Issue #9
June 2011
In This Issue
Going Hog Wild
Did You Know?
DBA Family Day
Show Us Your Logo!
Happy Father's Day
Where Are You?
The Diamond Blackfan Anemia Foundation (DBAF) is
committed to keeping you updated and connected to the
entire DBA community. The Diamond Blackfan Anemia
Foundation is YOUR Foundation! We encourage you to
share your ideas, photos, and stories for our website and
upcoming newsletters. Contact us at
DBAFoundation@juno.com.
Did You Know?
DBAF Journal Club
Going Hog Wild for DBA
Recognizing the importance of getting involved,
many DBA families draw on their family's
occupations, talents and personal resources to raise
money to support the mission of the DBA
Foundation. When the Sisemore family decided that
they wanted to do a fundraiser in honor of their
son, Milledge, they tried to think of a way to set
their efforts apart in their community. "All we
needed to do was look around our family's farm,
where we raise beef, pork, and chicken for sale at
area farmers' markets, and we knew that our family
was in a unique position to raise money in a fun
way that utilizes our farm's bounty while also
Many of our families and friends "like" the Diamond
Blackfan Anemia Foundation's Facebook page, and we
encourage you to visit our page often. The page allows us
to provide regular updates and "real time" news. We also
recognize Facebook has its limitations. It is easy to miss a
news feed and not everyone is a Facebook user. Our goal is
to keep all DBA families informed and updated. For those
preferring to receive information and support via email, the
DBA community has an email-based Yahoo support group.
You
can
join
the
group
by
visiting
www.DBAFoundation.org.
Our Facebook page posts DBA facts written by DBA nurse,
Ellen Muir, RN, MSN. Ellen has shared
four well received DBA facts and has
agreed to allow us to print the DBA facts
in our e-newsletters. This month, we will
catch everyone up on the past facts, and
future issues will include subsequent
DBA facts. Thanks Ellen!
DBA Fact #1: REMISSION
Approximately 20% of those affected with DBA have a
chance of going into spontaneous remission. These can be
long lasting. It is possible to go into and out of remission at
any point of your life. Remission for DBA is when no
treatment (steroids or transfusion) are required for 6 months
raising awareness of and rallying support for DBA in or more.
our community," stated Milledge's mom, Melanie.
DBA Fact #2: IRON CONTENT
During the month of June, the Sisemore family's
Red Haven Farm is sponsoring the Whole Hog
Raffle! The Grand Prize is - you guessed it! - a
whole pasture-raised hog, custom butchered, cut
and delivered to the lucky winner. Thanks to the
generosity of the Southeastern Pennsylvania
sustainable farming and farmers' market
community, additional raffle prizes have been
donated by their fellow farmers market vendors. In
addition to the grand prize hog, raffle items include
gift baskets and gift certificates from farmers,
bakers, cheese makers, restaurants, and others,
including locally and nationally acclaimed cheeses
from Birch Run Hill Farms and the Saveur
magazine-lauded, Talula's Table.
One unit of blood contains 200mg of iron, which would be
the same amount of iron as eating 69 lean 3oz steaks. One
3oz steak contains 2.9mg of iron.
Food restrictions of iron are unnecessary in preventing iron
overload, however supplemental vitamins should be
avoided. (Women's One a Day vitamin contains18mg iron,
Men's One a Day vitamin contains 0mg iron).
DBA Fact #3: RED BLOOD CELL PRODUCTION AND
MEDICATION
Red blood cells (RBCs) are produced in the bone marrow.
The RBCs carry hemoglobin to all the cells of the body,
providing oxygen for function. Reticulocytes (retics) are
Raffle tickets are just $5 and can be purchased
during the entire month of June at any of the
immature red blood cells. The % will tell us how hard the
Sisemore's farmers' markets or by contacting
bone marrow is working. It is not uncommon in a bone
melanie@redhavenfarm.com. The drawing will take marrow failure syndrome such as DBA to have a retic of
place on July 1. Families in Southeastern
<1%.
Pennsylvania or surrounding areas who wish to
purchase and/or help sell tickets can contact
Melanie at (267) 918-8675.
Drugs which have been studied to improve RBC production
include:
Thank you Sisemore Family for your creative and
very generous donation. Bring home the bacon!
Corticosteroids (prednisone, prelone, prednisolone) Has
been the standard drug for treating DBA with a response
rate of 80%. Many side effects with long term use, or at high
doses, including growth stunting, high blood pressure,
cataracts, diabetes, and osteoporosis to name a few. With
an initial trial of high doses, there is a risk of infection,
especially a serious form of pneumonia. Bactrim can be
given to prevent this from happening. If there is a response
in hemoglobin and retics, the dose is tapered to a more
tolerable lower dose (ideally 0.5 mg/kg every other day)
Cyclosporine A (CSA) and Antithymocyte Globulin (ATG)
has been studied in DBA patients with limited success. An
NIH-sponsored protocol combining CSA and ATG closed
due to poor responses. These drugs are associated with
serious side effects, including compromising the immune
system and kidney failure.
Upcoming Events
Whole Hog Raffle
Month of June
Epogen (procrit, epo, erythropoietin) Erytropoietin is
produced naturally by the kidney to help improve production
Red Haven Farm
Southeastern PA
Contact:
Melanie Sisemore
melanie@redhavenfarm.com
of RBCs. It can be supplemented by injection for low levels
in the system. Patients with DBA have no problem with
production, in fact usually have very high levels. Even giving
high doses will not increase RBC production in DBA. Proven
not to work.
267.918.8675
Garage Sale for DBA
June 18, 2011
Buffalo, NY
Contact:
Scott & Becky Kozlowski
scott.kozlowski@gmail.com
rebe_20@hotmail.com
716.863.8082
Metoclopramide (Reglan) Has shown to be effective in DBA.
A 33% hematologic response rate in a small group of
patients with DBA using metoclopramide, an inexpensive,
commonly used drug for reflux, induces the release of
prolactin from the pituitary gland, thereby increasing
prolactin levels. It was proposed that prolactin likely
improves erythropoiesis by stimulating cells in the
microenvironment of erythroblasts. Unfortunately other
studies in the US and Europe did not confirm these
responses but showed a 10% response rate.
Fun Day for DBA
June 25, 2011
396 Wilson Street
Clinton, MA
Contact:
Matthew Pulnik & Julie Grady
julie.grady@comcast.net
978.733.1609
Zumba Fitness Fundraiser
for DBA
July 31, 2011
Berea Recreation Center
Berea, Ohio
Contact:
Carol Mancuso
c-mancuso@sbcglobal.net
Friends of DBAF Golf
Outing & Silent Auction
September 17, 2011
Cherokee Hills Golf Club
Valley City, Ohio
Contact:
Jim and Carol Mancuso
c-mancuso@sbcglobal.net
Leucine (L-leucine) Leucine is a branched chain amino acid
(BCAA) used by muscle for energy. Amino acids are the
building blocks of protien and commonly found in food.
Recently, leucine has been tried in one patient in the
literature with DBA. A complete response was associated
with its administration (discontinuation of transfusion). In
unpublished data 5 more patients have been placed on a
leucine trial with partial responses in 4 of the 5 patients
(either decreased need for treatment or discontinuation of
treatment). Recently we have secured funding, from the
Department of Defense (DOD) with the help of the DMAF, to
study the safety and possibility of giving leucine to 50 DBA
patients on transfusion. This study is soon to open, once the
protocol goes through the approval process of the DOD,
FDA and hospital review board.
Other drugs undergoing investigation presently or in the
near future are: lenalidomide (Revlimid), and drugs used for
cancer treatment with a side effect of increased hemoglobin.
No results are available yet.
DBA Fact #4: MANAGEMENT OF IRON WITH
TRANSFUSION
ONGOING:
Criteria for starting chelation:
Wristbands Available
Contact:
Twila Edwards
twilak@cox.net
At transfusion # 10- 20 measure serum ferritin. If between
10 and 20 transfusions serum ferritin is greater than 10001500 ng/ml, on 2 separate occasions (a month apart), start
chelation. Ferritin levels are elevated with any stress on the
body...the flu, a cold, virus, etc. It is considered 'an acute
phase reactant'. Need to monitor ferritin as a trend, slowly
going up or down, not a jump. If ferritin is high for age or
with number of transfusions, you should be tested for the
hemochromatosis gene (HFE) which is another disorder
which the body retains iron, causing the same problems as
transfusions. Combine with transfusion- double trouble.
Before starting chelation, should have hearing and vision
testing as well as an echocardiocram and EKG as a
baseline and then once a year.
Tribute Cards Available
(2 styles)
In honor of...
In memory of...
Contact:
Dawn Baumgardner
dbaumgardner@dbafoundation.org
716.674.2818
- Dosing of Desferal (Deferoxamine, DFO) 40mg/kg 7 nights
a week, then may taper to 5 nights a week. A Desferal
challenge may be done before starting DFO, which is
admission to the hospital, collecting urine for 24 hrs to
measure iron without DFO and then start DFO, collecting
urine for another 24 hrs for iron quantification. If not enough
iron is being excreted, may need to hold off starting due to
high possiblity of toxicity from DFO.
Desferal only works while it is being infused. Once it is
disconnected, the free iron has nothing to bind to in order to
be eliminated from the body.
Some doctors like to use vitamin C with chelation. Must be
used with caution. It should not be taken when the DFO is
not being infused!!! The vitamin C pulls iron from the
tissues into circulation. If there is nothing there to attach to
(DFO), it will deposit somewhere else- possibly the heart!!!
DBA Cookbooks Available
Contact:
Betty Lightner
betty.lightner@gmail.com
To download your order form:
http://issuu.com/bhivemom/docs/cookbook_order_
form-pdf
- Exjade (deferasirox) dosing is 20 mg/kg and may be
escalated to 40 mg/kg maximum dose. Exjade works well
to maintain iron balance, does not bring ferritin levels down
very quickly. May be used at the same time as DFO ie.
DFO 12 hrs over night, then Exjade in the morning.
Iron Overload is a Serious Health Condition with no
symptoms until it is too late. Some complications
include:
cirrhosis or fibrosis of the liver
cardiac arrythmias, which can be lethal
diabetes
reproductive organ failure
growth stunting
endocrine failure affecting the thyroid
Good Search/Good Shop
Raise money for DBAF just by searching the web
and shopping online!
Just download the GoodSearch - Diamond Blackfan
Anemia Foundation - DBAF toolbar at
http://www.goodsearch.com/toolbar/diamondblackfan-anemia-foundation-dbaf
as well as others.
Please call me with any questions. Iron overload is
reversible, even if in trouble with cardiac issues. Diabetes
and reproductive failure may not be reversed. Ellen Muir,
RN, MSN 1-877-DBA-NURSe (322-6877)
DBA Family Day 2011 - Seattle,
WA
Quick Links
Make a Donation
From Washington to California, West Coast DBA adults met in
Seattle to participate in DBA Family Day
Our Website
Join the DBA Yahoo Group
:: 716-674-2818
A fun-filled, informative day was had by all on April 30,
2011. Seattle Children's Hospital graciously hosted a
DBA Family Day giving DBA families the opportunity
to meet, share their stories, and learn more about
Diamond Blackfan Anemia. Dr. Akiko Shimamura and
Kathleen McGregor MN/MPH organized the event and
presentations were given by Dr. Akiko Shimamura,
Dr. Bertil Glader, Dr. Laurie Burroughs, and Dr.
Sioban Keel. Thanks to all for making DBA Family
Day 2011 - Seattle a smashing success! Love the
shirt, Shelly!
Take the Challenge ~ Show Us
Your Logo
T-shirts,
hats, coffee
mugs, face
paintings,
tattoos,
bags,
pumpkins ...
our logo is
showing up
everywhere! We are thrilled that our beautiful logo is proudly
being worn and displayed by patients, families, and friends.
Two-legged and four-legged friends and family members of
Jacob and Scarlett Buckmaster show their support for Jacob
and all DBA families at a recent 5K Walk/Run for DBA held
in Republic, MO.
Here's the challenge: we'd like to see how many places
we can show off our logo! Snap
a picture sporting our logo and
send us your story. Draw it, print it
out, wear it, wave it, tattoo it, carve
it... be creative! Take us to school,
on vacation, to the hospital, on a
plane, to the game, in your home...
anywhere! Show us your logo!
Send your photos and stories to
DBAFoundation@juno.com.
Happy Father's Day
The Diamond Blackfan Anemia
Foundation extends our sincerest
wishes to all the extraordinary
fathers, grandfathers, uncles,
brothers, friends, and all the special
men who touch the lives of our DBA
families. We recognize and applaud the difficult and
rewarding job you do. Relax and enjoy your special day!
Do you know about our Mother's Day to Father's Day
Challenge? Click here to learn more Celebrate DBA
Moms & Dads.
Where Are You?
Did you receive the latest 16 page DBA Newsletter last
week? Help us to help you! If you did not receive the DBA
Newsletter in the mail, it may mean we do not have your
current mailing address. Update your information at
http://www.dbafoundation.org/registration.php
If you have any questions, contact Dawn at
DBAFoundation@juno.com.
Journal Club
This month's Journal Club is, in
part, a literary piece including a
biography of one of the authors of
the manuscript under
consideration. This biography will
be in the Hellenist tradition,
focusing on big picture items,
rather than a detailed chronology
of a person's life. Is this
biography of one of the elder
Steven R. Ellis, PhD
statesmen (or women) in the DBA
Research Directo
field? Actually not, this person is
in his late 20's early 30's max, but
has already accomplished much
at this young age. The subject of this biography is Dr.
Johan Flygare, physician/scientist by choice, Swede by
birth. When I entered the DBA field in the mid 2000's,
Johan was already making a name for himself as a
graduate student in Dr. Stefan Karlsson's lab at Lund
University in Sweden. Their group had created one of the
more sophisticated cellular models of DBA. During this
period, Johan also spent a brief period in my laboratory and
together with Dr. Anna Aspeci, who was visiting from Irma
Dianzani's lab in Italy, we were able to show a ribosome
biogenesis defect in cells from DBA patients. In the late
2000's Johan had to return to clinical training, but after
receiving his MD he returned to the Karlsson lab briefly
before entering the laboratory of Dr. Harvey Lodish at the
Whitehead Institute in Boston. It is a manuscript stemming
from his time in the Lodish lab that is the subject of this
Journal Club. This manuscript has substantial implications
for the development of improved therapies for Diamond
Blackfan anemia.
The manuscript (Flygare et al) published in Blood (2011)
117:3435-3444 is entitled "HIF1α synergizes with
glucocorticoids to promote BFU-E progenitor self-renewal".
As you are all aware, steroids are a therapeutic option for
DBA, but come with a number of potential complications.
The work by Flygare and colleagues shows that drugs that
increase the amount of the protein HIF1α work together with
glucocorticoids to stimulate the production of erythorid
progenitor cells found in reduced amounts in DBA patients.
These studies suggest that it might be possible someday to
treat DBA with reduced steroid doses, or eliminate
exogenous steroids altogether using drugs that increase
HIF1α levels. Much still remains to be worked out before
this approach will translate to the clinic, but it is encouraging
to note that drugs targeting HIF prolyl hydroxylases are
currently being considered as alternative treatments for
EPO-responsive anemias so their toxicity profiles and other
pharmacological properties are currently being examined
(Muchnik & Kaplan).
Let us turn our attention back to the Flygare manuscript.
The study begins by describing a new technique to isolate
the hematopoietic progenitor cell populations thought to be
primarily affected in DBA. They were then able to show that
it is the BFU-E progenitor cells that are responsive to
glucorticoids, stimulating their self renewal and thereby
increasing the amount of erythroblasts that can be derived
from individual BFU-Es approximately 40-fold. To
understand how glucocorticoids were having this effect,
Flygare and colleagues examined changes in gene
expression induced by glucocorticoids. Somewhat
surprisingly, the authors found that many of the genes
upregulated by glucocorticoids contained DNA sequence
signatures characteristic of genes regulated by the protein
HIF1α. HIF1α regulates gene expression in response to low
oxygen concentrations. A role for HIF1α in erythropoiesis
has been known for some time as a regulator of
erythropoietin (EPO), which makes a great deal of sense,
because if oxygen concentrations are low, a reasonable
response would be to induce erythropoietin expression and
make more red blood cells. HIF1α itself is regulated by a
family of enzymes known as HIF prolyl hydroxylases, which
use molecular oxygen to label the HIF1α protein for
degradation. When oxygen partial pressures are low, the
HIF prolyl hydroxylases targeting HIF1α are inhibited,
leading to higher levels of HIF1α which in turn stimulate
erythropoietin production. The surprise in the Flygare
manuscript however, was that HIF1α also appears to be
involved in inducing erythropoiesis at an earlier stage
upstream of EPO, acting on BFU-E's to stimulate their selfrenewal.
The authors reasoned that by inhibiting the HIF prolyl
hydroxylases targeting HIF1α they could potentially increase
HIF1α levels and stimulate erythropoiesis at the progenitor
level. Moreover, they felt that glucocorticoids and prolyl
hydroxylase inhibitors might work together or at least show
some partial overlap in stimulating erythropoiesis at the
progenitor stage. When put to the test, they were able to
show that a drug targeting HIF prolyl hydroxylases
enhanced the effect of glucocorticoids in stimulating BFUE's by about 7 fold. Thus, the two drugs have a synergistic
effect in inducing the production of CFU-E's and
erythroblasts from BFU-E's.
What has all this to do with DBA? Plenty, in fact. To quote
the authors, "A group of patients who directly could benefit
from the CFU-E-promoting effect of PHIs [Prolyl
Hydroxylase Inhibitors] are those with the red cell progenitor
disorder DBA." The results from Flygare et al. suggest that
with the synergistic effect seen with prolyl hydroxylase
inhibitors it may be possible to reduce steroid
concentrations in treating DBA patients or possibly eliminate
exogenous steroids altogether through the ability of prolyl
hydroxylase inhibitors to synergize with endogenous levels
of steroids found in DBA patients.
So is there a downside to all of this? Well, yes; inhibiting
prolyl hydroxylases that target HIF1α for degradation could
lead to an enhanced risk of cancer. Once marked for
degradation by prolyl hydroxylases, another protein is
necessary to direct the actual degradation of HIF1α. A
genetic deficiency of this other protein leads to von HippelLindau syndrome, a strong cancer predisposition
syndrome. The rationale for this increased incidence of
cancer is in part, that tumors are frequently hypoxic
(reduced oxygen supply) and need HIF1α expression to
counteract the hypoxia. Thus, promoting HIF1α expression
by using prolyl hydroxylase inhibitors could in principle lead
to an increased risk for cancer. While there is certainly
cause for proceeding with caution on the potential use of
prolyl hydroxylase inhibitors as a treatment option for DBA,
these studies nevertheless open a new window of
opportunity for improved treatment options for patients with
DBA.
One final note in this rather lengthy journal club is that Dr.
Flygare has been supported by the DBA Foundation at
various points in his career. He is transitioning from the
Lodish lab to begin his own laboratory at the same Institute
as that of Stefan Karlsson in Lund Sweden. One of the
proposals currently under review for funding from the DBA
Foundation is from Dr. Flygare as he starts this new phase
of an extremely productive career.
Flygare J, Rayon Estrada V, Shin C, Gupta S, Lodish HF HIF1alpha
synergizes with glucocorticoids to promote BFU-E progenitor selfrenewal. Blood 117(12): 3435-3444
Muchnik E, Kaplan J HIF prolyl hydroxylase inhibitors for anemia. Expert
Opin Investig Drugs 20(5): 645-656