Agranulocytosis in patients with <scp>Diamond‐Blackfan</scp> anaemia (DBA) treated with deferiprone for post‐transfusion iron overload: A retrospective study of the French <scp>DBA</scp> cohort

Abstract

Diamond-Blackfan anaemia (DBA) is the first cause of congenital erythroblastopenia characterised by non-regenerative macrocytic anaemia, congenital malformations, and predisposition to malignancies. It was first described in 19381 and later identified as the first ribosomopathy.2, 3 Recommended treatments are red blood cell transfusions, corticosteroids and haematopoietic stem cell transplantation (HSCT).4-6 Corticosteroids should be tested for every patient; 40% of patients with DBA are classified either as primary steroid resistant or poor responders to steroids e.g., patients requiring high dosage (>0.3 mg/kg/day) and have to enter into a long-term transfusion support programme.6 Early and severe iron overload is reported in patients with DBA.7, 8 Iron chelation is recommended when ferritin is above 500–1000 ng/ml or after 10 blood transfusions. Deferasirox (DFX) can be used for children aged >2 years and may be associated with deferoxamine (DFO) if needed. Deferiprone (DFP) is an oral chelator, known to be effective, especially for treating cardiac iron overload,9, 10 but is rarely used in patients with DBA because of the severe agranulocytosis risk.10-12 Therefore, currents DBA guidelines consider DFP use only in third line.4 Here, we report the experience of DFP use in paediatric and adult patients with DBA registered in the French DBA cohort (OFABD). The OFABD registry (Observatoire Français de l'Anémie de Blackfan-Diamond) was initiated in 1995 and the institutional ethics committee (CPPRB-A, Bordeaux, France) approved the cohort study and OFABD database was registered with the national data protection authority (CNIL, 1396823 V0). All patients or their parents signed an informed consent for the collection and analysis of clinical data. A local ethics committee (CLEA-2022-248) approved this study. Referring physicians were individually contacted; all replied. The end-point for our analysis was the 06/01/2021. Neutropenia was defined by an absolute neutrophil count (ANC) of between 1.5 and 0.5 × 109/L. Agranulocytosis is defined by an ANC of <0.5 × 109/L. On the 6 January 2021, out of 423 OFABD-registered patients, 28 patients had received or were treated with DFP. Five patients were excluded for missing data, including one patient with known non-severe agranulocytosis and lost to follow-up. Characteristics of the 23 remaining patients' data on DFP are given in Table 1. The male:female ratio was 1:1.3. The median (range) age at DFP introduction was 21 (1–36) years. All patients were on regular transfusions; no patient had received HSCT. Genetic diagnosis was available for 14 patients (61%). DFP was used as first chelation therapy for two patients. When DFP was used as a second chelation therapy, the first therapy was DFO alone for 13 patients (58%), DFX alone for seven (29%), and DFX + DFO for one (4%). DFP was used as monotherapy for 11 patients and associated with another chelating agent, initially or after, for 17 patients with either DFO (16) or DFX (one). Overall, patients contributed 118 person-years of exposure to DFP. DFP was stopped for nine patients (39%), including three cases of agranulocytosis. The median (range) delay between the introduction and the discontinuation of DFP was 25 (3.75–48) months. The median (range) duration of DFP exposure for patients who did not stop DFP and had a good control of iron overload was 89 (34–112) months. Agranulocytosis was reported for three patients: one child and two adults. The clinical outcome and the associated complications are given in Table 2. The calculated incidence rate of agranulocytosis was 2.56 cases per 100 patient-years. The median (range) delay between DFP introduction and agranulocytosis was 133 (90–771) days. The DFP median (range) dose at the event was 62 (59–66) mg/kg/day; not different from the one for patients who did not develop agranulocytosis: 71 (44–75) mg/kg/day. The median (range) ANC before DFP introduction was 2.106 (1.848–2.673) × 109/L for the patients who did develop agranulocytosis and 2.400 (1.120–5.740) × 109/L for those who did not. Patients with DBA may have mild neutropenia, and this can also be the case when they are on DFP, but neutrophils fluctuations seem not to be predictive for agranulocytosis. The DFP was stopped in all patients who developed agranulocytosis without any re-introduction thereafter. Agranulocytosis lasted for a median (range) of 7 (3–34) days. In a review mainly in thalassaemic patients, the rate of agranulocytosis on DFP was estimated to be 0.24 per 100 patient-years of drug exposure.9 A recent randomised study comparing DFX and DFP in paediatric patients with transfusion-dependent haemoglobinopathies reported on three cases of non-fatal agranulocytosis out of 194 children on DFP with a median follow-up of 379 days.13 In one short report, a child with DBA who developed an agranulocytosis had a very poor outcome post-DFP.12 The last published guidelines on DBA care4 did underline that DFP should be used only in third line. This warning explains the paucity of reports on DFP use in patients with DBA. We confirm in this report that the risk of agranulocytosis is significant higher in patients with DBA than observed in thalassaemic patients but seems to have the same characteristics.9 In our patients, agranulocytosis had a very standard and short course with no fatal outcome. As in other patients, we observed no significant impact of previous neutropenia or dose.9 Of note, for patients in our cohort, the maximum DFP dose was 75 mg/kg/day. The limited number of patients in our study precludes any statistical analysis for potential risk factors. Iron loading is known to occur very early and to be especially severe in patients with DBA.14 We suggest that DFP use should be discussed only in selected patients with DBA with severe and uncontrolled haemochromatosis, especially in patients with cardiac overload. Indications in children must be closely discussed as they may be at higher risk of agranulocytosis. We do not recommend dose above 75 mg/kg/day. Education is known to be the key to reduce the severity of DFP-associated agranulocytosis9, 14 and must be given to every patient with DBA or their parents and to all involved caregivers. As in any patients with agranulocytosis and fever, patients with DBA should be hospitalised, receive intravenous antibiotics and granulocyte-colony stimulating factor. Nicolas Lecornec and Thierry Leblanc designed the research study, performed the research, and oversaw the project; Nicolas Lecornec, Marie-Pierre Castex, Yves Réguerre, Philippe Moreau, Isabelle Marie, Loïc Garçon, Lydie Da Costa provided patients or materials; Nicolas Lecornec and Thierry Leblanc collected and analysed the data and wrote the manuscript. All authors approved the manuscript. This project is supported by the French National PHRC OFABD (DBA registry). We thank Isabelle Marie for her work for the OFABD cohort. We thank the patients with DBA and their families and the French DBA patients' association AFMBD. We thank all the referring physicians of patients with DBA: Nathalie Aladjidi, MD; Giorgia Battipaglia, MD; Sandrine Bohrer, MD; Marie-Pierre Castex, MD; Loïc Garçon, MD, PhD; Bénédicte Hivert, MD; Justyna Kanold-Lastawiecka, MD, PhD; Philippe Moreau, MD, PhD; Corinne Pondarre, MD, PhD; Caroline Thomas, MD; Fabienne Vacheret, MD. The authors declare no competing financial interests. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Appendix S1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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