Lymphoma and Myeloma Drugs

Patrick Sosnay
Slide credits: Richard Ambinder

definitions
Lymphoma: cancer of the lymphocytes, solid
tumor. (CLL and lymphoma closely related)

Multiple Myeloma: cancer of plasma cells.

Disease can be from the tumor itself or the
circulating antibodies

Drugs to cover
Vinca alkyloids (vincristine)
Taxanes (paclitaxel)

Immunomodulatory Drugs (Thalidomide)

Antibodies (Rituximab)
Bortezomib

Vinca alkyloids
Derivative of periwinkle
Bind tubulin, inhibit assembly of microtubules and inhibit
mitosis
All of the vincas are associated with peripheral neurotoxicity
Paresthesias, especially in the fingers and toes
Constipation
Discovered because they lead to myelosuppresion
Hepatic clearance, needs to be given IV
Key drugs in the treatment of lymphoma, acute lymphocytic
leukemia, multiple myeloma

Paclitaxel

Derived from the bark of the yew tree

Stabilize GDP-bound tubulin, disrupt mitosis
Also results in significant myelosuppresion, and
neuropathy
Also hepatic clearance, IV dosing
Used in lung, breast, ovarian, prostate cancers

Microtubules

Mixture of alpha and beta tubulin

Vital in cell division
Both vinca alkyloids and paclitaxel target these
Non-specific inhibitor or rapidly dividing cells

Thalidomide

1957 tranquilizer, pain killer, antiemetic for

morning sickness birth defects, especially
limb abnormalities in early 60s
Seen to have activity as an anti-inflammatory
agent perhaps related to anti-TNF effects in
leprosy approved by the FDA for treatment
of erythema nodosum leprosum in 1998
Anti-angiogenesis effects?

Thalidomide
Oral agent
Toxicity mainly teratogenic, also peripheral
neuropathy, fatigue. Little to know
myelosuppresion
Eliminated by hydrolysis in the blood
Newer agent: Lenalidomide (oral)approved for
myeloma and myelodysplasia
Much more potent inhibitor of TNF alpha
Causes cytopenias (neutropenia, thrombocytopenia)
Doesnt cause birth defects in animal models

Antibodies
Rituximab - anti-CD20 is the prototype
Several other examples not just for lymphoma:
Brentuximab (anti-CD30) Hodgkin's lymphoma
Trastuzumab (anti-her2) breast cancer
New ones being developed

Early example mouse anti-human specific for

the idiotype of the B cell.

Rituxumab
Hematopoietic
stem cell

B cell

Plasma cell

CD20

CD20 is only present on the B cells

Antibody recognition leads to:
Directly induces apoptosis (lymphocytes are built with
multiple self-destruct mechanisms. CD20 binding turns
one or more of those on).
Antibody dependent cell mediated cytotoxicity (marks
tumor cells for killing by other cells such as NK cells)
Fixes complement leading to cell lysis

Chimeric vs Humanized

Chimeric antibodies have a mouse variable

region spliced to a human constant region.
human

mouse

A variety of manipulations can yield

antibodies whose variable regions are also
partially human (humanized).
human

humanized

Serum sickness
Limiting the use of all of these agents
(chimeras more than humanized) is
development of serum sickness: fever,
urticaria, polyarthralgias, hypotension, and
lymphadenopathy
Antibody-antigen complex deposit in vascular
endothelium and activate immune response
Type III hypersensitivity reaction
Can also see antibodies against the antigen

Rituxamab paradox
Serum sickness is infrequently seen with
rituximab therapy why?

Bortezomib
An inhibitor of proteasome-mediated protein
degradation used in the treatment of multiple
myeloma
Disrupts multiple intracellular signaling cascades,
leading to apoptosis
It activates the cell's stereotypical "unfolded protein
response" or UPR, in which abnormal protein
conformation activates adaptive signaling pathways in the
cell. The composite effect leads to irreversible
commitment of myeloma cells to apoptosis.

Review - IMPORTANT
Disrupting microtubules will interfere with
rapidly dividing cells (vinca alkyloids, taxanes)

Antibody therapy allows specificity for certain

types of cancer, but is limited by escape
mechanisms and serum sickness