Yvonne Daniel

Alternate day pomalidomide retains anti‐myeloma effect with reduced adverse events and evidence of in vivo immunomodulation

We previously reported that daily dose pomalidomide (CC‐4047), a thalidomide analogue, has excellent anti‐myeloma activity but is associated with myelosuppression and deep vein thrombosis. We report here a phase 1 study to determine the maximum tolerated dose (MTD) of pomalidomide at 1 mg, 2 mg, 5 mg and 10 mg on alternate days (ad). Twenty patients with relapsed myeloma were treated. Grade 4 neutropenia occurred in all patients receiving 10 mg and the MTD was defined as 5 mg ad. No thrombotic events were observed. Pomalidomide was continued following the 4‐week MTD study in 17/20 patients for a median of 14 months. 10% of patients had a complete response and >50% reduction in paraprotein was achieved in 50% of subjects. Progression‐free survival was 10·5 months and median overall survival was 33 months. A significant rise was observed in the proportion of CD8+ cells. Alternate day pomalidomide was associated with a marked reduction in the incidence of thrombosis whilst maintaining excellent anti‐myeloma activity. This trial provides further in vivo evidence that pomalidomide modulates the immune system in myeloma patients. Phase 2 studies to further assess the optimal schedule of administration and anti‐myeloma activity of this agent are planned.

Relationship between the clinical manifestations of sickle cell disease and the expression of adhesion molecules on white blood cells

Abstract: Background: The severity of sickle cell disease (SCD) increases with leukocyte count. The biological basis could be that leukocyte adherence to vascular endothelium mediated by adhesion molecules (AMs) facilitates vaso‐occlusion, the basic pathological process in SCD. Objective: To find out if there is a relationship between expression of AMs by leukocytes and the clinical manifestations of SCD. Methods: Flow cytometry was used to study the relationship between leukocyte AM expression and disease manifestations in 100 patients with homozygous (HbSS) sickle cell disease and 34 genotype HbAA controls. The effect of hydroxyurea therapy on AM expression was also examined. We excluded HbSS patients with any other disease, pregnancy in the previous 3 months, or Haemogloben F (HbF) ≥ 10%. Results: Patients with complications of SCD showed high expression of αMβ integrin by the neutrophils; and l‐selectin by lymphocytes and neutrophils (P < 0.03). CD18 was highly expressed by neutrophils in patients with sickle nephropathy (P = 0.018), and l‐selectin by lymphocytes in those with stroke (P = 0.03). Monocyte l‐selectin increased in sickle cell crisis relative to steady state (P = 0.04). Expression of αLβ2 integrin by neutrophils, monocytes, and lymphocytes decreased within a month of hydroxyurea therapy (P < 0.05), with symptomatic improvement in the patients and no more than 3.3% rise in HbF level. Conclusions: The findings suggest that in SCD (1): High steady‐state expression of αMβ2 integrin and l‐selectin by leukocytes predisposes to severe manifestations. (2) Increased leukocyte AM expression above steady‐state levels could be important in the genesis of crisis. (3) The early symptomatic improvement that follows hydroxyurea therapy is mediated via mechanisms independent of increased HbF, and may involve reduced AM expression in leukocytes. (4) Other treatment modalities that reduce leukocyte AM expression might also confer clinical benefit.

The linear effects of alpha-thalassaemia, the UGT1A1 and HMOX1 polymorphisms on cholelithiasis in sickle cell disease

Serum bilirubin levels and predisposition to gallstones in sickle cell disease (SCD) are influenced by genetic variation in the hepatic uridine diphosphate (UDP)‐glucuronosyltransferase (UGT1A1) gene, but the association is not consistent. This study investigated whether variation in the gene encoding haem oxygenase (HMOX1), a rate‐limiting enzyme upstream of UGT1A in the haem catabolic pathway, and α‐thalassaemia could explain some of the inconsistent effects. The UGT1A1 [TA]n and HMOX1 [GT]n promoter polymorphisms and α globin genotypes were determined in 263 SCD patients (199 HbSS, 5 HbS/β0, 59 HbSC). Detection of gallstones was based on ultrasound of the liver/biliary tree. Regression analysis showed that serum bilirubin levels and the incidence of gallstones were strongly associated with the number of UGT1A1 [TA] repeats in all subjects (P < 0·0001 and P < 0·01, respectively). While HMOX1 genotype had no effect, co‐inheritance of α‐thalassaemia reduced serum bilirubin levels in all SCD patients independently of the number of UGT1A1 [TA] repeats. Each additional [TA] repeat is associated with an increase in mean serum bilirubin levels of 21% and cholelithiasis risk of 87% in SCD.

Sickle Cell Disease Screening in Northern Nigeria: The Co-Existence of ÃÂ-Thalassemia Inheritance

Background: Despite the high burden of Sickle Cell Disease (SCD) in Nigeria, the underlying haemoglobinopathy profile remains uncertain. Although a number of urbanised areas have pilot hospital-based newborn screening programmes, the impact of the disease in rural areas is unknown. Methods: From January 2010 to December 2011 this community-based study screened children aged 0-60 months in 29 randomly selected local communities of three adjoining northern Nigerian states - Abuja, Kaduna and Katsina. For infants 0-6 months, blood spots were used and for infants 7-60 months EDTA blood samples were analysed using high performance liquid chromatography (HPLC). 31 selected sample with high Hb A2 (3.5-7.4%) were further analysed using molecular diagnosis to ascertain the presence of the Beta Thalassemia gene. Findings of 10,001 infants and children screened, 269 (2.69%) had a SCD diagnosis; 90% of which were HbSS (n=243), 5% HbSC (n=13), 3% with high A2 > 6% (possible S with existence β thalassaemia (n=9) and 1% HbSD (n=2). 74% of infants screened were HbAA (n=7,391). 2,341 (23%) were carriers; 96% HbAS (n=2,236), 2% HbAC (n=51), 1% HbAD (n=25) and 1% HbABeta-thal (n=22). HbSβo was confirmed by molecular analysis from the 31 selected samples. Conclusion: Early infant diagnosis of SCD in Northern reports an incidence of 1.72%, Homozygous SS accounts for over 90% of cases; double heterozygous SC is very low (4%). The presence of beta (β) thalassemia coinheritance is now confirmed using molecular analysis. Community and family counselling and educational material in Northern Nigeria must include the risk of beta thalasemia inheritance.

Sickle cell/β0-thalassemia associated with the 1393 bp deletion can be associated with a severe phenotype.

In patients who have inherited both the sickle cell gene and the β-thalassemia (β-thal) gene, the nature of the β-thal mutation will impact on the disease phenotype. The β-thal mutation caused by the 1393 bp deletion has previously been described as having a mild clinical phenotype when inherited with the sickle gene. We describe three members of a family with this deletion who present with a more severe phenotype. The severity cannot be explained by their Hb F levels, or the XmnI-HBG2 polymorphism. This deletion cannot be presumed to be associated with a mild disease phenotype and we recommend that patients with Hb S/β0-thal are screened for this deletion.

Newborn Screening for Sickle Cell Disease through Use of Tandem Mass Spectrometry

We read with interest the recent report by Boemer et al. (1) describing the use of tandem mass spectrometry for screening of newborns for sickle cell disease. We congratulate the authors on an excellent study that follows the peptide-based philosophy and approach described in our previous publications(2)(3). Unfortunately, we believe that the authors have substantially misrepresented our data and their own originality. The authors suggest that our original communication (2) indicated that there was insufficient analytical sensitivity to distinguish homozygous and heterozygous samples. Clearly, this assertion is not the case, because we presented figures demonstrating heterozygous and homozygous signals for hemoglobin S (Hb S), …

Evaluation of the validity of Hb A2 and mean corpuscular haemoglobin action values in antenatal screening for beta thalassaemia carriers in England.

National antenatal screening of all pregnant women in England is carried out using standards and guidelines produced by the National Health Service Sickle Cell and Thalassaemia Screening Programme. The algorithms for detection of beta thalassaemia carrier status rely on action criteria, which are set using the percentage Hb A2 and mean corpuscular haemoglobin (MCH) values. Three groups of samples: MCH <27 pg and Hb A2 3·5–3·9%, MCH ≥27 pg and Hb A2 4–4·3% and MCH ≥27 pg and Hb A2 3·5–3·9% were selected from a sample population of 59 500 to assess the validity and predictive value of the action criteria – 25 false positives (0·042% of total) and nine false negatives (0·015% of total) were detected. These findings support the continuation of the current action values.