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
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
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
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
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
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.