Treatment Response and Outcome in Childhood t(1;19)/TCF3-PBX1 Positive Acute Lymphoblastic Leukemia: A Report from the Austrian BFM Group.
Authors: Kager Leo , Lion Thomas , Attarbaschi Andishe , Koenig Margit , Strehl Sabine , Haas Oskar A. , Dworzak Michael N. , Schrappe Martin , Gadner Helmut , Mann Georg 
Published: April 2020

Abstract
The translocation t(1;19)(q23;p13) occurs in up to 5% of children (more commonly in those of African origin) with acute lymphoblastic leukemia (ALL). In 90–95% it results in a fusion of TCF3 (previously termed E2A) at 19p13 with PBX1 at 1q23 by creating a TCF3-PBX1 fusion gene that encodes TCF3-PBX1 proteins with transforming properties. When treated by conventional antimetabolite based therapies, t(1;19)/TCF3-PBX1 positive patients had a poor prognosis, but treatment intensification resulted in improved outcomes. However, it is unknown which treatment element(s) are responsible for this therapeutic success. To analyze demographic, diagnostic, treatment, response, and survival data in patients with t(1;19)/TCF3-PBX1 positive ALL, we performed a retrospective analysis in 860 consecutively recruited children (≤18 years) with newly diagnosed ALL enrolled in 4 Austrian ALL-BFM (Berlin-Frankfurt-Muenster) treatment trials between October 1986 and October 2003. A t(1;19)(q23;p13) and/or TCF3/PBX1 was identified in 33/860 patients (3.8%). Nineteen children were male and 14 female. The median age was 4.3 (range, 0.8 to 17) years and the median WBC at diagnosis was 21,800/μL (range, 3,900 to 148,500/μL). Immunophenotype was pre-B in 23 (70%), and common ALL in 10 (30%) patients. Based on characteristics at presentation and early treatment response, children were stratified to standard risk (N = 9), medium risk (N = 21), or high risk (N = 3) therapy arms. Response to upfront prednisone was good (&lt;1,000 blasts in PB on day 8) in 30/33 patients. Day 15 bone marrow (BM) data were available in 27/33 patients; revealing M1 (&lt;5% lymphoblasts) in 19, and M2 (≥5% to 25% lymphoblasts) in 8 patients. All 33 children had M1 bone marrow on day 33. Overall survival rate was 90% ± 5% for the 33 patients. Leukemia relapsed very early in 4/33 patients (BM, N = 3; BM + CNS, N = 1) a median of 11 (range, 3 to 28) months from diagnosis and 3/4 children subsequently died from progression of disease (DOD). Median follow-up of the 30 survivors was 6.8 (range, 1.7 to 14.4) years. Outcome was better for the 26 patients treated on ALL-BFM 90, 95, and 2000 protocols (5-year event-free survival [EFS] 96% ± 4%) compared to the 7 patients treated on the ALL-BFM 86 protocol (5-year EFS 57% ± 19%) (P = 0.005). In addition, day 15 bone marrow findings correlated with outcome (M1, 5-year EFS 100% vs 75% ± 15% for M2; P = 0.024). Our results indicate occurrence of the t(1;19)/TCF3-PBX1 in 3.8% of Caucasian children with ALL. Outcome was excellent in children with t(1;19)/TCF3-PBX1 ALL who were treated on protocols with more condensed induction therapy (i.e., dose intensification in induction by a more rapid drug sequence) (only 1 of 26 patients experienced a very early relapse and DOD; all 23 patients recruited since 1992 remained in continuous first CR) and/or had M1 bone marrow on day 15; whereas patients who were treated on the ALL-BFM 86 protocol (less condensed induction) and/or had M2 bone marrow on day 15, had a higher rate of very early treatment failure.