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1588 Leukemic Stem Cells (LSCs) As Peri-Transplant MRD Assessment in AML Patients Undergoing Allogeneic Stem Cell Transplantation in CRClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 617. Acute Myeloid Leukemias: Biomarkers, Molecular Markers and Minimal Residual Disease in Diagnosis and Prognosis: Poster I
Hematology Disease Topics & Pathways:
Research, Acute Myeloid Malignancies, AML, Biological therapies, Clinical Research, health outcomes research, Diseases, Therapies, Myeloid Malignancies, Minimal Residual Disease , Transplantation
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Evgeny Klyuchnikov1*, Anita Badbaran2*, Radwan Massoud, BS, MD3*, Petra Freiberger4*, Christine Wolschke5*, Francis A. Ayuk, MD6*, Ulrike Bacher7* and Nicolaus Kroeger, MD5

1Department of Stem Cell Transplantation,, University Medical Center Hamburg Eppendorf, Hamburg, DEU
2Department of stem cell transplantation, University Hospital Hamburg Eppendorf, Hamburg, DEU
3Department of Stem Cell Transplantation, University Medical Center Hamburg Eppendorf, Hamburg, Germany
4Department for Stem Cell Transplantation, University Cancer Center Hamburg-Eppendorf, Hamburg, Germany
5Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
6University Hospital Hamburg, Hamburg, Germany
7Department of Hematology and Central Hematology Laboratory, Bern, CHE

Background: Several studies have shown that the leukemic stem cells (LSCs: CD34+CD38-CD45RA+/Combi-6+) play a crucial role in the development of relapses in AML patients (pts). LSCs are less sensitive to conventional therapy; moreover, their phenotypical characteristics may allow immune evasion promoting relapses after allo-SCT. Although ELN guidelines recommend including LSCs into MRD assessment, this approach has not yet been studied extensively in the allogeneic setting. Here we suggested that peri-transplant LSCs detection may provide additional prognostic information to conventional (c)MRD in AML pts allografted in CR.

Methods: 90 pts (male, n=46; median, 60.5 years, 19-76) with AML in CR and available pre-transplant cMRD data (multicolor flow cytometry, “different from normal” approach, according to ELN guidelines), who received allografts (matched, n=73; mismatched, n=17) during 2019-2022 years at the Department of Stem Cell Transplantation at University Medical Centre Hamburg were included. LSCs were assessed according to Zeijlemaker et al. 2019 before and after transplant at days +30 and +100. Both methods (cMRD and LSCs detection) were investigated solely and combined for their prognostic impact.

Results: Majority of pts had de novo AML (76%), adverse ELN risk (48%), received matched grafts (related, n=73, 81%; unrelated, n=17, 19%) and MAC regimen (n=55, 61%). ATG was used for GvHD prophylaxis in 70 pts (78%). There were 47 cMRDneg (52%) and 43 cMRDpos (48%) pts.

LSCs were detected in 39 (56%) pts with a median proportion of 0.01% (0.005-0.37%) of WBC. There was no correlation between LSCs proportion and cMRD status. The cMRDpos pts were more frequently LSCspos (67% vs 33%), and cMRDneg were more frequently LSCsneg (33% vs 67%, p=0.002). Before allo-SCT, 34 pts (38%) were cMRDneg/LSCsneg, 26 pts (29%) experienced cMRDpos/LSCspos, 17 pts (19%) had cMRDneg/LSCspos and 13 pts (14%) had cMRDpos/LSCsneg. The conformity between both assays was 67%.

During a median follow up of 10 months (1-29) there were 17 mortalities, 13 relapses and 11 NRM events. The 1-year OS and LFS were significantly better in LSCsneg than in LSCspos pts: 91% (77-97%) vs 73% (55-86%, p=0.012) and 88% (72-96%) vs 52% (35-68%, p=0.001), respectively. This was due to a higher relapse rate in LSCspos group: 33% (18-52%) vs 4% (1-20%, p=0.002). The median time to relapse was 180 days (40-395). The difference in NRM was not significant. The area under the ROC curve for relapses was 0.74 (0.61-0.88, p=0.006).

Regarding the combined used of LSCs/cMRD, the best 1-year OS (p=0.038) and LFS (p=0.002) were observed for the double negative group: 94% (77-99%) and 88% (65-97%); followed by cMRDpos/LSCsneg: 86% (59-96%) and 86% (61-97%); cMRDneg/LSCspos: 77% (43-94%) and 71% (39-90%); and the double positive group: 63% (43-79%) and 42% (25-61%)., respectively (Figure 1). This was due to in the differing relapse rate that was highest in cMRDneg/LSCspos group: 47% (17-79%), followed by double positive: 29% (14-50%), double negative: 7% (1-32%), and cMRDpos/LSCsneg group: 0% (p=0.02).

Post-transplant cMRD/LSCs data on days +30 and +100 were available in 70 consecutive pts. The post-transplant conversion rates (positive > negative) for LSCs, cMRD and cMRD/LSCs were 49%, 61%, and 63%, respectively. The majority of pts converted at day +30. We observed a higher conversion rate to LSCneg status after MAC vs RIC (12/16, 75% vs 5/11, 45%, p=0.12). Of nine pts who were MRDpos at day +30, six were LSCneg and three were LSCpos. One MRDpos/LSCneg pts died due to NRM while remaining five pts survived without relapse. All three MRDpos/LSCpos pts developed relapses with two mortalities.

Conclusion: Peri-transplant detection of LSCs has a strong predictive value for early post-transplant relapses in AML pts. This approach can improve pre-transplant risk assessment for cMRDpos patients by defining a population with better survival and low relapses (cMRDpos/LSCsneg) and one with worse survival and more relapses (cMRDpos/LSCspos). The post-transplant clearance of residual disease is associated with better survival regardless of the flow strategy being used (cMRD, LSCs, or both). Pts with persisting cMRD early after allo-SCT may be subdivided into different risk groups according to their LSCs status.

Figure 1. Leukemia-free survival according to pre-transplant cMRD/LSCs status in 90 AML patients.

Disclosures: Kroeger: Riemser: Research Funding; Celgene/BMS: Honoraria, Research Funding; AOP Orphan Pharmaceutical, JAZZ, Takeda, Astellas: Honoraria; Novartis, Neovii: Honoraria, Research Funding.

*signifies non-member of ASH