There generic nicotinell 35mg visa quit smoking with electronic cigarette, if the B cells receive suﬃcient stimulation from T cells discount nicotinell 35 mg mastercard quit smoking 001, they undergo rapid division to form germinal centers buy genuine nicotinell quit smoking nicorette. At these centers, the B cells hypermutate and proceed through aﬃnity maturation. AFFINITY WINDOW FOR EPITOPE-PARATOPE BINDING The naive B cell repertoire binds with varying aﬃnity to diﬀerent epi- topes of an antigen. The relative stimulation of diﬀerent B cell clones by an antigen determines progression to the next steps in B cell response. Stimulation depends on the aﬃnity of the BCR paratopes (binding sites) for their particular epitopes. Rao (1999) found an aﬃnity window for stimulation of B cells. Very strong epitope-paratope binding prevents stimulation; weakly binding Bcells are outcompeted for stimulatory signals. One of these epitopes stimulated the immunodominant IgG response; the other wasatthe opposite end of the peptide. I refer to the immunodominant epitope as D and the subdominant epitope as S. Surprisingly, the early antibody response was stronger against S 76 CHAPTER 6 than D. However, secreted antibodies against S bound so eﬃciently to Sthatthey outcompeted the matching BCR and prevented stimulation of the B cell lineage. By contrast, anti-D antibodies bound with lower aﬃnity and did not outcompete the matching BCR, allowing that B cell lineage to receive strong stimulation from the antigen. They began by constructing a peptide that had on one side a known B cell antigen of hepatitis B virus and on the other side a known T cell epitope from the malaria parasite Plasmodium falciparum. Theyinjected this chimeric peptide into mice and followed the antibody response. The early IgM response had speciﬁcities that spanned the entire hepatitis B segment. By contrast, the later IgG response focused on a single epitope in the hepatitis B segment composed of the four amino acids DPAF. Single amino acid changes in DPAF destroyed immunodominance by this epitope, causing nearby epitopes to dominate the IgG response. The anti-DPAF antibodies had aﬃnities between 8- and 60-fold higher than antibodies against neighboring epitopes. Immunodominance depended on competition for antigen-speciﬁchelperTcells, which arelimiting during the initial stages of an immune response. The stronger-binding BCRs take up antigen and present to T cells more eﬃciently than do the weaker-binding competitors. Insuﬃcient T cell stimulation leads to suppression of B cell clones. In laterexperiments, Agarwal and Rao (1997) manipulated the size of the helper T cell pool. Reduced numbers of T cells allowed IgM response but prevented the switch from the IgMstagetothe IgG stage. This sup- ports the hypothesis that competition for T cell help is the rate-limiting step in the transition from the broad IgM response to the narrow IgG response. EQUILIBRIUM BINDING AFFINITY MAY DETERMINE EARLY RESPONSE Antibody aﬃnity for epitopes inﬂuences initial IgM stimulation and subsequent competition for immunodominance during the switch to IgG. What determines antibody aﬃnity to individual epitopes during IMMUNODOMINANCE WITHIN HOSTS 77 these early phases of B cell competition? Rao (1999) summarizes stud- ies that rule out mouse MHC genotype and various physical properties of the epitope such as accessibility within the overall peptide structure. This led to the hypothesis that the Gibbs free-energy of binding between epitope and paratope determines antibody aﬃnity, and that the amino acid sequence of the epitope inﬂuences the potential free-energy of the bond. They suggested that the relative ordering of aﬃnities for particular epitopes could be predicted by the amino acid sequence of the epitope. In particular, the amino acid side chains of an epitope sequence determine the potential free-energy of binding to an antibody paratope. Chemical determination of free-energy seems particularly important in the early phases of antibody response, when the antibodies have not yet been optimized for binding by aﬃnity maturation. Unoptimized antibodies do not have strong spatial complementarity of binding; thus there is less steric and greater chemicalconstraintonbinding at this stage. After optimization, it may be that greater steric complementarity of antibody-epitope binding places more emphasis on spatial ﬁt and reduces the predictability of binding energy based solely on chemical composition of amino acid side chains. KINETIC BINDING ON-RATES MAY DETERMINE AFFINITY MATURATION So far, I have summarized the ﬁrst stage of antibody selection: IgM- producing B cells from the naive repertoire compete for T cell help, with the winner(s) dividing more rapidly and starting on the path to IgG pro- duction. Equilibrium binding aﬃnity drives this ﬁrst stage of antibody competition. Inowturntothe next stage, called aﬃnity maturation (Janeway et al. During this stage, B cells congregate in germinal centers of the lymphoid tissue and mutate their antibody paratopes at a high rate. Aselection process favors those mutated paratopes that bind relatively strongly to antigen, driving aﬃnity maturation of antibodies for the par- ticular epitopes. Rao’s group modiﬁed their model antigen by substituting cysteine amino acid residues in the two sites ﬂanking the DPAF epitope (Nayak et al. This changes the conformation of the DPAF peptide and inﬂuences the antibody-epitope binding reaction. They then compared binding of each of the two antibody types against the native and modi- ﬁed antigen. Antibodies raised against the native antigen bound with approximate- ly equal equilibrium aﬃnity to native and modiﬁed antigen. Antibodies raised against the modiﬁed antigen also bound at equilibrium approxi- mately equally against the two antigens. By contrast, the kinetic on-rates of binding were 50-fold higher for native antibody to native antigen than for native antibody to modiﬁed antigen. Kinetic on-rates were 14- to 25- fold higher for modiﬁed antibody to modiﬁed antigen than for modiﬁed antibody to native antigen. Kinetic on-rates measure rates atwhichbonds form, whereas equi- librium aﬃnity measures the ratio of on-rates to oﬀ-rates. Selection during aﬃnity maturation apparently favors faster rates of interaction with increases in both on-rates and oﬀ-rates: the on-rates rise, but the equilibrium aﬃnity does not change. In this model system, it appears that B cells compete by rate of anti- gen acquisition during aﬃnity maturation. B cells with paratopes that bind more quickly to antigen receive stronger stimulatory signals to di- vide and to dominate the population in the germinal centers. Thus, the optimized antibodies bind more quickly to antigen than unoptimized precursors, but optimized antibodies do not necessarily increase their equilibrium binding aﬃnity. In summary, Rao proposed an integrated, dynamic view of how the speciﬁcity of an antibody response develops.
This randomized cheap 17.5 mg nicotinell with visa quit smoking 15 months, patients in a randomized trial29 demonstrated an augmented HbF double-blind discount nicotinell 35 mg without a prescription quit smoking 4 life, placebo-controlled trial examined the efﬁcacy cheap nicotinell 35 mg with mastercard quit smoking injection, safety, response and highlighted the need for future multiagent trials. A and pharmacokinetics of GMI-1070 in hospitalized patients with dose-limiting toxicity for hydoxyurea can be myelosuppression. GlycoMimetics successfully enrolled 76 Two novel HbF-inducing agents, sodium dimethylbutyrate and patients 12 to 60 years of age at 22 trial sites in the United States and Hematology 2013 365 Table 2. Novel agents in clinical trials Category* Therapeutic agent Mechanism of action Reference HbF augmentation Vorinostat, panobinostat HDAC inhibition 43 Sodium dimethylbutyrate HDAC inhibition 31 Decitabine DNA demethylation 33 Pomalidomide Histone acetylation of -globin promoter 30 Adhesion GMI-1070 Pan-selectin inhibitor 21 IVIG Inhibits neutrophil activation and RBC capture 22, 23, 25 SelG1 Humanized anti-P-selectin monoclonal antibody Selexys Heparin (tinzaparin) Inhibits P-selectin 37 Propranolol Inhibits RBC adhesion to the endothelium 7 Inﬂammation Regadenoson A2AR agonist, blocks iNKT activation 39 Statins Anti-inﬂammatory 44 Zileuton 5-lipoxygenase inhibitor, used in asthma 45 Fructose-1,6-diphosphate (FDP) Reduces ischemia–induced tissue damage 46 MP4CO PEG carboxy-hemoglobin 47 Antiplatelet therapy Prasugrel ADP receptor blockade 42 Eptiﬁbatide IIb/ 3 antagonist 48 Oxidative injury Omega-3 fatty acids 40 Glutamine Increases NADPH 49 NAC Increased glutathione 41 Alpha-lipoic acid Inhibits NF- B, increases glutathione 50 Acetyl-L-carnitine Decreases lipid peroxidation Antisickling agent Aes-103 Binds sickle hemoglobin and shifts oxyhemoglobin 51 dissociation curve to the left Viscosity Poloxamer-188 Non-ionic surfactant, improves microvascular ﬂow 52 Vascular tone IV magnesium Vasodilatation 53 NO L-arginine Substrate for NO 54 *Sometherapieshavemultiplemechanismsofaction. Results of these studies have not yet been published in a phase 1/2 studies via a dose-escalation strategy. IVIG also inhibits leukocyte adhesion and activation (Figure unpublished observations, September 2013). Its role in SCD patients with acute VOC is being evaluated in Tinzaparin. Tinzaparin, a low-molecular-weight heparin, was studied in a randomized, double-blind clinical trial. Heparins act via inhibition of P-selectin–mediated adhesion35 and other anti- inﬂammatory effects36 in addition to their expected anticoagulant effect. After exclusion of patients with thrombocytopenia or CNS vasculopathy, 253 subjects were enrolled, 12 years of age and older, in a study in which reduced duration of VOC and no severe bleeding complications were reported. An oral P-selectin inhibitor with an order of magnitude greater potency than heparin demonstrated improved microvascular ﬂow in SCD patients in a phase 1 study, but has a very short half-life. Propranolol was administered to SCD patients in a phase 1 dose escalation study and signiﬁcantly reduced epinephrine- stimulated SS-RBC adhesion in a dose-dependent manner. These results imply that -blockers have a potential role as antiadhesive therapy via inhibition of Figure 2. Activating and inhibitory arms of neutrophil activation. A phase 2 study the up-regulation of the leukocyte integrin Mac-1 at the leading edge of of propranolol in SCD is currently open. GMI-1070 works principally by inhibiting E-selectin–mediated activation. Polarized expression of activated Mac-1 allows the capture of erythrocytes. IVIG administration works by binding Targeting inﬂammation to Fc RIII expressed on neutrophils, leading to the recruitment of SHP-1 Regadenoson. Regadenoson is an A2A receptor (A2AR) agonist that inhibits Mac-1 activation. Many important scientiﬁc and clinical contributions in SCD ing sites in the United States. We apologize to authors of positive ﬁndings in the biological end points, a phase 2 randomized, important contributions that could not be cited because of space placebo-controlled trial is currently ongoing. Disclosures Although the reduction in phospho-NF- B p65 was to baseline Conﬂict-of-interest disclosure: The authors declare no competing levels, the reduction in A2AR expression and IFN- levels did not ﬁnancial interests. Off-label drug use: Drugs described in research reach baseline. Omega-3 fatty acids are signiﬁcantly reduced in SCD patients. A randomized, placebo-controlled, double- Correspondence blind trial was conducted at a single center in Sudan. Enrolled Paul Frenette, Albert Einstein College of Medicine, Michael F. N-acetyl cysteine (NAC) inhibits dense cell References formation and irreversible sickle cells in SS-RBCs in vitro and 1. Sickle red cell- restores glutathione levels toward normal. The molecular pathobiology determine the efﬁcacy of NAC in decreasing dense cell and of cell membrane iron: the sickle red cell as a model. Free irreversible sickle cell formation and VOC episodes in SCD. Twenty-one subjects at a single center were enrolled in 4 treatment 3. Adhesion of sickle red cells to endothelium: groups. NAC inhibited dense cell formation, restored glutathione myths and future directions. Pathophysiology and therapy for haemo- validated in a larger, multicenter study. Inhibition Antiplatelet therapy of cell adhesion by anti-P-selectin aptamer: a new potential Prasugrel. Prasugrel is a novel thienopyridine P2Y12 ADP therapeutic agent for sickle cell disease. Turhan A, Weiss LA, Mohandas N, Coller BS, Frenette PS. Primary role for adherent leukocytes in sickle cell vascular There were no hemorrhagic events requiring medical intervention in occlusion: a new paradigm. Mean pain rates (percentage of days with pain) and 2002;99(5):3047-3051. However, these reductions did not reach statistical signiﬁ- activation of LW-mediated sickle cell adhesion and vaso- cance. Platelet surface P-selectin and plasma soluble P-selectin, occlusion in vivo. Novel epinephrine and SCD patients receiving prasugrel compared with placebo. Prasugrel cyclic AMP-mediated activation of BCAM/Lu-dependent sickle was well tolerated and a phase 3 trial in children is registered and (SS) RBC adhesion. Adrenergic nerves govern circadian leukocyte recruitment to tissues. In summary, understanding of the pathophysiology of sickle cell 10. Circadian control of VOC has led to several exciting new agents that are currently being the immune system. Recruitment in clinical trials and robust end points 11. Placenta growth factor continue to represent signiﬁcant challenges for translation to the activates monocytes and correlates with sickle cell disease clinical setting of even single agents. NKT cells mediate multitargeted multimodal approach will likely be required to pulmonary inﬂammation and dysfunction in murine sickle cell achieve the best outcome.
Rivaroxaban for thromboprophy- phylaxis in patients receiving chemotherapy for cancer discount nicotinell 52.5mg free shipping quit smoking body effects. Pattern of frequent but nontargeted pharmacologic thromboprophylaxis for hospitalized plus dalteparin thromboprophylaxis in pancreatic cancer generic nicotinell 35 mg overnight delivery quit smoking oils. Venous thromboembo- cancer patients: a randomised controlled trial nicotinell 35mg on-line quit smoking keep coughing. Society of Clinical Oncology clinical practice guideline update. Primary prophylaxis for venous American College of Chest Physicians Evidence-Based Clinical Prac- thromboembolism in ambulatory cancer patients receiving chemo- tice Guidelines. Antithrombotic therapy for VTE identiﬁcation of hospitalized medical patients at risk for venous disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: thromboembolism: the Padua Prediction Score. American College of Chest Physicians Evidence-Based Clinical Prac- 2010;8(11):2450-2457. Anticoagulation for the long-term lism (VTE) in cancer patients: ESMO Clinical Practice Guidelines. Ann treatment of venous thromboembolism in patients with cancer. Meta-analysis of the thromboembolic events in lymphoma. Kristinsson SY, Gridley G, Hoover RN, Check D, Landgren O. Effectiveness and Long-term risks after splenectomy among 8,149 cancer-free American safety of novel oral anticoagulants as compared with vitamin K 316 American Society of Hematology antagonists in the treatment of acute symptomatic venous thromboembo- 36. Apixaban for the treatment of lism: a systematic review and meta-analysis. Inﬂuence of active cancer parin, and heparin in vitro and in vivo. Dabigatran versus of acute venous thromboembolism: a pooled analysis from RE-COVER warfarin in patients with mechanical heart valves. Edoxaban for long-term challenging cases of patients with cancer associated thrombosis includ- treatment of venous thromboembolism in cancer patients[abstract]. Mikhael1 1Mayo Clinic in Arizona, Scottsdale, AZ There has been tremendous progress made in multiple myeloma in the last decade, resulting in improved overall survival for all patients, including those with high-risk disease and those ineligible for transplantation. However, despite the addition of several novel agents, unprecedented response rates, and our ability to achieve complete remission in the majority of patients, the disease remains incurable in nearly all and will require repeated therapies. With many options available to the clinician, there is no simple or ideal sequence of treatments that has been established, so the choice of relapsed therapy is based on a series of factors that include response and tolerability of prior therapies, risk status, available novel agents, aggressiveness of relapse, renal function, performance status, cost, etc. This chapter provides practical guidance in selecting relapsed therapies structured through a series of 5 questions that can inform the decision. Speciﬁc emphasis is placed on the 2 most recent novel agents, carﬁlzomib and pomalidomide, but agents in development are also included. It is preferable to specify refractory to a speciﬁc agent as selection of therapies for patients with relapsed multiple opposed to refractory in general. This becomes very important when myeloma deciding on potentially reinstituting agents as to whether the patient was simply exposed to an agent or genuinely refractory. This also Introduction facilitates terms such as “dual refractory” to 2 agents (such as The management of multiple myeloma has undergone tremendous bortezomib and lenalidomide). Finally, the phrase “primary refrac- evolution over the last decade. There have been waves of interven- tory” refers to patients who do not achieve a response to therapy. These have included the use of autologous stem cell increased options and the heterogeneity of myeloma, other agents transplantation (ASCT) and the novel agents thalidomide, bort- may confer a desirable response. Indeed, several modalities of treatment are now available, including novel agents, traditional chemo- in myeloma (Table 1). Selecting the ideal therapy requires the therapy, combinations of both novel and traditional agents, rescue consideration of several patient-related, disease-related, and treat- ASCT, and clinical trials. Balancing efﬁcacy, toxicity, and cost will ment-related factors (Table 2). To ensure that each of these is become ever more challenging with these increased options. This addressed appropriately, the following 5 questions should be asked chapter focuses on that approach, seeking to provide a practical (Table 3). Emerging therapies are also discussed brieﬂy because ibly heterogenous disease that may be very indolent, with relapse they will surely enhance treatment approaches in the future. This spectrum of disease is Deﬁning relapsed myeloma well appreciated in the untreated setting, with deﬁned categories of The terms “relapsed” and “refractory” are often used interchange- MGUS (monoclonal gammopathy of undetermined signiﬁcance) ably and may be confusing. The International Myeloma Working myeloma, smoldering (asymptomatic) myeloma, and overt multiple Group clariﬁed the deﬁnitions to facilitate uniform reporting. The general trigger for therapy in this setting is the general, “relapsed” refers to disease recurrence in the absence of presence of end organ damage, deﬁned by the acronym CRAB current therapy after the patient has had an established response. As dis- 100, may also deﬁne active disease due to imminent organ cussed in the next section, the sheer presence of biochemical relapse damage. Classes of current agents for the treatment of myeloma Table 3. Five critical questions in selecting relapsed therapy in myeloma Alkylators Melphalan 1. Have I considered an individualized, risk-stratiﬁed approach? Anthracyclines Doxorubicin Liposomal doxorubicin These options include combinations such as CyBorD (cyclophospha- Immunomodulatory drugs (IMiDs) mide, bortezomib, dexamethasone), VRD (bortezomib, lenalidomide, Thalidomide dexamethasone), KRD (carﬁlzomib, lenalidomide, dexamethasone), Lenalidomide PVD (pomalidomide, bortezomib, dexamethasone), KPD (carﬁl- Pomalidomide zomib, pomalidomide, dexamethasone), or traditional combinations Proteasome inhibitors Bortezomib such as DT-PACE (dexamethasone, thalidomide, cisplatin, adriamy- Carﬁlzomib cin, cyclophosphamide, etoposide) or DCEP (dexamethasone, cyclo- phosphamide, etoposide, cisplatin). First, myeloma is a heterogenous disease often with multiple clones8 and combinations may overcome several speciﬁc guidelines from the International Myeloma Workshop Consensus Panel have suggested that, at minimum, patients must clones together. Second, combinations result in less resistance have a doubling of the M component in 2 consecutive measurements against a single pathway. Third, combinations maximize different separated by 2 months or an increase in the absolute levels of the mechanisms of action (ideally without overlapping toxicities). M protein by 1 g/dL, involved free light chain 20 mg/dL (plus Finally, clinical experience has demonstrated that patients may an abnormal FLC ratio), or urine M protein 500 mg/24 hours in 2 respond to agents to which they were previously refractory when consecutive measurements in 2 months. For example, when patients genuinely CRAB criteria, these guidelines should result in the introduction of refractory to bortezomib and lenalidomide were treated with the relapsed therapy. However, if relapse is more indolent, without combination of bortezomib plus lenalidomide (and dexamethasone), 30% responded. This theory is illustrated in Figure 1, which highlights the beneﬁts of Identifying the “indolent” versus the “aggressive” relapse is crucial. Although the phenomenon of efﬁcacy, toxicity, and cost approach using 1-2 agents at a time, usually a proteasome inhibitor are not linear as presented in the ﬁgure, they must be considered or an immunomodulatory drug (IMiD) plus a steroid, with the when adding more agents to a patient’s regimen. The optimal expectation of prolonged response, eventually using all active balance of either extreme (too few vs too many agents) will depend agents in myeloma.
G. Orknarok. Ohio Northern University.