The initial management principles of DBA are initially to

  • Establish an accurate diagnosis
  • Treat the anemia with appropriate use of transfusions, corticosteroids and hematopoietic stem cell transplantation
  • Minimize complications from iron overload and steroids therapy
  • Exclude any associated congenital abnormalities.

 

The use of a co-ordinated multidisciplinary approach to DBA patients cannot be over emphasized. Currently in Africa there is no such facility and thus the DBA Africa foundation aims to assist with co-ordinating and advocating for the establishment of such facilities.

 

 

Initial Hematopoietic Treatment

The initial hematopoietic treatment is directed to correcting the anemia. The appropriate use of transfusions is important not only to optimize development of the child but also to prevent accelerated iron overload seen with regular chronic transfusions. Initially, regular blood transfusions with leukodepleted irradiated red blood cells is indicated. The optimal transfusion trigger is unknown, but most authorities use a Hb of 8.0g/dL, with 9.0g/dL during infancy when physiological demands associated with growth a prominent. Usually 10-15ml/kg of leukodepleted irradiated RBC is transfused every 3-5 weeks. Immediate family members should not be used as donors so as to prevent allosensitization which would adversely affect chances of a hematopoietic stem cell transplant (HSCT). Hemoglobin levels should ideally be maintained between 8-12g/dL

 

The major problem with long term transfusion therapy is iron overload and the toxic effects it presents to essential organs. There is currently no day facility dedicated to the needs of transfusion dependent children. The long-term goal of the Olive Children’s Foundation is to open a children’s transfusion day clinic where the transfusion needs of children can occur under direct doctor vision in a fun and holistic environment.

 

 

Steroid therapy

Approximately 80 percent of patients will initially respond to corticosteroid therapy, with the remaining 20 percent requiring chronic RBC transfusions. Guidelines differ in the literature with regards to the optimal timing of a steroid trial with most authorities suggest a steroid trial at 1 year of age. The adverse effects on linear growth, neurocognitive1 development and side effects of corticosteroids are the main reason for delaying a steroid trial to 1 year of age. Although some authorities suggest a trial at 6 months of age, we recommend deferring until 1 year of age unless a specific indication for an earlier treatment exists.

  • Indications for an earlier corticosteroid trial include:
    • Unsafe or unreliable blood products
    • Venous access problematic requiring placement of a venous access device2
    • Significant neutropenia not responsive to other treatment.

To promote an erythroid drive, commence steroid treatment 1-2 weeks following a transfusion (Hb ± 9-10g/dL). Many different regimes are described in the literature. We recommend those described by Vlachos et al2.

 

  • Starting dose: 2 mg/kg/day of prednisone or prednisolone for a maximum of 4 weeks.
    • Monitor CBC and reticulocytes weekly thereafter
    • Expect a hematological response within 2-3 weeks
    • Adequate response is a transfusion independent Hb >9g/dL
    • Failure occurs if Hb drops to below 9 and patient needs subsequent transfusion
    • Higher doses or prolonged steroid treatment beyond 4 weeks is not recommended.
    • A second trial to a partial response or failed response should be attempted after 12-18 months.

 

  • Once a response occurs, the steroid should be tapered.
    • Low dose, alternate day regime
    • Target maintenance dose 0.5mg/kg/day or 1mg/kd alternate days3.
    • If cannot be weaned to the target dose, then chronic transfusion therapy should be re-instituted.

 

  • The lowest effective steroid dose should be attempted in all patients.

 

 

Prophylaxis whilst on steroid treatment

Pneumocystitis jirovecii pneumonia antibiotic prophylaxis with trimethoprim/sulfamethoxazole should be implemented after the first month of high dose steroids, and should be continued until the patient is on the target low dose alternate day regime. In those with baseline neutropenia, pentamidine is recommended2.

  • Dose of trimethoprim/sulfamethoxazole should be 5mg/kg

To minimize gastric upset, twice daily steroid dosing together with a proton pump inhibitor such as lansoprazole or H2-blocker such as ranitidine should be used concurrently2.

 

 

Vaccinations

Vaccinations are generally safe and advocated in DBA patients. Live vaccines should be given unless severely neutropenic or on concurrent high dose steroid treatment. In such cases, live vaccinations should be deferred unless clinically warranted, as in high endemic areas {24}.

 

 

Ongoing Monitoring

General monitoring

On initial diagnosis, ideally a patient should be seen by a cardiologist, urologist and endocrinologist.

The frequency of blood count monitoring is dependent on the patient status and stability. Transfusion dependent patients should have:

  • CBC, reticulocytes, differential count done every 3-5 weeks

All patients should be referred through to endocrinologist by 5 years of age.

The complex nature of DBA necessitates the need for a multidisciplinary approach. Endocrinologic, oncological, cardiac, reproductive, ophthalmologic, hepatic and psychosocial specialist management is essential.

 

 

Complications of transfusion therapy

DBA patients inability to recycle iron release from RBC breakdown results in iron deposition in essential organs resulting in iron-induced injury3. Monitoring of the pituitary, thyroid, heart, liver and pancreas is essential.

  • Iron sequestration
    • Annual monitoring of cardiac function by MRI (T2), Echocardiogram and Holter monitoring is recommended.
    • Magnetic susceptometry (SQUID) is not available in most countries in Africa.
    • Liver biopsy should be performed if MRI is not available. If liver biopsy is not available, then ferritin level should be used, but one must be aware of the limitations to the use of ferritin levels.
    • Ferritin 3 monthly

 

 

Complications of steroid therapy

The adverse effects of chronic steroid dependency from infancy is specific to DBA patients.

  • Pathological fractures and avascular necrosis
    • Bone densitometry determinations
      • Baseline evaluation as soon as can be accomplished without sedation (normally 5 years of age).
      • Every 1-3 years thereafter if receiving a steroid dose of >7.5mg/Kg {27}
      • Bisphosphonate therapy although not standard of care5, has been used in those patients on steroid doses of >15mg/d for more than 6 months.
    • Growth
      • Growth curves should be monitored 6 monthly and more frequently during periods of high growth velocity (infancy and puberty)
        • Keep steroid dosage to minimum, and a growth plateau may indicate the need to interrupt steroids and implement a short-term transfusion program
      • Cataracts and glaucoma screening
        • 6 – 12 monthly ophthalmological consultations
      • Endocrinopathies6
        • Growth failure, diabetes mellitus, failure of the pituitary, thyroid, parathyroid, adrenals and gonads may be related to side effects of treatment
        • Screening for gonadal insufficiency in all patients with delayed puberty, cessation in pubertal development or loss of libido.
        • Hypothyroidism screening after the age of 14
        • Interval screening by morning cortisol measurement in iron overloaded patients, and cosyntropin testing after discontinuation of glucocorticoids.
        • Annual calcium:creatinine ratio
        • Annual screening for Diabetes Mellitus after the age of 14.
      • Hypertension
        • Blood pressure recording every 3 months

 

 

Oncological complications

Period history and physical examination with blood count monitoring at 4-6 month intervals in stable DBA patients

 

  • If abnormality found, then bone marrow aspirate, biopsy and cytogenetic studies (karyotype and FISH analysis for abnormalities in chromosomes 5,7 and 8)3.
  • Some authorities advocate annual bone marrow examination to identify early signs of myelodysplasia.

 

References

  1. Yeh, T. F., FAU, L. Y., FAU, H. C., FAU, C. Y., FAU, L. C., FAU, L. H., et al. (0917). Early dexamethasone therapy in preterm infants: A follow-up study.
  2. Vlachos, A., & Muir, E. (1216). How I treat diamond-blackfan anemia.
  3. Vlachos, A., Ball, S. F., Dahl N FAU – Alter, Blanche,P., FAU, A. B., Sheth, S. F., Ramenghi, U. F., et al. (1211). Diagnosing and treating diamond blackfan anaemia: Results of an international clinical consensus conference.
  4. Pickering, L. (2009). Immunocompromised children. In L. Pickering (Ed.), American academy of pediatrics; report of the committee on infectious diseases (28th ed., pp. 72-86). IL: Elk Grove Village.
  5. Ward, L., FAU, T. A., Phuong, P. F., Cranney, A. F., Barrowman, N. F., Gaboury, I. F., et al. (0117). Bisphosphonate therapy for children and adolescents with secondary osteoporosis.
  6. Lahoti, A., Harris, Y. T., Speiser, P. W., Atsidaftos, E., Lipton, J. M., & Vlachos, A. (0601). Endocrine dysfunction in diamond-blackfan anemia (DBA): A report from the DBA registry (DBAR) [adrenal insufficiency; growth; hypogonadism; iron overload; osteoporosis; vitamin D deficiency EDAT- 2015/10/27 06:00 MHDA- 2016/06/02 06:00 CRDT- 2015/10/27 06:00 PHST- 2015/06/11 [received] PHST- 2015/09/07 [accepted] AID – 10.1002/pbc.25780 [doi] PST – ppublish.

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