Donor lymphocyte infusions for recurrence of myeloid neoplasms after allogeneic hematopoietic cell transplantation in the era of hypomethylating agents and BCL2 inhibitors.

The combination of hypomethylating agents (HMA) and venetoclax (VEN) has transformed acute myeloid leukemia (AML) treatment. Data on donor lymphocyte infusion (DLI) with HMA/VEN for relapse after allogeneic hematopoietic cell transplantation (alloHCT) remain limited.We retrospectively analyzed 78 adults with relapsed myeloid neoplasms after first alloHCT between 2018 and 2025. DLI was given with HMA, HMA/VEN, or other/no treatments. The primary endpoint was event-free survival (EFS), defined as time to death or second alloHCT.Median time to relapse after alloHCT was 12.9 months (range 2.2-192.4). Initial DLI doses ranged from 0.3 to 8.14 × 10⁶ CD3⁺ cells/kg. Median EFS after first DLI was 15.2 months: with 16.2 (DLI/HMA), 14.3 (DLI/HMA/VEN), and 21.1 (DLI/other), respectively. Death occurred in 25.6% and second alloHCT in 32.1% of patients. GvHD of any kind after DLI treatment manifested in 30.8%, both events comparable across groups. Complete remission (CR) after DLI was achieved in 42.3% after a median of 4.2 months, including patients with TP53 mutations (n = 9).Approximately 40% of patients with relapsed myeloid malignancies were successfully salvaged with DLI and combination treatments. Patients with high-risk features such as morphological relapse were overrepresented in the DLI/HMA/VEN cohort but achieved comparable outcomes to the other treatment groups. This finding suggests successful treatment of even morphological relapse by addition of VEN to DLI/HMA regimens while supporting the need for controlled trials.