ASH 2018: Hodgkin lymphoma: beyond ABVD for everyone

Article by Maria Dalby. Interviews by Hannah Chatfield

Achieving the ultimate goals of maintaining cure and minimising long-term toxicity in Hodgkin lymphoma (HL) requires individualised therapy based on risk stratification of patients. Using active drugs that can overcome high-risk disease and adopting early markers that can predict long-term outcomes are essential building blocks in such individualised approaches. An educational session entitled “HL: beyond ABVD for everyone” focused on the role of PET-adapted therapy and incorporation of novel drugs in HL, both in the frontline setting and in relapsed/refractory disease.

In the first presentation Professor Ranjana Advani from Stanford University (California, USA) outlined how the emergence of escalated BEACOPP (eBEACOPP) as a new standard of care in advanced HL in Europe has accentuated the therapeutic dilemma that increasing the extent or intensity of therapy can increase the probability of a cure, but at the cost of increased morbidity. By performing interim PET scans it is possible to assess the response and modify therapy as needed to maximise response without unnecessary toxicity. This can be done in two ways: either by starting with an ABVD regimen and escalate or de-escalate based on the interim PET response, or by starting with a BEACOPP regimen and escalate or de-escalate based on the interim PET response. The first strategy has been shown in three randomised controlled trials to result in excellent OS, and three-year PFS rates of around 85% in patients who achieved PET-negativity (defined as a Deauville score of 1-3), and up to 68% in those who remain PET positive.^1-3

The second strategy was documented in a study in which initial therapy with eBEACOPP was de-escalated to ABVD following a negative interim PET scan;⁴ in this study patients achieved excellent OS with no significant differences in PFS or OS between patients who received PET-adapted therapy and those who did not.⁴ Another study in which patients were stratified by IPS prior to receiving either ABVD with escalation to eBEACOPP or eBEACOPP with de-escalation based on PET response suggests that patients with more advanced disease (stage IV or IPS 4-7) are less likely to achieve PET-negativity and will therefore benefit from therapy escalation.⁵ Incorporating novel agents such as CD30-targeting antibody-drug conjugate brentuximab vedotin (BV) or checkpoint inhibitor therapy into response-adapted strategies could potentially offer important therapeutic benefits for patients with higher-risk disease. The phase 3 ECHELON-1 study showed that adding BV to AVD resulted in prolonged PFS for patients with previously untreated stage III and IV HL, especially younger patients,⁶ patients treated in North America,⁷ and patients with positive interim PET scans.⁸ Adding BV to AVD did notably increase the rate of adverse events including febrile neutropenia and peripheral sensory neuropathy though, and the higher cost of treatment should also be considered.

Dr Alison Moskowitz from the Memorial Sloan Kettering Cancer Center (New York, USA) continued with a discussion of how the use of BV can be optimised in HL therapy. Recent study results indicate that in early stage disease, adding BV to AVD can reduce or eliminate the need for radiation therapy (RT) – patients with previously untreated early-stage HL with unfavourable risk features who achieved PET negativity after two or four cycles of BV plus AVD proceeded to radiation therapy and achieved a CR rate of 93% and one-year PFS of 93% irrespective of whether they received 30Gy or 20Gy; patients who received consolidation volume radiation achieved a CR rate of 86%.^9-11 Another potential benefit of adding BV to AVD in early disease is to increase the number of patients achieving PET negativity, as shown in the BREACH study.¹² In older patients with HL who are unfit for standard chemotherapy, frontline treatment with single-agent BV was shown in a phase 2 study to result in an ORR of 92% and a CR rate of 73%,¹³ and combination therapy with BV and dacarbazine achieved an ORR of 100%.¹⁴

In another phase 2 study, sequential treatment with BV and AVD in HL patients aged 60 and over resulted in an event-free survival rate of 80% and 93% OS at two years.¹⁵ In this study BV was very well tolerated – only 8% of patients developed grade-3 neuropathy, compared with 18% in the ECHELON-1 study. In the relapsed/refractory setting, adding BV to chemotherapy either in sequence^16-18 or in combination^19-21 increased the rate of interim PET negativity compared with single-agent BV and achieved PFS rates of 82% at three years and up to 76% at two years, respectively. The phase 3 AETHERA study showed that higher-risk patients who received maintenance therapy with BV after ASCT were significantly more likely to be alive after five years compared with those who received placebo (five-year PFS 59% in the BV arm versus 41% in the placebo arm; HR=0.521; 95% CI 0.379, 0.717) and that the survival benefit was especially pronounced in patients with two or more risk factors.^{22, 23} Dr Moskowitz’ concluding recommendation was that BV should be considered alone or as combination therapy as second-line therapy and in patients who relapse or are refractory to ASCT, and maintenance therapy with BV should be offered to patients with higher risk disease post-ASCT.

In the concluding presentation Dr Alex Herrera from City of Hope (California, USA) highlighted the emerging role of checkpoint inhibitors nivolumab and pembrolizumab in HL. The rationale for using PD-1 blockade in HL is that the tumour cells harbour near-universal alterations in the PD-L1 and PD-L2 genes on chromosome 9p24.1 which lead to overexpression of PD-1 ligands.²⁴ The interaction between PD-1 and PD-1 ligands which is known to downregulate T-cell responses can be blocked using antibodies;²⁵ a concept which has been proven in phase 1 studies that have shown that nivolumab and pembrolizumab as monotherapy are effective for achieving a clinical response in RRHL.^{26, 27} Phase 2 studies have confirmed these results – in the KEYNOTE-087 study around two thirds of patients achieved ORR and around 20% achieved CR, irrespective of previous exposure to BV and ASCT.²⁸ Similar ORR and CR rates were obtained for nivolumab in the CheckMate 205 study across the different cohorts.^29,30 Both studies have shown that the depth of response achieved can predict the duration of response, but not survival.^30,31 Importantly, although the survival benefit in patients whose best response was stable disease was less pronounced compared with patients who achieved CR and PR, PFS in this group was still nearly one year.³⁰ Continuing treatment with PD-1 blockade beyond progression was also associated with continued treatment benefit.^30,32

Although PD-1 blockade represents a major advance in HL therapy, Dr Herrera pointed out that there is still room for improvement in terms of achieving higher CR rates and preventing relapse. Combination therapy with nivolumab and BV has been shown to achieve a CR rate of 67%,³³ and adding chemotherapy to nivolumab or pembrolizumab in patients who have failed on PD-1 blockade monotherapy resulted in a CR rate of 45%.³⁴ The role of PD-1 blockade in HL therapy going forward is likely to move towards use earlier in therapy to improve cure rates. A study evaluating second-line therapy with nivolumab alone or in combination with ICE chemotherapy is in progress at Dr Herrera’s centre, and in a cohort of newly diagnosed HL patients in the CheckMate 205 study who received nivolumab as monotherapy followed by nivolumab and AVD in combination, 93% had ORR and 89% achieved CR.³⁵ In elderly HL patients, combination therapy with nivolumab and BV achieved an ORR of 82% and 55% CR.³⁶ However, in Dr Herrera’s opinion the most important place for PD-1 blockade in current therapy is in the post-ASCT or refractory setting, as a bridge to transplantation or delayed transplantation.

Among the poster presentations at ASH 2018 were several updates from the pivotal ECHELON-1 study for BV. Dr Andrew Evens from the Rutgers Cancer Institute (New Jersey, USA) presented an analysis of results from the ECHELON-1 study in patients aged 60 years or over (poster 1618). This analysis showed that the survival benefit with BV in combination with AVD that was seen in the overall study population was not evident among older patients. On the other hand older patients treated with BV plus AVD were more likely to develop adverse events than younger patients – the overall rate of febrile neutropenia among the older patients was 37%, compared with 17% among patients under 60, and the investigators concluded that G-CSF primary prophylaxis may be indicated in older patients receiving BV plus AVD. Dr Joseph Connors (Vancouver, Canada) presented a poster of two sensitivity analyses of modified and traditional PFS rates (poster 2904) which revealed that the survival benefit shown in the primary analysis was observed independently of including additional radiation therapy or chemotherapy as survival events alongside progression or death. And last but not least, Professor John Radford (Manchester, UK) presented the results of an important analysis from ECHELON-1 (poster 2921) which showed that of the 67% of patients in the BV plus AVD arm and 43% of patients in the ABVD arm who developed any-grade peripheral neuropathy during treatment, more than half (51% and 61%, respectively) had resolution or improvement at the time of the primary analysis, and symptoms continued to resolve or improve over approximately 2.5 years of continued follow-up. The symptoms of peripheral neuropathy were overall manageable and reversible in both study arms, and the majority of ongoing cases are grade 1 or 2. The investigators concluded that the sustained survival benefit and ongoing resolution and improvement of peripheral neuropathy symptoms indicate a sustained favourable benefit-risk profile with BV plus AVD compared with ABVD.

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