods

We did a research through the literature to identify the JAK 1/2 inhibitors which are already approved for treating MF or currently undergoing clinical trials. The most important clinical data concerning ruxolitinib, TG101348, SAR302503, CYT387, and SB1518 are described in more detail.

Results

Most of the relevant data documented clinical benefits of JAK inhibitors, particularly in terms of reducing splenomegaly and constitutional symptoms. However, there might also be a trend for better overall survival. The efficacy of ruxolitinib has been demonstrated in two large Phase III trials. In September 2012, the European Medicines Agency (EMA) approved ruxolitinib for the treatment of patients with intermediate or high-risk MF. The other drugs discussed here are still investigated in Phase II or III studies.

Conclusion

There is emerging evidence that supports the use of JAK-inhibitors for MF in clinical practice, especially for patients with splenomegaly and constitutional symptoms. Nevertheless, possible side effects such as anemia and thrombopenia must be considered when prescribing these substances.     

The New Landscape of Therapy for Myelofibrosis

The landscape of therapy for myelofibrosis (MF) is evolving at a pace not previously seen for this clonal myeloproliferative neoplasm. The discovery of the JAK2 V617F mutation in 2005 has led to the rapid development of therapy specifically developed for afflicted MF patients. Indeed, the successful phase III studies of ruxolitinib demonstrating improved symptomatic burden, splenomegaly and survival led to the first approved myelofibrosis drug in the United States and Europe. Multiple additional JAK2 inhibitors are currently in or nearing phase III testing, including SAR302503 (fedratinib), SB1518 (pacritinib) and CYT387 (momelotinib), seeking to offer incremental benefits to ruxolitinib in regards to cytopenias or other disease features. In parallel, phase III testing of pomalidomide is ongoing, with the goal of solidifying the role of immunomodulatory therapy in MF-associated anemia. Multiple single agents strategies are ongoing with histone deacetylase inhibitors, hedgehog inhibitors and hypomethylation agents. Incremental advances are further sought, either in additive or synergistic fashion, from combination strategies of ruxolitinib with multiple different approaches ranging from allogeneic stem cell transplant to current therapies mitigating anemia and further impacting the bone marrow microenvironment or histology. Transitioning from a pre-2011 era devoid of approved MF therapies to one of multiple agents that target not only disease course but symptomatic burden has indeed changed the platform from which MF providers are able to launch individualized treatment plans. In this article, we discuss the diagnostic and therapeutic milestones achieved through MF research and review the emerging pharmacologic agents on the treatment horizon.     

Proteasome inhibitors in the treatment of B-cell malignancies

The proteasome, which plays a pivotal role in the control of many cell cycle-regulatory processes, has become the focus of new approaches to the treatment of cancer, including B-cell malignancies, and the first proteasome inhibitor, bortezomib (VELCADE; formerly PS-341), has entered clinical trials. The proteasome controls the stability of numerous proteins that regulate progression through the cell cycle and apoptosis, such as cyclins, cyclin-dependent kinases, tumor suppressors, and the nuclear factor-kB. By altering the stability or activity of these proteins, proteasome inhibitors sensitize malignant cells to apoptosis. Bortezomib is a dipeptidyl boronic acid proteasome inhibitor that effectively and specifically inhibits proteasome activity. In preclinical studies, bortezomib and other proteasome inhibitors have shown activity against a variety of B-cell malignancies, including multiple myeloma, diffuse large B-cell lymphoma, mantle cell lymphoma, and Hodgkin's lymphoma. These agents can induce apoptosis and sensitize tumor cells to radiation or chemotherapy. Based on these findings, phase I clinical trials were conducted with bortezomib in various solid and hematologic malignancies. In these studies, bortezomib was generally well tolerated with manageable toxicities. Phase II trials have been initiated for relapsed and refractory multiple myeloma, refractory chronic lymphocytic leukemia, and non-Hodgkin's lymphoma. Preliminary data from the multiple myeloma phase II study indicate that a significant number of patients responded to therapy or exhibited stable disease and that the drug had manageable toxicities. These findings, along with extensive preclinical data, suggest that bortezomib and other proteasome inhibitors may have far-reaching potential in the treatment of various cancers, including B-cell malignancies.     

Novel Therapies for Myelofibrosis

Purpose of Review

The purpose of the review was to provide a contemporary update of novel agents and targets under investigation in myelofibrosis in the Janus kinase (JAK) inhibitor era.

Recent Findings

Myelofibrosis (MF) is a clonal stem cell disease characterized by marrow fibrosis and a heterogeneous disease phenotype with a variable degree of splenomegaly, cytopenias, and constitutional symptoms that significantly impact quality of life and survival. Overactive JAK/STAT signaling is a hallmark of MF. The only approved therapy for MF, JAK1/2 inhibitor ruxolitinib, can ameliorate splenomegaly, improve symptoms, and prolong survival in some patients. Therapeutic challenges remain, however. Myelosuppression limits the use of ruxolitinib in some patients, eventual drug resistance is common, and the underlying malignant clone persists despite therapy. A deeper understanding of the pathogenesis of MF has informed the development of additional agents.

Summary

Promising targets under investigation include JAK1 and JAK2 and downstream intermediates in related signaling pathways, epigenetic modifiers, pro-inflammatory cytokines, and immune regulators.

     

The Treatment Landscape of Myelofibrosis Before and After Ruxolitinib Approval

Introduction/BackgroundMyelofibrosis (MF) is a chronic myeloproliferative neoplasm that presents with a heterogeneous clinical phenotype and prognosis. Before the US Food and Drug Administration approval of ruxolitinib, treatment options were varied and had limited effect. The increased use of ruxolitinib has drastically altered the MF treatment landscape. In this study, we aimed to clarify the clinical situations in which ruxolitinib is being used and analyze its effect on this landscape.Patients and MethodsWe retrospectively assessed treatment choices for MF patients treated at our institution (n = 309). This population was divided into 2 cohorts on the basis of a diagnosis before (cohort BR: n = 174) or after (cohort AR: n = 135) ruxolitinib approval. Cohorts were further stratified for comparison according to presenting clinical factors.ResultsExpectedly, the first-line use of ruxolitinib markedly increased after its approval. AR patients were less likely to receive erythropoiesis-stimulating agents (ESAs; P = .0003) and thalidomide (P = .003) than BR patients. In patients with MF-related symptoms and/or splenomegaly, increased use of ruxolitinib was associated with decreased use of first-line ESA (P = .03) or thalidomide (P = .03). In anemic patients, increased use of first-line ruxolitinib was associated with a decreased use of thalidomide (P = .007). In patients with severe leukocytosis, ruxolitinib use did not significantly increase and hydroxyurea was the preferred first-line agent.ConclusionOverall, the increased use of ruxolitinib appears to have come predominantly at the expense of thalidomide and ESAs, while not having a large effect on the first-line use of hydroxyurea.     

Rationnel et modalités de prescription du ruxolitinib dans les myélofibroses

Ruxolitinib is a JAK/STAT inhibitor, which has demonstrated clinical benefits in patients with intermediate-2 and high-risk myelofibrosis. Moreover, first results of recent clinical trials show a trend to better overall survival with ruxolitinib, which allows to hope that we will soon be able to change the natural evolution of this poor outcome disease. With such results, ruxolitinib quickly obtained the Food and Drug Administration (FDA) approval in the United States of America. In France, ruxolitinib is now available, allowing its administration to symptomatic myelofibrosis patients.     

Ibrutinib and Indolent B-Cell Lymphomas

Most patients with indolent B-cell lymphomas fail to achieve complete remission with current treatment approaches and invariably relapse. During the past decade, innovative immunochemotherapy strategies have substantially improved disease control rates but not survival, thus providing the rationale for development of novel agents targeting dysregulated pathways that are operable in these hematological malignancies. Ibrutinib, a novel first-in-human Bruton's tyrosine kinase (BTK) inhibitor, has progressed into phase III trials after early-phase clinical studies demonstrated effective target inhibition, increased tumor response rates, and significant improvement in survival, particularly in patients with indolent B-cell lymphomas. Recently, the compound was designated a “breakthrough therapy” by the United States Food and Drug Administration for the treatment of patients with relapsed or refractory mantle cell lymphoma and Waldenström macroglobulinemia. This review summarizes recent achievements of ibrutinib, with a focus on its emerging role in the treatment of patients with indolent B-cell lymphoid malignancies.     

Patterns of Care for Older Patients With Myelofibrosis: A Population-based Study

BackgroundCurrent treatments for myelofibrosis (MF) are largely palliative, with the JAK inhibitor ruxolitinib being the breakthrough approved for higher-risk patients by the United States Food and Drug Administration in November 2011. There are limited data on the “real-world” clinical experiences among patients with MF who are treated in the JAK inhibitor era.Patients and MethodsWe evaluated patterns of care for older patients with MF before and after ruxolitinib approval, using the Surveillance, Epidemiology, and End Results-Medicare database. Treatment patterns were assessed using Medicare part B and D claims.ResultsThis study included 528 patients diagnosed during 2007 to 2015, with a median age at diagnosis of 76 years. Among 298 patients diagnosed in the ruxolitinib era (2012-2015), 113 (37.9%) were ruxolitinib users. Similar numbers of users started ruxolitinib at 5, 10, 15, or 20 milligrams twice a day (BID). Among 31 patients starting at 5 milligrams BID or less, 48.4% were unable to escalate the dose, and < 11 users could increase the dose to the maximum 25 mg BID. Approximately one-half of ruxolitinib users took hydroxyurea and/or prednisone simultaneously with ruxolitinib. The median time on ruxolitinib was 11.9 months (interquartile range, 4.2-21.7 months).ConclusionIt would be important to optimize the use of ruxolitinib and develop new drugs that may be administered together with or after ruxolitinib to accomplish better outcomes in older patients with MF.     

Targeting B-lymphocyte stimulator/B-cell activating factor and a proliferation-inducing ligand in hematologic malignancies

B-lymphocyte stimulator/B-cell activating factor (BLyS/BAFF) and a proliferation-inducing ligand (APRIL), members of the tumor necrosis family of ligands, are expressed by monocytes, macrophages, and dendritic cells, and increased expression of these ligands is noted in lymphomas and plasma cell malignancies. BLyS and APRIL are essential for the survival of normal and malignant B lymphocytes, and altered expression of BLyS or APRIL or the receptors B-cell maturation, transmembrane activator and calcium-modulating cyclophilin ligand interactor, or BAFF-R have been reported in various B-cell malignancies, including B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia, Hodgkin's lymphoma, multiple myeloma, and Waldenstrom's macroglobulinemia. Levels of BLyS (in the tumor and in the serum) increased with the transformation of the tumors to a more aggressive phenotype. A high BLyS level inversely correlated with a poor median overall survival, presence of constitutional symptoms, and increased levels of lactate dehydrogenase in patients with non-Hodgkin's lymphoma. Additionally, patients who responded to therapy had a lower BLyS level than those with progressive disease. Several agents targeting BLyS and APRIL are currently being pursued in phase I clinical studies in patients with B-cell malignancies.     

Successful treatment of gastrointestinal follicular lymphoma with rituxan and combination chemotherapy

The clinical course of follicular lymphoma (FL) is well known. Although it is a chemosensitive disease, thereby allowing substantial palliation, recurrence is the rule; only a small subset who presents with limited stage disease is cured. Multiple attempts have been made over the past two decades to improve the survival of patients with FL, and a large number of phase III trials have been reported. These have included a variety of different therapeutic interventions, such as combination chemotherapy, recombinant interferons, new cytotoxic drugs, and immunologic agents. Most studies have not demonstrated that the use of a particular therapy convincingly prolongs survival. Follicular lymphoma cells express CD20 and are associated in most cases with the t(14:18) chromosomal translocation. Rituximab is a chimeric monoclonal antibody directed against the B-cell CD20 antigen, which has been utilized for the therapy of B-cell non-Hodgkin's lymphoma. Rituximab was shown to be active in FL, and studies of its effectiveness in combination with cytotoxic chemotherapy to increase the response rate are forthcoming.     

B-Cell Receptor Pathobiology and Targeting in NHL

B-cell receptor signaling plays varied and critical roles in B-cell development, homeostasis and disease. The key players of the pathway and its many signaling modulators have been identified as well as some of the mechanisms by which the pathway is regulated. With the increased incidence of non-Hodgkin's lymphoma in recent years, there is a clear clinical need for novel agents to offer new options in resistant disease to potentially improve outcomes in curative settings. With the tremendous insight gained in the last 2 decades from basic science research, our understanding of the pathobiology of the B-cell receptor is leading to the discovery and clinical development of many new therapeutic targets such as Syk, Bruton's tyrosine kinase, and phosphatidylinositol 3-kinase. This review will emphasize contemporary and salient findings on novel agents targeting the B-cell receptor signaling pathway for the treatment of non-Hodgkin's lymphoma.     

Hitting back at lymphoma: How do modern diagnostics identify high-risk diffuse large B-cell lymphoma subsets and alter treatment?

Diffuse large B-cell lymphoma (DLBCL) is a clinically and biologically heterogeneous disease. Diagnostic tools in the clinic can now identify distinct subsets characterized by unique molecular features, which are increasingly transforming how these patients are managed. Activated B–cell-like DLBCL is characterized by NF-κB activation and chronic B-cell receptor signaling and may be targeted with lenalidomide or ibrutinib in the relapsed setting. Germinal center-like DLBCL is enriched for activating EZH2 mutations, and encouraging activity has been observed for the EZH2 inhibitor tazemetostat, which now has a fast-track US Food and Drug Administration designation. Double-hit lymphoma is a high-grade B-cell lymphoma characterized by translocations of MYC and BCL2 and/or BCL6 and carries a poor prognosis. Intensive chemoimmunotherapy strategies appear to be superior to standard R-CHOP (rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone) as initial therapy, and anti-CD19 chimeric antigen receptor T cells are inducing remission in patients with relapsed/refractory disease who previously had few available options. Primary mediastinal (thymic) large B-cell lymphoma is a molecularly distinct large-cell lymphoma with clinical and molecular features that overlap with those of classical Hodgkin lymphoma. R-CHOP has been associated with an unacceptably high rate of primary treatment failure in this young population, whereas dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab) produces durable remissions without the need for radiotherapy in most patients. For relapsed/refractory disease, immune checkpoint inhibitors targeting PD-1 have shown promising activity in chemotherapy-refractory disease, as have anti-CD19 chimeric antigen receptor T cells. Additional therapeutic targets, including JAK2, continue to be evaluated. The identification of discrete biological subsets is steadily moving us away from a “one-size-fits-all” approach in DLBCL.     

Definition and management of ruxolitinib treatment failure in myelofibrosis

Ruxolitinib, a Janus kinase (JAK)-1 and JAK-2 inhibitor, is the first-in-class drug to be licensed in the United States for the treatment of high- and intermediate-risk myelofibrosis (MF). Several other JAK inhibitors are in development with some currently undergoing phase-3 clinical trial testing. None of the currently available JAK inhibitors are specific to mutant JAK2; their mechanism of action involves attenuation of JAK-STAT signaling with downregulation of proinflammatory cytokines, rather than selective suppression of the disease clone. Accordingly, while ruxolitinib and other JAK inhibitors are effective in controlling splenomegaly and alleviating constitutional symptoms, their benefit in terms of reversing bone marrow fibrosis or inducing complete or partial remissions appears to be limited. The experience to date with ruxolitinib shows that despite its salutary effects on quality of life, over half of the patients discontinue treatment within 2–3 years. In the current perspective, we examine the incidence and causes of ruxolitinib ‘treatment failure'' in MF patients based on our personal experience as well as a review of the published literature. We also discuss the challenges in defining and classifying ruxolitinib failure, and within the context of several clinical scenarios, we provide recommendations for the post-ruxolitinib management of MF patients.