Hello, I am Dr. Martin Hutchings from Copenhagen, Denmark, and I am here to give you an overview of the current treatment guidelines in Hodgkin lymphoma as presented at the recent symposium here at the EHA Meeting in Milan. The meeting coincides with a revision of the ESMO guidelines for the treatment and management of Hodgkin lymphoma which will be published soon, so my presentation took its basis in these revised guidelines but also talks about future concepts.

Hodgkin lymphoma is divided into early stages and advanced stages, and the early stages are according to well-defined risk factors divided into limited stage, which is disease without any risk factors, and intermediate stage where one or more of the well-defined risks factors are present in the patient. So, long ago, the German Hodgkin Study Group, and the EORTC, and Gela Group in simultaneous trials showed that combined modality treatment using both chemotherapy and radiotherapy are superior to radiotherapy alone. And in subsequent trials, it was shown that 2 cycles of ABVD followed by involved-field radiotherapy is sufficient treatment for patients with limited-stage Hodgkin lymphoma.

Now, recent developments have been the incorporation of PET imaging after chemotherapy into the clinical trials. The attempt has been to identify patients who could perhaps be cured well without the need for radiotherapy after chemotherapy, so PET after 2 or 3 cycles of chemotherapy has been used to find these patients, and recent results from the UK rapid trial and from the EORTC, GELA, and Italian FIL H10 trial have shown that there is indeed some inferiority for patients PET negative after chemotherapy who were not given radiotherapy, but this inferiority is in the order of 3 to 4 percentage points, so it is still an open question whether in fact those patients responding really well to chemotherapy indeed do need radiotherapy which can give course to long-term treatment-related morbidity and mortality.

Now, in limited-stage Hodgkin lymphoma, there was also randomized German trial randomizing patients between either 20 Gy of involved-field radiotherapy or 30 Gy of involved-field radiotherapy after 2 cycles of chemotherapy, and indeed, there was no difference found. So the outcome is that the current recommendations for the treatment of limited stage disease is 2 cycles of ABVD followed by 20-Gy involved-field radiotherapy or even involved-site radiotherapy which is the most recent development from the radiotherapy world. In intermediate-stage disease, a randomized German trial gave patients either 20 Gy of involved-field radiotherapy or 30 Gy of involved-field radiotherapy after the 4 cycles of ABVD which was then the standard chemotherapy for intermediate-stage disease. And unlike the patients with limited-stage disease, patients with intermediate-stage disease had indeed a difference between these two radiotherapy doses, so 30-Gy radiotherapy is still the recommended standard for patients in this group.

As for the chemotherapy, there has been a randomized German trial giving either 4 cycles of ABVD as chemotherapy or 2 cycles of BEACOPP escalated followed by 2 cycles of ABVD. There is a slight superiority in terms of progression-free survival for those patients receiving BEACOPP and ABVD, and it is still an open question whether one or the other chemotherapy regimen is preferred. The ESMO Guidelines recommend 4 cycles of ABVD followed by 30-Gy involved-site radiotherapy for patients with intermediate-stage Hodgkin lymphoma but with an option to give BEACOPP 2 cycles followed by ABVD 2 cycles as an alternative chemotherapy regimen.

Patients with advanced-stage Hodgkin lymphoma are treated internationally either with 6 to 8 cycles of ABVD or with the German-intensive BEACOPP escalated regimen. There was a randomized trial called the German HD9 trial randomizing patients between either the BEACOPP escalated regimen, 8 cycles, or another variant of BEACOPP called the BEACOPP baseline regimen and the ABVD-like regimen called COPP ABVD, it is an alternate regimen. And there was indeed a striking event, fairly free survival advantage for patients treated with BEACOPP escalated x8. So from then on, the German standard for the treatment of advanced-stage Hodgkin lymphoma has been BEACOPP escalated, but the problem is that while ABVD cures approximately 65% to 70% of patients and BEACOPP cures perhaps 85% of patients, this comes at a significant cost in terms of acute and late toxicity. Particularly, the infertility which is the result of BEACOPP escalated and also the 3% to 4% risk of secondary AML or MDS is big problem if this treatment is given to all patients upfront. So, in other words, if ABVD is given to all patients, then one-third of the patients is perhaps being undertreated, and if BEACOPP escalated is given to patients, then two-thirds of the patients who would otherwise have been treated well with ABVD are getting overtreatment, and this schism has not been solved yet. Due to the high prognostic value of interim PET after 2 cycles of chemotherapy in advanced-stage Hodgkin lymphoma, a number of trials have been opened in recent years looking at PET response-adapted chemotherapy for advanced-stage Hodgkin lymphoma, and two concepts have been tested. One, to escalate therapy to those patients still PET positive after a couple of cycles of chemotherapy, and also to ameliorate or to de-escalate therapy to those patients who are PET negative after 2 cycles of chemotherapy, and there are only a few trials that have produced results as of yet. It looks as though a number of those patients still PET positive after 2 cycles of ABVD can be salvaged by escalating therapy too, for example BEACOPP escalated, but more mature results are eagerly awaited from these trials originating in different countries.

So the ESMO Guidelines recommend either 6 to 8 cycles of ABVD or 6 cycles of BEACOPP escalated for the treatment of advanced-stage Hodgkin lymphoma. Eight cycles of BEACOPP escalated is no longer given since a randomized trial from Germany, the HD15 trial, indeed showed superiority in terms of event-free survival and no difference in overall survival for patients treated with 6 cycles of BEACOPP escalated compared to those patients treated with 8 cycles.

It is up until recently been the standard to offer consolidation radiotherapy to patients with advanced-stage Hodgkin lymphoma upon completion of chemotherapy. The German HD15 trial only gave radiotherapy to those patients with a PET-positive residual lymphoma larger than 1.5 cm after the completion of radiotherapy. And in those patients PET negative after completion of chemotherapy, no radiotherapy was given, and yet, there was event-free survival after 2 to 3 years of around 90%, so this is highly satisfactory. Based on that, the ESMO guidelines do not recommend radiotherapy to patients who are PET negative after BEACOPP escalated, and even after ABVD, even though this is not being looked at in a proper perspective fashion, we do not recommend radiotherapy to be given if the patient is PET negative after the end of the chemotherapy. This is based on retrospective data primarily from the Canadian Vancouver group who have shown that this practice is indeed safe in ABVD-treated patients.

Patients who do relapse are treated with different induction chemotherapy regimens, IGEV, DHAP, ICE chemotherapy before high-dose chemotherapy with autologous stem cell support. Approximately half of those patients who relapse can be cured with the second-line treatment. It is being shown that PET, again, is a very prognostic tool so that patients who attain a PET-negative status before the high-dose chemotherapy and after induction treatment have a very good prognosis, unlike those who remain PET positive who have dismal prognosis and represent an unmet medical need. There are trials undergoing aiming at improving the induction chemotherapy, for example, with the incorporation of the new drug brentuximab vedotin into the induction regimens, and there are also results to prove that PET can indeed be used to so to say pick the winner. So if one induction regimen does not result in PET negativity, then another might be used, and if the patient becomes PET negative, then the results are really as good as those patients responding well to the first regimen.

Brentuximab vedotin is an anti-CD30 antibody drug conjugate which has been approved by the FDA and EMA recently for the treatment of patients with the relapsed and refractory Hodgkin lymphoma. So these are patients who have relapsed of the high-dose chemotherapy with autologous stem cell support or patients who have not been eligible for such an intensive treatment. This is based on impressive results from a pivotal phase II trial of 102 patients where we saw 75% overall response rates here of 36% complete responders, and this was in heavily pretreated patients. Like I said, all the patients had undergone previous high-dose chemotherapy or autologous stem cell support and the prior treatment lines ranged from 3 to 9 in that cohort. So, after this registration as monotherapy, there are several attempts to incorporate this highly active drug into the chemo regimens in first-line therapy and also second-line chemotherapy, and we eagerly await the results coming in the future from these trials. We are also, perhaps later this year, waiting for results from the randomized AETHERA trial which is a trial that investigates the value of giving maintenance brentuximab vedotin to patients at high risk of relapse after high-dose chemotherapy with autologous stem cell support.

So, the key messages from this talk: 1) it is still an open question whether early PET-negative patients with early stage disease indeed need radiotherapy, and we await the result from the German HD16 and HD17 trials to further elucidate this, 2) both ABVD and BEACOPP escalated can be preferred for advanced-stage disease, but this should depend on the individual characteristics, on risk factors, and possibly on the results of PET early during chemotherapy, and 3) brentuximab vedotin is registered for relapsed and refractory disease, and its role in front-line and salvage chemotherapy is being investigated.

The future challenges in the management of Hodgkin lymphoma are many. We are aiming at further reduction of treatment burden in early stage disease but without losing disease control. This is because patients are usually young and they have many years to live with the serious long-term side effects of treatment. Improvement of outcomes in advanced-stage disease and reduced toxicity both using chemotherapy in combination of the new agents and also using response-adapted therapy such as PET response-adapted. Also, we are looking at improvement of induction chemotherapy in patients with first relapse. Like I told you, there are trials incorporating, for example, brentuximab vedotin with salvage chemotherapy to these patients. Elderly and frail patients are an unmet need. Only half of those patients can be cured, and these are the patients who can actually tolerate chemotherapy. Maintenance therapy is an unknown field. It is being investigated like I said in the AETHERA trial, but its role yet has to be defined. Finally, but not least, we need to look for better prevention, screening, and management of the treatment-related treatment morbidity and mortality which is the result of the treatments that we give. Thank you.