Brentuximab vedotin plus chemotherapy for the treatment of frontline systemic anaplastic large cell lymphoma subgroup analysis of the ECHELON2 study at 5 years followup summary

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Britany: Welcome back to PACULit, your source for the latest clinical literature updates. Today, we’re discussing a pivotal 5-year subgroup analysis from the ECHELON-2 trial on frontline treatment for systemic anaplastic large cell lymphoma, or sALCL. Seth, this is a rare but aggressive peripheral T-cell lymphoma subtype, right?

Seth: Absolutely, Britany. sALCL is characterized by CD30 expression and has been treated with CHOP—cyclophosphamide, doxorubicin, vincristine, and prednisone. Outcomes have been suboptimal, with five-year overall survival around 50 to 60 percent. High relapse rates highlight the need for better frontline therapies.

Britany: That’s where ECHELON-2 comes in. The original study showed adding brentuximab vedotin to CHP chemotherapy—cyclophosphamide, doxorubicin, prednisone without vincristine—improved outcomes in CD30-positive peripheral T-cell lymphomas. But long-term data for the sALCL subgroup was limited until this recent five-year follow-up.

Seth: Exactly. This subgroup analysis by Domingo-Domènech and colleagues focuses on untreated, CD30-positive sALCL, including ALK-positive and ALK-negative subtypes. These patients often have aggressive disease and poor prognosis, so the data is highly relevant.

Britany: Let’s review the study design. ECHELON-2 was a phase three, randomized, double-blind, active-controlled trial. The subgroup analysis included sALCL patients from 452 adults with untreated CD30-positive peripheral T-cell lymphoma.

Seth: Inclusion criteria were adults eighteen or older with untreated CD30-positive PTCL, requiring at least ten percent CD30 expression. Diagnosis was confirmed by pathology, and patients had ECOG performance status zero to two. Exclusions included prior systemic chemotherapy or radiotherapy and significant comorbidities.

Britany: The intervention arm received brentuximab vedotin at 1.8 mg/kg IV plus CHP every three weeks for six to eight cycles. The comparator arm received standard CHOP on the same schedule.

Seth: The primary endpoint was progression-free survival, assessed by an independent review committee. Secondary endpoints included overall survival, complete response rate, safety, tolerability, and peripheral neuropathy incidence. Median follow-up was about five years, robust for a lymphoma trial.

Britany: Statistically, they used hazard ratios with 95% confidence intervals for time-to-event outcomes, Kaplan-Meier survival curves, and subgroup analyses by ALK status, age, and baseline factors. Safety was assessed by incidence and severity of adverse events graded by Common Terminology Criteria.

Seth: The median age was about 52 years, with balanced male and female distribution. Most had advanced-stage disease, stages three or four, consistent with aggressive sALCL.

Britany: Performance status was generally good, mostly ECOG zero to two. Significant comorbidities were exclusionary, so the trial population was relatively fit, important when interpreting tolerability.

Seth: Regarding safety, peripheral neuropathy was more common with brentuximab vedotin plus CHP—54% versus 32% with CHOP—but most cases were low grade and reversible.

Britany: That’s key. Monitoring neuropathy is essential, but most improved or resolved, supporting regimen safety. Also, febrile neutropenia was less frequent in the brentuximab arm—18% versus 31% with CHOP—which is somewhat surprising given the antibody-drug conjugate addition.

Seth: Indeed. This suggests brentuximab vedotin plus CHP may have a more favorable hematologic toxicity profile, possibly due to vincristine omission, which is known for neurotoxicity and myelosuppression.

Britany: On efficacy, median progression-free survival was not reached with brentuximab vedotin plus CHP, versus 29.4 months with CHOP. The hazard ratio was 0.71, p=0.011, indicating significant benefit.

Seth: Five-year overall survival was 70.1% with brentuximab vedotin plus CHP versus 60.9% with CHOP. Complete remission rates were higher—67% versus 50%. These are clinically meaningful improvements in a disease with poor outcomes.

Britany: The durability of response at five years confirms sustained benefit. This aligns with prior data from Pro et al. in 2019, which first showed superiority of this regimen in CD30-positive PTCL.

Seth: Real-world data from Sasaki et al. in Japan corroborate these findings, showing safety and durability of brentuximab vedotin plus CHP in frontline sALCL outside clinical trials.

Britany: A recent meta-analysis by Horwitz et al. further supports this regimen for improved long-term overall survival in CD30-positive lymphomas, reinforcing clinical relevance.

Seth: The National Comprehensive Cancer Network now recommends brentuximab vedotin plus CHP as a category one frontline treatment for sALCL, reflecting this evidence.

Britany: Mechanistically, brentuximab vedotin is an antibody-drug conjugate targeting CD30, delivering monomethyl auristatin E, a microtubule-disrupting agent, directly to malignant cells. This targeted approach likely improves efficacy and toxicity profile.

Seth: The dosing at 1.8 mg/kg every three weeks balances efficacy and safety. Monitoring for neuropathy and hematologic toxicity is essential, especially since vincristine is omitted to reduce overlapping neurotoxicity.

Britany: Drug interactions matter too. Brentuximab vedotin is metabolized via CYP3A4, so strong inhibitors or inducers could alter exposure. Clinicians should be cautious with azole antifungals or certain anticonvulsants.

Seth: Good point. Patients with hepatic impairment may need dose adjustments. The trial excluded those with significant comorbidities, so real-world use in frailer patients requires caution.

Britany: Another clinical pearl is the potential role of consolidative stem cell transplant after induction with brentuximab vedotin plus CHP in high-risk patients. While not extensively addressed in the trial, future research could clarify this.

Seth: Future studies should refine patient selection, optimize neuropathy management, and explore combination therapies to enhance outcomes.

Britany: To summarize, the five-year ECHELON-2 subgroup analysis confirms brentuximab vedotin plus CHP offers superior, durable progression-free and overall survival compared to CHOP in frontline sALCL.

Seth: The safety profile is manageable, with peripheral neuropathy as the main adverse event but mostly low grade and reversible. Febrile neutropenia rates were lower, which is encouraging.

Britany: This supports shifting clinical practice toward brentuximab vedotin plus CHP as the preferred first-line regimen for CD30-positive sALCL, improving long-term outcomes.

Seth: Absolutely. Staying current with these advances helps optimize therapy for this challenging lymphoma subtype.

Britany: Thanks for joining me today, Seth. And thank you to our listeners for tuning into PACULit. We’ll be back soon with more clinical literature updates.

Seth: Looking forward to it. Take care, everyone.