This was associated with a sustained decline in doses and schedules in MF are not yet deﬁned and that MF patients circulating CD34 cells in responding patients pyridium 200mg cheap. Toxicity was largely may be more susceptible to myelosuppression with these agents discount 200 mg pyridium overnight delivery, hematologic; there were few nonhematologic side effects generic pyridium 200 mg otc. There are ongoing efforts to determine have also been published case reports of clinical beneﬁt associated optimal combinations, potentially using lower doses that may with decitabine use in MF. There is emerging evidence to suggest that DNMT inhibitors may be active in the treatment of Ph MPNs that have progressed to There is preclinical evidence in vitro and in murine models to acute myeloid leukemia or myelodysplastic syndrome (MDS). These include This is a subgroup of patients with a very dismal outcome, typiﬁed combination of an HDAC inhibitor with a DNMT inhibitor to by an extremely short survival with conventional treatment ap- simultaneously effect 2 pathways of epigenetic silencing in MF. Median response duration was 9 months, suggest- explored. This approach is supported by preclinical studies demon- ing the need for additional alternative or consolidative approaches strating synergy in vitro in JAK2V617F mutant cell lines and in vivo to produce further improvements in outcome. HDAC inhibitors have also been investigated in clinical trials in MF. In a phase 1 dose-escalation study of panobinostat in 18 Additional work is necessary to determine whether other compo- patients with MF,22 3 of 5 evaluable patients who received more nents of the epigenetic regulation machinery, such as histone than 6 cycles of therapy had an improvement in spleen volume methyltransferases, histone demethylases, histone acetyltrans- and/or anemia. Reversible thrombocytopenia was the dose-limiting ferases, and sirtuins, are potential therapeutic targets in MF. Interestingly, one of these patients was reported to have preclinical studies suggest that the effects of mutant proteins such as achieved a near complete remission with signiﬁcant reduction in IDH1 and IDH2, which contribute to epigenetic dysregulation in BM ﬁbrosis and resolution of splenomegaly and leukoerythoblasto- myeloid neoplasia, can be abrogated by speciﬁc inhibitors of those proteins. The recommended phase 2 dose in this trial was 25 mg components of the epigenetic machinery has the potential to three times weekly, which was signiﬁcantly lower than the doses transform the epigenetic therapeutic landscape in myeloid neo- used in other early phase trials conducted with this agent. Interestingly, to inhibit lipopolysaccharide-induced inﬂammatory cytokines such the responses observed were independent of the JAK2 mutational as TNF , in addition to costimulation of T cells and augmentation status, suggesting that additional work is necessary to identify the of cytotoxic T- and NK-cell effector functions. The effects of these predictors of clinical activity given the pleiotropic effects of these agents are pleiotropic and include antiangiogenic effects. Combination approaches involving epigenetic Response rates with thalidomide-based regimens when reassessed modulators in MF recently by IWG criteria were in the 22% range for anemia and 8% The clinical trials conducted to date with DNMT and HDAC for splenomegaly, with a median duration of 8. The experi- eral neuropathy, constipation, and myelosuppression were the most ence with this class of agents in other myeloid neoplasms such as notable toxicities. Twenty-two percent of patients overall failed to MDS would suggest that repeated cycles are necessary for optimum complete 3 cycles of therapy and the thalidomide-prednisone clinical activity. Ongoing challenges include the fact that optimum regimen was the most tolerable of the 3 thalidomide-based regimens Hematology 2013 547 evaluated. Both wild-type JAK2 and JAK2V617F have been demonstrated to be client proteins of HSP90. In a phase 2, multicenter, randomized, double-blind, resulted in degradation of JAK2 protein, inhibition of JAK/STAT 36 signaling, and inhibition of cell growth. Prednisone was blood counts, decline of the JAK2V617F allele burden, and administered on a tapering schedule for 3 cycles starting at 30 mg/d improved survival in mice at a dose that did not affect JAK2 in in the ﬁrst cycle. The IWG anemia response rates in the 4 treatment 42 normal tissues or cause signiﬁcant toxicity. Interestingly, heterodi- arms were 23%, 16%, 36%, and 19%, respectively. Median duration meric JAK/STAT activation (heterodimerization of JAK2 with of response was 7. Pomalidomide was well tolerated in JAK1 or TYK2) has been implicated as a mechanism of persistent that trial, with relatively minimal myelosuppression observed (in disease in the face of JAK2 inhibitor therapy and cell lines that contrast to prior experience with lenalidomide), and there were no harbored this mechanism of activated JAK2 persistence retained signiﬁcant reports of peripheral neuropathy (in contrast to prior their sensitivity to HSP90 inhibitors. Overall, the results suggested that the to express JAK2 kinase domain mutations that conferred resistance 0. A subsequent report of the long-term outcome HSP90 inhibitors. The There is currently an ongoing single-agent trial of the HSP90 absence of a JAK2V617F mutation in the context of circulating inhibitor AUY922 in patients with Ph MPNs, including MF blasts 5% or palpable splenomegaly 10 cm was negatively (Table 1). Combination studies of HSP90 plus JAK inhibitors are correlated with the achievement of a response. Accrual has been Antiﬁbrosis agents completed for an ongoing placebo-controlled phase 3 trial of Allogeneic stem cell transplantation is the only therapeutic pomalidomide in transfusion-dependent MF (Table 1), and the modality to date that has been demonstrated conclusively to lead results of this trial are eagerly awaited. Given the demonstrable to a reversal of ﬁbrosis in MF. The pathogenetic mechanisms activity of thalidomide analogs in improving anemia in MF, there underlying the development of ﬁbrosis in MF are poorly are combination trials under way of ImiDs with other agents, understood. Although MF has been established to be a clonal including JAK inhibitors, in an effort to optimize the clinical disorder of pluripotent stem cell origin, the ﬁbroblasts have been activity of this class of drugs in MF (Table 2). The BM ﬁndings in MF include increases in the numbers of stromal cells and in levels of extracellular matrix IFN proteins, angiogenesis, and osteosclerosis. Multiple mechanisms have been proposed for IFN- activity in myeloid neoplasia, including effects on immunomodulatory cells Monoclonal antibodies such as T cells and NK cells, induction of proapototic genes, A current pathogenetic hypothesis with regard to the genesis of suppression of proliferation of hematopoietic progenitor cells, and 38 ﬁbrosis in MF is that clonal megakaryocytes secrete ﬁbrogenic and inhibition of angiogenesis. IFN- at conventional doses in estab- 46,47 angiogenic cytokines including TGF and MMP-9. A common lished MF is associated with signiﬁcant myelosuppression and theme emerging from several murine models of MF is that there nonhematologic toxicities such as fatigue that have limited its use in is a signiﬁcant association between increased numbers of mega- MF. With the availability of more tolerable pegylated preparations karyocytes and the development of an extracellular matrix and the demonstration that pegylated IFN can induce molecular typical of MF, and these ﬁndings lend credence to the hypothesis responses in polycythemia vera, there has been a recent interest in that megakaryocytes play a central role in ﬁbrogenesis. Novel agents targeting pathways downstream of the JAK/STAT signaling pathway in MF. Activated JAK2 signals through and activates downstream signaling intermediates such as STAT5, RAS/MAPK, and PI3K/AKT/mTOR pathways, leading to effects on proliferation and survival of MPN cells. JAK proteins can be down-modulated by the use of HSP90 inhibitors or HDAC inhibitors, which lead to targeting of both wild-type and mutant proteins for degradation by the proteosomal system. PI3K/AKT inhibitors, mTOR inhibitors, MEK inhibitors, and STAT inhibitors can inhibit the respective signaling intermediates downstream of JAK/STAT pathway. DNMT inhibitors can potentially reverse epigenetic silencing of various genes including the SOCS genes, which are negative regulators of the JAK/STAT signaling pathway. There several signaling intermediates downstream of the JAK/ The trial was terminated early due to drug supply issues after STAT signaling pathway (Figure 3) that constitute rational therapeu- enrollment of just 3 patients. The PI3K/AKT/mammalian target of rapamycin TGF in MF is supported by a recent study identifying abnormal (mTOR) pathway has been shown to be dysregulated in MPNs and genetic signatures in TGF 1 signaling in the spleen and BM AKT activation has been found to be critical for JAK2V617F- from the GATA-1low mouse, a murine model of MF. AKT and mTOR inhibitors have of TGF 1 signaling in this mouse model normalized this been associated with growth inhibition of primary MPN cells and aberrant gene expression signature, restored hematopoiesis and cell lines in vitro. These ﬁndings have led to the clinical investiga- megakaryocyte development, and reduced ﬁbrosis, neovascular- tion of mTOR inhibitors in MF. A minority of patients (15%- monoclonal antibody against lysyl oxidase (LOX)-like protein 2. LOX is a copper-dependent enzyme that initiates the covalent Although known targets of mTOR such as phosphor-p70S6K were cross-linking of collagen or elastin and was shown to be abundant in identiﬁed as potential biomarkers of response to the agent, there was the GATA-1low mouse, which is characterized by signiﬁcant MF and no signiﬁcant effect on MF-related biomarkers such as JAK2V617F high levels of low-ploidy megakaryocytes. Inhibition of LOX allelic burden, circulating CD34 cells, or cytokine levels. The drug enzymatic activity led to a signiﬁcant improvement of the ﬁbrotic was well tolerated, with grade 1-2 stomatitis being the most phenotype, leading to the speculation that LOX is a potential common toxicity. Combinations of JAK inhibitors and PI3K Aurora kinase inhibitors inhibitors may also be reasonable (Table 2) based on emerging Another potential target of the megakaryocyte-ﬁbrosis axis are preclinical evidence that suggests synergy. In acute megakaryocytic leukemia, a disease with a dismal prognosis characterized by expansion of immature mega- karyocytes and profound BM ﬁbrosis, aurora kinase A was identi- How I treat MF in the JAK kinase inhibitor era ﬁed as a mediator of polyploidization of malignant megakaryocytes. Given the variability in outcome associated with MF, a comprehen- Aurora kinase A inhibition in acute megakaryocytic leukemia led to sive assessment including risk stratiﬁcation according to contempo- apoptosis of malignant megakaryocytes and induced polyploidiza- rary prognostic scoring models such as the Dynamic International tion and expression of mature megakaryocyte markers. I use a watch and wait led to the speculation that aurora kinase A could be a valid approach in asymptomatic lower (low- and intermediate-1) risk therapeutic target in MF, and there are ongoing preclinical studies to patients, whereas those with higher (intermediate-2 and high-) risk validate these assertions. Given the emerging data for Hematology 2013 549 Figure 4. The DIPSS can be used for risk stratiﬁcation at any time point during the course of MF. Prognostic variables are each assigned a score of 1 point, except for anemia, which is assigned a score of 2 points. These variables include: age 65 years, anemia (deﬁned as hemoglobin 10 g/dL), WBC count 25 109/L, circulating blasts 1%, and constitutional systems. The recommended treatment algorithm according to risk stratum categories (low, intermediate 1 [Int-1]; intermediate 2 [Int-2], and high) is summarized in the ﬁgure. Early referral for allogeneic stem cell transplantation and/or enrollment in clinical trials is recommended for symptomatic or higher risk patients with signiﬁcant cytopenias (hemoglobin 10 g/dL, platelet count 100 K/ L) and/or prior JAK inhibitor exposure.
In several head- 3-11 to-head trials cheap pyridium 200mg line, beta blockers have similar effects on blood pressure control buy pyridium 200 mg line. No trials have examined whether beta blockers have different effects on all-cause mortality cheap pyridium 200 mg free shipping, cardiovascular mortality, or cardiovascular events among patients with hypertension. By the time beta blockers became available, diuretics had already been shown to prevent cardiovascular events, primarily strokes. It was considered unethical to compare a beta blocker to placebo in patients who were likely to benefit from a diuretic. For this reason, most large, long- term trials of beta blocker therapy for hypertension used a comparison group taking a diuretic rather than a placebo. Unlike diuretics, then, beta blockers have not been clearly demonstrated to be more effective than placebo in reducing cardiovascular events when used as initial therapy in the general population of patients with hypertension. The Medical Research Council trials, the International Prospective Primary Prevention Study in Hypertension, the Heart Attack Primary Prevention in Hypertension study, and the Metoprolol Atherosclerosis Prevention in Hypertensives study compared a beta blocker to a thiazide diuretic. Of these trials, only the 2 Medical Research Council trials compared a beta blocker to placebo. In 1 Medical Research Council trial, atenolol 50 mg daily was not better than placebo and less effective than a diuretic in adults ages 65 to 74 who had baseline blood 12 pressures of 160/115 mm Hg or higher. In the other Medical Research Council trial, which recruited 17 361 patients with mild diastolic hypertension (90 to 109 mm Hg), beta blocker therapy (atenolol) reduced the odds for stroke, but only in nonsmokers and to a smaller degree 13 than a low dose of a thiazide diuretic (bendrofluazide). Of the trials that compared a beta blocker with a diuretic, only 1 (Metoprolol Atherosclerosis Prevention in Hypertensives study) had any suggestion that the beta blocker was more effective. In that trial, deaths from heart attacks and strokes as well as total mortality were lower in the metoprolol treated group than in those treated with a diuretic (hydrochlorothiazide 14 or bendroflumethiazide). The trial continues to be cited as strong evidence that beta blockers reduce mortality when used as primary treatment for hypertension. However, it must be weighed against the mixed results of the Medical Research Council trials and other trials of beta blockers compared with diuretics. In a good-quality meta-analysis of 10 trials published in 1998 or earlier, beta blockers were ineffective, or less effective than comparator drugs, in preventing coronary heart disease, cardiovascular mortality, and all-cause mortality (odds ratios 1. Secondary treatment The Systolic Hypertension in the Elderly Program (SHEP) trial examined a stepped approach for 16 treating isolated systolic hypertension in the elderly. Atenolol was prescribed if the blood pressure goal could not be achieved with chlorthalidone 25 mg daily. Compared to placebo, stepped treatment prevented 55 cardiovascular events per 1000 patients over 5 years. The contribution of beta blocker therapy with atenolol to the overall benefit is not clear; most of the benefit was attributed to chlorthalidone. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial 17 (2002) did not include a beta blocker arm. Based on the results of this trial, the Joint National Beta blockers Page 20 of 122 Final Report Update 4 Drug Effectiveness Review Project Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC-7) recommends a diuretic as the first-line treatment for most patients who have Stage 1 18 hypertension without compelling indications. Quality of life There was no definitive evidence that 1 beta blocker yields a better quality of life than another 19 for patients who have hypertension. Eight trials directly compared different beta blockers on changes of quality of life-associated measures. We excluded 2 trials of atenolol compared with 7, 20 propranolol based on poor-quality ratings. The methods described in these publications were insufficient to rule out the possibilities that results were biased by inadequate randomization procedures (methods weren’t described and baseline characteristics weren’t reported) and/or by mishandling of missing data (attrition reasons not described and proportion of patients included in analyses not reported). Table 4 below summarizes the results of the fair-quality trials. The strongest evidence of any differences between beta blockers came from a 4 week trial of captopril, enalapril, propranolol, and atenolol that used a larger sample size (N=360) and 8 a parallel design. This was the only trial that is clearly industry-funded. Patients were all men that were “at least 21 years of age, employed or retired, educated at high-school level or equivalent, and married or living with a significant other. It remains unclear, however, as to whether these short-term results in men can be generalized to a broader population over a longer period of time. The strength of the evidence from the remaining trials was limited by smaller sample 5, 19, 21-23 sizes and, in the crossover trials, results that were averaged across treatment periods. Improvement in self-rated sexual interest (Minor Symptom Evaluation profile) was greater for 5 atenolol than metoprolol CR in 1 trial of 60 patients (mean age 58 years; 43. Two trials of metoprolol succinate compared to nebivolol examined quality of life measures. One trial was conducted in Germany and compared nebivolol 5 mg to metoprolol succinate 95 mg. After 12 weeks of treatment, 48 men (ages 40 to 55) with newly diagnosed hypertension experienced decreased sexual function on metoprolol 95 mg, but not nebivolol 5 23 mg. However, the article provides insufficient detail to determine how the metoprolol succinate 95 mg product compares to the metoprolol succinate product available in the United States and Canada. In another trial, after 6 weeks of treatment of 46 adults with mild hypertension, sleep quality, as measured by scores on the Pittsburgh Sleep Quality Index, was improved by treatment 19 with nebivolol 5 mg, but declined following treatment with metoprolol CR 100 mg. Beta blockers Page 21 of 122 Final Report Update 4 Drug Effectiveness Review Project Table 4. Quality-of-life outcomes in head-to-head trials of hypertensives Comparison Trial Design Duration Washout (quality) Sample size (weeks) (weeks) Results Atenolol superior to propranolol on some Atenolol vs. Steiner Psychologic General Well-Being, SCL-90-R, and 8 propranolol 1990 4 NA Life Satisfaction indices and no differences on Parallel (Fair) Insomnia Symptom Questionnaire or Sexual N=360 Function Questionnaire Atenolol vs. Atenolol superior to propranolol on 1 Minor Walle 5 metoprolol CR Symptom Evaluation item; no differences in all 1994 6 NR Crossover other Minor Symptom Evaluation and (Fair) N=16 Psychologic General Well-Being scores Buhler Atenolol vs. Nebivolol (32% poor sleepers) compared with 2008 Metoprolol ER 6 NR metoprolol (76% poor sleepers) (P=0. N=48 Abbreviations: NA, not applicable; NR, not reported; PSQI, Pittsburgh Sleep Quality Index. Two placebo-controlled trials reported the effect of long-term beta blocker therapy on quality of life in otherwise healthy patients who have hypertension (Evidence Tables 1 and 2). After 6 months, atenolol and placebo were similar on several dimensions from the Life Satisfaction Scale, the Physical Complaints Inventory, and the Symptoms Checklist, including summary (“total physical problems”, “overall psychological functioning”, “overall life satisfaction”), distress (“sexual physical problems”, “depression”, “anxiety”, “sleep disturbances”, “fatigue”), and well-being (“satisfaction with physical health”, 27 “sexual satisfaction”). In the second trial, there were no differences between propranolol and placebo in cognitive or psychological measures after 1 year of treatment. Beta blockers Page 22 of 122 Final Report Update 4 Drug Effectiveness Review Project Key Question 1b. For adult patients with angina, do beta blockers differ in efficacy or effectiveness? Summary There were no differences in exercise tolerance or attack frequency in head-to-head trials of carvedilol compared with metoprolol, pindolol compared with propranolol, betaxolol compared with propranolol, and betaxolol compared with metoprolol tartrate in patients with chronic stable angina. Atenolol and bisoprolol were equivalent in angina patients with chronic obstructive pulmonary disease. Atenolol and labetalol (when combined with chlorthalidone) were equivalent in angina patients with hypertension. Beta blockers that had intrinsic sympathomimetic activity reduced the resting heart rate less than other beta blockers, a potential disadvantage in patients suffering from angina pectoris. For this reason, experts recommend against using beta blockers with intrinsic sympathomimetic activity in patients with angina. Detailed Assessment In 1966 the first beta blocker, propranolol, was shown in a multicenter controlled trial to improve 28 symptoms in patients with angina pectoris. Several other beta blockers (acebutolol, atenolol, metoprolol tartrate, metoprolol succinate, nadolol, propranolol, and propranolol long-acting) have been demonstrated to reduce symptoms of angina in placebo-controlled trials. Most head-to-head trials of beta blockers in patients with angina pectoris observe patients 29-36 for only 2 to 4 weeks of treatment. In these trials, exercise tolerance, attack frequency, or nitroglycerin use were generally similar at comparable doses. Six fair-quality head-to-head trials evaluated angina symptoms after 2 or more months of treatment with beta blockers (Table 5, Evidence Tables 3 and 4). Exercise parameters were measured using bicycle ergometric 38, 39 testing in all but 2 trials, which used a treadmill. One study, however, did not include 37 exercise parameters in its study design.
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