are proteins that have a therapeutic e;ect when attached to a specific molecule in the
body. They are e;ective in the treatment of numerous cancer types and function in
several di;erent ways.
CLL is the most common type of leukemia diagnosed among
U.S. adults age 20 or older, with 15,720 new cases projected to
be diagnosed in 2014 ( 1). In the majority of cases, CLL arises
in immune cells called B cells, or B lymphocytes, that have a
protein called CD20 on their surface.
Given that CD20 is found only on B cells, both normal and
CLL B cells, therapeutic antibodies that target CD20 were
developed for the treatment of CLL. Two such therapeutic
antibodies, ofatumumab (Arzerra) and rituximab (Rituxan),
were approved by the FDA in October 2009 and February
2010, respectively. Although these two agents, when used in
combination with traditional chemotherapies, signi;cantly
increase survival for many patients ( 85), a substantial number
of patients have disease that does not respond to initial
treatment or eventually becomes resistant to it ( 85, 86). As a
result, researchers began working to develop more e;ective
CD20-targeted therapeutic antibodies.
A;er attaching to CD20 on the surface of CLL cells,
one of the ways in which rituximab and ofatumumab
exert antileukemic e;ects is by ;agging the CLL cells for
destruction by immune cells. As a result, these agents
can be considered molecularly targeted therapeutics
and immunotherapeutics (see sidebar on How
Immunotherapeutics Work, p. 65).
A;er basic immunology research uncovered a detailed
molecular understanding of how rituximab attracts immune
cells and instructs them to destroy the cells to which it is attached
( 87), bioengineers were able to create a new generation of CD20-
targeted antibodies with enhanced ability to recruit immune cells
and direct them to attack cancer cells ( 86).
One of the new generation of CD20-targeted antibodies,
obinutuzumab (Gazyva), was approved by the FDA for
the treatment of CLL in November 2013. ;is decision
was made a;er early results from a large clinical trial
showed that most patients with CLL lived signi;cantly
longer without their disease worsening when obinutuzmab
was added to their traditional chemotherapy treatment,
chlorambucil ( 88). Subsequent results from this clinical
trial have shown that the addition of obinutuzumab to
chlorambucil also provided an overall survival advantage
compared with chlorambucil alone ( 89).
;e FDA approval of obinutuzumab for the treatment of CLL
was not only an important decision for patients with CLL,
like David Rampe (see p. 54), but it was also a groundbreaking
moment for regulatory science. ;is is because the use of
obinutuzumab for the treatment of CLL was the ;rst time
a therapeutic was approved by the FDA a;er having been
designated a “breakthrough therapy” (see sidebar on FDA’s
Expedited Review Strategies, p. 40).