Background: Unlike therapy-related myeloid neoplasms, therapy-related acute lymphoblastic leukaemia (tr-ALL) is poorly defined due to its rarity. However, increasing reports have demonstrated that tr-ALL is a distinct entity with adverse genetic features and clinical outcomes. Methods: We compared the clinicopathological characteristics and outcomes of patients diagnosed with tr-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 tr-ALL and 63 dn-ALL patients were compared from a comprehensive next-generation sequencing panel. Results: All tr-ALL patients had the B-cell phenotype. 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 tr-ALL. tr-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. Conclusions: In this study, we determined the clinical and genetic profiles of Korean patients with tr-ALL. We found alterations in genes constituting the TP53/RB1 pathway are more frequent in tr-ALL. Due to the rarity of the disease, multi-institutional studies involving a larger number of patients are required in future study.

Background: AML is a heterogeneous disease, and despite intensive therapy, recurrence is still high in AML patients who achieve the criterion for cytomorphologic remission (residual tumor burden [measurable residual disease, MRD] < 5%). This study aimed to develop a targeted next-generation sequencing (NGS) panel to detect MRD in AML patients and validate its performance. Methods:We designed an error-corrected, targeted MRD-NGS panel without using physical molecular barcodes, including 24 genes. Fifty-four bone marrow and peripheral blood samples from 23 AML patients were sequenced using the panel. The panel design was validated using reference material, and accuracy was assessed using droplet digital PCR.Results: Dilution tests showed excellent linearity and a strong correlation between expected and observed clonal frequencies (R > 0.99). The test reproducibly detected MRD in three dilution series samples, with a sensitivity of 0.25% for single-nucleotide variants. More than half of samples from patients with morphologic remission after one month of chemotherapy had detectable mutations. NGS-MRD positivity for samples collected after one month of chemotherapy tended to be associated with poor overall survival and progression-free survival.Conclusions: Our highly sensitive and accurate NGS-MRD panel can be readily used to monitor most AML patients in clinical practice, including patients without gene rearrangement. In addition, this NGS-MRD panel may allow the detection of newly emerging clones during clinical relapse, leading to more reliable prognoses of AML.

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.