Unsuccessful Treatment with Lenalidomide in a Diamond-Blackfan Anemia Patient.
Authors: Joosten Peter , Hoogendoorn Mels , Storm Huib , Kibbelaar Robby 
Published: October 2019

Abstract
Abstract 4219

Background
Diamond-Blackfan Anemia (DBA) is an autosomal dominant inherited bone marrow failure syndrome due to a defect in the ribosomal protein (RP) synthesis. Diagnostic criteria consist of presentation of anemia before birth with near normal or slightly decreased neutrophil counts, variable platelet counts, reticulocytopenia, macrocytosis, and normal marrow cellularity with a paucity of red cell precursors (Diamond et al 1976).

Patient characteristics
In 2002 a 34 year old man was presented with a hemoglobin (Hb) level of 2.4 mmol/l, a MCV of 117 fl, no reticulocytes and a normal leukocyte and platelet count. Except shortness of breath he had no other complaints. He did not use any medication. On physical examination there was only a short stature. Marrow cytology showed 20% erythropoesis with some dyserythropoesis. Marrow histology and cytogenetic were normal. A recent parvovirus infection was excluded. His medical history started in 1968 at the age of five weeks. A DBA was diagnosed and treated successfully with corticosteroids. There was a relapse at the age of 3 with again a good response on corticosteroids.
In 2002 he was initially treated with 6 units of red blood cells, resulting in a rise of the Hb to 6.4 mmol/l. After five months he had a Hb of 3.8 mmol/l, a normal MCV and 50.109/l reticulocytes. Kidney and adrenal function were normal, there was no hypogonadism and no splenomegaly. Hb electrophoresis showed an elevated HbF of 6.4%. By exclusion of other causes of anemia, it was concluded that the anemia had to be considered as a relapse DBA. Corticosteroids (1 mg/kg) for 6 months did not show any improvement. Cyclosporine 100 mg two times a day raised the Hb above 8 mmol/l from November 2003 till May 2004. While on cyclosporine he relapsed again and became red blood cell transfusion dependent from February 2006. A search for a HLA identical donor at that time was unsuccessful. ATG, cyclosporine and corticosteroids did not diminish the need for red blood cell transfusion. In 2007 the RPS19 (ribosomal protein S19) mutation was demonstrated in this patient, which definitively confirmed the diagnosis made 35 years ago. In 2008, still red blood cell transfusion dependent, treatment with lenalidomide 10 mg/day for 21 days during each 28 days was initiated.

Treatment considerations
All mutated genes in DBA cause a decreased synthesis of ribosomal proteins. As a consequence erythroid progenitors and precursors are highly sensitive to apoptosis (Perdahl et al 1994). One of the mechanisms is activation of p53 (Danilova et al 2008). Both the 5q- syndrome and DBA show haploinsufficiency for closely related ribosomal proteins RPS-19 and RPS-14. It is assumed that the pathophysiology of the 5q- syndrome and DBA are the same (Ebert et al 2007). Because lenalidomide is effective in patients with the 5q- syndrome, lenalidomide was considered as treatment option in DBA at the Annual DBA International Consensus Conferences in 2008 and 2009.

Results
Due to severe pancytopenia, lenalidomide was stopped after 5 weeks. During the next 6 months a slow recovery of white blood cells and platelets was observed. Before and 3 months after the start of the lenalidomide treatment marrow cytology, histology and cytogenetics were done. Both times there was a red cell aplasia, no signs of myelodysplasia and no cytogenetic abnormalities. Rechallenge with lenalidomide in a dose of 10 mg each fourth day resulted again in a pancytopenia in 6 weeks time. Each 3 weeks 3 units of red blood cells are necessary ever since.

Discussion and Conclusion
Treatment of DBA with lenalidomide in this patient was unsuccessful and resulted in a temporarily and severe neutropenia and thrombocytopenia. These adverse effects are also documented in 62% of the 5q- syndrome patients treated with 10 mg Lenalidomide. Moreover, in retrospect, we doubt if lenalidomide can be effective when red cell aplasia is already present as a late complication of DBA.

Disclosures:
No relevant conflicts of interest to declare.