Lymphoma
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Transcript of Lymphoma
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Three major advancements in the field of Lymphoma Treatment in the 21st centuryDr. Raymond SM WongDepartment of Medicine & TherapeuticsPrince of Wales HospitalThe Chinese University of Hong Kong
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Major Advancements in Lymphoma Treatment
1. Improvement of efficacy of antibody-directed therapy• Antibody-drug conjugates
2. Targeting B-cell receptor (BCR) signaling• BCR Signal Transduction Inhibitor Therapy
3. Combating the epigenome• Epigenetic drugs
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Monoclonal antibody for lymphoma
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Overall Survival among 399 Patients with DLBCL Assigned to CHOP vs R-CHOP
Coiffier B et al. N Engl J Med 2002;346:235-242.
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Antibody-Drug Conjugates
• Most monoclonal antibodies are not sufficiently potent to be therapeutically active on their own
• Antibody–drug conjugates (ADCs) use antibodies to deliver a potent cytotoxic compound selectively to tumor cells, thus improving the therapeutic index of chemotherapeutic agents
• Becoming an increasingly important sub-class of antibody-related therapeutics
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Brentuximab vedotin
• Anti-CD30 monoclonal antibody linked to monomethyl auristatin E (MMAE), a microtubule-disrupting agent, by a cleavable linker
• Approved for use in relapsed classical Hodgkin lymphoma’s and in systemic anaplastic large cell lymphoma
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Hodgkin’s Lymphoma
• Conventional treatment relies on standard chemotherapy, radiation therapy, and autologous or allogeneic stem cell transplantation in cases of relapsed disease
• In spite of a high cure rate, patients who are not cured with first- or second-line therapy, including stem cell transplantation, have an estimated median survival of < 3 years
• No new drugs have been approved for HL by the US FDA in more than 30 years
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Younes A Hematology 2009;2009:507-519
©2009 by American Society of Hematology
Targeted therapy of HRS cells• HRS cells express a
variety of receptors and antigens that can be targeted by monoclonal antibodies.
• Many of these receptors trigger well-defined signaling pathways that promote HRS cell survival and can be targeted by a variety of small molecules.
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Mechanism of action of brentuximab vedotin
Siddiqi T, et al, 2014
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Pivotal Phase II Study of Brentuximab Vedotin for Patients With Relapsed or Refractory Hodgkin's Lymphoma
Younes A, et al. JCO 2012
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Batlevi C L , and Younes A Hematology 2013;2013:394-399
©2013 by American Society of Hematology
Response rate of select therapies in HL
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Development of novel antibody-drug conjugates
Siddiqi T, et al, 2014
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Targeting B-cell receptor signaling
Fowler N and Davis E. Hematology 2013
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B-cell receptor signaling
Bruton’s tyrosine kinase (BTK)
• is a non-receptor kinase
• its function is essential to normal B cells
• is phosphorylated by SYK and then phosphorylates phospholipase Cγ2, leading to activation of protein kinase C beta and, in turn, CARD11
Phosphoinositide 3-kinase (PI3K)
• PI3K/AKT pathway is critical for essential cellular processes such as metabolism, growth, and proliferation
• The p110 delta and p110 gamma isoforms are expressed primarily in cells of hematopoietic origin
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Mechanism of Action of Idelalisib and Ibrutinib
Fruman DA, Cantley LC. N Engl J Med 2014;370:1061-1062.
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Ibrutinib
• An orally available, selective inhibitor of Bruton's tyrosine kinase.
• It blocks BCR signaling in normal peripheral B cells and showed antitumor activity in several types of non-Hodgkin's lymphoma
• Bruton tyrosine kinase is commonly overexpressed in mantle cell lymphoma
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Ibrutinib phase 2 trial in mantle cell lymphoma
Wang ML et al. N Engl J Med 2013;369:507-516.
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Idelalisib (GS-1101 or CAL-101)
• An oral agent that primarily inhibits the delta isoform of PI3K
• Just been approved by FDA to treat patients with
• relapsed chronic lymphocytic leukemia (CLL)
• relapsed follicular lymphoma (FL)
• relapsed small lymphocytic lymphoma (SLL)
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Phase 2 study of Idelalisib for indolent lymphoma
Gopal AK, et al. NEJM 2014
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Idelalisib for indolent lymphoma
Gopal AK, et al. NEJM 2014
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BCR Inhibitors
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BCR Inhibitors
Fowler N and Davis E. Hematology 2013
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Targeting the epigenome• Recurrent mutations in epigenetic enzymes, such as chromatin
modifiers and DNA methyltransferases, have been discovered in NHL
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Alteractions of chromatin states in NHL due to mutations in chromatin-related protein
• CRC: chromatin remodeler
• DNMT: DNA methyltransferase
• HAT: Histone acetyltransferase
• HDAC: Histone deacetylase
• HMT: Histone methyltransferase
• PcG: polycomb group
• TF: Transcription factor
Hassler MR, et al. 2013
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Vorinostat
• an histone deacetylase inhibitor
• also known as suberoylanilide hydroxamic acid, SAHA
• Approved by FDA for the treatment of cutaneous T-cell lymphoma failed other treatment
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Phase 2 trial of Vorinostat for CTCL
Duvic M, et al. Blood 2007
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Phase 2 trial of Vorinostat for CTCL
Duvic M, et al. Blood 2007
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Selected epigenetic drugs in clinical development for DLBCL
Cerchietti L, et al. Hematology 2013
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Hassler MR, et al. 2013
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Summary• The rapid improvement of our understanding of the molecular
basis of various lymphomas have led to the development of many new treatment
• Many of these new agents have shown promising results in clinical trials and are going into clinical practice
• Despite early success as well as substantial and durable responses in some patients, there is still much work to be done
• The greatest impact these new treatment will likely to come from combination therapy, possibly in the frontline setting
• Further studies are needed to answer these key questions and ultimately lead to the development of highly effective mechanism based drug regimens
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The EndThank you