Eradicating CML????

[Guest guest]

and , I found this, would that support the theory about the newer

trials of withholding the meds? Didn't we have a discussion some time ago about

INF was responsible for killing off quiescent cells before we took Gleevec, thus

some had a deeper response, or did I dream that up? This is lengthy, but I

would read the whole article continued at the website, it's about killing off

the last CML cell. Let me know what you think about the article and how it

affects us as a whole.

16 September 2010

By: D M Ross, T P and J V Melo

" Both on imatinib and on interferon-a (IFN) treatment, the achievement of a

deeper cytogenetic response is associated with improved progression-free

survival. Within 18 months a complete cytogenetic response is observed in around

80% of the patients treated up-front with imatinib, and yet, even in this

low-risk group, it has been demonstrated that a further reduction of the level

of residual disease to 0.1% BCR–ABL, termed a major molecular response (MMR), is

associated with an improvement in progression-free survival. A proposed

definition of CMR requires undetectable BCR–ABL transcripts in an RQ-PCR assay

with a calculated sensitivity of at least 1.5 log below the level of MMR, and

confirmed on subsequent testing. In a subset of patients in the International

Randomised Study of Interferon versus STI571 (IRIS), loss of MMR was observed in

0/18 patients in CMR versus 6/22 (27%) of those in MMR who still had detectable

BCR–ABL, suggesting that CMR confers a more stable response. However, as the

progression-free survival of patients in MMR is close to 100%, it may be

impossible to demonstrate that patients in CMR have a survival advantage over

patients in MMR with detectable BCR–ABL, even if CMR does confer a better

prognosis. Most of the available evidence suggests that prognosis improves as

the level of MRD falls. It has not been proven that CMR confers a better

prognosis than MMR, but this makes sense from first principles. "

" ...two studies of kinetic modelling found that CML might be eradicated by

prolonged imatinib treatment. In one model, stem cells were depleted on the

basis that susceptibility to apoptosis in response to imatinib is restored as

quiescent stem cells enter the cell cycle. Long-term stem cells enter the cell

cycle infrequently, and were therefore depleted very gradually in the model. A

second study reached the same conclusion, but for a different reason. The

authors incorporated in their model the stochastic process of stem cell

exhaustion. Put simply, each time a precursor cell divides it gives rise to two

daughter cells and each of these daughter cells will be committed either to

differentiation or to self-renewal. The probability of each of these ‘choices’

is dependent upon the position of the cell in the haematopoietic hierarchy; more

mature precursor cells are more likely to commit to differentiation. Although,

on average, a sufficient number of stem cells will commit to self-renewal, in

the case of a single leukaemic stem cell it is possible that both progeny should

commit to differentiation and the leukaemic stem cell would then be extinct.

Based on assumptions about stem cell biology the authors constructed a

mathematical model of CML that incorporated a stochastic process of stem cell

renewal versus differentiation. In most iterations of the model the CML stem

cell pool was already exhausted before the ‘patient’ commenced treatment and the

proportion of ‘patients’ in whom the CML stem cell pool became extinct rose

progressively during imatinib treatment. As with any disease model, the validity

of these predictions is dependent upon the accuracy of the assumptions from

known disease biology. Considering this caveat, we have at least two potential

explanations for why a treatment that is apparently cytostatic to stem cells

could still have curative potential in CML. "

" IFN may induce proliferation of CML stem cells, thus contributing to stem cell

exhaustion and providing a rationale for combination therapy with tyrosine

kinase inhibitors, which are otherwise ineffective against quiescent CML stem

cells. "

http://tinyurl.com/22kvdzf

FYI,

Lottie Duthu