ICML 2017: How will Hodgkins lymphoma be managed in 2020?

By Maria Dalby (article) and Esther Drain (interviews)

Not only is the treatment ‘landscape’ in Hodgkin lymphoma (HL) changing rapidly both in the first-line and relapsed/refractory setting, but different interpretations can also be applied to study results to advocate different approaches.

Prof. John Radford (Manchester) chaired a meeting where UK delegates shared best practice. Here he summarises the issues raised in the management of R/R HL and the future of transplant in the UK.

Not only is the treatment ‘landscape’ in Hodgkin lymphoma (HL) changing rapidly both in the first-line and relapsed/refractory setting, but different interpretations can also be applied to study results to advocate different approaches. In a scientific exchange meeting organised by Takeda UK Ltd, three leading experts reviewed current and emerging treatment options and discussed issues that will be key in shaping the management of HL in the UK in the near future.

Professor John Radford from Manchester chaired the meeting and began by outlining how HL therapy is evolving in the frontline setting. Conventional chemotherapy with or without radiotherapy remains the mainstay therapy, although this may be challenged by targeted therapies and immunomodulatory agents – especially in older patients and patients with co-morbidities who currently have very poor outcomes. Following on from the NCIC/ECOG study which showed that HL patients who received first-line treatment chemotherapy alone had similar five-year overall survival (OS) to patients who received chemotherapy and radiotherapy, and (somewhat controversially) superior 12-year OS,^{1, 2} a number of studies have investigated the role of response-adapted therapy based on interim PET scanning (iPET). The H10 study found that patients who received chemotherapy alone after a negative iPET had slightly lower progression-free survival (PFS) rates than those who received chemotherapy with radiotherapy; the investigators concluded that radiotherapy should not be omitted based on these results.³ The UK the RAPID study showed similar results, but the investigators interpreted this data as showing that patients did extremely well on chemotherapy alone following a negative iPET scan and that the additional benefit of radiotherapy was not sufficient to justify the long-term risk.⁴ In advanced HL, the RATHL study shows that bleomycin can be omitted in patients who are iPET negative with excellent survival outcomes and reduced toxicity.⁵

These encouraging findings have led investigators to hypothesise that it may be possible to improve the prognostic precision and therapy selection even further by using additional biomarkers alongside iPET. Attempts at integrating gene expression profiling (GEP) have so far yielded variable results, but work is ongoing to develop a prognostic model based on GEP together with pre-treatment EORTC/GHSG scores, post-treatment PET risk and three-year PFS data from the RAPID study. In the RADAR study, brentuximab vedotin (BV) will be added to first-line AVD chemotherapy to achieve iPET negative rates of up to 95% and improve survival outcomes. The recently completed phase 3 study ECHELON-1 will be the first to document combination therapy with BV and AVD compared with ABVD alone in advanced HL; the results are expected to be presented later this year. Another new agent that is likely to play an increasingly important role, as monotherapy or in combination with BV, is checkpoint inhibitor nivolumab.

The discussion after Professor Radford’s talk highlighted the need for longer follow-up data to fully understand the long-term treatment effects. A recent updated analysis of the H10 study with 10 years of follow-up data showed a greater separation in PFS between the chemotherapy-alone and chemotherapy with radiotherapy arms than was seen in the interim report.⁶ Whilst iPET is a meaningful tool for guiding therapy, there is a need for additional biomarkers with real clinical utility to stratify patients and identify those most likely to benefit from non-chemotherapy treatment approaches. In addition, clinical studies should include comprehensive health economic evaluations to allow the full treatment costs including the risk of delayed toxic effects.

Dr Graham Collins and Dr Toby Eyre, both from Oxford, give their opinions on how  Hodgkin lymphoma will be managed in the future.

Professor Bruce Cheson from Washington highlighted the major new developments in relapsed and refractory HL. The introduction of BV in this setting has led to a dramatic increase in overall response rates (ORR), from around 40-50% with single and combination chemotherapy regimens^7-12 to 75%, with 33% of patients in complete remission (CR).¹³ Recent data shows that a proportion of patients who achieved CR on single-agent BV without a stem cell transplantation (SCT) remain in remission after five years, indicating that BV has the potential to be curative in this setting in a subset of patients.¹⁴ Bendamustine has ‘resurfaced’ as an option for relapsed and refractory HL in combination with rituximab, with 93% ORR and 74% CR; amendment of the treatment protocol to include pre-medication with corticosteroids and antihistamine has reduced the incidence of infusion-related reactions dramatically.¹⁵ However, the class of drugs that is revolutionising the way clinicians approach relapsed and refractory HL is the checkpoint inhibitors. Nivolumab in combination with BV has been shown to achieve a 90% ORR and a complete metabolic response (CmR) rate of 62%, with tolerable toxicity.¹⁶ Although the optimal sequencing of novel agents remains to be established, Professor Cheson proposed a treatment algorithm where patients with relapsed/refractory HL or who are ineligible for SCT receive BV followed by a checkpoint inhibitor at progression. This algorithm should also apply to BV-naïve patients who relapse post-ASCT, whereas patients with prior BV exposure should receive a checkpoint inhibitor. This proposed algorithm may change once the results of the ECHELON-1 and ACCRU trials become available, but Professor Cheson is certain that the cure rate and toxicity profile of HL will improve as treatments move away from conventional chemotherapy regimens.

In the discussion, Professor Cheson was asked whether the introduction of CAR T-cells could be a potential ‘game changer’ in the treatment of relapsed and refractory HL. He responded that although the efficacy results with CAR T-cells have been very encouraging, managing severe toxicity remains a key challenge. Only units with access to a fully staffed intensive care unit will be able to administer this therapy. That said, rituximab posed considerable challenges when it was first introduced; optimisation of patient selection, dosing schedules etc may help to resolve the problems with CAR T-cells in a similar way.

In the concluding session, Professor Karl Peggs from UCL outlined the current guidelines for SCT in HL and discussed how this may evolve in the future. The British Society for Haematology guidelines issued in 2014 state that ASCT is the standard of care for patients with relapsed and refractory HL that is sensitive to salvage therapy, but that patients should not proceed to ASCT unless they achieve an adequate response.¹⁷ Allogeneic SCT (alloSCT) may be considered in younger patients who relapse following ASCT.¹⁷ These guidelines are based to a great extent on data that predates the era of functional imaging; subsequent studies indicate that iPET results can be used to predict outcome and guide therapy post-ASCT.^{8, 18} The AETHERA study showed that early consolidation with BV post-ASCT improved PFS in patients with high-risk HL;¹⁹ a subgroup analysis shows that the lion share of this benefit was seen in patients who were iPET positive prior to ASCT. Professor Peggs speculated that the use of ASCT may increase in future as more effective salvage therapies will improve remission rates, but that on the other hand more effective front-line treatment options may reduce the number of relapsed and refractory HL patients and thus instead reduce the need for ASCT. The use of alloSCT is likely to decrease overall, although more effective frontline treatments may reduce the effectiveness of salvage and thus the proportion of patients considered for alloSCT may increase.

The discussion that followed Professor Peggs’ presentation picked up on concerns raised about the timing of alloSCT in relation to treatment with checkpoint inhibitors. There is emerging data that use of PD-1 checkpoint inhibitors prior to alloSCT could increase the rate and severity of graft-versus-host disease (GvHD). On the other hand, there have been anecdotal reports of good response with checkpoint inhibitor therapy after alloSCT. The consensus was that this should be addressed in clinical studies; Professor Peggs stated that pending study data his preference in the post-alloSCT setting would be for BV with donor lymphocyte infusions (DLI).

References

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