Durable remission despite transplantation with active disease in therapy-related NUP98::TOP1-rearranged acute myeloid...

Nucleoporin 98 (NUP98) rearrangements occur in approximately 2-3% of myeloid neoplasms and involve more than 40 partner genes. In acute myeloid leukemia (AML), they define distinct entities associated with adverse prognosis, high rates of chemoresistance, and frequent relapse even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we report two patients with therapy-related NUP98-rearranged AML carrying the rare NUP98::TOP1 fusion that occurred after treatment for relapsed/refractory lymphoma. Both patients received CPX-351 as induction therapy and proceeded to allo-HSCT with persistent disease, with approximately 5-10% residual bone marrow blasts. The transplant strategy consisted of an irradiation-based allo-HSCT platform combining total marrow/lymphoid irradiation (TMLI, 20 Gy) with adoptive transfer of regulatory and conventional T cells (Treg/Tcon), administered in the absence of post-transplant pharmacologic immunosuppression to preserve graft-versus-leukemia (GvL) activity while controlling graft-versus-host disease (GvHD). Both patients achieved sustained long-term remission and are alive at 69 and 55 months after allo-HSCT, respectively, without significant transplant-related complications. While no conclusions on treatment efficacy can be drawn from this limited case series, these observations document durable remission despite the active disease at transplant in an ultra-high-risk setting and support further investigation of immune-based transplant strategies in NUP98-rearranged AML.