Introduction
Acute myeloid leukemia (AML) with t(6;9)(p23;q34) resulting in the DEK::NUP214 fusion gene represents a rare (0.5-2% of AML) but particularly aggressive subtype classified as adverse-risk in current ELN guidelines. This chromosomal rearrangement frequently co-occurs with FLT3-ITD mutations (present in approximately 78% of cases), creating a dual molecular insult that drives leukemogenesis through disrupted nucleocytoplasmic transport and enhanced FLT3 signaling. Historically, patients with t(6;9) AML have shown poor responses to conventional chemotherapy, with reported 5-year overall survival rates below 20% with chemotherapy alone. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has emerged as the cornerstone of curative therapy, though comprehensive outcome data specific to this genetic subtype remain limited due to its rarity.
Study Design and Population
The European Society for Blood and Marrow Transplantation (EBMT) conducted this retrospective registry analysis of 544 patients with t(6;9) AML undergoing allo-HSCT between 2000-2022, representing the largest cohort study to date for this genetic subtype. Inclusion criteria mandated cytogenetic or molecular confirmation of t(6;9)/DEK::NUP214, with data captured through EBMT’s standardized reporting forms from 278 participating centers across 35 countries. The study cohort had a median age of 38 years (range 1.4-73.8), with 34.7% pediatric patients (<18 years), 31.3% adolescent/young adults (AYA, 18-39 years), and 34% adults (≥40 years). Transplant characteristics included:• 431 patients (79.2%) transplanted in first complete remission (CR1)• 70.4% received myeloablative conditioning• 45.6% had matched sibling donors, 36.2% unrelated donors• 59.6% received peripheral blood stem cellsPrimary endpoints included overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), non-relapse mortality (NRM), and GVHD-free/relapse-free survival (GRFS) at 2 years post-transplant. Multivariate analyses adjusted for age, disease status, FLT3-ITD status, donor type, conditioning intensity, and transplant period.
Key Clinical Findings
Overall Outcomes
For the entire cohort (N=544):• 2-year OS: 65.7% (95% CI 60.8-70.6)• 2-year LFS: 59.1% (54.1-64.1)• Cumulative RI: 23.0% (19.0-27.0)• NRM: 17.9% (14.4-21.4)• GRFS: 45.6% (40.6-50.6)
Impact of Remission Status
Patients transplanted in CR1 (n=431) showed significantly better outcomes than those with advanced disease:• CR1 OS: 71.7% vs. 44.5% for ≥CR2 (HR 0.51, p<0.001)• CR1 LFS: 65.8% vs. 37.2% (HR 0.48, p<0.001)• CR1 RI: 18.2% vs. 40.8% (p<0.001)• No significant difference in NRM (16.0% vs. 24.1%, p=0.08)
Age-Stratified Outcomes
The study revealed striking age-dependent differences:• Pediatric/AYA (≤39 years) in CR1: 2-year OS 77.4% vs. 57.4% in adults ≥40 years (p<0.001)• Patients ≥53 years showed particularly poor outcomes: OS 46.1%, RI 40.5%, GRFS 28.3%• No significant differences between pediatric and AYA groups (p=0.49)
FLT3-ITD Impact
In a balanced matched-pair analysis of 76 FLT3-ITD+ versus 76 FLT3-ITD- patients:• FLT3-ITD+ associated with 3.1-fold higher relapse risk (HR 3.07, p=0.001)• No OS difference between groups (HR 0.89, p=0.71)• No significant effect on NRM or acute/chronic GVHD
Mechanistic and Clinical Implications
The protective effect of allo-HSCT in t(6;9) AML likely stems from both the myeloablative conditioning regimen and potent graft-versus-leukemia (GVL) effects. The DEK::NUP214 fusion protein creates aberrant nuclear export that may render cells particularly susceptible to DNA damage from conditioning agents. Importantly, the GVL effect appears robust enough to overcome the adverse prognosis typically conferred by FLT3-ITD in non-transplant settings.For clinical practice, these findings support:1. Early referral for transplant evaluation in all t(6;9) AML cases2. Aggressive efforts to achieve CR1 before transplant3. Priority for myeloablative conditioning in fit patients4. Close post-transplant monitoring for FLT3-ITD+ cases
Limitations and Future Directions
As a registry study, limitations include:• Lack of uniform MRD assessment methods• Incomplete data on FLT3-ITD allelic ratios• Evolving transplant practices over the 22-year study periodFuture research should evaluate:• Role of FLT3 inhibitors in the peri-transplant setting• Optimal donor selection for FLT3-ITD+ cases• Reduced-intensity conditioning strategies for older adults
Conclusion
This landmark EBMT study establishes allo-HSCT as an effective therapy for high-risk t(6;9) AML, particularly when performed in CR1 for pediatric and AYA patients. While FLT3-ITD markedly increases relapse risk, it does not preclude transplant success, supporting aggressive curative approaches even in molecularly adverse cases. These findings should inform clinical decision-making and future study design for this rare but aggressive AML subtype.
