time to first treatment and remission?

[Guest guest]

Does anyone know of research on whether time to first treatment is a predictor

or either response to treatment or length of remission?

This is, of course, confounded by people being diagnosed years after onset, but

I believe there has been some study of the subject, though I can't find it at

present.

Thanks,

Heléne

[Guest guest]

At 01:25 PM 8/4/2011, Helen wrote:

>Does anyone know of research on whether time to

>first treatment is a predictor or either

>response to treatment or length of remission?

>This is, of course, confounded by people being

>diagnosed years after onset, but I believe there

>has been some study of the subject, though I can't find it at present.

In recent months (since Sept2010), I've made many

posts related to CLL patients who slowly progress

to having symptoms that require their first

treatment. Some of those posts have been on the

list (including my first three such

posts on Sept20 2010), but most of the subsequent

posts have been on the list.

One of the reasons most of my posts have been on

the listserve is because both Drs. Hamblin

& Furman post on that list, and I'd hoped they'd

answer questions about whether clinical studies

have provided information about how

slowly-progressed patients respond to different

initial treatments relative to how

rapidly-progressed patients respond to the same

treatment. I don't recall either doctor

providing a response to that question.

I expect trial data exist for which retrospective

analysis could provide comparisons between

response of slowly-progressed vs.

rapidly-progressed symptomatic patients receiving

their first treatments. Other retrospective

analyses have been performed by re-grouping

patients into different categories.

For example, a study by Byrd & co-workers (Woyach

et al., Feb/2011) was a retrospective re-analysis

of FR treatment of symptomatic untreated

patients, which compared responses of " low-risk "

(IgVH-mutated) patients vs. " high-risk " (e.g.

unmutated) patients, reporting that FR resulted

in longer-term PFS (progression-free survival)

and longer-term OS (overall survival) in mutated than in unmutated patients.

Abstract at:

http://jco.ascopubs.org/content/early/2011/02/14/JCO.2010.31.1811

I believe that slowly-progressed patients are

another category of low-risk patients,

particularly as it relates to their first

treatment. Slow progression is a clinical

indicator of all the biochemical events (known & unknown) of a given patient.

An important observation in the Byrd/coworkers FR

re-analysis (above) was that the long-term PFS &

OS were achieved with only partial elimination of

disease, without MRD negativity.

Both CAL-101 and PCI-32765 are providing only

partial disease elimination, however, with a lot

less toxicity than what is observed in response to FR.

My expectation is that untreated symptomatic

slowly-progressed patients (relative to

rapidly-progressed patients) may respond better

and/or longer-term, maybe even without the need

for continuous treatment with CAL-101 or

PCI-32765. Continuous treatment with these

agents seems to be needed for refractory patients.

Whatever the biochemical basis that permits a

given patient to progress slowly to first

treatment, that biochemical status is more likely

to be disrupted by a harsher treatment (e.g. FCR)

that is more likely to achieve MRD negativity

than a less harsh treatment (e.g. CAL-101) that

only causes partial disease elimination.

A theory ( " clonal competition " ) that I've

suggested that might explain different

progression rates is based on competition between

less-aggressive CLLcell clones and

more-aggressive CLLcell clones in a given

patient. In slowly-progressed patients, I've

suggested that proliferation centers (e.g. lymph

nodes) are more likely to be dominated by

less-aggressive CLLcell clones, and, in

rapidly-progressed patients, proliferation

centers are more likely to be dominated by more-aggressive CLLcell clones.

Harsh treatment (e.g. FCR) is more likely to

disrupt the biochemical status that allows

less-aggressive CLLcell clones to dominate

proliferation centers, permitting more-aggressive

CLLcell clones to become dominant.

A Sept/2010 online publication by Gross et al.

(reference below), described how aggressive

" side-populations " of CLL cells became more

prominent after patients were treated with fludarabine or bendamustin.

In summary, yes, I do believe it does matter how

rapidly a patient progresses to needed first

treatment. However, I've yet to see any of the

CLL specialists conducting analyses to assess

disease progression rate to first treatment as it

relates to responses to different initial treatments.

Al Janski

REFERENCE:

" B-chronic lymphocytic leukemia chemoresistance

involves innate and acquired leukemic side

population cells " (SP cells). Leukemia 24,

1885-1892 (November 2010); E Gross,

F-E L’Faqihi-Olive, L Ysebaert, M Brassac, S

Struski, S Kheirallah, J-J Fournié, G t and

A Quillet-; PMID: 20827287

<http://www.nature.com/leu/journal/v24/n11/full/leu2010176a.html>http://www.natu\

re.com/leu/journal/v24/n11/full/leu2010176a.html