Refractory Hodgkin lymphoma: time for targeted therapies?

With the use of targeted therapies in classical Hodgkin lymphoma (HL), the paradigm of salvage chemotherapy followed by autotransplant may have changed. In this issue of Blood, Herrera et al report positive results using targeted therapy for salvage treatment before autotransplantation.¹ 

Most patients with HL are cured with standard treatment, for example, chemotherapy alone or with radiation therapy. However, 10% to 15% of patients with early and 15% to 20% with advanced classical HL fail to respond or relapse after primary treatment.²  Patients with primary refractory HL (patients not achieving complete remission or relapsing <3 months after completion of treatment) have worse outcomes and a lower response to salvage chemotherapy compared with patients with late relapse.²  Patients with relapsed/refractory HL should receive salvage chemotherapy before high dose therapy (HDT) and autotransplant. Patients who respond to salvage chemotherapy have a greater chance of cure after autotransplantation than refractory patients.^2,3  Patients with relapsing/refractory HL who do survive have long-term therapy-related sequelae (eg, infertility, secondary malignancies, cardiotoxicity) greater than patients treated with 1 line. Second-line regimens have lower response rates than first-line treatment with 30% to 40% of complete response when evaluated by computed tomographic (CT) scans²  and 50% with 18-F fluorodeoxyglucose-positron emission tomography imaging (complete metabolic response [CMR]).³ 

Several targeted approaches to treatment of relapsed/refractory HL are being evaluated. Brentuximab vedotin (BV) is a chimeric anti-CD30 antibody conjugated to a microtubule-disrupting agent. BV was tested in a phase 2 trial in 102 patients with relapsed/refractory HL who had relapsed after autotransplant.⁴  In this pivotal, phase 2, multicenter trial, 75% of patients achieved an objective response and 34% obtained a CMR. Subsequently, BV has been given with salvage regimens (dexamethasone, cytarabine, and cisplatin; ifosfamide, carboplatin, and etoposide; etoposide, cytarabine, and cisplatin) administered before HDT (mostly ongoing studies) or with second-salvage regimens (gemcitabine, vinorelbine, and lioposomal doxorubicin; bendamustine).^5,6  Nivolumab and pembrolizumab are inhibitors of the programmed death-1 (PD-1) receptor and inhibit the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Recently, both have shown a high response rate with a low CMR rate, but prolonged clinical benefit in advanced patients with multiple relapses in phase 2 studies.^7,8 

The combination of BV and nivolumab given as the first salvage regimen for relapse/refractory HL patients provides 2 efficient drugs with different mechanism of actions and toxicities. This combination is manageable in an outpatient setting (whereas salvage regimens usually require hospitalization). In this issue of Blood, Herrera et al report the results of this interesting combination. Despite a high number of patients with refractory disease and early relapse (76%), the response rate is high (82%), with 61% CMR (50% in primary refractory HL). Sixty percent of patients could receive the HDT without other salvage CT and received no alkylating agents. The toxicity was reasonable with a low rate of febrile neutropenia, peripheral neuropathy developing in 10%, and the infusion-related reactions in 44% of patients.

Thus, the combination of BV and nivolumab has achieved respectable response rates while sparing patients the long-term toxicities associated with the use of alkylating agents. This may translate to a survival increase while decreasing the late effects of chemotherapy.

These agents may also be useful as consolidation therapy. In 2012, BV was reported to have activity in patients relapsing after autotransplant.³  In the AETHERA trial of refractory and high-risk relapse (early or with extranodal site) HL patients, the median progression-free survival post-autotransplant increase from 24 months to 42 months using 1-year BV consolidation was compared with a placebo.⁹  The low toxicity of BV was mostly neurotoxicity, and this consolidation may replace the use of tandem transplantation.² 

Is it the time to avoid autotransplantation in relapsed HL patients without adverse prognostic factors achieving CMR after targeted therapy? This would require a carefully designed clinical trial with very close monitoring. The emergence of minimal residual disease studies in HL may help.¹⁰  The combination of BV and nivolumab could be tested as the first salvage regimen in relapsed/refractory HL, and for those patients with CMR with no evidence of minimal residual disease, a strict follow-up or a BV consolidation could be evaluated with autotransplantation reserved for those at recurrence. Even if such an approach does not ultimately prove beneficial, the use of less toxic therapy for HL patients requiring transplantation for cure is certainly an exciting advance. Eventually, the issue of cost will have to be addressed because targeted therapies are very expensive.