Prognostic impact of the adverse molecular-genetic profile on long-term outcomes following allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia

2021 ◽  
Author(s):  
Georgina Daher-Reyes ◽  
TaeHyung Kim ◽  
Igor Novitzky-Basso ◽  
Kyuoung Ha Kim ◽  
Adam Smith ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Molecular Genetic ◽  
Genetic Profile ◽  
Prognostic Impact ◽  
Long Term Outcomes ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Role of Gene Mutations in Adult Acute Myeloid Leukemia Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3373-3373
Author(s):  
Sheng-Chieh Chou ◽  
Jih-Luh Tang ◽  
Liang-In Lin ◽  
Hsin-An Hou ◽  
Chien-Yuan Chen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Prognostic Impact ◽  
Hematopoietic Stem ◽  
Wbc Count ◽  
Acute Myeloid

Abstract Abstract 3373 Poster Board III-261 Purpose Several gene mutations had been found to have clinical implications in patients with acute myeloid leukemia (AML), especially in those with normal karyotype. However, the role of such gene mutations for AML patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT) was unclear and inconclusive. We retrospectively evaluated the prognostic impact of 8 gene mutations in adult AML patients undergoing allo-HSCT. Materials & Methods From 1995 to 2007, a total of 463 consecutive adult patients with de novo non-M3 AML had comprehensive gene mutation analyses at the National Taiwan University Hospital. Three hundred and twenty five patients who received conventional induction chemotherapy were enrolled in this study. Those who received only low dose chemotherapy or palliative treatment were excluded. The genetic alterations analyzed included NPM1, FLT3/ITD, FLT3/TKD, CEBPA, AML1/RUNX1, RAS, MLL/PTD, and WT1. The clinical implication of these genetic alterations in the patients receiving allo-HSCT was analyzed, and the result was compared with that in patients without allo-HSCT. Results The clinical characteristics in the patients receiving allo-HSCT (n=100) and those without (n=225) were similar with the exception of age, being younger in the former group (35.4 years vs. 49.5 years p<0.001). In univariate analysis, older age (Age > 45 years), higher initial WBC count (WBC>50K/μL), elevated LDH level, unfavorable karyotype, FLT3/ITD, mutations of AML1/RUNX1 were significantly associated with poorer overall survival (OS) in patients not receiving allo-HSCT; While NPM1mut/FLT3ITDneg and CEBPA mutations served as significantly good prognostic indicators. In multivariate analysis, age, WBC count, karyotype, FLT3/ITD, AML1/RUNX1, CEBPA and NPM1mut/FLT3ITDneg remained to be independent prognostic factors in non-allo-HSCT patients. However, in patients receiving allo-HSCT, only unfavorable karyotype and disease status (refractory or remission) at the time of transplantation were associated with poorer OS both in univariate and multivariate analyses. The similar prognostic impact of FLT3/ITD, CEBPA, AML1/RUNX1 and NPM1 on OS was not seen in patients receiving allo-HSCT. Furthermore, in contrast to its poor prognostic impact in non-allo-HSCT patients, mutation of AML1/RUNX1 was a significant good prognostic factor for relapse free survival (p=0.046), although not for OS, in allo-HSCT group. Conclusion FLT3/ITD, mutations of AML1/RUNX1, CEBPA and NPM1 have great prognostic implication for OS in AML patients not receiving allo-HSCT. However, their impact on OS is ameliorated in patients receiving allo-HSCT. The results need to be confirmed by further studies on more patients. Disclosures: No relevant conflicts of interest to declare.

High Expression of ZBTB7A at Diagnosis Associated with Inferior Outcome in Acute Myeloid Leukemia Patients Receiving Hematopoietic Stem Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5092-5092
Author(s):  
Juliane Grimm ◽  
Madlen Jentzsch ◽  
Marius Bill ◽  
Julia Schulz ◽  
Karoline Schubert ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Prognostic Impact ◽  
Surface Markers ◽  
Complex Karyotype ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract Introduction: The transcription factor ZBTB7A regulates early differentiation of hematopoietic progenitors & has been associated with oncogenic as well as oncosuppressive functions. While it was shown that ectopic overexpression of Zbtb7a in immature lymphocytes leads to the development of an aggressive T-cell lymphoblastic leukemia, high ZBTB7A expression in cytogenetically normal acute myeloid leukemia (CN-AML) is associated with improved outcomes. Furthermore, recently a leukemogenic cooperation between RUNX1/RUNX1T1 & ZBTB7A mutations in t(8;21)-associated AML was suggested. Here, we further evaluated the complex role of ZBTB7A expression in hematopoietic malignancies by assessing its potential prognostic impact in AML pts undergoing hematopoietic stem cell transplantation (HSCT) after non-myeloablative conditioning (NMA). Methods: We analyzed bone marrow (BM) at diagnosis of 140 pts (median age 63 years [y], range 37-75y) treated at our institution between 2000 & 2015. All pts received NMA conditioning (3x30mg/m2 Fludarabine on days -4 to -1 & 2Gy total body irradiation) followed by HSCT in complete remission with (CR; n=111; 79.3%) or without peripheral hematological recovery (CRi; n=29; 20.7%). Median follow-up for pts alive was 3.5y. Our cohort included pts with CN-AML (n=62, 44.3%), complex karyotype (n=17; P=12.1%) & other cytogenetic abnormalities (n=61; 43.6%). At diagnosis mutations in the genes CEBPA, DNMT3A, IDH1, IDH2, NPM1 & the presence of FLT3-ITD were determined. In diagnostic BM cytogenetics were analyzed using standard techniques for banding & fluorescence in-situ hybridization & the expression of common surface markers was analyzed using flow cytometry. The expression of ZBTB7A was assessed using quantitative RT-PCR & normalized to ABL1 as internal control. As a cut-off the third quartile of normalized gene expression was identified to group high & low ZBTB7A expressers. Results: At diagnosis pts with a high ZBTB7A expression more often had a complex karyotype (P=.02) & were less likely to have core-binding factor AML by trend (P=.18). Additionally, high ZBTB7A levels associated with significantly fewer blasts in peripheral blood (P=.008) & BM (P=.02). The BM mononuclear cells in high ZBTB7A expressers were to a smaller extent positive for myeloid markers (CD38 P=.03; CD33 P=.11; CD13 P=.13) & exhibited a higher percentage of erythroid (Glycophorin A P=.03) as well as monocytic (CD11b P=.04; CD14 P=.01) surface markers. We did not find any statistical associations between ZBTB7A levels & the mutation status of NPM1, CEBPA, IDH1, DNMT3A or the presence of FLT3-ITD. Yet, there was a trend for more IDH2 mutations in the group of high ZBTB7A expressers (P=.18). At diagnosis a high expression of ZBTB7A associated with a significantly higher cumulative incidence of relapse (CIR; P=.002, Figure 1A). This finding also translated into a significantly shorter overall survival (OS; P=.01; Figure 1B) for AML pts with high ZBTB7A levels at diagnosis. When we restricted our analyses to CN-AML, high ZBTB7A expression remained a negative prognostic factor by trend (CIR P=.16; OS P=.11). Conclusion: Expression of ZBTB7A associated with distinct biological features & surface marker pattern in AML. This underlines the results of recent studies which identified ZBTB7A as a novel player in leukemogenesis. However, our findings are in contrast with the previously shown favorable prognostic impact of high ZBTB7A levels in a CN-AML cohort mainly treated with chemotherapy. In contract all pts included in our studies were consolidated with NMA-HSCT. Since this treatment regimen is mainly based on the graft versus leukemia effect a high ZBTB7A expression could potentially interfere with the immunological recognition of the AML blasts resulting in a reduced response to NMA-HSCT. Consequently, future functional studies & clinical trials should aim at further characterize the complex role of ZBTB7A in AML. Figure Figure. Disclosures Poenisch: Mundipharma: Research Funding.

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