Impact of transplant on <i>TP53</i> ^MT configurational dynamics in myeloid neoplasms.

Abstract

6537 Background: Multihit TP53 clonal configurations in myeloid neoplasms (MN) confers poor prognosis but therapy alters allelic burden in general. Using our previously described algorithm, patients with up-trending or stable (UT/S) TP53 MT had worse OS than those who down-trended (DT); HSCT was associated with DT. We evaluated whether this pattern reflects intrinsic TP53 -driven disease biology or from treatment/ transplant effects. Methods: We analyzed a serially sequenced TP53 MT AML/MDS cohort from four academic centers using targeted NGS (Illumina MiSeqDx; 54-gene TruSight panel). TP53 configurations were defined per Bahaj et al.: single-hit TP53 MT as obligatory biallelic (VAF &gt;50%), probable biallelic (23–50%), or probable monoallelic (&lt;23%); combined VAF was used for double-hit TP53 MT . TP53 clearance was defined as VAF &lt;3%. Associations were tested with chi-square/Fisher tests and survival by Kaplan–Meier analysis. Clonal velocity (CV) was defined as the change in VAF from diagnosis to final serial sample post-transplant (Δ VAF) over post-HSCT survival time and categorized as stable (0 to −1), moderately downtrended (MD) (−1 to −5), or highly downtrended (HD) (≤−5). Results: Among 119 TP53 MT MN patients, 58 (49%) had pAML, 38 (32%) sAML, and 23 (19%) MDS. Median age was 65 years, 55% were male, and 20% had del(17p). Initial therapy included 7+3/CPX (34%), HMA+VEN (30%), or HMA alone (29%). 71 pts (60%) underwent HSCT (mOS 17 vs 5 mos in non-HSCT group; p&lt;0.001). Among 62 with serial samples, 76% down trended TP53 post-HSCT and 72% achieved TP53 clearance. Patients in the UT/S group more often had complex karyotype (93% vs 64%; p=0.04) and numerically shorter time to HSCT (4 vs 5 mos; p=0.11). In the DT group, pre-HSCT therapy included 7+3 (30%), HMA alone (23%), and HMA+VEN (25%); HMA monotherapy was more common in UT/S vs DT (53% vs 23%; p=0.03). Mismatched/haploidentical transplants (in 45%) had numerically lower mOS than matched donor transplant (13 vs 52 mos; p=0.27); class II mismatch showed numerically better survival than class I or haploidentical (37 vs 12 mos; p=0.27). mOS was worse in UT/S (14 vs 22 mos; p=0.03). When stratified by clonal velocity (CV), the DT group showed stepwise differences in mOS: stable (78 mos), MD (26 mos), and HD (11 mos; p&lt;0.0001). Stable CV was enriched for monoallelic TP53 at diagnosis (60% vs 14% vs 6%; p=0.004), higher chronic GVHD (60% vs 24% vs 13%; p=0.03), and greater TP53 clearance (100% vs 71% vs 56%; p=0.05), whereas HD CV was enriched for obligatory biallelic TP53 (p=0.001). PTCy use was highest in the MD group (30% vs 76% vs 50%; p=0.04). Conclusions: UT/S patients had higher pre-HSCT HMA monotherapy use and complex karyotypes. Stable CV was associated with monoallelic TP53 , lower PTCy use, higher chronic GVHD, greater TP53 clearance, and superior survival, suggesting that the rate of TP53 clonal contraction rather than clearance alone best predicts OS and reflects intrinsic TP53 MT disease biology.