56. Therapy-Related B-Lymphoblastic Leukemia in Adults is Associated with Frequent TP53 Alterations and Inferior Survival

Therapy-related B-Acute Lymphoblastic Leukemia (t-B-ALL) is a group of neoplasms arising in patients with cytotoxic therapy for a prior malignancy. We assessed clinical, cytogenetics, and molecular characteristics of 20 cases with a diagnosis of t-B-ALL identified in two collaborative institutions (5.3% of all newly diagnosed adult ALL). Hypodiploid karyotype was the most frequent cytogenetic feature (25%), followed by KMT2A translocations (20%), BCR-ABL1 fusion (15%), and KMT2A amplification (15%). The median latency period for the onset of t-B-ALL was 6 years, and this was significantly shorter for patients with KMT2A translocations (1.7 years) compared to those with hypodiploidy (7 years). Loss of TP53 due to mutations/deletions was significantly overrepresented in our cohort: loss of one allele in 35% (7/20) and loss of both alleles in 25% (5/20) of cases, predominantly in hypodiploid group. Patients with hypodiploid karyotype tend to be younger (median age 33 years) compared to those with other cytogenetic abnormalities (median age 50 years), suggestive of a possible germline predisposition. Intriguingly, the youngest patient with hypodiploid t-B-ALL had germline TP53 mutation, implying that germline testing might be relevant in t-B-ALL. t-B-ALL reveals poor median 2.2-year overall survival compared to de novo B-ALL (11% vs 68%), particularly inferior in hypodiploid type (1.1 y) and in t-B-ALL with KMT2A translocations (0.9 y). No differences were noted in the cytogenetic features and overall survival of patients treated with alkylating agents, topoisomerase II inhibitors or combination therapy. In conclusion, t-B-ALL is a distinct clinical entity with inferior prognosis and defined genetic signature.