UP FRONT
A Mile in Their Shoes
vember 2010 when I was ill and not responding
to chemotherapy.
About seven weeks into my disease course,
I was diagnosed with HHV-8-negative, idiopathic multicentric Castleman disease – a subtype of Castleman disease that is very poorly
understood.
Toward the end of that six-month period,
I traveled to Little Rock, Arkansas, to the
Myeloma Institute for Research and Therapy.
Frits van Rhee, MD, PhD, gave me a combination of seven different chemotherapy agents – a
multiple myeloma combination cocktail. I was
so sick before the chemotherapy that I felt better with every dose of doxorubicin, cyclophosphamide, and etoposide, and my disease finally
went into remission. Unfortunately, I have had
two relapses since then.
How is living with the disease now?
Right now, I’m in complete remission with no
sign of disease, researching and teaching at
the University of Pennsylvania. However, this
disease is incredibly episodic, and I know that
I could be on my deathbed with complete multiple organ failure with incompatible-with-life
lab values in just a few days from today.
Castleman disease is a complex disease. How
do you explain it to someone who might not
be familiar?
At its core, it involves activated immune cells
releasing cytokines that can cause subsequent
multiple organ dysfunction, but the etiology
of HHV-8-negative multicentric Castleman
disease is unknown.
It is heterogeneous: On one end of the
spectrum, patients exper ience mild flu-like or
mononucleosis-like symptoms; on the other
end of the spectrum, patients experience
sepsis-like multiple-organ system failure and
die. Fluid accumulation or edema is common,
as are multi-lineage cytopenias.
There are estimated to be about 5,000
new cases of Castleman disease a year, which
makes it as common as Lou Gehrig’s disease.
Castleman disease includes three subytpes: unicentric, HHV-8-associated multicentric, and
HHV-8-negative or idiopathic multicentric. We
know that the subtype that I have, idiopathic
multicentric, brings with it a five-year survival
rate of 65 percent, which is worse than the
five-year survival for subtypes of non-Hodgkin
lymphoma, Hodgkin lymphoma, and a number
of hematologic malignancies that we have been
able to make progress in.
There is, fortunately, one approved therapy,
an anti-IL-6 therapy, siltuximab, but unfortunately, that drug does not work for all patients.
Based on the only randomized controlled trial,
one-third of patients had a response to therapy,
and the other two-thirds were non-responders.
What led you to start the CDCN? What are
the goals of this group?
After my first relapse, I started asking my
doctor and other Castleman disease experts
targeted questions about the disease such as,
“What causes HHV-8-negative multicentric
Castleman disease? What are the immune cell
types that are driving this disorder? What are
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ASH Clinical News
key cytokines other than IL-6 that may be driving the disease anti-IL-6 non-responders?”
I realized very quickly that no one had
the answers, not even the world’s leading
experts. I decided that I would dedicate the
rest of my life to trying to solve the mystery of Castleman disease – to elucidate the
etiology of my subtype, identify the pathologic immune cells and signaling pathways,
uncover the cytokine cascade, and identify
new treatments and even a cure. I dedicated
my last year of medical school to conducting
research into idiopathic multicentric Casteman disease under the mentorship of Arthur
Rubenstein, MD. The result of that research
was a review article published in Blood in
May 2014 that outlined the current state of
knowledge for the disease, presented a new
classification system, and also proposed a
new model of pathogenesis.1
That’s also when Dr. van Rhee and I
co-founded the CDCN. We decided that we
would take a global approach to taking on
“With the Castleman Disease
Collaborative
Network, we
decided that we
would take a
global approach
to taking on Castleman disease.“
—DAVID FAJGENBAUM, MD, MBA, MSc
Castleman disease. Rather than raising funds
and having people apply to use the money
they saw fit, we would focus on global collaboration, identifying all of the physicians
and researchers worldwide who are interested
in Castleman disease. We would let them prioritize what research should be done and fund
the right person to do each of the studies,
while providing them with project management resources.
The goal of CDCN is to elucidate the
underlying mechanisms behind Castleman
disease and identify new treatments. The way
we are going about doing that is building a
network, prioritizing research, and driving
forward a high-impact research agenda.
Our biggest milestone, thus far, has been
constructing a new model for how we think
the disease works, based on the collaboration
and feedback from hundreds of physicians
in the CDCN. The medical community used
to consider the enlarged lymph nodes in
multicentric Castleman disease to be “Castleman tumors”; these lymph nodes tumors
were believed to secrete IL-6, and IL-6 caused
organ dysfunction and all the downstream
problems. What our new model proposes is
that the enlarged lymph nodes are not the
cause of cytokine release, but are a result or
reactive process due to the cytokine release.
Rather than thinking about it as a primary
lymph node tumor, we need to think about it
as a systemic inflammatory disorder. Now we
have to find out why the cytokines are being
released in the first place.
In the last year we launched four different research studies to try to understand the
disease. This year we are preparing to fund
another five to six studies. In aggregate, the
10 to 11 studies that we will be funding will
further the research necessary to uncovering
how this disease works.
Also, CDCN will be signing a collaborative partnership deal with a pharmaceutical
company to establish a global patient registry
and natural history study of Castleman disease,
called ACCELERATE (www.CDCN.org/ACCELERATE). This is going to be a major step to
help drive forward care for patients.
How has your experience with Castleman disease shaped you as a physician-researcher?
Being a patient has heightened my determination to ensure that my research and my colleagues’ research has the greatest potential to
have an impact for patients. Researchers often
can become focused on publishing papers and
receiving grants, since that is how many of us
are judged or evaluated for our careers. But that
incentive structure will encourage researchers to do lower-risk studies that will certainly
result in a paper, but maybe won’t answer the
key question for a disease. Of course, that’s a
broad generalization and certainly is not always
the case.
However, being a patient with this disease
means I couldn’t care less who publishes the
paper from my research and whether or not
I am an author. All I care about is figuring
out this disease. I see what it has done in my
life and what it does to thousands of other
patients and their family members. I have
friends who have lost their loved ones to this
disease, and I know what it feels like to have
the clock ticking for myself. I know that the
clock is ticking for other patients with my
disease.
I work with a sense of urgency that any
moment wasted is a moment that could have
saved someone’s life. When I’m looking at
research, I am focused purely on its impact.
How will this study contribute and how will
this study potentially have an impact on a
patient’s life? The last five years have included
some of the most fun years of my life as I
work with fellow clinicians, patients, and
researchers – our Castleman warrior army –
to take this disease down. I encourage anyone
interested in joining the fight to visit www.
CDCN.org or to email me at davidfa@mail.
med.upenn.edu. ●
REFERENCE
Fajgenbaum DC, van Rhee F, Nabel CS. HHV-8-negative, idiopathic multicentric
Castleman disease: novel insights into biology, pathogenesis, and therapy.
Blood. 2014;123:-2924-2933.
March 2016