An Intelligent Way to Deliver High Doses of a Very Potent Cytotoxic Agent Without Significant Toxicity
Published on 21st November
Surrounded by fantastical and modernist landmarks designed by Antoni Gaudí, Barcelona, in the northeast of Spain, is a surreal wonderland where mansions look like dragons… or giant ice-cream sundaes, the Museu Picasso and Fundació Joan Miró features modern art by their namesakes, Roman archaeological sites dot the entire city and the best know monument – the Sagrada Família – is a building site.
It’s a sheer delight to explore this colorful and flamboyant city, known for its infamous soccer team, its street theater with acrobats and dancers, where ‘Castellers‘ build human towers or castles for fun, where a crooked maze of streets in the old Barri Gòtic (the old Gothic Quarter), La Ribera & Sant Pere and El Raval are crammed with shops, restaurants and bars and where serious chocoholics with connoisseurial aspirations learn to excel in chocolate making or simply sit down to enjoy Xocolata amp melindros (the Catalan version of Churros y Chocolate in which churros or xurros is replaced by melindros – a light biscuit like a ‘lady finger’).
L’Hospitalet de Llobregat, located to the immediate southwest of this extravagant city, by population the second largest city in Catalonia and the sixteenth in Spain, is home to Institut Català d’Oncologia, the Catalan Institute of Oncology, one of Spain’s most prestigious medical research institutes.
The Institut Català d’Oncologic’s cutting edge center for the treatment of cancer at the Hospital Duran i Reynals (Avinguda de la Granvia, 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain), established in 1996, has become a leader in the treatment of low-frequency and highly therapeutically complex tumors. The Instiute is one of the most authoritative cancer research centers in Europe.
In October, following the the pharmaceutical industry meeting CPhI World Wide, held October 4 – 6, 2016 in Barcelona, Spain, and the 10th International Symposium on Hodgkin Lymphoma (ISHL) in Cologne, Germany, held October 22- 25, 2016, we sat down with Anna Sureda MD Ph.D, Head of the Hematology Department and Hematopoietic Stem Cell Transplant Programme; Institut Català d’Oncologia – Hospital Duran i Reynals, to discuss some of the exciting developments involving the treatment of patients with Hodgkin’s lymphoma, non-Hodgkin’s lymphoma and multiple myeloma.
According to the Lymphoma Coalition, a global network of worldwide not for profit lymphoma patient organizations, over 62,000 people worldwide are diagnosed with Hodgkin lymphoma each year and approximately 25,000 people die each year from this cancer, representing a major unmet medical need. 
… The treatment of patients with Hodgkin lymphoma … has completely changed with the advent of brentuximab vedotin…
Question: What is your background? Tell me about your organization and your research involving antibody-drug conjugates or ADCs, including the antibody-drug conjugate brentuximab vedotin (Adcetris®; Seattle Genetics/Takeda Pharmaceutical Co.) and (other) targeted and personalized therapies.
Answer: My name is Anna Sureda. Since June 2015 I am the Head of the Hematology Department of the Catalan Institut of Oncology – Hospital Duran i Reynals in Barcelona, Spain. I have been involved with GELTAMO, the Spanish Group of Lymphomas, for the last 15 years and have chaired the Hodgkin’s lymphoma committee for a period of two years.
In 2004, I was elected chair of the Lymphoma Working Party of the eBMT (The European Society for Blood and Marrow Transplantation
) and later on, secretary of the same organization (from 2010 to 2016) when I stepped down from my position as chair. Currently, I am co-chair of the Lymphoma committee of the Center for International Blood and Marrow Transplant Research (CIBMTR).
I have been very much involved in the clinical research of relapsed/refractory (r/r) Hodgkin’s lymphoma patient with special dedication to both autologous and allogeneic stem cell transplantation. I started to use brentuximab vedotin when I was a consultant in Cambridge, UK, back in 2010 and I have quite a lot of experience in the use of this agent, not only in Hodgkin’s lymphoma but also in systemic anaplastic large cell lymphoma. I have participated in several trials that included brentuximab vedotin: ECHELON-1 and ECHELON-2 prospective clinical trials and I am part of the steering committee of the AETHERA trial.
Treatment Options in Spain
Question: How does treatment of Hodgkin lymphoma (HL) in Spain differ from treatment in other countries? What are some of the key measures?
Answer: I do not think that treatment of Hodgkin lymphoma patients is significantly different in Spain in relation to other countries. First line therapy is based on ABVD (a chemotherapy regimen used in the first-line treatment of Hodgkin lymphoma consisting of concurrent treatment with doxorubicin (Adriamycin®), bleomycin, vinblastine and dacarbazine) in the vast majority of the patients.
A few centers may eventually use BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) escalated in young patients with high risk disease. PET CT, an advanced nuclear imaging technique combining positron emission tomography (PET) and computed tomography (CT) reveals information about both the structure and function of cells and tissues in the body during a single imaging session, is widely used at the time of diagnosis and at the end of therapy. Autologous stem cell transplantation is being offered to patients in chemo-sensitive relapse.
ESHAP (etoposide, methylprednisolone, cytarabine, also known as Ara-C, and cisplatin) is the most frequently used second line treatment for those patients who are primary refractory or relapse after first line therapy.
Brentuximab vedotin is being used in the two approved indications: for those patients who relapse after an autologous stem cell transplantation or ASCT (if the patient is young enough, has a HLA compatible donor and chemo-sensitive disease, in many cases as a bridge to an allogeneic stem cell transplantation) and in those patients who have failed at least two lines of chemotherapy and are not considered candidates for an autologous procedure.
Insurance and Reimbursement
Question: What about approval and reimbursement (of brentuximab vedotin) in Spain?
Answer: After approval by the European Medicines Agency (EMA), brentuximab vedotin was officially launched in October 2014 in Spain. As the Spanish health care system is a public one, all patients that fall within the indication have the drug paid by the health care system.
Question: Can you say something about Hodgkin lymphoma and the importance of novel treatment options? Unmet needs?
Answer: Hodgkin lymphoma is a highly curable hematological malignancy. In fact, with modern strategies more than 90% of the patients being diagnosed in early stages can be cured with first line treatments. Cure rates are not so high with patients diagnosed in advanced stages.
Unfortunately, 5 to 10% of patients are primary refractory to therapy (less with the use of BEACOPP escalated as first line therapy) and around 30% of the patients relapse after achieving a first complete remission. Autologous stem cell transplantation is the standard of care for those patients who are primary refractory or relapse but autologous transplant is able to only cure 50% of these patients. In this sense we still have a proportion of patients that represent a big unmet medical need and novel treatment options are needed for these patients.
International Symposium on Hodgkin Lymphoma
Question: Earlier this month, during the meeting of the ISHL, there were a large number of presentations by both Seattle Genetics and Takeda. What are some of the major findings? How do these benefit patients treated now and in the (near) future?
Answer: There were several updates of both company-sponsored (e.g. the AETHERA trial) and investigator developed prospective clinical trials that further indicate the efficacy and safety of the use of brentuximab vedotin in patients with relapsed / refractory (r/r) Hodgkin lymphoma. The results of these studies will further improve the outcome of r/r Hodgkin lymphoma patients.
Question: What are the benefits of these engineered and complex novel drugs in the treatment of Hodgkin lymphoma and other cancers?
Answer: They represent a completely different way to treat patients with Hodgkin lymphoma (and other types of hematological malignancies that express the CD30 antigen in the cell surface). It represents a very intelligent way to deliver high doses of a very potent cytotoxic agent without giving the patient significant toxicity.
CD30 is a cell surface antigen expressed on malignant HL Reed-Sternberg cells and targeted by brentuximab vedotin, which comprises a CD30-targeted monoclonal antibody conjugated to the microtubule disrupting agent called Monomethyl Auristatin E or MMAE via a protease-cleavable linker.
Question: How have ADCs changed the landscape for the treatment of Hodgkin lymphoma?
Answer: Until the advent of brentuximab vedotin in this case, the treatment of patients with Hodgkin lymphoma was essentially based on chemotherapy, more or less intensive, different drugs and combinations but only chemotherapy with the potential combination of radiotherapy in a significant proportion of patients. This landscape has completely changed with the advent of brentuximab vedotin.
Question: How does brentuximab changed the treatment options of patients with Hodgkin lymphoma and other hematological cancers?
Answer: Brentuximab vedotin allows the administration of a very potent anti-microtubule drug, MMAE into the target cells, Reed Sternberg cells in the case of patients with Hodgkin lymphoma. This mechanism of action has nothing to do with the mechanism of action of chemotherapy in general.
Question: What about safety findings?
Answer: Side effects are mild with the use of brentuximab vedotin precisely because of the type of molecule we are talking about. The complex circulates as a whole in the blood stream of the patient and only when the CD30 antibody is linked with the CD30 antigen in the cell Surface, MMAE is internalized into the cell cytoplasm and is released inside the cell. Because of this very local effect toxicity is very much acceptable.
Question: What are your expectations in the development of additional (therapeutic) indications of brentuximab vedotin?
Answer: Brentuximab vedotin is a very effective molecule in both patients with Hodgkin lympyhoma and sALCL if we consider the results of the pivotal phase II prospective clinical trials. Brentuximab vedotin single drug has also demonstrated a high effectivity in patients with relapsed cutaneous T cell lymphoma (aggressive types).
There are other lymphomas that also express the CD30 antigen in the cell surface of the malignant cells. I think the drug is also going to be very effective in these histologies that are still the subject of further investigations.
In addition to that, the clinical development of brentuximab vedotin is very quick in the setting of the already approved histologies and I am very much convinced that the results of all these evaluations are going to be very interesting.
Question: What about risk factors for relapse in patients with r/r Hodgkin lymphoma after autologous stem cell transplant?
Answer: Risk factors for relapse after ASCT in patients with Hodgkin lymphoma have never been studied prospectively. We have quite a high number of retrospective analyses that evaluate the role of potential clinical risk factors for these patients. Lately, the impact of PET CT status has also been taken into consideration.
This aspect has been a major issue when analyzing the results of the prospective clinical trial AETHERA that considers the use of brentuximab vedotin as consolidation therapy for those patients with Hodgkin lymphoma that are at a high relapse risk after the ASCT.
Brentuximab vedotin consolidation offers a significantly better survival after transplantation in comparison to placebo for those subgroups of patients that were included in the analysis.
Question: In some cases, researchers are looking at brentuximab vedition as a single use treatment options; others are looking at combination thereapies. What are your expectations? Where do you see the clear benefits in treatment of patients? For example: Single-agent brentuximab vedotin showed activity in r/r CD30+ HL patients ineligible for SCT or multi-agent chemotherapy.
Answer: Pivotal studies were developed using brentuximab vedotin single drug in both patients with Hodgkin lymphoma and systemic anaplastic large cell lymphoma (sALCL). Nevertheless, there is quite a lot of information already presented and eventually published that indicate that brentuximab vedotin is quite a safe drug to be combined with chemotherapy and that can eventually improve chemotherapy based results. In this sense, I will be quite interested in knowing and considering how to include in my own clinical practice if possible combinations of brentuximab vedotin with first line-chemotherapy and also salvage chemotherapy options.
Question: The first generation of ADCs use linking technologies that conjugate drugs non-selectively to cysteine or lysine residues in the antibody, resulting in a heterogeneous mixture of ADCs. This approach leads to suboptimal safety and efficacy properties and makes optimization of the biological, physical and pharmacological properties of an ADC challenging. Novel ADCs in (early) pre-clinical development may offer different approaches. What are your expectations for future of ADCs?
Answer: Future ADCs might be as effective as the one we have today (or even more), basically represented by brentuximab vedotin. I think it is a very intelligent and refined way of delivering cytotoxic drugs into the cells and should be further exploit in the future.
Question: Some drug developers are also looking to expanding the application of ADCs beyond oncology and hematology to other important disease areas. What are your expectations?
Answer: As I have said before this technology is extremely interesting and should be further explored. In this sense, other diseases / pathologies that can be targeted because of the expression of cellular antigens should be the focus of ADCs technologies.
Last Editorial Review: November 21, 2016
Photo 1.0: Anna Sureda MD Ph.D, Head of the Hematology Department and Hematopoietic Stem Cell Transplant Programme, Institut Català d’Oncologia – Hospital Duran i Reynals Courtesy: © 2016 Institut Català d’Oncologia – Hospital Duran i Reynals. Used with permission. Featured Image: The Park Güell, one of the major works of Antoni Gaudí, is part of Barcelona’s public park system composed of gardens and architectonic elements. Courtesy: © 2016 Fotolia. Used with permission.
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