Blood cancer — always at the forefront of research

There are some 250,000 people in the UK living with blood cancer, a sub-set of the disease that has caught up with 1 in 16 men alive today and 1 in 22 women. Some 40,000 people each year in the UK are diagnosed with blood cancer, and 15,000 people die from it.[1] This makes it the third biggest cancer killer in the UK, after breast and prostate.

It is a strangely intangible disease. Brains, lungs or breasts are easy to understand—we know where they are and what they are there for. By contrast, most of us know very little about our bone marrow, where blood cancer originates, or what our lymph glands do. There are about 100 different sub-categories of blood cancer, many categorised as leukaemia (from the Greek words for white blood) or lymphoma, which strikes in the lymph system.

But precisely because blood is so accessible for testing, this kind of cancer has always been at the forefront of cancer research. “The very first descriptions of genetic abnormalities happened in leukaemia,” says Prof John Gribben, one of the world’s leading blood cancer experts with more than 500 publications to his name. After a long career at Harvard, he is now based at the Barts Cancer Institute in London, specialising in leukaemias and lymphomas. “This led to our first proper understanding of the molecular make-up of cancers, and this in turn led to discoveries in the treatment of solid tumours.”Gribben pic

The breakthrough came in 1959 when researchers David Hungerford from the Fox Chase Center and Peter Nowell from the University of Pennsylvania School of Medicine identified the so-called Philadelphia Chromosome. Named after the city where both were based, this was the first time that a genetic mutation was linked to cancer. Nowell and Hungerford discovered that people with chronic myeloid leukaemia (CML) have one abnormally short chromosome (number 22).

A freakish translocation found to cause cancer

It took more than a decade for scientists to work out precisely what was going on: in the 1970s, Dr Janet Rowley from the University of Chicago demonstrated that the abnormality came about because of a freakish “translocation” of DNA from one gene to another. The new, malfunctioning hybrid gene (called BCR-ABL) switches on the production of cells – and never switches off. “It’s as if the traffic light is constantly on green when it should have been red,” says Gribben. Thus, scientists discovered the first oncogene – cancer gene – that led to a revolution in cancer treatment.

At the time, doctors were relying on chemotherapy – as we have seen a blunderbuss technique that blasts all cells, good and bad – or other drugs that offered short-term respite but not a cure. The prognosis for CML was poor, ditto for acute lymphoblastic leukaemia, where a similar oncogene was found to have a role an aggressive cancer. This is the most common type of the disease to be found in children and younger people. Kids could be offered a bone marrow transplant, a highly risky procedure that up to 50 per cent of patients would not survive. Doctors would be happy if they could keep their patients alive for a year or two after diagnosis. What if you could develop a drug that targeted a specific genetic abnormality?

Imatinib — the first wonder drug

The first of these so-called targeted therapies, aimed at CML and other blood cancers, came to market in 2001. Jointly developed by Drs Brian Druker (of Oregon Health and Science University) and Nicholas Lydon (then working for a drug company that became Novartis), Gleevec (or imatinib) was a wonder drug that had an astonishingly positive impact on patient outcomes. Early trials showed that 98 per cent of people on the drug were in full remission five years after treatment.

“For a lot of people, Gleevec was simply too good to be true. But these once-dying patients were getting out of bed, dancing, going hiking, doing yoga. The drug was amazing,” Dr. Druker said in a 2009 interview with the New York Times.* Now we know that people treated with this drug are as well as people who don’t have cancer at all. There is a more than 90 per cent chance of a full cure for children with acute lymphoblastic leukaemia, and the drug is approved for the treatment of ten different cancers. Not for nothing was this the first cancer drug to feature on the front cover of Time magazine.

It worked by targeting the malfunctioning gene, in effect producing a chemical reaction with the BCR-ABL abnormality, turning the traffic light to red and stopping the ceaseless reproduction of malignant cells. Although the absolute number of people with CML and associated diseases was small, the principle of targeted gene therapy was revolutionary and is at the heart of subsequent advances in the treatment of blood and other cancers.

*https://www.nytimes.com/2009/11/03/science/03conv.html

[1] Source: http://www.bloodwise.org.uk

RIP Clive James

Clive James, the Australian wit, broadcaster and poet died last Sunday at the age of 80, ten years after being diagnosed with CLL. Clive James pic

He wrote the best — the only? – poem about chemotherapy, specifically about Ibrutinib. the wonder drug that helped keep him and many thousands of others alive for a lot longer than expected. Here it is:

Ibrutinib

The Marvel Comic name should tip you off

That this new drug is heavy duty stuff.

You don’t get this one just to cure a cough.

A chemo pill, and powerful enough

To put the kibosh on your CLL,

It gets in there and gives the bastard hell.

 

Five years’ remission and the beast is back.

It’s in your bones the way the Viet Cong

Poured through their tunnels to the Tet attack,

And what comes next might not last very long.

But let’s see what Ibrutinib can do

To win the war whose battlefield is you.

 

Ibrutinib, you little cluster-bomb

Of goodness, get in there and do your thing!

All that the bad guys seek is martyrdom:

Their own demise is the death they bring.

They work in cells. There is no high command.

We let you in and then it’s hand to hand.

 

Should you prevail, we promise you a role

From here on until the natural end.

Just beat them back and it will be a stroll,

Unless you don’t, in which case things might tend

To go bananas in a serious way.

But not yet. Down the hatch. This is today.

***

Inspirational stuff — and Ibrutinib really is a remarkable drug, a pill rather poisonous goo, showing the way to targeted treatment of leukaemias and other cancers. Only Clive James could make it sound so poetic!

The Weirdness of Watching and Waiting

Not all cancers are treated quickly…

Lord Saatchi, the advertising mogul who lost his wife to cancer, has likened chemotherapy to medieval torture. As we saw in my last post, drugs like bendamustine are becoming more targeted, but still chemo is a blunt instrument. It does a lot of harm to other, perfectly healthy parts of your body, your immune system for example, as well as hitting cancer cells. This is a price worth paying perhaps if it is going to put your cancer into remission.

But not all people diagnosed with cancer are treated with chemo, or treated at all. Some 15,000 people in the UK are on what is known as a watch and wait routine, which is a bizarre state of affairs where your cancer is diagnosed but then left alone. This is counter-intuitive, in that we all know people die because their cancers are not spotted until too late. Early treatment surely makes the difference between a good and bad prognosis. So why delay? It seems strange, even reckless, to defer the inevitable, especially since the disease is still advancing.

…in fact, treatment can be postponed for as long as possible

For certain types of blood cancer, however, doctors say it does make sense to postpone treatment for as long as possible. These diseases have different properties from solid tumours that you might find in bowel, brain or breast, for example. With the latter, doctors will move as quickly as possible to excise the cancer, and treat the patient thereafter with radiotherapy and or chemo to mop up any remaining malignant cells. But blood cancers have often spread far and wide through the body by the time they are discovered, without cohering into one big lump that constitutes a target. Since there is often no prospect of a cure, there is no point in using up the arsenal of possible treatments before absolutely necessary.

Under these circumstances, the doctor’s job is to keep it under control and treat it when necessary, so it doesn’t get out of hand. Studies show that early deployment of chemo or similar conveys no advantage in terms of long-term survival, when compared to being treated later on. And in the meantime, the science of drugs medicine is advancing rapidly, which means that by the time you stop watching and waiting, there may well be new drugs available that will prolong your life.

But this is little consolation when you find yourself in the bizarre position of having advanced incurable cancer, yet being left alone as if the disease had never existed. One doctor told me his patients thought he was mad when he told them they were going on this regime: my sentiments exactly. In the battle with cancer, the enemy is identified, the guns cocked and loaded, but we’ve decided to hang out and be peaceful for a while. Meanwhile, you check your body every morning for lumps and bumps. Not for nothing is watch and wait often called the watch and worry regime.

Bombing of Bari

How WW2 raid was a milestone in history of cancer treatment

On the night of December 2, 1943, the German Luftwaffe launched a surprise attack on the port of Bari in southern Italy. The harbour was crammed with allied shipping and the city crowded with military personnel and civilians. Eighteen ships were destroyed in the raid, a further eight seriously damaged – and over 1,000 people were killed.

For the allies, massing troops and materiel for the assault on the Axis-controlled Europe via the Italian peninsula, this was the worst shipping disaster since Pearl Harbor. For countless Italian civilians, it was a human catastrophe. But, bizarrely enough, the bombing of Bari was also a milestone in the history of cancer treatment.

The allies were tragically complacent, thinking they were beyond the reach of German bombers. There wasn’t even a functioning radar system to give the alarm. There were gigantic explosions as one defenceless ship after another was hit. Multi-coloured flames leapt 1000 feet into the sky and the sea filled with fuel oil, flames blazing in a 40-foot wave of fire above the water. Clouds of suffocating black smoke settled on the harbour and on the town.

proper try bari

One of the American ships to be destroyed was the John Harvey, a merchant vessel that had been waiting in the harbour for days to unload its secret cargo of deadly mustard gas, a poison used to horrific effect in the trenches of the First World War. Responding to intelligence that the Axis forces were preparing for chemical warfare, President Franklin Delano Roosevelt had ordered his troops to be supplied with 100 tons of the gas, to be used in retaliation to Axis chemical attacks or to seal off territory from the enemy.

Merchant ship carrying secret cargo

Captain Knowles of the John Harvey, together with a handful of officers and crew, were aware of what they were carrying. But he was under strict orders not to tell a soul, even the harbourmaster who might have expedited the unloading of the clandestine load. It would have been a diplomatic disaster had the world learnt that the allies were shipping chemical weapons to the European theatre. So when the ship exploded, taking Knowles and his crew with it, there was nobody left alive in Bari who knew about the ship’s deadly cargo.

Equally, nobody was aware that the clouds of smoke blanketing were full of poison gas, or that the fuel oil in the harbour had also combined with the gas to create a deadly soup. Twelve to thirty-six hours after the attack, more than 800 servicemen and countless civilians who had inhaled the gas or even been in the contaminated water, began to present with mysterious blisters and burns all over their bodies. Many died agonising and inexplicable deaths, as none of the overstretched medical personnel knew what they were dealing with. Medics made matters worse by keeping the patients swaddled in blankets, the correct treatment for shock but precisely wrong for those dunked in the mustard-in-oil mixture.

Toxic agent suspected

In time, doctors came to suspect that some toxic agent was at work, thinking that the Germans had used chemical as well as high explosive bombs in their raid. Lieutenant Colonel Stewart Francis Alexander, a chemical weapons medical officer attached to the US general staff, was sent to investigate. He was working blind, without input from those US authorities who knew the Jean Harvey’s secret, but he quickly came to the conclusion that mustard gas was the culprit. He worked from first principles, examining the victims and the evidence of the raid. More than 600 patients were tested. Blood and liver changes were highly suggestive of mustard. He soon established that bomb casing from the bottom of the harbour contained traces of the gas as well, and that these bombs belonged to the allies rather than the Luftwaffe.

A surprising cancer connection

Alexander’s official medical report, circulated in May 1944, made clear that the mustard case had done especial damage to the victims’ lymphatic system and bone marrow. Thus the cancer connection: scientists at Yale University and elsewhere had long suspected that mustard-based chemicals would be effective in controlling certain cancers, particularly lymphoma and leukaemia which are caused by disorders of the tissues that form white blood cells. Alexander’s evidence was akin to an unorthodox drugs trial, proving as a result of tragic circumstances that mustard-based compounds could be effective in attacking these cancers.

This research remained intensely secret, as the allies wanted to keep under wraps the fact they had shipped the gas to Europe. Prime Minister Winston Churchill went so far as to ban any mention of mustard from British reports of the Bari disaster. Yet doctors made progress and in November 1947, Dr S. Farber of the Children’s Cancer Research Foundation gave a nitrogen mustard compound to a group of 16 children who were seriously ill with acute leukaemia. In ten out of 16 cases, the children saw a dramatic improvement, with tumours and lymph nodes shrinking and their bone marrow returning to normal. Doctors at Yale treated a man with an aggressive tumour in his neck caused by Non-Hodgkins Lymphoma: the drug had an immediate and positive impact.

At this stage in the development of chemotherapy, the drugs were exceedingly poisonous and mortality rates high. The focus of research in post-war US shifted to surgery and radiotherapy. But in East Germany, the former German Democratic Republic, research into mustard-based chemotherapy continued apace. In 1963, scientists succeeded in producing Bendamustine, a drug made from nitrogen mustard, used to this day to treat lymphomas and other blood cancers.

Bendamustine has the distinction of being the only major cancer drug to have emerged from behind the Iron Curtain. For decades, it was available in East Germany and nowhere else. After the wall came down in 1989, it was soon made available in Western Europe. The US, more suspicious and unwilling to remember the lessons of Bari, approved the drug only in 2008.

How Brexit nearly derailed a key cancer trial

In mid-February, leading oncologists received a letter from an international drugs company that appeared to confirm their worst fears about the impact of Brexit.

With the prospect of a no-deal looming, Kite, a subsidiary of the biotech giant Gilead Sciences, warned in the letter that it might have to cancel the UK part of a pioneering trial which aimed to prolong the lives of people suffering advanced blood cancer.

The trial, called Zuma 7, targets people suffering from relapsed/refractory diffuse large B-cell lymphoma, a common form of blood cancer. It was launched early last year as a global study involving hundreds of patients in 61 research locations around the world.

Zuma 7 involves CAR-T therapy, a state of the art technique under which cells are taken from patients and modified in the lab before being infused back into their bodies. In earlier trials, this has been proven to hold off the progress of cancer in advanced or otherwise hopeless cases.

This cellular engineering is at the cutting edge of anti-cancer science and demonstrates the complexity of supply chains in the pharmaceutical industry. With Brexit looming, this poses real problems for UK patients wanting to access world-class medicines.

Cancer cells taken from the patients were due to be harvested in the UK and exported to laboratories in the Netherlands for freezing, then shipped to Gilead’s facilities in California, before being returned to Europe for testing, then imported back into the UK where they would be given to patients.

At present, all the regulatory approvals to do this are in place, as the UK is part of the EU. The problem arose because genetically modified cells are considered medicines and, in the run up what looked likely to be a disorderly Brexit on March 30, needed approval to be imported from Europe. No-one knew, or knows what the new rules will be.

“The companies [looked set to decide that] that the risk of being unable to ship the cells back to the UK is too great and [were considering] calling off the UK arm of the study as a result,” said Prof John Gribben, a leading cancer specialist and head of the Centre for Haemeto-Oncology at Barts Hospital in London. “They didn’t want patients to be halfway through the treatment and then for us all to be stuck with not being able to get the cells back.”

It is understood that the MHRA, the UK regulatory authority, responded by writing to the UK industry as a whole, granting a six month grace period for companies involved in such cross-border trials. The previous rules would apply during that period, whatever the political outcomes.

Meanwhile approval from Dutch regulators was still required, and this took more time

Dozens more trials at risk

In the end, Kite received all the necessary assurances and wrote again to doctors in mid-March saying it would be proceeding with the trial after all.

The consequences of a decision not to proceed would have been extremely serious, for two reasons, scientists say. First, the patients are gravely ill and not responding to conventional treatments so are unlikely to survive until such time as the rules are clarified.

Second, there are dozens of trials involving genetic manipulation aimed at many different diseases. They are typically international in scope, with patients drawn from many different countries and drawing on the resources and expertise of biotech companies and clinicians around the world.

Despite the good news about Zuma 7, experts now fear that Brexit threatens the UK’s ability to participate in other cross-border cutting-edge trials.

“Collaboration plays an important role in cancer research, advancing scientific progress to help us understand disease and develop better treatments for cancer patients, comments Shaun Walsh, Head of Public Affairs and Campaigning at Cancer Research UK.

“Scientists from the UK and EU have a greater impact when working together – benefiting patients across the EU and beyond.”

Mr Walsh added that, whatever the outcome of Brexit, it was important to ensure that cancer scientists retained the ability to work across borders.

“The UK and EU should come to an agreement that supports researcher mobility and protects collaboration in cross-border clinical trials.”

Brexit is already having an impact on the flow of highly skilled experts into the UK.

Half of PhD students funded by Cancer Research and 76% of postdoctoral scientists at their institutes come from outside of the UK. There have been  declining proportions of EU applicants at some of their institutes since the EU referendum result. In 2016, 28% of post-doc applicants at CRUK’s Glasgow-based Beatson Institute, a leading cancer research centre, were from the EU, falling to 13% of applicants in 2018.

In addition, some oncologists now report a growing shortage of key drugs, which may be the result of stockpiling pre-Brexit.”We are having to stockpile certain cancer drugs and indeed some clinical trials may not able to continue as we have not stockpiled the relevant drugs,” one said.

For more details on how Car-T works, follow this link to see an infographic : CAR T How it works_

 

 

The prisoner in the bed next door

The guy was in a worse situation than me

Even in my feverish and befuddled state, I could work out that the guy in the adjacent bed was in a worse situation than me.

It was night two or three of my stay in hospital, I can’t remember exactly. I was in to sort out my pneumonia, which was a by-product of the cancer I was diagnosed with many years before.

I was on the heart ward, as there were no beds in oncology, my home from home. I would get there after three nights of being shunted around the hospital. All around, pallid and unhealthy looking men came and went from their operations.

My neighbor was chained to the bed and attached to two police guards. He was a good-looking chap, dark-haired and well-spoken from what I could hear through the curtain that separated us.

One guard was an ageing bruiser with grey hair and a stocky frame, ready I assumed to wrestle down any escaping convict with maximum force. The other was a delicate-looking woman in her thirties.

They announced their arrival with a clattering of unwinding chains, like a boat being launched off a ramp, then further noise as they fastened him to the bed and each other. It was as though Magwitch, the convict from Dickens’s Great Expectations, had clanked and clattered his way into hospital.

“I’m not going to run, I’ve got too much to lose,” the prisoner said, his manner charming, even cajoling. He spent a lot of time talking about his loyal girlfriend on the outside.

“This bed is total luxury,” he said of the skimpy hospital mattress. “It’s so much better than prison. I mustn’t get used it, take me back as quickly as you can.”

Whatever he had done, it seemed unlikely that he had murdered anyone. Drugs, I speculated, maybe coke that that ruined his heart. I listened, fascinated, to him explain how drugs were shipped in with drones, how it was widely assumed the prison governor was on the take, how the jail was filling up with “stabbers” – teenage murderers from the London suburbs, killing their own kind.

I drifted off, and when I woke, he, his guards and his chains had gone.

I did see the prisoner once more before I was moved on. It was after his surgery and he was spread-eagled on the bed, unconscious, a big bandage on his chest. His guards were still next to the bed, but they had released the chains.

He had at last found freedom of sorts.

The surprising upside of the cancer experience

Reflecting on the unexpectedly positive aspects of the direct and and indirect experience of cancer

You must think I am deranged to even think about writing an article about the positive aspects of going through cancer.

After all, this is a hideous disease which plunges your life into uncertainty and can often only be tackled with life-changing surgical and chemotherapeutic intervention, inflicting long-term psychological and emotional damage on those lucky enough to survive.

However, it is a peculiar fact that people do often derive some positives from the experience of cancer.

To cite American writer William Finnegan, “a lot of cancer patients and survivors report that they never really lived until till they got cancer, that it forced them to face things, to experience things more intensely”.

Or, as my therapist puts it, “cancer takes away – but it also gives.”

Talking to survivors, as well as drawing on my own experience, cancer does bring about a heightened appreciation of life and living. Even as you fear that it will all slip away from you, you are conscious of the value and meaning and beauty of life, to a degree that is far removed from humdrum everyday existence.

Seeing the world in technicolour

A friend explained this to me on a walk round Wimbledon Common: before she had cancer, she saw everything in drab blacks and whites and grays. Once the cancer struck, everything became more brightly coloured – and stayed that way for a long time until the cancer was a long way behind her.

By that time, she had completely changed her life – divorced, changed jobs and had a completely new circle of friends from the time B.C. – before cancer.

Another friend went through lung cancer. She is a journalist, used to casting a critical eye on people in authority.

She remembers driving home from the doctor’s appointment when she was first given the diagnosis, feeling sick with worry. “I felt that I was lugging home a horrible wound and I’d have to tell my kids and husband – I was a bearer of bad news to people who are perfectly healthy and I felt such a failure.”

After her family rallied round, and she had processed initial shock, she was overwhelmed by the kindness of those around her: the GP who took the trouble to call her up after the diagnosis, the nurse who held her hand, the surgeon’s incredible empathy.

“I knew it was a bad sign when on the morning of the operation, the surgeon sat on my bed.

“’I know you are frightened,’ he said, ‘but honestly, I do this every day of the week. You will feel beaten up and bruised but you will be fine.”

Depression can be worse than cancer

She was indeed fine, except that the tamoxifen she was prescribed led to terrible side-effects of depression and anxiety. She even considered suicide, before she came off the drug and got better.

“If anyone asked, would you have depression again, or cancer, I’d have cancer every time.”

causewaysunset

The cancer experience set her off on a personal journey of discovery as she re-evaluated everything about her life. She was in her fifties when the disease struck, and a very successful Fleet Street journalist, but suddenly none of the trappings of a successful career seemed to matter at all, compared to friends, family and meaningful work

“I look back now to where I was before cancer and I really think I didn’t know anything,” she says now. “I was a little girl thinking that a big by-line on an article was a big deal but measuring my life by by-line and achievement was all very ephemeral.”

She says now that she would not chose to go back to her pre-cancer self, an astonishing statement that shows how powerful the disease can be me in motivating personal change.

Of course, you may come to realise that your family is the most important thing in your life, but the strains caused by the disease may break up the family. Or you may lack the means to transform your life, and you have to go back to the dreary day job with a renewed sense of its total pointlessness

To take one more example: a woman whose husband went through a bone marrow transplant, and who was therefore at risk for a long time, was overcome by the kindness of the neighbours in the American suburb where they lived. Friends flocked by, leaving meals, ferrying kids to school, helping her to make the punishing hospital vigil.

Understanding the meaning of love

She is a committed Christian, but until this episode, she now recalls, love was a kind of abstraction. The kindness of her neighbours and acquaintances have given her a powerful and practical understanding of love as a force for good in her daily life.

We need not share her religious conviction, to know something of that she means. I think British people are not so demonstrative as Americans under such circumstances, but still, to the extent that friends and acquaintances rally round: that is a positive experience.

I was very touched, for example, to hear that some complete strangers at the local church, which I’d attended the sum total of once for Midnight Mass or similar, were praying for my recovery.

Let’s not get carried away: cancer is not exactly something you would wish upon yourself or your loved ones. But seeing life in technicolour for a while, and getting to re-evaluate what’s important and what is trivial, does offer some consolation.

Readers will have noticed that all the case studies are of women. If there are men out there who would like to talk about their feelings about cancer, please get in touch.