Efficacy and Safety of CHO(E)P Plus Novel Agents in Treatment-Naïve Peripheral T-Cell Lymphoma: Systemic Review and Meta-Analyses

Introduction:

Standard cyclophosphamide-doxorubicin-vincristine-prednisone therapy with or without etoposide (CHO(E)P) results in sub-optimal outcomes for peripheral T-cell lymphoma (PTCL) with 2-year progression-free survival (PFS) rates <40% (Maurer et al 2017, Bachy et al 2022, Horwitz et al 2021). Recent genomic sequencing has enabled a deeper understanding of the T-cell epigenome and molecular landscape, potentially leading to a more tailored first-line treatment option. We conducted a systemic review/meta-analysis investigating the efficacy and safety of adding novel agents to CHO(E)P (CHOPX) therapy in PTCL.

Methods:

MEDLINE, Embase, Cochrane databases and international conference proceedings were searched from January 2010 to December 2023. Prospective clinical studies evaluating and reporting the efficacy of CHOPX in treatment-naïve PTCL were included. Included trials were appraised by three reviewers and data was reviewed. Primary outcomes included disease control as estimated with pooled overall response rates (ORR) and complete response (CR) rates. Secondary outcomes included 2-year (y) PFS, overall survival (2-y OS) rates, and grade 3 or worse hematologic adverse events (AEs). The meta-analysis was conducted using a random-effects model due to the potential heterogeneity among studies.

Results:

Twelve abstracts and 18 full-text articles enrolling 2210 PTCL patients were included in the pooled analysis. Of these patients, 70% (n=1548) received CHOPX therapy. The different types of additional novel therapy included epigenetic modulators (50%, n=774, 14 trials), Brentuximab Vedotin (BV) (24.6%, n=381, 5 trials), Alemtuzumab (9.2%, n=143, 3 trials) and others (16.1%, n=250, 5 trials).

PTCL-subtypes represented were Angioimmunoblastic T-cell lymphoma (AITL, n=590, 39%), PTCL-Not Otherwise Specified (PTCL-NOS, n=439, 29%) and Anaplastic Large-Cell Lymphoma (ALCL, n=369, 24%). Baseline characteristics of CHOPX cohort included 65% being males (n=812), 84% with Stage III/IV (n=1139) and 73% with an IPI-score of ≥ 2 (n=1221).

For efficacy analysis, the pooled ORR 76% [95% confidence Interval (CI) 71-81%, I²=71%, 1474 patients (pts), 28 trials] and CR 55% [95% CI 49-61%, I²=71%, 1470 pts, 27 trials] rates of the CHOPX cohort at end of treatment indicated a favorable trend. The CR and rates for CHOPX patients treated with epigenetic modulators and BV combinations were 55% [95% CI 41-69%, I²= 92%,641 pts, 10 trials] and 82% [95% CI 55-100%, I²=97%, 252 pts, 2 trials]. The cumulative pooled 2-y PFS and OS rates for CHOPX therapies were 43% [95% CI 38-47%, I²=46%, 608 pts, 10 trials] and 63% [95% CI 59-67%, I²=10%, 706 pts, 12 trials]. The 2-y PFS rates for CHOPX patients treated with epigenetic modulators were 48% [95% CI 38-59%, I²=69%, 504 pts, 7 trials]. The 2y-PFS were with epigenetic modulators were relatively higher in the AITL cohort.

Regarding safety data, 26 trials provided safety data (n=1371). The rates of severe anemia 21% [95% CI 15-29%, I²=85%, 1287 pts, 24 trials], severe thrombocytopenia 24% [95% CI 18-32%, I²=79%, 963 pts, 21 trials] and severe neutropenia 54% [95% CI 45-63%, I²=83%,1161 pts, 22 trials] were similar to CHOP therapy.

Conclusion:

The use of novel agents in frontline PTCL therapy demonstrates a promising efficacy and safety trend compared with historical controls with CHO(E)P therapy. Our analysis was constrained by the inclusion of multiple smaller single-arm studies, which was necessary due to disease rarity and heterogeneity. Further cooperative efforts are needed to identify predictors of response and resistance associated with different novel agent classes targeting the molecular landscape.

No relevant conflicts of interest to declare.