Analysis of the B-HOLISTIC study and importance of relapsed/refractory Hodgkin lymphoma real world evidence data

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Published: 8 Dec 2020
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Prof Mark Hertzberg - Prince of Wales Hospital, Sydney, Australia

Prof Hertzberg speaks to ecancer about the B-HOLISTIC study which was presented at ASH 2020 and the importance of relapsed/refractory Hodgkin lymphoma real world evidence data. Initially he explains what the B-HOLISTIC study was about and then goes on to mention the key results obtained from this study.

Prof Hertzberg says that results from B-HOLISTIC show that PFS rates remain low in patients with R/R cHL receiving salvage therapy; the greatest risk was among patients with inadequate response to salvage chemotherapy.

The low PFS rates highlight the importance of considering novel targeted therapies to address unmet medical needs. He also highlights that overall, these results from 2010-2013 show that despite the differences in healthcare systems, ethnicities and treatment patterns in B-HOLISTIC, clinical outcomes remain consistent.

Prof Hertzberg then talks about the importance of real world evidence (RWE) data with regards to daily treatment of patients with R/R HL. In the end he mentions a few other studies of importance to R/R HL from ASH that contain RWE data.

This programme has been supported by an unrestricted educational grant from Takeda.

 

Most of the data that we have in advanced stage Hodgkin lymphoma derives from clinical trials and a few retrospective studies, particularly from European and North American academic centres. So there’s really a paucity of data from real world evidence. Now, we know that real world data is important because it hopefully recapitulates the data that we have seen from clinical trials but also because regulatory agencies and reimbursement authorities are now looking for real world data in order to better inform their decisions around drug approval and reimbursement.

So this study was designed to look at advanced stage Hodgkin lymphoma, particularly relapsed/refractory Hodgkin lymphoma but also first line therapy. Data was collected over a four year period across 13 countries in six major jurisdictions and regional areas. It was highly representative because 1,600 patients with classical Hodgkin lymphoma were identified and more than 400 patients with relapsed Hodgkin lymphoma were identified. So I feel that it was truly reflective of real world data and clinical practice. The data that was collected was very informative and when we look at relapsed/refractory disease it illustrated a number of key points.

When we look at relapsed/refractory Hodgkin lymphoma only about 50% of patients survive after three years, despite high dose chemotherapy and stem cell transplantation. Having learnt that from clinical trials, this was recapitulated clearly in the evidence that was obtained in the B-HOLISTIC study. So in relapsed/refractory Hodgkin lymphoma we have learned some very important data that in many ways is reflective of clinical trials, and that was reassuring, particularly in both relapsed/refractory and, of course, first line disease.

If we want to stick to relapsed/refractory disease it’s quite sobering. About nearly 90% of patients were able to receive intensive salvage chemotherapy but of those only 62% achieved a complete or partial response and, indeed, only 32% achieved a complete response. Furthermore, of the patients who were deemed eligible for high dose chemotherapy and stem cell transplantation, and that was about 70% of patients, only three-quarters of those ended up getting to transplant. So overall only 50% of patients got to transplant.

There are a number of key factors that were prognostic in determining the outcome of patients. That outcome was sobering because at three years progression free survival was only 40%. That’s pretty much reflective from clinical trials in the literature, perhaps slightly inferior, but it’s around the 40-50% mark. Clearly there is an unmet need.

So what we’ve learned in the relapsed/refractory cohort is that a number of adverse prognostic factors were identified. For example, the Josting score was confirmed as being prognostic since it included three factors – those patients who relapsed early, that is within 3-12 months; those patients who relapsed with advanced stage disease; and those patients who relapsed with anaemia. But the factor with the highest hazard ratio was, in fact, those patients who achieved an inadequate response to their salvage therapy and that hazard ratio was high at just under 6. It’s here where we clearly have the unmet need. That response rate and that adverse risk factor has been borne out in recent studies with the advent of PET imaging after salvage and before transplant. So it’s concordant with those results which have told us that those patients who have a complete metabolic response to salvage therapy and then go on to transplant do very well, with progression free survival at 3-4 years of around 75-80%, whereas those patients who do not achieve a complete metabolic response to their salvage have a poor outcome after transplant with progression free survival of only 25-30%.

So it’s that group that represents the clearest unmet need. That is, those patients who have an inadequate response to salvage therapy prior to going on to transplant. We need to improve that response rate, improve that complete metabolic response rate so that more patients can go on to transplant. Now, to date we haven’t had very good agents in order to do that. To date we’ve only had really three modalities, that is another cross-resistant chemotherapy regimen, we had radiation therapy and in some jurisdictions we’ve had tandem transplant. But now, with the advent of novel agents, it’s clear that this is where their role will become most important and it has been demonstrated already with the use of novel agents such as PD-1 inhibitors with toxin-coupled antibodies such as brentuximab vedotin, that using that, those agents, either alone or in combination with chemotherapy, either single agent such as bendamustine or combination chemotherapy such as DHAP or ICE, that more patients can be rescued to achieve a complete metabolic response and then go on to transplantation.

What would the impact of these results be on the future treatment of RRHL?

The impact is that it’s first recapitulating the data that we’ve learned from clinical trials, particularly around, as I said, PET assessed responses to first line salvage therapy. It’s shown in the real world that we have similar inadequate rates of complete response to salvage therapy, here only 32% and only 50% of patients going on to transplant.
So now we have the opportunity to use novel agents, as I said, alone or in combination to increase the number of patients achieving a complete response, this time to a second line salvage or possibly even a first line salvage, so that more patients can go on to transplant in remission, in a complete metabolic response and therefore have a greater likelihood of long-term disease free survival and cure.

Is there anything else you would like to add about this study?

The other thing we learned from this study was about first line therapy because we collected data on 1,600 patients with advanced stage Hodgkin lymphoma being treated with first line therapy. What it showed was that across all these jurisdictions is that the regimen ABVD represented the standard induction therapy in well over 85% of patients, again consistent with treatment across Northern America and Europe. Not only that, but the results in the use of ABVD chemotherapy were very similar to those results seen in recent clinical trials such as the ECHELON-1 study, such as some of the PET directed studies like RATHL and the SWOG study in which patients commenced on ABVD.
So I think that’s reassuring that patients being treated in these jurisdictions, in countries around the world, are achieving outcomes very similar, if not identical, to those that were seen in some of the big trials conducted in advanced stage Hodgkin lymphoma, as I said, in Europe and North America.

What is the importance of RWE data with regards to daily treatment of patients with RRHL?

In recent years we’ve really had to rely upon either phase III randomised studies or phase II studies that have been conducted in large academic institutions, particularly in Europe, North America and here in Australia. That doesn’t always reflect the real world patients that we see in the clinic because they have specific inclusion and exclusion criteria and because sometimes you might have to wait in order to have the patients enrolled, meanwhile they might be progressing and declaring themselves ineligible. It’s the real world data that is extremely important in providing information about our patients in the clinic, not only to benefit clinicians but, as I said, to benefit regulatory authorities because nowadays they are wanting more and more real world evidence when it comes to drug approval and registration and when it comes to reimbursement by the authorities in different jurisdictions.

So it’s studies like this that are going to become more and more important and we are already learning that, particularly in jurisdictions like Australia where cost effectiveness is important and it’s the real world data that can often provide that cost effectiveness when submissions are being made for drug approval.

Are there any other studies regarding RWE data from the virtual ASH 2020 meeting that you’d like to talk about?

This was the most important study of real world data in Hodgkin lymphoma presented at ASH. This is 1,600 patients with first line and 430 patients with relapsed/refractory disease so there’s nothing else that recapitulates that. There are other important studies now looking at trying to work on the back of the results of these studies in order, as I said, to improve the results that we’ve identified in these studies in terms of salvaging more patients successfully, getting them into remission before transplant and getting more patients to transplant.

There are a few studies recently of, for example, brentuximab vedotin combined with chemotherapy agents such as bendamustine or combination therapy regimens such as ICE, DHAP and ESHAP that have been shown to be very effective in improving the complete response rates and therefore improving long-term progression free and overall survival for those patients being salvaged and going on to stem cell transplantation.

So it’s going to be now the combination of these agents, both the checkpoint inhibitors such as pembrolizumab and nivolumab, combined either with another novel agent or with chemotherapy and then the toxin-coupled antibodies such as brentuximab vedotin, as I said, particularly combined with either single agent or combination chemotherapy regimens.

This study was a huge undertaking, as I said, because it involved 13 countries, six regions, including Latin America, the Middle East, South Africa, East Asia, Australia and Russia. This was a huge undertaking to collect this sort of data. I think it’s going to be very informative for future trials to have this data and for regulatory authorities as well.
The only potential disadvantage of the study was that we weren’t able to collect in a comprehensive manner adverse event data but that’s not surprising when you’re doing a study like this. But it certainly doesn’t detract from the key messages of the study around patient outcomes in the real world.

So I think investigators need to be commended for the comprehensive nature of the patient baseline characteristics, the patient outcomes, the details around their chemotherapy regimens, their response rates and their survival. Really it’s to be commended because it will be very useful in the future when conducting and designing clinical trials and when submitting to authorities for regulatory approval of new agents for both registration and reimbursement.