A splash of some tap water onto a few slides containing the blood smears of patients diagnosed with CML led to an interesting and significant discovery. It was 1960 and the study of the human chromosome was in its infancy. Well, actually, it was more like it was a neonate, after all it had only been determined just two years earlier, in 1958, that humans had 46 chromosomes. This was why, when Peter Nowell looked at his slides after inadvertently splashing them with tap water, he wasn't really sure what he was looking at. What he was looking at was chromosomes. It seems that tap water on slides caused the cells to expand, spilling their chromosomes. Lucky for all of us it just happened that he had slides of cells that were dividing. Another piece of luck came when Dr. Nowell decided not to throw the slides in the rubbish and brought them to someone else to have a look. This led him to collaborate with Dr. Hungerford and together these two scientists discovered the abnormal chromosome in patients diagnosed with CML, which we know as the Philadelphia chromosome. This was a great discovery, because now that we had this piece of information we perhaps could find out what caused it. Enter Dr. Janet Rowley, MD. Dr. Rowley had the foresight to preserve slides of specimens from tissue and blood smears taken from her CML patients. In 1973 a new technique was perfected that allowed human chromosomes to be banded. Banding means that we can see the various sections (genes) on each of the chromosomes. Using this technique we can Band our chromosomes which is called karyotyping. That means we can see each of our chromosomes and its various sections. Human cells have 23 pairs of large linear nuclear chromosomes, which is actually 22 pairs of autosomes and one pair of sex chromosomes.
Dr. Rowley decided to use this new banding technique to karyotype the specimens she had saved from her CML patients. Sitting at her dinning room table, she was after all also a working mother and wife, she saw a pattern emerge and realized that the odd chromosome, the Philadelphia chromosome, was actually a translocation. A translocation is when some genetic material from one chromosome exchanged some of it's material with another chromosome. She felt that this translocation caused cancer.
By 1983 we would have the proof, thanks mostly to the work and efforts of a team led by Nora C. Heisterkamp, PhD. She had localized c-abl adjacent to a translocation break point named BCR – which stand for breakpoint cluster region (which describes what it does). So, now we had a target c-abl and BCR, or as we know it today, BCR ABL.
Owen Witte determined that BCR ABL fused causing a fused protein that was a tyrosine kinase. The Tyrosine Kinase is a protein that can control other enzymes, and in the case of CML it leads to deregulated cell growth, meaning cells do not die, and they grow out of control. Work done in a lab by Dr. Levistki showed that Tryphosptins could inhibit tyrosine kinases and Jurg Zimmerman and Nick Lydon from (Ciba Geigy which had merged with the company called Sandoz) Novartis had a molecule in their lab that was being tested for glioblastoma's. With just a bit of tweaking of this molecule a new compound was formed and was finally tested in humans in 1998.
The results were astounding! Gleevec is a molecularly targeted therapy that is very effective in stopping the erroneous signal and targets only the cancerous cells, leaving healthy cells alone. Patients given the drug did remarkably well in the first clinical trials, and they continue to do well even today.
However, as Dr. Sawyers tells us, even during the phase I clinical trials there was evidence of drug resistance. Lucky for us that Bristol Myers Squibb had a molecule in their lab that worked well against various mutations that can develop when the disease does not respond to the drugs. But, I do not want to get ahead of myself....
Now that Novartis had a drug that worked, they were faced with a very significant challenge. How do they bring the drug to market when there are so few patients? They designed a very strategic business plan pricing the standard dose of Gleevec (400 mg daily) roughly equivalent with the front line therapy of the day, 10 million units of interferon. When it was launched Gleevec cost about $3,500.00 for a thirty day supply of 400 mg daily.
The good news was that patients were doing very well and saw a dramatic improvement in their quality of life as well as very good control of the disease. However, it was still very difficult for patients to access the drug. Novartis did a very good job of establishing patient access programs. The cost of the drug not only covered the cost of the research and the massive investment Novartis made to bring the drug to market, it helped to support programs that made the drug accessible to more patients.
We have often been told that Gleevec doesn't cure CML, yet in 2005 we started to see signs from Europe that perhaps, just maybe, we could dare to think in terms of a cure for CML. In Bordeaux France (oo la la - love the wine form there), 15 brave CML patients decided for reasons related to side effects with Gleevec that they wanted to try stopping the drug. Dr. F. Mahon monitored them very closely. 8 of the patients relapsed within a few months, but 7 did not. In looking through the charts he saw that the seven who did not relapse had been pre-treated with IFN. He wondered if this might hold a clue to possibly thinking in terms of some sort of combination therapy. He did a larger study, of 69 patients and the results from this were a bit confusing, as it showed that about the same number of patients who were either treated with IFN or not, relapsed, with a slight advantage to patients treated with IFN. Newer work in this area is starting to point to patients who had a good stable cytogenetic response on IFN, or at least were able to stay on IFN for 18 to 24 months, as well as Gleevec and patients who had a low sokal risk score as being more likely to achieve this type of solid remission. Additionally, the length of CMR (PCRU) remission also figures in the scenario, and patients holding a solid CMR for 2 years or more have a better chance to not relapse after stopping treatment.
Since the results of the study from France were reported in 2005 so much has changed. We now have three approved drugs for CML and about 5 other drugs in various stages of clinical trials. Most importantly we have trial sites in Europe and North America looking into stopping TKI treatment safely for CML patients. We are closer to the cure than we have ever been. There is a trial in Michigan looking at combining Pegylated IFN with Gleevec and stopping the drug after two years of CMR (PCRU), early results form Europe with a similar protocol are quite hopeful. Later this year there will be a trial combining Sprycel and Peg IFN. And, by the way, thanks to a merger of Merck and Schering Plough, Merck has now fully entered the CML drug market as they have inherited Pegylated IFN.
In Europe at the present time we have heard that there are about 100 patients who have been monitored for up to 5 years after stopping TKI therapy.
We continue to learn much about CML and just recently one top CML expert confirmed that CML patients can look forward to stopping their drugs, safely in 2 - 3 years.
Two things that are of very important concern is the cost of the drugs and the side effects, which I have not spent much time on. Not one of these drugs are entirely benign. Some side effects are much more significant than others. We have learned that even grade 1 and 2 side effects after time become just as debilitating as grade 3 and 4. Long term drug therapy often leads to problems with treatment adherence not to mention the stress of paying for the drug on a continued basis. The unfortunate downside is that patients who were being well serviced by the drug fall into a cycle of disease relapse that could be quite serious for them. There have been significant backlashes, some patients have lost their employment directly because of the high cost of the drugs and what it has done to insurance program premiums. Small employers are often forced to change insurance programs in an effort to stay ahead of dramatic increase in program premiums. Other patients have been denied promotions and have lost opportunities to develop their career paths. All of this is rather shameful. We have developed drugs that takes a dangerous life threatening disease and allows most patients to live fairly normal lives, yet society finds a way to select, isolate and discriminate these people.
Thankfully, these drugs work so well that the prevalence of CML is dramatically increasing on an annual basis. However, the newer drugs are being launched at twice the price of Gleevec.
Here is an interesting thought: we still do not know what gives rise to CML, 80% of the normal population will test positive for the BCR ABL fusion gene, yet only a handful of us will go on to develop CML (1 in 100,000).
We need to raise awareness of the absolute urgency of the situation. We desperately need to open up more trials in North America that will allow patients to safely stop TKI treatment.
If you are a patient, and if you qualify, please seriously consider entering the clinical trials aimed at stopping TKI therapy. Gleevec did not come to the market without important clinical trial data. We the patients have an important role in our own futures, in our health and in the future of clinical trials aimed at getting us safely off of these drugs.
We need to advocate for ourselves.