Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials

Grimwade, David; Hills, Robert Kerrin; Moorman, Anthony V.; Walker, Helen M.; Chatters, S; Goldstone, Anthony H.; Wheatley, Keith; Harrison, Christine J.; Burnett, Alan Kenneth

doi:10.1182/blood-2009-11-254441

Cited by 1,702 publications

(1,499 citation statements)

References 43 publications

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“…There was wide variation in the white blood cell (WBC) count and percentage of blasts at initial diagnosis. The risk stratification based on cytogenetic features 18 was shown. The majority of patients carry intermediate (40%) or high risk (56.7%), only 1 patient (3.3%) was categorized with favorable risk.…”

Section: Resultsmentioning

confidence: 99%

VISTA is highly expressed on MDSCs and mediates an inhibition of T cell response in patients with AML

et al. 2018

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Treatment of acute myeloid leukemia (AML) remains challenging. Enhancement of anti-tumor responses by blocking negative immune regulators is a promising strategy for novel effective leukemia therapeutics. V-domain Ig suppressor of T-cell activation (VISTA) is a recently defined negative regulator mediating immune evasion in cancer. To investigate the effect of VISTA on anti-leukemia immune response in AML, we initiated a study using clinical samples collected from AML patients. Here we report that VISTA is highly expressed on myeloid-derived suppressor cells (MDSCs) in the peripheral blood of AML patients. Both the frequency and intensity of VISTA expression on MDSCs are significantly higher in newly diagnosed AML than in healthy controls. Importantly knockdown of VISTA by specific siRNA potently reduced the MDSCs-mediated inhibition of CD8 T cell activity in AML, suggesting a suppressive effect of VISTA on anti-leukemia T cell response. Furthermore, we observed a strong positive association between MDSC expression of VISTA and T cell expression of PD-1 in AML. These results support the strategy of VISTA-targeted treatment for AML and underscore the strong potential for combined blockade of VISTA and PD-1 pathways in effective leukemia control.

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Section: Resultsmentioning

confidence: 99%

VISTA is highly expressed on MDSCs and mediates an inhibition of T cell response in patients with AML

et al. 2018

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“…However, primary treatment resistance seems to be the major reason for the poor outcome of secondary AML. As secondary AML is associated to known poor prognosis [2,7,8,11,23], multivariable models are essential. A recent population-based Danish study on secondary AML failed to show that secondary AML was an independent risk factor [2].…”

Section: Discussionmentioning

confidence: 99%

“…Data reported to the Swedish Acute Leukemia Registry include (among other data) date of diagnosis, age, gender, FAB type, cytogenetics [10], diagnostic procedures, performance status (PS), presence of antecedent hematological or other malignant disorder, type of treatment (i.e., chemotherapy or radiation) for the preceding disease, type of treatment for AML (intensive or palliative), CR date, and information on hematopoietic stem cell transplantation. Cytogenetic risk was defined according to the MRC criteria [11]. Dates of death were obtained from the Swedish Population Registry between March and June 2012, and the median follow-up of surviving patients was 9.6 years.…”

Section: Methodsmentioning

confidence: 99%

Characterization and prognostic features of secondary acute myeloid leukemia in a population‐based setting: A report from the Swedish Acute Leukemia Registry

et al. 2015

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Patients with secondary acute myeloid leukemia (AML) often escape inclusion in clinical trials and thus, population-based studies are crucial for its accurate characterization. In this first large population-based study on secondary AML, we studied AML with an antecedent hematological disease (AHD-AML) or therapyrelated AML (t-AML) in the population-based Swedish Acute Leukemia Registry. The study included 3,363 adult patients of which 2,474 (73.6%) had de novo AML, 630 (18.7%) AHD-AML, and 259 (7.7%) t-AML. Secondary AML differed significantly compared to de novo AML with respect to age, gender, and cytogenetic risk. Complete remission (CR) rates were significantly lower but early death rates similar in secondary AML. In a multivariable analysis, AHD-AML (HR 1.51; 95% CI 1.26-1.79) and t-AML (1.72; 1.38-2.15) were independent risk factors for poor survival. The negative impact of AHD-AML and t-AML on survival was highly age dependent with a considerable impact in younger patients, but without independent prognostic value in the elderly. Although patients with secondary leukemia did poorly with intensive treatment, early death rates and survival were significantly worse with palliative treatment. We conclude that secondary AML in a population-based setting has a striking impact on survival in younger AML patients, whereas it lacks prognostic value among the elderly patients.

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“…The myelodysplastic syndrome and chronic myelomonocytic leukemia karyotypes were stratified by the Comprehensive Cytogenetic Scoring System of the Revised International Prognostic Scoring System 6,25 and the acute myeloid leukemia karyotypes were stratified by the United Kingdom Medical Research Council system. 26 For analyses in which therapy-related myelodysplastic syndrome and therapy-related acute myeloid leukemia were considered together, high-risk karyotype was defined for therapy-related myelodysplastic syndrome/chronic myelomonocytic leukemia as Revised International Prognostic Scoring System high or very high risk and for therapy-related acute myeloid leukemia as United Kingdom Medical Research Council adverse risk. Therapies administered were recorded as supportive care (transfusion p53 Expression in therapy-related myeloid neoplasms AHG Cleven et al support and anti-infectives), low-intensity therapies (low-dose cytotoxic therapies, including hypomethylating agents), induction chemotherapy, or allogeneic stem-cell transplantation.…”

Section: Patient Population and Samplesmentioning

confidence: 99%

High p53 protein expression in therapy-related myeloid neoplasms is associated with adverse karyotype and poor outcome

Cleven

Nardi

et al. 2015

Modern Pathology

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Identification of p53-positive cells by immunohistochemistry in bone marrow from primary myelodysplastic syndrome patients correlates with the presence of TP53 mutations and poor prognosis. Mutations in the tumor suppressor gene TP53 are more frequent in therapy-related acute myeloid leukemia and myelodysplastic syndrome than in de novo disease, but the role of p53 immunohistochemistry in the therapy-related setting has not been specifically investigated. We studied p53 protein immunoreactivity in bone marrow biopsies of therapy-related myeloid neoplasms and correlated protein expression with TP53 mutation status, clinicopathologic features and outcome. We first studied 32 patients with therapy-related acute myeloid leukemia and 63 patients with therapy-related myelodysplastic syndrome/chronic myelomonocytic leukemia from one institution and then validated our results in a separate group of 32 patients with therapy-related acute myeloid leukemia and 56 patients with therapy-related myelodysplastic syndrome from a different institution. Strong p53 immunostaining in Z1% of bone marrow cells was highly predictive of a TP53 gene mutation (Po0.0001) and was strongly associated with a high-risk karyotype (Po0.0001). The presence of Z1% p53 strongly positive cells was associated with poorer overall and disease-specific survival, particularly in the subset of patients treated with stem-cell transplantation. In a multivariable Cox regression model, the presence of Z1% p53 strongly expressing cells was an independent prognostic marker for overall survival in both cohorts, with hazard ratios of 3.434 (CI: 1.751-6.735, Po0.0001) and 3.156 (CI: 1.502-6.628, P ¼ 0.002). Our data indicate that p53 protein expression, evaluated in bone marrow biopsies by a widely available immunohistochemical method, prognostically stratifies patients with therapy-related myeloid neoplasms independent of other risk factors. p53 immunostaining thus represents an easily applicable method to assess risk in therapy-related acute myeloid leukemia/myelodysplastic syndrome patients. Therapy-related myeloid neoplasms include acute myeloid leukemia, myelodysplastic syndrome, and less commonly myelodysplastic/myeloproliferative neoplasms such as chronic myelomonocytic leukemia. Therapy-related myeloid neoplasms occur as late complications of cytotoxic chemotherapy and/or radiotherapy given to treat malignancies or non-malignant conditions. 1,2 The etiology of therapy-related myeloid neoplasms is thought to be related to the mutagenic effect of cytotoxic therapy, including alkylating agents, ionizing radiation therapy, and topoisomerase inhibitors. 1 Typically, therapy-related myeloid neoplasms carry complex and usually unbalanced karyotypic abnormalities, particularly loss of material on the long arm of chromosomes 5 and 7 and rearrangements of the 11q23 region involving the MLL gene. 3 The prognosis of therapy-related myeloid neoplasms is poor, likely due at least in part to the high

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Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials

Cited by 1,702 publications

References 43 publications

VISTA is highly expressed on MDSCs and mediates an inhibition of T cell response in patients with AML

VISTA is highly expressed on MDSCs and mediates an inhibition of T cell response in patients with AML

Characterization and prognostic features of secondary acute myeloid leukemia in a population‐based setting: A report from the Swedish Acute Leukemia Registry

High p53 protein expression in therapy-related myeloid neoplasms is associated with adverse karyotype and poor outcome

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