AUTHORS
Julia M. Unglaub, MD, Andrew T Kent, MD, PhD2, Jason Sean Gilbert, MD3, Clara Burkhard-Meier4, Tim Richardson, MD5, Laura Polmann6, Rabia Shahswar7, Simon Renders8, Stefanie Gryzik9, Maike Janssen10, Tilman Schöning11, Richard F Schlenk, MD12, Michael Hundemer, MD13, Caroline Pabst, PD Dr. med.14, Thomas Luft, MD, PhD15, Michael Heuser, MD16, Jan-Henrik Mikesch, MD17, Christoph Schliemann, MD18, Lukas P Frenzel, PhD19, Peter Dreger, Prof. Dr. med.20, Daniel Pollyea, MD21, Carsten Müller-Tidow22, Tim Sauer, MD23
AFFILIATIONS
1 University Hospital Heidelberg, Heidelberg, Germany
2 University of Colorado, School of Medicine, Aurora, Colorado, United States
3 University of Colorado, School of Medicine, Aurora, Colorado, United States
4 Medical Faculty and University Hospital of Cologne, Cologne, Germany
5 Medical Faculty and University Hospital of Cologne, Cologne, Germany
6 University Hospital Muenster, Muenster, Germany
7 Hannover Medical School, Hannover, Germany, Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, Germany
8 University Hospital Heidelberg, Heidelberg, Germany
9 Laboratory for Hematological Diagnostics,, Heidelberg, Germany, University Hospital Heidelberg, Heidelberg, Germany
10 University Hospital Heidelberg, Heidelberg, Germany
11 Hospital Pharmacy, University Hospital Heidelberg, Heidelberg, Germany
12 University Hospital Heidelberg, Heidelberg, Germany
13 Laboratory for Hematological Diagnostics,, Heidelberg, Germany, University Hospital Heidelberg, Heidelberg, Germany
14 University Hospital Heidelberg, Heidelberg, Germany
15 University Hospital Heidelberg, Heidelberg, Germany
16 University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle, Germany
17 University Hospital Muenster, Muenster, Germany
18 University Hospital Muenster, Muenster, Germany
19 Medical Faculty and University Hospital of Cologne, Cologne, Germany
20 University Hospital Heidelberg, Heidelberg, Germany
21 University of Colorado, School of Medicine, Aurora, Colorado, United States
22 University Hospital Heidelberg, Heidelberg, Germany
23 University Hospital Heidelberg, Heidelberg, Germany
ABSTRACT
Venetoclax (VEN)-based combinations with hypomethylating agents (HMA) provide effective bridging to allogeneic hematopoietic cell transplantation (alloHCT) in AML patients relapsed or refractory (R/R) after intensive therapy. However, the depth of remission required prior to alloHCT remains unclear – whether to proceed after morphologic response or to pursue MRD negativity with additional VEN/HMA cycles. It is also uncertain whether remission is required at all, or if patients proceeding to alloHCT without remission derive comparable benefit. Thus, we evaluated the prognostic impact of pre-transplant remission status and flow-based MRD negativity in patients receiving VEN/HMA salvage as bridge to alloHCT.
We retrospectively analyzed patients with relapsed/refractory AML who received VEN/HMA salvage therapy as a bridge to allo-HCT across five academic transplant centers (University Hospitals of Heidelberg, Colorado, Cologne, Muenster, Halle) between June 2017 and August 2025.
We included 110 patients with R/R AML (median age 57 years; range, 19–72) who had failed prior intensive chemotherapy: 74 (67%) were refractory to induction and 36 (33%) had relapsed after an initial response. According to ELN 2022 classification, 59% were adverse-, 30% intermediate-, and 11% favorable-risk. Venetoclax was combined with azacitidine (n=103) or decitabine (n=7), and patients proceeded to alloHCT after a median of 2 cycles (range, 1–5). At the time of alloHCT, 85 patients (77%) had morphologic blast clearance (responders; CR/CRi/MLFS) and 24 (22%) had ≥ 5% blasts by cytomorphology (non-responders). Age (median 56 years in both groups; IQR 48–65 vs 38–62; p=0.36) and ELN risk were comparably distributed between responders and non-responders (adverse, 58% vs 61%; intermediate, 29% vs 35%; favorable, 13% vs 4%). After a median follow-up of 41.7 months, outcomes were not statistically different irrespective of pre-transplant remission status. Median OS (from the start of VEN/HMA salvage) was not reached in responders versus 35.8 months in non-responders (p=0.19). The 12- and 24-month OS were 77% and 66% in responders versus 63% and 54% in non-responders from the start of VEN/HMA salvage, and 77% and 67% versus 58% and 58% when calculated from alloHCT (p=0.24). Relapse-free survival (RFS) was not significantly different between responders and non-responders (median 41.4 vs 15.6 months; 24-month RFS, 59% vs 43%; p=0.29). Non-relapse mortality was 12% vs 22% at 12 months (Gray's p=0.36), and the cumulative incidence of relapse was 28% vs 38% at 24 months (Gray's p=0.84), in responders versus non-responders. In multivariable analyses adjusted for age and ELN risk, neither disease status at the time of transplantation (HR 1.57; 95% CI, 0.79–3.14; p=0.20) nor conditioning intensity (RIC vs myeloablative, HR 0.69; 95% CI, 0.33–1.43; p=0.32) was independently associated with OS. No significant differences in OS were observed between the five treating centers (log-rank p=0.49), and the association of remission status with OS was unchanged after stratification for center (HR 1.61; 95% CI, 0.72–3.58; p=0.24). Among the 76 responders with an evaluable pre-transplant flow-cytometric MRD assessment, 16 (21%) were MRD-positive. MRD status did not influence post-transplant outcomes: OS (median not reached vs 41.4 months; p=0.78), RFS (median 32.7 vs 41.4 months; p=0.93), and CIR (24-month, 28% vs 32%; Gray's p=0.78) were comparable between MRD-negative and MRD-positive patients.
In this multicenter cohort of R/R AML bridged to alloHCT with venetoclax-based salvage, neither morphologic remission nor pre-transplant flow-MRD negativity was significantly associated with OS, RFS, or relapse incidence, although there was a numerical OS/RFS benefit for responders. Nonetheless, patients transplanted with active disease still achieved substantial long-term survival, with a 24-month OS of 58% after alloHCT. Accordingly, achieving flow-MRD negativity prior to alloHCT did not translate into improved survival or lower relapse incidence, questioning the value of additional salvage cycles administered solely to deepen response prior to transplantation. Together, these data suggest that alloHCT can be curative after VEN/HMA salvage even in the absence of deep responses.
DISCLOSURES
Julia M. Unglaub, MD: No relevant conflicts of interest to declare.