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By F. Masil. Christopher Newport University.

Integration of new biological insights (MM should no comparing pomalidomide plus low-dose dexamethasone versus longer be considered as a single disease) with evidence-based drug high-dose dexamethasone in patients who had failed prior bort- combinations should place us on the road to success order lasix 40 mg with visa blood pressure chart and pulse. The second- PI060339; 06/1354; 02/0905; 01/0089/01-02; PS09/01897/01370) generation proteasome inhibitor carfilzomib has also shown encour- and the Asociacio´n Espan˜ola Contra el Ca´ncer (Grant aging efficacy in heavily pretreated MM patients discount lasix 100 mg without prescription arrhythmia on ekg, with a response GCB120981SAN) discount lasix 100mg line blood pressure chart cdc. The author thanks members of the Haematology rate of 50% ( PR) and a PFS of 8 months when used as single Departments of Salamanca and Pamplona for their support buy cheap lasix 100 mg on-line prehypertension blood pressure values, the agent and 16% responses in Bz-refractory patients. Combinations with lenalidomide, pomalidomide, cyclophosphamide, and panobinostat are also being Disclosures tested, including a phase 3 trial (CRd versus Rd) that already Conflict-of-interest disclosure: The author is on the advisory indicated superiority for the triple (CRd) combination. Ixazomib committees for Millennium, Celgene, Novartis, Onyx, Janssen, (MLN9708) has shown PR in 15% of relapse/refractory patients BMS, and MSD. Other oral proteasome inhibitors, such as oprozomib, are also in an early Correspondence phase of development. Bendamustine (a hybrid between an alkylat- Jesus San Miguel, Centro de Investigacio´n Me´dica Aplicada, ing agent and a purine analogue) as a single agent produced an Clinica Universidad de Navarra, Avda. Pio XII, n° 36, Pamplona overall response rate of 31% in relapsing patients, the figure being 31008, Spain; Phone: 34-948296296; Fax: 34-948296386; e-mail: twice as high in combinations. There is considerable interest in agents with novel mechanisms of References action, particularly monoclonal antibodies. Widespread genetic heterogeneity developed monoclonal antibody for multiple myeloma is elotu- in multiple myeloma: implications for targeted therapy. The genetic architecture of multiple F7), a humanized IgG1 antibody targeting the CS1 glycoprotein. Although elotuzumab monotherapy only elicits modest activity in 3. International Myeloma patients with MM, the addition of lenalidomide and low-dose Working Group molecular classification of multiple myeloma: spotlight dexamethasone has resulted in an overall response rate of 92% in review. Phase 2 and 3 trials currently in progress are 364(11):1046-1060. The second type of monoclonal antibody under investiga- KRAS significantly reduces myeloma sensitivity to single-agent bort- tion is anti-CD38 (daratumumab, SAR650984). The molecular classification of multiple monotherapy, with 30%–40% responses at the optimized doses and myeloma. Aberrant global methyl- ation patterns affect the molecular pathogenesis and prognosis of steroids. This has prompted the investigation of it in combination multiple myeloma. Gutierrez NC, Sarasquete ME, Misiewicz-Krzeminska I, et al. Deregula- tion of microRNA expression in the different genetic subtypes of Deacetylase inhibitors have exhibited only modest activity (minor multiple myeloma and correlation with gene expression profiling. Downregulation of p53-inducible clinical benefit compared with bortezomib as a single agent (PFS of microRNAs 192, 194, and 215 impairs the p53/MDM2 autoregulatory 7. SNP-based mapping proved to be superior to bortezomib/dexamethasone in a phase 3 arrays reveal high genomic complexity in monoclonal gammopathies, trial (PFS: 12 vs 8 months). More selective deacetylase inhibitors from MGUS to myeloma status. Heterogeneity of genomic (HLAC6, Acetylon) with improved tolerability are under investiga- evolution and mutational profiles in multiple myeloma. Other novel agents under investigation include the kinase 2014;5:2997. Identification of cereblon-binding 22% PR when combined with low-dose dexamethasone in proteins and relationship with response and survival after IMiDs in patients refractory to bortezomib, lenalidomide, and dexametha- multiple myeloma. PI3K/mTOR and the RAS/MEK/ERK pathways or checkpoint 2014;343(6168):256-257. High-risk cytogenetics and 6 American Society of Hematology persistent minimal residual disease by multiparameter flow cytometry 31. Lenalidomide after predict unsustained complete response after autologous stem cell stem-cell transplantation for multiple myeloma. Melphalan/prednisone/ biological implications of genetic abnormalities in multiple myeloma lenalidomide (MPR) versus high-dose melphalan and autologous trans- undergoing autologous stem cell transplantation: t(4;14) is the most plantation (MEL200) plus lenalidomide maintenance or no maintenance relevant adverse prognostic factor, whereas RB deletion as a unique in newly diagnosed multiple myeloma (MM) patients [abstract]. ASCO abnormality is not associated with adverse prognosis. Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. A novel prognostic model in induction and maintenance treatment in patients with newly diagnosed myeloma based on co-segregating adverse FISH lesions and the ISS: multiple myeloma: results of the randomized phase III HOVON-65/ analysis of patients treated in the MRC Myeloma IX trial. Bergsagel PL, Mateos MV, Gutierrez NC, Rajkumar SV, San Miguel Group consensus statement regarding the current status of allogeneic JF. Improving overall survival and overcoming adverse prognosis in the stem-cell transplantation for multiple myeloma. Double vs single autologous thalidomide versus melphalan and prednisone alone or reduced- stem cell transplantation after bortezomib-based induction regimens for intensity autologous stem cell transplantation in elderly patients with multiple myeloma: an integrated analysis of patient-level data from multiple myeloma (IFM 99-06): a randomised trial. Prognostic relevance of 18-F treatment for newly diagnosed multiple myeloma. FDG PET/CT in newly diagnosed multiple myeloma patients treated 2012;366(19):1759-1769. Minimal residual disease Versus Standard Thalidomide) trial (MM-020/IFM 07 01) in newly assessed by multiparameter flow cytometry in multiple myeloma: diagnosed multiple myeloma (NDMM) patients (pts) ineligible for stem impact on outcome in the Medical Research Council Myeloma IX cell transplantation (SCT) [abstract]. Bortezomib plus sequencing method for minimal residual disease detection in multiple melphalan and prednisone for initial treatment of multiple myeloma. Criteria for diagnosis, staging, risk stratifica- induction therapy followed by maintenance treatment with bortezomib tion and response assessment of multiple myeloma. Haematological cancer: thalidomide compared with bortezomib-melphalan-prednisone for ini- Redefining myeloma. Phenotypic, genomic and induction therapy before, and consolidation therapy after, double functional characterization reveals no differences between CD138 autologous stem-cell transplantation in newly diagnosed multiple my- and CD138low subpopulations in multiple myeloma cell lines. Thalidomide and hematopoietic- dexamethasone versus high-dose dexamethasone alone for patients with cell transplantation for multiple myeloma. A phase 2 study of single-agent transplantation improves survival in newly diagnosed multiple myeloma carfilzomib (PX-171-003-A1) in patients with relapsed and refractory patients [abstract]. Vorinostat or placebo in dexamethasone is superior to thalidomide-dexamethasone as consolida- combination with bortezomib in patients with multiple myeloma tion therapy after autologous hematopoietic stem cell transplantation in (VANTAGE 088): a multicentre, randomised, double-blind study. The role of maintenance panobinostat in combination with bortezomib and dexamethasone in thalidomide therapy in multiple myeloma: MRC Myeloma IX results patients with relapsed and bortezomib-refractory myeloma. However, at present, only the markers NPM1, CEBPA, and FLT3 have entered clinical practice. Treatment of intermediate-risk AML patients eligible for intensive therapy has not changed substantially. The “3 7” induction therapy still represents the standard of care. The addition of the immunoconjugate gemtuzumab ozogamicin to therapy has been shown to improve outcome; however, the drug is not approved for this use. A common standard for postremission therapy is the administration of repeated cycles of intermediate- to high-dose cytarabine. Allogeneic stem cell transplantation may offer a survival benefit for many patients with intermediate-risk AML. Patients are best selected based on the genetic profile of the leukemia cells and the risk associated with the transplantation itself. A myriad of novel agents targeting mutant leukemia drivers or deregulated pathways are in clinical development. In the past, many novel compounds have not met expectations; nonetheless, with the rapid developments in comprehensive molecular profiling and new drug design, there is the prospect of personalizing therapy and improving patient outcome. Among younger adult intermediate- ● To understand that AML with “intermediate-risk” cytogenet- risk patients, the second point mainly relates to the question of ics is a very heterogenous group of patients who now can be whether a patient should be assigned to allogeneic hematopoietic divided based on a large number of gene mutations stem cell transplantation (HSCT). Although this risk categorization in blood samples should be stored in a biobank general has also some validity in older patients, outcome of these ● To understand that novel therapies are in clinical development patients has remained very poor (Figure 1) and differences among that target specific mutant driver proteins and deregulated genetically defined subsets of the disease become rather marginal. Introduction Cytogenetic analysis to identify chromosome abnormalities has Intermediate-risk AML definition based on become well established in the clinical management of patients with conventional cytogenetics and molecular genetics acute myeloid leukemia (AML). The majority of AML patients have genomics technologies, numerous new mutations or gene expres- an intermediate cytogenetic risk, with most of them exhibiting a sion signatures have been identified that now allow us to decipher normal karyotype (Figure 2). In the recommendations by the the molecular heterogeneity of AML, in particular within the large European LeukemiaNet (ELN), for the first time, the 3 molecular subset of “intermediate-risk” AML. In terms of CEBPA mutations, there are emerging data Despite these tremendous advances in our understanding of the showing that only double, not single, CEBPA mutations confer a disease pathogenesis, translation of these insights into the clinical favorable prognosis. In daily practice, the decision ITD mutations affect outcome and, depending on the present algorithm follows 2 major assessments: (1) whether a patient is NPM1/FLT3-ITD genotype, this subset of CEBPA-mutated AML eligible for intensive standard anthracycline and cytarabine has a more or less favorable long-term outcome. Frequent cytogenetics defining intermediate-risk AML Normal karyotype* Structural rearrangements Balanced t(9;11)(p22;q23)† Unbalanced del(7q)‡ del(9q)‡ del(11q)† del(20q)§ Numerical aberrations Y 8 11 13 21 Figure 1. Shown in The categorization of the cytogenetic findings in the table is based on the classifica- black are patients 60 years of age (n 1188); in red are patients 60 tionsystemspublishedbySWOG/ECOG,3CALGB,4andMRC. These data were obtained from 1681 *Nochromosomeaberrationsafteranalysisof20ormoreBMmetaphases. Within the CALGB classification classified as adverse risk in terms of overall survival. Many of the molecular markers, such as DNMT3A (DNA (cytosine-5-)- data with respect to prognosis are quite consistent, whereas for methyltransferase 3 alpha), RUNX1 (runt-related transcription others, the picture is less clear (Table 3).

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At the time of initial reporting buy lasix 40mg cheap pulse pressure 93, the PFS was 85% and OS 81% generic 40 mg lasix amex blood pressure 9040. The cohort has expanded Therapy to 28 patients and order lasix visa blood pressure 2, with a median of 41 months follow-up cheap lasix 40 mg online blood pressure quit drinking, the PFS BL remains a challenge in both the HIV-1-negative and HIV-1- remains high at 78%. In addition, transplantation-related mortal- positive patient, with treatment remaining controversial. Concern ity was low and no patient succumbed to opportunistic infection. The minimize antiretroviral and chemotherapy drug interactions and AIDS Malignancy Consortium did a phase 2 trial of modified to maximize efforts to continue antiretrovirals through the period dose-intensive R-CODOX-M/IVAC in HIV-1 BL, reported in of the transplantation. The approach to the use of antiviral agents abstract form only, and showed that 14% of patients were taken off is shown in Table 1. The efficacy of this complex, intensive regimen remains unproven. The National Cancer Institute series of 29 patients with blood without ART; before autologous HCT and with high-dose BL treated with R-EPOCH included 10 who were HIV-1-positive melphalan therapy, there was viral rebound at day 6 with a peak of and the compete response rate and OS rate were an impressive 28 000 c/mL and a return to 50 c/mL by day 41 corresponding to 100% at 57 months of follow-up. Regain of viral control was associated with a potent CD8 response. Before ART, the need for alternate approaches transplantation period to control virus for those without such immunity. Approach to the use of antivirals* Raltegravir-based regimen NNRTI-based regimen Boosted PI regimen Continue through conditioning Continue through conditioning Discontinue 96 h prior to conditioning and resume after conditioning NNRTIindicatesNonnucleosidereversetranscriptaseinhibitor;andPI,proteaseinhibitor. However, cure of HIV-1 study enrollment and 2 at the time of stem cell mobilization. The remains the Holy Grail and HCT may provide us the route to this viral loads at study entry therefore ranged from 204 to 750 000 goal. Infusion of resistant allogeneic hematopoietic cells or manipu- copies/mL. Thirteen patients withdrew before stem cell collection, lation of autologous hematopoietic cells to render them resistant to the majority due to progressive disease. Ultimately, 27 of the initial the HIV-1, followed by reinfusion after ablative chemotherapy that 50 patients underwent HCT. The 3-year PFS for the patients who depletes the endogenous reservoir and allows engraftment, are proceeded to HCT was similar to the City of Hope group at 76. To date, the most successful method was the use Multivariate analysis for prognostic factors for survival showed that of allogeneic hematopoietic cells from a donor genetically resistant to HIV-1 into an AIDS patient with acute myelogenous leukemia. Individuals who are homozygous at this locus do not express CCR5 on their cell surface The Bone and Marrow Transplantation Clinical Trials Network 33 and therefore cannot be infected with CCR5 (R5) tropic HIV-1. The HCT, and the patient remains with undetectable HIV-1 RNA in primary end point of the trial is OS at 1 year; analysis is pending. Alternately, genetic modification of autologous hematopoi- level of clinical detection, suggested that a sanctuary site exists from 29 etic cells circumvents the issues of identifying donors and, given the which infection could always be recovered. The tissue repository far lower morbidity of autologous HCT, allows a more viable of HIV-1-infected cells from which this active replicating HIV-1 is 30 approach to hematopoietic cell therapy for HIV-1. The theoretical space that is considered the HIV-1 reservoir consists of CD4 T- A large phase 2 trial of gene-modified autologous hematopoietic lymphocytes and dendritic cells (DCs). DCs, predominantly in- cells infused without conditioning therapy showed only minimal fected by R5 strains of virus or by dual-tropic infection with R5 and detection of gene-marked cells in peripheral blood and a lack of CXCR4 strains, undergo stimulation by cytokines, leading to the significant effect on HIV-1 levels. Therefore, factors that stimulate cytokine release, effects of the genetically modified cells on the HIV infection. There including mucosal damage from high-dose chemotherapy, coinfec- were no long-term deleterious effects of the ATI, so this trial set the tion with microbes, and microbial translocation from the GI tract, platform for this approach in future trials. At the The favorable results of high-dose therapy and autologous in same time, the challenge was also to find a suitable patient HIV-1-associated lymphoma raised the question of whether the population for whom myeloablation could be justified. The lym- apheresis or the high-dose chemotherapy provided any beneficial phoma population was perfectly suited, especially given the poor effects on HIV-1 infection. For example, could the apheresis have long-term survival of patients with relapsed HIV lymphoma. The depleted the reservoir or could myeloablative chemotherapy ablate pilot trial treated 4 relapsed HIV-1-positive NHL patients with the infected lymphocyte pool? To address this, Cillo et al32 reported hematopoietic cells transduced with a lentivirus encoding 3 anti- HIV-1 RNAs, namely TAR, siRNA to tat/rev, and a ribozyme a retrospective analysis of frozen PBMC specimens from AIDS 37 targeting CCR5. The cells were infused in combination with lymphoma HCT recipients who remained on ART during much of unmodified cells after high-dose CBV therapy. Patients had no detectable HIV-1 RNA in the plasma at serious adverse events associated with the genetically modified variable time points after HCT. Specimens from blood, studied 36 cells, but, similar to the aforementioned Mitsuyasu study, levels of before HCT and at one other post-HCT time, used assays for HIV gene marking, although present in all patients in the peripheral RNA and DNA having single-copy sensitivity, a surrogate measure blood, were low at 0. No HIV-1 RNA was detected in plasma by due in part to competition with the much higher levels of unmodi- routine assays, but with the more sensitive assay, 9 of 10 patients fied hematopoietic cells that were infused concomitantly with the were viremic after HCT while on ART, with a range of 0. HIV-1 gene copies/mL, and 9/10 were found to have detectable HIV-1 DNA. This finding may have been due to 2 factors: (1) the The evolving paradigm is that success is contingent upon high levels autologous graft likely had infectious virus in contaminating T-cells of only genetically modified hematopoietic cells being infused or and (2) the endogenous reservoir was still present despite the selection of the protected cells after engraftment. Ultimately, the test cytoreductive conditioning regimen. Patients in cohort 1 (n 6) underwent a 12-week ATI of ART beginning 4 weeks after the T-cell infusion. HIV-1 viral load was undetectable at the start of ATI and became detectable in 4 of the 6 patients at 2-4 weeks after cessation of c-ART. There was a decline of CD4 counts during ATI, but this decline in CCR5-modified cells (1. Only one serious adverse event was associated with the cell infusion and was attributed to a transfusion reaction. Level of gene marking expressed as number of copies of trial has thus successfully set the platform for ZFN editing of cells as vector (WPRE) per 100 blood cells analyzed over time. Unique a viable and well-tolerated approach that may lead to in vivo patient identifiers are listed in the upper right corner of the graph. Limits resistance of these CCR5-edited cells to HIV-1. The future trial of of quantification (stippled) and limits of detection (diagonal lines) values ZFN-1-modified hematopoietic cells in conjunction with nonmyelo- were determined for each amplification reaction and typically were in the ablative busulfan conditioning in selected HIV-1-positive patients range of 0. We have adopted a stepwise approach, with Conflict-of-interest disclosures: A. In addition, infusion of only genetically modified hematopoi- etic Cell Transplantation, Beckman Research Institute, City of Hope etic cells could be justified in the nonmyeloablative setting because Medical Center, 1500 E Duarte Road, Duarte, CA 91010. Phone: early or late graft failure in this setting would not have the same 626-359-8111; Fax: 626-301-8973; e-mail: AKrishnan@coh. A pilot trial using busulfan at nonmyeloablative doses in first-remission HIV-1- References positive NHL patients is open at City of Hope (www. Changing incidence and prognostic factors of survival in AIDS-related non-Hodgkin’s lym- gov identifier #NCT01961063). Busulfan is not considered an antilymphoma therapy, so its use in 2. Primary effusion lym- the current trial is solely to facilitate engraftment. Clinical trials in phoma: a distinct clinicopathologic entity associated with the Kaposi’s human genetic diseases, especially in pediatric populations, using sarcoma-associated herpes virus. Sullivan RJ, Pantanowitz L, Casper C, Stebbing J, Dezube BJ. Candotti et al39 correlated busulfan HIV/AIDS: epidemiology, pathophysiology, and treatment of Kaposi dosing with area under the curve (AUC) measurements demonstrat- sarcoma-associated herpesvirus disease: Kaposi sarcoma, primary effu- 2 sion lymphoma, and multicentric Castleman disease. Emerging targets and novel strategies associated with engraftment. Toxicity was mild, with transient in the treatment of AIDS-related Kaposi’s sarcoma: bidirectional neutropenia, mild thrombocytopenia, and transient elevated liver translational science. The ultimate step for the HIV-1 trials is to use this 5. Distinct subsets of primary busulfan-based conditioning in HIV-1-infected patients without effusion lymphoma can be identified based on their cellular gene malignancy. Such a trial is planned at City of Hope and will use expression profile and viral association. AUC-targeted busulfan dosing, followed by infusion of a CCR5- 6. Prognostic factors and outcome of human herpesvirus 8-associated primary effusion lymphoma in negative product edited by a zinc finger nuclease (ZFN). Failure to eradicate AIDS-associated The ZFN construct has already been tested successfully with primary effusion lymphoma with high-dose chemotherapy and autolo- autologous T lymphocytes. AIDS for gene therapy because they are easily obtained from the donor’s Patient Care STDS. Successful reduced-intensity conditioning alloge- Indeed, limitations of cell number have been one of the challenges neic HSCT for HIV-related primary effusion lymphoma. CD30 targeting with brentuximab vedotin: a novel therapeutic approach to primary effusion therapeutic gene can be rapidly monitored for effects on cell lymphoma. Bortezomib (PS-341) in recognition specificity of zinc finger proteins with the strong patients with human herpesvirus 8-associated primary effusion lym- enzymatic activity of the cleavage domain of the restriction enzyme phoma.

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Phase I/II trial of death in Philadelphia chromosome-positive cells lasix 100mg free shipping blood pressure chart malaysia, including adding semisynthetic homoharringtonine in chronic myeloid primary CML stem cells order lasix blood pressure medication causing low blood pressure. The durable clearance of eloid leukemia cells cheap 100 mg lasix with visa heart attack 6 hours, by inhibition of late stage autophagy order 100 mg lasix amex blood pressure 7030. Carella AM, Beltrami G, Pica G, Carella A, Catania G. Clin Lymphoma Myeloma Clarithromycin potentiates tyrosine kinase inhibitor treatment Leuk. Nimmanapalli R, Fuino L, Stobaugh C, Richon V, Bhalla K. Imatinib plus apoptosis of Bcr-Abl-positive human acute leukemia cells. Combina- immunotherapy reduces tumor burden in chronic myeloid tion of pegylated IFN-alpha2b with imatinib increases molecu- leukemia patients with residual disease on imatinib mesylate. IFNalpha candidate chronic myeloid leukemia stem cells by antibody activates dormant haematopoietic stem cells in vivo. Selective killing of lar response with interferon alfa maintenance after induction candidate AML stem cells by antibody targeting of IL1RAP. Talpaz M, Hehlmann R, Quintas-Cardama A, Mercer J, Cortes 2013;84(1):7-20. Re-emergence of interferon-alpha in the treatment of 130. Specific human cellular cells to granulocyte-colony stimulating factor in vitro pro- immunity to bcr-abl oncogene-derived peptides. Growth factor stimulation multipeptide vaccine associated with imatinib or interferon in reduces residual quiescent chronic myelogenous leukemia patients with chronic myeloid leukaemia and persistent re- progenitors remaining after imatinib treatment. Clinical evaluation of continuous imatinib vs pulsed imatinib with or without G-CSF BCR-ABL peptide immunisation in chronic myeloid leukae- in CML patients who have achieved a complete cytogenetic mia: results of the EPIC study. Synthetic tumor- mediated protection of tyrosine kinase inhibitor-treated BCR- specific breakpoint peptide vaccine in patients with chronic ABL-expressing leukemia cells. Reduction of inhibition of stromal-derived PlGF prolongs survival of mice imatinib dose and persistence of complete molecular response with imatinib-resistant Bcr-Abl1( ) leukemia. Complete molecular mediated extrinsic survival signals restores sensitivity of CML response in CML after p210 BCR-ABL1-derived peptide cells to ABL inhibitors. WT1 peptide vaccine induces protection of CML stem and progenitor cells from tyrosine reduction in minimal residual disease in an Imatinib-treated kinase inhibitors through N-cadherin and Wnt-beta-catenin CML patient. Inhibition of cells and progenitors of chronic myeloid leukemia express CXCR4 in CML cells disrupts their interaction with the bone leukemia-associated antigens: implications for the graft-versus- marrow microenvironment and sensitizes them to nilotinib. PR1-specific T cells are plerixafor in combination with BCR-ABL kinase inhibition in associated with unmaintained cytogenetic remission of chronic a murine model of CML. Targeting of the MNK-eIF4E sustained high-avidity, epitope-specific CD8 T cells in axis in blast crisis chronic myeloid leukemia inhibits leukemia myeloid malignancies. Riches1 1Barts Cancer Institute, Queen Mary University of London, London, United Kingdom Although there have been recent advances with targeted therapies in chronic lymphocytic leukemia (CLL), chemoimmunotherapy remains the treatment of choice; however, this approach is not curative. A key feature of CLL is that it induces a state of immunosuppression, causing increased susceptibility to infections and failure of an antitumor immune response, often worsened by the immunosuppressive effect of treatment. Because of its improved specificity, immunotherapy potentially offers a way out of this dilemma. Allogeneic stem cell transplantation remains the only curative option, but is hampered by the toxicity of GVHD. After many years of promise but little reward, many other immunotherapeutic approaches are now in transition to the clinical setting. Clinical trials including CLL vaccines, CXCR4 antagonists, and adoptive cellular immunotherapies such as chimeric antigen receptor–modified T cells, CD40 ligand gene therapy, and the immunomodulatory drug lenalidomide are ongoing. Results to date suggest that immunotherapeutic approaches for the treatment of CLL might finally be fulfilling their promise. Introduction consideration of HSCT and when in their disease course HSCT Over the past decade, there have been significant advances in our should be offered. Combination immunochemotherapy with rituximab, fludarabine, exploit GVL in CLL while avoiding the significant morbidity and and cyclophosphamide is currently established as the frontline mortality associated with myeloablative conditioning. RIC regi- therapy of choice, with overall response rates of 95% and complete mens allow transplantation in older patients, making this approach remission (CR) rates of 44%. High-risk patients include those requiring treatment who Role of hematopoietic stem cell transplantation in CLL have p53 abnormalities (who merit allogeneic SCT in first response), Currently, allogeneic hematopoietic stem cell transplantation (HSCT) patients who fail to achieve CR or who progress within 12 months after remains the only curative option for CLL. The key to its activity is purine analogs, those who relapse within 24 months after having the GVL effect in which the transplanted hematopoietic stem cells achieved a response with purine-analog-based combination therapy, differentiate into effector cells capable of mounting an antitumor those who have relapsed after prior autologous SCT, or those patients immune response, which is likely directed at minor host antigenic who are fludarabine refractory. This effect is known to be primarily T-cell mediated, exception of cytogenetics for detection of p53 deletions, none of these although it remains unclear whether it is due to improved T-cell categories requires assessment of biologic risk factors. Ongoing function, the presence of allogeneic MHC molecules, or a combina- prospective clinical studies will determine the impact of biomarkers tion of both. HSCT is not a suitable treatment option for the majority of the identification of patients at sufficiently high risk to merit the use of patients with CLL. The disease usually follows an indolent course; allogeneic SCT in first CR. Allogeneic SCT has the potential to induce many patients never require any therapy and most patients are too long-term remission in patients with deletion 17p,13 and the mutational elderly to undergo this procedure. However, high-risk patients can status of the TP53, SF3B1, and NOTCH1 genes had no significant be identified using several clinical and biological features, and such effect on overall and event-free survival. The biggest challenges Perhaps the most convincing proof of the principle for GVL comes remain the decisions regarding which patients are eligible for from the ability of RIC plus allogeneic HSCT to induce durable Hematology 2013 151 Table 1. Results from the largest reported studies of RIC allogeneic transplantation in CLL Fred Hutchinson Dana-Farber German CLL Study Group8 MD Anderson Cancer Center9 Cancer Center10 Cancer Institute11 Number 90 86 82 76 Conditioning regimen Fludarabine/cyclophosphamide Fludarabine/cyclophosphamide Fludarabine/low-dose Fludarabine/busulfan antithymocyte globulin rituximab total body irradiation Matched sibling donors 41% 50% 63% 37% Median follow-up (mo) 72 37 60 61 Death within 100 days 3% 3% 10% 3% Non relapse mortality 23% 17% 23% 16% Acute GVHD (grade 3-4) 14% 7% 20% 17% Chronic extensive GVHD 55% 56% 53% 48% Progression-free survival 38% (6 y) 36% (5 y) 39% (5 y) 43% (5 y) Overall survival 58% (6 y) 51% (5 y) 50% (5 y) 63% (5 y) eradication of MRD. In a report from the German CLL Study therapy for CLL have been fraught with difficulties of overcoming Group, of 52 patients who were available for longitudinal MRD the T-cell defects induced in this disease and require a fuller monitoring, 54% were relapse free and MRD negative 12 months understanding of why patient T cells fail to recognize and attack the after allogeneic HSCT. Only 2 of these patients have subsequently CLL cells. Although autologous SCT improved an increased incidence of autoimmune anemia and thrombocytope- event-free survival, there was no difference in overall survival in 14 nia that are commonly seen in this disease. A retrospective matched-pair analysis is highly abnormal in CLL, with an increase in absolute numbers of suggested a survival advantage for autologous SCT over conven- 15 peripheral blood T cells, primarily accounted for by an increase in tional therapy, but its clinical role in the era of improved frontline CD8 T cells, with a fall in the CD4:CD8 ratio. Despite their therapy with modern chemoimmunotherapy approaches remains 16 increased numbers, these T cells show profound defects in function uncertain. Although a shift toward a type 2 T-cell response was an attractive Autologous T-cell responses against CLL hypothesis, CLL T cells have increased production of interferon- Attempting to bolster an antitumor immune response against CLL is (IFN- ) and tumor necrosis factor- (TNF- ), that can protect CLL a particularly attractive treatment option (Table 2). The specificity cells from apoptosis and induce proliferation. CLL T cells show of the adaptive immune response should make it possible to target evidence of chronic activation, with up-regulation of activation leukemia cells. Immune-mediated recognition and destruction has markers such as CD69, HLA-DR and CD57, down-regulation of the potential to circumvent established prognostic markers and CD28 and CD62L and expansions of clonal and oligoclonal T cells. Finally, ap- These oligoclonal expansions are primarily restricted to populations proaches aiming to enhance the immune response offer the capacity with an activated CD57 phenotype, suggesting a role for chronic to improve immunity to infection in addition to repairing the antigen stimulation in their development. However, attempts to use autologous T cells as “exhaustion,” seen in chronic viral infections and it remained unclear whether this was directly related to CLL, or whether other Table 2. Immunotherapeutic strategies in CLL factors such as cytomegalovirus (CMV) are involved. There is an expansion of CMV-specific CD4 and CD8 T cells in patients with Mechanism Examples 17 CLL, with an effector phenotype. However CD8 and CD4 Adoptive T-cell therapy Allogeneic HSCT/DLI T cells from both CMV seropositive and seronegative CLL patients Transgenic TCR T cells have increased expression of exhaustion markers CD244, CD160, CAR T cells and PD1, with expansion of a PD1 BLIMP1HI subset. In contrast to virally induced exhaustion, CLL T Dendritic cell vaccines cells showed increased production of IFN- and TNF and Transgenic TCR T cells increased expression of TBET, and normal IL-2 production. CAR T cells Enhanced T-cell costimulation Second- and third-generation T cells in CLL exhibit profound changes in their global gene CAR T cells expression profiles, with alterations in the expression of genes Ex vivo expansion with involved in cytoskeletal formation. The altered expression of cytoskeletal genes trans- Repair of CLL B-cell antigen- CD40L gene therapy lated into a functional defect in filamentous actin polymerization, presenting function Lenalidomide with CLL T cells exhibiting defective immunological synapse 152 American Society of Hematology Figure 1. Up-regulation of CD200, CD270, CD274, and CD276 induces impaired actin polymerization and immunological synapse formation in CLL T cells. This results in nonpolarized degranulation and impaired cytotoxicity. CD200 also promotes the differentiation of CD4 T cells into Tregs, which express CD152(CTLA-4). CD270(HVEM) and CD274(PD-L1) interact with their ligands, CD160 and CD279(PD-1), respectively, to inhibit T-cell activation and proliferation. Chronic antigenic stimulation of T cells by either TAAs expressed by the CLL cells or other auto-antigens/exogenous antigens drives T-cell exhaustion and increased expression of inhibitory ligands such as CD279(PD-1), CD160, and CD244. NLCs appear to promote CLL cell survival via CXCL12 and induce these T-cell changes and found that the proteins CD200, increased expression of B-cell-activating factor of the tumor CD270 (Herpes virus entry mediator; HVEM), CD274 (Pro- necrosis factor family (BAFF) and a proliferation inducing ligand grammed death ligand-1; PD-L1), and CD276 (B7-H3) induced (APRIL), perhaps explaining the increased numbers of T cells in impaired immunological synapse formation in both allogeneic and CLL pseudofollicles. Therefore, it is likely that CTLA-4 signaling is Immune checkpoint blockade yet another inhibitory pathway mediating T-cell dysfunction in Suppression of antitumor immunity by inhibitory pathways such as CLL, in addition to the PD-1:PD-L1, CD160:HVEM, and CD200: PDL1:PD1 appears to be an important mechanism underlying the CD200R axes (Figure 1). Furthermore, the use of an antibody receptor the effect of blocking the PD1:PDL1 axis. A recent phase 1 study of means that potential targets can be increased to include a wide range of an anti-PD1 monoclonal antibody (Nivolumab; BMS-936558) in surface proteins, sugars, and lipids. A single published phase 1 dose-escalation study of fortunately, the CAR T cells did not persist long term, with the another anti-PD1 antibody (CT-011; Pidilizumab) showed evidence anti-CD19 CAR becoming undetectable at 27 weeks, followed by of response in 6 of 18 patients. Of the 3 CLL patients who were the development of progressive disease at 32 weeks.

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