Hydroxyurea Is Associated with Later Onset of Occurrence of Acute Splenic Sequestration Episodes in Sickle Cell Disease: Lessons from the European Sickle Cell Disease Cohort - Hydroxyurea (ESCORT-HU) Study

Introduction: Acute splenic sequestration crisis (ASSC) is defined by the sudden enlargement of the spleen with an acute drop of Hb level >2g/dL. It results from a massive trapping of red blood cells in the spleen, promoted by the low velocity of blood in the open circulation of the splenic red pulp (Brousse, 2012). Splenic sequestration crises are among the first severe manifestations in patients with HbSS and HbS/β0thalassemia genotypes. A retrospective study of 190 children diagnosed at birth with these genotypes and followed in Paris conurbation between 2000 and 2009 found a median age at first episode of 1.4 years (0.1-7). The frequency of ASSC decreased with age, as functional asplenia developed (Brousse 2012). ASSC occur at a later age in patients with HbSC genotypes, in whom splenomegaly may persist until adulthood (Naymagon 2015).

The study analyses the age of onset of ASSC in a cohort of patients treated with hydroxyurea (HU).

Material and methods: The European Sickle Cell Disease Cohort - Hydroxyurea (ESCORT-HU) study was initiated when HU received an approval in SCD patients in Europe. This non-interventional prospective cohort study conducted in SCD patients treated with HU according to current clinical practice ended in 2019, after the recruitment of 1906 patients (45% children) in 4 European countries. Median duration of follow-up was 45 months, for a total of 7,309 patient-years of observation (de Montalembert 2021).

Results: 33 episodes of ASSC were reported in 23 patients (11 males and 12 females), all with HbSS genotype. Patients were treated with HU for a mean duration of 4.2 ± 3.9 years [1- 18.9]. Age at occurrence of ASSC was unknown for 3 patients and a possible history of ASSC was not recorded in 4 patients. A first episode as reported in 14 patients, with a median [IQR] age of 6.8 [3.4- 23.1] years. 15 episodes were recurrences. Overall, 10 episodes (32%) occurred in patients aged 1 to 5 years, 14 (45%) in patients aged 5.7 to 17. 9 years, and 6 (19.3%) in patients aged 26.6 to 64 years. All these episodes of ASSC were classified by investigators as disease-related and not related to HU treatment.

Discussion and conclusion: We observe that ASSC appeared in this cohort of patients treated with HU later than in previous publications in which a minority of children received HU. Various studies in the literature have evaluated the effect of HU on spleen function in SCD patients. While the BABY HUG trial comparing HU to placebo in very young children failed to demonstrate the efficacy of HU in preserving splenic function after 2 years of treatment, another study involving a group of 40 patients (mean age of 9.1 years) showed that after 3 years of HU treatment, 33% of patients had preservation or restoration of splenic filtration function assessed by liver/spleen scan (Nottage 2014).

We hypothesize that the later age at which HU patients experience ASSC is a consequence of improved splenic perfusion. A positive consequence is better protection against overwhelming infections, but physicians should be aware of the increased period at risk for ASSC, well beyond the 6-7 year age limit usually reported in HbSS and Sβ0 genotypes.

References:

• Brousse V, Elie C, Benkerrou M, et al. Acute splenic sequestration crisis in sickle cell disease: cohort study of 190 paediatric patients. Br J Haematol. 2012; 156:643-648.

• de Montalembert M, Voskaridou E, Oevermann L, et al. Real-Life experience with hydroxyurea in patients with sickle cell disease: Results from the prospective ESCORT-HU cohort study. Am J Hematol. 2021; 96:1223-1231. doi: 10.1002/ajh.26286. Epub 2021 Jul 23. PMID: 34224583.

• Naymagon L, Pendurti G, Billett HH. Acute Splenic Sequestration Crisis in Adult Sickle.

• Cell Disease: A Report of 16 Cases. Hemoglobin. 2015; 39:375-379. doi: 10.3109/03630269.2015.1072550. Epub 2015 Aug 17. PMID: 26287797.

• Nottage KA, Ware RE, Winter B, et al. Predictors of splenic function preservation in children with sickle cell anemia treated with hydroxyurea. Eur J Haematol. 2014; 93:377-383.

de Montalembert:Addmedica: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Vertex: Membership on an entity's Board of Directors or advisory committees. Galactéros:Addmedica: Membership on an entity's Board of Directors or advisory committees. Oevermann:Addmedica: Membership on an entity's Board of Directors or advisory committees. Cannas:Addmedica: Membership on an entity's Board of Directors or advisory committees. Elenga:Addmedica: Honoraria. Etienne-Julan:Addmedica: Membership on an entity's Board of Directors or advisory committees. Brousse:Addmedica: Membership on an entity's Board of Directors or advisory committees; Forma therapeutics: Membership on an entity's Board of Directors or advisory committees; GBT: Membership on an entity's Board of Directors or advisory committees; Beam Therapeutics: Consultancy; GBT: Other: Travel gant.