30 replies to this topic

[Buzzm1]

Early BCR-ABL Reduction Predictive of Response in Newly Diagnosed CML http://bit.ly/22aa7j9

 

For patients with newly diagnosed chronic myeloid leukemia (CML), an early BCR-ABL reduction is predictive of better event-free survival regardless of the tyrosine kinase inhibitor (TKI) used, a study published in the journal Clinical Lymphoma, Myeloma & Leukemia has shown.

 

Early molecular response is strongly predictive in CML and it has recently been determined that halving time has prognostic value, as well. Therefore, researchers sought to evaluate the prognostic significance of the 3 months time-point in newly diagnosed patients with CML receiving a TKI.

 

For the study, researchers retrospectively analyzed BCR-ABL transcript data at different time-points, event data, and survival data from 50 patients in chronic phase. Patients were treated with imatinib, nilotinib, or dasatinib, and had undergone molecular evaluation at 3 months.

 

Results showed that 68% (34/50) of patients had a BCR-ABL transcript of 10% or less at 3 months. Researchers found that 63% (10) of patients in the > 10% group (16/50) experienced an event compared with 12% (4) in the ≤ 10% group (34/50) by the median time of follow-up (P < .001).

 

The study further demonstrated that a halving of 17 days or less was associated with improved event-free survival, and no patients with a transcript > 10% at 3 months had a halving time ≤ 17 days.

 

Patients with BCR-ABL ≤ 10% and a halving time ≤ 17 days had a significantly improved event-free survival compared with patients with BCR-ABL ≤ 10% and halving time > 17 days and patients with BCR-ABL > 10% (P < .001).

 

The findings ultimately suggest that the use of ABL as a control gene is reliable for the determination of the halving time in the clinical setting, thus underscoring the importance of measuring the BCR-ABL transcript at the time of diagnosis.

 

Added: Early molecular response (EMR; BCR-ABL ≤10% on the International Scale at 3 months) has become an accepted benchmark for evaluating whether patients with CML-CP are responding optimally to frontline TKI therapy. Failure to achieve EMR is considered an inadequate initial response according to the National Comprehensive Cancer Network guidelines and a warning response according to the European LeukemiaNet recommendations. http://bit.ly/1RF9DQg

[Buzzm1]

Aside from forced TKI dosage reduction due to side-effects, early BCR-ABL reduction also likely means that the CML patient will be able to reduce TKI dosage earlier, and successfully cease TKI dosage earlier, minimizing the risk of possible organ damage created by longterm high TKI dosage.  

[kat73]

What was the follow-up time?  What constitutes an "event"?  Is this bad news for turtles?

[Trey]

Essentially, this only applies if someone never achieves MMR.  After achieving MMR the odds of reversal become slim.  So this formula is sort of non-useful since it excludes the MMR part of the equation thingy.

[Buzzm1]

If they hadn't followed the patients through their CML journey they wouldn't be able to state that "early BCR-ABL reduction is predictive of better event-free survival regardless of the tyrosine kinase inhibitor (TKI) used."  For the study, researchers retrospectively analyzed BCR-ABL transcript data at different time-points, event data, and survival data from 50 patients in chronic phase.

[kat73]

What was the endpoint for the study?  What was the definition of an "event"?  I must be missing something, because it seems the overall finding is, "if you respond right away, it means you're going to be a good responder."  But turtles sometimes hit MMR years later.  Unless this study followed people beyond 10 or 15 years, how can it tell us that early responders will eventually do better than turtles?

[JohnFromChicago]

What is meant by "halving time" ?

[kat73]

Good question, John; I had it, too.  I think what it means is, if your baseline leukemic load is reduced by half at 3 months of treatment, then you're in the golden response spot.  But I could be completely wrong.  Somebody smarter step in, please?

[tiredblood]

This may be a poorly thought out or poorly worded question. It is late, I'm tired, and the brain fog has rolled in.  Is leukemic cell burden higher in bone marrow than in peripheral blood if the tests were done simultaneously?

[gerry]

Yes - bone marrow should always be higher than peripheral.

[Buzzm1]

This may be a poorly thought out or poorly worded question. It is late, I'm tired, and the brain fog has rolled in.  Is leukemic cell burden higher in bone marrow than in peripheral blood if the tests were done simultaneously?

 

The differences and correlations of BCR-ABL transcripts between peripheral blood and bone marrow assays are associated with the molecular responses in the bone marrow for chronic myelogenous leukemia. http://www.ncbi.nlm....pubmed/22965919

 

Comparative testing of peripheral blood and bone marrow for BCR-ABL transcripts in patients post allogeneic bone marrow transplantation and during interferon treatment for chronic myeloid leukemia. http://www.ncbi.nlm....pubmed/10492072

[tiredblood]

Thanks. I had pictured it spilling over from bone marrow into peripheral blood, but wondered if I had just dreamed that up. 

 

Edit-  Also, thanks for the links below, Buzz

 

Yes - bone marrow should always be higher than peripheral.

 

[kat73]

Anybody know what "halving time" means?

[thatguy]

Anybody know what "halving time" means?

Pretty sure it means bcr-abl decline amount, via amount over time. Time for amount to cut in half.

[JohnFromChicago]

I am very curious what is meant by "halving time" as well. My initial thought was time for the PCR number to be cut in half is less than 17 days. Even though it seems people experience very dramatic drops in PCR from Month-0 to Month-3 I don't think there are very many of us who had a decrease at that rate (more than half reduction in 17 days). Of course It would have to be estimated based on the drop from 0 to 3 months since there is no such thing as a common practice Day-17 PCR another reason why I feel it may mean something completely different.

[kat73]

Calling Trey!

[Pin]

I think it means what you think it means - although, if they don't test it, they must be doing estimations...

 

This excerpt is from Iriyama (2015) Shorter halving time of BCR-ABL1 transcripts is a novel predictor for achievement of molecular responses in newly diagnosed chronic-phase chronic myeloid leukemia treated with dasatinib: Results of the D-first study of Kanto CML study group. Am J Hematol. 2015 Apr;90(4):282-7. doi: 10.1002/ajh.23923.

 

The halving time for BCR-ABL1 transcripts was expressed with following formula: Halving time = A × Log₁₀ 2/log₁₀ (B/C), where A = the actual treatment time in days, from the day of the initial evaluation of BCR-ABL1 before treatment to the evaluation for BCR-ABL1 transcript at 3 months; B = BCR-ABL1 transcript value before treatment (copies/μg RNA); and C = BCR-ABL1 transcript value at 3 months (copies/μg RNA).

 

My understanding of the point of these "halving time" papers, is that they are looking for further ways (as well as the 3-month less than 10% one) to predict how well people will do on the medications, presumably, so they can switch or do something to optimise outcomes in people who may not be likely to respond well longer term.

 

e.g., They already know that if you reach less than 10% at 3 months, you are more likely to reach MMR than someone who doesn't reach 10% at 3m months - so I think they are looking for further ways of discriminating the non-responders.

 

*I think* (please correct me if I'm wrong, Trey ) this paper above is trying to emphasise the importance of measuring BCR-ABL at baseline so you know how *fast* it is reducing as well as the raw number of the BCR-ABL at 3 months, both of which appear to be important.

[Pin]

Also, if anyone can actually work out their 'halving time' let us know!

[Trey]

I don't halve time for this.  But since some of you are halving trouble figuring this out, I will halve to explain it anyway.

 

If you didn't realize that first sentence was a joke, then there is no reason to keep reading.

 

Halving time is the researcher's way of describing the time it takes to reduce the subject of the test (BCR-ABL) by half.  It "would" be PCR=100 down to PCR=50 except that PCR result changes are logarithmic, so the math used must be equally squirrely and is not worth explaining (especially since PhilB -- Keeper of the Queens Royal Maths and Stormdoor Society -- would jump on my chili like Herodatus on a wet hickory stump if I mess up the math, so I will refrain).  The methods used here try to show that the starting point for each individual patient may be more important than the IS score, which is averaged across many patients.  That is the whole point here.  It is a small one.  Individual results may be watered down by IS stuff n' junk.

 

You all should not halve engaged in such small matters.  Such distractions halve become the norm for many.  And you all didn't halve to drag me into this.

 

If you did not realize that last sentence was a joke you should halve stopped reading long ago.  Just sayin'

[PhilB]

" no patients with a transcript > 10% at 3 months had a halving time ≤ 17 days."  No Sh## Sherlock.

 

That simply translates as 'none of our random sample of 50 people had a PCR at diagnosis of over 390%'   - as that's how high it would have to be to still be over 10% after 90 days if it was halving every 17 days.   A truly remarkable finding.  I think those researchers may be due a visit from a very grumpy squirrel.