In November 2011, ruxolitinib (Jakafi; Incyte/Novartis), a small-molecule inhibitor of Janus kinases, was approved by the US Food and Drug Administration for the treatment of patients with ...intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythaemia vera myelofibrosis and post-essential thrombocythaemia myelofibrosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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.
Myeloproliferative neoplasms, including polycythemia vera (PV), essential thrombocythemia, and myelofibrosis (MF) (both primary and secondary), are recognized for their burdensome symptom profiles, ...life-threatening complications, and risk of progression to acute leukemia. Recent advancements in our ability to diagnose and prognosticate these clonal malignancies have paralleled the development of MPN-targeted therapies that have had a significant impact on disease burden and quality of life. Ruxolitinib has shown success in alleviating the symptomatic burden, reducing splenomegaly and improving quality of life in patients with MF. The role and clinical expectations of JAK2 inhibition continues to expand to a variety of investigational arenas. Clinical trials for patients with MF focus on new JAK inhibitors with potentially less myelosuppression (pacritinib) or even activity for anemia (momelotinib). Further efforts focus on combination trials (including a JAK inhibitor base) or targeting new pathways (ie, telomerase). Similarly, therapy for PV continues to evolve with phase 3 trials investigating optimal frontline therapy (hydroxyurea or IFN) and second-line therapy for hydroxyurea-refractory or intolerant PV with JAK inhibitors. In this chapter, we review the evolving data and role of JAK inhibition (alone or in combination) in the management of patients with MPNs.
IFNα has been used to treat malignant and viral disorders for more than 25 years. Its efficacy is likely the consequence of its broad range of biologic activities, including direct effects on ...malignant cells, enhancement of anti-tumor immune responses, induction of proapoptotic genes, inhibition of angiogenesis, and promotion of the cycling of dormant malignant stem cells. Because of the recent development of “targeted” therapies, the use of IFN has been dramatically reduced over the last decade. The increasing awareness of the multistep pathogenesis of many malignancies has suggested, however, that such an approach using target-specific agents is not universally effective. These observations have resulted in a number of recent clinical trials utilizing IFNα in patients with chronic myeloid leukemia (CML), systemic mast cell disease, hypereosinophilic syndrome and the Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) with promising outcomes. These reports provide evidence that IFNα, alone or in combination with other agents, can induce surprisingly robust molecular response rates and possibly improve survival. Although IFNα at present remains an experimental form of therapy for patients with myeloid malignancies, these promising results suggest that it may become again an important component of the therapeutic arsenal for this group of hematologic malignancies.
The authors report on the clinical activity of a new oral inhibitor of Janus kinase 2 (JAK2) in patients with myelofibrosis. The drug improved a wide range of symptoms promptly, controlled them for ...>1 year, and appeared to inhibit disease progression to acute leukemia.
Myelofibrosis is manifested as primary myelofibrosis, post–essential thrombocythemia myelofibrosis, or post–polycythemia vera myelofibrosis and is characterized by clinical signs (e.g., progressive anemia, bone marrow fibrosis, and splenomegaly) and a constellation of debilitating symptoms (fatigue, weakness, bone pain, a hypercatabolic state, and weight loss).
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Survival in myelofibrosis is related to the number of risk factors and ranges from 2 to 4 years among patients with two or more risk factors (intermediate-2 or high risk) to 8 to 11 years among patients with no risk factors or one risk factor (intermediate-1 or low risk) (see Table 1A in the Supplementary Appendix, available with . . .
We conducted a genome-wide association study (GWAS) to identify novel predisposition alleles associated with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) and JAK2 V617F clonal ...hematopoiesis in the general population. We recruited a web-based cohort of 726 individuals with polycythemia vera, essential thrombocythemia, and myelofibrosis and 252 637 population controls unselected for hematologic phenotypes. Using a single-nucleotide polymorphism (SNP) array platform with custom probes for the JAK2 V617F mutation (V617F), we identified 497 individuals (0.2%) among the population controls who were V617F carriers. We performed a combined GWAS of the MPN cases plus V617F carriers in the control population (n = 1223) vs the remaining controls who were noncarriers for V617F (n = 252 140). For these MPN cases plus V617F carriers, we replicated the germ line JAK2 46/1 haplotype (rs59384377: odds ratio OR = 2.4, P = 6.6 × 10−89), previously associated with V617F-positive MPN. We also identified genome-wide significant associations in the TERT gene (rs7705526: OR = 1.8, P = 1.1 × 10−32), in SH2B3 (rs7310615: OR = 1.4, P = 3.1 × 10−14), and upstream of TET2 (rs1548483: OR = 2.0, P = 2.0 × 10−9). These associations were confirmed in a separate replication cohort of 446 V617F carriers vs 169 021 noncarriers. In a joint analysis of the combined GWAS and replication results, we identified additional genome-wide significant predisposition alleles associated with CHEK2, ATM, PINT, and GFI1B. All SNP ORs were similar for MPN patients and controls who were V617F carriers. These data indicate that the same germ line variants endow individuals with a predisposition not only to MPN, but also to JAK2 V617F clonal hematopoiesis, a more common phenomenon that may foreshadow the development of an overt neoplasm.
•Germ line variants in TERT, SH2B3, TET2, ATM, CHEK2, PINT, and GFI1B are associated with JAK2 V617F clonal hematopoiesis and MPNs.•Age-related JAK2 V617F clonal hematopoiesis is found in ∼2 out of 1000 individuals in the general population.
Managing patients with myelofibrosis (MF), either those with primary MF or those whose MF has evolved from antecedent polycythemia vera or essential thrombocythemia, presents many challenges to the ...hematologist. MF patients have a range of debilitating disease manifestations (eg, massive splenomegaly, cytopenias, constitutional symptoms, and transformation to a treatment-refractory blast phase). Cure is potentially achievable through allogeneic stem cell transplantation; however, this therapy is either inappropriate or not feasible for the majority of patients. Therefore, remaining therapies are palliative but can be of significant value to some MF patients. In particular, management of symptomatic splenomegaly remains one of the most perplexing aspects of MF clinical care. Using medications is the simplest approach for reducing splenomegaly, yet achieving symptomatic response without undue myelosuppression is challenging. Splenectomy or radiotherapy offers benefit, but careful patient selection and close monitoring are required because both have the potential for dangerous adverse effects. Experimental medical therapies, such as JAK2 inhibitors, show promise and may soon play an important role in the management of symptomatic splenomegaly in MF patients. Future care of MF patients, including splenomegaly management, will continue to require the hematologist to select therapeutic options carefully in the context of realistic, achievable goals.
Background
Primary myelofibrosis (PMF), essential thrombocythemia (ET), and polycythemia vera (PV) are BCR ABL‐negative myeloproliferative neoplasms (MPN). Published epidemiology data are scarce, and ...multiple sources are needed to assess the disease burden.
Methods
We assembled the most recent information available on the incidence and prevalence of myelofibrosis (MF), ET, and PV by conducting a structured and exhaustive literature review of the published peer‐reviewed literature in EMBASE and by reviewing online documentation from disease registries and relevant health registries in European countries. The search was restricted to human studies written in English or French and published between January 1, 2000, and December 6, 2012.
Results
Eleven articles identified from EMBASE, three online hematology or oncology registries, and two Web‐based databases or reports were used to summarize epidemiological estimates for MF, PV, and ET. The incidence rate of MF ranged from 0.1 per 100 000 per year to 1 per 100 000 per year. Among the various registries, the incidence of PV ranged from 0.4 per 100 000 per year to 2.8 per 100 000 per year, while the literature estimated the range of PV incidence to be 0.68 per 100 000 to 2.6 per 100 000 per year. The estimated incidence of ET was between 0.38 per 100 000 per year and 1.7 per 100 000 per year. While a few studies reported on the MPNs' prevalences, it is difficult to compare them as various types of prevalence were calculated (point prevalence vs. period prevalence) and standardization was made according to different populations (e.g., the world population and the European population).
Conclusion
There is a wide variation in both prevalence and incidence estimates observed across European data sources. Carefully designed studies, with standardized definitions of MPNs and complete ascertainment of patients including both primary and secondary MFs, should be conducted so that estimates of the population aimed to receive novel treatments for these neoplasms are better understood assist public health planning and provide valuable information about the burden of illness to policy makers, funding agencies, resource planners, healthcare insurers, and pharmaceutical manufacturers.
Purpose We evaluated the efficacy and safety of momelotinib, a potent and selective Janus kinase 1 and 2 inhibitor (JAKi), compared with ruxolitinib, in JAKi-naïve patients with myelofibrosis. ...Patients and Methods Patients (N = 432) with high risk or intermediate-2 risk or symptomatic intermediate-1 risk myelofibrosis were randomly assigned to receive 24 weeks of treatment with momelotinib 200 mg once daily or ruxolitinib 20 mg twice a day (or per label), after which all patients could receive open-label momelotinib. The primary end point was a ≥ 35% reduction in spleen volume at 24 weeks of therapy. Secondary end points were rates of symptom response and effects on RBC transfusion requirements. Results A ≥ 35% reduction in spleen volume at week 24 was achieved by a similar proportion of patients in both treatment arms: 26.5% of the momelotinib group and 29% of the ruxolitinib group (noninferior; P = .011). A ≥ 50% reduction in the total symptom score was observed in 28.4% and 42.2% of patients who received momelotinib and ruxolitinib, respectively, indicating that noninferiority was not met ( P = .98). Transfusion rate, transfusion independence, and transfusion dependence were improved with momelotinib (all with nominal P ≤ .019). The most common grade ≥ 3 hematologic abnormalities in either group were thrombocytopenia and anemia. Grade ≥ 3 infections occurred in 7% of patients who received momelotinib and 3% of patients who received ruxolitinib. Treatment-emergent peripheral neuropathy occurred in 10% of patients who received momelotinib (all grade ≤ 2) and 5% of patients who received ruxolitinib (all grade ≤ 3). Conclusion In JAKi-naïve patients with myelofibrosis, 24 weeks of momelotinib treatment was noninferior to ruxolitinib for spleen response but not for symptom response. Momelotinib treatment was associated with a reduced transfusion requirement.
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
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/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.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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