Brentuximab Vedotin Plus R-CHP a Frontline Treatment Option for Patients with NHL Subtypes

The CD30-directed immunoconjugate brentuximab vedotin has demonstrated efficacy in Hodgkin lymphoma (HL) and other T-cell lymphomas. According to research presented at the 2017 ASH Annual Meeting, brentuximab vedotin could represent a frontline option for this patient population.

In an open-label, multicenter, phase I/II study, all patients with CD30-positive B-cell non-Hodgkin lymphoma (NHL) responded to frontline treatment with brentuximab vedotin plus R-CHP (rituximab, cyclophosphamide, doxorubicin, prednisone). This included 25 patients (86%) who had a complete response (CR; 95% CI 72-98; overall response rate [ORR] and CR were primary endpoints of phase II), reported lead author Jakub Svoboda, MD, of the Lymphoma Program at Penn Medicine’s Abramson Cancer Center in Philadelphia, and colleagues.

The trial enrolled 33 treatment-naïve patients from three centers between January 2014 and June 2017. Patients had any Ann Arbor stage disease and at least equivocal CD30 expression on immunohistochemistry.

Phase I of the study used a 3+3 dose de-escalation design, with a starting dose of brentuximab vedotin 1.8 mg/kg, which was administered concurrently with R-CHP once every three weeks for a total of six cycles:

  • brentuximab vedotin 1.2 mg/kg or 1.8 mg/kg on day 2 of cycle 1, and day 1 of cycles 2-6
  • rituximab 375 mg/m2
  • cyclophosphamide 750 mg/m2
  • doxorubicin 50 mg/m2
  • prednisone 100 mg

Use of granulocyte-stimulating factor was permitted per institutional practice, and consolidative radiation after post-treatment imaging was administered at physician’s discretion.

One patient was re-classified from grey zone lymphoma (GZL) to HL prior to starting therapy and another patient withdrew consent. Of the remaining 31 patients, 23 (74%) had primary mediastinal large B-cell lymphoma (PMBCL), six (19%) had diffuse large B-cell lymphoma, and two (7%) had GZL. The median patient age was 37 years (range = 18-76 years), 74 percent (n=23) had bulky disease (≥7.5 cm in diameter), and 35 percent (n=11) had stage III/IV disease.

No treatment-related deaths occurred. One patient discontinued treatment after concurrent grade 3 sepsis and left ventricular (LV) systolic dysfunction after cycle four. Another patient discontinued treatment because of grade 2 pneumonitis during cycle five that was deemed “possibly related to brentuximab vedotin.”

Two patients receiving brentuximab vedotin 1.2 mg/kg required dose reductions because of sensory neuropathy. The most common grade 3/4 adverse events (AEs) included febrile neutropenia (n=4) and afebrile neutropenia (n=8). Grade 3 non-hematologic AEs that were “possibly related” to treatment included nausea/vomiting (n=1; 3%) and sepsis with LV systolic dysfunction (n=1; 3%). The most common grade 2 non-hematologic AEs were nausea (16%), sensory neuropathy (13%), diarrhea (10%), motor neuropathy (6%), and anorexia (6%). One patient who had a family history of acute myeloid leukemia (AML) developed AML two years after completion of chemotherapy and is in remission following allogeneic hematopoietic cell transplantation.

No dose-limiting toxicities (primary endpoint of phase I; defined as any grade 3/4 non-hematologic toxicity observed in cycle 1 requiring a dose delay >14 days from the planned day 1 of cycle 2) occurred. Given these results, the researchers selected the 1.8 mg/kg dose for phase II.

After a median follow-up of 15 months (range = 5-36 months), the ORR for 29 evaluable patients was 100 percent. Response rates by disease subtype are presented in the TABLE.

The median progression-free survival (PFS) and overall survival (OS; both secondary endpoints of phase II) were not reached for those still alive at assessment. Among the full patient cohort, one-year PFS was 86 percent (95% CI 63-95) and one-year OS was 100 percent.

The clinical benefit appeared to be highest in the PMBCL cohort: Median PFS was not reached, and one-year PFS was 87 percent (95% CI 57-97). Patients with stage I/II PMBCL (n=13) had a one-year PFS rate of 100 percent, while those with stage III/IV disease had a one-year PFS rate of 73 percent (95% CI 23-93). The authors also noted that PFS rates did not differ between those with PMBCL who received or did not receive radiation therapy (p=0.39).

The three patients who experienced disease progression had advanced-stage disease. One patient with GZL achieved CR after autologous HCT, and two patients with PMBCL have responded to immunotherapy after salvage chemotherapy failure.

These outcomes in the frontline setting “are encouraging and warrant further investigation, especially in patients with PMBCL,” the authors concluded.

The study is limited by its small patient population and lack of a comparator arm.

The corresponding authors report financial support from Bristol-Myers Squibb, Seattle Genetics, Merck, Kite, Pharmacyclics, Celgene, Takeda, Curis, Immunogen, and Incyte.


Reference

Svoboda J, Landsburg DJ, Dwivedy Nasta S, et al. Brentuximab vedotin with R-CHP chemotherapy as frontline treatment for patients with CD30 positive primary mediastinal large B-cell, diffuse large B-cell, and grey zone lymphomas: results of a phase I/II multisite trial. Abstract #191. Presented at the 2017 American Society of Hematology Annual Meeting, December 9, 2017; Atlanta, GA.

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