Part I CML Patient Meeting - October 29, 2005 -Montreal

[Guest guest]

CML Patient Meeting - October 29, 2005

Hello Everyone,

This is a very long post.

As promised, I am happy to provide a summary of the meeting.

First of all, it just wouldn't be a meeting without the people who take time

and join us. We were about 40 patients, family/friends. Thank you to

everyone for joining us.

We had plenty of time for socializing over delicious food while catching up

with old friends and making new ones.

The meeting started just after 1:00 PM. We recognized some neat milestones

from some of the members:

- Janet is back from her year sabbatical which included hiking up Mt.

Kilimanjaro, Africa's highest peak, without oxygen. She brought me back a

rock and a lovely photo of her and her husband Rick standing on the top of

Kili. I should also mention that Janet is the first patient in Canada to

take the 400mg tablet.

- has moved from Halifax to Ottawa and is a part time resident in

Montreal, staying with me while she participates in the BMS trial at the

Royal Vic. We've started calling her Aunt and we are enjoying her

company very much. Our fingers are crossed and send her much love and good

wishes for a good response to the BMS drug.

- raised over $10,000 for the Canadian Cancer Society for the relay for

life. Yeah - big congratulations

-Rita started art classes and provided us with the idea (and championed the

project) of commissioning the portrait of Dr. Laneuville. Rita also

presented me with a pastel of " feverfew " I think this should be our " mascot "

flower!

-Dr. Laneuville was presented with a portrait of himself done by a local

artist. The gift was given with deep appreciation for all he does for us as

our Medical CML guru. He attends every one of our meetings and always stays

late answering our questions. We very much appreciate that he is " always

there " for us. He was very happy to receive the portrait.

Dr. Laneuville started off the learning part of the meeting by reviewing

CML, the components of blood, RBC's, Platelets and WBC's and the

Philadelphia Chromosome. BCR ABL is a protein tyrosine kinase and is found

on the shortened Philadelphia chromosome as a result of the translocation.

Gleevec (Imatinib Mesylate) works by fitting in the " pocket " on BCR ABL

effectively blocking the ability of ATP (an energy pack, like a battery) to

dock into the pocket.

Laboratory tests are important for monitoring the disease. Most of us are

familiar with the tests:

n CBC (Complete blood count)

n Biochemistry (liver, kidney, others)

n Bone marrow aspirate and biopsy

n Cytogenetics

n Fluorescent in-situ hybridization (FISH)

n Real-time Quantitative Polymerase Chain Reaction (RQ-PCR)

n Abl kinase domain mutation screening

FISH -

.. Results blood = bone marrow

.. Report % positive (Ph) cells

.. Unreliable below 5%

RQ-PCR

n Real-time quantitative reverse transcriptase polymerase chain

reaction (RQ-PCR)

n Results reported relative to average newly diagnosed CML (log

reduction)

DNA Sequencing can help in the detection of ABL kinase domain (KD) testing

Definitions of clinical responses:

n CHR = complete hematological remission

l Normal CBC, normal exam

n MCR = major cytogenetic remission

l < 39% Ph+ve cells (cytogenetics, FISH)

n CCR = complete cytogenetic remission

l 0% Ph+ve cells (cytogenetics; FISH. RQ-PCR)

n MMR = major molecular remission

l BCR/ABL reduced 1000 fold = -3.0 logs (RQ-PCR)

n PCRU = undetectable by PCR

l Varies depending on sensitivity of the PCR assay

Quantitating Leukemic Cell Load

CML patients at diagnosis typically have a total body load of about 1012

cells. Patients in complete cytogenetic response (CCR) have no apparent

disease after a 2-log reduction of their disease burden, yet they may still

harbour up to 1010 cells. Q-PCR is the only technique that is sufficiently

sensitive to monitor disease response below a 2-log, down to about a 6-log,

reduction. Up to 106 cells may still remain at the limit of Q-PCR

sensitivity.

Estimated response to first line with Imatinib

(n= number of patients at 42 months with response)

CHR n=531 98% (96%, 100%)

MCyR n=487 91% (88%, 94%)

CCyR n=444 84% (81%, 88%)

More data was discussed on the IRIS trial, but we have already discussed

this here as it was published at ASH last year.

Dr. L continued on with a presentation/overview of the Canadian Guidelines

for the treatment of CML

Canadian Consensus Group for the Management of CML (CCGM-CML)

~ 80 Canadian Hematology Experts

Development of Treatment Guidelines

Standardization of RQ-PCR and Abl mutation Sequencing

He reviewed what the outcome of the consensus was and told us that the

guidelines will be published in a Canadian peer reviewed journal probably in

January. We will all get a copy of the guidelines when they are published.

He talked about data supporting dose escalation:

n Kantarjian H. (2003)

l Phase II, suboptimal response, DEIM to 600 mg (CP) & 800 mg (AP, BC)

l ~ 50% improved MCR rate, 65% improved CHR rate

n Cortez J. (2004)

l Phase II, two cohorts CML CP, 400 mg/d then later, 800 mg/d

l CCR 81% vs 96% (p=0.0002), MMR 47% vs 67% (p=0.0007)

n T. (2004)

l Phase II, Tidal Trial, CML CP DEIM 600 to 800 mg/d if fail milestones

l Compared to IRIS (IM 400 mg/d), CCR 69% vs 88.5% (p<0.001)

CML Trials in Canada - Dose Escalation of imatinib mesylate ?

n NCIC CTG (SWOG)

l Newly diagnosed CML CP

l Randomized 400 vs 800 mg/day IM

l Addition 3rd arm ? (BMS 354825)

n Novartis (Global)

l Newly diagnosed CML CP

l Randomized 400 vs 800 mg/day IM

n GLEEM (Novartis)

l CML CP, IM > 1 year, MMR<response>CCR

l Randomized to 400 mg/d vs 800 mg/d IM

l MMR Control group

l Rate MMR primary end point at 12 months

BMS-354825 -Dasatinib

SRC kinase family inhibitor (includes Abl)

~ 200X more potent than imatinib mesylate

CML Trials in Canada - New PTKIs

n BMS 354825 (Dasatinib, BMS)

l First series phase II studies completed 07/2005

l New phase II studies, 034/035

l Relapsed, refractory, intolerant to IM

l CML CP, AP, BC

l SWITCH (BMS) - GLEEM study competitor?

n AMN107, CAMN107A201(Novartis)

l Phase IA/II, refractory/intolerant IM

l CML CP, AP, BC, Ph+ ALL, HES, SM

l

n Phase III Trials dasatinib and AMN107 scheduled first half 2006

Summary:

n Imatinib mesylate (IM) has changed the natural history of CML and is

indicated for first line treatment in doses up to 800 mg/day.

n Proper monitoring is essential for defining primary or secondary

failure of IM treatment, and for decisions regarding alternative

treatment.ASCT, dose escalation, new kinase inhibitors (dasatinib, AMN 107),

palliation.