Re: Off CAL-101 trial, and Bone marrow response

[Guest guest]

Friends

I seemed to have missed the data on the new kinase

inhibitors and how good a job they do on cleaning up the

marrow. I know the nodes shrink and the ALC may go up, but I

don't know what the patients in the trial are finding on

their bone marrow biopsies.

Any data or even personal results would be welcome.

Thanks. We are all in this together.

[Guest guest]

, you really did ask the crucial question about CAL

101. Evidently bone marrow biopsy is not a protocol

requirement for the current trials so the degree to which

CAL 101 is effective on the bone marrow is apparently

unestablished. Most CLL clinical trials do require bone

marrow biopsies to evaluate effectiveness.

[Guest guest]

It is most important to remember that the best measure of

bone marrow involvement are the neutrophil, hemoglobin, and

platelet counts. The bone marrow biopsy just assesses one

small area, while the peripheral counts assess the whole

marrow. The best measure of impacting upon the bone marrow

will therefore be seen with an improvement in the CBC.

Rick Furman

>

> , you really did ask the crucial question about CAL

> 101. Evidently bone marrow biopsy is not a protocol

> requirement for the current trials so the degree to which

> CAL 101 is effective on the bone marrow is apparently

> unestablished. Most CLL clinical trials do require bone

> marrow biopsies to evaluate effectiveness.

>

[Guest guest]

At 01:22 AM 4/30/2011, Koffman wrote:

> I know the nodes shrink and the ALC may go up, but I don't know

> what the patients in the trial are finding on their bone marrow biopsies.

At 10:31 AM 4/30/2011, Diane wrote:

>Evidently bone marrow biopsy is not a protocol requirement for the

>current trials ..........

Calistoga may have added marrow biopsies for at least some

of the patients who are responding to CAL-101+Rituxan. That

information is from a blog that discusses the experiences of

one of the patients ( " n " ) in the CAL-101+Rituxan study

of previously untreated patients. See SNIPs below.

----quotes-------

http://sharihowerton.blogspot.com/search?q=marrow

Posted by Shari at 3/17/2011

SNIP.......

" The only surprise today is that n will have to have

another Bone Marrow Biopsy tomorrow. We were not expecting

that. But the pharmaceutical company has added the BMB to

this study (at the end of six cycles) for patients who had

substantial bone marrow involvement at the beginning of

treatment. They want to know if the marrow is responding as

well as the blood and lymph nodes are. "

Posted by Shari at 3/31/2011

SNIP.......

" We found out today that n's bone marrow has been

reduced from 80-90% CLL infiltration to 30%. She began

treatment with CAL-101 the first week of October. I fully

expected an improvement in her marrow considering the great

response in her blood and lymph nodes. "

Posted by Shari at 10/28/2010

SNIP.......

" n, 's mom, was diagnosed in January of 2008. She

has progressed steadily but very gradually and has only

recently needed to begin treatment. She is enrolled in a

clinical trial studying Rituxan in combination with

CAL-101. "

------end of quotes--------

n is the type of patient (i.e. a previously untreated

patient who slowly progressed to needing treatment) who I

thought might benefit from incomplete elimination of CLL

disease (i.e. from 90% to 30% marrow infiltration in

n's case), although I would also like to see similar

slowly-progressed untreated patients treated with CAL-101

monotherapy.

My " clonal competition " theory is based on the idea that

slow disease progression to a point of having pathologies

that need treatment is an indication of less-aggressive

CLLcell clones dominating proliferation centers (nodes,

spleen, marrow) of that patient, and the initial treatment

of such slowly-progressed patients, with low-tox therapies

to eliminate the pathologies but retain the dominance of

less-aggressive CLLcell clones, might result in both longer

PFS and longer OS than if these patients are treated with

the objective of eliminating all CLL disease, which is more

likely to end the dominance of the less-aggressive CLLcell

clones and, consequently, permit the residual more-

aggressive, resistant CLLcell clones to become the dominate

clones in the proliferation centers.

From the same blog, " n's " son " " also has CLL and

was refractory to FCR before entering the CAL-101

monotherapy trial for relapsed/refractory patients, and has

also responded well to CAL-101 (50mg dose).

Is anyone aware of marrow biopsies being done

retrospectively on any patients in the CAL-101 monotherapy

trials?

However, as Dr. Furman has stated, neutrophil, hemoglobin,

and platelet counts are better indicators of the marrow

functionality. Biopsies only sample the 'content' (not the

function) of one area of the marrow.

Al Janski

[Guest guest]

At 06:58 PM 4/30/2011, Rick Furman wrote:

>It is most important to remember that the best measure of bone

>marrow involvement are the neutrophil, hemoglobin, and platelet counts.

Dr. Furman can you share what you have been observing thus

far for CLL patients treated with CAL-101 as it relates to

neutrophil, hemoglobin and platelet counts?, particularly

for patients who's indication for treatment was primarily a

result pathologies related to one or more of these blood

counts being low.

Al Janski

[Guest guest]

Hi, I'm Shari! I just joined the group as a result of a

comment on my blog. My husband and his mother are

participating in CAL-101 clinical trials under Dr. Ian Flinn

in Nashville. My MIL began treatment with 80-90% bone marrow

infiltration and recently had a BMB to determine how much

improvement since starting CAL-101 in October. It showed her

BM infiltration has been reduced to 30%. They required the

BMB in order to determine if her BM was responding as well

as her blood and nodes seemed to indicate. My husband's

biggest CLL challenge has always been his lymph nodes. They

did not even respond to FCR. But responded immediately to

CAL-101 and have remained stable ever since. He just

completed the 12 28-day cycles of the initial study and has

been rolled over into the extended study. He is taking the

lowest dose (50 mg.) and has had no side effects. However,

he still has fatigue at times (not bad enough to miss work).

is unmutated and his mom (n) is mutated. They have

different markers. And while 's big problem has always

been lymph nodes, not his blood; his mom's reason for

treatment was her blood and bone marrow. She only had

slightly enlarged nodes that didn't show or bother her. But

both are currently doing very well. She had a tough bout

with pneumonia in January and we don't know if that was

related to her CLL and/or treatment. She is 78 and her PCP

misdiagnosed her with bronchitis when she actually had

pneumonia. She lives three hours from here, but sees Dr.

Flinn for her CLL as I am her primary caregiver. We got her

out of the ville hospital and brought her immediately

to Dr. Flinn and he was able to get her well. But she was

hospitalized for two weeks. I document everything on my blog

for family, friends and other CLL patients. was

diagnosed in 2007 and he was very private about it in the

beginning. But eventually he loosened up and gave me

permission to share our experiences openly. So I have ever

since.

I haven't read all of the recent messages about CAL-101, but

I plan to. Just thought I would respond to this one and

introduce myself.

[Guest guest]

Dr. Furman: But would you agree there are other reasons

(besides bone marrow infiltration) why red blood cell and

platelet counts can change? For example as a result of

autoimmune disease? A recent article in " Blood " points out

the difference between infiltrative and autoimmune Binet

Stage C disease. It seems anemia or thrombocytopenia due to

bone marrow infiltration is far more dangerous than when the

problems arise due to some other cause. I cannot understand

why CAL-101 does not focus more on clearance of bone marrow

compartment.

>

> It is most important to remember that the best measure of

> bone marrow involvement are the neutrophil, hemoglobin, and

> platelet counts. The bone marrow biopsy just assesses one

> small area, while the peripheral counts assess the whole

> marrow. The best measure of impacting upon the bone marrow

> will therefore be seen with an improvement in the CBC.

>

> Rick Furman

>

[Guest guest]

Yes.

Rai stages 3 and 4 and Binet stage C only refer to

situations where the cytopenias (low platelets and red

cells) are due to marrow infiltration. If you have immune

mediated destruction as the cause of the anemia or

thrombocytopenia, you do not qualify as advanced stage.

Additionally, therapy directed at the CLL is not necessarily

the best treatment for the immune mediated diseases. Those

patients who have ITP or AIHA should not be treated with

PCI-32765 or CAL-101. This is why it is always a good idea

to perform a marrow prior to therapy.

Rick Furman

> >

> > It is most important to remember that the best measure of

> > bone marrow involvement are the neutrophil, hemoglobin, and

> > platelet counts. The bone marrow biopsy just assesses one

> > small area, while the peripheral counts assess the whole

> > marrow. The best measure of impacting upon the bone marrow

> > will therefore be seen with an improvement in the CBC.

> >

> > Rick Furman

> >

>

[Guest guest]

Dr Furman, you said:

" It is most important to remember that the best measure of

bone marrow involvement are the neutrophil, hemoglobin, and

platelet counts. "

I am confused about that. I and others have had > 90% BM

involvement with no low counts yet others with a much

smaller percent of CLL in the marrow have had significant

cytopenias (with no obvious auto-immune causes or

hypersplenism). It seems the health of the marrow is not

always directly reflected by the health of the blood.

Thanks for help with clarification.

[Guest guest]

Dr. Furman, you said:

> Additionally, therapy directed at the CLL is not necessarily

> the best treatment for the immune mediated diseases. Those

> patients who have ITP or AIHA should not be treated with

> PCI-32765 or CAL-101. This is why it is always a good idea

> to perform a marrow prior to therapy.

My husband is currently waiting to enter the PCI 32765 with

Ofatumamab some time in the next few weeks. He acquired

AIHA while receiving his first round of FCR in late

September, 2010, spent all of October in the hospital with

extreme amounts of whole blood transfusions and eventually

it came under control. His latest tests show the AIHA is in

remission.

Could you explain further your statement that people with

AIHA should not not be treated with PCI 32765 or Cal 101?

This is the first I've heard this.

Also heading in another direction, I am hearing that people

who have to come off of PCI 32765 for liver issues cropping

up or serious illnesses cropping up are finding that their

tumor load is coming back very quickly and possibly even

more advanced than before treatment with PCI 32765. Could

you please address this issue as well? Thanks in advance

for your time and your very helpful answers.

[Guest guest]

The comment that patients with AIHA or ITP should not be

treated with PCI-32765 or CAL-101 is because the best

treatments for those conditions are different than what

would be best for CLL. It is just a matter of making sure

one is treating the right condition, CLL versus immune

cytopenias. Some treatments work for both, we just do not

have any data yet for PCI-32765 and CAL-101.

Regarding the issue of a disease flare coming off treatment,

it mostly depends upon how much of a response patients had

before coming off. If patients had a good response, than in

general, they are not having a flare. Liver abnormalities

are not one of the toxicities seen regularly with PCI-32765.

With CAL-101, we have seen that almost exclusive in the

patients with lymphomas other than CLL.

Rick Furman, MD

> Could you explain further your statement that people with

> AIHA should not not be treated with PCI 32765 or Cal 101?

> This is the first I've heard this.

>

> Also heading in another direction, I am hearing that people

> who have to come off of PCI 32765 for liver issues cropping

> up or serious illnesses cropping up are finding that their

> tumor load is coming back very quickly and possibly even

> more advanced than before treatment with PCI 32765. Could

> you please address this issue as well? Thanks in advance

> for your time and your very helpful answers.

[Guest guest]

On the contrary, the health of the marrow is not related

necessarily to the amount of involvement seen on bone marrow

biopsy. The bone marrow biopsy really just sees one small

area. The counts are a better assessment of the marrow

overall.

Rick Furman

>

> Dr Furman, you said:

>

> " It is most important to remember that the best measure of

> bone marrow involvement are the neutrophil, hemoglobin, and

> platelet counts. "

>

> I am confused about that. I and others have had > 90% BM

> involvement with no low counts yet others with a much

> smaller percent of CLL in the marrow have had significant

> cytopenias (with no obvious auto-immune causes or

> hypersplenism). It seems the health of the marrow is not

> always directly reflected by the health of the blood.

>

> Thanks for help with clarification.