Early Clinical Manifestations, Presence Of a Single Bantou Haplotype and High Baseline Reticulocyte Count Predict Severity In a Sickle Cell Anemia Newborn Cohort

Sickle cell anemia (SCA) is a monogenic disease with multigenic expressivity. The ability to identify high-risk SCA-children would permit accurate prognostication and better genetic counselling, and facilitate the planning of clinical trials. Miller et al. (CSSCD) reported in 2000 that early dactylitis, baseline Hb level<7g/dl, and leukocytosis correlated significantly with adverse outcomes later in life. However, Quinn et al. reported in 2007 in the Dallas newborn cohort that none of the events before age 3 predicted death or stroke after age 3.

This study revisits this issue using the Créteil Newborn Cohort (1986-2011). The dates and nature of the 1^st SCA-related manifestations and further clinical events were prospectively recorded: vaso-occlusive crises (VOC) including dactylitis, acute chest syndromes (ACS), strokes, splenic sequestrations and acute anemia < 6g/dl. Alpha-genes, beta-globin haplotypes, G6PD activity, CD36 platelet expression were determined and baseline biological parameters (WBC, PMN, platelets, Hb, Hct, MCV, reticulocytes, HbF%, LDH) were recorded between 1-2 years of age, a minimum of 3 months away from a transfusion, one month from a painful episode and before any intensive therapy. The criteria of severity retained for this study were death or events requiring intensive therapy, defined as hydroxycarbamide (HC) prescribed for patients having experienced at least 3 VOC/year or 2 ACS or with baseline Hb<7g/dl; transfusion program (TP) for those with recurrent splenic sequestrations or strokes or abnormal velocities on Doppler (TCD); stem cell transplantation (HSCT) for those with indication of intensive therapy and genoidentical donor. Cox regression was used to analyze the predictive factors of severity.

This newborn cohort consists of 363 patients (55 SC,28 Sb+,262 SS,15 Sb0,3 SDPunjab). Median age at last visit was 6.4 years, providing 2827 patient-years of follow-up. As no SC or Sb+ patient died or experienced events requiring intensive therapy, analysis of severity criteria was only performed on SS, Sb0, SDPunjab, referred as SCA-patients (n=280). Alpha-thalassemia was present in 41.6%, Bantou/Bantou beta haplotype in 43.4% (vs 5.9% in the CSSCD cohort), Benin/Benin in 22.9%, Senegal/Senegal in 10.2%, “other” in 23.4%. G6PD deficiency was observed in 11.4% and CD36 non-expression in 7%. Kaplan-Meier estimates of survival by age 5 and 18 were 97.6% (95%CI:95.6-99.6%). One-hundred-fifty-one/280 SCA-patients (54%) required intensive therapy at the median age of 3.8yr (0.1-20): 69 HC, 136 TP, and 41 HSCT (patients may have successively received HC, TP and HSCT). Cumulative risk of severity criteria was 45% by age 5 and 70% by age 10. Univariate Cox analysis showed that Bantou presence (52.6%), CD36 non-expression, early SCA-1^st manifestation (<1 and <3 year of age), baseline high level of WBC, reticulocytes and LDH, low levels of Hb and Hct were significantly associated with severity whereas platelets, HbF, MCV, alpha genes number and G6PD were not. Multivariate Cox analysis retained as significant and independent predictive risk factors for severity: high reticulocyte level (>400x10⁹/L) (HR=2.82,95%CI:1.70-4.69,p<0.001); the presence of a single Bantou haplotype (HR=1.76,95% CI:1.18-2.60,p=0.007); and early (<1 year of age) first SCA-clinical manifestation (HR=2.35,95%CI:1.55-3.56,p<0.001).

This study confirms Miller’s report, showing that the risk level can be estimated by age 2 in SCA-patients, a result potentially useful for prospective trials (HC/HSCT). Moreover, we show for the first time that the presence of a single Bantou haplotype has predictive value for severity in this cohort where its frequency is much higher than in the CSSCD cohort.

Bernaudin:Novartis: Research Funding.