Trabolsi, Asaad

Abstract INTRODUCTION The ECHELON-2 trial for newly diagnosed CD30+ peripheral T-cell lymphomas (PTCL) demonstrated superior overall survival with brentuximab vedotin plus chemotherapy (BV-CHP) compared to CHOP. However, total enrollment was restricted to only 30% of patients with non-anaplastic large cell lymphoma (ALCL) histologies and was not powered to analyze survival benefits in this cohort. Thus, the benefit of BV-CHP in non-ALCL patients remains less clear. Adding to this uncertainty, CHOP plus etoposide (CHOEP) remains a standard regimen for many non-ALCL PTCL histologies for patients <60 years of age. Which of these three regimens offers superior outcomes for patients with CD30+ non-ALCL PTCL remains to be determined, is a critical knowledge gap in this area, and could meaningfully inform the management of these patients. METHODS We conducted a retrospective analysis of chemotherapy-naïve CD30+ (≥1%) PTCL from 7 centers in the United States. Histologies were limited to PTCL-NOS and PTCL with a T follicular helper phenotype (PTCL-TFH). Frontline regimens were defined as BV-based (BV-CHP), etoposide-based (CHOEP/EPOCH), novel-CHOP (CHOP/CHOEP + novel drug on a clinical trial), or CHOP. CD30 was considered positive if any expression was reported, and when available, stratified as ≥10% or <10% of the total lymphocyte population. RESULTS The CD30+ PTCL cohort consisted of 194 patients with a median age of 68 years at diagnosis and a male (65%) predominance. Nodal PTCL-TFH (65%) was the most common histology. Most had stage III-IV disease (89%) with a high-intermediate to high-risk IPI score of 3-5 (54%). 18% had an ECOG of ≥2, 45% had ≥2 extranodal sites, and 43% had bone marrow involvement, although biopsies were not performed in all patients. CD30 expression in ≥10% of malignant T cells was observed in 55% of all quantitatively reported cases. Frontline therapy consisted of BV-based (36%), etoposide-based (30%), CHOP (27%), and novel-CHOP (7%). Baseline characteristics and CD30 expression were similar between treatment groups. The ORR was 72% (64% CR, 8% PR), with no differences observed by treatment or histology. On multivariate analysis (MVA), a high LDH was associated with lower CR (OR 2.84, p=0.003). For the patients who demonstrated a CR to frontline therapy, 61% underwent ASCT. With a median follow-up of 26.1 months (IQR 12.3-51.6), the median PFS and OS were 11.4 (9.8-14.2) and 47 (32-60.3) months, respectively. The 2-year PFS and OS were 34.9% (28.1-41.7) and 62% (54.5-68.6), respectively. PFS and OS were similar for PTCL-NOS compared to PTCL-TFH, and AITL fared similarly to non-AITL PTCL-TFH. By treatment, novel-CHOP demonstrated the most favorable PFS (median 41.9 months) and OS (median 68.1 months). Survival curves overlapped continuously with all other treatment regimens and was not statistically significant. For patients <60, PFS and OS were equivocal with BV-based (n=17) compared to etoposide-based (n=26) regimens. On MVA, stage III/IV disease conferred an inferior PFS (HR 2.00, p=0.018) as did an IPI score of 3-5 for OS (HR 2.15, p=0.001). Neither histology nor frontline treatment impacted PFS or OS. The chosen frontline treatment also had no survival impact in key subgroup analyses including patients <60 (n=56) or with CD30-expression ≥10% (n=43). For patients with CR to frontline therapy, ASCT demonstrated a significant PFS benefit (HR 0.59, p=0.028) but no statistically significant difference in OS benefit (HR 0.58, p=0.073). CONCLUSION These data provide valuable insight into the lesser-represented patient population from the pivotal ECHELON-2 trial. In this cohort of CD30+ (≥1%) non-ALCL PTCL, there was no clearly superior standard frontline regimen. The number of patients with quantitively reported CD30 expression was too small for definitive conclusions in the ≥10% CD30+ cohort and retrospective pathology review is ongoing. ASCT for patients in CR offered superior outcomes, supporting this strategy regardless of the frontline regimen, recognizing the limitations of non-randomized, retrospective analyses. Novel-CHOP regimens demonstrated encouraging survival, and clinical trials should maintain priority over standard regimens for patients with CD30+ (1-10%) PTCL-NOS and PTCL-TFH.

AbstractCheckpoint inhibitor (CPI) therapy with anti–PD-1 antibodies has been associated with mixed outcomes in small cohorts of patients with relapsed aggressive B-cell lymphomas after CAR-T failure. To define CPI therapy efficacy more definitively in this population, we retrospectively evaluated clinical outcomes in a large cohort of 96 patients with aggressive B-cell lymphomas receiving CPI therapy after CAR-T failure across 15 US academic centers. Most patients (53%) had diffuse large B-cell lymphoma, were treated with axicabtagene ciloleucel (53%), relapsed early (≤180 days) after CAR-T (83%), and received pembrolizumab (49%) or nivolumab (43%). CPI therapy was associated with an overall response rate of 19% and a complete response rate of 10%. Median duration of response was 221 days. Median progression-free survival (PFS) and overall survival (OS) were 54 and 159 days, respectively. Outcomes to CPI therapy were significantly improved in patients with primary mediastinal B-cell lymphoma. PFS (128 vs 51 days) and OS (387 vs 131 days) were significantly longer in patients with late (>180 days) vs early (≤180 days) relapse after CAR-T. Grade ≥3 adverse events occurred in 19% of patients treated with CPI. Most patients (83%) died, commonly because of progressive disease. Only 5% had durable responses to CPI therapy. In the largest cohort of patients with aggressive B-cell lymphoma treated with CPI therapy after CAR-T relapse, our results reveal poor outcomes, particularly among those relapsing early after CAR-T. In conclusion, CPI therapy is not an effective salvage strategy for most patients after CAR-T, where alternative approaches are needed to improve post–CAR-T outcomes.