Confusion about time for treatment

[Guest guest]

Wrote:

" so, high-risk does not mean treatment is needed but there

is a higher than normal incidence of needing treatment

sooner than low risk patients? "

High risk means the EXPECTATION is higher for the need of

earlier TX. High risk regarding unfavorable prognostic

markers, such as Tom's " V3.21 gene for his unmutated

status. " carries with them the IMPLICATION that it will be

harder to find a treatment that his CLL will respond to with

regard to depth of remission and duration of remission.

" When do you throw all the high risk features out of the

equation? "

Answer: You don't, you use them as tools for drug protocol

selection, when feasable and strategizing.

" do these newer inhibitors change the rules? "

Answer: Yes as they give one more better option to keep the

" BEAR " from dancing patients like Tom to an earlier demise

or from keeping the standard drug therapies from hastening

the demise of patients like me who are severely allergic to

them.

" Can he hold a remission status as long as he is on PCI?

And, if so, then is this similar to a cure or long term

remission? "

Answer from the desk of the uncredentialed: Too early to

tell yet. I suspect that individuals will vary as to how

long responders will remain in remission based on data from

Gleevec (Imatinib) with CML patients and the one patient I

spoke with that indicated he was not responding to PCI. PCI

and CAL-101 are not to be thought of as cures but hold the

hope, barring the appearance nasty side effects, that long

remissions are indeed POSSIBLE for some patients. Trials are

too early and varied as to PCI dosage and usage with other

drugs like Ofatumumab to begin to predict efficacy and

durability. We who are on PCI must expect to stay on PCI

until either of two conditions are revealed: 1) bad side

effects or 2)evidence the " Bear " has found a new signaling

pathway to resume the " dance " .

Hope this clarifies confusion,

WWW

[Guest guest]

Yes, Wayne, you have helped me understand tremendously.

Next question that I need help with.

Tom has been told he has double allele deletion of 13q.

Deletion on P53 and 17p--(only at 12% deletion two years

ago) After two straight years of some treatment or

another---Rituximab/lenalidimide and now PCI shows some

changes in these deletions.

Following Rituximab/lenalidimide he showed no deletions at

all. I am not sure what he would show at this point. My

question is does treatment " fix " these deletions and put

them back in order or does remission make it hard for

Fishing? I don't know if Tom has these deletions anymore.

Something I can't seem to google.

Thanks for any help.

[Guest guest]

Lou,

Regarding your question when you wrote:

....Snip... " Following Rituximab/Lenalidimide he [Tom] showed

no deletions at all. I am not sure what he would show at

this point. My question is does treatment " fix " these

deletions and put them back in order or does remission make

it hard for Fishing? I don't know if Tom has these

deletions, anymore. " .....Snip...

Not seeing a GROUP reply from the credentialed and finding

your question a good one that others may have, I will

attempt to answer it in the interest of furthering

discussion and of course subject to clarification and or

corrections.

Although you do not report Tom's IgVH mutation status I

would guess that he is unmutated which usually means a

greater chance of clonal evolution which fits with his

double allele 13q del. and 17p del. FISH results. Cells

carrying these deletions may have been present all along but

in undetectable numbers or areas of node and marrow tissue

not examined. In any case, the failure to achieve a CR with

the big guns of FCR speaks to the power of Tom's resistant

cancer cell population. The cancer cells vulnerable to the

mechanisms of cell lysis by Tom's earlier TXs were largely

done in, leaving the resistant clones to proliferate. The

use of F & C could have actually contributed to clonal

evolution promotion. Tom's remission most likely made the

deletions difficult to find. In any case, the deletions were

not " fixed " or restored but the less resistant ones were

certainly lysed (killed).

Looking briefly at the different mechanisms by which our

drug choices affect us and our CLL: The chemos have

generally been divided into Purine analogues and Alkylating

agents. Alkylating agents (Chlorambucil, Cyclophosphamide &

Bendamustine) damage DNA preventing cell replication

particularly in rapidly dividing cells. These agents are

damaging to the normally fast growing epithelial cells and

are known to be carcinogenic. Chlorambucil less toxic - less

effective, Cyclophosphamide most toxic but more effective

and Bendamustine unkown for front-line TX but with shown

effectiveness and hematological toxicity. Purine analogues

(Fludarabine, Pentostatin etc.) are antimetabolites and

inhibit DNA synthesis, particularly effective against

rapidly dividing cells. Both classes of drugs are not cancer

cell specific and are generally immunosuppressive.

Interestingly, Allopurinol, used to prevent Tumor Lysis

particularly in 1st TX is also a Purine analogue that has

some potentially bad side effects but does not kill cancer

cells.

mAbs or Monoclonal antibodies are the next group of drugs to

consider and are immunomodulatory in activity: Rituximab,

Alemtuzumab, Lumiliximab, Ofatumumab etc. are large

molecules that are designed to target a specific cell

surface features called CDs on the cell line that gives rise

to the cancer. In our case the " B " lymphocyte cells express

Clusters of Definition CD20, CD52, CD23 & again CD20

respectively as targets for the mAbs mentioned. These drugs

act primarily to activate our immune systems to initiate

cell lysis rather than chemically poisoning the cells like

the chemos. Although specifically using a cellular CD target

they are not cancer cell specific and they can be as toxic

as the chemos causing severe immuno-suppression allowing

life threatening diseases to arise or in some infrequent

cases, life threatening reactions to the mAbs. In the case

of at least Rituximab, when given in high dose, we have some

evidence that immune function can be potentially restored

for some patients. Click on this link:

http://www.springerlink.com/content/1u29q14j87k25722/

I think of Revlimid (Lenalidomide) as unique in the class of

immunomodulatory drugs in that it does not target a CD and

aside from its ability to directly kill tumor cells it has

the most evidence of immune function restoration among our

drug choices. Patients on Revlimid show improved IgG, IgA

and IgM levels and it has a stimulatory effect on NK and T-

cells. Revlimid is not without toxicity but it is the first

drug to address " fixing " immune dysfunction in a number of

ways. The improvement does not fix or restore damaged

chromosomes posed by 's question that are characterized

by FISH probes e.g. 13q del., 17p del., trisomy 12., 11q

del., etc. See Terry Hamblin's recent Blog for a detailed

review of Revlimid: http://mutated-unmuated.blogspot.com/

The newest class of drugs are small molecular

pharmaceuticals that specifically target and inhibit cell

signaling pathways inside the cell, blocking kinases. I

think of Kinases as protein signal distribution centers

where instead of the kinase performing a normal function of

regulated signal distribution from cell surface to the

nucleus it has been hijacked by the cancer, " jammed " open

allowing chronic stimulation by a cell surface antigen to

direct rapid cell proliferation and inhibit natural cell

death (apoptosis). The dramatic effect of blocking the

signal through the Kinase " switch " is interruption of the

bio-chemical attraction of the cancer cells to accumulate in

the lymph nodes and hopefully also in the bone marrow. Soon

after taking Kinase Inhibitors, e.g. CAL-101, PCI-32765 or

AVL-292 the CLL cells leave the nodes, migrating into the

blood until the tissue compartments are empty. Most patients

see a decline in peripheral blood volume of their tumor

burden at this time, at least with PCI but not necessarily

with CAL-101.

The use of this class of drugs, in early Trials, suggests

that they " fix " a pathological signaling mechanism created

by the cancer/antigen complex and partially restores the

body's ability to deal with the cancer tumor burden. What is

so promising by this class of drugs is the ability for the

body to regain control over the cancer without the need to

chemically poison the cancer cells with associated

collateral damage to healthy cells.

The latest drug therapy of a targeted nature is a multi-

approach development of mAb (monoclonal antibody), gene

therapy, small molecular blockers and vaccines that are

planned to target a surface CLL " B " -cell specific signaling

receptor, ROR1. This target is not found on healthy B cells

and may offer the best shot to date, at reducing the cancer

burden without bad side effects.

For an overview see:

http://www.cllglobal.org/Resource_Files/CLL_NL_RM_Fall_09.pdf

For a detailed look at ROR1 see:

http://onlinelibrary.wiley.com/doi/10.1002/ijc.23587/full

For gene therapy against ROR1 see:

http://www.sciencedaily.com/releases/2008/02/080211172550.htm

For mAb therapy against ROR1 see:

http://ash.confex.com/ash/2010/webprogram/Paper32507.html

Therapy choices are expanding in number and complexity and I

offer this abbreviated sketch of some options in the hope of

clarifying the direction and implications of our therapy

choices and their chronological progression.

WWW - Lab Rat for PCI-32765 currently into cycle 5.

[Guest guest]

When I went to the recent LRF Conference in Brooklyn NY I

was happy to see my friend Koffman. For new members,

is an MD and has generously advised and mentored

patients in our forum communities for several years.

He emailed me offering a correction/clarification on my

description of mAbs (monoclonal antibodies). He wrote: " I

would say that the mABs are biologicals, not immune

modulators, as their effect on the immune system is minimal

and secondary to their destruction of their target "

My objective was to distinguish the mAbs from the Chemos in

that they were the first drugs engineered to target a

specific cell surface feature (CDs) and when " docked " to

their target, the mAbs then elicit various immune mechanism

responses in killing the attached cells. Rituximab, one of

the most widely used in the class of mAbs, has functions of

cell lysis and limited immune restoration for some patients

that are not clearly understood, even by the researchers.

Despite its overall tremendous benefit for most patients it

can cause life threatening reactions, such as I experienced

in March, for the unfortunate few.

and I were at a Conference Table where we met a newly

diagnosed woman and I got to see in action as

mentor/advisor. He deserves a " Patient Asset " award for his

manner in delivering straight talk and spot on advice. Our

collective journey is made more humane by his presence.

Thanks ,

WWW

[Guest guest]

Wayne,

If you don't mind telling, what was your life threatening

reaction to Rituxan?

Best wishes,

Marc - Long Beach, CA

Dx atypical MCL(CD5-) Stage 4, Leukemic Phase 3/26/02

(age 53) 96.9% mutation of V4-59 gene, p27KIP1 = .48

Current status - Age 63, Stable Disease??, No TX yet

http://livingwithmcl.com

The future is just a concept we use to avoid living today

[Guest guest]

Wayne,

This post was timely for me. I just read 's response to

another poster. My thought was that if this poster is new,

he may not know that is an MD. In my opinion, 's

posts always carry more weight as he is a Medical

Professional. I am assuming he is now retired, but he is

very knowligible and is helpful to us all with his posts.

Since you have now met , could I suggest that you

suggest to that in his Signature line, he might put

something like " retired MD " or something that would alert

people that his advice is likely more valuable than mine.

Just a thought for the benefit of new posters. And as

always, thanks for your informative posts. Dave

Wayne wrote:

/message/16279

[Guest guest]

Hi Marc,

Let me preface my R-reaction experience by stating that we

need individualized patient treatment for two very important

reasons: 1) predict drug appropriateness to kill cancer

cells or reduce tumor burden to a nonthreatening level and

2) predict potential crippling or life threatening reactions

to the drugs we are given.

Fludarabine came on the scene in 1968 and was a significant

advance over previous TX option of chlorambucil but as we

now know, most patients with 17p del. don't fare well on

Fludara and if they have TP53 mutation or p53 del., Fludara

is more often a poison to the patient than the cancer

because some drugs like Fludara need a functioning TP53/p53

gene expression to slay the cancer cells. Because we now

know of this relationship between drug and cell biology we

can better asses risk for a patient prior to TX through the

tool of FISH (Fluorescence In Situ Hybridization). Problem

was that Fludara existed way before FISH was introduced, I

believe in 1980 and has evolved since that time. How many

CLL patients with 17p - & p53 - were treated with Fludara,

referred to by health workers in a Wikipedia article as

" Aids in a bottle " because FISH was unknown or not

available? The cytogenetic chromosomal aberration picture

dealing with 17p- alone reaches further degrees of

complexity than just the recognition of the deletion. For

the morbidly curious see:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1867431/ &

http://bloodjournal.hematologylibrary.org/content/114/5/957.full

When I began my CLL journey in 2006 I was in great physical

shape with no comorbidities. My CLL began to degrade my

kidney function in some non hemic autoimmune fashion still

not understood. My first TX was RF concurrent in summer of

'09 and during the 2nd cycle I went into stage 4 renal

failure from Acute Tubular Necrosis or ATN. The presumed

culprit was a rare allergic reaction from Fludarabine. BTW -

I have a 13q -, mutated IgVH and CD38- profile. The good

news was that I had a very good response in reducing bulky

nodes and dropping ALC from near 300k down to less than 20k.

The bad news was, I almost died in the process. In Feb of

this year it was clear I needed to retreat, due primarily to

the cancer's resumed attack on my kidneys. I opted for

Rituximab High Dose monotherapy (R-HD). One reason for this

choice was that I never suffered from the 1st infusion

reactions so common in many patients and there was little to

indicate that I might not get a reasonably good PR from

Rituxan by itself.

R-HD began with an expectation of receiving R three days a

week for 4 weeks. Dosage would begin at 100mg/m2 on day one

(Mon), 250mg/m2 on day 2 (Weds), 250mg/m2 on day 3 (Fri)

then on week two I would begin getting the standard dose of

375mg/m2 for Mon. Weds. and Fri. and so on. We lodged about

two and a half miles from the hospital and although cold

because it was the last week in Feb. I walked to the

hospital and back to our lodging after infusion all that

week. On the first day I did get shaky chills that delayed

the infusion but they went away and the next two days were

uneventful. Saturday however I began to feel hot,

particularly in my feet. Sunday night I felt light headed

and my feet and jaw were becoming painful without rash or

swelling. I could not complete my Tai-Chi form that night

and literally crawled into bed. Monday morning I could not

walk and my wife had to get a wheelchair for me to get to

our truck. My jaw was so painful I could not eat any food

requiring chewing. At the infusion center I was found to be

in severe hypotension and going into renal failure again.

For the rest of the week I was monitored and received IV

saline. By the second day I was walking and the pain all but

vanished by the end of that week, though one week after, I

had a severe sinus pain similar to the feet and jaw for

which I had to take a Vicodin to sleep. That too vanished,

at least clinical symptom wise.

So what caused this unexpected Rituxan reaction? My ALC at

time of 1st infusion was under 30k. I explored with my NY

Heme/Onc., an Immunologist, my Nephrologist and Dr. Byrd the

possibilities of cytokine storm, Kappa light chain

deposition, vasculitis, mouse protein allergic reaction,

hypogammaglobulinemia, Complement dysregulation of the ones

that come to mind. The response of numerous tests were

inconclusive. Doc reactions ranged from " you're a mystery "

to " Wayne, You do not want to be this interesting " . See

Terry Hamblin's explanation for Rituxan reactions:

http://mutated-unmuated.blogspot.com/2008/09/rituxin-and-high-white-counts.html

or http://tinyurl.com/63vm8n2

In the aftermath of the R-reaction I had contemplated using

Ofatumumab on the theory that it was the mouse protein in

the Rituxan that had caused my reaction. I asked Dr. Byrd if

he could do a HAMA or HACA test to confirm my theory. His

reasoning was that the cell killing mechanism for Ofatumumab

was too similar to Rituxan to risk the chance that if I had

Complement dysregulation as the basis for the reaction that

it would be independent from the mouse protein, thereby Ofa

could put me at a real risk of death given the severity of

my previous reaction. Amplifying my next TX dilemma was that

my NY heme/onc was suggesting Ofa and my nephrologist was

still hopeful that a low dose Rituxan accompanied by

steroids would work well with my kidney issues. Byrd's

logic had a ring to it and was the beginning of my

exploration of Clinical Trail drugs like CAL-101 & PCI-32765

which I am now on.

Most people get an anaphylactoid reaction (shake & bake)

with their first infusion which is easily managed. Although

not frequent, I have met others who have had life

threatening reactions to Rituxan similar to mine. One such

person was a Follicular Lymphoma patient I met at the Hope

Lodge this March. The hope of Ofatumumab is that it is a

fully humanized anti CD20 mAb and will lesson reactions in

more patients. Time will tell.

This is only one tale of lack of knowledge leading to my TX

related injury. There are too many more out there. We seek

models of those who have gone before us as a talisman for

our own experience as we face TX especially for the first

time. Take FCR for example, who would not want to follow the

path of Schorr a 16 year to date surviver?

Unfortunately there are the persons who represent the flip

side of the coin and are permanently neutropenic or become

myelodysplatic from their TX with FCR. This is probably true

for every TX protocol including the newly touted wonder

child Bendamustine and Rituxan (BR). For those that it will

work it will be a miracle but for those it won't, it will

mean a hindsight of regret or bitterness. We need to know

more about which treatments will be suited to which

patients. High resolution scanning is part of the solution

and funding to streamline the complex analysis in connecting

the " dots " will be a priority for the next great advance in

our TX improvement. Costs will be steep and we as patient

advocates need to heighten awareness and bully the

politicians into the necessary funding to accomplish this

goal.

WWW - learning the hard way - May your path be well chosen