Allogeneic Hematopoietic Cell Transplantation in Adult Acute Myeloid Leukemia with t(16;21)(p11;q22)

Background: The chromosomal translocation t(16;21)(p11;q22), which results in the FUS::ERG fusion gene, is a rare but nonrandom genetic abnormality in acute myeloid leukemia (AML). According to a recent cytogenetic stratification, the sole abnormality of t(16;21)(p11;q22) is classified as intermediate-risk, while limited previous case reports and case series suggest that AML with t(16;21)(p11;q22) may be a subtype with a poor prognosis. However, evidence regarding allogeneic hematopoietic stem cell transplantation (HSCT) for AML with t(16;21)(p11;q22) is lacking.

Methods: We conducted a retrospective study of AML patients aged ≥16 years who underwent their first allogeneic HSCT between 1986 and 2021 using the Transplant Registry Unified Management Program of the Japan Society for Transplantation and Cellular Therapy and the Japanese Data Center for Hematopoietic Cell Transplantation. We included AML patients with t(16;21)(p11;q22) and those without the translocation as the reference cohort. Patients with favorable-risk karyotypes were excluded from the study. Our data had some patients without information regarding the breakpoint of the t(16;21) translocation. We considered them as harboring t(16;21)(p11;q22) in our analysis because t(16;21)(q24;q22), the other candidate for translocation, is notably rare in adult AML patients. Additionally, we performed a sensitivity analysis to evaluate patient characteristics and transplant outcomes to check for misclassifications. We then compared patients with and without t(16;21)(p11;q22) in each chromosomal risk group (intermediate- and poor-risk groups). We estimated the 3-year overall survival (OS), progression-free survival (PFS), cumulative incidence of relapse (CIR), and cumulative incidence of non-relapse mortality (NRM) using the Kaplan–Meier and Gray methods. The impact of t(16;21)(p11;q22) was estimated using multivariable Cox proportional hazard and Fine–Gray models. The covariates included age, sex, etiology, disease status, extramedullary lesions, hematopoietic cell transplantation-specific comorbidity index, donor source, conditioning regimen intensities, and prophylaxis of graft versus host disease.

Results: We enrolled 15,432 patients aged 16–85 years (median, 51 years). There were 104 patients with t(16;21)(p11;q22). For these patients, ages ranged from 18-70 years (median, 41 years) and 58 patients (56.3%) were complete remission at the time of transplantation. Regarding transplant outcomes, the 3-year PFS and OS were 5.3% (95% CI: 2.1–13.1%) and 11.2% (95% CI: 6.2–20.3%), respectively. Furthermore, 81 patients were classified as intermediate-risk and 23 as poor-risk due to additional poor prognostic chromosomal abnormalities. Next, we compared their transplant outcomes with those of the reference cohort (intermediate-risk patients: 11,340; poor-risk patients: 3988). For the intermediate-risk group, the 3-year PFS was 5.8% (95% CI: 2.1–15.9%) in patients with t(16;21)(p11;q22) vs 47.5% (95% CI: 46.5–48.4%) in the reference cohort (P < 0.001). In the multivariable analysis, the adjusted hazard ratio (HR) for PFS was 2.66 (95% CI: 1.97–3.60, P < 0.001). The 3-year OS, CIR, and NRM were 12.2% (95% CI: 6.3–23.7%) vs 51.4% (95% CI: 50.5–52.4%) (P < 0.001), 57.9% (95% CI: 45.2–68.6%) vs 28.6% (95% CI: 27.7–29.4%) (P < 0.001), and 36.3% (95% CI: 25.0–47.7%) vs 24.0% (95% CI: 23.2–24.8%) (P = 0.16) for the patients with t(16;21)(p11;q22) vs the reference cohort, respectively. For the poor-risk groups, the 3-year PFS was 4.4% (95% CI: 0.6–29.6%) in patients with t(16;21)(p11;q22) vs 26.6% (95% CI: 25.2–28.0%) in the reference cohort, respectively (P = 0.249). The adjusted HR for PFS was 1.90 (95% CI: 1.16–3.12, P = 0.011). The 3-year OS, CIR and NRM were 8.7% (95% CI: 2.3–32.7%) vs 30.2% (95% CI: 28.8–31.7%) (P = 0.592), 82.6% (95% CI: 56.8–93.7%) vs 49.5% (95% CI: 47.9–51.0%) (P = 0.012), and 13.0% (95% CI: 2.5–32.6%) vs 24.0% (95% CI: 22.6–25.3%) (P = 0.17), for the patients with t(16;21)(p11;q22) vs the reference cohort, respectively.

Conclusions: AML patients with t(16;21)(p11;q22) demonstrate poor outcomes after allogeneic HSCT, primarily because of high relapse rates. These findings highlight the need to label this genetic mutation as a poor-risk group and develop novel therapeutic strategies to improve the poor prognosis.