Brother dx with CML about a year ago. Need information.

Hi and welcome.

It is difficult to know exactly where to start. I cannot comment specifically about your brothers case as it is obviously complex,but I can try and give an overview- first of CML and the therapy available and secondly try to advise in the context of your brothers situation...

I will try to advise you in a general way about what some of the options might be for your brother. But- my advice is that you really do need to talk to his doctors and ask for a clear explanation of what they plan to do now and why....
and/OR get a second opinion.

I am not sure where exactly you are based- I assume your are in the US or Canada, because you use the US spelling of Gleevec.
Just to offset my confusing you further, I should explain that In Europe it is referred to as Glivec and generally on this forum we usually refer to it by its generic name i.e imatinib.-
so if you read a post that says something about imatinib then we are talking about Glivec (EU) or Gleevec (US).

ALSO:
There are 2 other very similar drugs you will read about on this forum...
dasatinib (Sprycel) and nilotinib (Tasigna)...
both of these are newer therapies and are used very effectively in cases where imatinib is not working either because of resistance or intolerance. I have explained more about this below.

If you go to our FAQ section you might take some time to study the information on there... but I understand that you are very new to all this and there is an awful lot to learn. We will try our best to help you.

I hope the following covers your initial questions, but if it proves too much to take in then please ask again.
We are here to help and try to explain, but it is complex and your brothers doctors might well be doing the best they can in the circumstances.
But if you are not satisfied with the care he has received then you need another clinical opinion.

CML comes in 3 stages:
1sr or Chronic Phase (3-6years)
2nd or Acclerated Phase (around 8-12months)
3rd of Blastic Phase. (3- months)

Chronic phase (CP)- most people are diagnosed in this first phase (chronic in this case means slow moving) of the disease, it has very few symptoms and usually lasts between 3- 5 years if not adequately treated.

Accelerated phase- this is when the disease becomes more complex and the symptoms more obvious. There might be a high white cell count, high platelet count, low haemaglobin/red cell counts which cause anaemia, enlargement of spleen to name a few. The blast cell population increases and generally is anything between 5-30%

Blastic phase is terminal and resembles Acute Leukaemia. Athough sometimes people can be rescued from this acute stage with very high dose chemotherapy.... this can return them back to a genrally short lived 2nd chronic phase- at this point stem cell transplanation is the only effective option for survival... if a donor is available.

**Dasatinib (see below) has been shown to be effective in a minority of patients with blast stage CML..
but in general it is very difficult to treat CML once it has reached this acute stage.

Imatinib (Glivec/Gleevec) has revolutionised the treatment of CML and if you respond well to this drug in chronic phase you will most likely live out your normal life span. The drug has to be taken every day.

The majority of people (approx 60%) diagnosed in chronic phase (CP) respond well to 400mg or 600mg imatinib (Glivec/Gleevec)
However a minority of people find some side effects hard to live with, whilst others develop resistance to this particular drug-
for both groups of people there are other options.

There are now 2 other TKI drugs available- they work on exactly the same principle as imatinib.
They are called the 2nd generation to imatinib which is the 1st generation of this kind of targeted therapy.

All these drugs are called Tyrosine kinase Inhibitors or TKIs for short, and are designed to target only the white blood cells that carry the abnormal Ph chromosome which causes CML-
this is a very rare disease (1-2 people in every 100,000) and in people under 19 it is even rarer)

The Ph chromosome is not inherited- It is somehow formed from genetic damage....and thought to be a consequence of some kind of damaging environmental exposure perhaps to radiation or some other kind of chemical exposure such as benzene etc. However, it is not known exactly what causes the chromosomal damage. Some people can be exposed to the same environment and never go on to develop CML.

However, a minority do go on to develop genetic damage in a particular kind of white cell.
This genetic damage causes 2 normal chromosomes, numbers 9 and 22, to exchange parts with each other ( this event is called a translocation) which then goes on to form an abnormal chromosome 22 - this is called the Ph chromosome- and is the cause of CML. This all happens on a molecular level in the bone marrow and it only takes one abnormal stem cell with this genetic damage to go on to produce 'daughter' cells which all the PH+ white cells develop from. These cells have lost their signal switch which is the natural control process in all our cells. So they never die, but go on over years to crowed out all the normal white cells. This effectively shuts down the immune response to infections etc.

For those who do not respond well enough to imatinib because they might have developed some kind of resistance
or for those who are intolerant, there are alternative TKIs available:

1. dasatinib- Sprycel made by BMS
2. nilotinib- Tasigna made by Novartis who also make imatinib

Both the above TKIs are recognised as an improvement on the first TKi ( imatinib) - a lot of people who have not responded well to imatinib can and do respond very well to either dasatinib and/or nilotinib.

Some people have more complex CML which is more difficult to treat. Or their disease is not treated effectively in the first place or they do not take their drug regularly- this might cause their CML to progress.

Some progress slowly into the accelerated phase (AP) which means that they need more proactive therapy and monitoring.
It may be that your brother did not respond well to imatinib (Glivec/Gleevel) and now needs a change in therapy.

If his blood counts crashed during his TKI therapy... you say they are still very low, it might be difficult for his doctors to continue with treating him withthis kind of TKI therapy.

You say that he has had 2 or more blood transfusions- I assume these transfusions were giving him platelets? -
Platelets are the cells that make your blood clot and stop you bleeding. Low platelets can be a side effect of TKI therapy but they will recover eventually and TKI therapy can be safely resumed.
However, this does not seem to have happened in your brother case. So is might be that his disease was already progressing over the first year of TKi therapy.
If your are sure he was consistent in taking his therapy every day - it might be that he had a resistant mutation that was not identified and this might have caused his disease to progress whilst his therapy was stopped because of low blood counts.
You would have to ask his doctor if this might be a reason.

If his platelet count was/is abnormally low (under 50 per ml) then it might have been considered too dangerous to continue with his TKi therapy- and his drug therapy was stopped until his doctors could get his platelet count up- by platelet transfusions? .....but I am guessing here as you do not say what kind of blood transfusion he had.

You also need to ask his doctor if he has an imatinib resistant mutation... i.e iif a mutation analysis been done on his blood.

There are a lot of imatinib resistant mutations and most are dealt with very well by a change in treatment to one or other of the 2nd generation TKIs (either dasatinib or nilotinib)...
it would depend on exactly which mutation is identified, as to which of the 2 other drugs would be most effective.

However:
There is one mutation that is resistant to all 3 TKI drugs mentioned above.. it is called T315i.

If he has this mutation then he might need either
a stem cell transplant - if a HLA matched donor can be identified- OR
he could enrol on a clinical trial of a new TKI drug called ponatinib (made by ARIAD) ...
this is a drug similar to the others, but that has been developed specifically to help those patients who exhibit the T315i mutation... it is proving to be very effective and is also effective in many other cases besides those with the T315i mutation, of drug resistant or more complex CML.

As his disease is now deemed to be in AP (accelerated phase) he will need more proactive therapy to stop it progressing any further.
Do you know the % of blast cells he has?

It might be that if he does not have the T351i mutation and his counts eventually recover to safer levels, then he can restart TKI therapy with one of the 2nd generation TKIs....either dasatinib (Sprycel) or nilotinib (Tasigna).

safer blood count level:
blood clotting platelets should be at least 50 ('normal' safe levels are between 200 to 450)
Total white cells i.e lymphocytes, neutrophils etc- should be between 3 and 12
(infection fighting neutrophils should be at least over 1.0 but pref around 2.5)

His bone marrow biopsy will have shown a number of blast cells ... anything between 5% to 30% shows the disease to be in accelerated phase
Blast cells are immature white cells that do not develop into normal mature white cells and so will never be part of an effective immune response to infections.

The most hard to treat stage of CML is the 3rd or Blastic Phase... this is where the blast cell population in the marrow is well over 30%.
The blast phase normally lasts between 3 and 6 months. It is very difficult to treat effectively with chemotherapy but some people to respond to stem cell transplantation if a suitably matched donor is available.

I hope this has helped explain things. it is difficult to advise you without knowing the precise detail of your brothers case and even then it would depend on so many clinical factors specific to him. His doctor might well be doing the right things... sometime very complex cases do present themselves.

I assume you and any other siblings he has have now been tested to see if you are HLA matches? If you are a match you could be a potential stem cell donor.
If not then an unrelated donor could be looked for on the international registries. If that is not successful in finding a suitable match and his doctor feels he needs a stem cell transplant then it might be possible to use umbilical cord blood for a source of stem cells.

You and your family need to urgently talk with his doctor to find out what exactly are the options are now.

Best wishes,
Sandy