Crizanlizumab; a new, effective drug for sickle cell?

The results of a major, new trial in sickle cell disease (SUSTAIN) have just been published in the New England Journal of Medicine and presented at the American Society of Haematology meeting in San Diego. The trial involved the novel drug crizanlizumab (SEG101 or SelG1), a humanised monoclonal antibody. The drug was developed by Selexys Pharmaceuticals who were bought out by Novartis in 2016, on the back of this successful trial, for a reputed sum of $665 million. Crizanlizumab binds to P-selectin. a chemical located on the inner lining of blood vessels, or endothelium, and thereby prevents the adhesion of red cells, neutrophils and monocytes. It is administered by a 30 minute intravenous infusion usually given every month.

A painful vaso-occlusive crisis is initiated by the formation of sickled red cells and the adhesion of these sickled red cells, together with white cells, to the inner lining of blood vessels. Adhesion is a vital process, accelerating the blockage of small blood vessels by clumps of red cell and white cells, which restricts blood flow and the supply of oxygen and leads to the development of pain. In patients with sickle cell disease both the red cells and the endothelium are “stickier” than normal due to the activation or up-regulation of a variety of chemicals promoting cellular adhesion. One of these key chemicals is P-selectin, which is stored inside endothelial cells and re-located to the cell surface when the endothelial cells are activated. It is therefore a key molecule to target if the aim is to prevent cell adhesion.

Crizanlizumab was tested in a Phase II randomised control trial led by Professor Kenneth Atago from Chapel Hill, North Carolina, USA. 60 centres participated in the study, the majority in the USA with others in Brazil and Jamaica. 198 patients, aged 16-65 years, with different types of sickle cell disease, participated in the study; they all had between 2 and 10 painful crises during the previous 12 months and a significant number were taking hydroxycarbamide as well. They were randomised to three groups; high (67) and low (66) dose crizanlizumab and placebo (65). Neither the patients nor the doctors looking after them knew which group they had been allocated to. Each patient received a monthly IV infusion of crizanlizumab or placebo for 52 weeks, depending on which group they had been allocated to, after which the results were analysed.

The headline result was that high dose crizanlizumab significantly reduced the frequency of all sickle cell crises by 45% compared with the placebo group and doubled the proportion of patients who experienced no pain at all during the year long study (from 17% in the placebo group to 36% in the high dose group). Beneficial effects on pain reduction were seen in all types of sickle cell and irrespective of whether or not patients were taking hydroxycarbamide. In addition, the time from starting treatment to first crisis was prolonged from 1.4 months in the placebo group to 4.1 months in the high dose group and the number of days spent in hospital during the year were reduced by 42% (from 6.9 days in the placebo group to 4.0 days in the high dose group). Disappointingly, given the major reduction in the frequency of crises, the researchers were unable to demonstrate any improvement in the patient’s quality of life, although this may just reflect the limitations of the questionnaires that were used.

In terms of side effects, these seemed to be minimal and to consist mainly of influenza-like symptoms, such as fever and muscular-skeletal aching, together with diarrhoea, itching, vomiting and chest pain, which affected a minority of patients . Five patients died during the study, but these occurred equally in all groups and were due to sickle cell related problems like the acute chest syndrome. 55 serious adverse events were recorded but again these were equally distributed between the three groups  and cannot therefore be attributed to the effects of crizanlizumab.

This is a very important trial for all those with sickle cell disease. It is the first time in the last 20 years, since the publication, also in the New England Journal of Medicine, of the results of the hydroxycarbamide trial in 1995, that a drug has been shown to reduce the frequency of painful crises in a well controlled clinical trial. Remarkably, the effectiveness of crizanlizumab is very similar to hydroxycarbamide; the latter reduced the frequency of painful crises by 44%, compared to 45% for crizanlizumab. The next step, of course, will be to make sure these positive results can be replicated in a second study and to try and work out which patients with sickle cell disease are likely to benefit the most from this innovative treatment.

There is potentially a major problem though. Monoclonal antibodies, such as crizanlizumab are eye wateringley expensive; in 2012 the average cost of a years treatment with this class of drug in the USA was approximately $200,000 (=£164,000). This compares with less than £200 for a years treatment with hydroxycarbamide. Clearly, at these sorts of prices it will never be possible to use crizanlizumab in the developing world, where most people with sickle cell actually live. It’s use in the UK, for the estimated 12,500 patients with sickle cell here, would increase the drug budget of the NHS by an astronomical amount. What crizanlizumab will actually cost is unclear at the moment and it remains to be seen whether Novartis, who have just paid out $665 million for the rights to the drug, will market it at a price health care services can afford.

Listen to Dr Kenneth Ataga discuss the crizanlizumab trial at the American Society of Haematology meeting in San Diego last December.

Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease K.I. Ataga, A. Kutlar, J. Kanter, D. Liles, R. Cancado, J. Friedrisch, T.H. Guthrie, J. Knight-Madden, O.A. Alvarez, V.R. Gordeuk, S. Gualandro, M.P. Colella, W.R. Smith, S.A. Rollins, J.W. Stocker, and R.P. Rother. New England Journal of Medicine 3rd December 2016 DOI: 10.1056/NEJMoa1611770

Effect of Hydroxyurea on the Frequency of Painful Crises in Sickle Cell Anemia Samuel Charache, M.D., Michael L. Terrin, M.D., Richard D. Moore, M.D., George J. Dover, M.D., Franca B. Barton, M.S., Susan V. Eckert, Robert P. McMahon, Ph.D., Duane R. Bonds, M.D., and *the Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. New England Journal of Medicine (1995), volume 332: pages 1317-1322

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Hydroxycarbamide and “silent cerebral infarcts”

The first reports dating from 1995 showed that taking hydroxycarbamide regularly reduced the frequency of painful crises and of the acute chest syndrome and also reduced the need for blood transfusion. This breakthrough has since been followed by numerous reports from around the world demonstrating unequivocally that treatment with hydroxycarbamide fundamentally changes the natural history of sickle cell disease for the better.

As well as having beneficial effects on the most feared acute complications of sickle cell disease, such as the acute chest syndrome, hydroxycarbamide also prevents many of the chronic complications of the disease. It restores low oxygen levels improving the functioning of the lungs, it reduces protein loss in the urine preventing kidney failure, it reduces the chance of chronic liver disease and it reduces the risk of stroke. Perhaps most importantly of all, taken regularly in the long term, it also has a profound effect on survival; in one study it reduced the risk of death during the study period by 40% and in another study increased the probability of survival at 10 years follow up to 86%, in the treated group, compared with 68% in the patients who did not take hydroxycarbamide.

A recent report in the British Journal of Haematology, from a group of researchers in Memphis, Tennessee, has added another important piece information to our knowledge about the beneficial effects of hydroxycarbamide in sickle cell disease. The researchers looked at the damaging effects of sickle cell disease on the brain. The most obvious complication of sickle cell is a stroke, which can result in paralysis, seizures and loss of speech, and is a devastating complication which, without any intervention, will occur in 24% of individuals by the age of 45 years. Screening for early signs of an increased risk of stroke in children by transcranial doppler and prompt blood transfusion have greatly reduced the risk of this complication.

But sickle cell also has more subtle detrimental effects on brain structure and function. Over time so-called “silent cerebral infarcts” or SCI’s appear in the white matter of the brain. These SCI’s gradually increase in frequency and by 18 years of age are found in 39% of individuals. For many years they were not thought to be harmful but we now know, on the contrary, that SCI’s are associated with a significant decrease in IQ, learning difficulties and poor performance in neuropsychological tests, with overall negative effects on educational attainment and employment prospects.

The study from Memphis looked at 50 children with sickle cell anaemia who were all taking hydroxycarbamide long term. Effects on the brain were evaluated by detailed brain scans after 3 years and again after 6 years of treatment. Normally, it would be expected that the number of children in whom SCI’s were found would increase progressively over this six year period but, in these children, all taking hydroxycarbamide, the number of SCI’s remained unchanged and stable. The implication is therefore that treatment with hydroxycarbamide will prevent the development of SCI’s and the serious neuropsychological sequelae associated with them.

This is an important study. Not only does it emphasis yet again the value of hydroxycarbamide, but for the first time it demonstrates that there is a practicable alternative to blood transfusion to prevent this insidious complication of sickle cell, affecting large numbers of individuals with the disease.

Hydroxycarbamide treatment and brain MRI/MRA findings in children with sickle cell anaemia. Kerri Nottage, Russell Ware, Banu Aygun, Matthew Smeltzer, Guolian Kang, Joseph Moen, Winifred Wang, Jane Hankins and Kathleen Helton. British Journal of Haematology (2016), volume 175, pages 331-338

Other blogs of interest

The TWITCH trial – a major improvement in the care of children at risk of stroke (18/02/16)

More on hydroxycarbamide (07/01/15)

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A long life with sickle cell disease

Sickle cell disease is often described as a “life limiting disorder”. Not so long ago children and teenagers were sometimes told that they would be “lucky to see their 21st birthday”. In many parts of the world it remains the case that children die young as a result of sickle cell, but the situation in Europe and America has improved enormously over the last few decades. As an example, in a series of 252 children, followed from birth in East London, childhood mortality was virtually eliminated with 99% of children surviving to reach their teenage years. With good medical care survival into middle age is now the norm, although the cumulative damage caused by sickle cell can become more and more of a burden as the years pass.

Although this improvement in mortality in the developed world is the result of better medical care, a recent publication from the USA makes it clear that there active steps patients themselves can take which will improve their overall life expectancy. The report, in the journal Blood, describes four remarkable patients with sickle cell disease who survived into their 80’s; two with sickle cell anaemia (Hb SS) and two with Hb SC disease. It wasn’t as if these four patients had escaped undamaged by their sickle cell; all four had significant complications including, retinopathy, the acute chest syndrome, avascular necrosis, leg ulcers, gallstones, an enlarged spleen, severe anaemia, heart failure and iron overload. A daunting disease burden for anyone to carry and yet they survived into old age – how was this possible?

Well some of the reasons were just related to the luck of the draw. Two had Hb SC disease and this is known to be a milder condition than Hb SS disease; in addition to which, the two patients with Hb SS disease both had a naturally high Hb F level, which we know would have helped to protect them. As a result, all four individuals reported only infrequent painful crises, less than 3 times a year. Finally, all four were women; from the teenage years onwards men with sickle cell tend to have higher mortality rates than women. This maybe because women with sickle cell generally have a lower haemoglobin level than men and this will tend to reduce the frequency of painful crises. But, we also know, that men in general indulge in more high risk behaviours than women and this may be just as relevant to their chances of survival as their haemoglobin levels.

Type of sickle cell disease; male or female; Hb F level – you cannot really change any of these factors, although you can choose to artificially raise your Hb F level by taking hydroxycarbamide and, if you are a man, you can minimise risk taking behaviour. But the authors did identify other factors in their four patients, which are very much under individual control, and which may be just as important in determining longevity.

Firstly, all four patients maintained a “healthy lifestyle” – they did not smoke or drink alcohol and they were not overweight. Secondly, they were all “good patients” – meaning they took their drugs and other medications regularly and always came to outpatient and clinic appointments. Thirdly, they all had “supportive family networks” – either their husbands, brothers and sisters or children, who were all very active and involved in looking after them. Finally, although not commented on by the authors, all four patients had excellent medical care throughout their lives and this is also likely to be relevant to their longevity.

So, you could be an octogenarian as well, and it’s not high tech rocket science! Think seriously about taking hydroxycarbamide, live a healthy lifestyle, try to do what your doctor or nurse says and cherish your family, you need them. Finally, don’t settle for second best in your medical and nursing care.

Case series of octogenarians with sickle cell disease. Samir K. Ballas, E. Dianne Pulte, Clarisse Lobo and Gaye Riddick-Burden. 

Clinical outcomes in children with sickle cell disease living in England: a neonatal cohort in East London. Telfer P, Coen P, Chakravorty S, Wilkey O, Evans J, Newell H, Smalling B, Amos R, Stephens A, Rogers D and Kirkham F. Haematologica (2007), volume 92, pages 905-12.

Other relevant blogs

Lifestyle choices and sickle cell – 10/06/14

More on the benefits of exercise – 03/05/15

How the world around you affects the severity of sickle cell disease – 13/10/15

Reassurance about the effects of exercise – 18/12/15

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Knock down of BCL11A

There is great excitement in the sickle cell world at the moment about, what may turn out to be, a turning point in the the long road to find a practicable cure for sickle cell. A recent paper from the United States in the Journal of Clinical Investigation describes experiments using  the tools of genetic engineering to switch off the BCL11A gene. This is the gene which normally suppresses the production of foetal haemoglobin (Hb F). Successful “knockdown” of the BCL11a gene allowed unrestrained synthesis of Hb F, which reached levels in red cells more than enough to block all of the complications of sickle cell.

It has been known for a long time that Hb F prevents sickle haemoglobin (Hb S) from polymerising or “sickling” and that this, in turn, greatly reduces or prevents all the problems normally associated with sickle cell disease. There are four main lines of evidence supporting the view that Hb F is protective in sickle cell.

New born babies: In the first six months of life, babies with sickle cell are well with very few problems from their sickle cell disease. This “well window” exactly matches the period of time when they have a very high concentration of Hb F in their red cells.

Co-inheritence of sickle cell and HPFH: People who inherit a combination of sickle cell and a condition called hereditary persistence of foetal haemoglobin (HPFH), have levels of Hb F in their red cells in excess of 30%. They are essentially well with very few sickle cell related complications.

Individual level of Hb F: In people with classical sickle cell disease (Hb SS), the amount of Hb F varies from person to person from <1.0% to as much as 15%. Generally speaking, the higher an individual’s Hb F level the fewer problems they have from their sickle cell.

Hydroxycarbamide: Finally, you will all know that if you take the drug hydroxycarbamide regularly it can increase your Hb F levels to values up to about 20%. Successful treatment with hydroxycarbamide has been proven to significantly reduce the frequency of sickle cell related problems, improve anaemia and prolong life.

We are all born with large amounts of Hb F in our red cells but, during the first year of life, the gamma globin gene, which produces Hb F, is silenced and the beta globin gene, which produces adult haemoglobin (Hb A) or, if you have sickle cell disease, Hb S, is activated. For many years the Holy Grail of sickle cell research has therefore been a search for a way to reverse this “switch”, to re-activate the gamma globin gene and allow the production of sufficient amounts of Hb F to block the sickling process.

Following the discovery of hydroxycarbamide, one whole area of research concentrated on trying to identify other drugs able to promote the synthesis of Hb F which were at the same time free of serious side effects. Many drugs have come and gone over the years usually because, at the doses required to produce a useful effect, they were far too toxic. The latest, pomalidomide, was discussed in a blog on the 2nd of April this year. Another approach has been to use the tools of genetic engineering to insert additional copies of the gamma globin gene, which produces Hb F, into the patients’ stem cells.

The biochemistry underlying this “switch” from making one type of haemoglobin to the other is complex and has taken many years of painstaking research to finally work out. Many different genes are involved in the process but it became clear a few years ago that one gene in particular, called BCL11A, was critical in this switch. The protein made by the BCL11A gene is the key element in silencing the Hb F gene and also in promoting the synthesis of beta haemoglobin. The attention of researches since then has focused on trying to stop BCL11A working and whether this would mean that red cells would continue to make Hb F long term.

The first problem was that BCL11A appeared to have other functions, particularly in the brain and immune system, and the fear was that indiscriminate knockdown of BCL11A would have widespread deleterious effects as well as positive affects on Hb F production. The second problem was that the stem cells in which BCL11A had been silenced proved very difficult to grow in mice, the cells tending to die off after a few generations.

These problems seem to have been overcome by a team of researchers at The Dana Faber Institute and the Boston Children’s Cancer and Blood Disorders Centre, in Boston Massachusetts, led by Professor Samuel Orkin. They used sophisticated genetic engineering tools to construct a highly specific “molecular spanner” to inactivate BCL11A, and packaged the “spanner” within a modified Lentivirus so that it is delivered directly to blood stem cells, the precursors of all the red cells in the body. In the test tube they found that blood cells treated with this “molecular spanner” produced large amounts of Hb F, up to 80% of the total. What is more they were able to replicate these results when the cells were transplanted into mice with “sickle cell disease”. The mice also produced large amounts of Hb F and showed clear evidence of improvement in their sickle cell. In their final experiment, again in the test tube, they showed that blood cells from 4 patients with sickle cell disease, were also able to successfully incorporate the “molecular spanner” and achieved similar levels of Hb F.

Although technically very complicated, the approach used here is simple in concept. The red cells own biochemical machinery is genetically manipulated to re-activate the gamma globin gene and allow the  production of high levels of Hb F. The team of researchers in Boston are hoping to begin a clinical trial of the new technique using patients with sickle cell disease in early 2017.

Lineage-specific BCL11A knockdown circumvents toxicities and reverses sickle phenotype

Christian Brendel, Swaroopa Guda, Raffaele Renella, Daniel E. Bauer, Matthew C. Canver, Young-Jo Kim, Matthew M. Heeney, Denise Klatt, Jonathan Fogel, Michael D. Milsom, Stuart H. Orkin, Richard I. Gregory and David A. Williams

The Journal of Clinical Investigation 2016. doi:10.1172/JCI87885.

Check out some other blogs:

2nd April 2016: Pomalidomide – more action on the foetal haemoglobin front

23rd May 2015: More on gene therapy

3rd December 2015: The foetal haemoglobin story just got more complicated

26th July 2014: Homing in on BCL11A

3rd November 2014: Gene therapy

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Poloxamer 188 – helpful during a painful crisis or not?

Research involving Poloxamer 188 (also know as RheothRx or MST 188) continues to appear in the journals. The latest is some interesting work from a team working in Hungary and France published in the British Journal of Haematology (1).

Poloxamer 188 is an intravenous preparation which improves the flow properties of the blood and which was hoped would shorten or terminate a painful vaso-occlusive crisis, see previous blog from 03/06/14 “Update on clinical trials in sickle cell disease”. It’s initial use in sickle cell was reported 19 years ago in 1997, when indeed the results were very encouraging (2). But a follow up study in 2001, by the same group of doctors from the University of Tennessee, with a larger group of patients, did not show such positive results (3). Nevertheless, there was still some reduction in the length of a painful crisis and the time spent in hospital, particularly noticeable in children. A further study in 2004, this time restricted to patients admitted with the acute chest syndrome, failed to show any positive benefit on outcome (4).

Despite these disappointing clinical results, experimental work in the laboratory continues to suggest that poloxamer 188 may be a useful therapeutic option in sickle cell. The latest research (1) looked at blood collected from patients with sickle cell anaemia and assessed its “flow” and “adhesive” properties using a variety of tests, both with and without pre-exposure of the red cells to poloxamer 188. The investigators found that pre-exposure to poloxamer 188 reduced the viscosity or “thickness” of the blood, reduced the tendency of the sickle red cells to aggregate together and reduced the tendency of sickle red cells to stick to endothelial cells, which the lining of the inside of blood vessels. As the authors point out, all three of these properties would be expected to improve blood flow and therefore have a beneficial effect in a painful crisis, where the pain is thought to be caused by sickle cells obstructing blood flow and limiting oxygen supply to the tissues downstream.

Each poloxamer 188 molecule has one "sticky" part (in white) and two "slippery" parts (in blue). The sticky part fastens to damaged areas of the red cell membrane leaving the slippery parts to encourage red cells to flow more easily past each other and along the inside lining of the blood vessels.

Each poloxamer 188 molecule has one “sticky” part (in white) and two “slippery” parts (in blue). The sticky part fastens to damaged areas of the red cell membrane leaving the slippery parts to encourage red cells to flow more easily past each other and along the inside lining of the blood vessels.

The contrast between the marked effects found in the test tube and the limited benefits found in the clinical studies may be because by the time the pain begins to be felt the damage has already been done. The lack of oxygen downstream has already led to the death of tissues and cells and initiated an acute inflammatory reaction, which is the source of the pain. Improving blood flow at this point using poloxamer 188 would not necessarily have a major effect on the course on the crisis.

However, the question will only be resolved by a formal clinical trial with sufficient numbers of patients to give statistically significant results. Such a multi-centre trial, known as the EPIC trial (Evaluation of Purified poloxamer 188 or MST 188 In Crisis), was begun in May 2013 in hospitals across the USA. The trial is looking at children, aged 8-17 years, with sickle cell anaemia in crisis. The key factor will be whether treatment with poloxamer 188 shortens the duration of the crisis (time from admission to the time of the last dose of opiate painkiller) by 16 hours or more. The organisers of the trial thought they would need 388 patients to prove whether this is possible or not, and enrolment of sufficient numbers of patients was completed in February this year. Hopefully we will not have to wait much longer to know whether poloxamer 188 is of any practical use in sickle cell or not.

  1. Effects of poloxamer 188 on red blood cell membrane properties in sickle cell anaemia. Sandor B, Marin M, Lapoumeroulie C et al. British Journal of Haematology (2016), volume 173, pages 137-144.
  2. RheothRx (poloxamer 188) injection for the acute painful episode of sickle cell disease: a pilot study. Adams-Graves P, Kedar A, Koshy M et al. Blood (1997), volume 90, pages 2041-2046.
  3. Purified poloxamer 188 for the treatment of the acute vaso-occlusive crisis of sickle cell disease. Orringer E, Casella J, Ataga K et al. Journal of the American Medical Association (2001), volume 286, pages 2099-2106.
  4. Safety of purified poloxamer 188 in sickle cell disease: phase 1 study of non-ionic surfactant in the management of the acute chest syndrome. Ballas S, Files B, Luchtman-Jones L et al. Hemoglobin (2004), volume 28, pages 85-102.
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More on asthma and sickle cell

A team of French sickle cell doctors, from the Robert-Debre Hospital in the Sorbonne, Paris, have been studying a group of 375 babies identified at birth with sickle cell disease. Following them up carefully, recording what happens to them and noting the results of all the tests they have had done. “Cohort” studies such as this are a very powerful way of looking at how often various complications occur and what makes some individuals more at risk of these complications than others.

The team were particularly interested in strokes, which are a frequent and devastating event in children with sickle cell. What were the risk factors for having a stroke? And were there are any interventions which could protect the children most at risk? A lot is known about strokes in sickle cell and major improvements in care followed the publication of the STOP trials and the TWITCH trial (see a blog on “The TWITCH trial ….. posted on 18/02/16 for more information) but despite these efforts some children still suffer this life changing complication.

In the French cohort, by the age of 14 years, 26% of the children had developed evidence of cerebral macrovasculopathy detected by transcranial Doppler ultrasound (TCD). In plain English, by their early teens just over a quarter of the children had abnormal blood vessels in the brain predisposing them to a stroke. Despite the immediate implementation of a regular blood transfusion programme followed by hydroxycarbamide therapy after two years a small number of the children still went on to have a serious stroke.

The team found three factors which increased the risk of  developing abnormal brain blood vessels and one protective factor. As you might guess the protective factor was a high foetal haemoglobin (Hb F) level. A high Hb F is a key variable protecting individuals with sickle cell from painful crises, the acute chest syndrome, stroke and early death. This study demonstrates that it also protects the blood vessels in the brain.

The three factors increasing the risk of damage to the brain’s blood vessels were:

Upper airway obstruction – this is usually indicated by either snoring at night or by episodes of suspended breathing whilst asleep (sleep apnoea) and is commonly found in children with enlarged tonsils or adenoids. It can be effectively treated either by nasal steroid sprays or surgical removal. It was already known that intermittent obstruction to the upper airways while asleep caused low levels of oxygen in the blood (nocturnal hypoxaemia) and that this was associated with an increased risk of large or small strokes and seizures or fits. This study demonstrated that the low oxygen levels directly damage the blood vessels in the brain causing the cerebral macrovasculopathy which is in turn the precursor of a stroke.

Lower airway obstruction – this presented with wheezing and chronic cough together with evidence on lung function testing (spirometry) of narrowing of the airways in the lungs. These are all features of asthma. The previous blog (Asthma and sickle cell disease – posted 20/06/16) discussed how asthma is associated with frequent painful crises and the acute chest syndrome. This study also documents that a diagnosis of asthma also has an effect on the blood vessels in the brain. Like all patients with asthma the symptoms in patients with sickle cell can be controlled with inhaled drugs, steroids or bronchodilators, which help to relax and increase the diameter of the airways.

High reticulocyte count – reticulocytes or “retics” are the very young red blood cells which have just been released from the bone marrow. Everyone with sickle cell breaks their red cells down faster than normal, which is why it is called sickle cell anaemia. But the rate of breakdown or haemolysis varies from person to person. The higher the reticulocyte count the faster the rate of haemolysis and a fast rate of haemolysis, as this study documents, will damage the blood vessels in the brain resulting in cerebral macrovasculopathy and an increased risk of stroke.

As the authors themselves comment, treatment with hydroxycarbamide not only increases the Hb F level but also reduces the rate of haemolysis and the reticulocyte count. Hydroxycarbamide therefore has a double protective effect in children at risk of stroke. Emphasising once again the potential usefulness of this drug in people with sickle cell. One of the other interesting treatment implications of this careful study is that you don’t have to have a “miracle cure” to have a major effect on the well being of patients with sickle cell. Simple treatments, which have been used for a long time and are known to be safe, targeted at those at high risk, can also have a very significant impact.


Clinical and haematological risk factors for cerebral macrovasculopathy in a sickle cell disease newborn cohort: prospective study. Julie Sommet, Corinne Alberti, Nathalie Couque, Suzanne Verlhac, Zinedine Haouari, Damir Mohamed, Martine Francßois, Florence Missud, Laurent Holvoet, Monique Elmaleh, Ghislaine Ithier, Andre´Denjean, Jacques Elion, Andre Baruchel and Malika Benkerrou. British Journal of Haematology (March 2016), volume 172, pages 966-977.

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Asthma and sickle cell disease

In celebration of World Sickle Cell Day on June 19th The Lancet has published a series of specially commissioned articles on controversial topics in sickle cell. The first, written by Michael DeBaun, from Vanderbilt University, Nashville and Robert Strunk, from Washington University, St Louis, concentrated on the difficult and confusing association between asthma and sickle cell disease.

Professor Robert Strunk died suddenly in April 2016, before this article was published. He was a renowned and much loved Paediatrician and specialist in childhood asthma whose own childhood had been limited by asthma.

Professor Robert Strunk died suddenly in April 2016, shortly before this article was published. He was a renowned and much loved Paediatrician and specialist in childhood asthma. His own childhood had been affected by asthma, an experience which informed his life long work.

Asthma is common and familiar to most of us. Around 5.4 million individuals receive treatment for asthma in the UK, approximately 1 in every 12 adults and children. Asthma UK defines the condition as one that affects the airways, “the tubes that carry air in and out of your lungs. You could say that someone with asthma has sensitive airways that are inflamed and ready to react when they come into contact with something they don’t like”. Many “asthma triggers” are known including, infections such as colds and flu, cigarette smoke, stress and anxiety, exercise, cold air and allergies to pollen or pets. To quote Asthma UK again, “when a person with asthma comes into contact with something that irritates their sensitive airways it causes their body to react in three ways:

  1. the muscles around the walls of the airways tighten so that the airways become narrower
  2. the lining of the airways becomes inflamed and starts to swell
  3. sticky mucus or phlegm sometimes builds up, which can narrow the airways even more.

These reactions cause the airways to become narrower and irritated – making it difficult to breathe and leading to symptoms such as chest tightness, wheezing and coughing” – symptoms of a classic a asthma attack.

Because asthma is so common it is inevitable that some individuals with sickle cell disease will also have asthma, but the two diseases do not just occur together from time to time, they also interact in ways that have been difficult for doctors to disentangle and sort out.

The first problem is that it can be very difficult, particularly in young children, to distinguish between an episode of the acute chest syndrome and an acute asthma attack. Shortness of breath, wheezing and cough are symptoms common to both conditions and it is not uncommon for patients to be treated for both conditions at the same time.

Secondly, asthma and asthma-like symptoms are more common in children with sickle cell than in the general population. Wheezing, which is one of the classic symptom of asthma, is present in up to 70% of children with sickle cell and a formal diagnosis of asthma is made in 15-28% of sickle cell children.

Finally, if you have asthma it will make your sickle cell worse. Attacks of the acute chest syndrome occur more often, earlier in life and are associated with longer stays in hospital in the presence of asthma. Individuals with asthma will also have with more frequent painful crises. Recurrent attacks of the acute chest syndrome and frequent painful crises are associated with early mortality in sickle cell and, it is not surprising therefore, that a diagnosis of asthma also predicts earlier death.

How are we to understand the complex interaction between these two diseases? Professors DeBaun and Strunk suggest that an episode of the acute chest syndrome early in life sensitises the patient’s airways, either provoking full blown asthma or wheezing in susceptible individuals. A “second hit” with an asthma trigger such as a viral infection (young children have on average 6 a year), cigarette smoke or exposure to an allergen such as pollen, will provoke an asthma attack, but, in addition, by stimulating inflammation and reducing the flow of air and oxygen into the lungs, the episode of asthma can also evolve rapidly into the acute chest syndrome.

Whatever the details of the relationship between asthma and sickle cell disease, we know that individuals with both conditions are at increased risk. The authors emphasise how important it is for all sickle cell patients to be screened for asthma at each clinic visit, including the regular use of spirometry to measure their lung function. Once diagnosed the asthma needs to be treated effectively and treatment of the underlying sickle cell disease needs to be intensified, to prevent the two conditions interacting with each other in such a negative way.

The intersection between asthma and acute chest syndrome in children with sickle-cell anaemia – Michael R DeBaun and Robert C Strunk. The Lancet (June 18th 2016), volume 387, pages 2545-2553.

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Re-wiring the brain and chronic pain

Pain is a deceptively simple experience. If you hit your thumb with a hammer you feel instant pain, which peaks rapidly and then gradually resolves over a few days as the damaged tissues repair themselves.


In theory a painful crisis is just the same; the conventional wisdom is that the flow of blood inside the blood vessels within bones is blocked by sickled red cells, the tissues downstream are starved of blood and oxygen, and the resulting tissue death leads to an acute inflammatory response and severe pain. In the normal course of events, the pain resolves over a period of a week to ten days as the damage caused by the lack of oxygen is made good.

Of course, this is a gross over-simplification in so many ways. For example, the perception of pain, what you actually feel, is altered by many different factors. The classic example is of soldiers in the midst of battle, who may suffer horrific injuries but report feeling no pain until they are well away from the scene of the fighting. The stress and excitement of battle seems to be able, temporarily, to switch off pain sensation. Many other factors act in the opposite direction and will heighten pain experiences, including sleep deprivation, depression, lack of control, fear and many others. Clearly, what goes on in the brain is able to dramatically alter how we feel and respond to pain.


Pain messages are transmitted from the damaged area to the brain via nerve fibres in the spinal cord. The brain not only modifies our perception of pain but can also block or reduce upwards transmission of pain impulses via descending, modulatory pathways in the spinal cord. This is the so called “gate mechanism”.; the brain is able to control how wide or narrow the pain gate is.

One of the important ways in which pain perception is modified is known as central sensitisation. In this condition the pain circuits in the brain are fundamentally altered, usually in response to repeated, severe, poorly controlled pain experiences. Central sensitisation affects different people in different ways, but all have in common the fact that more pain is felt over longer periods of time. The pain may be experienced more intensely (hyperalgesia) or sensations which are not normally painful may be experienced as pain (allodynia); the area over which pain is felt may expand way beyond the damaged area or painful sensations may continue long after the initial cause of the pain has resolved.

Graph illustrating the concepts of hyperalgesia and allodynia

This graph illustrates the concepts of hyperalgesia and allodynia. In the normal course of events, as the intensity of the pain stimulus increases the pain experienced also increases (blue line). No surprise there!  However, repeated painful experiences, can result in central sensitisation which shifts the graph to the left (red line). The perception of pain is heightened at all levels of pain stimulus and non-painful sensations are now experienced as pain. 

Maybe as many as a one third of patients with sickle cell disease are said to have “chronic pain”; pain is experienced on a more or less continuous basis, with little if any pain free periods. It has always been difficult to understand this in terms of the simplistic notions of a painful crisis discussed above, but it is looking increasingly likely that the explanation lies in the concept of central sensitisation. When you think about it, patients with sickle cell disease are a high risk group for this complication of pain; they experience repeated episodes of severe pain throughout life and the pain is often poorly managed and ineffectively controlled. In a proportion of patients, this results in changes in pain wiring in the brain, which alters the disease from a condition characterised by intermittent episodes of pain, with long pain free intervals in-between, to one where the experience of pain is virtually continuous.

Some of the best evidence for this view comes from patients whose sickle cell has been “cured” by a successful bone marrow transplant, or where the disease activity has been effectively suppressed by regular automated exchange transfusions. In both circumstances, patients may, paradoxically, continue to experience severe pain, often requiring treatment with powerful, opiate pain killers, a situation which can persist for several years. Re-setting of the aberrant wiring in the brain, and neutralisation of the central sensitisation, eventually leads to a gradual cessation of these pain experiences.

The importance of central sensitisation, as a process which significantly adds to the misery of life for some people with sickle cell, has been highlighted in a study from John Hopkins Medical College, which is due to be published shortly in the Journal of Pain. The researchers studied 83 adult patients with sickle cell disease, testing their responses to a standard heat pain stimulus in a variety of different contexts. The subjects were then given a variety of psychological questionnaires to complete and kept a daily pain and sleep diary for the next 18 months.

From the results of the pain experiments the researchers identified two sub-groups; one, a group of 21 individuals, who scored high for central sensitisation markers and another, of 17 individuals, who had low scores. When the two groups were compared the patients with high scores for central sensitisation experienced more frequent crises and had more pain in-between crisis days, as a result they also had more contact with hospitals and doctors. Psychologically, they had an increased tendency to catastrophise, in other words they always assumed the worst was going to happen, and they had profound disturbances of sleep.

None of this may seem particularly surprising but, in terms of quality of life, it indicates that central sensitisation is a very damaging condition and demonstrates, importantly, that it is a major factor driving patients to seek repeated medical help. The authors make the point that addressing the underlying problem either by preventing the development of central sensitisation in the first place, by providing effective, rapid pain relief at all times, or diagnosing and treating the established condition, should be key therapeutic aims. Short circuiting central sensitisation would go a long way to improve the quality of life of a subset of sickle cell patients and potentially save the health service significant amounts of money. A win win situation!

An evaluation of central sensitization in patients with sickle cell disease. C C Campbell, G Moscou-Jackson, P Carroll, K Kiley, C Haywood, S Lanzkrom, M Hand, R R Edwards & J A Haythornthwaite. Journal of Pain (accepted for publication) DOI: 10.1016/j.pain.2016.01.475

For more on chronic pain see:

Cannabis, sickle cell and new concepts in chronic pain: 15th October 2015

Chronic pain conference: 14th and 17th December 2014

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Pomalidomide – more action on the foetal haemoglobin front

As many of you will know hydroxycarbamide is the only drug licensed for the treatment of sickle cell disease. It’s potential benefits in sickle cell were only discovered by accident, many years ago, when patients were being treated with the drug for something else entirely and were noted to have increased amounts of foetal haemoglobin (Hb F) in their blood. In a similar fashion, researchers in the US have just reported investigations into another drug, pomalidomide, which was also found to increase Hb F, when it was being used to treat a completely different disease, in this case, multiple myeloma, a form of blood cancer.

Large amounts of Hb F, whether occurring naturally or stimulated by taking hydroxycarbamide, inhibit sickling and greatly improve patients lives. Many drugs have the potential to increase Hb F , so why is pomalidomide any different? Well, importantly it is already being used to treat patients with multiple myeloma, so we know it can be given safely to people and its effect on Hb F production appears to be very dramatic.

The researchers in the US found that in human bone marrow cells, cultured in a test tube, and in mice, genetically engineered to have sickle cell disease, pomalidomide increased Hb F production x5-6 fold, raising Hb F levels from  a baseline of 5% to a maximum of 30%. In comparison, hydroxycarbamide only achieved a modest x2 increase in Hb F. In the mice with sickle cell disease, pomalidomide also reduced the production of sickle haemoglobin (Hb S) by 40%, a very significant decrease. So, pomalidomide reduces the synthesis of Hb S, the “bad guy” and replaces it with Hb F, the “good guy”.

Pomalidomide was found to work by significantly reducing, by up to 70%, the concentration of many of the chemicals, or transcription factors, which normally silence the gamma globin genes which make Hb F. These chemicals include the weirdly named SOX6, GATA1, KLF1 and LSD1 and, most importantly, the “master regulator” of gamma globin gene silencing, BCL11A. Removing these inhibitors allowed the gamma globin genes to start working again producing Hb F. In fact, pomalidomide appeared to re-programme the haemoglobin producing cells so that they behaved more like bone marrow cells from a newborn baby, when virtually all the haemoglobin produced is Hb F, rather than bone marrow cells from an adult.

These exciting results mean that pomalidomide can now be added to the growing list of drugs which increase the production of Hb F. It remains to be seen whether, when pomalidomide is used to treat patients with sickle cell disease, increased Hb F production is translated into reduced sickling and significant clinical improvement.

Pomalidomide reverses gamma-globin silencing through the transcriptional reprogramming of adult hematopoietic progenitors Brian M. Dulmovits, Abena O. Appiah-Kubi, Julien Papoin, John Hale, Mingzhu He, Yousef Al-Abed, Sebastien Didier, Michael Gould, Sehba Husain-Krautter, Sharon A. Singh, Kyle W. H. Chan, Adrianna Vlachos, Steven L. Allen,Naomi Taylor, Philippe Marambaud, Xiuli An, Patrick G. Gallagher, Narla Mohandas, Jeffrey M. Lipton, Johnson M. Liu and Lionel Blanc. Blood (2016), volume 127, pages 1481-1492

The foetal haemoglobin story just got more complicated – 12th March 2015

More on hydroxycarbamide – 7th January 2015

Homing in on BCL11A – 26th July 2014

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Automated red cell exchange transfusion – NICE gives the OK

NICE, the National Institute for Clinical Excellence, has just published guidance on the preferred way of undertaking exchange transfusions in sickle cell disease. These recommendations have major implications for all those living with sickle cell in the UK, and will no doubt have an impact on how services are organised, in order to ensure that all patients have access to the most advances treatments. An exchange blood transfusion is an important treatment option in sickle cell and has been in use for many years. It can be used in one off emergency situations but can also be repeated, on a regular basis, to manage some of the long term complications of sickle cell.

The aim of most blood transfusions is to raise the patient’s haemoglobin concentration rapidly because they have become dangerously anaemic. This is sometimes necessary in sickle cell and is then often referred to as a “top-up” transfusion. The purpose of an exchange transfusion however is different; the main requirement is to reduce the number of sickle red cells in the patient’s blood stream, rather than increase the haemoglobin level. The frequency and severity of sickle cell related events are directly related to the amount of sickle haemoglobin in the blood; reduce the number of sickle red cells and the risk of a sickle cell event will also drop in proportion. This is why an exchange transfusion can be potentially lifesaving in something like the acute chest syndrome, by stopping further sickling in the lungs, and also why regular exchange transfusions, repeated every 4-6 weeks, can protect against recurrent attacks of pain, strokes or priapism, prevent deterioration in conditions like pulmonary hypertension (high blood pressure in the lungs) and heal chronic leg ulcers. All good news, but there are some significant problems with exchange transfusions.

In the past “an exchange” was always done manually; blood was removed from the patient using a large cannula and syringe and then replaced with exactly the same volume of blood from a blood donor. This cycle was repeated over and over again until the sickle cell concentration (Hb S%) had fallen to the desired level. In someone with sickle cell anaemia (Hb SS disease), who has not been recently transfused, the Hb S level will be 100%, in other words all the red cells will be sickle red cells. During a manual exchange transfusion the aim was to reduce the Hb S level to about 20%; meaning that only 1/5th of the red cells would be sickle red cells and the rest would be normal, transfused red cells containing haemoglobin (Hb A). In practice, this was often difficult to achieve and would frequently take all day, an exhausting business for the patient and the doctor or nurse doing the exchange.

In addition, as with all blood transfusions there were always concerns about transfusion reactions and the risk of inadvertently immunising the patient against blood group antigens. Both of these risks of increased concern in an exchange because of the large volume of blood which had to be used, often 10 to 12 bags per exchange. When regular manual exchange transfusions were used to manage chronic complications over a period of months or years, there was the added worry of iron overload, or the build up of iron in the body derived from the transfused blood.

The importance of the NICE guidance is that it recommends moving away from manual exchange transfusions and instead making use of technology which can automate the whole process. The automated systems remove blood from the patient, centrifuge, or spin, it to separate red cells from plasma, then mix the patient’s own plasma with donor red cells in the correct proportion before finally returning the re-constituted blood to the patient.

The Spectra Optia automated red cell exchange machine in action

The Spectra Optia (manufactured by Terumo BCT) is the automated red cell apheresis system preferred by NICE.

The big advantage of an automated red cell exchange transfusion is that it is quick, taking at the most 2-3 hours rather than a whole day. It is also much more efficient and will routinely bring the Hb S level down to 10% or even less leaving, in other words, only 1 in 10 sickle red cells behind. Since the risk of a sickle cell related event is directly related to the proportion of sickle red cells, the very low levels achieved with an automated transfusion virtually banish sickling completely. In addition, if the patient is on a regular programme, it is only necessary to repeat the procedure every 8-12 weeks rather than every 4-6 weeks, because it takes the sickle red cells a long time to recover from such low levels. Another big plus. Finally, it looks as if the automated exchange is “iron neutral”. In other words the quantity of red cells removed, together with the iron they contain, exactly balances the quantity of red cells and iron returned to the patient, preventing any build up of iron and iron overload. Not only are there many advantages for the patient but NICE also estimates that, using an automated exchange for all sickle patients in the UK on a regular transfusion programme could save the NHS in England £13 million a year.

There are downsides, of course. The machine is expensive, about £45,000 and staff have to be specially trained in it’s use the and the trouble shooting any problems. Then there is the vexed issue of vascular access. A manual exchange uses just one venous line, usually placed in a large vein in the arm. Blood is alternately taken out and put in using the same line. The automated systems need two large, venous lines, one out and the other in, which in practice is often achieved by using a double-barrelled femoral line placed in the large, femoral vein in the groin. Needless to say femoral lines are not popular with patients and insertion requires highly skilled staff. Fortunately, these access problems have to a large extent been overcome as expertise has developed and nowadays many patients have repeated automated exchanges through arm veins, with the two cannulae placed under ultrasound guidance, greatly improving the “hit rate”.

Hopefully, the NICE guidance will prompt a move towards the more widespread use of automated exchange transfusion technology in sickle cell, opening the way for many more patients to benefit from this innovative treatment. NICE has also called for clinicians to work together to define how regular automated red cell exchange transfusions can benefit patients with different sorts of complications. So, expect to see a burst of research activity in the near future which will define the role of this intervention in sickle cell disease more precisely.

Read the guidance from NICE:

Curtis explains the problems:

For background information on blood transfusion:

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