Combinational therapy of CAR T-cell and HDT/ASCT demonstrates impressive clinical efficacy and improved CAR T-cell behavior in relapsed/refractory large B-cell lymphoma.

BACKGROUND: Approximately two-thirds of patients with relapsed or refractory large B-cell lymphoma (R/R LBCL) do not respond to or relapse after anti-CD19 chimeric antigen receptor T (CAR T)-cell therapy, leading to poor outcomes. Previous studies have suggested that intensified lymphodepletion and hematological stem cell infusion can promote adoptively transferred T-cell expansion, enhancing antitumor effects. Therefore, we conducted a phase I/II clinical trial in which CNCT19 (an anti-CD19 CAR T-cell) was administered after myeloablative high-dose chemotherapy and autologous stem cell transplantation (HDT/ASCT) in patients with R/R LBCL. METHODS: Transplant-eligible patients with LBCL who were refractory to first-line immunochemotherapy or experiencing R/R status after salvage chemotherapy were enrolled. The study aimed to evaluate the safety and efficacy of this combinational therapy. Additionally, frozen peripheral blood mononuclear cell samples from this trial and CNCT19 monotherapy studies for R/R LBCL were used to evaluate the impact of the combination therapy on the in vivo behavior of CNCT19 cells. RESULTS: A total of 25 patients with R/R LBCL were enrolled in this study. The overall response and complete response rates were 92.0% and 72.0%, respectively. The 2-year progression-free survival rate was 62.3%, and the overall survival was 68.5% after a median follow-up of 27.0 months. No unexpected toxicities were observed. All cases of cytokine release syndrome were of low grade. Two cases (8%) experienced grade 3 or higher CAR T-cell-related encephalopathy syndrome. The comparison of CNCT19 in vivo behavior showed that patients in the combinational therapy group exhibited enhanced in vivo expansion of CNCT19 cells and reduced long-term exhaustion formation, as opposed to those receiving CNCT19 monotherapy. CONCLUSIONS: The combinational therapy of HDT/ASCT and CNCT19 demonstrates impressive efficacy, improved CNCT19 behavior, and a favorable safety profile. TRIAL REGISTRATION NUMBERS: ChiCTR1900025419 and NCT04690192.

Dynamic monitoring of circulating tumor DNA reveals outcomes and genomic alterations in patients with relapsed or refractory large B-cell lymphoma undergoing CAR T-cell therapy.

BACKGROUND: Over 50% of patients with relapsed or refractory large B-cell lymphoma (r/r LBCL) receiving CD19-targeted chimeric antigen receptor (CAR19) T-cell therapy fail to achieve durable remission. Early identification of relapse or progression remains a significant challenge. In this study, we prospectively investigate the prognostic value of dynamic circulating tumor DNA (ctDNA) and track genetic evolution non-invasively, for the first time in an Asian population of r/r patients undergoing CAR19 T-cell therapy. METHODS: Longitudinal plasma samples were prospectively collected both before lymphodepletion and at multiple timepoints after CAR19 T-cell infusion. ctDNA was detected using a capture-based next-generation sequencing which has been validated in untreated LBCL. RESULTS: The study enrolled 23 patients with r/r LBCL and collected a total of 101 ctDNA samples. Higher pretreatment ctDNA levels were associated with inferior progression-free survival (PFS) (p=0.031) and overall survival (OS) (p=0.023). Patients with undetectable ctDNA negative (ctDNA-) at day 14 (D14) achieved an impressive 3-month complete response rate of 77.8% vs 22.2% (p=0.015) in patients with detectable ctDNA positive (ctDNA+), similar results observed for D28. CtDNA- at D28 predicted significantly longer 1-year PFS (90.9% vs 27.3%; p=0.004) and OS (90.9% vs 49.1%; p=0.003) compared with patients who remained ctDNA+. Notably, it is the first time to report that shorter ctDNA fragments (<170 base pairs) were significantly associated with poorer PFS (p=0.031 for D14; p=0.002 for D28) and OS (p=0.013 for D14; p=0.008 for D28) in patients with LBCL receiving CAR T-cell therapy. Multiple mutated genes exhibited an elevated prevalence among patients with progressive disease, including TP53, IGLL5, PIM1, BTG1, CD79B, GNA13, and P2RY8. Notably, we observed a significant correlation between IGLL5 mutation and inferior PFS (p=0.008) and OS (p=0.014). CONCLUSIONS: Our study highlights that dynamic ctDNA monitoring during CAR T-cell therapy can be a promising non-invasive method for early predicting treatment response and survival outcomes. Additionally, the ctDNA mutational profile provides novel insights into the mechanisms of tumor-intrinsic resistance to CAR19 T-cell therapy.

Gemcitabine-based conditioning compared to BEAM/BEAC conditioning prior to autologous stem cell transplantation for non-Hodgkin lymphoma: No difference in outcomes.

BACKGROUND: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) remains an effective treatment for non-Hodgkin lymphoma (NHL). The limited availability of carmustine has prompted the exploration of novel alternative conditioning regimens. This study aimed to compare the efficacy and safety profile of GBM/GBC (gemcitabine, busulfan, and melphalan or cyclophosphamide) conditioning compared with the standard BEAM/BEAC regimens (carmustine, etoposide, cytarabine, and melphalan or cyclophosphamide) for ASCT in patients with NHL. METHODS: A retrospective analysis was conducted on 231 NHL patients, who underwent ASCT from October 2010 to October 2021 at the Institute of Hematology & Blood Disease Hospital, including both first-line and salvage settings. This resulted in the inclusion of 112 patients in the GBM/GBC arm and 92 in the BEAM/BEAC arm. Propensity score matching was employed to validate the results. RESULTS: Disease subtype distribution was similar between the GBM/GBC and BEAM/BEAC groups, with diffuse large B-cell lymphoma being the most common (58.9% vs. 58.7%), followed by PTCL (17.0% vs. 18.5%) and MCL (14.3% vs. 14.1%). At 3 months post-ASCT, complete response (CR) rates were comparable (GBM/GBC 93.5% vs. BEAM/BEAC 91.1%; p = 0.607). The 4-year progression-free survival (78.4% vs. 82.3%; p = 0.455) and 4-year overall survival (88.1% vs. 87.7%; p = 0.575) were also similar. Both groups exhibited low non-relapse mortality at 4 years (GBM/GBC 1.8% vs. BEAM/BEAC 3.5%; p = 0.790) with no transplant-related mortalities reported. The GBM/GBC cohort demonstrated a higher incidence of grade 3/4 oral mucositis and hepatic toxicity, whereas the BEAM/BEAC group had more frequent cases of bacteremia or sepsis (13 cases vs. 5 in GBM/GBC). CONCLUSIONS: The GBM/GBC regimen is effective and well-tolerated, offering outcomes that are highly comparable to those in NHL patients conditioned with BEAM/BEAC, as demonstrated in a prognostically matched cohort.