First-Line Treatment of Advanced stage Hodgkin Lymphoma - Final Results of a Systematic Review and Network Meta-Analysis

EHA 2014: Meeting Highlights in Hodgkin Lymphoma published on July 16, 2014
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Peter Borchmann, MD
Scientific Secretary
German Hodgkin Study Group
Department of Internal Medicine
University Hospital of Cologne
Cologne, Germany
First-Line Treatment of Advanced stage Hodgkin Lymphoma - Final Results of a Systematic Review and Network Meta-Analysis

Hello to everybody. My name is Peter Borchmann. I am from the University Hospital of Cologne, Senior Consultant of the First Department of Internal Medicine, and I am the Study Secretary of the German Hodgkin Study Group.

Here I report from the EHA in Milan on our presentation on the targeted BEACOPP study. This study is development of a well-known BEACOPP escalated regimen. We are using BEACOPP escalated within the German Hodgkin Study Group for advanced-stage Hodgkin lymphoma patients because the efficacy is outstanding, and in network meta-analysis, we have recently shown that the overall survival is roughly 10% better at 5 years than with ABVD. That is why we call our BEACOPP escalated as standard of care for advanced-stage Hodgkin lymphoma patients. Nonetheless, although the overall survival with BEACOPP escalated is very good, there is treatment-related toxicity which is a concern, not only for the patients but also for the physicians because it is really rather toxic, the regimen, it is demanding for both the patients and the physicians. That is why we would like to improve on the toxicity profile of BEACOPP, and let’s have a closer look to the different toxicities we have to face when we are using BEACOPP escalated. First of all, there is the early mortality and there are severe infections, which might be due to the use of steroids. We are administering steroids over a period of 2 weeks with each cycle, and we are giving steroids during cytopenia. Usually, we have high rate with more than 20% severe infections. Second, we have secondary neoplasia like secondary acute myeloleukemia or MDS which is a very severe complication and occurs in up to 1% or 2% of all our patients due to the high DNA damage potential of all the cytotoxic agents we are using within this regimen, but mainly we believe this is also due to procarbazine which could be shown in the HD15 study actually. Then, we have infertility which affects the majority of our patients. This is certainly true for men but also for women. Half of the women will be infertile after treatment with BEACOPP escalated, which obviously is a serious concern. And in the end, we have organ toxicity, non-hematological organ toxicity affecting almost all organs basically but mainly obviously the nervous system due to the use of vincristine with up to 10% of severe like grade 3 or 4 side effects with BEACOPP escalated.

Also, bleomycin might be a problem, and we have to see some pulmonary side effects with our BEACOPP escalated regimen. So that is why, we wanted to improve, and this is hard with using chemotherapy. We are using conventional chemotherapy. We have to face these side effects. This has been changed with the advent of brentuximab vedotin which is a more targeted treatment, although it is conventional chemotherapy in terms of the active compound, but this is bound to an antibody, and the antibody then is reaching the target which is CD30 on the malignant cell and is delivering the cytotoxic agent directly into the cell. So, this promises to be more active and less toxic, but it has still to be shown to be safely administered in combination with conventional chemotherapy. So we tried to modify our BEACOPP regimen by using this new compound, and here you see the drugs that we are using and the doses. We have replaced vincristine by brentuximab vedotin in our new regimen which is called the BrECADD regimen and also took the chance to replace procarbazine by dacarbazine and to reduce the duration of steroid treatment from 14 to 4 days, and we omitted bleomycin because we know we cannot give it together with brentuximab vedotin, and we do not think that it is very important for the efficacy of our regimen. And we have a more conservative regimen, so-called BrECADD in which we only change brentuximab vedotin and vincristine, and these two new regimens were tested in the so-called targeted BEACOPP study. In the study, we have now included 104 patients; 103 is on the slide, but it is actually 104, and these patients are very well matched to our standard patient from our first-line studies as you can see on the right hand of the slide. We have the HD15 data. We can see that the patient characteristics concerning age, sex, B-symptoms, and stage are pretty much the same.

There is one difference concerning the risk factor, large mediastinal mass which is the most important single risk factor in all of our analyses. So, there are many more patients in the targeted BEACOPP study with a large mediastinal mass than we usually see in our first-line studies, which is 41% compared to roughly 30% usually. The most important endpoint obviously is efficacy because we have to be active in this situation. We know patients failing first-line treatment do have a higher risk of actually dying from the disease, so we have to get control over the lymphoma, and so the primary endpoint of this phase II study is efficacy defined by remission rate. And here you see the total remission rate of all 70 patients who have been treated with 6 cycles which is the number of cycles we are using. So, at the end of treatment, there are 70 patients and you see that 90% of them actually ended either a CR or PET-negative PR which is then regarded as CR. Let’s compare to the HD18 trial which is currently running. It is pretty much the same, there we have 91.9%. Looking at our favorite modified BEACOPP regimen, the BrECADD regimen, you see that response rate is 95%, CR or PET-negative PR which obviously is very good.

In terms of toxicities which is the other major endpoint, we are modifying our regimen to be less toxic. We are looking at the non-hematological organ toxicity, and on the right hand side, you can see what we see in the HD18 trial which is currently running and it is almost the same patient population as I have shown before, and you see there we have to face like around 15%, it is 14.3% exactly, of severe non-hematological organ toxicities, with the BrECADD regimen with 38 patients who have received 6 cycles of treatment, we have just one event which is 3%, and this reflects the feasibility actually in practical terms, so we have treated many patients in Cologne where I am coming from, 20 patients, and this regimen certainly is very well feasible. It is easy to administer on an outpatient basis, and it is very much different from BEACOPP escalated which is quite demanding for the patients. Of course, neurotoxicity is a concern. I guess you have heard from the phase I/II study of the combination of ABVD and brentuximab vedotin. The active component of brentuximab vedotin is MMAE which is the tubulin inhibitor which of course then causes neurotoxicity, and in combination with vinblastine and the ABVD regimen, the grade 1 and 2 neurotoxicity rate was more than 70% which is a high number. Here in our regimen, we have replaced vincristine by brentuximab vedotin. We do not combine two tubulin inhibitors, and as you can see here, we have just 30% of mild grade 1 or 2 neurotoxicity and just one event of grade 3 which is just 1%. So this is not only much better than we are seeing with the combination of AVD plus brentuximab, but also this is much better than we see with BEACOPP which is our standard of care where we have in the HD18 5% of severe neurotoxicity, and looking on our database, we are facing roughly about 9% to 10%. So, we are way below this number with the new regimen, so also in terms of neurotoxicity, this new regimen is very well feasible.

To summarize the data of the study, the primary endpoint CR after chemotherapy seems to be reached. It is a bit early. We have to wait another half a year, so all of our patients have gone through the full treatment. Nonetheless, these data are very promising, and we can say today that we will not miss our primary objective of the study because data are so good for the moment. The feasibility of these new regimens, both of them, is very good and certainly much better than for BEACOPP escalated, so this is the development which might be a benefit for the patient as well.

In terms of toxicity, we have toxicity regarding hematotoxicity which is comparable to BEACOPP escalated which is not a surprise because we are giving chemo also in this new regimen. The non-hematological toxicity though is much lower than with BEACOPP escalated, which is promising for us and I think also for the patients. Especially, neurotoxicity is no major problem at all. To conclude from the study, especially the BrECADD regimen seems to be highly active and safe. Of course, we have to have a longer followup to judge on progression-free survival which is the most important endpoint in late toxicities. We are not able to judge on, for example, fertility for the time being, so we have to wait a little bit longer. Nonetheless, this new regimen might enable us to maintain the excellent lymphoma control we see with BEACOPP escalated and at the same time to expose them to less toxicities, and by this, I would like to thank you for your attention.

Last modified: July 16, 2014

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