Adrianna Vlachos and Ellen Muir. How I treat Diamond Blackfan anemia. Blood First Edition Paper, prepublished online July 22, 2010.

Abstract

Diamond Blackfan anemia is characterized by red cell failure, the presence of congenital anomalies, and cancer predisposition. In addition to being an inherited bone marrow failure syndrome, DBA is also categorized as a ribosomopathy as, in over 50% of cases, the syndrome appears to result from haploinsufficiency of either a small or large subunit-associated ribosomal protein. Nonetheless, the exact mechanism by which haploinsufficiency results in erythroid failure, as well as the other clinical manifestations, remains uncertain. New knowledge regarding genetic and molecular mechanisms combined with robust clinical data from a number of international patient registries has provided important insights into the diagnosis of DBA and may, in the future, provide new treatments as well. Diagnostic criteria have been expanded to include patients with little or no clinical findings. Patient management is therefore centered upon accurate diagnosis, appropriate use of transfusions and iron chelation, corticosteroids, hematopoietic stem cell transplantation, and a coordinated multidisciplinary approach to these complex patients.

Because this is a prepublished version of the paper, we are currently unable to post the article in full. To purchase the paper in its entirety, click here. This paper is a great resource for doctors, patients, and families. As soon as it is legally possible, we will post the full article on the DBAF website.

 

 

Thank you friends and family for all your efforts. DBAF Funds more research!

Paul de Figuieredo, Ph.D., Assistant Professor, Texas A&M University was awarded a $43,256 grant for the project “Discovering therapeutics for DBA .” The long-term goal of this study is to develop small molecule therapeutics for Diamond Blackfan Anemia (DBA), by screening for molecules that overcome growth defects associated with decreased expression of ribosomal protein S19 in a yeast model of DBA. Yeast are remarkably versatile microorganisms that share many aspects of ribosome biology with humans. Because of their small size and ease of growth they are readily amenable to what are known as high throughput drug screens where thousands of compounds can be assessed for their effects on cell growth. The Figuieredo lab will initially screen 25,000 chemical compounds for their ability to reverse the effects of reduced expression of Rps19 on cell growth. Any compounds identified in the yeast screen will be examined for their ability to compensate for reduced expression of Rps19 in human cell lines. Dr. Figuieredo has had substantial success using a similar approach to identify lead compounds for therapeutic development in another ribosome-related bone marrow failure syndrome Shwachman Diamond syndrome (SDS).

Hanna T. Gazda, M.D. Instructor in Pediatrics Harvard Medical School was awarded $51,512 to continue her efforts to identify genes mutated in patients with DBA. Dr. Gazda has played a major role in the identification of most of the 11 known DBA genes. Her discoveries have clearly established DBA as a ribosomopathy which has helped direct research efforts on many aspects of this disease. Approximately 50% of DBA patients have mutations in one of the 11 known genes. In the remaining patients, the defective genes have evaded detection by conventional DNA sequencing. Dr. Gazda now plans to use sophisticated whole genome approaches to identify these remaining genes. The aim of this study is (1) to perform comparative genomic hybridization to search for deletions and duplications in ribosomal protein genes that could not have been picked up by DNA sequencing; (2) to perform whole exome sequencing (“next generation” sequencing) to potentially identify non-ribosomal protein genes that may be mutated in DBA. This latter approach is daunting in that 10’s of thousands of genes will need to be sequenced and analyzed for sequence changes that may be linked to patients with DBA. This project will result in a more complete picture of the genetic causes of DBA and the pathogenic mechanisms that result.  

 

 

Stanford University Announces Lenalidomide Trial for Adult DBA Patients

Dear DBA Patients and Families:

We are pleased to announce the opening of the “Pilot Study of Lenalidomide (Revlimid) in Adult Patients with Red Blood Cell Transfusion-Dependent Anemia” at the Stanford University Medical Center.

The rationale for evaluating lenalidomide in DBA comes from the study of an acquired form of bone marrow failure named myelodysplastic syndrome (MDS).  Although DBA is inherited, and MDS usually develops in older adults, they share several clinical and laboratory features:  poor production of red blood cells often leading to a need for frequent blood transfusions, and a somewhat increased risk of developing acute leukemia.  Iron overload from chronic red blood cell transfusions is a common and serious problem. 

Mutations in more than 10 ribosomal proteins have now been identified in greater than 50% of DBA patients and are now implicated as the cause of the disease.  In a very important  report published in Nature in 2008, Dr. Benjamin Ebert and colleagues at Harvard discovered that loss of the gene encoding ribosomal protein S14 was critical to the cause of a form of MDS called 5q- syndrome.  In this subtype of MDS, a region of the long arm of chromosome 5 is missing, and ribosomal protein gene S14 is located in this missing segment.  This was an unexpected and important finding, since it was the first time that a common biologic link was found between DBA and MDS.

In patients with 5q- MDS who depend on red blood cell transfusions, the oral medication lenalidomide (Revlimid) can eliminate the need for transfusions in 70% of subjects.  Given the outstanding red blood cell response rate to lenalidomide in 5q- MDS in which loss of ribosomal protein S14 has emerged as an important discovery, there is a strong reason for investigating lenalidomide in DBA in which ribosomal protein deficiency is also linked to impaired red blood cell production. 

The following are some of the basic inclusion and exclusion criteria for this pilot trial:

Inclusion Criteria

Exclusion criteria

Please refer to the website link: http://www.clinicaltrials.gov and enter the search term “Diamond-Blackfan Anemia and lenalidomide” for full eligibility criteria and additional trial information.

NOTE:  BECAUSE THIS STUDY IS CURRENTLY ONLY BEING CONDUCTED AT STANFORD, WE HAVE FUNDS TO COVER PATIENT TRAVEL EXPENSES. 

CONTACT INFORMATION
Principal Investigator:  Dr. Jason Gotlib, Stanford University School of Medicine

Co-Investigator:  Dr. Bertil Glader, Stanford University School of Medicine

Scientific Co-Investigators:  Dr. Hanna Gazda, Boston Children’s Hospital/Harvard
Dr. Benjamin Ebert, Brigham and Women’s Hospital/Harvard

We appreciate the support and commitment of Drs. Adrianna Vlachos and Jeffrey Lipton and their leadership of the DBA Registry in making this study possible.

Please contact our study nurse, Andrea Linder:

TEL:  650-725-4047
FAX:  650-723-1269
Email: alinder@stanford.edu

Also, feel free to contact Dr. Gotlib by email: jason.gotlib@stanford.edu

 

 

Update on Leucine Trial for DBA Patients

A Message from Ellen, DBA Nurse

We need to find out how many are interested in the leucine trial so we can report back to the reviewers for funding. It is a slow process but we are about 3/4 of the way there. It already passed the pre- approval, proposal internal review, and proposal external review. Once it is approved, we can put it through our Institutional Review Board (IRB) and have doctors from other sites submit a letter of collaboration so their patients can enroll.

Our total enrollment will be 50 DBA transfused patients over the age of 2, willing to take the leucine powder mixed in food 3 times a day, and have periodic leucine levels drawn (hopefully timed around transfusions).

Please contact Ellen directly at the contact information provided below:

Ellen Muir, RN, CNS, CPON
Diamond Blackfan Anemia
Surveillance and Awareness Program
718-470-3605 / 1-877-DBA-NURSE
emuir@nshs.edu

 

 

DBA Patients and the H1N1 Virus

Dear DBA Community,

It cannot be stressed enough that every DBA patient has a different situation and response to illness.  Please work with your hematologist, pediatrician or internist in deciding what are the best options for you and your family. These are general recommendations.  The care of each patient should be individualized with his or her physician.

There have been several inquiries about H1N1 (swine flu) and DBA.  We at the DBA Registry advise the patients treated here at Schneider Children's Hospital in New York to get immunized for both the H1N1 virus as well as the seasonal flu.  If you have received the seasonal flu vaccine in the past with no issues, the H1N1 vaccine is being prepared in the same way and should potentially be safe for you or your child.

 If you have severe, life threatening allergies, reactions or events to any of the substances in the vaccine, you should not get receive it (eggs or preservative).  There is a preservative free form of the vaccine which contains no Thimerosal.  It comes in a prefilled syringe.  Only the inactivated form of any flu vaccine should be given for DBA patients as well as family members.  The nasal mist (given up the nose) is live virus and should not be used. The vaccine has been given to neutropenic cancer patients receiving chemotherapy. 

The goal is prevention so vaccination is preferred to the actual virus.  If the DBA patient is not a candidate for the H1N1 vaccine then the members of the household should be vaccinated in hopes of protecting the patient.

If your child should get the H1N1 virus, Tamiflu (Oseltamivir) and Relenza (Zanamivir) are the only antivirals to help reduce the time that you have the virus and minimize the symptoms.  It does not "cure" the virus.  Relenza is not to be used if you have asthma or lung disease and are younger than 7 years of age.

In 1976, an earlier type of swine flu vaccine was associated with cases of Guillian-Barre Syndrome (GBS). Since then, flu vaccines have not been clearly linked to GBS. For more information please on GBS, see http://www.cdc.gov/h1n1flu/vaccination/gbs_qa.htm.

For more information on the H1N1 flu and the vaccine go to:
www.flu.gov
www.cdc.gov/h1n1flu/

For high risk students:

http://www.flu.gov/professional/school/k12techreport.html

 

Principal Investigator: Dr. Johan Flygare
Research: Characterizing the mechanism of glucocorticoid treatment in DBA.

Glucocorticoids have been used as a DBA treatment for many years. How glucocorticoids work to stimulate haemoglobin levels in DBA patients is unknown. Dr. Flygare’s goal is to understand the mechanism of action by which glucocorticoids exert their positive effects in certain DBA patients. By understanding the mechanisms through which glucocorticoids work it may be possible to develop less toxic drugs that have similar or improved clinical benefits.

Principal Investigator: Dr. Shuo Lin, co-PI: Nadia Danilova
Research: Mechanism underlying erythroid deficiency in DBA using a zebrafish model.

Dr. Lin and a co-investigator Dr. Kathy Sakamoto received funding on 2005 from the DBAF to develop an animal model of DBA. With these funds they developed a zebrafish model of DBA which recapitulates some of the clinical features of DBA in humans. They were able to show that these clinical features could be rescued by genetically targeting a protein known as p53 or with drugs that inactivate p53. These studies had a dramatic affect on DBA research. Dr. Lin will use the current award to further investigate the zebrafish model of DBA with an eye towards understanding the role played by p53 in DBA pathology. Understanding this pathway could lead to molecular targets for the development of new therapeutics for use in DBA.

Principal Investigator: Dr Lydie Da Costa
Research: Genotype/phenotype relationships in DBA

DBA is a very heterogeneous disease. All genes identified to date known to be affected in DBA encode ribosomal proteins. These proteins can be components of the large or small ribosomal subunits. A growing number of studies indicate that the clinical presentation of DBA may be influenced by the nature of the ribosomal protein affected. Dr. Da Costa’s group has shown that different ribosomal protein mutations have distinct affects on the behaviour of cells derived from the marrow of DBA patients. These studies will provide insight into the clinical variability of DBA and perhaps ultimately lead to designer therapies.

Scientific Conference: 3rd Congress of the International BioIron Society and the 8th International Symposium on Microbial Iron Transport, Storage, and Metabolism.

Iron overload and chelation therapies continue to be major topics of interest to DBA families. The DBAF was a bronze level sponsor of the 3rd Congress of the International BioIron Society where investigators from all over the world congregate to advance the fields related to iron metabolism.

 

Congratulations George Buchanan, M.D., ASH Mentor Award Winner 2008

The ASH Mentor Award was established in 2006 to recognize hematologists who have excelled at mentoring trainees and colleagues. Those selected to receive the award are chosen because they have shown a sustained commitment to mentoring, have made a significant, positive impact on their mentees’ careers, and have advanced research and patient care in the field of hematology through their mentees.

This award is based on the training experiences and success of the nominee’s mentees, not the mentor’s personal career achievements. Those selected as superb mentors are chosen because they are involved in the  process of guiding, supporting, and promoting the training and career development of others. Two awards are given each year, one in the basic sciences and one in clinical investigation and training.

The clinical investigation award was presented to George Buchanan, M.D. Dr. Buchanan is a pediatric hematologist at the University of Texas Southwestern Medical Center. He is the Children’s Cancer Fund Distinguished Chair in Pediatric Oncology and Hematology and the director of the Barrett Family Center for Pediatric Oncology. We are pleased to congratulate Dr. Buchanan, a member of our Scientific Advisory Board, for his outstanding commitment to his students and colleagues.

 

Congratulations Emily Devlin, B.A., ASH Merit Award Winner 2008

The American Society of Hematology recognized abstract presenters who received the highest ranking in their categories of undergraduate student, medical student, graduate student, resident physician, and postdoctoral fellow. Merit Award winners receive a $500 honorarium plus annual meeting travel reimbursement. This year's 2008 ASH Merit Award for an undergraduate student was Emily Devlin, B.A. for her abstract A Mouse Model for Diamond-Blackfan Anemia Demonstrates a Dominant Negative Effect of a Point Mutation in the RPS19 Gene. We are pleased to congratulate Emily and proud to financially support the research she and Dr. Bodine are conducting.

 

DBAF funds study on "Development and Characterization of Mouse Models for DBA"

Thanks to the support of our famiies and friends we were able to fund another worthwhile DBA research project. Dr. David M. Bodine from the NIH is being funded for his research to create and analyze mouse models for some of the mutations that cause Diamond-Blackfan Anemia (DBA). An animal model of DBA will allow an in depth analysis of the defect(s) caused by each of the DBA mutations in untreated animals, allowing the mechanism of the disease to be understood. Once the mechanism has been identified, the effectiveness of conventional therapies can be evaluated and novel therapies designed to target the specific defect can be developed. The mouse model created will be distributed to the DBA community for analysis and the testing and development of therapies for DBA.

 

International Ribosome Synthesis Meeting funded in part by DBAF

DBAF is a proud co-sponsor of a Ribosome Synthesis Meeting held tri-annually. This meeting is International and brings together investigators from all over the world to focus on issues related to ribosome synthesis. The meeting alternates every third year between the US and Europe. The meeting in August 2009 will be held in Germany. In 2009, as was the case in 2006, there will be a session devoted to ribosome synthesis and disease where DBA figures prominently. There are so many important connections now being made between defects in ribosome synthesis and triggers of cell death and these connections provide new opportunities for drug development. Moreover, these are central pathways within cells that are being studied just as intensely by investigators in other fields. Therefore, the next big development in understanding DBA can come from virtually anywhere. To see an acknowledgment of the Foundation's support for this upcoming meeting follow the link below and scroll down. http://cwp.embo.org/cfs09-09/index.html

 

DBA International Clinical Care Consensus Document (2008)

Through the coordination of international experts in DBA at the annual International Consensus Conference (ICC) sponsored by the Daniella Maria Arturi Foundation and Co-sponsored by the Diamond Blackfan Anemia Foundation we share with you this Clinical Care Consensus Document, which has been published in the British Journal of Haematology and offers the latest opinions on how to diagnose and manage the care of patients with DBA.

 

Leucine Publication (2007)

Leucine is an amino acid that is available as a nutritional substance. It is sold over-the-counter in many nutritional supplements, in many combinations. For everyone's knowledge, over-the-counter nutritional supplements are not FDA monitored. The drugs are not purified and are in combination forms. 500mg of leucine in one combination product may really only be 350 mg or 620 mg, for example. There is no FDA oversight in the preparation of these supplements.

The medical community is therefore not recommending starting all DBA patients on these over-the-counter leucine/combo product. However the DBA community is very interested in leucine. Since Dr. Pospisilova presented these data at the DBA International Conference in March the DBAR team led by Dr. Vlachos and the Arturi Foundation have been working on finding out more. The DBAR team is trying to find a company that makes a purified leucine product, get them to be interested in a trial for DBA patients, at a controlled dose with a controlled product.

Everyone is anxious to start leucine, but trying a combination, unpurified product may yield poor results and then everyone will be disappointed, much the less may make others unwilling to try the purified product for fear of failure. Please let's do this in an orderly way. Waiting is a lot to ask and everyone wants a quick cure but we should try get the best product available for the best results. The Czech Republic patient was a single experience so we have to be careful. The leucine seems to be well tolerated but again it has been only a handful of patients.

I hope this is helpful to all. We will keep you posted.

Adrianna Vlachos, MD
Head, Bone Marrow Failure Program
Associate Head, Stem Cell Transplant Program,
Schneider Children's Hospital,
New Hyde Park, NY 11040

 

 

 

Printable Fact Sheets prepared by the CDC:

DBA Brochure

Blood Transfusion Therapy

Corticosteroids

Chelation

Stem Cell Transplant