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`Future Medicine·\ :\..
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`111
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`I NEWS & VIEWS
`INTERNATIONAL JOURNAL OF HEMATOLOGIC ONCOLOGY, VOL. 2, NO. 5
`Conference Scene: Recent developments in the
`understanding and treatment of hematological
`malignancies
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`0 Free Access
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`Sarah BrumskillE:::1\/ictoria Walker&Mary-Ann Campbell
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`Published Online: 8 Oct 2013 I https://doi.org/10.2217/ijh.13.52
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`& About:= Sections
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`Abstract
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`~ Tools < Share
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`The 18th Congress of the European Hematology Association, Stockholm, Sweden, 13-16 June 2013
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`The European Hematology Association (EHA) is a nonprofit scientific organization created in 1992,
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`whose aim is to provide a forum for European medical professionals to unite and share researrh
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`develop education and promote excellence within the clinic. Today, the EHA has over 3000 mE
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`from various countries throughout the world, governed by an executive board and councilors
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`by members. The multidisciplinary nature of the Annual Congress of the EHA is an opportunity for
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`medical professionals with an interest in hematology to exchange information on various topics from
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`novel therapeutics to best clinical practice, such as the ethical issues involved in biobanking. Here we
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`have outlined some of the research that was of most interest at this meeting.
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`Role of Bruton's tyrosine kinase in 8-cell malignancies
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`Bruton's tyrosine kinase (BTK) is a key component of the 8-cell receptor (BCR) signaling pathway
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`and has been indicated to play a role in the interaction between B cells and the tumor
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`microenvironment [1]. This is an important aspect of 8 -cell malignancies since factors found on the
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`surface of malignant B cells encourage the cells to stay in proliferative centers like the lymph nodes,
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`allowing chemoresistance to occur [2].
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`BTK inhibitors have been found to have great efficacy in the clinic, in particular Pharmacyclics (CA,
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`USA) has had astonishing results with their first-in-class BTK inhibitor ibrutinib (PCl-32765) against
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`chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL) and the activated B-cell (ABC)
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`subtype of diffuse large B-cell lymphoma (DLBCL). A Phase II study of the activity of ibrutinib against
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`ABC DLBCL was presented at this meeting. The aim of the study was to find an overall response rate
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`(ORR) to this single agent in relapsed/refractory ABC DLBCL [3]. Seventy patients were enrolled in
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`this study with a median age of 64 years. In ABC patients, responses were observed in 12 out of 29
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`patients, giving an ORR of 41 %, whereas in the germinal center B-cell patients, a response was seen
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`in only one out of 20 patients, giving an ORR of 5%. This agent also demonstrated a very favorable
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`safety profile and these results confirm the hypothesis that a greater response would be shown in
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`the ABC subtype due to its reliance on chronic BCR signaling compared with germinal center B-cell
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`DLBCL, which arises from B cells found in secondary lymphoid organs and do not have a BCR
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`signaling component.
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`The results of an interim study of an international, multicenter Phase II study of ibrutinib against
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`relapsed/refractory MCL were also reported [4] . MCL is an aggressive subtype of non-Hodgkin
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`lymphoma and many patients are prone to relapse. The patients enrolled in this study were either
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`bortezomib-naive or -exposed, relapsed/refractory MCL patients. Bortezomib is the licensed
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`treatment for MCL. lbrutinib 560 mg per os every day (q.d.) was administered until disease
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`progression occurred and responses were measured every 2 months. One hundred and fifteen
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`patients were enrolled with a median age of 68 years and the median number of prior treatments
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`was three. Treatment-related adverse effects were found in less than 20% of patients, the median
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`time on the study was 9.2 months and 47% of patients remain on therapy. Interestingly, it wa:
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`that the longer a patient followed the treatment, the faster the observed response rate, and a
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`of longer follow-up periods showed how durable the response to ibrutinib could be. In addition, no
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`significant difference was observed between the response in the patients that were bortezomib(cid:173)
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`naive or -exposed. Further studies have been started as a result.
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`Results from a Phase I study of another highly selective BTK inhibitor, CC-292, which was recently
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`acquired by Celgene (NJ, USA) were presented [5] . The aim of this study was to identify dose-limiting
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`toxicities and to assess the clinical activity of this molecule in patients suffering from CLL or B-cell
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`non-Hodgkin lymphoma (B-NHL). Cohorts of 3-12 patients who had more than one prior treatment
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`for CLL or B-NHL were given doses of the drug from 125, 250, 400, 625, 750 and 1000 mg q.d. or
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`375 and 500 mg twice daily (b.i.d.). An expansion cohort of 750 mg q.d. for CLL patients was also
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`included. All patients underwent continual dosing in 28-day cycles until progressive disease or
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`intolerable toxicity occurred. Eighty six patients were enrolled in this study and many had high risk
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`factors (e.g., unmutated /GHVor deletion of 11q22). The median time on this therapy was 144 days,
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`however, the minimum toxic dose was not reached and the most frequent adverse effects were
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`fatigue and diarrhea, which were found in less than 10% of patients. This study demonstrated how
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`well tolerated this agent is with minimal adverse events seen over the full dose range. Seventeen CLL
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`patients and one 8-NHL patient achieved partial remission at doses of 750 mg q.d., 1000 mg q.d.,
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`375 mg b.i.d. and 500 mg b.i.d .. A trend towards improving responses as the dose increased was
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`observed. The half-life of CC-292 is 2 h and BTK resynthesis occurs after 12 h, therefore b.i.d. dosing
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`maintains BTK inhibition. The results of this study will determine the conditions for the Phase II study
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`on this agent. As with other BTK inhibitors, a significant reduction in the size of lymph nodes was
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`noted, as well as an increase in peripheral lymphocytosis, further strengthening the notion that BTK
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`has an important role in maintaining the tumor microenvironment and encouraging malignant 8 cells
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`to stay in proliferative centers such as secondary lymphoid organs. Further evidence to support the
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`existence of this poorly understood interaction between 8 cells and the lymphoid microenvironment,
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`combined with the exciting results of BTK inhibitors in the clinic, has made BTK a hot topic at the
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`European Hematology Association (EHA) congress this year.
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`'Sleeping Beauty' system to generate CD 19+ T cells
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`This novel research described the use of the 'Sleeping Beauty' system of gene transfer to create both
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`autologous and allogenic T cells expressing a CD19-specific chimeric antigen receptor (CAR) [6] ,
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`conferring a new antigen specificity on the T cell, which can be manipulated to target malignant
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`cells. In this case, the CAR was created against CD19, which is found on the surface of normal and
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`malignant 8 cells and is a popular target for gene therapy treatments against B-cell cancers. In
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`addition it has been suggested that CD19 causes the upregulation of the MYC oncoprotein th
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`the PAX5 transcription factor [7] In this study, 11 patients received the T cells, all had shown
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`relapses of acute lymphoblastic leukemia (ALL; n = 4) or 8-cell lymphoma (n = 7) after autologous (n
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`= 3), allogenic (n = 3) or cord blood (n = 1) hematopoietic stem cell transplantation. When patients
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`were dosed with 106 T cells/m 2, a prolonged persistence of CAR+ T cells was not observed and these
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`patients relapsed. Subsequently, two patients with ALL received an increased dose of 107 T cells/m 2,
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`one patient relapsed, however the other obtained complete remission with continued expression of
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`CAR+ T cells 4 months after the infusion. This new approach to treating 8-cell malignancies has an
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`impressive safety profile with no adverse effects due to treatment experienced by any patient
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`enrolled on the study, which gives it an advantage over the current chemotherapy regimen available
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`for patients. This could be the next upcoming treatment for maintaining remission in CD19+ lymphoid
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`cancers.
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`Ongoing debate on Notch: oncogene or tumor suppressor?
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`The Notch gene was first discovered in Drosophila and is responsible for the Notched wing
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`phenotype. Now, Notch has been found to have multiple functions within multicellular organisms
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`from the maintenance of stem cell populations and influencing cell fate decisions to tumorigenesis.
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`The ongoing debate in oncology is whether Notch genes are oncogenes or tumor suppressors. Freddy
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`Radtke's research (Ecole Polytechnique Federale de Lausanne, Life Sciences Switzerland) showed
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`that the best example of Notch acting as a tumor suppressor is in the skin, where it is normally
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`expressed within the basal layer and is involved in cell differentiation [8]. When this expression is
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`inactivated, mice develop tumors within 1 year. Interestingly, when all Notch signaling in the skin is
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`blocked, the mice develop a severe form of inflammation similar to atopic dermatitis, indicating this
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`gene's role in controlling the immune system. Jon Aster (Brigham and Womens Hospital, MA, USA)
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`reported that frequent loss-of-function mutations in the Notch1 gene are found in T-cell ALL (T-ALL),
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`CLL and squamous cell carcinoma [9]. Radtke's group also worked to investigate the role of Notch1
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`as an oncogene by knocking out Dicer in an early onset T-ALL mouse model. Dicer is an
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`endoribonuclease, which is absolutely essential for Notch signaling in hematopoietic cell lineages. All
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`control animals died within 90 days whereas the Dicer knockouts survived. In addition, primary T(cid:173)
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`ALL patient samples were treated with Notch inhibitors and all patients whose cells expressed the
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`NCID Notchl biomarker showed a positive result. These data imply that Notchl signaling has a role
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`to play in T-ALL. Notch signaling in oncology is not yet well understood but it has the potential to
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`become an important therapeutic target in the future.
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`BKT140 in the treatment of chronic myeloid leukemia
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`Tyrosine kinase inhibitors have revolutionized the treatment of chronic myeloid leukemia (CML);
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`however, drug resistance and relapse are common with this myeloproliferative disorder. The reason
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`for relapse is believed to be due to the presence of leukemic stem cells in the bone marrow, w l PDF
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`chemokine-rich bone marrow microenvironment lends protection to the leukemic stem cells. T
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`CXCR4 receptor and its ligand CXCL12 are thought to be involved in the maintenance of these cells
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`within the bone marrow, making CXCR4 an attractive target. Katia Seider (Sheba Medical Center, Tel
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`HaShomer, Israel) presented the findings of her study on the role of CXCR4 in CML and the effect of
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`the CXCR4 antagonist BKT140 on CML cell survival and sensitivity to imatinib [10]. BKT140 is a
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`unique CXCR4 antagonist that binds with high affinity and induces cell death. The results showed
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`that BKT140 inhibited CML cell proliferation by 40-60%. When a coculture system was set up using
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`CML cells and primary human bone marrow stromal cells, increased levels of imatinib resistance
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`were observed; however, when BKT140 was added in combination with imatinib the amount of
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`proliferation was reduced and an apoptotic effect was observed.
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`Conclusion
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`This brief overview is a summary of some of the presentations that were of most interest and does
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`not encompass the vast amount of research and clinical data presented at the 18th Congress of the
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`EHA. Many other interesting reports were presented at both plenary and poster sessions alike. This
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`meeting of European oncology professionals provided the opportunity for the presentation of
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`excellent translational research and clinical data, as well as education sessions, which gave in-depth
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`information into the biology of disease progression.
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`Financial & competing interests disclosure
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`S Brumski/1 is an Associate Scientist at Redx Oncology, V Walker is a Senior Pharmacologist at Redx
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`Oncology and M-A Campbell is Head of Pharmacology at Redx Oncology. The authors have no other
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`relevant affiliations or financial involvement with any organization or entity with a financial interest
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`in or financial conflict with the subject matter or materials discussed in the manuscript apart from
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`those disclosed.
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`No writing assistance was utilized in the production of this manuscript.
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