St. Jude investigator led multi-center effort to define Diamond Blackfan anemia syndromes’ guidelines

Diamond Blackfan anemia (DBA) syndrome is a rare congenital disease whose hallmark is low red blood cell production, but there are other heterogeneous clinical features in many patients. In 2008, a group of experts created consensus clinical guidelines for DBA, as the low prevalence makes clinical trials impractical. However, the ensuing 16 years brought about many advances in research, uncovering multiple genetic causes of the disease and an increase in treatment outcome information. Therefore, Marcin Wlodarski, MD, PhD, St. Jude Department of Hematology, a DBA and bone marrow failure expert, led a multinational effort to create new DBA treatment guidelines that incorporated the best and most recent evidence, published recently in The Lancet Haematology.

“Now that we have these guidelines,” Wlodarski said. “We can disseminate them across the world and make them freely available, which we hope will improve patient care and ultimately lead to improved patient outcomes.”

The new guidelines represent a major update to DBA identification and treatment. Several genetic forms of DBA were unknown when the original guidelines were created. In the intervening years, physicians realized that clinical disease presentation was also heterogeneous. Fundamental understanding of the disease has improved dramatically, as has the collective experience of physicians caring for these patients, including observing long-term outcomes of different treatment approaches. To combine that knowledge and experience, Wlodarski led an international consensus-building task force, which created the new guidelines. The writing team consisted of Wlodarski with co-contributors Adrianna Vlachos, MD, and Jeffrey Lipton, MD, PhD, both of Cohen Children’s Medical Center, Jason E. Farrar, MD, Arkansan Children’s Research Institute, and Thierry Leblanc, MD, Robert Debré Hospital. In total, more than 50 international experts were involved in developing these guidelines.

“It was a panel of clinical providers collectively caring for more than 2,500 children, adolescents and adults with this syndrome,” Wlodarski said. “It is a rare disease, but collectively, we had the experience of caring for many patients with DBA syndrome. Since many patients can present without anemia, we agreed to call the condition DBA syndrome to allow for the inclusion of other clinical phenotypes associated with this disease, such as certain birth defects or cancers.”

Updating DBA syndromes’ treatment

The task force agreed on multiple improvements to treatment. Since DBA syndromes’ recognition, there have only been three approved treatments to address it: red blood cell transfusions, corticosteroid therapy and hematopoietic stem cell transplantation. While the number of therapeutic options has not increased, the panel recognized ways to optimize these treatments for patients with DBA syndrome.

They changed the recommendations for transplants. “This is also a major change in the guidelines,” Wlodarski said. “Now, we are recommending, if needed, a transplant from a matched unrelated donor because recent years have shown excellent transplant outcomes with this type of donor. Before, the standard of care was only matched sibling donors.”

The task force also focused on collecting and dissemination other treatment improvements learned over the last decade.

“For example, now we better know how to assess the iron burden in patients,” Wlodarski explained, “and we have good drugs called iron chelators to remove the excess iron from frequent transfusions.”

Due to problems in creating red blood cells, many patients with DBA syndrome need to receive life-long blood transfusions. They also need higher hemoglobin levels compared to patients with short-lasting anemia, such as those with cancer undergoing chemotherapy. In DBA syndrome, severe anemia can be lifelong, and hemoglobin levels must be maintained at appropriate levels to ensure adequate growth and development. The guidelines provide directions on maintaining appropriate hemoglobin levels while balancing iron toxicity prevention with iron chelation therapy.

“Our consensus among experts is that hemoglobin levels prior to transfusions should be maintained at a minimum of 9-10 g/dL — this is something that many clinicians need to learn, and we hope our guidelines will help implement changes,” Wlodarski said.

Similarly, the guidelines are a resource for learning what is currently considered best practice during corticosteroid therapy. For corticosteroids, the group recommends restricting the long-term maintenance dose of prednisone or prednisolone to 0.3 mg/kg per day to avoid treatment-related side effects.

Collectively, the new expert-led guidelines represent the best DBA treatments currently known. Their true value is as a resource to local physicians who may lack experience with this rare disorder.

Helping physicians, patients and families identify and treat DBA syndromes

One of the largest problems with treating and studying DBA syndrome is its rarity. Many physicians and health care facilities have never encountered affected patients, which have an incidence of 5-10 cases per million live births. That makes identifying the disease an uncommon experience. More recent research and experience revealed a significant heterogeneity in disease causes and presentation, complicating the problem.

“In the last few years, we’ve discovered new genes that cause the disease,” Wlodarski said. “It’s caused mostly by mutations in the ribosome system. This can cause severe anemia, which, over time, can develop into full bone marrow failure and immunodeficiencies. Additionally, at least half of the patients are born with congenital defects, such as heart, skeletal, kidney or other organ system defects.”

Instead of every physician needing to become an expert on DBA syndrome genetics, the guidelines provide detailed information on the current landscape of genes affected in DBA syndrome. For example, one in five people with DBA syndrome has a mutation in the ribosomal protein S19 (RPS19) gene. In total, the authors agreed on 28 genes that cause DBA syndrome, of which 26 directly affect the ribosome system, and two are other genes, such as GATA1 and TP53, which can cause DBA syndrome.

The guidelines also provide a starting point to plan treatments based on new and simplified diagnostic criteria. The authors agreed that DBA syndrome can be diagnosed based on clinical presentation, after exclusion of other differential diagnoses, or based on genetic testing. To that end, St. Jude created a resource for all interested parties.

“We created a website where clinicians, patients and families can easily access the different aspects of disease diagnosis and management,” Wlodarski said. The St. Jude–hosted website is now freely available and contains the material from the consensus, including tables with detailed information and the corresponding text. The guidelines were also published as a peer-reviewed article by The Lancet Haematology and are available on the journal’s page. The goal is to help standardize treatment for patients with this rare disease, not only for children but also for adults.

“It’s important for physicians to adopt the standards at their institutions — and follow them — because we believe they will improve the long-term outcomes,” Wlodarski emphasized.

A global consensus to improve the lives of patients with DBA syndrome

“We wanted to achieve standardization across the world, not only in one country,” Wlodarski explained. “We included representatives from 27 countries — and a total of 53 experts were involved — to create this comprehensive piece of work that takes into account various aspects of the disease in an international multidisciplinary effort.” The task force consisted of physicians, scientists and patient advocates, representing many different points of view as well.

The group produced the guidelines using the Delphi consensus-building method. Each accepted statement had to receive approval from at least 85% of the task force. This undertaking was difficult, as many different hospitals, health care systems and resource availabilities were reflected throughout the group.

“It took lots of effort, but also, it was a good way to learn more about the most recent advances in DBA syndrome and treatment approaches throughout the world,” Wlodarski said. “For example, we agreed to change the name because patients might present without anemia, with cancers, or with congenital abnormalities, like a skeletal abnormality. So, that’s why we prefer calling it DBA syndrome. It’s a grouping of symptoms, not only anemia.”

Wlodarski helped co-lead the group through these votes, discussions and debates over four years. In some cases, the group did not reach a consensus. Fortunately, in many cases, they did, such as for increasing surveillance due to the increased cancer risk posed by DBA syndromes.

“We were able to reach unanimous consensus on the higher risk for cancer,” Wlodarski explained. “Colon cancer risk is increased, even in young adults. So, the group’s consensus was to start colonoscopies at 20 years old and not wait until 45-50, as we do for the general population in most countries. We all agreed that if we want to catch cancer early, we need to start looking for it early in these patients.”

The final guidelines presented in The Lancet Haematology are the current consensus recommendations that the international and interdisciplinary group found compelling scientific evidence and/or clinical experience to endorse.

“If we have these guidelines and can disseminate them across the world, patients will now have a document to show to their doctors, who may not be experts in the disease,” Wlodarski concluded, “or doctors can discover on their own, to get patients with DBA syndromes the treatments that they need.”