Non-Relapse Mortality in TP53-Mutated MDS/AML - a Multi-Center Collaborative Study

Abstract

Background: Patients with TP53 MUT MDS/AML experience poor clinical outcomes with high rates of disease recurrence and short overall survival (OS). Characterization of these individuals' post-HCT mortality is uniquely challenging due to competing risks from disease relapse and treatment toxicity. Transplant registries contain high-level outcomes data, however, there is a lack of detailed data in molecularly defined subsets of diease. This analysis was undertaken to bridge this gap. Methods: Allogeneic HCT recipients between 1/2014 and 12/2018 were retrospectively studied. Key inclusion criteria were TP53 MUT by NGS or deletion of chromosome 17/17p by FISH/cytogenetics. The primary outcome of non-relapse mortality (NRM) was defined as death from any cause other than disease with relapse as competing risk. Secondary outcomes for this analysis were OS, cumulative incidence of relapse (CIR), and relapse free survival (RFS). Relapse was defined as relapse/progression with NRM as competing risk. Results: 384 TP53 MUT MDS/AML patients were analyzed. 55% of patients were transplanted for AML, 41% received myeloablative conditioning (MAC), 39% had secondary MDS/AML, and 26% received prior chemo and/or radiation therapy (XRT). Median time from HCT to last follow-up was 321 days (range 8-2,385 days). Mutational data was available in 264 patients and cytogenetic data was available in 368 patients; 78% of patients had a complex karyotype (CK), 82% had TP53 missense mutations, and 74% had bi-allelic targeting of the TP53 gene. The incidence of all-grade acute and chronic GVHD (cGVHD) was 52% and 31%, respectively. One and 2 year OS was 48.5% and 30.9%, respectively. Estimated CIR at 1 and 2 years was 49% and 54.9%, respectively. The 1 year NRM was 13.7% and 2 year NRM was 18.1%. In multivariate analysis (MVA), there was no association between NRM and the clinical, molecular, or genetic features of TP53 MUT MDS/AML. HCT diagnosis of MDS (HR: 0.67, 95% CI: 0.46-0.97, p: 0.036), mono-allelic TP53 MUT (HR: 0.6, 95% CI: 0.39-0.94, p: 0.023), achievement of full donor PB chimerism (HR: 0.33, 95% CI: 0.14-0.85, p: 0.022), BM chimerism (HR: 0.33, 95% CI: 0.18-0.60, p: 0.003), and cGVHD (HR: 0.35, 95% CI: 0.23-0.51, p: <0.001) correlated with lower rates of relapse while CK predicted for increased relapse (HR: 2.5, 95% CI: 1.49-4.19, p: 0.001). Inferior OS was associated with CK (HR: 1.84, 95% CI: 1.19-2.85, p: 0.006) and history of prior chemo/XRT (HR: 1.84, 95% CI: 1.01-1.93, p: 0.006) whereas high KPS (HR: 0.98, 95% CI: 0.97-1, p: 0.046), mono-allelic TP53 mutations (HR: 0.52, HR: 0.36-0.77, p: 0.001), full donor PB chimerism (HR: 0.36, 95% CI: 0.19-0.68, p: 0.002), BM chimerism (HR: 0.3, 95% CI: 0.19-0.49, p: <0.001), and cGVHD (HR: 0.36, 95% CI: 0.18-0.36, p: <0.001) were associated with improved OS. In subgroup analysis, history of chemo and/or XRT increased NRM in AML (HR: 4.24, 95% CI: 1.35-13.39, p: 0.014). Pre-HCT TP53 MUT persistence by NGS (HR: 3.59, 95% CI: 1.43-9, p: 0.007) predicted for post-HCT relapse whereas pre-HCT CR (HR: 2.93, 95% CI: 1.54-5.59, p: 0.001) and full donor BM chimerism (HR: 0.14, 95% CI: 0.05-0.38, p: <0.001) were associated with lower rates of relapse. High KPS (HR: 0.96, 95% CI: 0.98-0.99, p: 0.021) and cGVHD (HR: 0.3, 95% CI: 0.16-0.56, p: <0.001) corresponded with improved OS. Prior chemo/XRT was associated with shorter OS (HR: 2.11, 95% CI: 1.06-4.18, p: 0.033) No significant NRM associations were identified in MDS. CK (HR: 5.04, 95% CI: 1.95-13.01, p: <0.001) and RIC/NMA conditioning intensity (HR: 2.54, 95% CI: 1.26-5.1, p: 0.009) increased risk of post-HCT relapse while full donor BM chimerism (HR: 0.15 95% CI: 0.08-0.31, p: <0.001), full donor PB chimerism (HR: 0.17, 95% CI: 0.17, p: <0.001), and cGVHD (HR: 0.17, 95% CI: 0.07-0.42, p:<0.001) reduced this risk. OS was improved with mono-allelic mutations (HR: 0.54, 95% CI: 0.32-0.96, p: 0.034), full donor BM (HR: 0.24, 95% CI: 0.12-0.71, p: <0.001), PB (HR: 0.29, 95% CI: 0.09-0.3, p: 0.007) chimerism, and cGVHD (HR: 0.16, 95% CI: 0.09-0.3, p: <0.001). Conclusions: From this large multi-institutional cohort of TP53 MUT myeloid neoplasms, we report a low NRM rate, likely due to high rates of post-HCT relapse/progression. These data demonstrate associations between bi-allelic TP53m/CK and post-HCT outcomes. Our work highlights the importance donor chimerism after HCT and provides new understanding of the importance of chronic GVHD in TP53 MUT MDS/AML. Figure 1 Figure 1. Disclosures Byrne: Karyopharm: Research Funding. Logan: Amgen, Pfizer, AbbVie: Consultancy; Pharmacyclics, Astellas, Jazz, Kite, Kadmon, Autolus, Amphivena: Research Funding. Lee: CareDx: Membership on an entity's Board of Directors or advisory committees; Kadmon: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Fresensius Kabi: Consultancy; Jazz,: Consultancy; Incyte: Research Funding. Goodman: Seattle Genetics: Consultancy, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria. Gill: Interius Biotherapeutics: Current holder of stock options in a privately-held company, Research Funding; Novartis: Other: licensed intellectual property, Research Funding; Carisma Therapeutics: Current holder of stock options in a privately-held company, Research Funding. Jimenez: Takeda: Research Funding; AbbVie: Research Funding. Metheny: Pharmacosmos: Honoraria; Incyte: Speakers Bureau. Bhatnagar: Pfizer: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Cell Therapeutics: Honoraria, Research Funding; Kite: Honoraria; Karyopharm: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Research Funding. Hamilton: Syndax: Membership on an entity's Board of Directors or advisory committees; Equilium: Membership on an entity's Board of Directors or advisory committees. Mishra: Novartis: Research Funding. Savona: BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding.

Eprenetapopt Plus Azacitidine After Allogeneic Hematopoietic Stem-Cell Transplantation for TP53-Mutant Acute Myeloid Leukemia and Myelodysplastic Syndromes

“…Among the 22 patients who did not receive study treatment, two were excluded because of relapse, whereas the remainder did not initiate therapy because of patient/physician decision and not meeting eligibility criteria post-HCT, reflecting the high-risk status of the study population and the real-world issues involved in bringing m TP53 patients safely to transplant. This screen failure rate raises the possibility that the enrolled study population represents a highly selected group of patients who were both alive and suitably healthy to receive post-HCT maintenance therapy, which is supported by the low NRM compared with the CIBMTR study and data in the study by Byrne et al However, the potential benefit of the eprenetapopt plus azacitidine regimen in preventing disease relapse is supported by the 1-year CIR, which is lower than both the CIBMTR study and the study by Byrne et al, 19 and the median RFS and OS are still very encouraging. A more accurate determination of the potential benefit of eprenetapopt plus azacitidine would require accounting for the effect of immortal time bias using formal landmark analyses on registry controls who met eligibility criteria to start maintenance therapy.…”

“…The 1-year RFS for patients who received maintenance therapy with eprenetapopt and azacitidine met our prespecified hypothesis that the 1-year RFS would be ≥ 50%, on the basis of a 1-year RFS of approximately 30% reported for patients with m TP53 MDS published by Lindsley et al 7 A retrospective registry analysis conducted by the Center for International Blood and Marrow Transplant Research (CIBMTR) highlighted the traditionally poor outcomes in this population, with a 1-year RFS of 36% in patients with AML with m TP53 and complex cytogenetics and 35% in patients with MDS with m TP53 and/or complex cytogenetics; the 1-year CIR was 48% and 52%, respectively, the 1-year NRM was 16% in both cohorts, and the median OS was 7.0 and 6.9 months, respectively (unpublished; see the Data Supplement). Another retrospective analysis of patients with m TP53 MDS/AML who had undergone allogeneic HCT (N = 384) by Byrne et al 19 found a 1-year OS of 48.5%, a median OS of approximately 12 months, a 1-year CIR of 49%, and a 1-year NRM of 13.7%.…”

Tp53-Mutated Myelodysplasia and Acute Myeloid Leukemia

“…Byrne et al reported the retrospective analysis of 384 TP53 -mutant MDS/AML patients undergoing allo-HSCT: the post-transplant OS of MDS and AML patients was similar; patients with chronic GVHD displayed a significantly better OS and lower relapse rate than patients without chronic GVHD; patients with biallelic TP53 disease or those with CK have a worse outcome compared to those with monoallelic TP53 disease or without CK, respectively; pre-transplantation TP53 mutations persistence by NGS predicted post-transplantation relapse, whereas pre-transplantation CR and full donor BM chimerism were associated with a lower rate of relapse. 214 …”

“…213 Byrne et al reported the retrospective analysis of 384 TP53-mutant MDS/AML patients undergoing allo-HSCT: the post-transplant OS of MDS and AML patients was similar; patients with chronic GVHD displayed a significantly better OS and lower relapse rate than patients without chronic GVHD; patients with biallelic TP53 disease or those with CK have a worse outcome compared to those with monoallelic TP53 disease or without CK, respectively; pre-transplantation TP53 mutations persistence by NGS predicted posttransplantation relapse, whereas pre-transplantation CR and full donor BM chimerism were associated with a lower rate of relapse. 214 The European society for Blood and Bone Marrow Transplantation retrospectively analyzed the outcome of 179 AML patients with TP53 mutations and of 601 AML patients without TP53 mutations: in patients with TP53 mutations without CK or chromosome 17p loss the 2year OS was 65%, while in patients with TP53 mutations, with either chromosome 17p loss or CK the 2-year OS was 24.6%. 215 Importantly, the 2-year OS of TP53 mutant patients without 17p loss or CK is like that observed for TP53-WT patients (65.2% vs 70.4%).…”