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. 2025 May 13;9(9):2159-2172.
doi: 10.1182/bloodadvances.2024014986.

TP53 mutations are associated with CD19- relapse and inferior outcomes after blinatumomab in adults with ALL

Ibrahim Aldoss  1 , Shanpeng Li  2 , Jianying Zhang  2 , Mary C Clark  1 , Vaibhav Agrawal  1 , Hoda Pourhassan  1 , Paul Koller  1 , Ahmed Aribi  1 , Haris Ali  1 , Amanda Blackmon  1 , Salman Otoukesh  1 , Karamjeet Sandhu  1 , Brian Ball  1 , Shukaib Arslan  1 , Andrew Artz  1 , Idoroenyi Amanam  1 , Monzr M Al Malki  1 , Amandeep Salhotra  1 , Tibor Kovacsovics  3 , Lindsey Murphy  4 , Michelle Afkhami  5 , Dat Ngo  6 , Jose Tinajero  6 , Zhaohui Gu  2 , Pamela S Becker  1 , Ryotaro Nakamura  1 , Anthony Stein  1 , Guido Marcucci  1 , Stephen J Forman  1 , Vinod Pullarkat  1
Affiliations

TP53 mutations are associated with CD19- relapse and inferior outcomes after blinatumomab in adults with ALL

Ibrahim Aldoss et al. Blood Adv. .

Abstract

Despite the success of the CD19 × CD3 T-cell engager blinatumomab in B-cell acute lymphoblastic leukemia (B-ALL), treatment failure is common and can manifest with antigen loss and extramedullary disease (EMD) relapse. To understand the impact of leukemia genetics on outcomes, we reviewed 267 adult patients with B-ALL treated with blinatumomab and used next-generation sequencing to identify molecular alterations. Patients received blinatumomab for relapsed/refractory (R/R) disease (n = 150) and minimal residual disease (MRD; n = 88), upfront as induction (n = 10) or as consolidation in MRD-negative state (n = 19). In the overall cohort, 50 patients (19%) had Philadelphia chromosome (Ph)-positive ALL, 80 (30%) had Ph-like ALL, 35 (13%) had TP53 mutations (TP53m), 7 (3%) had KMT2A rearrangement, and 8 (3%) had PAX5 alterations. For patients treated for R/R ALL, the overall complete remission (CR)/CR with incomplete hematological recovery (CRi) rate was 59%. Only pretreatment high disease burden (P < .01) and active EMD (P < .01) were associated with inferior CR/CRi rate. Of 169 patients in CR/CRi after blinatumomab, 79 (47%) patients relapsed, including 22 (28%) with CD19- and 54 (68%) with CD19+ relapse. In multivariable analysis, TP53m was associated with an increased risk of CD19- relapse (hazard ratio [HR], 6.84; 95% confidence interval [CI], 2.68-17.45; P < .01). Post-blinatumomab allogeneic stem cell transplantation consolidation was associated with a lower risk of CD19- relapse (HR, 0.10; 95% CI, 0.03-0.37; P < .01) and EMD relapse (HR, 0.36; 95% CI, 0.18-0.73; P < .01). In conclusion, leukemia genetics may predict patterns of blinatumomab failure, with TP53m associated with CD19- relapse.

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Conflict of interest statement

Conflict-of-interest disclosure: I. Aldoss reports advisory board fees from Amgen, Kite, Pfizer, Jazz, AbbVie, Adaptive, Takeda, Syndax, and Agios; consulting fees from Pfizer, Takeda, Jazz, and Amgen; and research support from AbbVie, MacroGenics, and Jazz. M.M.A.M. reports advisory board fees from Hansa Biopharma, Stemline Therapeutics, Gilead, and Incyte; consultant fees from NexImmune, TScan, Tr1X, and CareDx; and research funding from NexImmune, Gilead, Miltenyi Biotec, and Incyte. L.M. reports advisory board fees from Jazz. A. Stein is a member of the speakers’ bureau for Amgen. G.M. is a member of the speakers’ bureau for AbbVie. V.P. has served on the advisory boards for AbbVie and Jazz Pharmaceuticals, and is a member of the speakers’ bureaus for Jazz Pharmaceuticals, Amgen, Novartis, and AbbVie. P.K. reports advisory board/consulting fees from Ascentage, Daiichi Sankyo, Bristol Myers Squibb, Novartis, and Takeda, and has served on the safety review committee with Treadwell Therapeutics. P.S.B. reports institutional research funding from GPCR Therapeutics; has served on the scientific advisory board for Patient Advocate Foundation; and has served on the medical advisory board for the AAMDS International Foundation. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Oncoprint for responders and patterns of CD19 relapse. The cohort of patients in this analysis were grouped by genetic subtype as well as response and patterns of relapse (CD19+/−).
Figure 2.
Figure 2.
Probability of LFS after blinatumomab therapy. (A-D) Kaplan Meier estimator of LFS across all genetic subgroups (A); NOS, Ph+, and Ph-like B-ALL subtypes (B); TP53m vs non-TP53m (C); and Ph-like patients treated for R/R vs MRD positivity (D).
Figure 2.
Figure 2.
Probability of LFS after blinatumomab therapy. (A-D) Kaplan Meier estimator of LFS across all genetic subgroups (A); NOS, Ph+, and Ph-like B-ALL subtypes (B); TP53m vs non-TP53m (C); and Ph-like patients treated for R/R vs MRD positivity (D).
Figure 3.
Figure 3.
Probability of OS after blinatumomab therapy from the date of relapse. Kaplan-Meier estimator of OS by CD19 status (A) and EMD relapse (B).
See this image and copyright information in PMC

References

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