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

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

Monoclonal antibody for lymphoma

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.

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

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

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

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.

Mechanism of action of brentuximab vedotin

Siddiqi T, et al, 2014

Pivotal Phase II Study of Brentuximab Vedotin for Patients With Relapsed or Refractory Hodgkin's Lymphoma

Younes A, et al. JCO 2012

Batlevi C L , and Younes A Hematology 2013;2013:394-399

©2013 by American Society of Hematology

Response rate of select therapies in HL

Development of novel antibody-drug conjugates

Siddiqi T, et al, 2014

Targeting B-cell receptor signaling

Fowler N and Davis E. Hematology 2013

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

Mechanism of Action of Idelalisib and Ibrutinib

Fruman DA, Cantley LC. N Engl J Med 2014;370:1061-1062.

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

Ibrutinib phase 2 trial in mantle cell lymphoma

Wang ML et al. N Engl J Med 2013;369:507-516.

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)

Phase 2 study of Idelalisib for indolent lymphoma

Gopal AK, et al. NEJM 2014

Idelalisib for indolent lymphoma

Gopal AK, et al. NEJM 2014

BCR Inhibitors

BCR Inhibitors

Fowler N and Davis E. Hematology 2013

Targeting the epigenome• Recurrent mutations in epigenetic enzymes, such as chromatin

modifiers and DNA methyltransferases, have been discovered in NHL

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

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

Phase 2 trial of Vorinostat for CTCL

Duvic M, et al. Blood 2007

Phase 2 trial of Vorinostat for CTCL

Duvic M, et al. Blood 2007

Selected epigenetic drugs in clinical development for DLBCL

Cerchietti L, et al. Hematology 2013

Hassler MR, et al. 2013

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

The EndThank you