Transplant versus no transplant in myelodysplastic syndrome and acute myeloid leukemia with TP53 mutation; a referral center experience.
AML
MDS
TP53 mutation
allogeneic stem cell transplant
Journal
European journal of haematology
ISSN: 1600-0609
Titre abrégé: Eur J Haematol
Pays: England
ID NLM: 8703985
Informations de publication
Date de publication:
21 Mar 2024
21 Mar 2024
Historique:
revised:
16
02
2024
received:
03
01
2024
accepted:
21
02
2024
medline:
21
3
2024
pubmed:
21
3
2024
entrez:
21
3
2024
Statut:
aheadofprint
Résumé
A remarkably high rate of post-transplant relapse in patients with TP53-mutated myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) calls to question the utility of allogeneic stem cell transplant (HSCT). We, therefore, performed a retrospective analysis to compare the outcomes between HSCT (N = 38) versus non-HSCT (N = 45) approaches. Patients in the HSCT cohort were younger (median age 63 vs. 72) while patients in the non-HSCT cohort more commonly had complex karyotype with chromosome 17 aberrancy and 5q deletion (p < .01). A total of 69 TP53 variants including 64 pathogenic variants, and 5 variants of undetermined significance were detected. Nine patients (4 in HSCT and 5 in non-HSCT) had multi-hit TP53 variants. After induction: 57.9% versus 56.6% in the HSCT versus non-HSCT cohort achieved morphologic complete remission. Median time to HSCT was 6 months and median follow-up was 15.1 months for HSCT and 5.7 months for non-HSCT. Median disease-free survival (DFS) and overall survival (OS) were 11.7 and 15.9 months for HSCT, and 4.1 and 5.7 months for non-HSCT cohorts, respectively. Non-relapse mortality at 12 months was 22% versus 44% for HSCT versus non-HSCT. In the HSCT cohort, the rate of grade II-IV acute and chronic graft-versus-host disease (GVHD) was 55% and 18%, respectively. None of the patients from the non-HSCT cohort were alive while four patients from the HSCT cohort were alive, in remission, and without GVHD (GRFS) at the time of abstraction. Better treatment strategies for patients with TP53-mutated MDS/AML remain an area of unmet clinical need.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.
Références
Dohner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022;140(12):1345‐1377. doi:10.1182/blood.2022016867
Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424‐447. doi:10.1182/blood‐2016‐08‐733196
Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3‐mutated AML. N Engl J Med. 2019;381(18):1728‐1740. doi:10.1056/NEJMoa1902688
Roboz GJ, DiNardo CD, Stein EM, et al. Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1‐mutant acute myeloid leukemia. Blood. 2020;135(7):463‐471. doi:10.1182/blood.2019002140
Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722‐731. doi:10.1182/blood‐2017‐04‐779405
Hassin O, Oren M. Drugging p53 in cancer: one protein, many targets. Nat Rev Drug Discov. 2023;22(2):127‐144. doi:10.1038/s41573‐022‐00571‐8
Muller PA, Vousden KH. Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell. 2014;25(3):304‐317. doi:10.1016/j.ccr.2014.01.021
DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and Venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617‐629. doi:10.1056/NEJMoa2012971
Badar T, Atallah E, Shallis R, et al. Survival of TP53‐mutated acute myeloid leukemia patients receiving allogeneic stem cell transplantation after first induction or salvage therapy: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND). Leukemia. 2023;37(4):799‐806. doi:10.1038/s41375‐023‐01847‐7
Zhao D, Zarif M, Zhou Q, et al. TP53 mutations in AML patients are associated with dismal clinical outcome irrespective of frontline induction regimen and allogeneic hematopoietic cell transplantation. Cancers (Basel). 2023;15(12):1‐12. doi:10.3390/cancers15123210
Li MM, Datto M, Duncavage EJ, et al. Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn. 2017;19(1):4‐23. doi:10.1016/j.jmoldx.2016.10.002
Granowicz EM, Jonas BA. Targeting TP53‐mutated acute myeloid leukemia: research and clinical developments. Onco Targets Ther. 2022;15:423‐436. doi:10.2147/OTT.S265637
Baugh EH, Ke H, Levine AJ, Bonneau RA, Chan CS. Why are there hotspot mutations in the TP53 gene in human cancers? Cell Death Differ. 2018;25(1):154‐160. doi:10.1038/cdd.2017.180
Yan B, Chen Q, Xu J, Li W, Xu B, Qiu Y. Low‐frequency TP53 hotspot mutation contributes to chemoresistance through clonal expansion in acute myeloid leukemia. Leukemia. 2020;34(7):1816‐1827. doi:10.1038/s41375‐020‐0710‐7
McCurdy SR, Luger SM. Dose intensity for induction in acute myeloid leukemia: what, when, and for whom? Haematologica. 2021;106(10):2544‐2554. doi:10.3324/haematol.2020.269134
Zeidan AM, Platzbecker U, Bewersdorf JP, et al. Consensus proposal for revised International Working Group 2023 response criteria for higher‐risk myelodysplastic syndromes. Blood. 2023;141(17):2047‐2061. doi:10.1182/blood.2022018604
Bacigalupo A, Ballen K, Rizzo D, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant. 2009;15(12):1628‐1633. doi:10.1016/j.bbmt.2009.07.004
Mishra A, Tamari R, DeZern AE, et al. Eprenetapopt plus Azacitidine after allogeneic hematopoietic stem‐cell transplantation for TP53‐mutant acute myeloid leukemia and myelodysplastic syndromes. J Clin Oncol. 2022;40(34):3985‐3993. doi:10.1200/JCO.22.00181
Zhu H, Gao H, Ji Y, et al. Targeting p53‐MDM2 interaction by small‐molecule inhibitors: learning from MDM2 inhibitors in clinical trials. J Hematol Oncol. 2022;15(1):91. doi:10.1186/s13045‐022‐01314‐3
Garcia‐Manero G, Daver NG, Xu J, et al. Magrolimab plus azacitidine versus azacitidine plus placebo in untreated higher risk (HR) myelodysplastic syndrome (MDS): the phase 3, randomized, ENHANCE study. J Clin Oncol. 2021;39(15):1‐12.
Zeidan AM, DeZern AE, Borate U, et al. Stimulus MDS‐US trial in progress: evaluating Sabatolimab in combination with hypomethylating agents (HMAs) in patients with intermediate‐, high‐, or very high‐risk myelodysplastic syndrome (MDS). Blood. 2022;140:4069‐4070.
Ades L, Girshova L, Doronin VA, et al. Pevonedistat plus azacitidine vs azacitidine alone in higher‐risk MDS/chronic myelomonocytic leukemia or low‐blast‐percentage AML. Blood Adv. 2022;6(17):5132‐5145. doi:10.1182/bloodadvances.2022007334
Issa GC, Aldoss I, DiPersio J, et al. The menin inhibitor revumenib in KMT2A‐rearranged or NPM1‐mutant leukaemia. Nature. 2023;615(7954):920‐924. doi:10.1038/s41586‐023‐05812‐3
Badar T, Manna A, Gadd ME, Kharfan‐Dabaja MA, Qin H. Prospect of CAR T‐cell therapy in acute myeloid leukemia. Expert Opin Investig Drugs. 2022;31(2):211‐220. doi:10.1080/13543784.2022.2032642
Uy GL, Aldoss I, Foster MC, et al. Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia. Blood. 2021;137(6):751‐762. doi:10.1182/blood.2020007732
Sabapathy K, Lane DP. Therapeutic targeting of p53: all mutants are equal, but some mutants are more equal than others. Nat Rev Clin Oncol. 2018;15(1):13‐30. doi:10.1038/nrclinonc.2017.151
Yoshida S, Onozawa M, Miyashita N, et al. Clinical features of complex karyotype in newly diagnosed acute myeloid leukemia. Int J Hematol. 2023;117(4):544‐552.
Agarwal P, Moshier E, Ru M, et al. Immortal time bias in observational studies of time‐to‐event outcomes: assessing effects of postmastectomy radiation therapy using the National Cancer Database. Cancer Control. 2018;25(1):1‐7. doi:10.1177/1073274818789355
Short NJ, Montalban‐Bravo G, Hwang H, et al. Prognostic and therapeutic impacts of mutant TP53 variant allelic frequency in newly diagnosed acute myeloid leukemia. Blood Adv. 2020;4(22):5681‐5689. doi:10.1182/bloodadvances.2020003120
Chan O, Hunter A, Talati C, et al. Impact of TP53 gene mutation clearance and conditioning intensity on outcome in MDS or AML patients prior to allogeneic stem cell transplantation. Blood. 2019;134:149.