Adam Gibb

Brentuximab vedotin in refractory CD30+ lymphomas: a bridge to allogeneic transplantation in approximately one quarter of patients treated on a Named Patient Programme at a single UK center.

The CD30-targeted agent brentuximab vedotin has shown impressive activity in relapsed/refractory Hodgkin lymphoma and anaplastic large cell lymphoma in phase II studies. We have treated 24 patients with relapsed/refratory disease enrolled onto a Named Patient Programme during 2010-11 at a single UK center. Overall response rate across all histologies was 67% (Hodgkin 72%; anaplastic large cell 60%), complete response rate 25% (Hodgkin 17%; anaplastic large cell 60%), median progression-free survival 5.1 months, and toxicity mild to moderate in the majority of cases. Six patients proceeded to allogeneic transplantation and one patient awaits this procedure. These results are similar to phase II data and show that brentuximab vedotin provides a bridge to allogeneic transplantation in approximately one quarter of patients refractory to conventional salvage therapies. Best response was seen after four doses, so consideration of allogeneic transplantation should be made early and scheduled following the first assessment indicating response.

Allogeneic transplant following brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma

Abstract Brentuximab vedotin is an antibody drug conjugate that induces durable objective responses in patients with relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Fifteen of 160 patients who participated in two pivotal phase 2 studies received a consolidative allogeneic stem cell transplant (allo-SCT) following brentuximab vedotin treatment. This case series describes their experience. The studies were approved by Institutional Review Boards prior to patient enrollment. Patients received 1.8 mg/kg brentuximab vedotin every 3 weeks for up to 16 cycles. The estimated 2-year progression-free survival (PFS) rate was 66%, and the median PFS has not yet been reached. Eleven of the 15 patients were alive and the estimated 2-year survival rate was 80%. The safety of brentuximab vedotin treatment in this series was consistent with the known safety profile in this setting. Brentuximab vedotin is a compelling option for reducing tumor burden to facilitate a consolidative allo-SCT.

Results of a multicentre UK‐wide retrospective study evaluating the efficacy of brentuximab vedotin in relapsed, refractory classical Hodgkin lymphoma in the transplant naive setting

Relapsed or refractory classical Hodgkin lymphoma (cHL) is associated with a poor outcome when standard chemotherapy fails. Brentuximab vedotin (BV) is an anti‐CD30 monoclonal antibody‐drug conjugate licensed for use at relapse after autologous stem cell transplant (ASCT) or following two prior therapies in those unsuitable for ASCT. There are limited data assessing the ability of BV to enable curative SCT. We performed a UK‐wide retrospective study of 99 SCT‐naïve relapsed/refractory cHL. All had received 2 prior lines and were deemed fit for transplant but had an insufficient remission to proceed. The median age was 32 years. Most had nodular sclerosis subtype, Eastern Cooperative Oncology Group performance status 0–1 and advanced stage disease. The median progression‐free survival (PFS) was 5·6 months and median overall survival (OS) was 37·2 months. The overall response rate was 56% (29% complete response; 27% partial response). 61% reached SCT: 34% immediately post‐BV and 27% following an inadequate BV response but were salvaged and underwent deferred SCT. Patients consolidated with SCT had a superior PFS and OS to those not receiving SCT (P < 0·001). BV is an effective, non‐toxic bridge to immediate SCT in 34% and deferred SCT in 27%. 39% never reached SCT with a PFS of 3·0 months, demonstrating the unmet need to improve outcomes in those unsuitable for SCT post‐BV.

Bendamustine can be a bridge to allogeneic transplantation in relapsed Hodgkin lymphoma refractory to brentuximab vedotin

Hodgkin lymphoma (HL) affects approximately 1500 new patients annually in the UK (Smith et al, 2011). Most patients are cured with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine)-based treatment. Of those who relapse, about 60% achieve durable remission with salvage chemotherapy followed by consolidation high dose therapy (HDT) and autologous stem cell transplantation (ASCT). Treatment options at relapse after ASCT are limited and after second relapse, cure is infrequent. Brentuximab vedotin (BV) (Adcetris) is a CD30-directed antibody drug conjugate with an established role in treating relapsed/refractory HL (Gopal et al, 2012; Younes et al, 2012). In the UK, BV has been successfully used as a bridge to allogeneic stem cell transplantation (alloSCT) in approximately 25% of patients (Gibb et al, 2013). Nivolumab and other emerging PD-1 (PD1)/PD-L1 (CD274) checkpoint inhibitors are novel agents with very promising results in early phase clinical trials. In a phase l study of nivolumab involving 23 patients (including 78% post-ACST and 78% post-BV) the overall response rate (ORR) was 87% with 86% progression-free survival (PFS) at 24 weeks (Ansell et al, 2015).

Outcomes following front-line chemotherapy in peripheral T-cell lymphoma: 10-year experience at The Royal Marsden and The Christie Hospital

Abstract We evaluated the outcomes for patients with peripheral T-cell lymphoma (PTCL) undergoing front-line chemotherapy at our institutions between 2002 and 2012. One hundred and fifty-six patients were eligible, comprising PTCL not otherwise specified (NOS) (n = 50, 32.0%), angioimmunoblastic T-cell lymphoma (AITL) (n = 44, 28.2%), anaplastic large-cell lymphoma (ALCL) ALK negative (n = 23, 14.7%), ALCL ALK positive (n = 16, 10.3%), and other (n = 23, 14.7%). Most patients received CHOP (66.0%) and 13.0% received an autologous hematopoietic progenitor cell transplant (HPCT). With a median follow-up of 63.4 months, 5-year overall survival (OS) and progression-free survival (PFS) was 38.8% and 19.8% respectively. Independent risk factors for inferior OS were age >60 years, International Prognostic Index (IPI) ≥ 2 and lack of complete response to induction. When responding patients were compared by receipt of an autologous HPCT versus not, HPCT was associated with improved PFS (p = .001) and OS (p = .046) and remained significant for PFS in multivariate analysis suggesting a possible therapeutic benefit.

Profile of brentuximab vedotin and its potential in the treatment of relapsed or refractory Hodgkin lymphoma

Correspondence: Tim Illidge School of Cancer and Enabling Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester, M20 4BX, UK Tel +44 16 1446 8110 Fax +44 16 1446 8001 Email tmi@manchester.ac.uk Abstract: Treatment of primary refractory and relapsed classical Hodgkin lymphoma remains challenging, with disappointing results overall and only a minority of patients enjoying a longterm cure. Until recently, antibody therapy has not played any role in the management of this form of Hodgkin lymphoma. The CD30 antigen was first identified in the Hodgkin Reed– Sternberg malignant cell of Hodgkin lymphoma and emerged as a promising potential target for antibody treatment. The first-generation monoclonal anti-CD30 antibodies proved disappointing with little clinical efficacy. More recently, a novel class of antibody-drug conjugates has emerged. Antibody-drug conjugates offer the potential to target tumor tissue more specifically and deliver potent drug therapies with minimal or less systemic toxicity. Brentuximab vedotin (SGN-35) is one such drug of this class and combines an anti-CD30 monoclonal antibody and the antitubulin agent, monomethyl auristatin E. Initial Phase I studies of brentuximab vedotin showed a promising 52% overall response rate in relapsed Hodgkin lymphoma, with minimal toxicity. More recently, the pivotal Phase II study in 102 patients demonstrated an overall response rate of 75% and a complete response rate of 34%. The median duration of response was 6.7 months, but this was extended to 20.5 months in those who achieved a complete response. This review outlines the development of the antibody-drug conjugate, brentuximab vedotin, for relapsed or refractory classical Hodgkin lymphoma.