hist

HISTORY OF CML

An Edinburgh physician called Hughes Bennett first described the disease in
1845 and thought it was an infection.

Rudolph Virchow, in 1845, postulated that the disease was non-infectious and
coined the word “leukemia.”

That the leukemic cells originated from the bone marrow was recognized by
Neumann in 1870.

In the 19th century, the first compound used for the treatment of the disease
was Fowler’s solution. Arsenic was the ingredient and even to this day,
clinical trials are going on in CML with arsenic compounds in drug form.

Splenic irradiation was the only treatment before the 1950’s and offered
symptomatic relief but probably not prolonging life.

Before the 1950’s, the median survival of CML patients was 30 months.

In 1950, Busulfan (Myleran) was introduced and it prolonged the median
survival to 3.5-4 years. Nowadays, Busulfan is not used in CML management
because it was found to be a better killer of normal stem cells than CML stem
cells.

Since Busulfan killed a lot of normal stem cells, in the 1960s,

Hydroxyurea was introduced since it does not kill stem cells. Hydrea
had a transient effect on CML but was less toxic than Busulfan. It
did prolong survival over Busulfan. The median survival in the 1960s-
1980s, was prolonged to 4.5 years with Hydrea.

In 1960, two researchers called Nowell and Hungerford pointed out at a
conference in Philadelphia that CML patients had a characteristic genetic
defect, a short chromosome which they called the Philadelphia chromosome.

In 1973, Janet Rowley established the fact that the Philadelphia chromosome
found in CML patients arose as a result of a translocation between the long
arms of chromosomes 9 and 22.

The 1970s saw the advent of bone marrow transplantation, the only

treatment capable of disease eradication, with majority of patients
achieving RT-PCR negativity (Savage and Goldman, 1997). Unfortunately, this
procedure is limited to patients who have a suitable donor, and are medically fit to
undergo the procedure which involves high-dose chemotherapy and total body
irradiation.

In 1980, Dr. Talpaz introduced alpha interferon, a natural

substance called cytokine, for the treatment of CML. Cytokines help
regulate the immunity of cells. However, this treatment was very
toxic although it prolonged median survival to 7.5 years for CML
patients. In the pre-Interferon era, only 5% CML patients were alive
at 10 years. With the advent of Interferon, 40% of CML patients were
alive at 10 years. With combo of Interferon/chemotherapy (Ara-C),
this 10 year survival was further improved to 60%. The mechanism of
how Interferon acts is not well understood.

Early 1980’s saw the identification of the two genes that flank the
translocation breakpoint- the ABL gene on chromosome 9 and the BCR gene
on chromosome 22.

In 1990, Lugo and coworkers made the important discovery that the protein
derived from the BCR-ABL gene had protein tyrosine kinase activity (PTK)
and could transform cells by signaling pathways to a malignant phenotype.
BCR-ABL protein- the CML enemy had been identified. In the Second
World War, carpet bombing was done, hitting the target and areas around it
while in the modern day, targeted missiles are used that only hit the target.
This analogy is easily applied to the evolution of CML therapies, going from
chemotherapy drugs to the first cancer molecular target- Gleevec.

In 1990, several groups described that a CML-like disease could be induced in
mice transplanted with bone marrow infected with the BCR-ABL retrovirus.
This proved that BCR-ABL is the causative agent and not just the marker of
the disease.

In 1996, Dr. Brian Druker and colleagues described CGP57148, a highly
specific inhibitor of the BCR-ABL tyrosine kinase activity that selectively
suppressed the growth of BCR-ABL positive cells. This compound was
named STI-571 and then Imatinib.(Gleevec)

Gleevec's story is a remarkable one in medicine. It is a

transition from carpet bombing to targeted missiles and here’s a recap of how
Gleevec came about. The Ph chromosome was discovered by Hungerford and
Nowell in Philadelphia in 1960. It took another 24 years for thecancer specific gene
BCR-ABL to be characterized. In 1985, the
product of the abnormal gene, the BCR-ABL protein, was discovered.
This was an important discovery and even more important was the fact
that the protein sits in the cell cytoplasm. A cell has a nucleus
and a cytoplasm (jelly like material that fills the cell) and it is
easy for drugs to get into the cytoplasm rather than the nucleus.

The BCR-ABL protein is also an enzyme and this is important because
enzymes are mini-factories delivering phosphorus to other proteins, a
factory that can be potentially shut off. It is much more difficult
to shut off a protein that does not function as an enzyme. It was
very lucky that the BCR-ABL protein firstly resides in the cytoplasm
where drugs can get into and that it is an enzyme that can be shut
off.

It took another 10 years before Novartis and a team of
investigators developed the small molecule, Gleevec. A smart bomb.
Gleevec specifically inhibits the BCR-ABL enzyme. To function, the
BCR-ABL enzyme delivers phosphorus. It takes ATP, a source of
energy, and delivers phosphorus from the ATP to another protein,
creating a cascade of energy in the cell. So, the cell becomes very
active, divides, proliferates. However, since it is a cancer cell,
it is not dying at the right time, not going to the right place,
etc. Gleevec competes with ATP for binding to the BCR-ABL enzyme so
that if Gleevec binds, the energy source in the cell is cut off and
the cancer cell dies. The cell cannot do without the enzyme energy
and dies. Normal cells do not have this enzyme so are not affected
making Gleevec a revolutionary targeted therapy in not only CML, but
in medicine, in general. Normal cells survive the Gleevec attack
because it does not have BCR-ABL.

Gleevec clinical trials started in 1998. After 4 years follow-up,

only 6% of 553 patients in Phase III trials progressed into advanced
phases of CML. 16% of patients became resistant to treatment. This
is not at all the same as progression, it included patients who lost
their chromosome response, hematologic response or could not tolerate
the drug. The disease did not transform for them. In chronic phase
CML with Gleevec, the average progression per year is 4% and
progression to advanced phases is only 2% per year.(follow-up time 4
years) The figures for the fifth year shows that the numbers are not
increasing but actually declining.

Most CML experts believe that you can freeze CML to be a benign

disease, then it is as good as a cure.(functional cure)

For patients in whom Gleevec does not work anymore, they are

being treated with a new generation of kinase inhibitors, the
BMS354825 and AMN107. Dasatinib or BMS354825 in the test-tube is 300-1000
fold more powerful than Gleevec in inhibiting the enzyme
activity of BCR-ABL. Most patients become resistant to Gleevec
because of mutations in the BCR-ABL protein that disallow Gleevec
from binding. Gleevec is rejected and cannot block. Dasatinib is a
smaller molecule and comes in from another angle and gets into the
pocket. In the lab, it has been able to overcome 14/15 resistance-
inducing mutations.

In the Phase I Dasatinib trial, 8 patients were studied who could

not tolerate Gleevec because of rash or fluid retention. All did
very well on Dasatinib with no side-effects and had good response as
well. Half of them had complete remissions on Dasatinib. So, now we have three
inhibitors to control the disease long-term.

There are also trials of other CML drugs like Decitabine, vaccines and
Imatinib combos going on so that patients are treated with drugs that can
inhibit different pathways that cells have to proliferate.

Over a period of 40 years, CML has seen the development of
historical events like links in a chain. Without each link, the
chain cannot form. This is rational therapy, good reason to go from
one step to the next and it all paid off.