P468: mrd as a biomarker for response to donor lymphocyte infusion after al-logeneic hematopoietic cell transplantation in patients with acute myeloid leukemia

Background: Donor lymphocyte infusions (DLIs) can be employed for acute myeloid leukemia (AML) patients as therapeutic or prophylactic treatment after allogeneic hematopoietic cell transplantation (alloHCT). Application of DLI after alloHCT may induce graft-versus-host disease (GVHD). Therefore, biomarkers that predict the effect of DLIs may be useful to guide DLI use. Molecular measurable residual disease (MRD) is prognostic for the response to standard chemotherapy as well as for targeted therapies. Aims: To evaluate MRD as a prognostic marker for DLIs after alloHCT. Methods: Patients with AML or myelodysplastic syndrome (MDS) aged ≥18 years undergoing DLI at Hannover Medical School between 1998 and 2018 with available PB and/or BM DNA samples were included. Patients were excluded if they had no detectable mutations at diagnosis, had a second alloHCT in the observed time or if MDS patients had <10% bone marrow blasts at diagnosis. DNA libraries were prepared using the TruSight Myeloid Panel or Nextera Flex for enrichment (Illumina) and sequenced on a MiSeq device. Error-corrected sequencing of patient specific mutations was performed 30 days (Follow Up 30 days, FU30) and 90 days (FU90) after the first DLI. All mutations detected at diagnosis were used for MRD monitoring. Marker positivity was defined as variant allele frequency above the limit of detection as not all patients were in complete remission (CR), in CR with incomplete hematological recovery (CRi) or in morphologic leukemia free state (MLFS). Results: The median time from alloHCT to DLI was 11.3 months (range 3.1 to 74.4 months). Of 78 patients, 24 patients were marker negative and 54 patients were marker positive before DLI (of the marker positive patients 23 were in CR/CRi/MLFS). As expected, marker negative patients before DLI had a significantly better overall survival (OS), event-free survival (EFS) and relapse-free survival (RFS) than marker positive patients. From the 54 marker positive patients before DLI, 27 patients were in CR/CRi at FU90, 22 patients did not reach CR/CRi and five patients died before FU90. OS, EFS and RFS were significantly improved in patients that were in CR/CRi at FU90. CR/CRi status at FU90 correlated strongly with remission status before DLI (p<0.001). Next, the prognostic effect of MRD in CR/CRi patients at FU90 (n=27) was analyzed. 18 patients reached MRD negativity at FU90 and nine patients stayed MRD positive. Baseline characteristics such as patient sex, cytogenetic risk group, age at diagnosis, the median time between alloHCT and DLI or use of prophylactic vs. therapeutic DLIs were similar between MRD negative and positive patients. Treatment intensity until FU90 was similar between the two groups. Remission status before DLI was not associated with MRD negativity at FU90 (p=0.782). There was no significant difference in OS (p=0.593), EFS (p=0.229) and RFS (p=0.226) between FU90 MRD negative and positive patients. Exclusion of DTA (DNMT3A, TET2, ASXL1) mutations as MRD markers affected the number of patients in CR/CRi at FU90 (20 patients MRD negative and five patients MRD positive), while patient characteristics and outcome did not differ between the two groups. Summary/Conclusion: Patients that achieve CR/CRi until FU90 after DLIs have a significantly better outcome than the remaining patients. However, the MRD status in patients in CR/CRi at FU90 had no prognostic effect in the patient cohort investigated here.