Re: MRD negativity - not for everyone

[Guest guest]

I don't think I am alone in thinking it's the 'R'. I think I have the

German Army behind me. There is a small Houston militia backing the 'C'.

Terry Hamblin MD

In a message dated 03/03/2011 07:59:22 GMT Standard Time,

Hclark@... writes:

I have been waiting for some results like this.

Since the full article requires a subscription or purchase, do you know if

they reported on the stats for 11q patients?

Many people with 11q would prefer to avoid FCR, but most have felt " C " is

needed for them, except for Dr. Hamblin who feels it is the " R " .

It would be very significant to know if less toxic, if incomplete, disease

eradication can work for 11q patients.

Thanks,

Heléne

On Mar 3, 2011, at 12:36 AM, Al Janski wrote:

(snipped by Moderator)

> 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. "

(snipped by Moderator)

------------------------------------

Groups Links

[Guest guest]

I have been waiting for some results like this.

Since the full article requires a subscription or purchase, do you know if they

reported on the stats for 11q patients?

Many people with 11q would prefer to avoid FCR, but most have felt " C " is needed

for them, except for Dr. Hamblin who feels it is the " R " .

It would be very significant to know if less toxic, if incomplete, disease

eradication can work for 11q patients.

Thanks,

Heléne

On Mar 3, 2011, at 12:36 AM, Al Janski wrote:

(snipped by Moderator)

> 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. "

(snipped by Moderator)

[Guest guest]

Dr. Hamblin,

I am in support of what you are saying. I am in my

ninth year since F R !

Joan

_____________

I don't think I am alone in thinking it's the 'R'. I think I have the

German Army behind me. There is a small Houston militia backing the 'C'.

Terry Hamblin MD

[Guest guest]

This is a major theory. I am wondering if this is true, and

those with more indolent disease reach the point where they

need their lst time tx., would that person be better off

with a less toxic treatment such as the new kinase drugs

such as Cal-101, or one of the other two? Any thoughts on

this from our experts and fellow CLLers?

R

Adks NY and AZ

[Guest guest]

I would just like to mention the work of Dr. J. Connors on FR

Here is an abstract from ASH 2009.

http://ash.confex.com/ash/2009/webprogram/Paper16972.html

Dr. Connors is head of the BC Cancer Agency here in Canada and

FR is used frequently and across a wider patient population than

FCR is indicated for.

~chris

>

> Re: Fludarabine and Rituximab Produces Extended OS & PFS

[Guest guest]

At 11:48 PM 3/2/2011, Heléne wrote:

>It would be very significant to know if less

>toxic, if incomplete, disease eradication can work for 11q patients.

See the following SNIPs from the paper's Discussion.

Al Janski

" Chemoimmunotherapy With Fludarabine and

Rituximab Produces Extended Overall Survival and

Progression-Free Survival in Chronic Lymphocytic

Leukemia: Long-Term Follow-Up of CALGB Study

9712 " . Journal of Clinical Oncology, 2011

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

DISCUSSION:

SNIP......

" Given the greater acute toxicity and the

long-term risks of t-MN after FCR-based therapy,

a reasonable approach might be to consider FR for

low-risk genomic patients, whereas patients with

CLL and with del(11q22.3) should receive FCR

therapy. High ORR and CR rates as well as

extended PFS have been seen with both FCR and FR,

and it is as yet unclear which regimen is

superior for individual patients in intermediate risk groups. "

[therapy-related myeloid neoplasm (t-MN), such as MDS]

SNIP........

" As identified previously (reference 21),

patients with CLL treated with FR who have

IgVH-mutated disease or who lack del(11q22.3) or

del(17p13.1) abnormalities have better outcomes.

In separate multivariable analyses, unmutated

IgVH was significantly associated with inferior

PFS and OS compared with mutated IgVH, whereas

the presence of poor-risk cytogenetic

abnormalities del(17p13.1) and del(11q22.3)

tended to be associated with poor PFS and

significantly associated with poor OS compared

with those not harboring these cytogenetic

abnormalities. In the models for OS, age was the

only other variable significant with P .05, and,

in the models for PFS, no other variable was

significant. Because poor-risk cytogenetics tend

to be associated with unmutated IgVH, a

prospective study with larger numbers of patients

would be required to determine the relative

contributions of these two variables. "

Reference 21: 21. Byrd JC, Gribben JG,

BL, et al: Select high-risk genetic features

predict earlier progression following chemoimmunotherapy with

fludarabine and rituximab in chronic lymphocytic

leukemia: Justification for risk-adapted

therapy. J Clin Oncol 24:437-443, 2006

[Guest guest]

At 11:48 PM 3/2/2011, Heléne wrote:

>It would be very significant to know if less

>toxic, if incomplete, disease eradication can work for 11q patients.

Below are additional, relevant SNIPs that were not in my previous post.

Al Janski

" Chemoimmunotherapy With Fludarabine and

Rituximab Produces Extended Overall Survival and

Progression-Free Survival in Chronic Lymphocytic

Leukemia: Long-Term Follow-Up of CALGB Study

9712 " . Journal of Clinical Oncology, 2011

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

DISCUSSION:

SNIP......

" A randomized, phase III study comparing FCR with

FC demonstrated improved CR, ORR, PFS, and OS

with combination chemoimmunotherapy (ref.18, below)

Benefit in that study was observed for most

genetic groups except for patients with

del(17p13.1) or normal karyotypes. Other

studies examining either FCR- or FC based therapy

have demonstrated that patients with del(11q22.3)

gain benefit from the fractioned

cyclophosphamide, changing this genomic factor to

a neutral predictive prognostic factor (ref.31).

In contrast, in this study, for which no

alkylating agent was included, patients with

del(11q22.3) did not do as well as those without this cytogenetic marker.

This is similar to other fludarabine-based

studies that did not include an alkylating agent

and substantiates the claim that patients with

del(11q22.3) should be treated with FCR as a

first-line regimen. Given the greater acute

toxicity and the long-term risks of t-MN after

FCR-based therapy, a reasonable approach might be

to consider FR for low-risk genomic patients,

whereas patients with CLL and with del(11q22.3) should receive FCR therapy.

High ORR and CR rates as well as extended PFS

have been seen with both FCR and FR, and it is as

yet unclear which regimen is superior for

individual patients in intermediate risk groups.

Differences in follow-up make direct comparison

of published studies difficult. However, a

randomized, US intergroup study(CALGB10404) is

examining this important scientific question. "

Ref. 18. Hallek M, Fischer K, Fingerle-Rowson G,

et al: Addition of rituximab to fludarabine and

cyclophosphamide in patients with chronic

lymphocytic leukaemia: A randomised, open-label,

phase 3 trial. Lancet 376:1164-1174, 2010

Ref. 31. Tsimberidou AM, Tam C, Abruzzo LV, et

al: Chemoimmunotherapy may overcome the adverse

prognostic significance of 11q deletion in

previously untreated patients with chronic

lymphocytic leukemia. Cancer 115:373-380, 2009

[Guest guest]

At 09:04 AM 3/3/2011, The Randolphs wrote:

>I am wondering if this is true, and those with more indolent disease

>reach the point where they need their lst time tx., would that

>person be better off

>with a less toxic treatment such as the new kinase drugs such as

>Cal-101, or one of the other two?

The last comment of my original post on this thread was a suggestion

that CAL-101 monotherapy is an example of therapy that might be an

even better therapy (than FR) for " low-risk patients " , e.g.

slowly-progressed patients; i.e.

At 11:36 PM 3/2/2011, Al Janski wrote:

>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.

Thus far, clinical trials of CAL-101 monotherapy have only been

conducted on relapsed or refractory patients, and (as Dr. Furman has

indicated) in those studies CAL-101 did not clear marrow of CLLcells

as well as it cleared nodes of CLLcells.

However, compared with previously untreated low-risk patients (e.g.

slowly-progressed patients), relapsed/refractory CLL patients are

probably more likely to have more aggressive (treatment-resistant)

CLL cell clones residing in their marrow, aggressive cells with more

stroma-dependent biochemical mechanisms by which to protect those

cells from attack by agents like CAL-101.

As such, CAL-101 may be more effective in clearing marrow in

untreated patients who slowly progressed to needing treatment, marrow

which is more likely to be dominated by less aggressive CLLcell

clones, with fewer mechanisms to override (e.g. via alternative

biochemical pathways) the tyrosine kinase inhibition by CAL-101.

Complete marrow clearance may not be achieved with CAL-101 even in

untreated slowly-progressed patients; however, as indicated in my

original post, that may be a good thing for low-risk patients with

less aggressive dominant CLLcell clones.

Al Janski

[Guest guest]

Re: Re: CAL-101 for SLL ~ Untreated Patients

At 07:51 PM 3/4/2011, lynnb65 wrote:

>......keeping minimal disease under control may be better than

>wiping the slate clean except for a few nasties, who can then become

>the dominant population. (Am I getting it right?)

Yes, that is a way of the describing a bottom-line of the theory

( " clonal competition " ) that I've suggested for why some patients

slowly-progress toward needing treatment, and why some of these

slowly-progressed patients progress more rapidly after they are

treated to the point of MRD negativity, instead of treating to a

point of incomplete disease elimination.

Consistent with that perspective, the recent paper by Woyach et al.

demonstrated that incomplete disease elimination (by FR treatment)

leads to longer-term remissions (PFS & OS) in low-risk (IgVH-mutated)

patients.

I think that patients who slowly progress to needing treatment,

regardless of their prognostic indicators, may be worthy of being

considered low-risk patients who may benefit from incomplete disease

elimination.

At 07:51 PM 3/4/2011, lynnb65 wrote

>However, not sure where patients such as I fit in, with 13q deletion

>but 80-90% marrow infiltration. Are we still low risk or does the

>marrow reality trump the deletions?

I expect a small minority of patients who reach a stage of having

80-90% marrow infiltration would continue to slowly progress (toward

developing pathologies that require treatment).

However, if patients slowly progressed to the point of having 80-90%

infiltration without needing treatment, but soon after, develop

pathologies needing treatment, then these patients may also benefit

(in longer-term PFS & OS) from incomplete elimination of disease. In

contrast, if they rapidly progressed to that level of infiltration,

then I would expect they would be less likely to benefit from partial

disease elimination.

The hope would be that the factors (identified & unidentified) that

existed to permit slow progression, would continue to exist after the

disease burden (e.g. marrow infiltration) is reduced enough to

eliminate the pathologies, such that the post-treatment rate of

progression would again be slow, i.e. return of a watchful-waiting status.

As I suggested in a previous post, 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. Unlike

biochemical indicators (e.g. mutation status, genetic

abnormalities status), which are indicators of probabilities for PFS

& OS for a population of patients, the rate of progression of disease

pathologies in a given patient is an actual clinical outcome of all

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

I can't help but wonder whether studies have already been conducted

on untreated symptomatic patients in which only partial disease

elimination was achieved but pathologies of the disease were reduced

to being manageable or eliminated. It would be very interesting to

retrospectively separate patients in such studies into two groups,

i.e. patients with slow progression (e.g. >5yrs after diagnosis) to

needing treatment vs. patients with rapid progression (e.g. <5yrs

after diagnosis) 'before' treatment. Then compare PFS in the two

groups 'after' treatment. My expectation would be PFS would be

longer for the pre-treatment slowly-progressed patients than for the

pre-treatment rapidly-progressed patients.

Drs. Hamblin and Furman, are you aware of historic CLL trials with

these characteristics for which such retrospective analyses might be

usefully conducted?

Al Janski