In:
Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 4-5
Abstract:
Background: Mutations in the protein tyrosine phosphatase gene PTPN11 (also known as SHP2) are found in approximately 10% of adult patients with acute myeloid leukemia (AML). A recent study reported that mutated PTPN11 associates with inferior response rates and shorter survival among intensively treated AML patients, independently of the ELN prognostic groups (Alfayez et al., Leukemia 2020). Earlier analyses of the genomic landscape of AML did not uncover a similar prognostic relevance of PTPN11 mutations. Therefore, our aim was to clarify the prognostic relevance of mutated PTPN11 variants in AML patients receiving intensive front-line therapy. Patients and Methods: We studied 1116 AML patients enrolled on two subsequent multicenter phase III trials of the German AML Cooperative Group (AML-CG 1999, NCT00266136; and AML-CG 2008, NCT01382147) who were genetically characterized by amplicon-based targeted next-generation sequencing (Herold et al., Leukemia 2020). All patients had received induction chemotherapy containing cytarabine and daunorubicin or mitoxantrone. Results: We identified 146 PTPN11 mutations in 114 of 1116 patients (10%). Mutations clustered in two hotspot regions (5': codons 52-79; n=108 and 3': codons 491-512, n=38) as previously reported. Associations of PTPN11 mutations with baseline clinical and genetic patient characteristics are shown in Figure A. PTPN11 mutations were most frequent in the European LeukemiaNet (ELN) "favorable" genetic risk group, and associated with higher leukocyte counts. Patients with mutated PTPN11more commonly had mutated NPM1, IDH1 and DNMT3A, and less frequently had FLT3-ITD, IDH2 and TP53 mutations, compared to patients with wild-type PTPN11. With regard to treatment outcomes, the rate of complete remission was similar among patients with mutated and wild-type PTPN11 (65% vs. 59%, P=.25). In univariate analyses, PTPN11-mutated patients had significantly longer relapse-free survival (RFS; 5-year estimate, 55% vs 33% for PTPN11-wild type patients; P=.001; Figure B) and tended to have longer overall survival (OS; 5-year estimate, 43% vs 32%; P=.06; Figure C). However, in multivariable models adjusting for age, sex, leukocyte count, AML type (de novo/sAML/tAML) and ELN-2017 genetic risk group, mutated PTPN11 no longer associated with RFS (hazard ratio [HR], 0.89, 95% confidence interval [CI] , 0.63 - 1.27; P=0.53) or OS (HR, 1.03; 95% CI, 0.80 - 1.33; P=.79). Moreover, PTPN11 mutations did not significantly associate with RFS or OS within any of the ELN genetic risk groups. Finally, we detected no significant differences in baseline characteristics or outcomes between patients with PTPN11 mutations affecting the 5' hotspot region (n=82), the 3' hotspot region (n=21), or mutations at both hotspots (n=11). Conclusion: In our cohort of newly diagnosed and intensively treated AML patients, mutations in PTPN11 occurred in 10% and associated with prognostically favorable genetic characteristics such as mutated NPM1 and absence of FLT3-ITD and TP53mutations. Consequently, PTPN11 mutations were most commonly found within the ELN-2017 favorable risk category. While patients with PTPN11 mutations had relatively favorable survival outcomes, multivariable models suggest this observation is confounded by the frequent co-occurrence of known favorable genetic markers. Our data are in disagreement with a recently published study on 880 newly diagnosed patients that found an unfavourable prognostic impact of mutated PTPN11, particularly among the 410 patients who received intensive treatment. Possible explanations for these discrepant results include differences in treatment regimens between the two cohorts, as well as the play of chance when studying a relatively rare gene mutation in medium-sized cohorts. In summary, our data do not support a role of PTPN11 mutations as an adverse prognostic biomarker in newly diagnosed, intensively treated adult AML patients. Figure Disclosures Metzeler: Daiichi Sankyo: Honoraria; Otsuka Pharma: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Astellas: Honoraria. Subklewe:AMGEN: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Morphosys: Research Funding; Seattle Genetics: Research Funding; Roche AG: Consultancy, Research Funding; Gilead Sciences: Consultancy, Honoraria, Research Funding.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood-2020-137487
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2020
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
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