Gleevec breaks

[Guest guest]

Hi ,

> Date: Mon, 19 Dec 2005 12:51:17 -1000

> From: " " <pmuraki@...>

> Subject: RE: Re: Off Gleevec

>

> I started on Gleevec in October 2004. I have been cycled on and off Gleevec,

> five (5) times since starting treatment. My problem is primarily neutropenia

> (low neutrophils) or thrombocytopenia (low platelets). I have had to reduce

> my dosage from 400 mg to 300mg and still no success. I am in CHR and have

> had a partial cytogenetic response.

> (San Francisco)

I'm curious to know how long and how frequent your breaks from IM have been.

As others on this list know, and you may too, I have been cycling off IM for

one month out of every three for the past 3.5 years, without adverse effects

as far as I can tell. On the contrary, over the same period, I have

experienced a decrease in my leukemia burden from a PCR of 0.003 when I

began to 0.000023 at last count. I also feel quite a lot better than I did

when I was taking IM continuously - especially, of course, during my month

off.

Back in October, Emile asked for my rationale for doing this. I began a

post then, but I'm afraid ended up on a rather remote back burner. I

apologize for not getting back to you sooner, Emile. Following is a

continuation of that post.

***

Cycling on and off IM (officially called " pulse therapy " - a term which I'll

use from now on) is frowned upon by most treating physicians. I, too, would

disapprove of certain approaches to pulsing - in particular, skipping a few

doses now and then. I sympathize with the folks who do this when their side

effects become unmanageable, but as their docs and others on this list do, I

worry that this will increase their risk of developing IM-resistant disease.

I'll explain why in a bit.

Many doctors think that my approach is equally risky, but others - including

myself, obviously - do not. On the contrary, given my level of remission, I

believe it's at least as likely that cycling will reduce my risk of

resistance, increase my chances of eradicating quiescent CML stem cells, and

decrease the risk that I will develop long-term adverse effects from IM.

I do want to emphasize, however, that there is no direct evidence to support

cycling. Moreover, by explaining why I have chosen to cycle I am in no way

advocating that you or anyone else should try it. It is my right to

experiment with my own health and life, but not with anyone else's. Nor am I

a specialist of any kind (I am trained and practiced as a family physician),

so you should not place too much weight on what I say because of my

background in medicine. I know what constitutes good science, but I am not a

researcher myself. Finally, you should know that I would not be doing any of

this had I not achieved a 3-log qPCR reduction in my first year on IM. I'll

say more about this later.

To explain why I've chosen IM pulse therapy, I must begin with a rather

heretical statement: chronic phase CML is not really cancer. It inevitably

turns into one if you don't treat it, and a very nasty one at that. But by

itself, CP CML is a pre-malignant condition.

Once I realized this fact a few years back, I was able (metaphorically, at

least) to take a deep calming breath and let go of that initial panicky

desire to kill as many cells as fast and aggressively as I could, never mind

the collateral damage. And I began to ask the question, if CML isn't like

cancer, what is it like? If it resembles other illnesses, what can we learn

from treatment approaches to these?

As a premalignant condition, CML is akin to actinic keratoses of the skin

(see http://www.skincancer.org/ak/index.php): benign, rather slow growing

tumors which are worth treating, because if you don't, many of them will

develop into squamous cell carcinomas. But you can treat actinic keratoses

with topical drugs like fluorouricil or Ara-C once a year. Like IM and CML,

this doesn't kill all the cells, but it prevents them from turning into

cancer - presumably because there are too few of them to make cancerous

mutation statistically likely.

CP CML also shares similarities with dysplastic polyps of the large

intestine to which some people are prone: though benign in themselves, most

of these will develop into colon cancer if you don't remove them. Conversely

if you do take them out - via colonoscopy every every few years (they grow

very slowly so every few years is enough) - you'll never get a colon cancer

even though there are undoubtedly still dysplastic cells hanging around.

By the way, it's understandable that most treating physicians still think of

CP CML as a scary cancer because until Gleevec came along it used to

progress to blast phase so rapidly - and blast phase CML is a true and

uniformly deadly cancer. But the fact remains that genetically,

morphologically (referring to the architecture of the cells), and

behaviorally CP CML cells are not cancerous.

Another analogy I found instructive is parasitic disease such as malaria.

Single celled malaria parasites are just as complex capable as individual

mammalian cells in terms of their ability to defend themselves against

threats such as anti-biotics in the case of parasites, or cancer drugs in

the case of cancers, by way of intrinsic defenses or through mutation. The

kinetics of parasite killing are also comparable to treatment of early CP

CML. The malaria " load " in infected patients prior to treatment is between

one and ten trillion (10^13) malaria organisms - similar to 10^13 Phillies

at diagnosis in CML. A single antibiotic (quinine derivatives in regions

where malaria is not yet resistant to them; or more recently, a new drug

derived from the Chinese herb, artemesinin) can reduce the number of

organisms by up to 7 orders of magnitude (down to one in 10 million), but

not eliminate them. The best you can expect is to reduce to number of bugs

to a million or so - again, similar to the IM experience with CML.

Where a second equally effective anti-parasitic agent is available, by the

way, the second agent can produce a similar log reduction and potentially

kill all the remaining organisms. Similarly in CML a cure may be possible

if we can develop a new agent that kills quiescent CML cells as effectively

as IM killed the dividing ones - but unfortunately no such drug is yet on

the horizon. (Note: some people do get cured from malaria using a single

drug, but in these cases there is always a highly effective second agent:

their own immune systems. Unfortunately, the immune systems of

non-transplanted CML patients are just as ineffective against our remaining

cells as they were against the disease when it first began. Hopefully

vaccine therapies will change this some day, but we're not there yet).

But here's the part I consider most relevant to CML: where parasitologists

have only one effective drug against a given parasite, they use it just long

enough to achieve the estimated maximum parasite kill, then they stop, wait

a while, and start again. Their rationale for pulse therapy is thus: the

various resistance mutations that protect parasites against antibiotics

exact a high metabolic toll on these bugs. This puts them at a competitive

disadvantage during breaks when such burdensome " skills " aren't needed.

During these times, resistant bugs are out-competed and crowded out by their

wild-type, non resistance-bearing peers (an analogy within an analogy:

imagine an army of millions of people trying to travel hundreds of miles on

foot across difficult terrain to a new land. While under continuous attack,

those carrying heavy armor will be more likely to survive, but during

periods of travel though friendly territory, the soldiers carrying lighter

loads will get much farther (or something like that! ;-)). Thus pulse

therapy keeps the level of resistance the same and over time and allows you

to maintain (or even improve upon) your best level of success. Conversely,

continuous use of a single drug that can't kill all the bugs, usually

produces resistant organisms which will increase in number over time.

Will the lessons of single-drug treatment in parasitology apply to CML?

Besides the success I've had with pulsing over the past several years, there

is anecdotal evidence to suggest that it might work in others as well. A

couple of years ago there were reports (from Hochaus' group, I think?) of

patients whose PCR's had plateaued, having to stop IM for a month or more

due to side effects. When they restarted, their PCRs plateaued at a new,

lower value. This all makes sense to me. Given that continuous IM obviously

doesn't kill whatever Phillies remain once you're in MMR, it's not

unreasonable to fear that their level of resistance might increase over

time, leading to relapse. Pulse therapy should not have this effect and may

even decrease the fraction of burdensome-resistance carrying Phillies.

Once again a caveat, though. Since the probability of any mutation is

directly proportional to the number cells prone to mutate, I consider my

chances of any sort of deleterious mutation - either to IM resistance or of

transformation from chronic to blast phase - to be acceptably low even if

I'm wrong about the logic of pulse therapy. However, I WOULD NOT be taking

this chance had I not reached MMR early on, and I'd strongly recommend

against this approach for anyone who has not reached this milestone - at

least until the results of clinical trials (underway in Scotland now) are

in. Logic is one thing; scientific evidence is another.

A couple more points, then I'm done.

Why did I choose a three month cycle time? The idea is that I end each break

right when I'm due for my next PCR so that if I were relapsing, I'd be

likely to catch it right away.

Why do I take month-long breaks? That's actually a work in progress. I began

with two weeks off out of every three months and gradually worked my way up

to month-long breaks. My eventual goal is six weeks on, six weeks off.

Longer breaks improve my quality of life, of course, but I believe they may

also increase the chance that some of my Phillies will come out of

quiescence, start cycling, and get killed once I restart IM.

Why are shorter pulses, such as a few days off every couple of weeks, a bad

idea? Because it takes nearly a week for IM to get out of the system and

during much of that time the IM serum level is high enough to exert

resistance selection pressure but too low kill the Phillies - the ideal

situation for creating resistance. I recommend against this.

What about pulse therapy and long-term adverse effects from IM? There's as

yet no evidence that IM will be harmful in the long run, but not much reason

to believe that it won't be, either. I do take it as a good sign that some

folks have been on IM for seven years now and seem in perfectly good health

(I'd expect any common long-term effects to distribute normally over time,

that is, some would show up quite early, some very late, and most in the

middle term; the fact that I've heard of no early onset nasty effects

suggests that we MIGHT get off easy over time), but I'd rather not take any

chances. Giving my body a chance intermittently to recover from whatever

might be building up seems only prudent.

Phew, that's all. Writing this up took way longer than I expected. I hope

some of you find it interesting. Now, back to ASH.

Regards,

R