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If a serious infection develops purchase 150 mg wellbutrin sr, interrupt ACTEMRA until the infection is controlled generic 150 mg wellbutrin sr fast delivery. Reported infections include: • Active tuberculosis safe wellbutrin sr 150mg, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before ACTEMRA use and during therapy. Treatment for latent infection should be initiated prior to ACTEMRA use. Patients with invasive fungal infections may present with disseminated, rather than localized, disease. The risks and benefits of treatment with ACTEMRA should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with ACTEMRA, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy Stelara Not listed Ustekinumab Appendix F References 1. Targeted immune modulators 177 of 195 Final Update 3 Report Drug Effectiveness Review Project Appendix G. Excluded studies The following full-text trials were considered for inclusion but failed to meet the criteria for this report. Exclusion codes: 1=non English language, 2=ineligible outcome, 3=ineligible intervention, 4=ineligible population, 5=ineligible publication type, 6=ineligible study design Exclusion Excluded trials code Aalto K, Honkanen V, Lahdenne P. Iron status during anti-TNF therapy in children with 2 juvenile idiopathic arthritis. Aletaha D, Funovits J, Breedveld FC, Sharp J, Segurado O, Smolen JS. Rheumatoid arthritis joint progression in sustained remission is determined by disease activity levels preceding the period of radiographic assessment. Physical disability in rheumatoid arthritis is associated with 6 cartilage damage rather than bone destruction. The effect of etanercept on work productivity in patients with early active rheumatoid arthritis: results from the COMET study. Atzeni F, Boccassini L, Antivalle M, Salaffi F, Sarzi-Puttini P. Etanercept plus ciclosporin versus etanercept plus methotrexate for maintaining clinical control over psoriatic arthritis: a 6 randomised pilot study. Persistent clinical efficacy and safety of infliximab in ankylosing spondylitis after 8 years-early clinical response predicts long-term outcome. Improvement in hemoglobin levels in patients with 2 ankylosing spondylitis treated with infliximab. Efficacy and safety of adalimumab in 1 patients with rheumatoid arthritis. Validation of minimal disease activity criteria for psoriatic arthritis 2 using interventional trial data. Continued inhibition of structural damage over 2 years in patients with rheumatoid arthritis treated with rituximab in combination with 2 methotrexate. Efficacy, safety and patient-reported outcomes of combination etanercept and sulfasalazine versus etanercept alone in patients with rheumatoid 6 arthritis: a double-blind randomised 2-year study. Infliximab therapy in children with concurrent perianal Crohn disease: observations from REACH. Two-year clinical and radiographic results with combination etanercept-methotrexate therapy versus monotherapy in early rheumatoid 4 arthritis: a two-year, double-blind, randomized study. The Effects of Golimumab on Radiographic Progression in Rheumatoid Arthritis Results of Randomized Controlled Studies of Golimumab 2 Before Methotrexate Therapy and Golimumab After Methotrexate Therapy. Targeted immune modulators 178 of 195 Final Update 3 Report Drug Effectiveness Review Project Exclusion Excluded trials code Emery P, Fleischmann RM, Moreland LW, et al. Golimumab, a human anti-tumor necrosis factor (alpha) monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: Twenty-four-week results of a 4 phase III, multicenter, randomized, double-blind, placebo-controlled study of golimumab before methotrexate as first-line therapy for early-onset rheumatoid arthritis. Emery P, Genovese MC, van Vollenhoven R, Sharp JT, Patra K, Sasso EH. Less radiographic progression with adalimumab plus methotrexate versus methotrexate 2 monotherapy across the spectrum of clinical response in early rheumatoid arthritis. Fasanmade AA, Adedokun OJ, Olson A, Strauss R, Davis HM. Serum albumin concentration: a predictive factor of infliximab pharmacokinetics and clinical response in patients with 2 ulcerative colitis. Safety of biological therapies following rituximab treatment in rheumatoid arthritis patients. Preclinical and clinical investigation of a CCR5 antagonist, AZD5672, in patients with rheumatoid arthritis receiving methotrexate. A 2-year comparative open label randomized study of efficacy and safety of etanercept and infliximab in patients with ankylosing spondylitis. Rheumatoid arthritis disease-modifying antirheumatic drug intervention and utilization study: safety and etanercept utilization 6 analyses from the RADIUS 1 and RADIUS 2 registries. Gladman DD, Mease PJ, Choy EH, Ritchlin CT, Perdok RJ, Sasso EH. Risk factors for radiographic progression in psoriatic arthritis: subanalysis of the randomized controlled trial 2 ADEPT. Gottlieb AB, Leonardi C, Kerdel F, Mehlis S, Olds M, Williams DA. Grijalva CG, Kaltenbach L, Arbogast PG, Mitchel EF, Griffin MR. Initiation of rheumatoid 3 arthritis treatments and the risk of serious infections. Clinical trial: Colectomy after rescue therapy in ulcerative colitis - 3-year follow-up of the Swedish-Danish controlled infliximab study. A combination of biochemical markers of cartilage and bone turnover, radiographic damage and body mass index to predict the progression of joint destruction in patients with rheumatoid arthritis treated with disease- 6 modifying anti-rheumatic drugs. Modern rheumatology / the Japan Rheumatism Association. Bone loss in patients with active early rheumatoid arthritis: infliximab and methotrexate compared with methotrexate treatment 6 alone. Explorative analysis from a 12-month randomised, double-blind, placebo-controlled study. Population approach for exposure- response modeling of golimumab in patients with rheumatoid arthritis. Anakinra in the treatment of polyarticular-course juvenile rheumatoid arthritis: safety and preliminary efficacy results of a randomized multicenter study. Adalimumab response in patients with early versus 2 established rheumatoid arthritis: DE019 randomized controlled trial subanalysis. Clinical Targeted immune modulators 179 of 195 Final Update 3 Report Drug Effectiveness Review Project Exclusion Excluded trials code Rheumatology. The AMBITION trial: tocilizumab monotherapy for rheumatoid arthritis. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Serum levels of transforming growth factor- (beta)1 in patients with mild psoriasis vulgaris and effect of treatment with biological drugs. Etanercept (ETN) with methotrexate (MTX) is better than ETN monotherapy in patients with active rheumatoid arthritis despite MTX therapy: A 6 randomized trial. Patient-reported outcomes improve with etanercept plus methotrexate in active early rheumatoid arthritis and the improvement is strongly associated 6 with remission: the COMET trial. Rapid Improvement in the Signs and Symptoms of Rheumatoid Arthritis Following Certolizumab Pegol Treatment Predicts Better 2 Longterm Outcomes: Post-hoc Analysis of a Randomized Controlled Trial. Keystone EC, Kavanaugh A, Weinblatt ME, Patra K, Pangan AL. Clinical consequences of delayed addition of adalimumab to methotrexate therapy over 5 years in patients with 2 rheumatoid arthritis. Klarenbeek NB, van der Kooij SM, Huizinga TJ, et al. Blood pressure changes in patients with recent-onset rheumatoid arthritis treated with four different treatment strategies: a post hoc 6 analysis from the BeSt trial. Epitope-specific immunotherapy of rheumatoid arthritis: clinical responsiveness occurs with immune deviation and relies on the expression of 2 a cluster of molecules associated with T cell tolerance in a double-blind, placebo-controlled, pilot phase II trial.

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Voriconazole is given at a dosage of 4 mg IV/kg BID (loading dose: 6 mg/kg BID on day 1 buy 150 mg wellbutrin sr overnight delivery, oral therapy with 200 mg BID start- ing from day 7) buy wellbutrin sr 150mg mastercard. Main adverse events are visual disturbances (20%) and (reversible) increases of liver enzymes buy discount wellbutrin sr 150mg. An alternative approach is amphotericin B, whose inferiority to voriconazole is ques- tioned by some (Jorgensen 2006). The effect of combinations is not proven (Garbati 2012). Salvage therapy includes lipid-based formulations of amphotericin B, caspo- fungin, high-dose itraconazole or posaconazole (Dockrell 2008). A systematic steroid therapy should be stopped if possible and every patient should receive antiretrovi- ral treatment immediately. Some case reports describe that permanent therapy can be dropped if immune reconstitution is sufficient (Yoganathan 2009). Opportunistic Infections (OIs) 403 References Dockrell DH. The role of combination antifungal therapy in the treatment of invasive aspergillosis: a systematic review. Voriconazole versus amphotericin B for primary therapy of inva- sive aspergillosis. Voriconazole versus amphotericin B in cancer patients with neutrope- nia. Pulmonary aspergillosis and invasive disease in AIDS: review of 342 cases. Mylonakis E, Paliou M, Sax PE, Skolnik PR, Baron MJ, Rich JD. Central nervous system aspergillosis in patients with HIV infection. Improved outcome in central nervous system aspergillosis, using voricona- zole treatment. Long-term suppressive therapy for pulmonary aspergilloma in an immunocompromised man with AIDS. Bacillary angiomatosis Bacillary angiomatosis in HIV+ patients was first described in the 1980s (Review: Maguina 2000). Bacillary angiomatosis is caused by the rickettsial species Bartonella henselae and Bartonella quintana (“Rochalimaea” until the beginning of the 1990s). While Bartonella henselae is typically associated with cats, its primary host, and cat fleas, its vector; Bartonella quintana frequently affects homeless patients and is asso- ciated with poor hygiene and social-economic conditions. Several possible reservoirs have been discussed for such cases (Gasquet 1998). In a Spanish study of 340 HIV+ patients, 22% patients reacted to one or more Bartonella antigens. Of all the studied seroprevalence factors, only age was statistically significant (Pons 2008). Reportedly, Bartonella occurs more often in North and South America than in Europe. In a study of 382 febrile HIV+ patients in San Francisco, Bartonella was found to be the causative organism in 18% (Koehler 2003). Bacillary angiomatosis remains a significant differential diagnosis in all cases with skin lesions of unknown etiology. The pseudoneoplastic, vascular skin proliferation is quite often clinically and histologically mistaken for Kaposi’s sarcoma or heman- gioma. The vascular nodules or tumors may be isolated, but are usually multiple and reminiscent of fresh Kaposi’s sarcoma, with cherry red or purple nodules. One quarter of the cases may have bone involvement with painful osteolytic foci (AP elevation). Here, the skin lesions sometimes resemble dry hyperkeratotic changes such as those seen in psoriasis. In a collection of 21 cases, 19 patients had skin, 5 bone and 4 liver involvement (Plettenberg 2000). Mani- festations in lymph nodes, muscle, CNS, eye, gingiva and gastrointestinal tract have also been reported. The gram-negative bacteria are only visible on biopsy samples stained with Warthin-Starry silver stain. If this stain method is not applied, then bacillary angiomatosis will not be found. Moreover, pathologists should be informed of the suspected diagnosis, as the Warthin-Starry silver stain is not routinely performed. Reference labs should be contacted for further diagnostic details. Treatment of bacillary angiomatosis is with erythromycin (at least four weeks with 500 mg QID) or clarithromycin. Relapses are common, which is why some physi- cians favor therapy for at least three months. Supposedly effective, doxycyclin is the 404 AIDS therapy of choice for CNS involvement. Since transmission is generally via cats, US guidelines recommend not having cats as pets. Preferably, cats should be healthy and older than one year; and scratches should be avoided. Bacillary angiomatosis: a newly characterized, pseudoneoplastic, infectious, cutaneous vascular disorder. Molecular epidemiology of bartonella infections in patients with bacil- lary angiomatosis-peliosis. Prevalence of Bartonella infection among hiv-infected patients with fever. LeBoit PE, Berger TG, Egbert BM, Beckstead JH, Yen TSB, Stoler MH. Bacillary angiomatosis: the histopathology and differential diagnosis of a pseudoneoplastic infection in patients with HIV disease. Komplett im Plettenberg A, Lorenzen T, Burtsche BT, et al. Bacillary angiomatosis in HIV-infected patients—an epidemiologi- cal and clinical study. Stoler MH, Bonfiglio TA, Steigbigel RB, et al: An atypical subcutaneous infection associated with AIDS. Histoplasmosis Histoplasma capsulatum is a dimorphic mold, found largely in moist soil and without a capsule despite its name. The Southern and Midwestern of regions of the US as well as Central America and Africa are endemic areas. Even in the HAART era, morbidity and mortality due to histoplasmosis remains a public heatlh problem in low-income and high-income countries (Review: Adenis 2014). In HIV patients with impaired immunity (85% have less than 100 CD4 T cells/µl), infection leads to an acute, life- threatening disease with dry cough, fever, dyspnea and malaise (Gutierrez 2005, Mora 2008). Miliary TB and PCP are important differential diagnoses. Disseminated courses of disease may also occur, in which the fungus can be detected in bone marrow or by liver biopsy (Albrecht 1994). Skin ulcerations, oropharynx or CNS involvement may also occur (Scheinfeld 2003, Wheat 2005, Antonello 2011). Hepatosplenomegaly is common, occurring in almost 90% of the patients (Mora 2008). Histoplasmosis is an AIDS-defining illness whose pathogen like that of cryptococcal antigen can be reliably detected in the blood with an antigen test. Laboratory eval- uations often reveal significantly elevated LDH and alkaline phosphatase as well as transaminases. Amphotericin B should be given as initial treatment. Liposomal amphotericin B (3 mg/kg daily for 14 days) is not only less toxic, but possibly also more effective (Johnson 2002). In milder cases, itraconazole (200 mg BID or TID) is effective, and can also be used as a secondary prophylaxis. It is significantly more effective than fluconazole (Wheat 2002), but is associated with a high risk of interactions, partic- ularly with ritonavir, but also with efavirenz (Crommentuyn 2004, Andrade 2009, Hills-Nieminen 2009).

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For example purchase 150 mg wellbutrin sr otc, in one study order 150mg wellbutrin sr amex, 10% 52 genes were investigated in plasma cells derived from healthy No end-organ damage* SMM Serum M-protein 3 g/dL and/or light-chain controls 150mg wellbutrin sr amex, MGUS, SMM, and multiple myeloma patients; the investi- restricted BM plasma cells 10% gators showed that hierarchical clustering identified 4 groups from No end-organ damage* GEP analysis. The percentage of plasma cells is low (by End-organ damage* definition 10%), so that there is significant contamination with other kinds of cells despite selection of CD138 cells on magnetic Based on expert discussions at the IMWG meeting in Stockholm in June 2013, it is anticipatedthatupdatedconsensuscriteriawillbedefinedinthenearfuture. In addition, in MGUS patients—unlike in multiple myeloma studies suggest that additional features such as BM plasmacytosis 60%,48 an patients—monoclonal plasma cells are likely to be significantly abnormal sFLC ratio 100 (involved kappa) or 0. Until we have *One or many of the following features: hypercalcemia with calcium level 11. Among 71 patients who (through loss of heterozygosity, gene amplification, mutation, or during a 10-year follow-up time developed multiple myeloma, epigenetic changes) additional genetic hits over time. Based on current nant clonal population and fail to take into account the presence of standard technologies (eg, FISH), the molecular makeup of my- 24,25 intratumoral subclonal heterogeneity. Using single nucleotide eloma precursor disease states and multiple myeloma are strikingly polymorphism–based mapping arrays, a progressive increase in the similar and no defining molecular features unique to multiple incidence of copy number abnormalities from MGUS to SMM and myeloma have been identified. In addition, the transformative to multiple myeloma (median 5, 7. The hyperdiploid group includes recurrent tri- somies with 48-74 chromosomes. IgH rearrangements were found at similar preva- lence rates among 78/189 (41%) MGUS, 44/125 (35%) SMM, and from MGUS/SMM to multiple myeloma is likely, from a Darwinian- 183/398 (46%) multiple myeloma patients. Based on this understand- myeloma patients compared with MGUS patients (25%), studies ing, it is becoming increasingly plausible that, after disease initia- suggest a higher frequency among patients with t(4,14) and t(4,16) tion, the molecular events that are necessary for myeloma develop- rearrangements. Indeed, the BM microenvironment consists of 3 components: the cellular component (hematopoietic and nonhema- topoietic cells, including the vasculature); the extracellular matrix component (fibrous proteins, proteoglycans, glycosaminoglycans, and small integrin-binding ligand N-linked glycoproteins [SIBLING]); and the soluble component (cytokines, growth factors, adhesion molecules, and other factors). Shared positive and negative interactions among a range of cells in the BM (such as: stromal cells, osteoclasts, osteoblasts, immune cells (T lymphocytes, dendritic cells), other hematopoietic cells and their precursors, and vascular endothelial cells34,35) are mediated by a variety of adhesion molecules, cyto- kines, and receptors. Additional stimuli such as hypoxia result in activation of HIF-1 and secretion of VEGF. Such aspects include homing to the BM, spread to secondary BM sites by the bloodstream, generation of paracrine factors (eg, IL-6, IGF-1, and APRIL), osteoclastogenesis, inhibition of osteogenesis, humoral and cellular immunodeficiency, angiogenesis, and ane- Figure 1. However, it is more likely that the pathway to myeloma is qualitatively similar to those of abnormal plasma cells; however, in through branching pathways typical of those that are associated with the MGUS/SMM, the composition of cells in the BM microenviron- evolution of species (B). The key molecular events leading to disease ment is altered. This simple branching model clearly has implications for cells, if the altered composition of cells in the BM microenviron- targeted treatment because the multiple distinct subclones could lead to ment precedes proliferation/activation of abnormal plasma cells, or differential responses to treatment. Reprinted with permission from if there is a combination of these mechanisms. The sFLC ratio has been used as a prognostic indicator both in patients Little is known about the epigenetic changes necessary for progres- with MGUS37 and SMM. Based on recent advances in immunophenotyping plasma cells and The BM microenvironment plays a key role in MGUS/SMM measuring sFLC, 2 independent risk stratification schemes for initiation and propagation. At 20 years, patients with risk-factor models, the most recently updated 2010 IMWG guide- no risk factors had a 5% risk of progression compared with 21%, lines6 propose the following clinical management of individuals 37%, and 58% for patients with 1, 2, or 3 risk factors, respectively. Recently, a study screening for sFLC abnormalities without a detectable M-protein found a much lower risk of progression to multiple myeloma compared with conventional MGUS. At 5 years, risk of progression to multiple myeloma Aggressive disease monitoring is based on whether patients fit into was 25%, 51%, and 76% for patients with 1, 2 or 3 risk factors, MGUS or SMM precursor disease and the above outlined risk 8,38 factors in the Mayo Clinic model and Spanish study group model. In contrast, the risk stratification scheme of the PETHEMA Study Group has focused on the use of multiparameter For the first time, the 2010 IMWG guidelines suggest risk stratify- flow cytometry of the BM to quantify the ratio of abnormal, ing all patients with MGUS and SMM and differentially monitoring neoplastic plasma cells (aPCs) to normal plasma cells. At 5 years of patients on the basis of their risk category. Per study protocol, each MGUS patients with any risk factor (ie, intermediate- or high-risk patient was assigned risk scores based on both the Mayo and the MGUS) should be evaluated with baseline BM examination with Spanish models. The Mayo Clinic model identified 38, 35, and 4 cytogenetics and FISH studies in addition to bone imaging studies patients as low, medium, and high risk, respectively. There was significant discor- 6 first year, followed by annual SPEP and routine laboratory tests. In SMM, beyond mandatory baseline before clinicians can determine whether initiation of early treatment BM examination and skeletal survey, the guidelines recommend is beneficial to patients with high-risk SMM. Using baseline serum It is critical to recognize that in a disease such as multiple myeloma, samples (available for 999 persons) obtained within 30 days of an in which defining criteria rely on the presence or absence of MGUS diagnosis at Mayo Clinic (1960-1994), quantitation of end-organ damage, diagnosis is only as good as the tools and individual heavy/light chains (for example, IgG in IgG MGUS technology able to detect end-organ damage. HLC- while playing a central role in disease monitoring. For example, in pair suppression was a significant risk factor for progression (hazard SMM or high-risk MGUS patients highly suspicious as harboring ratio [HR] 2. MGUS or SMM M-spike concentration, heavy chain isotype, and sFLC ratio patients with unexplained anemia or renal disease should be (HR 1. The finding that HLC-pair evaluated for other underlying causes and with complete BM suppression predicts progression in MGUS and occurs several years examination including cytogenetics and FISH studies. MRI of the BM in healthy controls and in patients with multiple myeloma. As already discussed in part (see “Clinical predictors of progres- information regarding disease activity. Based on expert discussions at the IMWG shorter time (median time to progression: 13 months vs not reached) meeting in Stockholm in June 2013, it is anticipated that updated to develop multiple myeloma compared with SMM patients with consensus criteria will be defined in the near future (Table 1). Accord- retrospective study of 23 patients with SMM and 10 patients with ing to the most recent consensus guidelines of the IMWG updated in lytic lesions but no symptoms. These patients were treated with 1 of 2011, radiological skeletal survey is still the gold standard for the 2 chemotherapy regimens, but the study failed to show a statistically initial workup of patients with multiple myeloma. For example, it is widely treatment with melphalan-prednisone for 50 patients with SMM or available and comparatively cheap. With current digital scanners, indolent multiple myeloma (asymptomatic disease but with evi- the radiation dose is low (about 3-4 mSv). However, conventional dence of end-organ damage) was performed, finding no difference X-ray has also some important drawbacks. First of all, it has been in response rate, response duration, or survival (Table 3). However, both of course of disease from MGUS to SMM to symptomatic disease, the these studies were performed when the best available treatment for occurrence of bone destruction is a relatively late event. Some parts of the The development of modern therapies with improved efficacy and skeleton project one upon the other if the patient is placed in the less toxicity have renewed interest in the treatment of SMM. It is not infrequent that Thalidomide is a noncytotoxic drug used to treat refractory multiple intestinal gas, especially if located in front of the osseous pelvis, mimics osteolyses. Focal versus diffuse infiltration of the BM in SMM and multiple myeloma based on MRI (see Figure 2) New imaging techniques allow detection of myeloma manifesta- tions earlier than conventional radiography. In addition to those functional techniques AdaptedfromHillengassetal. In 2008, a single-arm phase 2 trial including 76 patients curcumin, a traditional Indian spice with preclinical antimyeloma with SMM treated with thalidomide and pamidronate did not show a activity70-73; and bisphosphonates, believed to block the initial clear overall benefit to treatment (Table 3). Paradoxically, patients formation of lytic lesions and alter the BM microenvironment who initially displayed at least a partial response to thalidomide had (Table 3). Some peripheral neuropathy and dizziness resulting in discontinuation in data are further limited by use of nonstandard end points and greater than half of patients. The 3-year survival rate was also higher in the treatment group (94% vs 80%; Overall, treatment trials for MGUS patients are complicated be- HR for death 0. A partial cause these individuals are relatively healthy and the majority have response or better was achieved in 79% of patients in the treatment a low lifetime risk of progression, especially when other causes of group after the induction phase and in 90% during the maintenance death are taken into account. These data serve propose that an ideal treatment would be very effective, nontoxic, as proof of principle that the treatment of high-risk SMM can be and directed toward patients with high risk of progression. We are accomplished without excessive toxicity and may delay progression nearing this end point, but fundamental unanswered questions to multiple myeloma. Finally, we do not know whether patients in the lenalidomide-dexamethasone The high rate of progression of SMM into symptomatic disease treatment arm who later will develop multiple myeloma may have makes the idea of an early treatment strategy attractive to patients an altered susceptibility to therapy. Several promising clinical trials are already in questions that need to be addressed as soon as follow-up data are progress both in Europe and in the United States (Table 1). In the mature and allow formal, sufficiently powered statistical analysis. Newer drugs with more favorable side effect profiles in the United States.

Ongoing PT-1 trials will describe the an original diagnosis of ET or PV buy 150 mg wellbutrin sr with amex, although there is a correlation natural history of ET and the response to aspirin versus aspirin plus between degree of thrombocytosis and BM reticulin grade purchase wellbutrin sr 150mg amex,17 there HU for an intermediate-risk group defined by age 40-60 years with are no convincing data to suggest that the degree of thrombocytosis no high-risk features (ie buy 150mg wellbutrin sr overnight delivery, age 60 years, no prior thrombosis, predicts transformation to either MF or leukemia. However, differ- platelets 1500 109/L) or cardiovascular risk factors. High-risk ential effects of therapy on rates of transformation to MF, for PV has in the past been less well defined than ET, but recent studies example, as observed in the PT-1 study, suggest that manipulation have improved this situation. Any novel 350 American Society of Hematology markers for risk stratification should be robust and easily measur- Phlebotomy able. Current candidates include reticulin grade,17 JAK2V617F Concerning phlebotomy or venesection, the hematocrit target in PV allele burden,20 and, for ET, the presence of the CALR mutation. The investigators concluded that the although there is evidence from the ECLAP study for this strategy in 13 range of hematocrit ( 55%) encountered in the study population PV, the use of low-dose aspirin remains controversial in ET. The had no impact on the outcome of PV patients treated by current ECLAP study enrolled 518 patients with PV who lacked a clear therapeutic strategies. This question has now been fully addressed in indication or contraindication for aspirin into a double-blind, the recently reported CYTO PV study, in which PV patients were placebo-controlled, randomized trial to assess the safety and effi- randomized to either a target hematocrit of 0. After cacy of prophylaxis with low-dose aspirin (100 mg daily). The 2 a median follow-up of 31 months, the primary end point was primary end points for this study were: (1) the cumulative rate of recorded in 2. The primary cardiovascular causes and (2) these events plus pulmonary embo- end point plus superficial vein thrombosis occurred in 4. After a follow-up of 3 years, patients in the low-hematocrit group, compared with 10. Therefore, the CYTO PV study reduced the risk of the combined primary end point of nonfatal strongly supports control of the hematocrit to at least 0. The use of low-dose aspirin also reduced the 24,25 reduction in thrombosis. There is no evidence to support a risk of the second combined end point to a statistically significant targeting the hematocrit 0. The incidence of major bleeding episodes was not related but unanswered dilemma that arises in clinical practice is significantly increased in the low-dose aspirin group (relative risk, whether to control the hematocrit of a patient with a diagnosis of ET 1. Interestingly, neither who has the JAK2V617F mutation and whose hematocrit is above overall mortality nor cardiovascular mortality was significantly 0. Masked PV should reduced; the trial was probably not adequately powered to address 13 certainly be excluded in these patients. In ET, the use of aspirin has never been addressed in distinction would include use of RBC mass, but because this test is a randomized controlled trial. Some studies, such as PT-1, included not widely available, other factors need to be considered. Such aspirin for all high-risk ET patients, whereas other more recent 15,16 additional factors would include: careful review of BM histology, studies, such as ANAHYDRET, did not. This reflects a di- replenishment of iron stores, review of erythropoietin level, and chotomy of opinion in the field. These include concerns that testing for endogenous erythroid colonies; sometimes, careful bleeding is a particular risk for patients with very high platelet observation until more obvious signs appear has to suffice. Regarding treatment targets, the European LeukemiaNet used a standard consensus approach to produce criteria for response; these For “low-risk” ET, a retrospective analysis from a group of Spanish criteria are designed primarily for clinical trials and also include investigators suggests variable benefits for low-dose aspirin. Interna- treated with antiplatelet drugs (mainly aspirin) as monotherapy tional practice varies widely, as demonstrated in the ongoing (n 198) or followed with careful observation (n 102). Fol- EXELS study with a recently published analysis of treatment low-up was 802 and 848 person-years for antiplatelet therapy and patterns for high-risk ET across Europe,27 and there are many strong observation, respectively. Rates of thrombotic events were not opinions regarding whether HU or IFN should be the treatment of different at 21. IFN and HU form a mainstay of therapy and there is an therapy and observation, respectively (P. Subgroup analyses ongoing increase in interest in IFN, especially pegylated forms with suggested that JAK2V617F-positive patients not receiving antiplate- disease-moderating effects. Pioneering studies with IFN were let medication showed an increased risk of venous thrombosis reported by Silver in 1988. Major bleeding was observed in patients with platelet when started at low doses. This targeting of the JAK2V617F-mutated clone by this agent. In the remaining low-risk tion of IFN from AOP pharma is also of interest in this context, with ET patients, aspirin does not appear to be effective for primary provisional results approximately equivalent to that for other prophylaxis of thrombosis and observation may be an adequate formulations of IFN. Recommendations for therapy in ET and PV PV ET All patients All patients Assess and manage for cardiovascular risk factors Treat with low-dose aspirin (unless contraindicated) and screen for disease-related symptoms High-risk patients* Venesection to target hematocrit 0. Two such trials are currently ments at weeks 24 and 144, respectively. Clinically meaningful ongoing internationally: MPD RC112, a phase 3 randomized study improvements in pruritus, night sweats, and bone pain were of HU versus Pegasys in newly diagnosed high-risk ET and PV, and observed within 4 weeks of the initiation of therapy and were PROUD-PV, a phase 3 study with AOP IFN in PV. It is absolutely maintained with continued treatment. Thrombocytopenia and ane- critical that the field addresses the relative superiority of IFN and mia were the most common adverse events, thrombocytopenia of HU by completing the phase 3 trials because they will inform the grade 3 or anemia of grade 3 occurred in 9% of patients each (1 relative benefits, efficacy, and toxicities of these medications. The phenomenon of HU resistance or intolerance is important and Two large phase 3 commercially sponsored studies of ruxolitinib identifies a group of ET and PV patients with a poor prognosis32 are fully recruited; the results of one (RESPONSE) were reported at who require a change of treatment and for whom novel therapies the recent American Society of Clinical Oncology (ASCO) and may be attractive. Options for management in the face of HU European Haematology Association (EHA) meetings. Ruxolitinib resistance would include adjusting therapeutic targets (eg, to a 9 was superior to best-available therapy for the composite primary platelet count of 600 10 /L) or to switch to an alternative agent end point of 35% spleen size reduction and freedom from venesec- either alone or in combination. This trial studied a highly selected group of patients who were when used with or succeeded by agents such as busulfan, will intolerant or resistant to HU yet had splenomegaly and still required significantly increase long-term risks of leukemia. A confounding aspect is that 50% of the control arm nonleukemogenic agents such as IFN or anagrelide are more was treated with HU, perhaps reflecting limited options for these appropriate in this setting. Most interesting was the reduction in thrombosis for ance are the group of ET and PV patients for whom novel therapies are currently being evaluated. Three important Impact of JAK inhibitors and other novel therapies safety concerns have arisen with regard to JAK inhibition: a There are data supporting the ability of some JAK inhibitors to “withdrawal syndrome,” neurological toxicity, and risk of infec- control myeloproliferation in patients with PV and ET. An early report suggested a risk of severe inflammatory beyond this, aspects that are uncertain include whether they prevent syndrome after ruxolitinib withdrawal and that these patients had a thrombosis and if they affect the probability of accelerated-phase 37 poor outcome. The COMFORT studies have not reported this as a disease such as MF or even leukemia. The size and duration of risk, but a slow taper or consideration of steroid cover when studies required to evaluate these aspects will be challenging. A second JAK2 inhibitor, first study in this context using CEP 701 (Cephalon) reported fedratinib, has recently been put on full clinical hold due to the negative data; while there were responses in splenomegaly, pruritus, development of complications similar to Wernicke’s encephalopa- and phlebotomy requirements, CEP 701 treatment was not associ- ated with a reduction in either leukocytosis or thrombosis and 5 thy. Although this complication has not been reported with rux- thrombotic events occurred. Toxicities with these further data for the ET cohort is available. In the updated analysis, agents are variable and the administration of vorinostat in a phase 2 the PV cohort received ruxolitinib for a median of 152 weeks; a study led to a high discontinuation rate. Givinostat continues to be hematocrit 45% without phlebotomy was achieved in 97% of evaluated. The oral telomerase inhibitor imetelstat was investigated patients by week 24, with only one patient requiring a phle- in ET, demonstrating molecular responses but also significant rates botomy after week 4. Among patients with palpable splenomegaly of hematological toxicity. It is very encouraging to witness recent developments in our Semin Thromb Hemost. Efficacy and safety of low-dose that these new options can provide to patients. Correlation of blood counts combined with data from clinical trials underpin these improve- with vascular complications in essential thrombocythemia: analysis of the prospective PT1 cohort. There is an urgent need to complete studies to assess the 15. Hydroxyurea compared with relative benefits of HU and IFN as first-line therapies for both ET anagrelide in high-risk essential thrombocythemia.

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