Prolonged Overall Survival (OS) in a Subset of Responders to the Combination of Brentuximab Vedotin (Bv) and Bendamustine (B) in Heavily Treated Patients with Relapsed or Refractory Hodgkin Lymphoma (HL): Results of an International Multi- Center Phase I/II Experience
Authors: Sawas Ahmed , Kuruvilla John , Lue Jennifer Kimberly , Deng Changchun , Amengual Jennifer E , Montanari Francesca , Savage Kerry J , Elgedawe Hager , Villa Diego , Crump Michael , Connors Joseph M , O'Connor Owen A. 
Published: October 2019

Introduction

Prognosis for patients who fail to respond to high-dose chemotherapy or progress after high dose chemotherapy and autologous stem cell transplant (ASCT) is particularly poor, with a recent study reporting 71% of patients dying in year 1 and 90% by year 2, with a median -progression survival of 1.3 years [1]. In our study of brentuximab vedotin plus bendamustine (BvB) in patients with relapsed or refractory Hodgkin's lymphoma, we recently reported an overall response rate (ORR) and complete response rate (CR) of 71% and a 32% respectively (N=65) in a heavily treated patient population [2]. Having noted several patients with a progression free survival (PFS) of 1 year or longer, we reviewed all enrolled patients for protracted duration of benefit, raising the question as to whether these patients may have been cured by BvB in the salvage setting. (ClinicalTrials.gov #NCT01657331).

Methods

Among 65 enrolled patients we identified 23 with a PFS of more than one year after treatment with BvB. Patients had received Bv on Day 1 with B on Days 1 and 2 of a 3-week cycle for up to 6 cycles. In the Phase 1 study 4 dose levels were evaluated: (1) Bv = 1.2mg/kg; B = 70mg/m2; (2) Bv = 1.2mg/kg; B = 80mg/m2; (3) Bv = 1.8mg/kg; B = 80mg/m2; and (4) Bv = 1.8mg/kg; B = 90. Accrual followed a classic Fibonacci dose escalation, with 3 patients being treated at each dose level. Dose Limiting Toxicity (DLT), defined as any CTC version 4 Grade 3 or 4 toxicity led to expansion of the dose cohort. The recommended phase II dose was Bv 1.8 mg/kg on Day 1 and B 90 mg/m2 on Days 1 and 2. The Phase 2 portion of the study accrued an additional 37 patients. Response was assessed by the investigator per Cheson 2007 after cycles 2 and 6. Patients were followed post completion of therapy every 3 month until disease progression and imaging was conducted every 3- 6 months. Study procedures and follow-up were concluded on June 30th 2018. In addition, plasma and serum biomarkers were prospectively collected for correlation with toxicity and response.

Results

With a median follow-up of 33 months (range 20-58 month) we identified 23/65 patients (43% male) with a median age of 34 years (range, 18-55) who experienced a PFS of 1 year or more. The median number of prior systemic therapies was 3 (range 1-6); with 11 patients having had prior ASCT and 10 patients receiving prior radiation therapy. Median number of BvB cycles administered was 4 (range 2-6).

A best response of CR was documented for 17 patients (74%) and partial response (PR) was documented for 6 patients (26%). Consolidation with HDCT-ASCT was performed in 10 patients, 3 of whom received maintenance Bv post-transplant. The median duration of response (DOR), PFS and OS among this group was 28, 32 and 34 months, respectively. All responses are ongoing with no evidence of relapse. Long term survival with no further therapy after a median of 6 cycles of BvB ( range 2-6) was observed in 13 patients (20% of the treated population) (median post-BvB PFS 36 months, range 20-58).

Exploratory analysis of the correlation between disease outcome and changes from baseline in select biomarkers demonstrated a significantly lower mean baseline sCD30 level among long term responders (p=0.01). No correlations were noted between other clinical outcome metrics and sCD30, nor with other biomarkers including TARC, CD163, or galectin.

Conclusion

In this heavily treated population with HL, the combination of BvB represents an effective and tolerable outpatient salvage regimen with long term response and protracted survival among a subset of patients, and raises the prospect that these patients, with a historically poor outcome may be cured with BvB. We intend to follow these patients to obtain additional information on their longer term outcome.

ReferencesZagadailov, E.A., et al., Real-world effectiveness of brentuximab vedotin versus physicians' choice chemotherapy in patients with relapsed/refractory Hodgkin lymphoma following autologous stem cell transplantation in the United Kingdom and Germany. Leuk Lymphoma, 2018. 59(6): p. 1413-1419.O'Connor, O.A., et al., Brentuximab vedotin plus bendamustine in relapsed or refractory Hodgkin's lymphoma: an international, multicentre, single-arm, phase 1-2 trial. Lancet Oncol, 2018. 19(2): p. 257-266.

Disclosures

Kuruvilla: Princess Margaret Cancer Foundation: Research Funding; Merck: Consultancy, Honoraria; Leukemia and Lymphoma Society Canada: Research Funding; Lundbeck: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Honoraria; BMS: Consultancy, Honoraria; Abbvie: Consultancy; Seattle Genetics: Consultancy, Honoraria; Karyopharm: Honoraria; Celgene: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria. O'Connor:ADC Therapeutics: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding.