Thrombocytopenia in Patients With Myelofibrosis: Pathogenesis,Prevalence, Prognostic Impact,and Treatment

Myelofibrosis (MF) is a clonal hematopoietic stem cell neoplasm, characterized by pathologic myeloproliferation associated with inflammatory and pro-angiogenic cytokine release, that results in functional compromise of the bone marrow. Thrombocytopenia is a disease-related feature of MF, which portends a poor prognosis impacting overall survival (OS) and leukemia free survival. Thrombocytopenia in MF has multiple causes including ineffective hematopoiesis, splenic sequestration, and treatment-related effects. Presently, allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curable treatment for MF, which, unfortunately, is only a viable option for a minority of patients. All other currently available therapies are either focused on improving cytopenias or the alleviating systemic symptoms and burdensome splenomegaly. While JAK2 inhibitors have moved to the forefront of MF therapy, available JAK inhibitors are advised against in patients with severe thrombocytopenia (platelets < 50 × 10⁹/L). In this review, we describe the pathogenesis, prevalence, and prognostic significance of thrombocytopenia in MF. We also explore the value and limitations of treatments directed at addressing cytopenias, splenomegaly and symptom burden, and those with potential disease modification. We conclude by proposing a treatment algorithm for patients with MF and severe thrombocytopenia.     

Evaluating the serial use of the Myelofibrosis Symptom Assessment Form for measuring symptomatic improvement: performance in 87 myelofibrosis patients on a JAK1 and JAK2 inhibitor (INCB018424) clinical trial

BACKGROUND:

Symptomatic burden from constitutional symptoms, anemia, and splenomegaly‐related symptoms are common and morbidity inducing in patients with myelofibrosis (MF). The authors previously developed a MF‐specific instrument for capturing the burden of MF‐associated disease‐related symptoms, the Myelofibrosis Symptom Assessment Form.

METHODS:

The authors evaluated the usefulness of serial administration of the Myelofibrosis Symptom Assessment Form as an instrument for the assessment of symptomatic burden and improvement in conjunction with the therapeutic clinical trial of the open label phase 2 trial of the JAK1 and JAK2 inhibitor INCB018424 in patients with MF.

RESULTS:

The analysis cohort of 87 patients treated in this trial demonstrated that the instrument was comprehensive and sensitive to symptoms present at trial enrollment. In addition, baseline Myelofibrosis Symptom Assessment Form symptom scores correlated well with objective parameters such as splenomegaly and impaired performance status assessed by the 6‐minute walk test. Serial administration while on therapy with INCB018424 demonstrated the instrument to be sensitive to symptomatic change, and that improvements in symptoms correlated well with objective improvements in both weight loss and performance status (6‐minute walk test).

CONCLUSIONS:

The use of the Myelofibrosis Symptom Assessment Form in this phase 2 trial helped characterize the symptomatic improvements observed with use of INCB018424 in MF patients. In an era of many targeted therapies undergoing testing for MF with potential symptomatic benefit, the Myelofibrosis Symptom Assessment Form may provide a useful tool for objective symptomatic assessment and potentially allow some nonrandomized comparison between therapeutic agents. Cancer 2011;. © 2011 American Cancer Society.     

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.     

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.

     

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.     

State-of-the-Art Review on Myelofibrosis Therapies

Myelofibrosis (MF) is a BCR-ABL1–negative myeloproliferative neoplasm characterized by anemia, extramedullary hematopoiesis, bone marrow fibrosis, splenomegaly, constitutional symptoms and acute myeloid leukemia progression. Currently, allogeneic haematopoietic stem cell transplantation (AHSCT) therapy is the only curative option for MF patients. However, AHSCT is strictly limited due to the high rates of morbidity and mortality. Janus kinase 2 (JAK2) inhibitor Ruxolitinib is the first-line treatment for intermediate-II or high-risk MF patients with splenomegaly and constitutional symptoms, but most MF patients develop resistance or intolerance to Ruxolitinib. Therefore, MF treatment is a challenge for the medical community. This review summarizes 3 investigated directions for MF therapy: monotherapies of JAK inhibitors, monotherapies of non-JAK targeted agents, combination therapies of Ruxolitinib and other agents. We emphasize combination of Ruxolitinib and other agents is a promising strategy.     

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.     

Spleen deflation and beyond: The pros and cons of Janus kinase 2 inhibitor therapy for patients with myeloproliferative neoplasms

The myeloproliferative neoplasms (MPNs) essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (MF) are malignancies that frequently harbor the recurrent somatic point mutation JAK2^V617F. The discovery of this mutation has fueled the development of Janus kinase 2 (JAK2) inhibitors. Available results have indicated that JAK2 inhibitors are particularly effective at reducing spleen size. However, the activity of these agents is multifaceted and also involves a marked improvement of systemic symptoms and, for those agents with dual JAK1 and JAK2 inhibitory activity, a marked reduction in the levels of circulating cytokines involved in the pathogenesis of the disease. Because JAK2 inhibitors are not specific for JAK2^V617F, responses have also been observed in JAK2^V617F‐negative MPNs because of the inhibition of wild‐type JAK2, which is also likely responsible for the induction of cytopenias in patients with MF and for the normalization of peripheral blood counts observed in patients with ET or PV. Given the distinct mortality and morbidity associated with ET, PV, and MF, the use of JAK2 inhibitors appears reasonable for patients with MF as well as for those with ET or PV who have become resistant or intolerant to hydroxyurea. Ongoing randomized, placebo‐controlled, phase 3 trials will further delineate the role of these agents in the management of patients with MPNs. The pros and cons of JAK2 kinase inhibitor therapy are herein discussed. Cancer 2012;. © 2011 American Cancer Society.     

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.     

Thrombocytopenia in Patients With Myelofibrosis: A Practical Management Guide

Patients with myelofibrosis (MF) frequently develop thrombocytopenia as a consequence of bone marrow fibrosis, splenic sequestration, and myelosuppression from an inflammatory microenvironmental milieu. Thrombocytopenia occurs frequently at diagnosis, worsens with disease progression, is an independent adverse prognostic factor, and limits effective dosing of JAK2 inhibitors. Recently, pacritinib was approved for patients with MF and extreme thrombocytopenia. However, this JAK2/IRAK1 inhibitor is not primarily used to attain improvement in platelet count. In this narrative review, we discuss strategies to specifically address thrombocytopenia in MF patients including immunomodulatory drugs, synthetic androgens, hypomethylating agents and splenectomy, all of which have only modest efficacy in alleviating thrombocytopenia. We also detail transfusion approaches, including diagnostic and therapeutic consideration for platelet transfusion refractoriness. We end by discussing novel therapies, including TGFβ traps and recombinant pentraxin-2, which may increase platelet counts in MF patients. Despite recent therapeutic advancements in MF, there remains a near paucity of agents that can effectively alleviate thrombocytopenia.     

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.     

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.     

Classical Philadelphia-negative myeloproliferative neoplasms: focus on mutations and JAK2 inhibitors

Classical Philadelphia- negative myeloproliferative neoplasms (MPNs) encompass three main myeloid malignancies: polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). Phenotype-driver mutations in Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL) genes are mutually exclusive and occur with a variable frequency. Driver mutations influence disease phenotype and prognosis. PV patients with JAK2 exon 14 mutation do not differ in number of thrombotic events, risk of leukemic and fibrotic transformation, and overall survival to those with JAK2 exon 12 mutation. Type 2-like CALR-mutated ET patients have lower risk of thrombosis if compared with those carrying JAK2 or type 1-like CALR mutation. For ET, overall survival is comparable between patients with JAK2 and either type 1-like and type 2-like CALR mutations. For MF, better OS is demonstrated for patients harboring a type 1-like CALR mutation than those with type 2-like CALR or JAK2. The discovery of driver mutations in MPNs has prompted the development of molecularly targeted therapy. Among JAK2 inhibitors, ruxolitinib (RUX) has been approved for (1) treatment of intermediate-2 and high-risk MF and (2) PV patients who are resistant to or intolerant to hydroxyurea. RUX reduces spleen size and alleviates disease symptoms in a proportion of MF patients. RUX in MF leads to prolonged survival and reduces risk of death. RUX controls hematocrit, reduces spleen size and alleviates symptoms in PV. Adverse events of RUX are moderate, however, its long-term use may be associated with opportunistic infections. Trials with other JAK2 inhibitors are ongoing.     

New approaches in the treatment of myelofibrosis

Myelofibrosis with myeloid metaplasia (MMM) is a chronic clonal neoangiogenesis disorder characterized by bone marrow fibrosis and neoangiogensis with extramedullary hematopoiesis. Identification of prognostic factors associated with MMM have not impacted the treatment of the disease, which continues to be palliative with the exception of allogeneic stem cell transplantation (SCT) for potential long-term disease-free survival in selected patients. Additional insights into the pathophysiology of MMM have resulted in the use of novel therapeutic strategies in the treatment of this disease. The rationale for the investigation of these agents in MMM and the status of clinical trials with various modalities such as angiogenesis inhibitors (e.g., thalidomide), tyrosine kinase inhibitors (e.g., imatinib mesylate), farnesyl transferase inhibitors (e.g., R115777), and other agents are reviewed, in addition to the potential roles of autologous and allogeneic SCT.     

真性红细胞增多症患者JAK2基因突变的临床意义

真性红细胞增多症（polycythemia vera,PV）为一种以红细胞增多为特征的骨髓增殖性肿瘤（myeloproliferative neoplasm,MPN）。PV的发病机制尚未阐明,可能和JAK2基因的功能获得性体细胞突变相关,JAK2基因突变为PV提供了分子学诊断标准。JAK2基因突变和等位基因突变负荷可推测PV患者的临床特征和发展趋势。JAK2基因突变的发现促进了分子靶向治疗的发展,JAK2抑制剂ruxolitinib已应用于临床,治疗效果和安全性均良好。JAK2等位基因突变负荷与白细胞增多、转化为骨髓纤维化（myelofibrosis,MF）密切相关,高JAK2等位基因突变负荷可能为PV患者预后不良的危险因素。本文对PV患者JAK2基因突变的临床意义进行综述。      

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.     

Allogeneic Stem Cell Transplant vs. Janus Kinase Inhibition in the Treatment of Primary Myelofibrosis or Myelofibrosis After Essential Thrombocythemia or Polycythemia Vera

Primary myelofibrosis is one of the Philadelphia chromosome–negative myeloproliferative neoplasms and is the member of that group with the worst survival and the most significant limitations in quality of life. Hepatosplenomegaly due to extramedullary hematopoiesis, constitutional symptoms, and cytopenias are the main manifestations. The natural history is highly variable, and up to 30% of patients can experience acceleration to acute myelogenous leukemia. Conventional therapy is only palliative and not always effective. However, huge advances have been achieved in the past 2 decades toward a better understanding of the pathogenesis of this disease, as well as improved management. Powerful risk stratification systems are now available and can reliably separate the patients into different prognostic categories to aid clinical management. Allogeneic stem cell transplant can offer cure but is still not universally applicable owing to the treatment-related mortality and toxicity. Nevertheless, outcomes of transplant are improving, owing to the introduction of reduced-intensity conditioning regimens and the optimization of remission monitoring techniques and relapse prevention strategies. The discovery of the V617F mutation of JAK2 (Janus kinase 2) and some other molecular aberrations has shed more light on the molecular pathogenesis of the disease and has led to the introduction of novel therapies such as JAK2 inhibitors. In fact, JAK inhibitors have shown promising symptomatic efficacy, and the JAK inhibitor ruxolitinib has also shown a potential survival benefit. Future effort should be made to combine allogeneic stem cell transplant with JAK inhibition.     

The Myelodepletive Phenotype in Myelofibrosis: Clinical Relevance and Therapeutic Implication

Myelofibrosis (MF) is a BCR-ABL1⁻ myeloproliferative neoplasm that arises from hematopoietic stem and progenitor cells frequently harboring a somatic driver mutation in 1 of 3 genes: JAK2, CALR, or MPL. The pathologic features of this hematologic malignancy include myeloproliferation, diffuse bone marrow fibrosis, and overactivation of the JAK-STAT pathway, resulting in enhanced inflammatory cytokine release. The common clinical manifestations of MF include systemic symptoms, abnormal peripheral blood count levels, and splenomegaly. However, it has become increasingly appreciated that significant clinical heterogeneity exists among patients with MF. Two distinct MF clinical phenotypes include the myeloproliferative and myelodepletive phenotype, with peripheral blood counts being the main discerning feature. Patients with the myeloproliferative phenotype will present with elevated peripheral blood counts and often experience significant constitutional symptoms and progressive splenomegaly. In contrast, patients with the myelodepletive phenotype will have low peripheral blood counts and will frequently require transfusion support. Current frontline therapies for MF, include ruxolitinib and fedratinib, which can exacerbate cytopenias and thereby pose an impediment to effective treatment of the myelodepletive patient. The present review discusses the clinical and prognostic implications of the myelodepletive phenotype and the therapeutic options and limitations for this subset of patients, representing an unmet clinical need.     

The clinical dilemma of JAK inhibitor failure in myelofibrosis: Predictive characteristics and outcomes

Two Janus-associated kinase inhibitors (JAKi) (initially ruxolitinib and, more recently, fedratinib) have been approved as treatment options for patients who have intermediate-risk and high-risk myelofibrosis (MF), with pivotal trials demonstrating improvements in spleen volume, disease symptoms, and quality of life. At the same time, however, clinical trial experiences with JAKi agents in MF have demonstrated a high frequency of discontinuations because of adverse events or progressive disease. In addition, overall survival benefits and clinical and molecular predictors of response have not been established in this population, for which the disease burden is high and treatment options are limited. Consistently poor outcomes have been documented after JAKi discontinuation, with survival durations after ruxolitinib ranging from 11 to 16 months across several studies. To address such a high unmet therapeutic need, various non-JAKi agents are being actively explored (in combination with ruxolitinib in first-line or salvage settings and/or as monotherapy in JAKi-pretreated patients) in phase 3 clinical trials, including pelabresib (a bromodomain and extraterminal domain inhibitor), navitoclax (a B-cell lymphoma 2/B-cell lymphoma 2-xL inhibitor), parsaclisib (a phosphoinositide 3-kinase inhibitor), navtemadlin (formerly KRT-232; a murine double-minute chromosome 2 inhibitor), and imetelstat (a telomerase inhibitor). The breadth of data expected from these trials will provide insight into the ability of non-JAKi treatments to modify the natural history of MF.     

骨髓纤维化的发病机制及临床表现

骨髓纤维化是骨髓增殖性肿瘤的一种,预后差,生存期短。最近的研究对其发病的分子机制、临床表现及并发症都有进展,对此种疾病的临床诊断、治疗及预后评估都有帮助。本文对以上内容的研究进展进行综述。