Factors associated with survival after allogeneic transplantation for myeloid neoplasms harboring TP53 mutations

Abstract

Allogeneic hematopoietic stem cell transplant (alloHCT) is considered for all patients with myeloid neoplasms (MNs) harboring TP53 mutations (TP53mut). The aim of this international study across 7 transplant centers in the United States and Australia was to identify factors associated with improved post-alloHCT survival. Of 134 TP53mut MN cases who underwent alloHCT, 80% harbored complex karyotype; 94% of TP53 variants were localized to the DNA-binding domain (DBD). Most common comutations were ASXL1 (7%), TET2 (7%), and DNMT3A (6%). Median post-HCT survival was 1.03 years, and overall survival (OS) at 1 year, 2 years, and 3 years was 51.4%, 35.1%, and 25.1%, respectively. A total of 103 cases (76.9%) met the International Consensus Classification (ICC) criteria for MN with mutated TP53 (referred to as ICC-defined TP53mut MN hereafter). The 3-year OS of ICC-defined TP53mut was significantly shorter compared with that of other TP53mut MNs (3-year OS, 16.9% vs 54.9%; P = .002). ICC-defined TP53mut MNs was independently associated with inferior OS (hazard ratio [HR], 2.62; P = .019). The presence of non-DBD TP53mut only (HR, 3.40; P = .005), DNMT3A comutation (HR, 2.64; P = .016), and pre-alloHCT bone marrow blasts ≥5% (HR, 2.76; P = .006) was independently associated with inferior relapse-free survival (RFS), whereas melphalan-based conditioning was associated with superior RFS (HR, 0.52; P = .005). Combining these variables, we constructed a hierarchical model that stratified patients into low-, intermediate-, and high-risk categories with 1-year RFS of 81.3%, 31.3%, and 6.7%, respectively (P < .001). In conclusion, a subset of MN harboring TP53mut who have low blasts pre-alloHCT and received melphalan-based conditioning derived long-term benefit from alloHCT.

Graphical abstract

Figure 1.

Biological characteristics of TP53^mut MDS and AML. (A) Blast percent in BM and peripheral blood. (B) Oncoplot depicting comutations, associated chromosomal abnormalities, non-DBD mutations, and allelic status. Top 5 associated gene mutations are illustrated. (C) TP53^mut VAF stratified using the ICC classification. (D) Lollipop plot of the associated TP53 mutations. Most variants were in the DBD. (E) BM blast percentage stratified by single-hit or multihit TP53. Chr.5.abn, chromosome 5 abnormalities.

Figure 2.

OS at 3 years after transplant. (A) Entire cohort and stratified by (B) CK, (C) meeting the ICC for “TP53^mut MN,” (D) the use of venetoclax before alloHCT, (E) pre-alloHCT BM blast percent, and (F) cytogenetic response before transplant.

Figure 3.

Factors affecting 3-year post-alloHCT OS. (A) Impact of TP53^mut VAF on 3-year OS. (B) OS stratified by TP53^mut VAF ≥10%.

Figure 4.

Nonrelapse mortality and relapse incidence stratified by risk factors. Competing risk analysis for NRM and RI stratified by (A) pre-alloHCT cytogenetic response, (B) inclusion of melphalan in conditioning regimen, (C) PTCy for GVHD prophylaxis, and (D) presence of only non-DBD TP53^mut.

Figure 5.

CART analysis. (A) Factors associated with RFS at 3 years post-alloHCT, and (B) 3-year RFS stratified in 3 categories identified by recursive partitioning (RPART) analysis in panel A.