competition between CLL clones

[Guest guest]

Re: Why CLL is uncurable

At 03:48 PM 9/20/2010, Gach wrote:

" B-chronic lymphocytic

leukemia chemoresistance involves innate and acquired leukemic side

population cells " , E Gross et al., Leukemia advance online

publication, 9 September 2010; doi:10.1038/leu.2010.176. PMID: 20827287

SP cells appeared resistant to conventional B-CLL treatments.....

Fludarabine selected not only innate SP cells but also induced some

acquired SP cells, which arose from non-SP by drug-driven

evolution.

There may be a corollary to these observations of a chemo-resistant

side-population of CLL cells ( " SP-CLL cells " , innate or

chemo-induced) more rapidly proliferating 'after' treatment with

different chemo agents.

Specifically, it's reasonable to conjecture that expansion of these

SP-CLL cells may be inhibited by competition (e.g. for space, nutrients,

etc. in proliferation centers) from the larger population of

non-resistant CLL cells.

If such a mechanism of competition is at least part of the reason the

SP-CLL cells do not become more rapidly the dominant CLL population

before chemo, then it begs the question as to whether there is a basis

for a therapeutic strategy (for select patients) that does 'not' aim to

eliminate all of the non-resistant CLL cells.

For example, would it be possible to achieve a balance whereby one

therapeutically greatly reduces the pathological effects (e.g. disruption

of marrow production of normal blood cells) of the dominant non-resistant

CLL cells, yet maintains a population of those non-resistant CLL cells

sufficient to continue to effectively compete against and, thus, keep at

low levels the minority population of more pathogenic SP-CLL

cells?

Effectively, this would be a strategy for prolonging an indolent

watch-and-wait phase for a patient.

If such a strategy has any potential, the method of therapy for partial

elimination of non-resistant CLL cells would have to be a method that

does not promote evolution of non-resistant cells to SP-CLL cells.

Therapeutic candidates could be screened for whether they induce SP-CLL

cells, but the " SP techniques " described Gross et al. probably

would not be sufficient for assessing clonal evolution to more pathogenic

CLL clones. I would not be surprised if selection of the

therapeutic would be different for different patients, requiring some

type of in vitro pre-screening.

Such a strategy sounds like what may be possible by modification of some

so-called maintenance therapies (e.g. using rituximab).

However, my guess is that no known therapeutic agent yet exists that

could meet the criteria (for enough CLL patients) for reduction of

pathologies without inducing clonal evolution to SP-CLL cells, or

whatever one labels the more pathogenic clones.

I expect that the CLL experts have previously assessed similar

strategies. I'm wondering whether the new insights from Gross et

al. adds anything useful to the discussion.

Al Janski