Clonal Evolution Including Partial Loss of Human Leukocyte Antigen Genes Favoring Extramedullary Acute Myeloid Leukemia Relapse After Matched Related Allogeneic Hematopoietic Stem Cell Transplantation

Stölzel, Friedrich; Hackmann, Karl; Kuithan, Friederike; Mohr, Brigitte; Füssel, Monika; Oelschlägel, Uta; Thiede, Christian; Röllig, Christoph; Platzbecker, Uwe; Schetelig, Johannes; Illmer, Thomas; Schaich, Markus; Seliger, Barbara; Hartmann, Arndt; Baretton, Gustavo; Zietz, Christian; Ehninger, Gerhard; Schröck, Evelin; Bornhäuser, Martin

doi:10.1097/tp.0b013e3182481113

Cited by 49 publications

(37 citation statements)

References 16 publications

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“…Both variables have been described to play a major role for outcome after conventional therapy and alloHSCT, and also seemed to modify the role of other mutations, such as NPM1 mut . 16,[22][23][24] However, heterogeneity, methodologic problems, and the relatively low sensitivity of most polymerase chain reaction assays, as well as a missing general agreement concerning a cutoff level for the FLT3-ITD/wildtype AR, 11,16,[23][24][25][26][27] have prompted the suggestion to generally classify all non-APL FLT3-ITD cases as poor risk. 10,28 Further, no role of the mutant/wild-type AR on CIR after alloHSCT could be shown by the recent AML-SG study, 11 and next-generation sequencing revealed the presence of different FLT3-ITD clones within the same patient both at diagnosis and during the course of the disease.…”

Section: Discussionmentioning

confidence: 99%

Outcome of patients with distinct molecular genotypes and cytogenetically normal AML after allogeneic transplantation

Schmid

Labopin

Socié

et al. 2015

Blood

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Key Points• In AML with normal cytogenetics, age, response to induction, and FLT3-ITD allow for an estimate of outcome after allogeneic HSCT in CR1.• Neither variation of classical transplant techniques nor development of chronic GVHD outweighs the negative impact of FLT3-ITD.To analyze the influence of distinct combinations of molecular aberrations on outcome after allogeneic hematopoietic stem cell transplantation (HSCT) for cytogenetically normal acute myeloid leukemia (CN-AML), a retrospective registry analysis was performed on 702 adults undergoing HSCT in first complete remission (CR). Patients were grouped according to presence or absence of NPM1 mutations (NPM1 mut ) and FLT3 internal tandem duplications (FLT3-ITD). Double-negative patients were evaluated for mutations of the CCAAT/enhancer binding protein a gene (CEBPa). The influence of genotypes on relapse, non-relapse mortality, leukemia-free survival (LFS) and overall survival (OS), and a prognostic classification combining NPM1/FLT3-ITD profile and classical risk factors were calculated. Two-year OS from HSCT was 81 6 5% in NPM1 wt revealed excellent results both in patients with CEBPa mut and with a triple negative genotype (2-year OS: 100%/77 6 3%). In a Cox-model of predefined variables, age, FLT3-ITD and >1 course of chemotherapy to reach CR were risk factors associated with inferior outcome, regardless of NPM1 mutational status, variations of transplant protocols, or development of graft-versus-host disease. In a prognostic risk classification, 2-year OS/LFS rates were 88 6 3%/79 6 4% without any, 77 6 2%/73 6 3% with one, and 53 6 4%/50 6 4 with ‡2 risk factors (P 5

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Section: Discussionmentioning

confidence: 99%

Outcome of patients with distinct molecular genotypes and cytogenetically normal AML after allogeneic transplantation

Schmid

Labopin

Socié

et al. 2015

Blood

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“…Apart from the inhibitory role of the Treg cells, CTLs might be unable to elicit response due to the fact that leukemia associated antigens are not immunogenic because of diminished MHC class I expression on leukemic cells which results in deficiencies in antigen presentation and thus malignant cells escaping immunosurveillance [104,105].…”

Section: Leukemia Immune Microenvironmentmentioning

confidence: 99%

“…Disruption of the interaction of VLA-4 with its ligands to induce rapid and reversible mobilization of HSCs into the peripheral circulation and reduce BM chemoprotective effect [7,[104][105][106][107]188] c-kit -SCF c-kit binding to SCF activates proliferation, migration, and differentiation of HSCs.…”

Section: G-csf -G-csfrmentioning

confidence: 99%

The role of microenvironment and immunity in drug response in leukemia

Bakker

Qattan

Mutti

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Leukemia is a cancer of the white blood cells, with over 54,000 new cases per year diagnosed worldwide and a 5-year survival rate below 60%. This highlights a need for research into the mechanisms behind its etiology and causes of therapy failure. The bone marrow microenvironment, in which adult stem cells are maintained in healthy individuals, has been implicated as a source of chemoresistance and disease relapse. Here the various ways that the microenvironment can contribute to the resistance and persistence of leukemia are discussed. The targeting of the microenvironment by leukemia cells to create an environment more suitable for cancer progression is described. The role of soluble factors, drug transporters, microvesicles, as well as the importance of direct cell-cell contact, in addition to the effects of inflammation and immune surveillance in microenvironment-mediated drug resistance are discussed. An overview of the clinical potential of translating research findings to patients is also provided. Understanding of and further research into the role of the bone marrow microenvironment in leukemia progression and relapse are crucial towards developing more effective treatments and reduction in patient morbidity. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.

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“…After haploidentical HSCT for AML, loss of mismatched HLA haplotype due to uniparental disomy of chromosome 6p was reported as one of the mechanisms of post-transplant relapse [Vago et al 2009;Crucitti et al 2015]. Subsequently, partial loss of HLA was demonstrated and implicated as the cause of post-transplant leukemic relapse in matched related [Stolzel et al 2012] and unrelated donor HSCT [Toffalori et al 2012]. Factors that affect the ability of HLA molecules to present antigen to T lymphocytes also matter: class II associated invariant chain peptide (CLIP) occupies the HLA-class II antigen groove and must be released before antigenic peptides can bind to the groove [Romagnoli and Germain, 1994;Sloan et al 1995].…”

Section: Leukemia Evasion From Immune Attackmentioning

confidence: 99%

Novel immunotherapeutic approaches for the treatment of acute leukemia (myeloid and lymphoblastic)

Ishii

Barrett

2015

Therapeutic Advances in Hematology

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How leukemia evades the immune systemRecent studies have revealed a broad range of strategies employed by leukemia to block cytotoxicity of T cells and NK cells against leukemia. Most research has involved myeloid malignancies and less is known about acute lymphoblastic leukemia (ALL). In the process of disabling immune Novel immunotherapeutic approaches for the treatment of acute leukemia (myeloid and lymphoblastic) Kazusa Ishii and Austin J. Barrett Abstract: There have been major advances in our understanding of the multiple interactions between malignant cells and the innate and adaptive immune system. While the attention of immunologists has hitherto focused on solid tumors, the specific immunobiology of acute leukemias is now becoming defined. These discoveries have pointed the way to immune interventions building on the established graft-versus-leukemia (GVL) effect from hematopoietic stem-cell transplant (HSCT) and extending immunotherapy beyond HSCT to individuals with acute leukemia with a diversity of immune manipulations early in the course of the leukemia. At present, clinical results are in their infancy. In the coming years larger studies will better define the place of immunotherapy in the management of acute leukemias and lead to treatment approaches that combine conventional chemotherapy, immunotherapy and HSCT to achieve durable cures.

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Clonal Evolution Including Partial Loss of Human Leukocyte Antigen Genes Favoring Extramedullary Acute Myeloid Leukemia Relapse After Matched Related Allogeneic Hematopoietic Stem Cell Transplantation

Cited by 49 publications

References 16 publications

Outcome of patients with distinct molecular genotypes and cytogenetically normal AML after allogeneic transplantation

Outcome of patients with distinct molecular genotypes and cytogenetically normal AML after allogeneic transplantation

The role of microenvironment and immunity in drug response in leukemia

Novel immunotherapeutic approaches for the treatment of acute leukemia (myeloid and lymphoblastic)

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