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.

Zanubrutinib plus salvage chemotherapy for relapsed or refractory diffuse large B-cell lymphoma

“…In a retrospective study, in R/R DLBCL patients not treated with CAR-T cells, TP53 mutation was an independent inferior prognostic factor for OS, but in the CAR-T cell group, this significance could not be shown ( 31 ). CAR19/22 T-cell therapy combined with ASCT is efficacious in r/r aggressive B-NHL with TP53 alterations, producing a best ORR and CRR of 92.9% and 82.1%, respectively ( 32 ). However, in another retrospective study, TP53 alterations (mutations and/or copy number alterations) were still associated with inferior CR and OS rates in R/R DLBCL treated with CD19-CAR-T treatment ( 33 ).…”

Combination strategies to optimize the efficacy of chimeric antigen receptor T cell therapy in haematological malignancies

“…The feasibility of CAR T cell therapy shortly following high-dose chemotherapy and ASCT (HDT-ASCT) has been confirmed in several clinical studies (Table 2). Wei et al compared CAR T cell infusion after ASCT and CAR T cells alone and demonstrated that the best ORR, CR rate and long-term outcomes improved significantly in the combination group (62). In another study comparing CAR T cell infusion after ASCT and ASCT alone, the combination group showed higher CR rate (71% vs. 33%; p=0.003) and 3year PFS (80% vs. 44%; p=0.036) than the ASCT group, and demonstrated lower 3 year relapse/progression rate (15% vs. 56%; p=0.015) (63).…”

“…The most common combination scheme is cocktail infusion of CD19/CD22 CAR T cells in B cell malignancies (Figure 4) (62,192). Wang et al administered CD19 CAR T and CD22 CAR T cells at Day 0 and Day 2, respectively, to B-ALL and B-NHL patients.…”

“…CD19/CD22 CAR T cell cocktail therapy is also promising in improving the outcome of B cell malignancies with the TP53 mutation, which confers a higher rate of CD19-negative relapse and poor prognosis (56,193). The optimal ORR of 32 TP53-mutated lymphoma patients who received cocktail therapy was similar to that of 34 lymphoma patients without the mutation (87.1% vs. 88.2%, P=0.927) (62). In terms of R/R MM, CD19/BCMA CAR T cell cocktail therapy was designed to extend the target range, covering a proportion of CD19-positive myeloma-like stem cells with drug resistance and propagating characteristics (194).…”

Clinical Strategies for Enhancing the Efficacy of CAR T-Cell Therapy for Hematological Malignancies

“…After determining that a patient is suitable for CAR T-cell therapy, it is necessary to determine the lymphatic clearance scheme and dosing strategy according to the patient’s basic condition, to help the patient obtain the best blood environment and maximize the utilization of CAR T-cells [ 17 ]. Furthermore, for refractory and relapsed hematological malignancies, the combined application of multiple treatments may lead to longer event-free survival for patients [ 18 , 19 ]. The implementation of combined strategies to increase the persistence or antitumor activity of CAR T-cells has become a research hotspot.…”