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Best Practice & Research. Clinical Haematology

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https://www.readbyqxmd.com/read/29156207/intracellular-protein-degradation-from-a-vague-idea-thru-the-lysosome-and-the-ubiquitin-proteasome-system-and-onto-human-diseases-and-drug-targeting
#1
REVIEW
Aaron Ciechanover
Between the 1950s and 1980s, scientists were focusing mostly on how the genetic code is transcribed to RNA and translated to proteins, but how proteins are degraded has remained a neglected research area. With the discovery of the lysosome by Christian de Duve it was assumed that cellular proteins are degraded within this organelle. Yet, several independent lines of experimental evidence strongly suggested that intracellular proteolysis is largely non-lysosomal, but the mechanisms involved remained obscure...
December 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29156206/cytokine-release-syndrome-who-is-at-risk-and-how-to-treat
#2
REVIEW
Noelle Frey
T-cell engaging therapies such as blinatumomab and anti-CD19 chimeric antigen receptor (CAR) T cells have revolutionized our approach to patients with relapsed and refractory acute lymphoblastic leukemia (ALL). However, the immune activation responsible for high remission rates is also responsible for the unique treatment-related toxicity of cytokine release syndrome (CRS). The clinical signs of CRS include fever, hemodynamic instability, and capillary leak, which correlate with T-cell activation and elevated cytokine levels...
December 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29156205/which-factors-influence-the-development-of-gvhd-in-hla-matched-or-mismatched-transplants
#3
REVIEW
Effie W Petersdorf
The sheer diversity of HLA alleles makes the probability of finding matched unrelated donors for patients requiring hematopoietic cell transplantation (HCT) a complex situation. New evidence suggests that mismatching at certain HLA loci may provide a greater benefit in terms of graft-versus-leukemia effect than other mismatches when HLA-matched donors are not available. This review summarizes the current understanding of HLA matching requirements for unrelated donor HCT.
December 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29156204/autologous-hematopoietic-cell-transplantation-for-adult-acute-myeloid-leukemia-an-obsolete-or-resurfacing-concept
#4
REVIEW
Hillard M Lazarus, Najla El Jurdi
Improving long-term outcomes of adult acute myeloid leukemia (AML) patients remains a challenge. Major scientific and clinical advances have led to a better understanding of the disease biology, and the majority of patients achieve a complete remission (CR) after induction therapy. Relapse risk, however, remains considerable and is the leading cause of death in this patient population. Significant efforts to improve outcomes emphasize use of post-remission therapies such as hematopoietic cell transplantation (HCT), an increasingly utilized modality...
December 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29156203/impact-of-allogeneic-hematopoietic-cell-transplantation-on-the-outcome-of-older-patients-with-acute-myeloid-leukemia
#5
REVIEW
Frederick R Appelbaum
For younger patients with intermediate- or high-risk acute myeloid leukemia (AML) in first remission, allogeneic hematopoietic cell transplantation (HCT) offers the best chance of cure and therefore is the treatment of choice. The role of allogeneic HCT in the treatment of older patients is less well defined. In this review, four issues concerning the role of HCT in the treatment of older AML patients will be addressed: the frequency of allogeneic HCT in the older AML population in the US; the impact of age on the outcome of HCT; the comparative outcome of allogeneic HCT versus chemotherapy in older AML patients; and some of the barriers to the effective use of HCT in older AML patients...
December 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29156202/relapsed-acute-lymphoblastic-leukemia-is-it-crucial-to-achieve-molecular-remission-prior-to-transplant
#6
REVIEW
Mary Eapen
In patients with acute lymphoblastic leukemia (ALL) the risk of recurrent leukemia influences the choice of treatment between chemotherapy and allogeneic hematopoietic cell transplantation. The evaluation of minimal residual disease (MRD) is now considered to be the greatest progress in risk stratification in regard to leukemia recurrence. Achieving molecular remission at the end of induction therapy after diagnosis or after relapse has influenced treatment choice. Failure to achieve molecular remission is considered "high risk" and allogeneic hematopoietic cell transplantation with a suitable donor, the accepted standard...
December 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29156201/which-new-agents-will-be-incorporated-into-frontline-therapy-in-acute-myeloid-leukemia
#7
REVIEW
Richard M Stone
For 4 decades, new agents had not been permanently approved for use in treating acute myeloid leukemia (AML). The long dry spell was broken in 2017, however, with the approval of several agents: midostaurin for addition to chemotherapy in mutant FLT3 patients undergoing intensive chemotherapy, enasidenib in advanced mutant IDH2 patients, CPX-351 in secondary AML patients, and gemtuzumab ozogamicin in conjunction with standard chemotherapy in AML. This review surveys the use of tyrosine kinase inhibitors to treat patients with mutant FLT3 AML, mutant KIT AML, as well as IDH inhibitors and explores some questions regarding their integration into the treatment armamentarium for AML...
December 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29156200/do-cytogenetics-affect-the-post-remission-strategy-for-older-patients-with-aml-in-cr1
#8
REVIEW
James M Foran
Data have shown that intensified cytarabine in consolidation for treatment of acute myeloid leukemia (AML) does not equally benefit patients older than 60 years, and older patients experience significantly more neurotoxicity than younger patients. In addition, older patients are more likely to have abnormal or unfavorable cytogenetics, which also tend to confer limited efficacy with intensified cytarabine. This poses a treatment dilemma as to the best post remission therapy to treat older patients. This review explores some of the consolidation treatment strategies and options available for the older AML patient...
December 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29156199/how-can-one-optimize-induction-therapy-in-aml
#9
REVIEW
Selina M Luger
Induction therapy for acute myeloid leukemia has not changed much since 1973, when the 7 + 3 regimen of cytarabine and daunorubicin was born. Since then, various strategies have been evaluated to improve patient response, including dose intensification, the incorporation of additional agents into the regimen, the development of novel agents, and modified approaches for older patients. Recently, two novel agents, CPX-351 and gemtuzumab ozogamicin, have been approved by the US Food and Drug Administration. This review discusses each of the induction strategies and their impact on patient outcomes...
December 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29156198/the-evolving-role-of-genomic-testing-in-assessing-prognosis-of-patients-with-myelodysplastic-syndromes
#10
REVIEW
David P Steensma
The introduction into routine hematology-oncology clinical practice of molecular genetic testing assays based on next-generation sequencing platforms is prompting reassessment of the importance of molecular assay results in comparison to existing disease-specific risk stratification tools based on clinical assessment and light microscopy. For patients with myelodysplastic syndromes (MDS), the most commonly used tools for prognostication currently include the International Prognostic Scoring System (IPSS) and the Revised IPSS (IPSS-R), which are based on marrow blast proportion, number and degree of cytopenias, and the metaphase karyotype...
December 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29156197/mutational-complexity-in-myelodysplasia
#11
REVIEW
R Coleman Lindsley
Myelodysplastic syndromes are characterized by genetic and clinical heterogeneity. Some mutations are able to drive clonal hematopoiesis without causing clinical consequences, while other mutations may have significant impact, including the transformation to leukemia. This review aims to describe the pathogenesis of myelodysplastic syndromes (MDS) by focusing on 3 aspects: combinatorial genetic events, environmental factors, and inherited genetic conditions.
December 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29156196/familial-myelodysplastic-syndrome-acute-myeloid-leukemia
#12
REVIEW
Jane E Churpek
A growing number of inherited genetic loci that contribute to myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) development in both children as well as adults are rapidly being identified. In recognition of the clinical impact of this emerging field, the World Health Organization, National Comprehensive Cancer Network, and European LeukemiaNet have all added consideration of inherited predisposition to MDS/AML classification and management. Study of these disorders is providing unique insight into the biology of both sporadic and familial MDS/AML...
December 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29156195/aml-in-2017-advances-in-clinical-practice
#13
REVIEW
Jacob M Rowe
Numerous advances have been made in the biology and treatment of acute myeloid leukemia (AML) in 2017. These include the integration of the assessment of minimal residual disease (MRD) into clinical practice, the approval and near approval of new agents, improvement in therapy for older patients, and the development of a number of promising new agents, including IDH inhibitors, a Hedgehog signaling pathway inhibitor, and a histone deacetylase inhibitor. In addition, the concept of chemotherapy manipulation is still valid and can increase efficacy in some AML populations, and transplant patterns have shifted, enabling more patients to receive a hematopoietic stem cell transplant...
December 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29050700/the-what-when-and-how-of-car-t-cell-therapy-for-all
#14
REVIEW
Noelle Frey
Chimeric Antigen Receptor (CAR) T cells that have been engineered to target CD19 have shown great promise in patients with relapsed and refractory B cell acute lymphocytic leukemia with remission rates of 70-90%. Some remissions have successfully bridged patients to a curable allogeneic stem cell transplant, some responses have been durable without further treatment, and some patients have achieved durable remissions for relapsed ALL after allogeneic stem cell transplant. Cytokine release syndrome, correlating with the in vivo activation and expansion of T cells, and neurologic toxicity are the most significant side effects and approaches to better understand and manage these events are the subject of ongoing clinical trials...
September 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29050699/how-should-we-treat-a-patient-with-relapsed-ph-negative-b-all-and-what-novel-approaches-are-being-investigated
#15
REVIEW
Nicola Gökbuget
Despite significant improvements in outcome of newly diagnosed B-precursor ALL, the results in relapsed or refractory adult ALL are overall poor. Large retrospective studies revealed significant differences in terms of outcome, with particularly poor response rates in early or refractory relapses, whereas late relapses usually respond very well to repeated standard induction. Particularly new immunotherapy compounds like the CD19 bispecific antibody Blinatumomab and the conjugated CD22 antibody Inotuzumab yielded promising response rates compared to standard therapies in randomised trials...
September 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29050698/which-patients-should-i-transplant-with-acute-lymphoblastic-leukemia
#16
REVIEW
Tsofia Inbar, Jacob M Rowe, Netanel A Horowitz
Allogeneic hematopoietic cell transplantation for acute lymphoblastic leukemia (ALL) offers curative therapy for patients who are in complete remission. Historically, there was great hesitation to offer this modality to patients with ALL due to the high attendant morbidity and mortality. Furthermore, the outstanding results in childhood ALL led many to believe that significant long-term survival could be achieved using chemotherapy-based regimens alone. The International ALL Study jointly conducted by ECOG and MRC completely changed perceptions indicating, surprisingly to many, that transplantation - particularly for patients at standard risk - offered a significant survival advantage...
September 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29050697/how-do-we-measure-mrd-in-all-and-how-should-measurements-affect-decisions-re-treatment-and-prognosis
#17
REVIEW
Xueyan Chen, Brent L Wood
Minimal residual disease (MRD) is the most significant independent prognostic factor in acute lymphocytic leukemia (ALL). Monitoring MRD using sensitive techniques, including multiparametric flow cytometry (MFC) and quantitative polymerase chain reaction (qPCR)-based methods, has improved the assessment of treatment response and risk stratification for clinical management. New molecular methods, such as high-throughput next-generation sequencing (NGS), have evolved into routine laboratory tools to improve the sensitivity and specificity of MRD detection...
September 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29050696/pharmacogenomics-in-acute-lymphoblastic-leukemia
#18
REVIEW
Shawn H R Lee, Jun J Yang
Pharmacogenomics is a fast-growing field of personalized medicine using a patient's genomic profile to determine drug disposition or response to drug therapy, in order to develop safer and more effective pharmacotherapy. Childhood acute lymphoblastic leukemia (ALL), being the most common malignancy in childhood, which is treated with uniform and standardized clinical trials, is remarkably poised for pharmacogenomic studies. In the last decade, unbiased genome-wide association studies have identified multiple germline risk factors that strongly modify host response to drug therapy...
September 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29050695/how-is-the-ph-like-signature-being-incorporated-into-all-therapy
#19
REVIEW
Luke Maese, Sarah K Tasian, Elizabeth A Raetz
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a recently identified high risk disease subtype characterized by a gene expression profile similar to that observed in Philadelphia chromosome-positive (Ph-positive) ALL, but without an underlying BCR-ABL1 translocation. Adults and children with Ph-like ALL harbor a diversity of alterations that all lead to activated kinase signaling. Outcomes for patients with Ph-like ALL are poor, which has prompted investigation into the role of tyrosine kinase inhibitor (TKI)-based therapies for this disease...
September 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29050694/the-biology-of-philadelphia-chromosome-like-all
#20
REVIEW
Kathryn G Roberts
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a recently described subtype of B-cell precursor ALL with a gene expression profile similar to Ph-positive ALL and a high frequency of IKZF1 alterations. The prevalence of Ph-like ALL increases with age, ranging from 10-15% of children to over 25% of young adults with ALL. It occurs more frequently in males and is associated with adverse clinical features including elevated minimal residual disease levels and poor survival in both children and adults...
September 2017: Best Practice & Research. Clinical Haematology
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