Lymphoma
Upcoming SlideShare
Loading in...5
×
 

Like this? Share it with your network

Share

Lymphoma

on

  • 224 views

Three major advancements in the field of lymphoma treatment in the 21st century

Three major advancements in the field of lymphoma treatment in the 21st century
Raymond Wong, MD

Statistics

Views

Total Views
224
Views on SlideShare
112
Embed Views
112

Actions

Likes
0
Downloads
8
Comments
0

4 Embeds 112

http://aphcon.org 85
http://www.aphcon.org 17
http://www2.dragndropbuilder.com 9
https://www.aphcon.org 1

Accessibility

Categories

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment
  • 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. These signaling pathways can be targeted by a variety of small molecules.
  • Response rate of select therapies in HL.

Lymphoma Presentation Transcript

  • 1. Three major advancements in the field of Lymphoma Treatment in the 21st century Dr. Raymond SM Wong Department of Medicine & Therapeutics Prince of Wales Hospital The Chinese University of Hong Kong
  • 2. 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
  • 3. Monoclonal antibody for lymphoma
  • 4. 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.
  • 5. 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
  • 6. 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
  • 7. 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
  • 8. Targeted therapy of HRS cells Younes A Hematology 2009;2009:507-519 ©2009 by American Society of Hematology • 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.
  • 9. Mechanism of action of brentuximab vedotin Siddiqi T, et al, 2014
  • 10. Pivotal Phase II Study of Brentuximab Vedotin for Patients With Relapsed or Refractory Hodgkin's Lymphoma Younes A, et al. JCO 2012
  • 11. Response rate of select therapies in HL Batlevi C L , and Younes A Hematology 2013;2013:394-399 ©2013 by American Society of Hematology
  • 12. Development of novel antibody-drug conjugates Siddiqi T, et al, 2014
  • 13. Targeting B-cell receptor signaling Fowler N and Davis E. Hematology 2013
  • 14. 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
  • 15. Mechanism of Action of Idelalisib and Ibrutinib Fruman DA, Cantley LC. N Engl J Med 2014;370:1061-1062.
  • 16. 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
  • 17. Ibrutinib phase 2 trial in mantle cell lymphoma Wang ML et al. N Engl J Med 2013;369:507-516.
  • 18. 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)
  • 19. Phase 2 study of Idelalisib for indolent lymphoma Gopal AK, et al. NEJM 2014
  • 20. Idelalisib for indolent lymphoma Gopal AK, et al. NEJM 2014
  • 21. BCR Inhibitors
  • 22. BCR Inhibitors Fowler N and Davis E. Hematology 2013
  • 23. Targeting the epigenome • Recurrent mutations in epigenetic enzymes, such as chromatin modifiers and DNA methyltransferases, have been discovered in NHL
  • 24. 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
  • 25. 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
  • 26. Phase 2 trial of Vorinostat for CTCL Duvic M, et al. Blood 2007
  • 27. Phase 2 trial of Vorinostat for CTCL Duvic M, et al. Blood 2007
  • 28. Selected epigenetic drugs in clinical development for DLBCL Cerchietti L, et al. Hematology 2013
  • 29. Hassler MR, et al. 2013
  • 30. 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
  • 31. The End Thank you