Therapy-related acute lymphoblastic leukaemia has a unique genetic profile compared to de novo acute lymphoblastic leukaemia

Abstract

Unlike therapy-related myeloid neoplasms, therapy-related acute lymphoblastic leukaemia (t-ALL) is poorly defined due to its rarity. However, increasing reports have demonstrated that t-ALL is a distinct entity with adverse genetic features and clinical outcomes. We compared the clinicopathological characteristics and outcomes of patients diagnosed with t-ALL (n = 9) or de novo ALL (dn-ALL; n = 162) at a single institution from January 2012 to March 2021. The mutational landscapes of eight t-ALL and 63 dn-ALL patients were compared from a comprehensive next-generation sequencing panel. The most frequently mutated genes were IKZF1 (37%), CDKN2A (14%), SETD2 (13%), and CDKN2B (11%) in dn-ALL, whereas TP53 (38%) and RB1 (25%) mutations were most common in t-ALL. KMT2A rearrangement showed higher frequency in the t-ALL compared to the dn-ALL, 11.1% vs. 3.1%. Due to the limited sample size, t-ALL patients did not show a statistically significant difference in overall survival (p = 0.70) or progression-free survival (p = 0.94) compared to dn-ALL patients. t-ALL patients with remaining malignancy showed poorer prognoses than did t-ALL patients successfully treated for their initial conditions (p = 0.008). Overall, we demonstrate that t-ALL is a rare but distinct disease entity with a different genetic profile than dn-ALL.