Frontline Treatment of CD30+ Peripheral T-Cell Lymphomas with Brentuximab Vedotin in Combination with CHP: 3-Year Durability and Survival Follow-up

Background: Peripheral T-cell lymphomas (PTCL) encompass a subset of aggressive non-Hodgkin lymphomas.  Many PTCL tumor cells express the surface marker CD30, including systemic anaplastic large cell lymphoma (ALCL) where CD30 is uniformly expressed.  Multi-agent chemotherapy regimens provide inadequate long-term outcomes: complete remission (CR) rates range from 39-53% and 5-year overall survival (OS) rates are 12-49%, depending on subtype.  Three-year progression-free survival (PFS) and OS rates are approximately 30% and <40% (excluding anaplastic lymphoma kinase [ALK] -positive), respectively (Vose 2008; Reimer 2009; D'Amore 2012).  A phase 1 trial evaluated brentuximab vedotin (ADCETRIS^®; BV), a CD30-directed antibody-drug conjugate, in sequence with CHOP or in combination with CHP (CHOP without vincristine) in treatment-naive pts with PTCL, including systemic ALCL (Fanale 2014; ClinicalTrials.gov NCT01309789).   We are presenting updated durability data and peripheral neuropathy resolution from the combination-therapy arm of this trial.

Methods: The analysis set consisted of patients who received the combination treatment (tx) regimen (BV+CHP; 6 cycles, q3wk, IV).  Patients who achieved at least a partial remission (PR) following BV + CHP could subsequently receive up to 10 additional cycles of single-agent BV (1.8 mg/kg q3wk).  ALK+ systemic ALCL pts must have had an International Prognostic Index (IPI) score ≥2.  Antitumor response assessments were per investigator according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007).  Efficacy endpoints included PFS and OS, which were estimated using Kaplan-Meier methodology.

Results:  Twenty-six pts received BV + CHP combination treatment.  Diagnoses included systemic ALCL (n=19; 3ALK+, 16 ALK-), peripheral T-cell lymphoma-NOS (n=2), angioimmunoblastic T-cell lymphoma (n=2), adult T-cell leukemia/lymphoma (n=2), and enteropathy-associated T-cell lymphoma (n=1).  The objective response rate to tx was 100% and CR rate was 88%.  Treatment-emergent adverse events (TEAEs) with a severity of at least Grade 3 (≥10% incidence) were febrile neutropenia, neutropenia, anemia and pulmonary embolism with 73% reporting any grade peripheral neuropathy. 

At the time of this analysis, 20 pts remained on study for long term follow-up (LTFU).  The median observation  time from first dose was 38.7 months (range, 4.6 to 44.3).  The 3‑year OS rate was 80% (95% CI: 59, 91 months) and the median PFS was not reached (95% CI: 12.3, -).  Twenty one pts received a median of 10 doses (range, 1 to 10) of BV post BV-CHP.  Nine/19 (47%) ALCL and 5/7 (71%) non-ALCL pts have not experienced disease progression or death.  A Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) was performed for peripheral neuropathy (PN).  Eighteen of 19 (95%) patients who received combination therapy experienced either complete resolution (n=7, 37%) or improvement by at least 1 grade level (n=11, 58%) in neuropathy symptoms.  There were a total of 44 PN events of which 23 (52%) resolved and 14 (32%) improved.  Five pts (19%) who experienced disease progression after completing treatment received subsequent treatment with BV in LTFU, and 3 patients received stem cell transplants (1 autologous, 2 allogenic).  There were no patients who received a consolidative stem cell transplant in first remission.

Conclusions: Durable remissions were observed with BV in combination with CHP in newly diagnosed pts with PTCL.  After over 3 years of follow-up, clinical outcomes compare favorably with historical data in PTCL pts.  An ongoing randomized trial with 450 pts is comparing BV+CHP with CHOP for the frontline treatment of CD30+ PTCL (ClinicalTrials.gov NCT01777152).  Final results from this trial are expected in 2017 to 2018.

 

Progression-Free Survival: Brentuximab Vedotin in Combination with CHP