Abnormalities associated with a favorable prognosis

Core-binding factor (CBF) AML includes cases with RUNX1::RUNX1T1 and CBFB::MYH11 gene fusions.

Core-binding factor (CBF) AML includes cases with RUNX1::RUNX1T1 and CBFB::MYH11 gene fusions.

AML with RUNX1::RUNX1T1 gene fusions (t(8;21)(q22;q22.1)). In leukemias with t(8;21), the RUNX1 gene on chromosome 21 is fused with the RUNX1T1 gene on chromosome 8. The t(8;21) translocation is associated with the FAB M2 subtype and with granulocytic sarcomas. Adults with t(8;21) have a more favorable prognosis than do adults with other types of AML.[209] The t(8;21) translocation occurs in approximately 12% of children with AML [210,211,224] and is associated with a more favorable outcome than AML characterized by normal or complex karyotypes.[209,225-227] Overall, the translocation is associated with 5-year overall survival (OS) rates of 74% to 90%.[210,211,224]

Core-binding factor (CBF) AML includes cases with RUNX1::RUNX1T1 and CBFB::MYH11 gene fusions.

AML with CBFB::MYH11 gene fusions (inv(16)(p13.1;q22) or t(16;16)(p13.1;q22)). In leukemias with inv(16), the CBFB gene at chromosome band 16q22 is fused with the MYH11 gene at chromosome band 16p13. The inv(16) translocation is associated with the FAB M4Eo subtype and confers a favorable prognosis for both adults and children with AML.[209,225-227] Inv(16) occurs in 7% to 9% of children with AML, for whom the 5-year OS rate is approximately 85%.[210,211] Cases with CBFB::MYH11 or RUNX1::RUNX1T1 fusions have distinctive secondary variants, with CBFB::MYH11 secondary variants primarily restricted to genes that activate receptor tyrosine kinase signaling (NRAS, FLT3, and KIT).[228,229] The prognostic significance of activating KIT variants in adults with CBF AML has been studied with conflicting results. A meta-analysis found that KIT variants appear to increase the risk of relapse without an impact on OS for adults with AML and RUNX1::RUNX1T1 fusions.[230] The prognostic significance of KIT variants in pediatric CBF AML remains unclear. Some studies have found no impact of KIT variants on outcomes,[231-233] although, in some instances, the treatment used was heterogenous, potentially confounding the analysis. Other studies have reported a higher risk of treatment failure when KIT variants are present.[234-239] An analysis of a subset of pediatric patients treated with a uniform chemotherapy backbone on the COG AAML0531 study demonstrated that the subset of patients with KIT exon 17 variants had inferior outcomes, compared with patients with CBF AML who did not have the variant. However, treatment with gemtuzumab ozogamicin abrogated this negative prognostic impact.[238] While there was a trend toward inferior outcomes for patients with CBF AML with co-occurring KIT exon 8 abnormalities, this finding was not statistically significant. A second study of 46 patients who were treated uniformly found that KIT exon 17 variants only had prognostic significance in AML with RUNX1::RUNX1T1 fusions but not CBFB::MYH11 fusions.[239] While KIT variants are seen in both CBF AML subsets, other secondary variants tend to cluster with one of the two fusions. For example, patients with RUNX1::RUNX1T1 fusions also have frequent variants in genes regulating chromatin conformation (e.g., ASXL1 and ASXL2) (40% of cases) and genes encoding members of the cohesin complex (20% of cases). Variants in ASXL1 and ASXL2 and variants in members of the cohesin complex are rare in cases with leukemia and CBFB::MYH11 fusions.[228,229] Despite this correlation, a study of 204 adults with AML and RUNX1::RUNX1T1 fusions found that ASXL2 variants (present in 17% of cases) and ASXL1 or ASXL2 variants (present in 25% of cases) lacked prognostic significance.[240] Similar results, albeit with smaller numbers, were reported for children with the same abnormalities.[241]

AML with NPM1 variant. NPM1 is a protein that has been linked to ribosomal protein assembly and transport, as well as being a molecular chaperone involved in preventing protein aggregation in the nucleolus. Immunohistochemical methods can be used to accurately identify patients with NPM1 variants by the demonstration of cytoplasmic localization of NPM. Variants in the NPM1 protein that diminish its nuclear localization are primarily associated with a subset of AML with a normal karyotype, absence of CD34 expression, and an improved prognosis in the absence of FLT3 ITD variants in adults and younger adults.[242-247]Studies of children with AML suggest a lower rate of occurrence of NPM1 variants in children compared with adults with normal cytogenetics. NPM1 variants occur in approximately 8% of pediatric patients with AML and are uncommon in children younger than 2 years.[214,215,248,249] NPM1 variants are associated with a favorable prognosis in patients with AML characterized by a normal karyotype.[214,215,249] For the pediatric population, conflicting reports have been published regarding the prognostic significance of an NPM1 variant when a FLT3 ITD variant is also present. One study reported that an NPM1 variant did not completely abrogate the poor prognosis associated with having a FLT3 ITD variant,[214,250] but other studies showed no impact of a FLT3 ITD variant on the favorable prognosis associated with an NPM1 variant.[215,219,249] In a comprehensive analysis of serial COG trials, outcomes of patients with an NPM1 variant and co-occurring FLT3 ITD variants were favorable and comparable to those of patients with an NPM1 variant who did not have co-occurring FLT3 ITD variants. The event-free survival (EFS) and OS rates ranged from 70% to 75% for both groups.[251] A significant number of patients analyzed had an NPM1 variant and received an HSCT in earlier clinical trials, leading to speculation that their outcomes may be comparable because of the favorable impact of HSCT on patients with AML who have NPM1 and FLT3 ITD variants. The COG AAML1831 (NCT04293562) trial will determine if patients with NPM1 and FLT3 ITD variants who are MRD negative after induction 1 can avoid an HSCT and still have excellent outcomes comparable to those of patients with NPM1 variants who do not have FLT3 ITD abnormalities.

AML with CEBPA variants. Variants in the CEBPA gene occur in a subset of children and adults with cytogenetically normal AML.[252,253] In adults younger than 60 years, approximately 15% of cytogenetically normal AML cases have variants in CEBPA.[246] Outcomes for adults with AML with CEBPA variants appear to be relatively favorable and similar to that of patients with CBF leukemias.[246,254] Initial studies in adults with AML demonstrated that CEBPA double-variant, but not single-variant, abnormalities were independently associated with a favorable prognosis,[255-260] leading to the WHO 2016 revision that required biallelic variants for the disease definition.[106] However, a study of over 4,700 adults with AML found that patients with single CEBPA variants in the bZIP C-terminal domain have clinical characteristics and favorable outcomes similar to those of patients with double-variant CEBPA AML.[260]CEBPA variants occur in approximately 5% of children with AML and have been preferentially found in the cytogenetically normal subtype of AML with FAB M1 or M2.Given these findings in pediatric AML with CEBPA variants, the presence of a bZIP variant alone confers a favorable prognosis. Importantly, however, there is a small subset of patients with AML and CEBPA variants who have less-favorable outcomes. Specifically, CSF3R variants occur in 10% to 15% of patients with AML and CEBPA variants. CSF3R variants appear to be associated with an increased risk of relapse, but without an impact on OS.[253,262] At present, the occurrence of this secondary variant does not result in stratification to more intensified therapy in pediatric patients with AML.While not common, a small percentage of children with AML and CEBPA variants may have an underlying germline variant. In newly diagnosed patients with double-variant CEBPA AML, germline screening should be considered in addition to usual family history queries because 5% to 10% of these patients have a germline CEBPA abnormality that confers an increased malignancy risk.[252,263] For more information, see CEBPA-Associated Familial Acute Myeloid Leukemia.

AML with CEBPA variants. Variants in the CEBPA gene occur in a subset of children and adults with cytogenetically normal AML.[252,253] In adults younger than 60 years, approximately 15% of cytogenetically normal AML cases have variants in CEBPA.[246] Outcomes for adults with AML with CEBPA variants appear to be relatively favorable and similar to that of patients with CBF leukemias.[246,254] Initial studies in adults with AML demonstrated that CEBPA double-variant, but not single-variant, abnormalities were independently associated with a favorable prognosis,[255-260] leading to the WHO 2016 revision that required biallelic variants for the disease definition.[106] However, a study of over 4,700 adults with AML found that patients with single CEBPA variants in the bZIP C-terminal domain have clinical characteristics and favorable outcomes similar to those of patients with double-variant CEBPA AML.[260]CEBPA variants occur in approximately 5% of children with AML and have been preferentially found in the cytogenetically normal subtype of AML with FAB M1 or M2.Given these findings in pediatric AML with CEBPA variants, the presence of a bZIP variant alone confers a favorable prognosis. Importantly, however, there is a small subset of patients with AML and CEBPA variants who have less-favorable outcomes. Specifically, CSF3R variants occur in 10% to 15% of patients with AML and CEBPA variants. CSF3R variants appear to be associated with an increased risk of relapse, but without an impact on OS.[253,262] At present, the occurrence of this secondary variant does not result in stratification to more intensified therapy in pediatric patients with AML.While not common, a small percentage of children with AML and CEBPA variants may have an underlying germline variant. In newly diagnosed patients with double-variant CEBPA AML, germline screening should be considered in addition to usual family history queries because 5% to 10% of these patients have a germline CEBPA abnormality that confers an increased malignancy risk.[252,263] For more information, see CEBPA-Associated Familial Acute Myeloid Leukemia.

Patients with double CEBPA variants or with single CEBPA bZIP variants have a median age of presentation of 12 to 13 years and have gene expression profiles that are highly related to each other.[253]

AML with CEBPA variants. Variants in the CEBPA gene occur in a subset of children and adults with cytogenetically normal AML.[252,253] In adults younger than 60 years, approximately 15% of cytogenetically normal AML cases have variants in CEBPA.[246] Outcomes for adults with AML with CEBPA variants appear to be relatively favorable and similar to that of patients with CBF leukemias.[246,254] Initial studies in adults with AML demonstrated that CEBPA double-variant, but not single-variant, abnormalities were independently associated with a favorable prognosis,[255-260] leading to the WHO 2016 revision that required biallelic variants for the disease definition.[106] However, a study of over 4,700 adults with AML found that patients with single CEBPA variants in the bZIP C-terminal domain have clinical characteristics and favorable outcomes similar to those of patients with double-variant CEBPA AML.[260]CEBPA variants occur in approximately 5% of children with AML and have been preferentially found in the cytogenetically normal subtype of AML with FAB M1 or M2.Given these findings in pediatric AML with CEBPA variants, the presence of a bZIP variant alone confers a favorable prognosis. Importantly, however, there is a small subset of patients with AML and CEBPA variants who have less-favorable outcomes. Specifically, CSF3R variants occur in 10% to 15% of patients with AML and CEBPA variants. CSF3R variants appear to be associated with an increased risk of relapse, but without an impact on OS.[253,262] At present, the occurrence of this secondary variant does not result in stratification to more intensified therapy in pediatric patients with AML.While not common, a small percentage of children with AML and CEBPA variants may have an underlying germline variant. In newly diagnosed patients with double-variant CEBPA AML, germline screening should be considered in addition to usual family history queries because 5% to 10% of these patients have a germline CEBPA abnormality that confers an increased malignancy risk.[252,263] For more information, see CEBPA-Associated Familial Acute Myeloid Leukemia.

Approximately 80% of pediatric patients have double-variant alleles (i.e., cases with both a CEBPA TAD domain and a CEBPA bZIP domain variant), which is predictive of significantly improved survival, similar to the effect observed in adult studies.[253,261]

AML with CEBPA variants. Variants in the CEBPA gene occur in a subset of children and adults with cytogenetically normal AML.[252,253] In adults younger than 60 years, approximately 15% of cytogenetically normal AML cases have variants in CEBPA.[246] Outcomes for adults with AML with CEBPA variants appear to be relatively favorable and similar to that of patients with CBF leukemias.[246,254] Initial studies in adults with AML demonstrated that CEBPA double-variant, but not single-variant, abnormalities were independently associated with a favorable prognosis,[255-260] leading to the WHO 2016 revision that required biallelic variants for the disease definition.[106] However, a study of over 4,700 adults with AML found that patients with single CEBPA variants in the bZIP C-terminal domain have clinical characteristics and favorable outcomes similar to those of patients with double-variant CEBPA AML.[260]CEBPA variants occur in approximately 5% of children with AML and have been preferentially found in the cytogenetically normal subtype of AML with FAB M1 or M2.Given these findings in pediatric AML with CEBPA variants, the presence of a bZIP variant alone confers a favorable prognosis. Importantly, however, there is a small subset of patients with AML and CEBPA variants who have less-favorable outcomes. Specifically, CSF3R variants occur in 10% to 15% of patients with AML and CEBPA variants. CSF3R variants appear to be associated with an increased risk of relapse, but without an impact on OS.[253,262] At present, the occurrence of this secondary variant does not result in stratification to more intensified therapy in pediatric patients with AML.While not common, a small percentage of children with AML and CEBPA variants may have an underlying germline variant. In newly diagnosed patients with double-variant CEBPA AML, germline screening should be considered in addition to usual family history queries because 5% to 10% of these patients have a germline CEBPA abnormality that confers an increased malignancy risk.[252,263] For more information, see CEBPA-Associated Familial Acute Myeloid Leukemia.

In a study of nearly 3,000 children with AML, both patients with CEBPA double variants and those with only a bZIP domain variant were observed to have a favorable prognosis, compared with patients with wild-type CEBPA.[253]