Abstract
BACKGROUND CAR T-cell therapy is now the standard salvage therapy for relapsed/refractory DLBCL (R/R DLBCL), but approximately 50-60% of patients do not respond to CAR T-cell therapy or relapse after CAR T-cell therapy. The tumor biology characteristics of DLBCL that are detrimental to CAR T-cell therapy are currently unclear and remain to be explored. High-grade B-cell lymphomas with MYC abnormalities and DLBCL with TP53 abnormalities are resistant to conventional chemotherapy and have a poor prognosis.However, whether MYC and/or TP53 abnormalities represent a potential resistance mechanism for CAR T-cell therapy is still controversial.
METHODS We conducted a retrospective analysis of patients with R/R DLBCL treated with CAR T-cells at our centre from January 1, 2018 to June 1, 2022. Prior to treatment with CAR T cells, 172 patients underwent MYC-FISH, P53-FISH and NGS test. FISH analysis was performed on FFPE sections to detect MYC rearrangement and P53 deletion. TP53 and MYC mutations were detected from pathological section by NGS through the Illumina NextSeq TM 550.
Of these patients, 172 cases had MYC and/or TP53 abnormalities. The mean age was 50 (13-86) years, 94/172(54.7%) patients were male.The 172 DLBCL patients were divided into four groups: the double-negative (DN) group for MYC (-)/TP53(-), the MYC (M) group for MYC (+)/TP53-; the T53(T) group for MYC (-)/TP53(+),and the double-positive (DP) group for MYC (+)/TP53(+).
The efficacy was assessed 3 months after CAR T-cell infusion by PET/CT. Statistical analysis of the 3-month assessment was measured by efficacy (3-month rate CR and 3-month ORR). The primary end points were PFS and OS. PFS was defined as the time from randomization to disease stabilisation or progression at or after month 3 assessment or death.
RESULTS Of the 172 patients, the DN group accounted for 78/172 (45.3%) cases and 21/172 (12.2%) belonged to the M group; 58/172 (33.7%) cases in the T group and 15/172 (8.7%) cases in the DP group. There was no difference in the median age of the patients in the four groups(P=0.9528). Patients in the four groups were DN 44/78 (56.4%), M 11/21 (52.4%), T 32/58 (55.2%) and DP 7/15 (46.7%) according to Ann Arbor classification as stage III /IV, respectively (p=0.9122). International Prognostic Index (IPI) scores ≥3 in the four groups were DN 49/78 (62.8%), M 16/21 (76.2%), T 43/58 (74.1%) and DP 14/15 (93.3%) respectively (P=0.0831). The median number of treatment lines and other disease characteristics were balanced between treatment groups.
The ORR at 3 months after CAR T-cell therapy was 61.54% in the DN group, including a CR rate of 32.05%; the ORR rate and CR in the M group were 38.10% and 23.81%, respectively; the ORR and CR in the T group were 51.72% and 17.24%, respectively; and the ORR and CR in the DP group were 33.33% and 13.33%, respectively. There was no significant difference in ORR(P=0.0971) and CR(P=0.1776) among the four groups.
With a median follow-up of 18.73 months (95% CI: 17.13-20.12), the median PFS was 4.87 months, and the median OS was not reached in the DN group. The median PFS and OS were 3.02 months and 9.67 months in the M group and 5.72 months and 14.24 months in the T group, respectively. The median PFS and OS in the DP group were 2.79 months and 4.70 months, respectively, and were significantly lower than those in the DN group (OS P=0.0042, PFS P=0.0342) and the T group (OS P=0.0352, PFS P=0.0423). Fig. A shows the survival probability after treatment.
CONCLUSIONS Our data suggest that CAR T-cell therapy may still be an effective option for R/R DLBCL patients with MYC or TP53 abnormalities alone. However, the poor clinical outcomes in patients with both MYC and TP53 abnormalities call for potential therapeutic strategies.
KeyWords：relapsed/refractory DLBCL,MYC,TP53 ,CAR T-cell therapy
Disclosures
No relevant conflicts of interest to declare.
