Fall 2001 - Fanconi Anemia Research Fund

24 Pages·2002·0.6 MB·English

by  Tanya Harvey

F
AMILY
N
EWSLETTER
#30 A Semi-annual Newsletter on Fanconi Anemia for Families, Physicians, and Research Scientists Fall 2001
Medical Controversy
Emerges at Family
Meeting
An FA transplant expert sparked
controversy and intense discussion by
recommending that FA patients with
matched, unrelated donors should, in
most cases, go to transplant without
undergoing androgen treatment. This
subject dominated discussion among
parents and treating physicians at the
summer meeting and did not produce
Families Learn, Share Experience,
a clear consensus among those in
and Have Fun at Annual Family Meeting attendance.
continued on page 10
Families from all over the world clearly added to the strength of the
arrived eagerly in Williams Bay, Wis- meeting. HIGHLIGHTS
consin, for the 11th annual FA Fami- Again this year, Rob Sawyer and
ly Meeting. This meeting, held on the the members of his teen group from
Harris Presents Guidelines for
campus of Aurora University on the Rotary International in Trenton,
Treatment of FA...................... 2
shores of Lake Geneva, brought Michigan, provided childcare and a
Wagner Advocates Earlier
together FA families and eminent FA recreation program for the children
Transplantation For Patients
researchers and clinicians for a three who attended. This group of excep-
with HLA Matched,
and one-half day meeting filled with tional teenagers raised money via events Unrelated Donors....................3
science, practical advice, new friends, throughout the year to finance their
Five Patients Transplanted
and fun. trip to Lake Geneva. Rob also brought
with Mismatched Donors
Thirty-seven FA families with a a number of wonderful and energetic Do Well......................................4
total of 41 children from Germany, adult volunteers this year. Our sincere
Gene Therapy Trial Produces
Norway, Argentina, Brazil, Canada, thanks to our Trenton, Michigan, friends.
First Encouraging Results.......5
and the United States attended this The speakers at this meeting were
event. Old-timers were awed by the outstanding. You are strongly encour- Regional Meetings.......................11
number of new families at the meeting. aged to read the Science Letter and Family News.................................13
This year, the Fund was able to offer Medical News section of this Newslet-
Creative Fundraising .................21
eight scholarships to new and old ter for detailed information on all
families alike, so many more families medical and scientific presentations. Science Letter.....................enclosed
were able to attend. The new families continued on page 23
MEDICAL NEWS
Harris Presents Guidelines for Treatment of FA
At our August 2001 Family Meet- minimize the risk of patient sensitiza-
ing, Richard Harris, Children’s Hos- tion to blood products. Harris stated
pital, Cincinnati, presented an that it is the number of different
overview of different treatment options donors and not the number of trans-
for FA patients, including the benefits fusions that can lead to complications
and risks of each option (see Science at the time of transplant.
Letterfor details). Harris noted that androgens often
Harris urges patients with matched work for years and there is a low risk
sibling donors to go to transplant when of early death. The disadvantages are
platelets fall below 50,000. Combining that androgens can cause serious side
statistics from all transplant centers, effects (adenomas, adenocarcinoma,
between 65% and 85% of patients are and lakes of dilated blood vessels in
now alive two years or more following the liver) and reduce the chance of a
a matched sibling donor (MSD) trans- good outcome of a later transplant. graft-versus-host disease (GVHD) in
plant. Cincinnati has now performed For most patients, Harris is no longer combination with an aspergillus infec-
30 of these transplants. Ten patients recommending use of androgens prior tion; one was due to pulmonary failure.
received prior androgen therapy. Twen- to a matched unrelated transplant. Three patients experienced significant
ty-five are currently alive, for an over- Cincinnati has now performed GVHD. Harris estimates that between
all survival rate of 83%. eight unrelated donor transplants using 60% and 70% will now survive an
The options are more complicated the new fludarabine protocol. Five unrelated donor transplant. The high
for the 75% of patients who lack a sib- patients received bone marrow; three risk of dying within the first three
ling donor. Harris discussed transfu- received peripheral blood stem cells. months (estimated at around 30%) is
sions, androgens and cytokines, out- Harris does not recommend cord obviously the greatest drawback to an
lining the advantages and drawbacks blood for unrelated transplants. Of unrelated transplant. The primary
of each option. For those choosing these eight patients, six are alive from advantage is that a successful trans-
transfusions, he urged the use of des- three to twenty-five months post-trans- plant is curative of the bone marrow
ignated donors and blood filters, to plant. One death was due to chronic complications of FA. u
Reducing Toxicity – Transplant Results in Germany
Wolfram Ebell of Children’s Char- had leukemia at the time of transplant. Ebell believes that it is still too early
ité Hospital, Berlin, reported on 17 All six patients with matched sibling to recommend an unrelated transplant
FA transplants at our recent Family donors, and seven of eleven with alter- before a trial of androgens. He notes
Meeting. By eliminating radiation and nate donors survive. Of the four who that many patients respond well to
cyclophosphamide, Ebell hopes to died, three died of infection and one of these hormones for a long time. Almost
reduce secondary tumors and toxici- leukemia. Toxicity was very limited. all of the patients he has transplanted
ty. Engraftment is achieved by using Five patients suffered graft failure after have been on androgens for extensive
fludarabine, high stem cell doses and the first transplant. Four of these periods of time. Ebell has not seen seri-
T cell antibodies. patients engrafted after the second ous complications related to androgen
Six patients received stem cells from transplant, and one after the third. usage during transplantation, and does
matched sibling donors; eleven had Ebell has modified his protocol in an not consider androgens a risk factor
alternate donors. Eight patients had effort to prevent graft failures. Mean for transplantation. u
severe aplastic anemia, six patients had follow up post-transplant is 18 months.
myelodysplastic syndrome and three See Science Letter for details.
2 FA Family Newsletter
Wagner Advocates Earlier Transplantation For Alter Questions
Patients with HLA Matched, Unrelated Donors Changing Guidelines
At our August, 2001 Family Meet- outcomes were strikingly different At our recent Family Meeting,
ing, John Wagner, University of Min- between patients classified as “standard Blanch Alter, National Cancer Insti-
nesota, discussed the use of androgens risk” and those who were deemed to tute, questioned the wisdom of chang-
in the treatment of bone marrow fail- be “high risk” patients. Standard risk ing the guidelines established at the
ure, and recent survival outcomes at patients had aplastic anemia with or 1998 Consensus Conference con-
his center following the use of the con- without abnormal clones, or early signs cerning androgen therapy for patients
ditioning agent fludarabine. Based on of myelodysplasia, and no history of with matched, unrelated donors. As
his latest data analysis, he now recom- major infections. High risk patients transplant technology improves, a
mends that most patients with HLA had infections, myelodysplasia or change in direction may well be justi-
matched, unrelated donors proceed to leukemia at the time of transplant. Of fied. At the present time, however, Alter
transplant without first undergoing a 14 standard risk patients, 12 survive. believes that there is insufficient evi-
trial of androgens. Of nine poor risk patients, only two dence to make this change in policy.
Androgens are successful in increas- survive. The Conference recommended that
ing blood production in approximately For the first time, survival rates patients lacking a matched sibling
50% of FA patients. Red cells, white comparable to those of matched sibling donor begin androgen therapy when
cells and platelets can all be affected. donor recipients can be achieved, at one of the following is present: Hb
Many patients can taper the dosage of least short term, in FA patients who <8g/dl or symptoms from anemia;
androgens and still maintain stable come to transplant without infections, platelets <30,000/mm3, and neutrophils
counts, but eventually these drugs are myelodysplasia or leukemia. Because <500/mm3. Alter stated that the hemo-
no longer effective. Wagner outlined of this, and considering the adverse globin usually improves in >50% of
the many side effects of androgen ther- effects of androgen therapy, Wagner patients within one to three months,
apy (see Science Letter), and his con- advocates earlier transplants for most and platelets in a smaller proportion
cern that androgens may be associated patients, before initiating a trial of by 4 to 6 months. Neutrophils may or
with lower rates of survival following androgens. may not respond, and improve more
bone marrow transplantation. Andro- Wagner believes that androgens slowly than the other cell lines. Alter
gens delay the time to transplant, should be considered for patients at stated that there are patients who have
increasing the likelihood of infections higher risk for problems with unrelat- been treated with androgens for up to
and other complications. In some cases, ed donor BMT. These patients include 40 years, as well as patients who have
androgens have been implicated in adults, those with HLA mismatched taken androgens for 5 to 10 years, after
organ toxicity during transplantation. donors, and those with pre-existing which they no longer needed andro-
Several studies cite androgens as a risk significant organ dysfunction. Andro- gens to maintain blood counts.
factor in transplantation outcomes. gens may also be used to delay trans- The side effects of androgens are
In the past, graft failure was the plantation in families attempting in potentially extensive, although many
major cause of death in FA patients vitrofertilization and pre-implantation are reversible when the treatment is dis-
undergoing an unrelated bone mar- genetic diagnosis in an effort to have a continued (see Science Letter). Alter ad-
row transplant. (In 1998, Wagner healthy, HLA matched sibling. dressed the concern that androgens are
reported that approximately 39% failed Because of the poor survival rate in implicated in poor transplant outcomes.
to engraft). Between April 1999 and high risk patients, Wagner is changing While androgens are often used by
July 2001, 23 patients at the Univer- his protocol for this population. He patients with low neutrophils, they are
sity of Minnesota were conditioned will eliminate total body irradiation not the cause of infections. And inad-
with a new protocol, which included and use busulfan, fludarabine, cyclo- equate monitoring can lead to higher
the drug fludarabine. Primary neu- phosphamide and ATG in an effort to dosages than necessary, increasing the
trophil engraftment was achieved in improve outcomes. u likelihood of liver toxicities. While
20/20 evaluable patients. Probability acknowledging the worrisome side effects
of one-year survival was 46%. How- of androgen therapy, Alter believes that
ever, when survival outcomes were ana- this drug still plays an important role
lyzed according to several risk factors, in the management of FA. u
Fall 2001 3
Five Patients Transplanted with Mismatched Donors Do Well
Farid Boulad, MD, Memorial fifth patient cannot yet be evaluated. Boulad writes that it has been “very
Sloan-Kettering, reports that he has All five are alive and well; the first three tough” getting her through these
now transplanted five FA patients using patients are alive three years, two years complications.
related (4 patients) or unrelated (1 and one year post-transplant, while the The number transplanted under
patient) mismatched donors. Two were last two are alive 10 months and 5 this protocol at Memorial Sloan-Ket-
mismatched at two antigens; three were months post transplant. No patient tering is very small, but the outcomes
mismatched at one antigen. For the has yet experienced acute or chronic to date are encouraging. Boulad con-
first patient, this was a second trans- graft-versus-host disease. The third tinues to be optimistic about these very
plant; for the subsequent four patients, patient had post-transplant complica- promising results. u
it was a first transplant. Dates of trans- tions (CMV infection and EBV lym-
plant were 5/27/98, 3/31/99, 1/20/00, phoma), which have been resolved.
10/26/00 and 4/5/01. Except for the Most of these five patients were
patient receiving a second transplant, considered very high risk. The first
Use of Logo
patients received total body irradia- patient had aplastic anemia. Patients
tion. Protocols included fludarabine 2, 3 and 4 had myelodysplastic syn- This is just a reminder to our FA
and cyclophosphamide. Four patients drome (MDS) with abnormal mor- families: please use our logo or
letterhead only after you have
received G-CSF-mobilized peripheral phology, increased blasts and cytoge-
consulted the staff of the FA
blood stem cells and one patient re- netic abnormalities. Patient 5 had
Research Fund, and received their
ceived bone marrow stem cells. All stem morphological evidence of MDS only.
approval. This is necessary to be
cells were T cell depleted to prevent She had no cytogenetic abnormalities
sure our messages are accurate
graft-versus-host disease (GVHD). and no increase in blasts. The fifth
and consistent. It also helps to
All five patients engrafted early patient was age 21 at the time of trans-
avoid legal complications. We are
(between days 9 and 11 post-trans- plant. Her donor was a one antigen
happy to collaborate on fundrais-
plant). Immune reconstitution oc- mismatched unrelated donor, and she
ers and mailings.
curred at 6-8 months for three patients engrafted with no GVHD. She has
and 12 months for one patient. The had candida and herpes infections;
Centers Eliminate Radiation Hoping
to Reduce Later Malignancies
The Thirteenth
Researchers and treating physicians bine and ATG. Between November
Annual
have long suspected that transplant 1996 and June 2001, 12 FA patients
International patients have a high risk of later can- were transplanted with this fludara-
cers, especially of the head and neck. bine regimen. All engrafted and no
FA Scientific
Among the risk factors are the use of patient developed severe acute GVHD
radiation and the development of or chronic GVHD. Two patients later
Symposium
GVHD. In an effort to reduce the risk lost their grafts, but were successfully
of later malignancies, several transplant transplanted a second time. One pa-
NOVEMBER 14-17, centers, including Hadassah Universi- tient died from a malignancy two years
ty Hospital, Israel, University of Min- after transplantation. The remaining
2001
nesota, Cincinnati Children’s Hospital, eleven patients are alive and well. Long-
and University Hospital Charité, Berlin term follow-up is needed to determine
Hilton Hotel
have eliminated radiation for some or if this approach reduces the risk of later
Portland, Oregon
all of their FA transplants. malignancies. u
For FA patients with matched, relat-
ed donors, the University of Minnesota
has replaced radiation with fludara-
4 FA Family Newsletter
Preimplantation Genetic Diagnosis
Allen Horwitz, MD, PhD, the matched embryos are available. The child with FA and/or one who is not
Director of Medical Genetics at the average cost for the first cycle is an HLA-match for the FA-affected sib-
Reproductive Genetics Institute (RGI) $18,000. Subsequent cycles cost ling. Dr. Horwitz reported that RGI
in Chicago, spoke at the Family Meet- $12,000 - $14,000 each. In the expe- has a 98% accuracy rate in selecting
ing regarding Preimplantation Genet- rience of RGI, many insurance com- an embryo via PGD. He reported that
ic Diagnosis (PGD). The Institute was panies will pay for the IVF part of the the unknown effects of biopsies are the
in the news last year with the birth of cycle only if the couple is infertile. fourth risk of PGD.
Adam Nash, whose cord blood was With rare exceptions, insurance will For inquiries about PGD, contact
used to transplant his sister Molly, who not pay for the genetic testing. can be made through hematologists and
has FA. In PGD, unaffected embryos According to Dr. Horwitz, the risks geneticists or directly by contacting:
can be tested before implantation in of PGD are the risks that are related
association with in vitrofertilization. to the in vitro fertilization procedure Christina Masciangelo, MS, Genetic
Dr. Horwitz emphasized that FA because it is a medical/surgical proce- Counselor
families do not have to travel to the dure. In addition, the in vitro process or Dr. Horwitz at:
RGI in Chicago frequently for this pro- could result in multiple pregnancies. [phone]
cedure. The RGI will work with in A third risk factor is that a PGD mis- fax [phone]
vitro fertilization clinics around the diagnosis could result in the birth of a e-mail: [email protected] u
country, making it unnecessary to trav-
el to Chicago until the last week of the
process.
Although it is preferable that the Gene Therapy Trial Produces
specific DNA mutation be known First Encouraging Results
prior to undergoing PGD, for FA-A
it may be possible to perform linkage Christopher Walsh, University of Analysis of blood and bone marrow
analysis on parents and affected and North Carolina Gene Therapy Cen- samples revealed that two of the four
unaffected children to help in the FA ter, reported on results from an on patients had significant long-term gene
diagnosis part of the PGD. At the pre- going FA gene therapy trial at his cen- transfer.
sent time the DNA mutation needs to ter (see Science Letter). Four FA-A A year and a half after gene transfer,
be known for the other FA comple- patients, ranging in age from 11 to 48 one patient shows evidence of a clini-
mentation groups. years, have entered this trial. Three of cal response to gene therapy. This
The time required for PGD, not the four patients had severe pancy- response has become increasingly
including the 40 weeks for a pregnan- topenia requiring blood transfusions impressive with time. At the time of
cy, varies greatly dependent on the indi- and/or androgen support. gene transfer therapy, this patient had
vidual, but is between 18 and 36 Early blood stem cells, called 2,000 white cells, hemoglobin of 9, and
weeks. This includes 12 to 24 weeks to CD34+ cells, were mobilized, either 120,000 platelets. Today, this patient
custom develop the DNA testing from the patient’s peripheral blood or has 5,000 white cells, hemoglobin of
required to select an embryo free of from a bone marrow harvest. Bone 12, and 240,000 platelets. This patient
FA and to select an embryo that will be marrow produced far more cells than has had a significant increase over time
an HLA match for the FA-affected the peripheral blood, but the number in the number of peripheral blood cells
child. This also includes 6 to 12 weeks of cells collected was only a fraction of carrying the FANCAgene. This result
for the stimulation of the mother’s the number expected from a person is extremely encouraging.
ovaries for the harvest of the ova used with normal bone marrow (from 1/10 Walsh has now developed new vec-
in this process. to 1/100). In the laboratory, cells were tors based on the lentiviral virus system
Dr. Horwitz reported that there is then transduced with the normal and believes these will be superior to
about an 18% chance of an unaffect- FANCA gene, using a retroviral vec- the vector he is using in his clinical
ed match in a given batch of fertilized tor, and returned to the patient. trial. He is requesting patient bone
eggs, and 30% chance of a pregnancy All four patients tolerated the pro- marrow samples, and anticipates future
in a cycle via PGD if two unaffected cedure without adverse complications. clinical trials using the new vectors. u
Fall 2001 5
Oral Cancer Precautions
At the FA Regional Meeting in growth. Toluidene blue will stain • Make certain that the dentist is
Columbia, Maryland, on June 16, premalignant or malignant cells, aware that the patient has FA and
Stephen Engroff, MD, DDS, Chief thereby helping the oral surgeon that FA patients are at extremely
Resident at the University of Mary- determine the area of biopsy. high risk for oral cancer.
land Cancer Center, Oral and Max-
• Erythroplakia is a red patch of oral • Ask the dentist to examine the entire
illofacial Surgery, presented informa-
mucosa. With erythroplakia, more oral cavity, not just the teeth or the
tion on behalf of Robert Ord, MD,
so than leukoplakia, the changes gums surrounding the teeth.
DDS, from that department. Ord has
that have occurred in the tissues of
• If a suspicious lesion is identified,
extensive experience with oral cancer in
the mouth are more frequently dys-
consultation by the dentist or
FA patients and recently co-authored
plasia, carcinoma in-situ or frank
referral to an oral surgeon with
a landmark article in the Journal of
carcinoma. Erythroplakia that has
expertise in FA would be extreme-
Oral and Maxillofacial Surgeryentitled
formed in a leukoplakia is partic-
ly helpful.
“Squamous Cell Carcinoma of the
ularly worrisome. Engroff recom-
Dr. Engroff emphasized that, if pre-
Tongue After Bone Marrow Trans-
mends a biopsy if erythroplakia is
malignant lesions are identified early,
plantation in a Patient with Fanconi’s
suspected.
treatment may prevent the progression
Anemia.”
• In the general population, oral can- to cancer. If carcinoma does develop,
Dr. Engroff reported that:
cers commonly occur on the floor cure rates are much improved when
• Over 90% of oral cancers are squa-
of the mouth, on the sides of the lesions are treated at an early stage.
mous cell carcinoma.
tongue, and the lower lip. These Thus, frequent and thorough check-
• There are five types of premalignant are areas where saliva pools, or, in ups by a dentist well versed in the high
lesions in oral cancer. Three of these the case of the lower lip, areas risk of FA patients for oral cancer are
(submucous fibrosis; lichen planus; exposed to the sun. However, in FA critical. u
and discoid lupus) are unlikely to patients, oral cancers also occur on
occur in FA patients. The remain- the top of the tongue and elsewhere
ing two, leukoplakia and erythro- in the oral cavity.
plakia, are implicated in oral cancers
• Treatment varies depending on the
of FA patients.
location and extent of the lesion, More Information in
• Leukoplakia is the most common but often involves surgical or laser Science Letter
pre-malignant lesion. Dr. Engroff excision of the lesion. Laser exci-
defined leukoplakia as “a white sion does less damage to the non- Families frequently seek guide-
patch or plaque of oral mucosa that cancerous tissue surrounding the lines concerning how and how
cannot be rubbed off and cannot lesion. Studies on other treatments, often to monitor liver function
be characterized as any other dis- such as mouthwashes that may be while a patient is on androgens.
ease.” Other white patches that may effective and on photodynamic The reader is referred to the
occur in the mouth, such as thrush therapy are currently in progress. article by John Wagner on page
or candida, can be rubbed off. 6 in the Science Letterfor guide-
Based on this information, Dr.
lines on this subject.
• Leukoplakia is painless. Engroff recommended that FA patients
take the following precautions regard-
• In the general population, there is Blanche Alter presented helpful
up to a 17% risk of conversion of ing oral cancer: guidelines to families on how and
leukoplakia to squamous cell car- • In the absence of any danger signs, when to screen for cancer in FA
cinoma per year. This may be high- have a complete dental examina- patients at our recent Family
er in the FA population. tion at least once every six months, Meeting. She also discussed
starting very early in the child’s life. androgens and screening for liver
• If leukoplakia is identified, the den-
Dental examinations must occur dysfunction. The reader is re-
tist or oral surgeon can apply a solu-
more often if there are any suspi- ferred to her articles on these
tion of toluidene blue to the oral
cious lesions. subjects in the Science Letter.
cavity to help identify areas that
contain cells undergoing abnormal
6 FA Family Newsletter
Oral Health and Bone Marrow Transplantation
– Some Precautions
Dr. Mark Schubert, Director of severity of mucositis.
Oral Medicine, Seattle Cancer Care Chemotherapy and radiation can
Alliance, is quoted at length in a July leave a patient without a healthy
2001 article in Center News, a publi- immune system. This sets the stage for
cation of the Fred Hutchinson Can- bacterial, fungal and viral infections.
cer Research Institute. He discusses the Schubert notes that we all have bacte-
importance of oral health as it relates ria that live inside our mouths. If there
to bone marrow transplantation. is a way to gain entry into the blood,
Chemotherapy and radiation given microbes usually considered harmless
prior to transplantation can lead to can cause serious problems. Particu-
oral mucositis, an inflammation and larly worrisome is the potential sys-
ulceration of the moist tissue lining temic spread of infection to various
the oral cavity. Mucositis can be wors- organs. Severe mucositis can make the involved with routine dental treatment
ened by preexisting dental disease and spread of infection more likely. can result in patients inhaling bacte-
conditions such as trauma or irrita- Schubert also recommends that ria and debris that can significantly
tion. Schubert strongly recommends patients not get their teeth cleaned for increase the risk of pneumonia. If
a thorough oral examination and treat- six to nine months after transplant. patients have graft-versus-host disease,
ing oral problems prior to transplan- “With the immune system still recov- routine dental treatment often needs to
tation, in the hope of lessening the ering, the spraying and splashing be delayed longer.” u
Grant to Fund International FA Transcriptome Consortium
The FA Research Fund has just done by studying the pattern of gene blueprints from the genes to the part
awarded a two-year grant to Grover expression in normal bone marrow cells of the cell that translates the blueprints
Bagby, Jr., MD, to establish the Inter- and in cells from FA patients in vari- into proteins. It is the proteins that
national FA Transcriptome Consor- ous complementation groups. The pat- carry out many of the essential func-
tium. Bagby is Director of the Cancer tern of gene expression in marrow cells tions of the cells.
Institute, Oregon Health Sciences Uni- can be measured by the “transcrip- Using modern “DNA chip” tech-
versity, Portland. The Transcriptome tome” (see below). Differences in the nology, researchers will place on a single
Consortium builds on the recent transcriptomes of bone marrow cells small silicon chip the DNA sequences
sequencing of the human genome and from children with FA and with both that code for all normal human
on the collaboration of several bone FA and myelodysplasia may reveal clues mRNAs. They will then add mRNA
marrow transplant centers as a result of to the molecular cause of leukemia in from normal bone marrow, as well as
the Bone Marrow Transplant Confer- patients with FA. cells collected from FA patients in
ence (sponsored by the FA Research Each human cell contains about different complementation groups,
Fund) in Chicago in April 2001. 30,000-50,000 genes, but only some of including those with bone marrow
Five transplant centers are partici- these genes are active (expressed or failure, myelodysplasia, and AML.
pating in the Transcriptome Consor- turned on) at any one time in any cell Researchers will be able to visualize
tium: Curitiba, Brazil; Capetown, type. An active gene is one that is pro- and compare which genes are turned
South Africa; University of Minneso- ducing messenger RNA (mRNA). The “on” and “off” in normal and FA cells.
ta; Children’s Hospital, Cincinnati; production of mRNA by a gene is By comparing gene expression in dif-
and St. Jude’s Hospital, Memphis, TN. called transcription. The array of all ferent types of cells, researchers hope to
The purpose of this project is to the various mRNAs produced by the reveal important pathways for target-
study the causes of bone marrow fail- cell at one time is called a transcrip- ed therapy. u
ure and leukemia in FA. This will be tome. The mRNAs carry the genetic
Fall 2001 7
20th Anniversary of the International Fanconi Anemia Registry (IFAR)
by Arleen D. Auerbach, Ph.D.
In 2002 The International Fanconi and by mutation screening. Mutations order to investigate the incidence,
Anemia Registry (IFAR) will have its are recorded in the Fanconi Anemia prevalence and the risk of squamous
20th anniversary. For this occasion, we Mutation Database: http://www.rock- cell carcinoma in patients with FA.
are attempting to get a complete clin- efeller.edu/fanconi/mutate/. It would Applying the knowledge gained from
ical update on all patients in the Reg- be helpful for this research project for this initial clinical project, we will begin
istry. When my laboratory at The any family in the IFAR (or willing to to investigate the genetic and molecu-
Rockefeller University founded the be registered in the IFAR) to contact lar changes that cause this increased
IFAR in 1982, we didn’t yet know any- me by e-mail, mail, or by phone ( ask incidence of cancer. Our hope is to
thing about the genetic complexity of for Kathy Mah, our genetics coun- develop human and mouse models to
the disease (at least 8 complementa- selor). We are able to work with fam- explore the genetic relationship be-
tion groups and many different muta- ilies in the IFAR to help them obtain tween this disease and epithelial can-
tions within groups). The IFAR was information they need regarding cer. If you are interested in participat-
started with the goal of identifying a preimplantation genetic diagnosis ing in this study or have questions
large number of patients with this rare (PGD)/in-vitrofertilization and other concerning Fanconi-specific screening
disorder in order to study the clinical prenatal testing, as well as carrier test- and treatment of cancer, contact Dr.
and genetic features in FA. We hoped ing, where appropriate. Kutler.
to better define this heterogeneous dis- As part of the IFAR investigation,
order and differentiate it from other two new studies have recently been Contacts
syndromes with overlapping features. initiated. The Grandparent Study, in To register in the IFAR:
Questions relating to diagnosis, nat- collaboration with Marianne Berwick,
Dr. Arleen D. Auerbach
ural history of the disease, prognosis, PhD, an epidemiologist at Memorial
The Rockefeller University
treatment, and cancer incidence in FA Sloan-Kettering Cancer Center
1230 York Ave., Box 77
are being addressed by the IFAR stud- (MSKCC) in New York, investigates
New York, NY 10021
ies. Information regarding genotype- whether carriers of FA have an
[email protected]
phenotype correlation is being increased risk to develop cancer. For
212-327-8862
obtained; we hope this will help to this study, we are asking grandparents
(ask for Kathy Mah)
determine the physiologic roles of the of individuals diagnosed with FA to
cloned genes. We have recently updat- participate. Participation involves send-
For information about the Grand-
ed our laboratory website, and infor- ing a blood sample to our lab for car-
parent study:
mation on the IFAR can be found at rier testing and filling out a health sur-
Katherine Mah, genetics counselor
http://www.rockefeller.edu/lab- vey and consent forms. If you would
(Dr. Auerbach’s office)
heads/auerbach/auerbach.html. like more information about this study,
212-327-8862
To date, the IFAR has registered please contact Katherine Mah in Dr.
[email protected]
755 patients from North America Auerbach’s office.
affected with FA, as well as many Dr. David Kutler and Dr. Bhu-
For information about the Cancer
patients from Brazil and other coun- vanesh Singh (Laboratory of Epithe-
Study:
tries. Diagnosis was confirmed by lial Cancer Biology, MSKCC) are col-
hypersensitivity to the clastogenic effect laborating with the IFAR to investigate Dr. David Kutler
of DEB in all cases. We have deter- a growing body of evidence that sug- [email protected].
mined the complementation group for gests a relationship between FA and
341 of the North American patients. cancer, particularly squamous cell car-
The distribution of IFAR patients is cinomas. Many patients with FA who
FA-A: 207; FA-D2: 2; FA-C: 78; FA- survive into adulthood develop mul-
F: 8; FA-G: 46. We are actively deter- tiple oral cavity and vaginal squamous
mining complementation groups for cell carcinomas at a relatively young
additional patients by functional com- age and have a poor prognosis. Dr.
plementation with retroviral vectors Kutler is working with the IFAR in
8 FA Family Newsletter
Bone Marrow Transplant Conference Held in Chicago
The FA Research Fund sponsored The participants at this meeting, which was also attended by several mem-
a one-day meeting of bone marrow bers of the FARF Board of Directors, Ralf Dietrich from the German FA group,
transplant physicians at the O’Hare and Lorne Shelson from FA Canada, were:
Hilton in Chicago on April 28, 2001.
Physicians from eight countries and
Grover Bagby, Jr, MD, Oregon Cancer Institute, OHSU, Portland;
five continents attended this landmark
Farid Boulad, MD, Memorial Sloan-Kettering, New York;
meeting, which allowed physicians who
perform FA transplants to share their Martin Champagne, MD, Hôpital St. Justine, Montreal;
protocols, learn from one another, and
Joachim Deeg, MD, Fred Hutchinson Cancer Center, Seattle;
collaborate in the future.
Ygal Dror, MD, Hospital for Sick Children, Toronto;
Although participants did not agree
on a uniform transplant protocol for Wolfram Ebell, MD, Children’s Charité Hospital, Berlin;
FA patients, the meeting was distin-
Alfred P. Gillio, MD, Hackensack University Medical Center; New Jersey;
guished by a high level of collabora-
Eliane Gluckman, MD, Hôpital St. Louis, Paris;
tion and the willingness of all to share
their experience, listen, and, in some Helmut Hanenberg, MD, Heinrich Heine University, Düsseldorf;
cases, modify a protocol because of the Richard Harris, MD, Children’s Hospital Medical Center, Cincinnati;
information presented at the meeting.
Mary Horowitz, MD, IBMTR/ABMTR, Milwaukee;
A number of transplanters at this meet-
Peter Jacobs, MD, Constantiaberg Medi-Clinic, Capetown, South Africa;
ing will collaborate in the immediate
future on a project entitled the Inter- Hans-Peter Kiem, MD, Fred Hutchinson Cancer Research Center, Seattle;
national Fanconi Anemia Transcrip-
Leslie Lehmann, MD, Dana-Farber Cancer Institute, Boston;
tome Consortium sponsored by the
FA Research Fund (see page 7). u Alexei Maschan, MD, Children’s Hospital, University of Moscow, Russia;
Jose Zanis Neto, MD, Federal University of Parana, Curitiba, Brazil;
Shimon Slavin, MD, Hadassah University, Jerusalem, Israel;
Franklin Smith, MD, Indiana University School of Medicine;
Joanne Van Burik, MD, University of Minnesota Medical School;
John Wagner, MD, University of Minnesota Medical School, Minneapolis;
Donna Wall, MD, Cardinal Glennon Children’s Hospital, St. Louis.
Fall 2001 9
Medical Controversy Emerges at mize toxicity related to prior andro- survive transplantation, and children
Family Meeting gen therapy, and recommends trans- doing well at present risk losing every-
continued from page 1 plantation only after the failure of thing. Unrelated FA transplant out-
androgens. Blanche Alter, National comes are much better, but the total
The Standards for Clinical Care Cancer Institute, stated that androgens number of children transplanted is
handbook, developed at a May 1998 may not always be the cause of trans- small and the time post-transplant is
medical conference, provided guide- plant problems, but may be suffering still short.
lines concerning the timing of bone from “guilt by association.” Androgens Some parents were concerned that
marrow transplantation for Fanconi do not cause infections, but may be a child’s prior use of androgens would
anemia patients. Survival outcomes for used by patients with severe neu- jeopardize the transplant outcome. It
patients having matched sibling donors tropenia who are at greater risk of in- should be noted, however, that almost
had improved steadily over the years. fection. While not denying the impor- all of the children transplanted to date
When the Standards were published tance of androgen-induced liver with alternate donors had taken andro-
in 1999, the survival rate for patients problems in transplant, Alter suggests gens, some for many years. Many of
transplanted after 1997 was 83%. that the judicious use of androgens has these patients appear to be long-term
Patients with severe aplastic anemia a definite role in the longevity of many transplant survivors.
and a matched sibling donor were patients. Your editors advise readers who are
advised to go to transplant after the Many parents whose children’s contemplating transplantation with
onset of bone marrow failure, and blood counts have been stabilized on alternate donors to read articles relat-
before attempting other therapies. androgen therapy expressed anxiety ed to this subject in this Newsletterand
However, transplantation from an and confusion following the presenta- in the Science Letter, and to discuss
alternate (i.e., mismatched related or tions. Androgens might buy time, and these issues with your treating physi-
unrelated) donor then was associated time could bring less toxic transplant cian. Remember that positive news—
with relatively poor survival (~30%). preparatory regimens and better out- improved transplantation outcomes—
For this reason, transplanters recom- comes. Greatly improved statistics are has led to a close examination of this
mended that other treatment options, no guarantee that any one child will subject. u
such as androgens or hematopoietic
growth factor therapy, should be
attempted first. Transplantation was Cincinnati Children’s Opens FA Center
recommended after the failure of these
therapies, or after evidence of myelo- Drs. Richard Harris and David The Center will offer a thorough
dysplasia or leukemia. Williams have announced the open- evaluation, including confirmation of
At our August 2001 Family Meet- ing of the Fanconi Anemia Compre- diagnosis and genetic typing, HLA typ-
ing, John Wagner, University of Min- hensive Care Center at Children’s Hos- ing, and multi-system evaluation. On-
nesota, proposed a change to these pital Medical Center in Cincinnati. going care can be provided on site or
guidelines. He now believes that most Harris, the Medical Director of the through consultation with the refer-
patients with bone marrow failure and BMT Outpatient Clinic, has extensive ring physician. The Center will also
an HLA-matched unrelated donor experience in the transplantation of continue to research and evaluate new
should go to transplant prior to the FA patients. Williams, Director of FA therapies, and FA patients are invit-
use of androgen therapy. He cited Experimental Hematology, has exten- ed to participate in the clinical trials
greatly improved transplant outcomes sively researched blood stem cell biol- conducted by the Center.
in “standard risk” patients and con- ogy and gene therapy. For more information, call the FA
cerns that androgens may be an added Experts in the following areas of Care Coordinator at [phone]
risk factor. (See Wagner article, page specialty will design individual treat- or write
3). Richard Harris, Children’s Hospi- ment regimens for patients: bone mar- CHMC
tal, Cincinnati, later concurred with row transplantation; cardiology; 3333 Burnet Avenue
Wagner’s recommendation. endocrinology; genetics; hematology; Cincinnati, OH 45229-3039. u
Wolfram Ebell, Children’s Charité nephrology and urology; orthopedics
Hospital, Berlin, stated that milder and hand surgery; and psychosocial
conditioning regimens should mini- support.
10 FA Family Newsletter