Accepted Manuscript Title: Are we altering the natural history of primary myelofibrosis? Author: Michael R. Savona PII: DOI: Reference:
S0145-2126(14)00123-4 http://dx.doi.org/doi:10.1016/j.leukres.2014.04.012 LR 5162
To appear in:
Leukemia Research
Received date: Revised date: Accepted date:
10-3-2014 14-4-2014 24-4-2014
Please cite this article as: Savona MR, Are we altering the natural history of primary myelofibrosis?, Leukemia Research (2014), http://dx.doi.org/10.1016/j.leukres.2014.04.012 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Are we altering the natural history of primary myelofibrosis?
Michael R. Savona, MD, FACP*
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Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
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*Corresponding author: Division of Hematology/Oncology, Vanderbilt University Medical
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Center, 2220 Pierce Avenue, 777 PRB, Nashville, TN 37232, USA. Tel: +1 615-3434677; Fax: +1 615-343-7602.
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E-mail address: [email protected] (M.R. Savona)
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ABSTRACT Primary myelofibrosis (PMF) is a clonal hematologic malignancy with a variable disease
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course; survival ranges from months to years. Historically, only allogeneic
hematopoietic stem cell transplantation (alloHSCT) has demonstrated an ability to alter
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the natural history of PMF, but high treatment-related mortality risks limit the utility of
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alloHSCT to a minority of patients with PMF or myelofibrosis secondary to other myeloproliferative neoplasms. The recent development of therapies that regulate the
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Janus kinase–signal transducer and activator of transcription signaling pathway has changed the treatment landscape from primarily palliative treatment to potential disease
JAK inhibitors
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Myelofibrosis
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Keywords (max = 6):
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modification.
Proinflammatory cytokines Spleen volume
Targeted therapy
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1. Introduction Primary myelofibrosis (PMF) is a Philadelphia chromosome–negative
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myeloproliferative neoplasm (MPN) characterized by progressive bone marrow fibrosis resulting in increasingly ineffective hematopoiesis, extramedullary hematopoiesis, a
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variety of inflammatory and vascular complications, and shortened survival. Patients
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with PMF have high circulating levels of proinflammatory cytokines believed to be responsible for constitutional symptoms and much of the morbidity associated with the
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disease. Common clinical manifestations of PMF include progressive hepatosplenomegaly, abnormal blood counts, and debilitating symptoms such as
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fatigue, weight loss, night sweats, fever, pruritus, bone pain, early satiety, abdominal
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pain or discomfort, arthralgias, myalgias, parasthesias, and even thromboembolic
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disease [1,2]. Both post-essential thrombocythemia (ET) myelofibrosis (PET-MF) and post-polycythemia vera (PV) myelofibrosis (PPV-MF) are phenotypically similar to PMF
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and all 3 diseases have a similar clinical course [3]. Consequently, most recent and ongoing clinical trials have mixed study populations of patients with PMF, PPV-MF, or PET-MF. In the absence of a clonal MPN, fibrosis in the bone marrow can occur in nonneoplastic states. However, for the sake of simplicity and for the purposes of this manuscript, PMF, PPV-MF, or PET-MF will be collectively described as myelofibrosis (MF). MF pathogenesis involves aberrant activation of the Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway, which may result from somatic mutations directly affecting JAK activity, excessive cytokine stimulation, and/or
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epigenetic modifications of chromatin structure interfering with normal regulation of gene expression [4-6]. The JAK2V617F gain-of-function mutation was identified several years ago and its association with myeloproliferative phenotypes of PMF, ET, and PV is
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well established [7-10]. Additional mutations within the JAK-STAT pathway have been identified since, and recent evidence suggests that mutations outside of the JAK-STAT
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pathway such as TET2 and ASXL1 also have important roles in pathogenesis [4,5].
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Dysregulation within the JAK-STAT pathway and epigenetic modifiers that influence the JAK-STAT pathway are commonly seen in MPNs, but no single dominant, sufficient,
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genetic mutation has been identified.
The discovery of the JAK2V617F mutation in patients with MPNs prompted
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further investigation in preclinical models and eventually led to the clinical development
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of JAK-targeted therapy for PMF. Several JAK inhibitors are currently in development
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(Table 1), and one agent, the oral JAK1/JAK2 inhibitor ruxolitinib, has been approved for patients with intermediate-1, intermediate-2, or high-risk PMF, PPV-MF, or PET-MF.
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In 2 phase III clinical trials in patients with intermediate-2 or high-risk MF, ruxolitinib has been shown to significantly reduce spleen volume and to alleviate MF-related symptoms compared with placebo or best available therapy (BAT) [11,12]. These advantages translated into clinically important improvements in quality of life (QOL) measures [1214], and long-term follow-up data from the 2 studies suggest that ruxolitinib prolongs overall survival versus both placebo and BAT in patients with MF [15,16]. Aside from allogeneic hematopoietic stem cell transplantation (alloHSCT), previously used therapies for PMF have been palliative, but with limited benefits in QOL and symptom management. Until recently, the only treatment with a clearly
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demonstrated impact on disease progression has been alloHSCT, but treatment-related mortality is high and only a minority of patients qualify for this intensive therapy [17]. New agents have the potential to alter the natural history and make a long-term impact
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on the disease. The aim of this article is to explore current evidence that new rationally
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designed therapy may alter the natural history of MF.
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2. Markers of disease progression and incompleteness of prognostic scoring systems
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The prognosis of PMF is variable. Risk stratification with the International Prognostic Scoring System (IPSS) [18], the Dynamic IPSS (DIPSS) [19], or the DIPSS-
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Plus [20] has helped clinicians to assign risk and determine appropriate candidates for
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alloHSCT. Each scoring system incorporates assorted patient risk factors for survival in
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predictive models based on multiparametric regression analyses. Important disease characteristics predictive of poor survival that are included in all of these scoring
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systems are age of >65 years, presence of constitutional symptoms (weight loss >10% of the baseline value in the year preceding diagnosis and/or unexplained fever or excessive sweats persisting for >1 month), hemoglobin 25 × 109/L, and circulating blasts ≥1% [18-20]. In addition, DIPSS-Plus includes unfavorable karyotype, platelet count 95% of patients with PV [42]. It results in
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constitutive activity of JAK2, which leads to excessive production of proinflammatory cytokines and transcription of cell survival–promoting molecules and anti-apoptotic
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molecules. The JAK-STAT pathway also may be overactive in patients who do not
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harbor the JAK2V617F mutation. For example, mutations in JAK2 exon 12 and the myeloproliferative leukemia virus proto-oncogene (MPL) encoding the thrombopoietin
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receptor, as well as in KIT, CBL, and TET2, have been consistently identified in patients with MPNs [1]. Recent analyses showed that most patients without a JAK2 or MPL
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mutation harbor mutations in the calreticulin gene (CALR), and cells expressing these
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mutations in CALR were sensitive to JAK2 inhibition [38,43]. In addition, patients without
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the JAK2V617F mutation have shown clinical responses to JAK inhibitor therapy [11], including individual patients with CALR mutations [44]. Altered gene expression as a
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result of epigenetic dysregulation in MPNs also may affect genes that play a role in cell survival, differentiation, and/or proliferation, including those encoding calcitonin A, ABL1, SFRP2, WIF-1, SOCS1, SOCS3, CXCR4, and RARβ2 [4]. For example, ASXL1 mutations have been associated with epigenetic dysregulation resulting in the loss of transcriptional repression of leukemogenic genes and in the silencing of tumor suppressor genes [45]. Thus, aberrant expression of numerous genes may contribute to the pathogenesis of PMF, regardless of the presence or absence of the JAK2V617F mutation.
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4. JAK inhibition: treatment responses and effect on survival Studies of JAK inhibition have shown benefits with regard to spleen volume, MFrelated symptoms, QOL, body weight, cholesterol levels, biomarkers and
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histopathology, and overall survival.
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4.1. Spleen volume
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The durability of spleen volume reductions with ruxolitinib treatment in patients with intermediate-2 or high-risk MF has now been demonstrated by long-term follow-up
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data from both COMFORT-I and COMFORT-II. In COMFORT-I, almost two-thirds of the patients who achieved a ≥35% reduction in spleen volume from baseline maintained
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this level of reduction for at least 2 years [15], and the probability of maintaining this
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response for >132 weeks was 53% [46]. Durable reductions in spleen volume also were
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observed in long-term analyses of data from COMFORT-II [16]. Treatment of patients with intermediate- or high-risk MF with the JAK1/2 inhibitor momelotinib (CYT387) for up
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to 2.5 years in a phase I/II trial resulted in reductions in palpable spleen size of ≥50% in more than half of the eligible patients, with a maximal response duration of almost 2 years [47]. Data from studies of other JAK inhibitors have thus far shorter periods of follow-up. Nonetheless, they also demonstrate the efficacy of JAK inhibition in improving splenomegaly. In a phase II trial, treatment with the JAK2 inhibitor pacritinib provided a ≥35% reduction in spleen volume at week 24 from baseline in 32% of patients with MF, and at the time of the report, the median duration of response had not been reached [48]. Similarly, considerable reductions in splenomegaly have been seen in early phase clinical trials with the JAK2 inhibitors fedratinib (SAR302503/TG101348) [49,50] and
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lestaurtinib [51], and with LY2784544 [52,53], a selective JAK2V617F inhibitor. In a phase II study of fedratinib, 30% to 64% of patients with MF achieved a ≥35% reduction in spleen volume after three 28-day cycles of therapy, illustrating the speed of
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considerable spleen size reduction [49]. (Unfortunately, clinical development of the drug was discontinued because of safety concerns prompted by reports of cases of
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Wernicke’s encephalopathy [54]).
4.2. Myelofibrosis-related symptoms and quality of life
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JAK inhibition improves MF-related symptoms, which seems to improve QOL. Ruxolitinib treatment has been shown to improve MF symptoms and QOL measures
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compared with both placebo and BAT [11,12]. In addition, spleen volume reductions
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were correlated with improvements in MF symptoms and QOL in COMFORT-I [13]. In
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the phase I trial of momelotinib, most treated patients experienced an improvement in constitutional symptoms [47]. Pacritinib therapy was associated with significant
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reductions in MF symptoms at 6 months, which included abdominal pain, bone pain, early satiety, worst fatigue, inactivity, night sweats, and pruritus [48]. The clinical experience with fedratinib also is marked with improvement or resolution of early satiety, fatigue, night sweats, itching, abdominal pain, and abdominal discomfort [49,50]. Reductions of symptom burden with LY2784544 were seen within the first 2 treatment cycles and included improvements in key MPN-related symptoms, fatigue/enjoyment of life, fatigue/walking ability, itching, early satiety, inactivity, bone pain, and night sweats [52]. At 12 weeks, a ≥50% reduction in total symptom burden was observed in 56% of patients [53].
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4.3. Body weight and metabolic status Cachexia is a common manifestation of disease progression, and unwanted
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weight loss has been established as a negative prognostic factor [18,23]. Cachexia in patients with MF likely is related to the excessive production of cytokines such as
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interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α), which are elevated in these
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patients [55]. Elevated blood levels of IL-6, which signals through the JAK-STAT pathway, have been associated with cancer-related cachexia in clinical studies [56,57],
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and TNF-α infusion recently has been shown to promote muscle protein loss and increased IL-6 release in healthy individuals [58]. In COMFORT-I, ruxolitinib treatment
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was associated with increases in body weight and total cholesterol from baseline,
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whereas both parameters decreased over time in patients who received placebo [59].
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Specific effects of JAK inhibition on cachexia are not well illustrated, but improvement of appetite and metabolic status are strongly correlated with spleen size reduction.
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Changes in body weight or total cholesterol with JAK inhibitors other than ruxolitinib have not been reported to date.
4.4. Biomarkers of inflammation
Chronically elevated levels of proinflammatory cytokines have been implicated in the pathogenesis of bone marrow fibrosis [60] as well as in the mediation of noxious effects underlying the compromised metabolic/nutritional status in affected patients [6,11,55]. In addition, the circulating levels of some cytokines, including IL-8, IL-2R, IL12, and IL-15, have been shown to be independent prognostic factors of survival in
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patients with MF, which suggests a possible role in disease progression [6]. Because these cytokines may support the tumor microenvironment through autocrine signaling that promotes tumor cell survival and proliferation, it is reasonable to hypothesize that
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the normalization of circulating cytokine levels may alter the trajectory of disease
evolution. Rapid reductions in plasma levels of proinflammatory cytokines have been
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observed in response to ruxolitinib (IL-8, IL-6, and TNF-α) [11,55] and fedratinib (TNF-α,
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IL-1RA, and IL-18) [49]. Given the association between elevated cytokine expression
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and survival [6], this decrease in inflammatory biomarkers is encouraging.
4.5. Bone marrow fibrosis
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Bone marrow fibrosis is variable and typically graded by the density of reticulin
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and collagen fibers in marrow replacement [61]. In PMF, marrow fibrosis is usually
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progressive and there is increasing evidence that bone marrow fibrosis grade has prognostic significance [21,22]. Marrow fibrosis may resolve spontaneously in rare
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cases [62,63] or with alloHSCT [64] and may respond to treatment with interferon-alpha (IFN-α) in select patients [65]. Otherwise, reversal of marrow fibrosis has not been seen with traditional therapies. However, a post hoc analysis from the ruxolitinib phase I/II study suggests that JAK inhibition may be able to slow the progression of bone marrow fibrosis in some patients [66,67]. Bone marrow biopsies from patients treated with ruxolitinib in a single institution phase I/II study were matched to historical control bone marrow biopsies from patients who received BAT in Europe at corresponding time points. At 5 years of follow-up, 35% of ruxolitinib-treated compared with 3% of BATtreated patients showed improvement in bone marrow fibrosis grade. Furthermore, the
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odds for worsening bone fibrosis was significantly greater with BAT (76%; n=29) than ruxolitinib (26%; n=23) [67]. Consistent with the notion that JAK inhibition may have a positive impact on bone marrow fibrosis [68], data from the phase I study of LY2784544
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showed that after 5 cycles of therapy, bone marrow fibrosis grade was reduced in 3 of 5 MF patients analyzed [52].
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Although encouraging, the improvement in bone marrow fibrosis observed in
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patients receiving JAK inhibitors generally occurred slowly and overall was modest. For many patients lasting improvement of bone marrow function may require a multifaceted
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approach beyond the use of JAK inhibitors. In the future, this approach may include the use of epigenetic modifiers such as the histone deacetylase (HDAC) inhibitor
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panobinostat [69,70], or antifibrotic agents such as PRM-151 (recombinant human
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pentraxin-2) [71] and a monoclonal antibody against LOXL-2 [72]. These agents will be
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4.6. Overall survival
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discussed in more detail in Section 5.
Follow-up data from COMFORT-I and COMFORT-II suggest that ruxolitinib therapy was associated with a survival advantage compared with both placebo and BAT [15,16]. These analyses were based on randomized treatment allocation at the beginning of the studies, and the control arms included patients who crossed over to ruxolitinib treatment after meeting prespecified conditions of disease progression. In COMFORT-I, all patients randomized to placebo had discontinued or were receiving ruxolitinib within 3 months after the primary analysis [15]. The short exposure to placebo taken together with the growing exposure to ruxolitinib treatment in the placebo group
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has made interpretation of survival benefits difficult [46]. Exploratory statistical analyses suggest that the diminished survival disadvantage of the placebo arm (compared with the ruxolitinib arm) at 3 versus 2 years follow-up may be a direct result of the crossover
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to ruxolitinib in this treatment arm [46]. A corresponding effect was not observed in COMFORT-II [16], likely because of delayed crossover from BAT to ruxolitinib
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consequent to differences in crossover rules between the COMFORT studies.
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Nonetheless, depending on the time of analysis, patients randomized to ruxolitinib generally had a survival advantage of 30% to 50% compared with those randomized to
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placebo [11,15] or BAT [16]. Consistent with these findings, a comparison of survival data from patients with PMF from the COMFORT-II study with those from a matched
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control population of the DIPSS study [73] revealed a 36% reduction in the risk of death
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with ruxolitinib versus conventional therapy (HR = 0.64; 95% confidence interval:
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0.4‒0.96; P = 0.034). Additional analyses showed that the use of ruxolitinib doubled the 8-year survival probability at diagnosis from 15.9% to 32.2%. Together, these data
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suggest that ruxolitinib may affect disease progression and alter the natural history of the disease.
5. Rational approaches to modification of disease beyond JAK inhibition In addition to the investigational JAK inhibitors, agents targeted to other signaling pathways or to epigenetic modifiers are in various stages of clinical development for the treatment of MPN-associated MF. They include HDAC inhibitors and immunomodulatory drugs. In addition, the antifibrotic monoclonal antibodies fresolimumab and GS-6624, recombinant PTX-2, and the telomerase inhibitor imetelstat
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(GRN163L) may have potential roles in treatment as single agents or in combination therapy. Recently, encouraging results were obtained in a single-center study of the telomerase inhibitor imetelstat in patients with intermediate-2 or high-risk MF. Of 18
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patients followed for at least 3 months, 8 (44%) had an overall response, including 4 patients with complete remission, as evidenced by the reversal of BM fibrosis and
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recovery of normal megakaryocyte morphology, and 1 patient with partial remission
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[74].
In addition to imetelstat, approaches complementary to JAK inhibitor therapy to
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reverse bone marrow fibrosis or retard its progression are being explored. The human monoclonal antibody fresolimumab antagonizes transforming growth factor beta
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(TGFβ), a mediator of bone marrow fibrosis in thrombopoietin-induced MF [75,76], and
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it has been safely administered to patients with focal segmental glomerulosclerosis [77].
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Likewise, a monoclonal antibody (GS6624, AB0023) targeting lysyl oxidase-like 2 (LOXL-2), a protein active in the remodeling of extracellular matrix architecture in
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pathologic fibrosis, has been shown to reduce TGFβ pathway signaling and fibroblast activation in murine models of fibrosis [72]. A phase II study of the anti-LOXL-2 antibody GS6624 as monotherapy or in combination with ruxolitinib is underway in patients with MF. PRM-151 (recombinant human serum amyloid P/pentraxin 2), an antifibrotic protein, has recently been shown in an initial phase I study to be well tolerated and to reduce fibrocyte numbers by 30% to 50% in patients with pulmonary fibrosis [78]. Investigation in patients with MF is underway. Panobinostat (LBH589) is a pan-HDAC inhibitor that was shown in a phase I trial to achieve a 100% reduction in palpable splenomegaly in 3 of 5 patients who received
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at least 6 cycles of treatment and were evaluable for response; the other 2 patients had stable disease [79]. One of the 3 patients who had 100% reduction in splenomegaly demonstrated bone marrow fibrosis resolution after 16 cycles [79]. In a phase II trial of
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22 patients with intermediate- or high-risk MF, the HDAC inhibitor pracinostat achieved a median 3-cm reduction in splenomegaly in 6 (27%) patients [80]. These and other
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targeted agents may be most effective when given in combination with JAK inhibitors to
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maximize blockade of disease mechanisms. Studies of combination therapy with rational combinations of these targeted agents are in progress. In a recent phase I
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study, prolonged therapy with panobinostat elicited dramatic reversal of bone marrow histopathologic abnormalities in 2 patients [79]. A combination study of panobinostat
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and ruxolitinib in patients with MF is ongoing.
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The use of IFN-α may lead to spleen size and symptom improvement as well as
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reduction in marrow fibrosis in some patients, particularly those with early-stage disease [65]. However, as a recent analysis of studies of IFN-α shows, widely variable
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responses among different groups of MF patients have been reported, and the use of IFN-α in more advanced disease is not recommended [81]. The value of IFN-α for certain subgroups of patients with MF or in combination with JAK inhibitors has yet to be demonstrated.
6. JAK inhibition and changing the natural history of myelofibrosis Development of therapy that regulates the JAK-STAT pathway represents an important step forward towards therapy that alters the natural history of the disease. Although the most salient benefits are the alleviation of splenomegaly and non-spleen–
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related symptoms, concomitant with an improvement in QOL measures [11,12], there is compelling evidence that these therapies may improve the prognosis of these patients [15,16,82]. The mitigation of cachexia-associated risk factors, including weight loss
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[18,59], hypocholesterolemia [23,24,59], and elevated inflammatory cytokines [6,11,55] likely contributes to the apparent improved survival seen with the use of ruxolitinib.
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Moreover, at least in some patients treated with these new agents, progression of
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fibrosis may be retarded or relent [67,68,74]. With our current understanding, worsening marrow fibrosis, while clearly associated with cytopenias and ineffective hematopoiesis,
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is not definitively linked with a decline in overall survival. Moreover, although most patients with marrow fibrosis improvements had corresponding improvements in
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symptoms and spleen size in observational studies, changes in marrow fibrosis do not
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always parallel spleen size reduction or relief of disease-related symptoms [65,67]. In
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addition, the rapid clinical improvements seen in the COMFORT-II study were not accompanied by or dependent on major changes in marrow histomorphology [12].
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This raises the intriguing possibility that new therapies delay disease progression, including symptom onset in asymptomatic patients. A thorough assessment of the benefits and risks of these agents for lower-risk patients may require further exploration in clinical trials. Intervention in early stages of PMF with targeted therapies capable of changing the disease trajectory (Fig. 2) may lead to better outcomes, including longer survival and increased QOL. Because of the inherent clinical and genetic heterogeneity of the disease, individualized risk assessment may be helpful in predicting the disease course of individual patients more accurately. It is conceivable that specific patterns of inflammatory cytokine expression or gene expression
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signatures may be used in the future to identify patients who are at risk of more rapid deterioration and therefore would be candidates for earlier intervention. Elevated expression of IL-8 in the serum, which appears to be secondary to increased expression
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of nuclear factor eythroid-2 [83], has been identified as an independent risk factor for shortened survival in PMF [6], and serum levels may revert to normal values in both
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JAK2V617F-positive and -negative patients in response to JAK inhibitor therapy [55].
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JAK inhibitors have shown to be effective in patients with and without the JAK2V617F mutation [11,84].
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There are conflicting arguments as to the extent by which JAK2V617F allele burden correlates with disease severity in ET, PV and MF [85-87], but the general
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consensus is that allele burden is higher in more severe disease, at least in the case of
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ET. Furthermore, low allele burden at baseline was associated with improved treatment
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response to IFN-α in patients with PV or ET [88], whereas allele burden >1% shortly after alloHSCT was associated with increased risk of relapse and poorer overall survival
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[89]. JAK2V617F allele burden, which can be measured reliably from either peripheral blood or bone marrow biopsies [90] may prove useful and convenient in some clinical settings, such as estimating the risks of myelofibrotic transformation or thrombosis in patients with ET or PV [91]. However, JAK2V617F allele burden has not yet proven useful as a prognostic marker or harbinger of clinical responses to JAK inhibitors [84,92].
7. Conclusions
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With the exception of alloHSCT, and perhaps IFN-α in a select group of patients, conventional therapies do not impact the natural history of PMF in any appreciable way. Considering the successes achieved with therapy targeting the JAK-STAT pathway and
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the promising results achieved in early trials with other therapies targeted to pathogenic mechanisms of PMF, the treatment strategies and expectations are changing. Major
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advances in the treatment have been realized with the introduction of JAK inhibitors,
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and now a more versatile armamentarium is needed, given both the heterogeneity of the disease and the diversity of risk factors. Antifibrotic agents, immunomodulators, and
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epigenetic modifiers, which are currently in clinical trials, are plausible candidates as monotherapy or in combination with JAK inhibitors. It is hoped that earlier identification
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of patients with poor prognosis, together with more options for disease-modifying
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patients.
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therapy, will eventually lead to greater improvements in survival in a greater number of
A growing sentiment that the new rational therapies may change the natural
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history of the disease is reflected in the new consensus recommendations by the International Working Group‒Myeloproliferative Neoplasms Research and Treatment and European LeukemiaNet [93]. In addition to specifying the clinical and hematologic criteria for clinical improvement, anemia response, spleen response, and symptom response, the consensus recommendations provide rigorous definitions for complete and partial remission based on cytogenetic and molecular response [93]. With the accumulation of evidence indicating the potential for targeted agents to modify the disease course, there is new optimism that the goal of obtaining a complete response with drug therapy in an increasing number of patients is within reach. Disease activity in
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these patients is manifested by a variety of symptoms and metabolic derangements that seem to improve with JAK inhibition. In a progressive catabolic state such as PMF, sustained mitigation of these clinical characteristics seems to lead to improved survival,
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consistent with the notion that the trajectory of the natural history in these patients has
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changed.
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Funding
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Medical writing support was funded by Incyte Corporation.
Conflicts of interest
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Dr. Savona is a consultant for Karyopharm, Gilead Corporation, and Celgene Corporation, and serves on advisory boards for Karyopharm, Celgene, Bristol-Myers
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Acknowledgments
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Squibb, Novartis, and Incyte Corporation.
I thank Professor Jerry Spivak for key observations and thoughtful suggestions. Medical writing support, funded by Incyte Corporation, was provided by Stephanie Leinbach, PhD, and by Roland Tacke, PhD, of Evidence Scientific Solutions.
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33 Page 33 of 40
Table 1 JAK inhibitors in development for the treatment of PMF, PPV-MF, and PET-MF. Phase of
inhibited
development
Pacritinib (SB1518)
JAK2
III
Momelotinib (CYT387)
JAK1, JAK2
III
Lestaurtinib (CEP-701)
JAK2
II
LY2784544
JAK2V617F
II
AZD1480
JAK2
I/II
BMS-911543
JAK2
NS-018
JAK2
Company
ip t
JAK(s)
cr
Cell Therapeutics, Inc. Gilead Sciences, Inc.
an
us
Teva Pharmaceuticals
Eli Lilly and Company AstraZeneca
I/II
Bristol-Myers Squibb
I/II
NS Pharma, Inc.
M
Agent
JAK, Janus Kinase; PET-MF, post-essential thrombocythemia myelofibrosis; PMF,
Ac ce p
te
d
primary myelofibrosis; PPV-MF, post-polycythemia vera myelofibrosis.
34 Page 34 of 40
ip t cr
Table 2
us
DIPSS-Plus risk factors and major clinical manifestations of disease progression not captured by DIPSS-Plus. Validated laboratory risk factors not
Clinical risk factors not included in
included in DIPSS-Plus
DIPSS-Plus
Age >65
Elevated cytokines (eg, IL-8, IL-2R,
Marked splenomegaly (>10 cm below
Constitutional symptomsa
IL-12, and Il-15) [6]
left costal margin) [23] or increased
Somatic mutations (eg, ASXL1) [26]
spleen volume [25]
Hypocholesterolemia [23,24]
ce pt
(anemia)
ed
Hemoglobin 25 × 109/L (leukocytosis)
MF-related symptom burden aside from constitutional symptomsa Worsening bone marrow fibrosis [21,22]
9
Ac
Platelet count 10% of the baseline value in the year preceding diagnosis and/or unexplained fever or excessive sweats
cr
a
b
us
persisting for more than 1 month.
Complex karyotype or sole or 2 abnormalities that include +8, ‒7/7q-, i(17q), ‒5/5q-, 12p-, inv(3), or 11q23
M an
rearrangement.
Ac
ce pt
ed
DIPSS, Dynamic International Prognostic Scoring System; IL, interleukin; RBC, red blood cell; WBC, white blood cell.
36 Page 36 of 40
Figure Legends Fig. 1. Primary myelofibrosis (PMF) pathogenesis. Common overexpression of Janus Kinase 2 (JAK2) may result in additive activation of the Janus kinase–signal transducer
ip t
and activator of transcription (JAK2-STAT) pathway by facilitating increased cell surface expression of hematopoietic growth factor receptors. Somatic mutations in the
cr
thrombopoietin (TPO) receptor gene MPL or in JAK2 (ie, JAK2V617F) result in
us
constitutive activation of the JAK-STAT pathway in hematopoietic stem cells. JAK2V617F may cause epigenetic dysregulation by preventing histone H2A and H4
an
methylation through inactivation of protein arginine methyl transferase 5 or by decreasing chromatin-binding of HP1α, a repressor of heterochromatin activity. Other
M
epigenetic mutations associated with PMF, which may occur antecedent or precedent to
d
the acquisition of the JAK2V617 mutation [39], may affect the status of DNA methylation
te
(TET2), histone H3 methylation (EZH2), or chemical histone modification (ASXL1), resulting in dysregulated transcriptional activity [4,5]. CALR mutations, which are
Ac ce p
mutually exclusive with JAK2 and MPL mutations, appear to be early events in PMF pathogenesis, and, on occasion, have been associated with cytokine-independent STAT5 activation [38].
Fig. 2. Theoretical changes in hematopoietic potential with treatment of primary myelofibrosis (PMF) with rationally designed therapy. Hematopoietic function declines normally with age (gray dotted line), but under normal circumstances this doesn’t not contribute to mortality. Patients with PMF have shortened overall survival associated with progressive decline in normal hematopoiesis (red line), but therapeutic intervention
37 Page 37 of 40
may diminish progression of disease (green lines) to normal physiologic conditions or even lead to the resumption of hematopoiesis expected in age-matched controls (green dotted line). It is hoped that future efforts tailored to earlier intervention with rational
ip t
therapies will delay the accumulation of high-risk genetic lesions and consequent
Ac ce p
te
d
M
an
us
cr
clinical progression.
38 Page 38 of 40
TPO
an
us
cr
ip t
Figure 1
M
TPO TPO
TPO
JAK2
JAK K2 JAK2
JAK2
Ac ce p
JAK2 JAK2
te
d
MPL mutations
JAK2
Regulated activation of JAK-STAT
Overactivation of JAK-STAT
Additive STAT activation
STAT
STAT
STAT
STAT
?
JAK2 JAK2 V617F
JAK1/ JAK2
JAK2V617F activity results in chromatin demethylation and decreased binding of HP1α
STAT STAT
CALR mutations
Myeloproliferation Cell Survival Inflammatory cytokine expression
Epigenetic mutations (eg, TET2, ASXL1, EZH2)
Page 39 of 40
Hypothetical changes in the natural history of PMF with new therapies
Ac ce p
Expected natural history of PMF
te
d
M
an
us
cr
ip t
Figure 2
Hematopoiesis
Asymptomatic Symptomatic
Increasing BM impairment, clonal expansion, and declining performance status
Earlier vs later intervention may improve prognosis
Potential reversal of BM fibrosis and normalization of hematopoiesis?
Page 40 of 40
Increasing Age
S0145-2126(14)00123-4 http://dx.doi.org/doi:10.1016/j.leukres.2014.04.012 LR 5162
To appear in:
Leukemia Research
Received date: Revised date: Accepted date:
10-3-2014 14-4-2014 24-4-2014
Please cite this article as: Savona MR, Are we altering the natural history of primary myelofibrosis?, Leukemia Research (2014), http://dx.doi.org/10.1016/j.leukres.2014.04.012 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Are we altering the natural history of primary myelofibrosis?
Michael R. Savona, MD, FACP*
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Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
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*Corresponding author: Division of Hematology/Oncology, Vanderbilt University Medical
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Center, 2220 Pierce Avenue, 777 PRB, Nashville, TN 37232, USA. Tel: +1 615-3434677; Fax: +1 615-343-7602.
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E-mail address: [email protected] (M.R. Savona)
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ABSTRACT Primary myelofibrosis (PMF) is a clonal hematologic malignancy with a variable disease
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course; survival ranges from months to years. Historically, only allogeneic
hematopoietic stem cell transplantation (alloHSCT) has demonstrated an ability to alter
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the natural history of PMF, but high treatment-related mortality risks limit the utility of
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alloHSCT to a minority of patients with PMF or myelofibrosis secondary to other myeloproliferative neoplasms. The recent development of therapies that regulate the
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Janus kinase–signal transducer and activator of transcription signaling pathway has changed the treatment landscape from primarily palliative treatment to potential disease
JAK inhibitors
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Myelofibrosis
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Keywords (max = 6):
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modification.
Proinflammatory cytokines Spleen volume
Targeted therapy
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1. Introduction Primary myelofibrosis (PMF) is a Philadelphia chromosome–negative
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myeloproliferative neoplasm (MPN) characterized by progressive bone marrow fibrosis resulting in increasingly ineffective hematopoiesis, extramedullary hematopoiesis, a
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variety of inflammatory and vascular complications, and shortened survival. Patients
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with PMF have high circulating levels of proinflammatory cytokines believed to be responsible for constitutional symptoms and much of the morbidity associated with the
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disease. Common clinical manifestations of PMF include progressive hepatosplenomegaly, abnormal blood counts, and debilitating symptoms such as
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fatigue, weight loss, night sweats, fever, pruritus, bone pain, early satiety, abdominal
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pain or discomfort, arthralgias, myalgias, parasthesias, and even thromboembolic
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disease [1,2]. Both post-essential thrombocythemia (ET) myelofibrosis (PET-MF) and post-polycythemia vera (PV) myelofibrosis (PPV-MF) are phenotypically similar to PMF
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and all 3 diseases have a similar clinical course [3]. Consequently, most recent and ongoing clinical trials have mixed study populations of patients with PMF, PPV-MF, or PET-MF. In the absence of a clonal MPN, fibrosis in the bone marrow can occur in nonneoplastic states. However, for the sake of simplicity and for the purposes of this manuscript, PMF, PPV-MF, or PET-MF will be collectively described as myelofibrosis (MF). MF pathogenesis involves aberrant activation of the Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway, which may result from somatic mutations directly affecting JAK activity, excessive cytokine stimulation, and/or
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epigenetic modifications of chromatin structure interfering with normal regulation of gene expression [4-6]. The JAK2V617F gain-of-function mutation was identified several years ago and its association with myeloproliferative phenotypes of PMF, ET, and PV is
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well established [7-10]. Additional mutations within the JAK-STAT pathway have been identified since, and recent evidence suggests that mutations outside of the JAK-STAT
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pathway such as TET2 and ASXL1 also have important roles in pathogenesis [4,5].
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Dysregulation within the JAK-STAT pathway and epigenetic modifiers that influence the JAK-STAT pathway are commonly seen in MPNs, but no single dominant, sufficient,
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genetic mutation has been identified.
The discovery of the JAK2V617F mutation in patients with MPNs prompted
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further investigation in preclinical models and eventually led to the clinical development
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of JAK-targeted therapy for PMF. Several JAK inhibitors are currently in development
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(Table 1), and one agent, the oral JAK1/JAK2 inhibitor ruxolitinib, has been approved for patients with intermediate-1, intermediate-2, or high-risk PMF, PPV-MF, or PET-MF.
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In 2 phase III clinical trials in patients with intermediate-2 or high-risk MF, ruxolitinib has been shown to significantly reduce spleen volume and to alleviate MF-related symptoms compared with placebo or best available therapy (BAT) [11,12]. These advantages translated into clinically important improvements in quality of life (QOL) measures [1214], and long-term follow-up data from the 2 studies suggest that ruxolitinib prolongs overall survival versus both placebo and BAT in patients with MF [15,16]. Aside from allogeneic hematopoietic stem cell transplantation (alloHSCT), previously used therapies for PMF have been palliative, but with limited benefits in QOL and symptom management. Until recently, the only treatment with a clearly
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demonstrated impact on disease progression has been alloHSCT, but treatment-related mortality is high and only a minority of patients qualify for this intensive therapy [17]. New agents have the potential to alter the natural history and make a long-term impact
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on the disease. The aim of this article is to explore current evidence that new rationally
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designed therapy may alter the natural history of MF.
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2. Markers of disease progression and incompleteness of prognostic scoring systems
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The prognosis of PMF is variable. Risk stratification with the International Prognostic Scoring System (IPSS) [18], the Dynamic IPSS (DIPSS) [19], or the DIPSS-
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Plus [20] has helped clinicians to assign risk and determine appropriate candidates for
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alloHSCT. Each scoring system incorporates assorted patient risk factors for survival in
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predictive models based on multiparametric regression analyses. Important disease characteristics predictive of poor survival that are included in all of these scoring
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systems are age of >65 years, presence of constitutional symptoms (weight loss >10% of the baseline value in the year preceding diagnosis and/or unexplained fever or excessive sweats persisting for >1 month), hemoglobin 25 × 109/L, and circulating blasts ≥1% [18-20]. In addition, DIPSS-Plus includes unfavorable karyotype, platelet count 95% of patients with PV [42]. It results in
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constitutive activity of JAK2, which leads to excessive production of proinflammatory cytokines and transcription of cell survival–promoting molecules and anti-apoptotic
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molecules. The JAK-STAT pathway also may be overactive in patients who do not
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harbor the JAK2V617F mutation. For example, mutations in JAK2 exon 12 and the myeloproliferative leukemia virus proto-oncogene (MPL) encoding the thrombopoietin
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receptor, as well as in KIT, CBL, and TET2, have been consistently identified in patients with MPNs [1]. Recent analyses showed that most patients without a JAK2 or MPL
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mutation harbor mutations in the calreticulin gene (CALR), and cells expressing these
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mutations in CALR were sensitive to JAK2 inhibition [38,43]. In addition, patients without
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the JAK2V617F mutation have shown clinical responses to JAK inhibitor therapy [11], including individual patients with CALR mutations [44]. Altered gene expression as a
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result of epigenetic dysregulation in MPNs also may affect genes that play a role in cell survival, differentiation, and/or proliferation, including those encoding calcitonin A, ABL1, SFRP2, WIF-1, SOCS1, SOCS3, CXCR4, and RARβ2 [4]. For example, ASXL1 mutations have been associated with epigenetic dysregulation resulting in the loss of transcriptional repression of leukemogenic genes and in the silencing of tumor suppressor genes [45]. Thus, aberrant expression of numerous genes may contribute to the pathogenesis of PMF, regardless of the presence or absence of the JAK2V617F mutation.
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4. JAK inhibition: treatment responses and effect on survival Studies of JAK inhibition have shown benefits with regard to spleen volume, MFrelated symptoms, QOL, body weight, cholesterol levels, biomarkers and
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histopathology, and overall survival.
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4.1. Spleen volume
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The durability of spleen volume reductions with ruxolitinib treatment in patients with intermediate-2 or high-risk MF has now been demonstrated by long-term follow-up
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data from both COMFORT-I and COMFORT-II. In COMFORT-I, almost two-thirds of the patients who achieved a ≥35% reduction in spleen volume from baseline maintained
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this level of reduction for at least 2 years [15], and the probability of maintaining this
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response for >132 weeks was 53% [46]. Durable reductions in spleen volume also were
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observed in long-term analyses of data from COMFORT-II [16]. Treatment of patients with intermediate- or high-risk MF with the JAK1/2 inhibitor momelotinib (CYT387) for up
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to 2.5 years in a phase I/II trial resulted in reductions in palpable spleen size of ≥50% in more than half of the eligible patients, with a maximal response duration of almost 2 years [47]. Data from studies of other JAK inhibitors have thus far shorter periods of follow-up. Nonetheless, they also demonstrate the efficacy of JAK inhibition in improving splenomegaly. In a phase II trial, treatment with the JAK2 inhibitor pacritinib provided a ≥35% reduction in spleen volume at week 24 from baseline in 32% of patients with MF, and at the time of the report, the median duration of response had not been reached [48]. Similarly, considerable reductions in splenomegaly have been seen in early phase clinical trials with the JAK2 inhibitors fedratinib (SAR302503/TG101348) [49,50] and
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lestaurtinib [51], and with LY2784544 [52,53], a selective JAK2V617F inhibitor. In a phase II study of fedratinib, 30% to 64% of patients with MF achieved a ≥35% reduction in spleen volume after three 28-day cycles of therapy, illustrating the speed of
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considerable spleen size reduction [49]. (Unfortunately, clinical development of the drug was discontinued because of safety concerns prompted by reports of cases of
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Wernicke’s encephalopathy [54]).
4.2. Myelofibrosis-related symptoms and quality of life
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JAK inhibition improves MF-related symptoms, which seems to improve QOL. Ruxolitinib treatment has been shown to improve MF symptoms and QOL measures
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compared with both placebo and BAT [11,12]. In addition, spleen volume reductions
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were correlated with improvements in MF symptoms and QOL in COMFORT-I [13]. In
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the phase I trial of momelotinib, most treated patients experienced an improvement in constitutional symptoms [47]. Pacritinib therapy was associated with significant
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reductions in MF symptoms at 6 months, which included abdominal pain, bone pain, early satiety, worst fatigue, inactivity, night sweats, and pruritus [48]. The clinical experience with fedratinib also is marked with improvement or resolution of early satiety, fatigue, night sweats, itching, abdominal pain, and abdominal discomfort [49,50]. Reductions of symptom burden with LY2784544 were seen within the first 2 treatment cycles and included improvements in key MPN-related symptoms, fatigue/enjoyment of life, fatigue/walking ability, itching, early satiety, inactivity, bone pain, and night sweats [52]. At 12 weeks, a ≥50% reduction in total symptom burden was observed in 56% of patients [53].
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4.3. Body weight and metabolic status Cachexia is a common manifestation of disease progression, and unwanted
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weight loss has been established as a negative prognostic factor [18,23]. Cachexia in patients with MF likely is related to the excessive production of cytokines such as
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interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α), which are elevated in these
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patients [55]. Elevated blood levels of IL-6, which signals through the JAK-STAT pathway, have been associated with cancer-related cachexia in clinical studies [56,57],
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and TNF-α infusion recently has been shown to promote muscle protein loss and increased IL-6 release in healthy individuals [58]. In COMFORT-I, ruxolitinib treatment
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was associated with increases in body weight and total cholesterol from baseline,
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whereas both parameters decreased over time in patients who received placebo [59].
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Specific effects of JAK inhibition on cachexia are not well illustrated, but improvement of appetite and metabolic status are strongly correlated with spleen size reduction.
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Changes in body weight or total cholesterol with JAK inhibitors other than ruxolitinib have not been reported to date.
4.4. Biomarkers of inflammation
Chronically elevated levels of proinflammatory cytokines have been implicated in the pathogenesis of bone marrow fibrosis [60] as well as in the mediation of noxious effects underlying the compromised metabolic/nutritional status in affected patients [6,11,55]. In addition, the circulating levels of some cytokines, including IL-8, IL-2R, IL12, and IL-15, have been shown to be independent prognostic factors of survival in
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patients with MF, which suggests a possible role in disease progression [6]. Because these cytokines may support the tumor microenvironment through autocrine signaling that promotes tumor cell survival and proliferation, it is reasonable to hypothesize that
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the normalization of circulating cytokine levels may alter the trajectory of disease
evolution. Rapid reductions in plasma levels of proinflammatory cytokines have been
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observed in response to ruxolitinib (IL-8, IL-6, and TNF-α) [11,55] and fedratinib (TNF-α,
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IL-1RA, and IL-18) [49]. Given the association between elevated cytokine expression
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and survival [6], this decrease in inflammatory biomarkers is encouraging.
4.5. Bone marrow fibrosis
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Bone marrow fibrosis is variable and typically graded by the density of reticulin
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and collagen fibers in marrow replacement [61]. In PMF, marrow fibrosis is usually
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progressive and there is increasing evidence that bone marrow fibrosis grade has prognostic significance [21,22]. Marrow fibrosis may resolve spontaneously in rare
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cases [62,63] or with alloHSCT [64] and may respond to treatment with interferon-alpha (IFN-α) in select patients [65]. Otherwise, reversal of marrow fibrosis has not been seen with traditional therapies. However, a post hoc analysis from the ruxolitinib phase I/II study suggests that JAK inhibition may be able to slow the progression of bone marrow fibrosis in some patients [66,67]. Bone marrow biopsies from patients treated with ruxolitinib in a single institution phase I/II study were matched to historical control bone marrow biopsies from patients who received BAT in Europe at corresponding time points. At 5 years of follow-up, 35% of ruxolitinib-treated compared with 3% of BATtreated patients showed improvement in bone marrow fibrosis grade. Furthermore, the
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odds for worsening bone fibrosis was significantly greater with BAT (76%; n=29) than ruxolitinib (26%; n=23) [67]. Consistent with the notion that JAK inhibition may have a positive impact on bone marrow fibrosis [68], data from the phase I study of LY2784544
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showed that after 5 cycles of therapy, bone marrow fibrosis grade was reduced in 3 of 5 MF patients analyzed [52].
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Although encouraging, the improvement in bone marrow fibrosis observed in
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patients receiving JAK inhibitors generally occurred slowly and overall was modest. For many patients lasting improvement of bone marrow function may require a multifaceted
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approach beyond the use of JAK inhibitors. In the future, this approach may include the use of epigenetic modifiers such as the histone deacetylase (HDAC) inhibitor
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panobinostat [69,70], or antifibrotic agents such as PRM-151 (recombinant human
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pentraxin-2) [71] and a monoclonal antibody against LOXL-2 [72]. These agents will be
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4.6. Overall survival
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discussed in more detail in Section 5.
Follow-up data from COMFORT-I and COMFORT-II suggest that ruxolitinib therapy was associated with a survival advantage compared with both placebo and BAT [15,16]. These analyses were based on randomized treatment allocation at the beginning of the studies, and the control arms included patients who crossed over to ruxolitinib treatment after meeting prespecified conditions of disease progression. In COMFORT-I, all patients randomized to placebo had discontinued or were receiving ruxolitinib within 3 months after the primary analysis [15]. The short exposure to placebo taken together with the growing exposure to ruxolitinib treatment in the placebo group
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has made interpretation of survival benefits difficult [46]. Exploratory statistical analyses suggest that the diminished survival disadvantage of the placebo arm (compared with the ruxolitinib arm) at 3 versus 2 years follow-up may be a direct result of the crossover
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to ruxolitinib in this treatment arm [46]. A corresponding effect was not observed in COMFORT-II [16], likely because of delayed crossover from BAT to ruxolitinib
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consequent to differences in crossover rules between the COMFORT studies.
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Nonetheless, depending on the time of analysis, patients randomized to ruxolitinib generally had a survival advantage of 30% to 50% compared with those randomized to
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placebo [11,15] or BAT [16]. Consistent with these findings, a comparison of survival data from patients with PMF from the COMFORT-II study with those from a matched
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control population of the DIPSS study [73] revealed a 36% reduction in the risk of death
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with ruxolitinib versus conventional therapy (HR = 0.64; 95% confidence interval:
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0.4‒0.96; P = 0.034). Additional analyses showed that the use of ruxolitinib doubled the 8-year survival probability at diagnosis from 15.9% to 32.2%. Together, these data
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suggest that ruxolitinib may affect disease progression and alter the natural history of the disease.
5. Rational approaches to modification of disease beyond JAK inhibition In addition to the investigational JAK inhibitors, agents targeted to other signaling pathways or to epigenetic modifiers are in various stages of clinical development for the treatment of MPN-associated MF. They include HDAC inhibitors and immunomodulatory drugs. In addition, the antifibrotic monoclonal antibodies fresolimumab and GS-6624, recombinant PTX-2, and the telomerase inhibitor imetelstat
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(GRN163L) may have potential roles in treatment as single agents or in combination therapy. Recently, encouraging results were obtained in a single-center study of the telomerase inhibitor imetelstat in patients with intermediate-2 or high-risk MF. Of 18
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patients followed for at least 3 months, 8 (44%) had an overall response, including 4 patients with complete remission, as evidenced by the reversal of BM fibrosis and
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recovery of normal megakaryocyte morphology, and 1 patient with partial remission
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[74].
In addition to imetelstat, approaches complementary to JAK inhibitor therapy to
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reverse bone marrow fibrosis or retard its progression are being explored. The human monoclonal antibody fresolimumab antagonizes transforming growth factor beta
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(TGFβ), a mediator of bone marrow fibrosis in thrombopoietin-induced MF [75,76], and
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it has been safely administered to patients with focal segmental glomerulosclerosis [77].
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Likewise, a monoclonal antibody (GS6624, AB0023) targeting lysyl oxidase-like 2 (LOXL-2), a protein active in the remodeling of extracellular matrix architecture in
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pathologic fibrosis, has been shown to reduce TGFβ pathway signaling and fibroblast activation in murine models of fibrosis [72]. A phase II study of the anti-LOXL-2 antibody GS6624 as monotherapy or in combination with ruxolitinib is underway in patients with MF. PRM-151 (recombinant human serum amyloid P/pentraxin 2), an antifibrotic protein, has recently been shown in an initial phase I study to be well tolerated and to reduce fibrocyte numbers by 30% to 50% in patients with pulmonary fibrosis [78]. Investigation in patients with MF is underway. Panobinostat (LBH589) is a pan-HDAC inhibitor that was shown in a phase I trial to achieve a 100% reduction in palpable splenomegaly in 3 of 5 patients who received
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at least 6 cycles of treatment and were evaluable for response; the other 2 patients had stable disease [79]. One of the 3 patients who had 100% reduction in splenomegaly demonstrated bone marrow fibrosis resolution after 16 cycles [79]. In a phase II trial of
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22 patients with intermediate- or high-risk MF, the HDAC inhibitor pracinostat achieved a median 3-cm reduction in splenomegaly in 6 (27%) patients [80]. These and other
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targeted agents may be most effective when given in combination with JAK inhibitors to
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maximize blockade of disease mechanisms. Studies of combination therapy with rational combinations of these targeted agents are in progress. In a recent phase I
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study, prolonged therapy with panobinostat elicited dramatic reversal of bone marrow histopathologic abnormalities in 2 patients [79]. A combination study of panobinostat
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and ruxolitinib in patients with MF is ongoing.
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The use of IFN-α may lead to spleen size and symptom improvement as well as
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reduction in marrow fibrosis in some patients, particularly those with early-stage disease [65]. However, as a recent analysis of studies of IFN-α shows, widely variable
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responses among different groups of MF patients have been reported, and the use of IFN-α in more advanced disease is not recommended [81]. The value of IFN-α for certain subgroups of patients with MF or in combination with JAK inhibitors has yet to be demonstrated.
6. JAK inhibition and changing the natural history of myelofibrosis Development of therapy that regulates the JAK-STAT pathway represents an important step forward towards therapy that alters the natural history of the disease. Although the most salient benefits are the alleviation of splenomegaly and non-spleen–
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related symptoms, concomitant with an improvement in QOL measures [11,12], there is compelling evidence that these therapies may improve the prognosis of these patients [15,16,82]. The mitigation of cachexia-associated risk factors, including weight loss
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[18,59], hypocholesterolemia [23,24,59], and elevated inflammatory cytokines [6,11,55] likely contributes to the apparent improved survival seen with the use of ruxolitinib.
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Moreover, at least in some patients treated with these new agents, progression of
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fibrosis may be retarded or relent [67,68,74]. With our current understanding, worsening marrow fibrosis, while clearly associated with cytopenias and ineffective hematopoiesis,
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is not definitively linked with a decline in overall survival. Moreover, although most patients with marrow fibrosis improvements had corresponding improvements in
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symptoms and spleen size in observational studies, changes in marrow fibrosis do not
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always parallel spleen size reduction or relief of disease-related symptoms [65,67]. In
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addition, the rapid clinical improvements seen in the COMFORT-II study were not accompanied by or dependent on major changes in marrow histomorphology [12].
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This raises the intriguing possibility that new therapies delay disease progression, including symptom onset in asymptomatic patients. A thorough assessment of the benefits and risks of these agents for lower-risk patients may require further exploration in clinical trials. Intervention in early stages of PMF with targeted therapies capable of changing the disease trajectory (Fig. 2) may lead to better outcomes, including longer survival and increased QOL. Because of the inherent clinical and genetic heterogeneity of the disease, individualized risk assessment may be helpful in predicting the disease course of individual patients more accurately. It is conceivable that specific patterns of inflammatory cytokine expression or gene expression
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signatures may be used in the future to identify patients who are at risk of more rapid deterioration and therefore would be candidates for earlier intervention. Elevated expression of IL-8 in the serum, which appears to be secondary to increased expression
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of nuclear factor eythroid-2 [83], has been identified as an independent risk factor for shortened survival in PMF [6], and serum levels may revert to normal values in both
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JAK2V617F-positive and -negative patients in response to JAK inhibitor therapy [55].
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JAK inhibitors have shown to be effective in patients with and without the JAK2V617F mutation [11,84].
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There are conflicting arguments as to the extent by which JAK2V617F allele burden correlates with disease severity in ET, PV and MF [85-87], but the general
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consensus is that allele burden is higher in more severe disease, at least in the case of
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ET. Furthermore, low allele burden at baseline was associated with improved treatment
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response to IFN-α in patients with PV or ET [88], whereas allele burden >1% shortly after alloHSCT was associated with increased risk of relapse and poorer overall survival
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[89]. JAK2V617F allele burden, which can be measured reliably from either peripheral blood or bone marrow biopsies [90] may prove useful and convenient in some clinical settings, such as estimating the risks of myelofibrotic transformation or thrombosis in patients with ET or PV [91]. However, JAK2V617F allele burden has not yet proven useful as a prognostic marker or harbinger of clinical responses to JAK inhibitors [84,92].
7. Conclusions
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With the exception of alloHSCT, and perhaps IFN-α in a select group of patients, conventional therapies do not impact the natural history of PMF in any appreciable way. Considering the successes achieved with therapy targeting the JAK-STAT pathway and
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the promising results achieved in early trials with other therapies targeted to pathogenic mechanisms of PMF, the treatment strategies and expectations are changing. Major
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advances in the treatment have been realized with the introduction of JAK inhibitors,
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and now a more versatile armamentarium is needed, given both the heterogeneity of the disease and the diversity of risk factors. Antifibrotic agents, immunomodulators, and
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epigenetic modifiers, which are currently in clinical trials, are plausible candidates as monotherapy or in combination with JAK inhibitors. It is hoped that earlier identification
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of patients with poor prognosis, together with more options for disease-modifying
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patients.
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therapy, will eventually lead to greater improvements in survival in a greater number of
A growing sentiment that the new rational therapies may change the natural
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history of the disease is reflected in the new consensus recommendations by the International Working Group‒Myeloproliferative Neoplasms Research and Treatment and European LeukemiaNet [93]. In addition to specifying the clinical and hematologic criteria for clinical improvement, anemia response, spleen response, and symptom response, the consensus recommendations provide rigorous definitions for complete and partial remission based on cytogenetic and molecular response [93]. With the accumulation of evidence indicating the potential for targeted agents to modify the disease course, there is new optimism that the goal of obtaining a complete response with drug therapy in an increasing number of patients is within reach. Disease activity in
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these patients is manifested by a variety of symptoms and metabolic derangements that seem to improve with JAK inhibition. In a progressive catabolic state such as PMF, sustained mitigation of these clinical characteristics seems to lead to improved survival,
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consistent with the notion that the trajectory of the natural history in these patients has
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changed.
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Funding
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Medical writing support was funded by Incyte Corporation.
Conflicts of interest
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Dr. Savona is a consultant for Karyopharm, Gilead Corporation, and Celgene Corporation, and serves on advisory boards for Karyopharm, Celgene, Bristol-Myers
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Acknowledgments
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Squibb, Novartis, and Incyte Corporation.
I thank Professor Jerry Spivak for key observations and thoughtful suggestions. Medical writing support, funded by Incyte Corporation, was provided by Stephanie Leinbach, PhD, and by Roland Tacke, PhD, of Evidence Scientific Solutions.
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33 Page 33 of 40
Table 1 JAK inhibitors in development for the treatment of PMF, PPV-MF, and PET-MF. Phase of
inhibited
development
Pacritinib (SB1518)
JAK2
III
Momelotinib (CYT387)
JAK1, JAK2
III
Lestaurtinib (CEP-701)
JAK2
II
LY2784544
JAK2V617F
II
AZD1480
JAK2
I/II
BMS-911543
JAK2
NS-018
JAK2
Company
ip t
JAK(s)
cr
Cell Therapeutics, Inc. Gilead Sciences, Inc.
an
us
Teva Pharmaceuticals
Eli Lilly and Company AstraZeneca
I/II
Bristol-Myers Squibb
I/II
NS Pharma, Inc.
M
Agent
JAK, Janus Kinase; PET-MF, post-essential thrombocythemia myelofibrosis; PMF,
Ac ce p
te
d
primary myelofibrosis; PPV-MF, post-polycythemia vera myelofibrosis.
34 Page 34 of 40
ip t cr
Table 2
us
DIPSS-Plus risk factors and major clinical manifestations of disease progression not captured by DIPSS-Plus. Validated laboratory risk factors not
Clinical risk factors not included in
included in DIPSS-Plus
DIPSS-Plus
Age >65
Elevated cytokines (eg, IL-8, IL-2R,
Marked splenomegaly (>10 cm below
Constitutional symptomsa
IL-12, and Il-15) [6]
left costal margin) [23] or increased
Somatic mutations (eg, ASXL1) [26]
spleen volume [25]
Hypocholesterolemia [23,24]
ce pt
(anemia)
ed
Hemoglobin 25 × 109/L (leukocytosis)
MF-related symptom burden aside from constitutional symptomsa Worsening bone marrow fibrosis [21,22]
9
Ac
Platelet count 10% of the baseline value in the year preceding diagnosis and/or unexplained fever or excessive sweats
cr
a
b
us
persisting for more than 1 month.
Complex karyotype or sole or 2 abnormalities that include +8, ‒7/7q-, i(17q), ‒5/5q-, 12p-, inv(3), or 11q23
M an
rearrangement.
Ac
ce pt
ed
DIPSS, Dynamic International Prognostic Scoring System; IL, interleukin; RBC, red blood cell; WBC, white blood cell.
36 Page 36 of 40
Figure Legends Fig. 1. Primary myelofibrosis (PMF) pathogenesis. Common overexpression of Janus Kinase 2 (JAK2) may result in additive activation of the Janus kinase–signal transducer
ip t
and activator of transcription (JAK2-STAT) pathway by facilitating increased cell surface expression of hematopoietic growth factor receptors. Somatic mutations in the
cr
thrombopoietin (TPO) receptor gene MPL or in JAK2 (ie, JAK2V617F) result in
us
constitutive activation of the JAK-STAT pathway in hematopoietic stem cells. JAK2V617F may cause epigenetic dysregulation by preventing histone H2A and H4
an
methylation through inactivation of protein arginine methyl transferase 5 or by decreasing chromatin-binding of HP1α, a repressor of heterochromatin activity. Other
M
epigenetic mutations associated with PMF, which may occur antecedent or precedent to
d
the acquisition of the JAK2V617 mutation [39], may affect the status of DNA methylation
te
(TET2), histone H3 methylation (EZH2), or chemical histone modification (ASXL1), resulting in dysregulated transcriptional activity [4,5]. CALR mutations, which are
Ac ce p
mutually exclusive with JAK2 and MPL mutations, appear to be early events in PMF pathogenesis, and, on occasion, have been associated with cytokine-independent STAT5 activation [38].
Fig. 2. Theoretical changes in hematopoietic potential with treatment of primary myelofibrosis (PMF) with rationally designed therapy. Hematopoietic function declines normally with age (gray dotted line), but under normal circumstances this doesn’t not contribute to mortality. Patients with PMF have shortened overall survival associated with progressive decline in normal hematopoiesis (red line), but therapeutic intervention
37 Page 37 of 40
may diminish progression of disease (green lines) to normal physiologic conditions or even lead to the resumption of hematopoiesis expected in age-matched controls (green dotted line). It is hoped that future efforts tailored to earlier intervention with rational
ip t
therapies will delay the accumulation of high-risk genetic lesions and consequent
Ac ce p
te
d
M
an
us
cr
clinical progression.
38 Page 38 of 40
TPO
an
us
cr
ip t
Figure 1
M
TPO TPO
TPO
JAK2
JAK K2 JAK2
JAK2
Ac ce p
JAK2 JAK2
te
d
MPL mutations
JAK2
Regulated activation of JAK-STAT
Overactivation of JAK-STAT
Additive STAT activation
STAT
STAT
STAT
STAT
?
JAK2 JAK2 V617F
JAK1/ JAK2
JAK2V617F activity results in chromatin demethylation and decreased binding of HP1α
STAT STAT
CALR mutations
Myeloproliferation Cell Survival Inflammatory cytokine expression
Epigenetic mutations (eg, TET2, ASXL1, EZH2)
Page 39 of 40
Hypothetical changes in the natural history of PMF with new therapies
Ac ce p
Expected natural history of PMF
te
d
M
an
us
cr
ip t
Figure 2
Hematopoiesis
Asymptomatic Symptomatic
Increasing BM impairment, clonal expansion, and declining performance status
Earlier vs later intervention may improve prognosis
Potential reversal of BM fibrosis and normalization of hematopoiesis?
Page 40 of 40
Increasing Age
