Amsa/ARA-C Followed By TBI 4 Gy or High Dose Chemotherapy Conditioning Regimens in Primary Refractory AML – Significantly Worse Outcomes in Younger Patients Conditioned with 4 Gy TBI

Background:

Allogeneic stem cell transplantation (allo-SCT) plays a fundamental role in the management of acute myeloid leukemia (AML) and is generally recommended for patients with primary induction failure. The optimal conditioning regimen in preparation for SCT in this specific difficult contex has been the subject of continued controversy. Specifically, the role of total body irradiation (TBI) or chemotherapy (CT) as part of sequential conditioning, continues to be central to this debate. With improvement in CT delivery and the introduction of intravenous (IV) busulfan, the utilization of TBI has decreased in popularity. This is a retrospective, multi-center, registry-based, European Society of Blood and Marrow Transplantation (EBMT) study which aimed to compare the outcomes of allo-SCT with amsacrine (AMSA) /cytarabine (ARA-C) followed by TBI conditioning to CT-based conditioning and thus determine certain prognostic factors that could potentially aid in the decision to implement TBI into a patient’s conditioning regimen in preparation for allo-SCT.

Patients and Methods:

For this analysis, we identified 466 adult patients (58.8% male, median age: 55 years, range: 18-75) with primary refractory AML (73.6% de novo) transplanted between the years 2001 and 2021 (median: 2013) from matched sibling donors (MSD) or matched unrelated donors (MUD: 59.2%), who had received AMSA and ARA-C conditioning followed by CT or TBI sequential conditioning. In patients with available cytogenetic data, 50% had intermediate cytogenetics and 50% had poor cytogenetics. Karnofsky score at the time of transplant was >90 in 57.8% of the patients. The majority (73.1%) received a combination cyclosporine (CSA) and mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis and 92.7% underwent in vivo T-cell depletion.

Results:

Of the 466 eligible patients identified, 237 (50.8%) received sequential CT-based conditioning following high-dose AMSA/ARA-C with busulfan-fludarabine (BuFlu) or busulfan-cyclophosphamide-fludarabine (BuCyFlu) and 229 received sequential TBI-based conditioning following high-dose AMSA/ARA-C with a total of 4 Gy and cyclophosphamide-fludarabine (CyFlu). In univariate analysis, there was a significant difference in age between the two groups whereby patients receiving CT-based sequential conditioning were older (59.9 years vs 49.7 years, p<0.0001). Moreover, there was a significant difference in the proportions of MSD/MUD between the two groups with 67.9% being allografted from MUD in the CT group compared to 50.2% in the TBI group (p=0.0001). Given the significant interaction between age and conditioning (sequential TBI vs. CT), we stratified our sample by median age (<55 vs >= 55). In patients younger than 55 years, 2-year leukemia-free survival (LFS) was significantly higher in the CT group (51.9% vs 25.1%, p=0.002), as was overall survival (OS) (57.5% vs 38.3%, p=0.021). CT-based sequential conditioning was also associated with higher rates of grades II-IV and III-IV acute GVHD (38.1% vs 24.7%, p=0.02 and 19.8% vs 8.9%, p=0.022). In multivariate analysis, the use of TBI- vs CT-based sequential conditioning significantly influenced relapse (hazard ratio [HR] 1.98, p=0.018), non-relapse mortality (NRM: HR 2.7, p=0.038), LFS (HR 2.03, p=0.004), OS (HR 1.86 p=0.016) and acute GVHD II-IV (HR 0.45, p=0.014). Moreover, age (per 10 years) significantly impacted NRM (HR 2.42, p=0.0005), female to male donor impacted NRM (HR 2.41, p=0.032) and chronic GVHD incidence (HR 2.21, p=0.033) and in vivo T-cell depletion (TCD) impacted chronic GVHD (HR 0.32, p=0.03). In patients 55 years or older, there was no significant difference in post-allo-SCT outcome between patients who received TBI-based vs CT-based sequential conditioning.

Conclusion:

The above results highlight a significant difference in outcomes in AML patients receiving sequential TBI-based vs CT-based conditioning in preparation for allo-SCT according to age, whereby patients younger than 55 years had significantly worse outcomes after receiving TBI. This was not reflected in patients aged 55 years or more. Although only 4 Gy, these results emphasize the importance of age in the transplant physician’s decision to incorporate TBI into conditioning regimens to optimize outcomes.