Bendamustine for non-Hodgkin lymphoma

Abstract

Interview by Louise Rishton, Commissioning Editor

Professor John Gribben is Chair of the International Workshop on non-Hodgkin Lymphoma and the Gordon Hamilton Fairley Chair of Medical Oncology at St. Bartholomew’s Hospital, Bart’s Cancer Institute, London, UK, a Cancer Research UK Centre of Excellence. His doctoral studies were performed at University College London, UK as the recipient of a Wellcome Trust Fellowship Award and he continued post-doctoral training with Professor Lee Nadler at the Dana-Farber Cancer Institute (Harvard Medical School, MA, USA). In 1992, Gribben was appointed to the Faculty at Harvard Medical School, where he remained as Associate Professor of Medicine and an Attending Physician at the Dana-Farber Cancer Institute and Brigham and Women’s Hospital (MA, USA), until returning to London in 2005. Gribben is a founding member of the CLL Research Consortium, Associate Editor of Blood and was elected a Fellow of the Academy of Medical Science. His primary research interests include the immunotherapy of cancer (including stem cell transplantation), the identification of B-cell-tumor antigens and the detection and treatment of minimal residual disease in leukemia and lymphoma.

First, what led you to pursue a career in hematologic oncology?

I was interested both in seeing patients and in the science of the laboratory. Hematology is a very natural subject to enable you to combine this, as it is easy to get hold of the hematology cells to be able to study them more in a laboratory.

Are there any particular people that have influenced your research?

The very first person that got me interested in the field was very interested in bone marrow transplantation. As my original degree is in immunology, I became interested in the interaction between the cancer cell and the immune system.

This has completely influenced my whole career as I have focused on work both in hematological malignancies and on the cancer cells from which they derive, with the immune system being a particular focus.

What do you think has been your biggest achievement in the field so far?

I would say the 20 years I spent in the USA at Harvard University (MA, USA). I was involved in a project going all the way from cloning a molecule that had not been previously described, to characterizing it, looking into taking it into clinical trials, and then organizing those clinical trials. Only once in a lifetime can you take a project through from discovery to its application in a novel clinical trial.

A large part of what I continue to work on relates around the importance of these molecules, which are involved in how the immune system interacts with the T cells.

There has been a lot of interest in new therapies in non-Hodgkin lymphoma. Why do you think this is?

There are around 80 subtypes of lymphoma in the WHO classification, so although it has the term ‘lymphoma’ attached, you are really talking about a great many different diseases that are very different from each other.

Some of the new therapies look potentially applicable to many of the different subtypes, and some of the more targeted therapies are going to be specifically targeted toward a subtype’s specific pathway. Trying to understand these differences can give us a great deal of information about these diseases.

At the latest American Society of Hematology (ASH) meeting, there were 43 abstracts describing the use of bendamustine as a treatment for a number of lymphoid malignancies. This compound has a very interesting past. What do you think has led to so much recent interest?

We all call it the new–old drug. It came out of development from chemists in East Germany and was available at a time when compounds that we now take for granted were not available.

Clinicians in West Germany were in contact with colleagues from the east and have a lot of experience in using the drug. Now that data are emerging on both its toxicity and efficacy profile, it is becoming a drug of major interest in the west.

The latest results announced at the 2012 ASH have suggested promising data for a bendamustine–rituximab regimen in indolent non-Hodgkin lymphoma. Were you surprised by the results & what effect do you think this will have on the field?

This is a study that everyone has known about for a long time but has just been published [1]. Led by Mathias Rummel from the StiL group, this was a study considering the standard of care in these patients – cyclophosphamide, doxorubicin, vincristine and prednisolone, plus rituximab (R-CHOP) – and compared that with a bendamustine–rituximab combination [101]. This included both follicular lymphoma and mantle cell lymphoma patients, as well as a few other histological subtypes. The result was that bendamustine–rituximab was superior to R-CHOP in that study but was associated with much less toxicity in terms of side effect profile and of course, no serious loss of hair, which is a big issue to patients.

This adds to the results presented at American Society of Clinical Oncology 2012 (Chicago, IL, USA) by the StiL group [102], so what you have got is a drug combination that is less toxic and potentially more efficacious.

Clinical decisions are also supported by the results coming from the BRIGHT study [103]. Nobody likes to make changes to practice based on the results of a single study. Although the Rummel study was important in terms of awareness and because it included a large number of patients and a long follow-up [101], Flinn et al. have released the results of a quite large US noninferiority study comparing chemotherapy plus rituximab versus bendamustine plus rituximab in indolent non-Hodgkin and mantle cell lymphoma patients [103]. These results support the findings of lower toxicity, as well as showing very good efficacy. Therefore, we have a second study that confirms what we were already seeing from the German study. Two trials in two different continents reporting the same results manage to give clinicians confidence to use the drug.

Do you feel the results point to the need to increase clinical usage of the drug?

I think that there is a lot of interest. The number of abstracts in this meeting, as well as the market data, indicate that many more clinicians are starting to use this drug.

It is also the case that patients are much more savvy now due to the internet – patients are coming in and saying “I want the drug that doesn’t cause me to lose my hair.” While historically, the advice would be to say “lose your hair now and gain some benefit from the drug”, now clinicians could say “there is a chance this combination is just as effective and you will not lose your hair, so let us try it”.

In the past, it could be said that trials with bendamustine have been inconsistent. Why do you think this was & what do you think has changed with the latest trials?

In 2010, I was part of an International Consensus Panel discussing bendamustine [2]. We were becoming concerned by the inconsistencies in dose regimens between the currently ongoing trials, which made it very difficult to compare and contrast results and gain clinical insight.

The workshop purpose was to try to determine the optimal dose from the data, and following our recommendations, most of the studies are now using defined doses of bendamustine at specific points and that means most of the trials going forward tend to be much more consistent.

In short, they were inconsistent not by the results but by the design. Consistency in design allows us to know which dose and dose regimen are correct.

So do you think we will need further trials into the compound?

There are always going to be more trials. There are ongoing trials that will be published – 43 abstracts from this meeting and studies that are currently ongoing. I would not be surprised if there is a study there that does not completely confirm what has happened, as is the case with every disease. That is why you like to see confirmatory studies.

There is also a lot of interest in using this drug with the new agents that are appearing. These are oral targeted therapies with low side effect profiles that are showing good responses in patients. The big question is, can you combine these types of therapies with a chemotherapy drug with a lower toxicity? It does not surprise me that a lot of the new studies with these novel agents such as ibrutinib (a Bruton’s tyrosine kinase inhibitor) are using a bendamustine backbone of the therapy. So I think you will see a lot more studies using bendamustine in combination with the newer agents that are coming up behind it.

In your opinion, what has been the most important finding in the last 5 years of hematologic oncology research?

If you had asked me a while ago, I would have said that this was the development of monoclonal antibodies and particularly the addition of rituximab into chemotherapy, and this, of course, is still up there. However, what is really getting people excited at the 2012 ASH meeting is the new oral targeted therapies and seeing how quickly we have gone from basic scientific discoveries to clinical trials and approval. Overall, what we are seeing is the combination of scientific discoveries in cancer, and this science driving the therapies.

Do you think this links back to the first answer regarding why you developed an interest for hematology?

That is probably why I am a little bit biased! However, this is what I have found exciting and we do believe, particularly in lymphoma subtypes (and we are now experiencing subtypes within subtypes), that we may be moving away from an era in which everyone is treated with chemotherapy, into a setting where you target the therapy toward the science behind the patient, type of malignancy and even particular subtype biology.

Do you see this as a consequence of the postgenomic era?

Absolutely, I would say so. Again, there were lots of exciting abstracts presented at ASH discussing the genomics of the hematologic cancers, insights into their particular pathways and heterogeneity. Most importantly, this leaves us with the possibility of potentially targeting the gene for the cancer, switching the cancer cell off or ensuring that it differentiates in a normal way.

What do you see as the big topics for hematologic research over the next 5 years?

I think the big topic is going to be how we start applying the personalized medicine approach. Instead of taking all patients with follicular lymphoma and treating them with the same drug combinations, taking a genomic approach to determine what is the most rational drug combination for those patients. This raises challenges for clinical trial design. It raises challenges for the number of patients that any one center can have access to and how we get these studies completed, but I think that this is the way the field is going. I think over the next 5 years we will see more and more studies designed around a personalized medicine approach.

Financial & competing interests disclosure

J Gribben has received grant funding from NIH, Cancer Research UK and the Medical Research Council. He has also received honoraria for Advisory Boards and lectures from Roche/Genentech, GSK, Celgene and Napp/Mundipharma. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Editorial assistance, supported financially by Mundipharma, was provided by Flesichman-Hillard Ltd in the production of this manuscript.