Outcome of aggressive B-cell lymphoma with TP53 alterations administered with CAR T-cell cocktail alone or in combination with ASCT

Abstract

TP53 gene alteration confers inferior prognosis in refractory/relapse aggressive B-cell non-Hodgkin lymphoma (r/r B-NHL). From September 2016 to September 2020, 257 r/r B-NHL patients were assessed for eligibility for two trials in our center, assessing anti-CD19 and anti-CD22 chimeric antigen receptor (CAR19/22) T-cell cocktail treatment alone or in combination with autologous stem cell transplantation (ASCT). TP53 alterations were screened in 123 enrolled patients and confirmed in 60. CAR19/22 T-cell administration resulted in best objective (ORR) and complete (CRR) response rate of 87.1% and 45.2% in patients with TP53 alterations, respectively. Following a median follow-up of 16.7 months, median progression-free survival (PFS) was 14.8 months, and 24-month overall survival (OS) was estimated at 56.3%. Comparable ORR, PFS, and OS were determined in individuals with or without TP53 alterations, and in individuals at different risk levels based on functional stratification of TP53 alterations. CAR19/22 T-cell treatment in combination with ASCT resulted in higher ORR, CRR, PFS, and OS, but reduced occurrence of severe CRS in this patient population, even in individuals showing stable or progressive disease before transplantation. The best ORR and CRR in patients with TP53 alterations were 92.9% and 82.1%, respectively. Following a median follow-up of 21.2 months, 24-month PFS and OS rates in patients with TP53 alterations were estimated at 77.5% and 89.3%, respectively. In multivariable analysis, this combination strategy predicted improved OS. In conclusion, CAR19/22 T-cell therapy is efficacious in r/r aggressive B-NHL with TP53 alterations. Combining CAR-T cell administration with ASCT further improves long-term outcome of these patients.

Fig. 1

Mutational profile of TP53 alterations. a Heatmap showing individual non-synonymous somatic mutations found in individuals administered CAR-T cell infusion (n = 60). Each row represents one type of TP53 alterations, and each column represents a patient with R/R B-NHL. The horizonal bar graph shows gene mutation frequencies. b Venn diagram demonstrates different TP53 alterations identified in 60 cases. Totally 42 (70.0%) individuals harbored TP53 mutation(s) or sole del(17p), with 27 (45.0%) and 15 (25.0%) showing TP53 mutation(s) and deletions, respectively. The remaining 18 (30.0%) cases had biallelic TP53 aberrations (TP53 mutation and del(17p) in the first and second alleles, respectively). c TP53 mutations are plotted above the protein divided into the main domains. Among the 51 mutations identified, 37 were missense mutations (yellow), 6 were splice-site mutations (blue), 4 were nonsense mutations (red), 3 were frameshift insertions or deletions (indels; purple), and 1 was a non-frameshift indel (green). Recurrent mutations were identified in 3 codons, including R273 (n = 6), R248 (n = 4) and R175 (n = 3). The x-axis indicates the amino acid position

Fig. 2

Outcomes of r/r aggressive B-cell lymphoma cases according to TP53 alteration status after CAR19/22 T-cell infusion. a Best responses in r/r aggressive B-cell lymphoma cases with or without TP53 alterations. Kaplan–Meier analysis of DOR (b), PFS (c), and OS (d) in r/r aggressive B-cell lymphoma cases on the basis of TP53 alteration status. ORR, objective response rate; OR objective response; CR complete response; PR partial response; SD stable disease; DOR duration of response; W/O without

Fig. 3

Outcomes of r/r aggressive B-cell cases stratified by four functional classification systems of TP53 alterations after CAR19/22 T-cell infusion. In individuals with r/r aggressive B-cell lymphoma and concurrent TP53 mutations, PFS (a, c and e) and OS (b, d, and f) were compared according to functional classifications of TP53 mutations. Kaplan–Meier analysis of PFS (a) and OS (b) for the non-missense and missense mutation groups. Kaplan–Meier analysis of PFS (c) and OS (d) for the non-disruptive and disruptive mutation groups. Kaplan–Meier analysis of PFS (e) and OS (f) for EAp53 low-risk (<75) and EAp53 high-risk (≥75) mutation groups. Kaplan–Meier analysis of PFS (g) and OS (h) in the del(17p) and non-del(17p) groups

Fig. 4

Outcomes of r/r aggressive B-cell lymphoma cases with concurrent TP53 alterations after CAR19/22 T-cell infusion alone or combined with ASCT. a Best responses after CAR19/22 T-cell infusion alone or combined with ASCT. Kaplan-Meier analysis of DOR (b), PFS (c), and OS (d) is shown

Fig. 5

Outcomes of r/r aggressive B-cell lymphoma cases based on TP53 alteration status after ASCT combined with CAR19/22 T-cell infusion. a Best responses in r/r aggressive B-cell lymphoma cases with or without TP53 alterations. Kaplan–Meier analysis of DOR (b), PFS (c), and OS (d) is shown. ORR objective response rate; OR objective response; CR complete response; PR partial response; SD stable disease; DOR duration of response; W/O without