Combination of IKZF1 deletion and early molecular response show significant roles on prognostic stratification in Philadelphia chromosome-positive acute lymphoblastic leukemia patients

Abstract

We retrospectively analyzed the samples collected from 66 patients with PhALL enrolled on ChiCTR-TNRC-09000309 clinical trial. CR rate was 95.5%, and estimated 2-year OS and DFS were 51.7 ± 11.7% and 26.9 ± 11.6%, 3-year OS and DFS were 31.6 ± 12.0% and 23.4 ± 11.6%. By combining IKZF1 deletion and early molecular responses, we redefined the patients as low, intermediate, and high risk 3 groups separately. Patients with double negative in IKZF1 and early molecular response experienced significant superior survival, while patients with double positive would have the worst outcome, and patients who were one or the other with IKZF1 deletion or MRD status had intermediate outcome. Significant differences were found among 3 groups in regard to both OS (p < .001) and DFS (p < .001). Our findings suggest that PhALL is a heterogeneous group of diseases with significantly different prognosis. Combination of IKZF1 deletion and MRD status enable better risk stratification of patients for assignment to optimal therapeutic strategies.

Evaluation and management of measurable residual disease in acute lymphoblastic leukemia

“…In adults with Ph-positive ALL, detection of MRD measured by RT–PCR of BCR-ABL1 transcripts is associated with worse outcomes. 46–49 In one study, patients who received chemotherapy and tyrosine kinase inhibitor (TKI) and achieved a complete molecular response (CMR; defined as absence of a quantifiable BCR-ABL1 transcript by RT–PCR) after approximately 3 months of treatment had excellent long-term OS of 66% at 4 years in the absence of alloSCT. 50 Achievement of CMR was the only factor independently prognostic for OS.…”

Comparative study on allogeneic with autologous hematopoietic stem cell transplantation in adult patients with Philadelphia chromosome–positive acute lymphoblastic leukemia in the era of TKIs: a systematic review and meta-analysis

“…Genetic alterations were also an important factor influencing the outcomes of Ph+ ALL. IKAROS family zinc finger 1 (IKZF1) gene deletions were about 60-80% in adults with Ph+ ALL and were considered a poor prognostic factor of survival [33][34][35][36]. Otherwise, two studies suggested CDKN2A/B deletions were an unfavorable prognostic marker for adults with Ph+ ALL with lower survival rates and higher relapse rates [37,38], and IKZF1 deletions plus CDKN2A/B deletions or other alterations (PAX5, BTG1, EBF1, ETV6, and RB1) had worse survival than only IKZF1 deletions cases [38,39].…”

“…Otherwise, two studies suggested CDKN2A/B deletions were an unfavorable prognostic marker for adults with Ph+ ALL with lower survival rates and higher relapse rates [37,38], and IKZF1 deletions plus CDKN2A/B deletions or other alterations (PAX5, BTG1, EBF1, ETV6, and RB1) had worse survival than only IKZF1 deletions cases [38,39]. A combination of MRD response and IKZF1 deletions or others enable better risk stratification of patients with Ph+ ALL for assignment to optimal therapeutic strategies [36]. Auto-HSCT might be a recommended therapeutic strategy for the Ph+ ALL patients with early molecular response and non-IKZF1 deletions or other unfavorable factors.…”

Treatment of Adults With Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia—From Intensive Chemotherapy Combinations to Chemotherapy-Free Regimens

“…Recurring genetic abnormalities such as IKZF1 and CDKN2A/2B deletions identified in Ph-positive ALL were associated with poor prognosis . In an update of the GIMEMA LAL2116 D-ALBA trial, patients with the IKZF1 plus genotype had worse DFS at 30 months compared with patients with IKZF1 deletion alone or without IKZF1 deletions (41%, 55%, and 79%, respectively; P = .05).…”