Prognostic Impact of t(1;19) in Pediatric B-Cell Acute Lymphoblastic Leukemia (B-ALL) Patients Treated on Contemporary Children’s Oncology Group (COG) Protocols

Background

Translocation t(1;19)(q23;p13.3) resulting in the TCF3::PBX1 fusion is a recurrent cytogenetic alteration in 5-7% of B-cell acute lymphoblastic leukemia (B-ALL) that occurs more frequently in Black children. Historically, t(1;19) was associated with inferior outcomes with higher rates of central nervous system (CNS) relapse; contemporary prognostic impact is unclear. We assessed t(1;19) outcomes with modern Children’s Oncology Group (COG) therapy.

Methods

From 2010 to 2019, children and young adults with newly diagnosed B-ALL enrolled on standard risk (SR)(AALL0932; NCT01190930) or high risk (HR) (AALL1131; NCT02883049) protocols based on initial white blood cell count (WBC), age, extramedullary disease status, cytogenetic subtype, day 8 peripheral blood and end of induction (EOI) bone marrow flow cytometric minimal residual disease (MRD). Cytogenetic alterations were classified as favorable (ETV6::RUNX1 or double trisomies of chromosomes 4 and 10), unfavorable (iAMP21, KMT2A rearrangement, hypodiploidy) or neutral (all others). The t(1;19), detected by metaphase karyotyping and confirmed by central review, was considered a neutral cytogenetic lesion not impacting risk stratification. Patients 1-10 years of age with WBC <50,000/uL without unfavorable cytogenetics, CNS3 or testicular disease and EOI marrow MRD <0.01% were treated on AALL0932 while NCI HR (age ≥10 years and/or WBC ≥50,000/uL) and any patients with unfavorable cytogenetics, EOI MRD ≥0.01% and/or CNS3 or testicular leukemia or steroid pretreatment were treated on AALL1131. Patients with Down syndrome or Philadelphia chromosome-positive B-ALL were excluded from this analysis.

Results

Among 6417 patients 1-31 years, 270 (4.2%) had t(1;19) by karyotype, including 90 (33%) and 180 (67%) with a balanced and unbalanced translocation, respectively. The t(1;19) was associated with age ≥ 10 years, female sex, WBC ≥ 50,000/µL, CNS2/3 disease, Black race or Hispanic ethnicity, and Day 29 MRD < 0.01%. The 5-year (yr) disease-free (DFS) and overall survival (OS) for all patients with and without t(1;19) were not significantly different (DFS 92.1% ± 1.8% vs 91.2% ± 0.4%, P =0.39; OS 95.1% ± 1.4% vs 96.4% ± 0.3%, P=0.46) and there were no significant differences between balanced or unbalanced translocations (DFS 91.0% ± 3.2% vs 92.6% ± 2.1%, P = 0.61; OS 94.4% ± 2.6% vs 95.5% ± 1.7%, P=0.69).

When separately analyzing 5-yr DFS and OS among NCI SR and NCI HR patients with and without t(1;19), there were similarly no significant differences [NCI SR: DFS 96.8% ± 1.6% vs. 94.0% ± 0.4%, P=0.11 and OS 97.6% ± 1.4%, vs. 98.3% ± 0.2%, P=0.78; NCI HR: DFS 87.7% ± 3.0% vs. 83.4% ± 1.0%, P=0.14 and OS 92.8%±2.3% vs. 90.9% ± 0.8%, P=0.35].

When compared to other patients with neutral cytogenetics, patients with t(1;19) had improved 5-yr DFS and similar OS (DFS 92.1% ± 1.8% vs 87.2% ± 0.7%, P = 0.01; OS 95.1% ± 1.4% vs 94.6% ± 0.5%, P = 0.853). Notably, NCI SR patients with t(1;19) fared as well as those with favorable cytogenetics (DFS 96.8% ± 1.6% vs 95.9% ± 0.4%, P = 0.34, OS 97.6% ± 1.4% vs 98.9% ± 0.2%, P = 0.37).

Relapses occurred in 16 (5.9%) patients with t(1;19) compared to 480 (7.8%) without t(1;19) with a similar percentage of isolated CNS relapses (1.9% vs 1.7%), respectively. In a multivariable Cox regression model adjusted for other disease related variables, t(1;19) was significantly associated with decreased risk vs. unfavorable cytogenetics (hazard ratio 0.25, 95% CI: 0.15-0.41, P <.001) and other neutral cytogenetics (hazard ratio 0.62, 95% CI: 0.40-0.97, P = 0.04); and was not statistically significantly different than favorable cytogenetics outcomes (hazard ratio 1.27, 95% CI: 0.79-1.98, P = 0.33).

Conclusions

With contemporary therapy, t(1;19) did not confer an inferior prognosis overall. Notably, patients with t(1;19) had improved DFS and OS compared to those with other neutral cytogenetics and, among the NCI SR group, fared as well as those with favorable cytogenetics. T(1;19) did not confer an increase in CNS relapse. Our data support that patients with t(1;19) do not need therapy intensification when treated on contemporary risk-directed COG regimens.