Impact of IKZF1 deletions on long-term outcomes of allo-SCT following imatinib-based chemotherapy in adult Philadelphia chromosome-positive ALL

Abstract

We investigated the prognostic relevance of IKZF1 deletions in 118 adult Ph-positive ALL patients who had minimal residual disease (MRD) data under a uniform treatment of allo-SCT following first-line imatinib-based chemotherapy. IKZF1 deletions were identified in 93 patients (78.8%). IKZF1-deleted patients had a lower proportion of early-stable molecular responders compared with wild-type patients (28.0 vs 56.0%, P = 0.028). After a median follow-up of 72 months, IKZF1-deleted patients had a trend for higher cumulative incidence of relapse (CIR) (38.0 vs 13.3%, P = 0.052), particularly in a subgroup of early-stable molecular responders (n = 40; 21.4 vs 0%, P = 0.088), but comparable disease-free survival to wild-type patients. Patients with biallelic-null deletions showed higher CIR (74.6 vs 13.3%, P = 0.003) and lower disease-free survival (20.0 vs 67.5%, P = 0.022) than wild-type patients. In multivariate analysis, MRD kinetics were closely related to outcomes, while neither IKZF1 deletions nor their functional subtypes retained an independent statistical power. Within the limitation of sample size, however, considering both the negative impact of IKZF1 deletions on MRD kinetics and a trend for relationship between IKZF1 deletions and relapse in early-stable molecular responders, IKZF1 deletions may have a potentially additive effect on unfavorable prognosis in a specific MRD-based subgroup of adult Ph-positive ALL transplants.

Genomic CDKN2A/2B deletions in adult Ph+ ALL are adverse despite allogeneic stem cell transplantation

“…Thereby, only the presence CDKN2A/2B deletions but not IKZF1 deletions showed to be significantly adverse for all endpoints. On one side, this could possibly be attributed to the higher fraction of patients with IKZF-deletions, 75% in our cohort versus 50 % in the cohort of Kim et al 28 and as compared to the frequency of CDKN2A/2B deletions, which were more evenly distributed so that the prognostic value of IKZF1 deletions was weaker than that of CDKN2A/2B deletions.…”

“…27 Arguments possibly explaining an exceptionally strong role of CDKN2A/2B deletions in Ph+ ALL have been shown by functional biologic experiments indicating absence of gene expression from the CDKN2A/2B locus co-operates with the BCR-ABL oncogene to enhance the aggressiveness of the disease by strongly increasing the self-renewal capacity of leukemia cells, increasing clonal turnover and thereby conferring resistance to TKI therapy. [48][49][50] Furthermore, our results are also not in disagreement with the study by Kim et al 28 , where a negative impact of IKZF1 deletions was shown for relapse, which was however not retained in multivariable analysis. Furthermore, in that study, no comparison regarding the prognostic value of IKZF1 deletions in combination with other deletions was made because other lesions were not examined.…”

“…This method had been employed as the sole detection method in several previous studies. 22,23,28 Expectedly, this validation led to a confirmation of SNP array data in most cases. In a few exceptions, MLPA analysis led to a call of deletions, where SNP array analysis did not, i.e.…”

“…There, the investigators could show a trend for higher incidence of relapse in patients with IKZF1 deletions, albeit not reaching significance nor independent statistical power in multivariate analyses. 28 We therefore addressed the question whether in adult Ph+ ALL the putative adverse prognosis conferred by IKZF1 and/or other frequent microdeletions of genes associated with B-cell development can be overcome by aSCT, and whether these genomic alterations are predictive of outcome independently of, or in addition to, levels of minimal residual disease (MRD) during front-line therapy. By SNP microarray analysis and validation with multiplex ligation-dependent probe amplification (MLPA), we examined adult Ph+ ALL samples obtained at initial diagnosis from n=97 patients who received Imatinib as part of their treatment and underwent aSCT in CR1, and correlated the genomic data with outcome after aSCT.…”

Chromosomal microarray analysis is superior in identifying cryptic aberrations in patients with acute lymphoblastic leukemia at diagnosis/relapse as a single assay

“…Copy number alterations identified by CMA in these cases are of prognostic significance. Deletion involving IKZF1 gene has been found to be associated with very poor prognosis in children and adversely affects treatment outcomes in both children and adult patients . Although findings are conflicting, patients with CDKN2A deletion deserve careful observation and management.…”