Abstract
TP53 alterations (including mutations and/or deletions) are among the most adverse genomic events in hematological malignancies, observed in 8-12% of de novo acute leukemia and MDS, and up to 40% of the therapy-related cases. These alterations often co-occur with complex cytogenetics resulting in treatment resistance and poor outcomes. Allogeneic HCT remains the only curative option, but post-HCT relapse is common in TP53 altered patients. Recent studies suggest that factors such as TP53 allelic burden, measurable residual disease (MRD) status, and karyotype complexity may influence HCT outcomes. We conducted a contemporary review of 158 consecutive allogeneic HCT patients with TP53-altered acute leukemia or MDS to evaluate HCT outcomes (primary objective), identify prognostic variables and refine HCT strategies.
In this single center retrospective analysis, 158 patients with TP53-altered AML, ALL, or MDS, age ≥18 years old who received T cell replete grafts and underwent their first HCT between 2011-2024 at City of Hope were included. TP53 alterations were defined as mutations and/or 17p deletion. We collected data on patient and HCT characteristics including demographics, cytogenetics, MRD by flow cytometry or PCR, TP53 variant allele frequency (VAF), FISH-based copy number loss, conditioning regimen, donor type, and graft-versus-host disease (GVHD) prophylaxis.
The median age at HCT was 63 years (range 20-79); 57% (n=90) were male, and indication for HCT was AML (n=81; 51.3%), ALL (n=30; 19%), or MDS (n=47; 30%). Disease risk index (DRI) was high-very high in 58.2% (n=92), HCT-CI was ≥ 3 in 59.5% (n=94). Pre-HCT MRD by MCF was positive in 40.5% (n=64), TP53 VAF was ≥ 5% in 50% (n=79), and 17p deletion was detected by FISH in 13.3% (n=21). TP53 copy number loss was reported in 20.3% (n=32), and complex karyotype was seen in 32.3% (n=51). Conditioning regimen was fludarabine/melphalan (58.9%), FTBI- or TMLI-based (32.9%), or fludarabine and cyclophosphamide with 200 cGy of TBI (8.2%). Most patients received peripheral blood stem cells as HCT graft (n=156; 98.7%). GVHD prophylaxis was tacrolimus/sirolimus-based (67.1%), post-transplant cyclophosphamide-based (30.4%), or tacrolimus/methotrexate-based (2.5%).
At the median follow-up duration of 36 months, the 2-year OS and PFS were 45.6% (95% CI: 37-53) and 36.6% (95% CI: 29-44), respectively. Cumulative incidence of relapse at 1 and 2 years post-HCT were 34.1% (95% CI: 27-42) and 37.8% (95% CI: 30-45), respectively. Cumulative incidence of NRM at 1 and 2-years post-HCT were 23% (95% CI: 17-30) and 25.3% (95% CI: 19-32), respectively.
Univariate analysis (UVA) showed inferior OS with age ≥60 (HR 1.64, 95% CI: 1.08-2.48; p=0.01), high-very high DRI (HR 1.50, 95% CI: 1.01-2.23; p=0.04), MRD positivity (HR 1.57, 95% CI: 1.05-2.32; p=0.02), and complex karyotype (HR 1.57, 95% CI: 1.06-2.34; p=0.02) with HCT-CI ≥3 trending toward inferior OS (HR 2.02, 95% CI: 1.05,3.89; p=0.07). High-very high DRI (HR 1.64, 95% CI: 1.12-2.41, p=0.009), MRD positivity (HR 2.10, 95% CI: 1.43-3.08; p<0.001), and complex karyotype (HR 1.65, 95% CI: 1.13-2.41; p=0.008) were also predictive of worse PFS. KPS ≤70 (p=0.02), high-very high DRI (p=0.04), and MRD+ status (p=0.03) were predictive of higher NRM by UVA, but none of the factors predicted relapse by UVA.
Multivariable analysis (MVA) confirmed independent inferior OS with age ≥60 (HR 1.56, 1.02-2.40; p=0.04), and high/very high DRI (HR 1.53, 95% CI: 1.02-2.28; p=0.04), with HCT-CI ≥3 trending toward inferior OS (HR 2.10, 95% CI: 1.06-4.16; p=0.08). For inferior PFS, only MRD positivity (by flow) remained significant (HR 2.28, 95% CI: 1.54,3.37; p<0.001) by MVA. None of the factors independently predicted relapse or NRM, though lower KPS trended toward higher NRM risk by MVA (HR 2.02, p=0.08).
In this single-institution cohort of HCT for TP53-altered acute leukemia and MDS, 36.6% of the patients remained alive and disease-free by 2 years post-HCT. Older patients with multiple comorbidities and high DRI had worse survival outcomes. MRD by MCF positivity was more predictive of PFS compared to other methods. Melphalan-based conditioning had similar performance compared to FTBI- based MAC and GvHD prophylaxis was not predictive of HCT outcomes. MRD-directed strategies and novel maintenance approaches are urgently needed to improve long-term outcomes in this high-risk population.
