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Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline

For those who might be worried about not hitting targets- especially the <10% at 3m, the following article which I posted on our Home page some weeks ago, puts the whole thing into a better perspective and is an interesting expansion on the previous Marin study of IM, which tested a much smaller cohort of patients.

Sandy

Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline
Key Points
Among patients with >10% BCR-ABL1 at 3 months the poorest risk group can be distinguished by the rate of BCR-ABL1 decline from baseline.
Patients with BCR-ABL1 values on a constant downward trajectory may rapidly reach the level considered optimal with additional follow up.

Abstract

In CML patients, a BCR-ABL1 value >10% at 3 months of therapy is statistically associated with poorer outcome, yet many of these patients still achieve satisfactory outcomes.
We investigated 528 first-line imatinib-treated patients to determine whether patients with the poorest outcome can be better discriminated at 3 months. All outcomes were significantly superior for the 410 patients with BCR-ABL1 ≤10% at 3 months, P<.001. However, the poorest outcomes among the 95 evaluable patients with BCR-ABL1 >10% at 3 months were identified by the rate of BCR-ABL1 decline from baseline; assessed by estimating the number of days over which BCR-ABL1 halved.
Patients with BCR-ABL1 halving time less than 76 days (n=74) had significantly superior outcomes compared to patients whose BCR-ABL1 values did not halve by 76 days (n=21); 4 year overall survival 95% versus 58%, P=.0002; progression-free survival 92% versus 63%, P=.008; failure-free survival 59% versus 6%, P<.0001; and MMR 54% versus 5%, P=.008. By multivariate analysis, the halving time was an independent predictor of outcome in this poor risk group.
Our study has highlighted that the rate of BCR-ABL1 decline may be a critical prognostic discriminator of the patients with very poor outcome among those >10% at 3 months.

Copyright © 2014 American Society of Hematology

http://bloodjournal.hematologylibrary.org/content/early/2014/05/23/blood...

Hi Sandy, thank you for posting this article which I found very interesting. Please can you explain what is meant by baseline being halved in 76 days? I thought that baseline was always rounded up to 100% regardless of original result, or have I read that wrong? Is it the cytogenetic result they mean? ( mine was 74% at diagnosis) does that mean my pcr at 76 days after diagnosis should have been half of 74% to still be in the "best" group? I don't think mine was measured at 76 days, it was every 3 months. Thanks

mmmm, interesting question. Like you I assumed that they meant the baseline at diagnosis. However, I have just read it again with your question in mind and I think they must mean from a baseline at the 3 month mark.?

Sandy

I have read the article again but am still confused! It would be reassuring if it put me in the "good" group but I think it puts me in the "poor" group! I have been diagnosed just over 2 yeArs now and just short of mmr by a fraction so I hope that's going to be good enough long term.

I think that's a PCR at diagnosis (baseline). we need to remember that those results were from a clinical trail where people where tested many times and the 76 days are just the estimate time and not the time when they were tested. There's another study that says that people who had half log reduction from the baseline has a better prognosis than that who didn't (for those who were above 10% at 3 months). i.e. if your baseline - diagnosis - was 100% pcr, than you should have less than 32% at 3 months for a better prognosis.

But remember: those results are in imatinib standart dose, and not in others tki. a lot of people fail to imatinib but do great in other tki. we have a lot of examples here; we have a lot of example of people doing great in high doses of imatinib too. Don't forget that as soon as you reach the responses (ccyr, mmr, etc) your prognosis change. prognosis is just that: what may happen, and not what is going to happen. I remember that guy who was dx in the 70's and lived more than 30 years with cml, many of than without tkis. If you're close to MMR and you'll get there, of if you have a stable CCYR you're in a good place and your prognosis is good. That's what i think. i'm not a specialist, but i read a lot and i'm seeing a lot of hematologists :D

Take care and good luck!!

Lucas

I read the article too and I found it interesting but we can't really draw any personal conclusion from it.
The data come from clinical trials where patients were tested more frequently and the baseline (i.e. the BCR-ABL1 values / PCR at diagnosis) was known. I was told, like many others, that my PCR was 100% at diagnosis but at Leeds HMDS labs the local definition of response is 55% This means that within the three cancer networks of Yorkshire, Humber & Yorkshire Coast and Lancashire and South Cumbria Cancer Networks, a major molecular response (3 log reduction) is 0.055%, instead of 0.1%. The values I get are also a simple ratio and not expressed on the IS. I did not reach the <10% at 3 months (or the 1% at 6 months) but I haven't even tried to calculate my rate of reduction and I have no idea if I'm in a "good" or "not so good" group.

Moreover, as Lucas pointed out, all this applies only to imatinib treated patients and should not be extrapolated to data from other TKIs
I think the only information we can get from the paper is that the faster the reduction the better the outcome...quite intuitive really.

Best wishes to all

Luisa

the response is individual. some people has great prognosis but fail and some people has a bad prognosis but get good responses. i think this paper show us another information: the importance to have a pcr at diagnosis.

i did the math and found that i'm in the "good" group, but i don't know if i'll get a great response. I'm living with a good quality of life and this is good. I met a woman who has cml for 17 years. she never had a ccyr, but she's alive and well. she tried INF, glivec, sprycel, tasigna and now she's back to glivec. I think we need to live our lifes and have joy. i've spent a lot of time worrying about my future - sometimes i still do this -, but now i'm more interested in live my life. i'm doing what i can to deal with cml: i take my medication everyday, i never missed an appointment, etc. etc. We need to remember that even a bad prognosis in cml is not that bad. there are other options.

One last storie: i saw a video about the first brazilian to take glivec. he was in the trial in 1999. he responded very well but went to blast phase and started to take dasatinib. pleural efusion and another blast phase. autologus SCT and tasigna. he's alive and was the founder of brazilian leukemia and lymphoma association. the message is : there is always hope but we don't know what tomorrow will bring, we need to stop worrying and love the bomb (life) :)

I am really not that clear what the authors mean, but thinking about it- and I am no expert, baselines generated from samples taken at diagnosis often vary because it depends on how many normal ABL genes are present in a given sample.

Obviously there is a wide variation in baselines at diagnosis because there are lots of factors that can affect the levels of Ph+ cells generated by tests used early on... i.e cytogenetics and/or FISH. PCR at this stage is generally used to confirm the presence of BCR-ABL1.

At diagnosis, virtually every white cell in a blood or marrow sample will be leukaemic (Ph+) so the result should, in theory, be 100% Ph+. However, because there are higher levels of Ph+ cells present at diagnosis, q-PCR lacks accuracy and Ph positivity can vary between 50% and 100%.

After the start of therapy, q-PCR is used at specific time points after cytogenetic/FISH tests have shown the Ph+ cell population has reduced. When levels of BCR-ABL1 are less than 10%, qPCR can more accurately quantify the level of residual disease left in the marrow.

If the patients in this study who did not achieve <10% at the 3m timepoint then I suppose the investigators would have taken the baseline of each individuals PH+ percentages at diagnosis.

However, if all of them had been 100% Ph+ at diagnosis then it follows that the individual rates of Ph+ decline would be the more relevant factor in deciding which patients would not achieve the next goal in the designated timeline. The slower the decline the greater the risk of a suboptimal response. But remember this is trying to assess the level of 'risk' of PFS and OS, and there is always an element of risk.

This study adds to the paper by Marin et al that identified BCR-ABL1 levels at 3 months to be a possible risk factor. It seems from this research that the speed of decline is another way of identifying those who need a change of TKI to ensure a lower risk of future problems.

Sandy

Thanks for your very helpful view on this Luisa, insightful as usual.

Sandy

Well, i think this paper correlates with this one:

http://www.cancernetwork.com/chronic-myeloid-leukemia/bcr-abl-cutoffs-3-...

We all want to be fast responder but, as everyone says: it's a marathon, not a sprint. Now we have some tools to acellerate this and the cientists are studying if once you get to MMR or a better response you can go back to glivec (if there's no mutation)"