MRD negativity - not for everyone

[Guest guest]

Re: Fludarabine and Rituximab Produces Extended OS & PFS

At 12:08 PM 2/16/2011, cllcanada wrote:

>The study concludes; " These long-term data support fludarabine plus

>rituximab as one acceptable first-line treatment for symptomatic

>patients with CLL. "

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

Observations in the above paper provide indirect support for the

theory (I've recently presented on this list) that CLL patients who

slowly progress to needing their first treatment may have better

outcomes [progression-free survival (PFS), overall survival (OS)] if

that first treatment only results in incomplete elimination of

disease, i.e. the treatment does not eliminate minimal residual

disease ( " MRD negativity " ).

Slow progression of CLL disease in a patient is likely associated

with the majority of CLL cells being less aggressive, vs. rapidly

progressing disease likely being associated with the majority of CLL

cells being more aggressive.

A biochemical basis for the theory is that slow progression may be

partially a result of less aggressive (non-resistant) CLLcell clones

out-competing more aggressive (treatment-resistant) CLLcell clones

for space in proliferation centers (nodes, spleen, marrow). When MRD

negativity (i.e. no 'measurable' CLL cells) is achieved, most of the

non-resistant CLLcell clones are eliminated, enabling the remaining

(unmeasurable) resistant CLLcell clones to better compete in

proliferation centers, resulting in more aggressive disease during

relapse of that patient. Thus, in slowly-progressed patients,

partial disease elimination may provide the needed reduction in

CLL-related pathologies yet maintain a sufficient population of

non-resistant CLLcell clones to continue their dominance, and thus

continuing a slow rate of disease progression but returning to a

status of a watch-and-wait manageable disease.

Yesterday's news story (entitled " Rituximab and Fludarabine Produce

Long-Term Remissions in Some Chronic Lymphocytic Leukemia Patients " )

about this paper is at:

http://www.sciencedaily.com/releases/2011/02/110225094938.htm

The story quoted the paper's first author (Dr. Woyach) as

indicating that:

" ....we show that it is possible to achieve long-term remission

without completely eliminating the disease, which challenges the

existing belief that it is necessary to completely eradicate the

disease for long-term remission in low-risk patients. "

and

" We learned from this study that many patients with low-risk disease

will have excellent outcomes with the two-drug combination, so they

can be spared the toxicity that comes with the addition of cyclophosphamide. "

and

" .....unlike the three-drug combination (FCR), fludarabine plus

rituximab does not increase the risk of therapy-related acute

leukemias in CLL patients. "

The paper's evidence defines " low-risk patients " as patients who are

IgVH mutated. Despite only incomplete disease elimination,

untreated (symptomatic) mutated patients had both longer-term PFS and

OS than did untreated (symptomatic) unmutated patients.

Slow progression (e.g. arbitrarily >5yrs after diagnosis) of patients

to a point at which their CLL requires treatment of pathologies may

be another (or even better) criteria for defining " low-risk patients "

who will benefit from incomplete disease elimination with longer-term

PFS and longer-term OS. Rate of disease progression might be

thought of as another prognostic indicator, in that it represents a

summation of all the biochemical characteristics and activities

(identified and unidentified) of a given patient's disease.

For example, it is known exceptions exist; i.e. a small minority

mutated patients will not have longer-term PFS & OS than unmutated

patients, and visa versa. These exceptions are likely the result of

the biochemical effects of factors that are not yet identified.

Thus, biochemical indicators (e.g. mutation status, genetic

abnormalities status) are indicators of probabilities for PFS & OS

for a population of patients. Whereas the progression rate of

disease for a given patient is an actual clinical outcome of all

factors (identified and unidentified) affecting that patient's disease.

As such, it is reasonable to think, when FR treatment results in

incomplete disease elimination (i.e. measurable MRD), that an even

stronger correlation may exist between PFS & OS and rate of disease

progression than between PFS & OS and mutation status.

Further, even less toxic alternatives to FR may achieve the same (or

better) long-term PFS & OS from incomplete disease elimination in

untreated slowly-progressed patients. For example, CAL-101

monotherapy has very low levels of toxicity and does not seem to be

able to achieve MRD negativity.

Al Janski