Core‐binding factor acute myeloid leukemia with t(8;21): Risk factors and a novel scoring system (I‐CBFit)

Abstract

BackgroundAlthough the prognosis of core‐binding factor (CBF) acute myeloid leukemia (AML) is better than other subtypes of AML, 30% of patients still relapse and may require allogeneic hematopoietic cell transplantation (alloHCT). However, there is no validated widely accepted scoring system to predict patient subsets with higher risk of relapse.MethodsEleven centers in the US and Europe evaluated 247 patients with t(8;21)(q22;q22).ResultsComplete remission (CR) rate was high (92.7%), yet relapse occurred in 27.1% of patients. A total of 24.7% of patients received alloHCT. The median disease‐free (DFS) and overall (OS) survival were 20.8 and 31.2 months, respectively. Age, KIT D816V mutated (11.3%) or nontested (36.4%) compared with KIT D816V wild type (52.5%), high white blood cell counts (WBC), and pseudodiploidy compared with hyper‐ or hypodiploidy were included in a scoring system (named I‐CBFit). DFS rate at 2 years was 76% for patients with a low‐risk I‐CBFit score compared with 36% for those with a high‐risk I‐CBFit score (P < 0.0001). Low‐ vs high‐risk OS at 2 years was 89% vs 51% (P < 0.0001).ConclusionsI‐CBFit composed of readily available risk factors can be useful to tailor the therapy of patients, especially for whom alloHCT is not need in CR1 (ie, patients with a low‐risk I‐CBFit score).

Core Binding Factor Leukemia: Chromatin Remodeling Moves Towards Oncogenic Transcription

“…Sex chromosome loss was reported as a favorable marker for two-year event-free survival (66.9% vs. 43.0%), and in another study showed a modestly favorable, but not significant, effect on disease-free survival (DFS) [103]. Moreover, this last study found that patients with pseudodiploid karyotypes had worse outcome compared with those with hypodiploidy or hyperdiploidy [103]. In contrast, loss of the Y chromosome showed shorter disease-free survival (DFS) for male patients [120].…”

“…KIT mutations are found in~40% of CBFL with t(8;21) and~33% with inv (16); additionally, an enrichment of exon 17 KIT mutations has been documented in RUNX1-RUNX1T1 patients, and are associated with worse outcome [87,[99][100][101]. Recent large study created an "International CBF group index for t(8;21)" and validated a new risk scoring system, showing that older age, higher WBC index at diagnosis [102], and KIT D816V/Y mutations were risk factors associated with treatment failure (relapse or death) [103]. These studies strongly support the adverse effect of a KIT mutation in the context of CBFL.…”

“…In addition, a novel finding indicates that pseudodiploidy was also a risk factor in t(8;21). High-risk score patients may benefit from more intensive approaches in the first complete remission (CR1) [103]. Mutations affecting FLT3-ITD are present in only 3% of inv(16) AML, whereas they occur in 10% of t(8;21) leukemia patients.…”

“…However, given that the whole sex chromosome is typically missing and not only the individual CSF2RA locus, it is likely that additional haploinsufficient factors on the sex chromosome are acting to enhance RUNX1-RUNX1T1-associated leukemogenesis [119]. Sex chromosome loss was reported as a favorable marker for two-year event-free survival (66.9% vs. 43.0%), and in another study showed a modestly favorable, but not significant, effect on disease-free survival (DFS) [103]. Moreover, this last study found that patients with pseudodiploid karyotypes had worse outcome compared with those with hypodiploidy or hyperdiploidy [103].…”

Genetic Hierarchy of Acute Myeloid Leukemia: From Clonal Hematopoiesis to Molecular Residual Disease

“…Concerning t(8;21)- and inv(16)-type AMLs, the same large cohort confirms the absence of association with mutations in NPM1 or in the previously cited transcription factor genes, and shows an association between t(8;21) and KIT in 38% of cases. This association has been shown to have poorer outcomes [24]. An even stronger association between inv(16) and NRAS mutations is found in 53% of cases.…”