Re: Shah on Treatment of IM-Resistant CML- L

[Guest guest]

Hi ,

I am sure will provide more information. But, yes, T315I is

the only mutation for which there is currently no drug that inhibit

it's effects. Unchecked, this mutation can cause the cascade of

events leading to blast crisis. That is why patients are being given

a pre trial mutation screening. If you do have T315I, they usually

will not admit you into a trial, either with Dasatinib or AMN107.

Interestingly enough, we had heard at ASH that Dasatinib, and AMN107

may actually improve the effects of T315I, which is a really bad

thing. The good news is that there is current work on a molecule

that specifically addresses this mutation. For the majority of

patients who have had a good response on IM or Dasatinib, CCR or

better, the risks of developing this mutation are significanly

reduced.

Hope this helps,

Cheers,

Cheryl-Anne

>

> Hi ,

>

> Thanks so much for your diligence and thorough reports. Did you

hear how soon they may try a clinical with imatinib and dasatinib

together? Also, I feel a little foolish asking this but is T3151 a

killer mutation? I've just always heard or read it in the context of

the boogey man. Since 's so busy, if someone else can answer

this, please do so.

>

> Best wishes,

>

> L

> [ ] Shah on Treatment of IM-Resistant CML

>

>

> Hi Folks,

>

> Following is the fourth of five presentations from the Friday

Corporate

> Symposium sponsored by Bristol Myers Squib, which I began

reporting on some

> time back. This presentation was by Dr. Neil Shah of UCLA, on

Treatment of

> IM-Resistant CML. After this, and one more by s Hochaus, I

will then

> have three more multi-speaker talks to go, along with a bunch of

really

> interesting ³poster sessions.² I apologize taking so long

already. The idea

> of reporting on all that remains seems daunting; however, I'm

scheduled to

> ski for five days after Christmas, and since the conditions in

Maine then

> are notoriously miserable (unless you¹re a teen) at this time of

year, I¹ll

> probably spend a lot of time by the fire working on my reports to

y¹all.

>

> Shah reviewed the fact that AMN107 (AMN, from now on) is

chemically very

> similar to IM from which it was derived, whereas Bristo Myers

Squibb¹s

> BMS354825 (dasatinib, or DS, for the purposes of this lazy

typist) is

> structurally unrelated to Novartis¹ drugs. Both AMN and DS are at

least 2

> logs (two powers of ten, or 100x) more potent than IM, so they

offer hope

> for effective treatment even in patients whose cells have learned

to

> over-express the bcr/abl enzyme (brief review: BCR/ABL is the CML

cancer

> gene [oncogene], whereas bcr/abl [in small letters] refers to the

tyrosine

> kinase enzyme that BCR/ABL codes for, and which actually causes

all the bad

> things in CML: increased growth and lifespan of the white cells,

increased

> mutation rate of these white, so that the disease becomes

increasingly

> cancerous, etc. For ease of typing, I¹m following the convention

of many

> authors nowadays, in referring to the BCR/ABL gene simply as

³BA² - though

> I¹ll continue to refer to the enzyme as bcr/abl).

>

> One reason for the increased potency of these new drugs is that

they are

> more ³tolerant² of bcr/abl¹s different shapes (called

³conformations² in the

> biochemistry's quaint lingo): they bind to bcr/abl no matter

whether it is

> ³open² (inactive), ³closed² (active), or in any intermediate

stat. IM, by

> contrast, only binds to the closed/active conformation.

>

> In theory, DS offers even greater efficacy because it inhibits

not only

> bcr/abl, but also one of the kinases (one called src, and

pronounced ³sarc²)

> responsible for carrying out bcr/abl¹s downstream dirty work

(Note: Shah

> didn¹t address whether scr inhibition actually makes a difference

clinically

> ­ nor did I find this out elsewhere at ASH. Do any of you know

whether DS¹s

> src-blocking has proven clinical utility?).

>

> Shah mentioned a curious thing about the dosing frequency of

dasatinib:

> although DS has a half life of only a few hours (5-6 times

shorter than IM),

> it was initially given only once a day in Phase I trials. This

means that

> patients spent much of each day with very low serum levels, which

would be a

> total no-no with IM, where continuous serum levels above a

certain threshold

> are deemed absolutely necessary to avoid resistance. Whatever the

reason

> though, they a single dose for a while, and it seemed to work

just fine. In

> fact it worked as well ­ and maybe even better than ­ the twice a

day dosage

> schedule that was later adopted. I really don¹t understand why

they began

> with only a single daily dose, and would appreciate any insights

any of you

> may have. Maybe DS is so potent that it remains at a therapeutic

level even

> after several half-life periods have passed. But if this is the

case, why

> don¹t they just give patients much less of it, but spread it out

during the

> day to keep drug levels stable? Were they concerned about reduced

> compliance?

>

> A few other facts:

>

> ? While AMN and DS treat most IM resistant mutations, they

engender some new

> resistances of their own. Surprisingly (given that DS and AMN

are quite

> different molecules), these resistance patterns are rather

similar to one

> another. The fact that IM is effective against many of the DS or

> AMN-specific mutations and vice versa, is one of the rationales

for trying a

> combination of IM and one of these new drugs together. For more

on this,

> see the abstract (with Shah as a lead author) at the end of this

post.

>

> ? Similar to the IM experience, some patients on DS experienced

low grade

> elevations of their liver enzymes (AST, in particular) and of

creatinine.

> A new and somewhat more worrisome side effect is pleural effusion

(fluid in

> the lining of the lung) experienced by some patients. Jumping

ahead of

> myself though, I heard at one of the poster session that these

effusions

> resolve and don¹t tend to recur if you stop the drug for a couple

of days,

> give corticosteroids (like prednisone), and then restart.

>

> ? Many IM resistant blast phase patients showed a response by DS,

though as

> expected, they shortly became resistant to this drug too (same

with AMN).

>

> ? The ³next frontier² is drugs that will treat T315I, which Shah

called the

> ³Achilles heel of small molecule TK inhibitors.² None of the

drugs that

> have reached clinical trials show activity against this mutation,

though

> several compounds under investigation in vitro show promise (see

my prior

> post on IM resistance). Appropriately, some of these compounds

have

> mysterious, rather heroic names such as the ³Auror kinase

inhibitor,² or

> (for sci-fi techies), VX680.

>

> OK, off we go with this one. Stay tuned for s Hochaus on

the

> Potential for Combining Targeted Agents Against CML.

>

> Cheers,

>

> R

>

> ______

>

> [1093] Molecular Analysis of Dasatinib Resistance Mechanisms in

CML Patients

> Identifies Novel BCR-ABL Mutations Predicted To Retain

Sensitivity to

> Imatinib: Rationale for Combination Tyrosine Kinase Inhibitor

Therapy.

> Session Type: Poster Session 251-I

>

> Neil P. Shah, M. Nicoll, Branford, P. ,

L.

> Paquette, Moshe Talpaz, Claude Nicaise, Fei Huang, L.

Sawyers .

> Medicine/Hematology-Oncology, The Geffen School of Medicine

at UCLA,

> Los Angeles, CA, USA; Hematology, Institute for Medical and

Veterinary

> Sciences, Adelaide, New South Wales, Australia; Bioimmunotherapy,

MD

> Cancer Center, Houston, TX, USA; Bristol-Myers Squibb

Oncology,

> Princeton, NJ, USA

>

> Point mutations within the BCR-ABL kinase domain represent the

most common

> mechanism of resistance to imatinib in patients with CML.

Preclinical

> studies have shown that dasatinib (BMS-354825) is effective at

inhibiting

> the kinase activity of imatinib-resistant BCR-ABL mutants with

the notable

> exception of the T315I mutation, which remains highly resistant

to imatinib,

> dasatinib, and AMN107 (Gorre et al, Science 2001; Shah et al,

Science 2004;

> Weisberg et al, Cancer Cell, 2005). Clinical data from Phase I

and II

> studies of dasatinib in CML confirms the in vitro findings. Each

of three

> imatinib-resistant patients bearing the T315I mutation (CP=1;

AP=2) did not

> achieve objective hematologic or cytogenetic responses during

treatment with

> dasatanib on a Phase I study. Additionally, each of two phase II

patients

> with the T315I mutation (CP=1; LBC=1) treated at UCLA showed no

evidence of

> objective response. We have also detected the T315I mutation in

each of two

> cases of acquired resistance in a phase II (LBC =2) study, and in

seven of

> nine patients with acquired resistance to dasatinib in phase I

and II

> studies (CP=1; MBC=3; LBC=2; Ph+ ALL=1).

> Notably, we detected a novel BCR-ABL mutation, T315A, in one of

the two

> patients who relapsed without a detectable T315I mutation. The

patient is a

> 53 year-old female whose chronic phase CML had progressed to

myeloid blast

> phase while being treated with imatinib. The imatinib-resistant

mutation

> M244V was identified prior to dasatinib treatment. The patient

achieved a

> major hematologic response (<5% blasts with partial recovery of

peripheral

> blood counts) on dasatinib 90 mg orally given twice daily, but

relapsed with

> MBC after six months. Sequence analysis of the BCR-ABL kinase

domain at the

> time of relapse revealed the presence of the imatinib-resistant

mutation

> M244V as well as the novel mutation T315A. This finding is of

particular

> interest because T315A and several other novel BCR-ABL mutations

were

> recently recovered in a saturation mutagenesis study designed to

define

> potential mechanisms of dasatinib resistance. Remarkably, many of

these

> mutations retain sensitivity to imatinib in vitro (Burgess et al,

PNAS,

> 2005). Through periodic molecular monitoring of other dasatinib-

treated

> patients, we have identified a second novel BCR-ABL mutant,

F317I, that

> developed in an imatinib-resistant CP patient after 9 months of

treatment.

> Similar to T315A, F317I was isolated in the saturation

mutagenesis screen

> for dasatinib resistance and is predicted to retain sensitivity

to imatinib.

> Taken together, our findings implicate the T315I mutation as the

principle

> mechanism of resistance to dasatinib, but more importantly,

strongly support

> the use for combination kinase inhibitor therapy in CML to

prevent emergence

> of drug resistant clones. A phase I trial to assess the safety of

combining

> imatinib with dasatinib is planned.

>

>

>

>

>

[Guest guest]

Thanks Cheryl,

Yes, you helped. Thanks very much.

Cheers!

[ ] Shah on Treatment of IM-Resistant CML

>

>

> Hi Folks,

>

> Following is the fourth of five presentations from the Friday

Corporate

> Symposium sponsored by Bristol Myers Squib, which I began

reporting on some

> time back. This presentation was by Dr. Neil Shah of UCLA, on

Treatment of

> IM-Resistant CML. After this, and one more by s Hochaus, I

will then

> have three more multi-speaker talks to go, along with a bunch of

really

> interesting ³poster sessions.² I apologize taking so long

already. The idea

> of reporting on all that remains seems daunting; however, I'm

scheduled to

> ski for five days after Christmas, and since the conditions in

Maine then

> are notoriously miserable (unless you¹re a teen) at this time of

year, I¹ll

> probably spend a lot of time by the fire working on my reports to

y¹all.

>

> Shah reviewed the fact that AMN107 (AMN, from now on) is

chemically very

> similar to IM from which it was derived, whereas Bristo Myers

Squibb¹s

> BMS354825 (dasatinib, or DS, for the purposes of this lazy

typist) is

> structurally unrelated to Novartis¹ drugs. Both AMN and DS are at

least 2

> logs (two powers of ten, or 100x) more potent than IM, so they

offer hope

> for effective treatment even in patients whose cells have learned

to

> over-express the bcr/abl enzyme (brief review: BCR/ABL is the CML

cancer

> gene [oncogene], whereas bcr/abl [in small letters] refers to the

tyrosine

> kinase enzyme that BCR/ABL codes for, and which actually causes

all the bad

> things in CML: increased growth and lifespan of the white cells,

increased

> mutation rate of these white, so that the disease becomes

increasingly

> cancerous, etc. For ease of typing, I¹m following the convention

of many

> authors nowadays, in referring to the BCR/ABL gene simply as

³BA² - though

> I¹ll continue to refer to the enzyme as bcr/abl).

>

> One reason for the increased potency of these new drugs is that

they are

> more ³tolerant² of bcr/abl¹s different shapes (called

³conformations² in the

> biochemistry's quaint lingo): they bind to bcr/abl no matter

whether it is

> ³open² (inactive), ³closed² (active), or in any intermediate

stat. IM, by

> contrast, only binds to the closed/active conformation.

>

> In theory, DS offers even greater efficacy because it inhibits

not only

> bcr/abl, but also one of the kinases (one called src, and

pronounced ³sarc²)

> responsible for carrying out bcr/abl¹s downstream dirty work

(Note: Shah

> didn¹t address whether scr inhibition actually makes a difference

clinically

> ­ nor did I find this out elsewhere at ASH. Do any of you know

whether DS¹s

> src-blocking has proven clinical utility?).

>

> Shah mentioned a curious thing about the dosing frequency of

dasatinib:

> although DS has a half life of only a few hours (5-6 times

shorter than IM),

> it was initially given only once a day in Phase I trials. This

means that

> patients spent much of each day with very low serum levels, which

would be a

> total no-no with IM, where continuous serum levels above a

certain threshold

> are deemed absolutely necessary to avoid resistance. Whatever the

reason

> though, they a single dose for a while, and it seemed to work

just fine. In

> fact it worked as well ­ and maybe even better than ­ the twice a

day dosage

> schedule that was later adopted. I really don¹t understand why

they began

> with only a single daily dose, and would appreciate any insights

any of you

> may have. Maybe DS is so potent that it remains at a therapeutic

level even

> after several half-life periods have passed. But if this is the

case, why

> don¹t they just give patients much less of it, but spread it out

during the

> day to keep drug levels stable? Were they concerned about reduced

> compliance?

>

> A few other facts:

>

> ? While AMN and DS treat most IM resistant mutations, they

engender some new

> resistances of their own. Surprisingly (given that DS and AMN

are quite

> different molecules), these resistance patterns are rather

similar to one

> another. The fact that IM is effective against many of the DS or

> AMN-specific mutations and vice versa, is one of the rationales

for trying a

> combination of IM and one of these new drugs together. For more

on this,

> see the abstract (with Shah as a lead author) at the end of this

post.

>

> ? Similar to the IM experience, some patients on DS experienced

low grade

> elevations of their liver enzymes (AST, in particular) and of

creatinine.

> A new and somewhat more worrisome side effect is pleural effusion

(fluid in

> the lining of the lung) experienced by some patients. Jumping

ahead of

> myself though, I heard at one of the poster session that these

effusions

> resolve and don¹t tend to recur if you stop the drug for a couple

of days,

> give corticosteroids (like prednisone), and then restart.

>

> ? Many IM resistant blast phase patients showed a response by DS,

though as

> expected, they shortly became resistant to this drug too (same

with AMN).

>

> ? The ³next frontier² is drugs that will treat T315I, which Shah

called the

> ³Achilles heel of small molecule TK inhibitors.² None of the

drugs that

> have reached clinical trials show activity against this mutation,

though

> several compounds under investigation in vitro show promise (see

my prior

> post on IM resistance). Appropriately, some of these compounds

have

> mysterious, rather heroic names such as the ³Auror kinase

inhibitor,² or

> (for sci-fi techies), VX680.

>

> OK, off we go with this one. Stay tuned for s Hochaus on

the

> Potential for Combining Targeted Agents Against CML.

>

> Cheers,

>

> R

>

> ______

>

> [1093] Molecular Analysis of Dasatinib Resistance Mechanisms in

CML Patients

> Identifies Novel BCR-ABL Mutations Predicted To Retain

Sensitivity to

> Imatinib: Rationale for Combination Tyrosine Kinase Inhibitor

Therapy.

> Session Type: Poster Session 251-I

>

> Neil P. Shah, M. Nicoll, Branford, P. ,

L.

> Paquette, Moshe Talpaz, Claude Nicaise, Fei Huang, L.

Sawyers .

> Medicine/Hematology-Oncology, The Geffen School of Medicine

at UCLA,

> Los Angeles, CA, USA; Hematology, Institute for Medical and

Veterinary

> Sciences, Adelaide, New South Wales, Australia; Bioimmunotherapy,

MD

> Cancer Center, Houston, TX, USA; Bristol-Myers Squibb

Oncology,

> Princeton, NJ, USA

>

> Point mutations within the BCR-ABL kinase domain represent the

most common

> mechanism of resistance to imatinib in patients with CML.

Preclinical

> studies have shown that dasatinib (BMS-354825) is effective at

inhibiting

> the kinase activity of imatinib-resistant BCR-ABL mutants with

the notable

> exception of the T315I mutation, which remains highly resistant

to imatinib,

> dasatinib, and AMN107 (Gorre et al, Science 2001; Shah et al,

Science 2004;

> Weisberg et al, Cancer Cell, 2005). Clinical data from Phase I

and II

> studies of dasatinib in CML confirms the in vitro findings. Each

of three

> imatinib-resistant patients bearing the T315I mutation (CP=1;

AP=2) did not

> achieve objective hematologic or cytogenetic responses during

treatment with

> dasatanib on a Phase I study. Additionally, each of two phase II

patients

> with the T315I mutation (CP=1; LBC=1) treated at UCLA showed no

evidence of

> objective response. We have also detected the T315I mutation in

each of two

> cases of acquired resistance in a phase II (LBC =2) study, and in

seven of

> nine patients with acquired resistance to dasatinib in phase I

and II

> studies (CP=1; MBC=3; LBC=2; Ph+ ALL=1).

> Notably, we detected a novel BCR-ABL mutation, T315A, in one of

the two

> patients who relapsed without a detectable T315I mutation. The

patient is a

> 53 year-old female whose chronic phase CML had progressed to

myeloid blast

> phase while being treated with imatinib. The imatinib-resistant

mutation

> M244V was identified prior to dasatinib treatment. The patient

achieved a

> major hematologic response (<5% blasts with partial recovery of

peripheral

> blood counts) on dasatinib 90 mg orally given twice daily, but

relapsed with

> MBC after six months. Sequence analysis of the BCR-ABL kinase

domain at the

> time of relapse revealed the presence of the imatinib-resistant

mutation

> M244V as well as the novel mutation T315A. This finding is of

particular

> interest because T315A and several other novel BCR-ABL mutations

were

> recently recovered in a saturation mutagenesis study designed to

define

> potential mechanisms of dasatinib resistance. Remarkably, many of

these

> mutations retain sensitivity to imatinib in vitro (Burgess et al,

PNAS,

> 2005). Through periodic molecular monitoring of other dasatinib-

treated

> patients, we have identified a second novel BCR-ABL mutant,

F317I, that

> developed in an imatinib-resistant CP patient after 9 months of

treatment.

> Similar to T315A, F317I was isolated in the saturation

mutagenesis screen

> for dasatinib resistance and is predicted to retain sensitivity

to imatinib.

> Taken together, our findings implicate the T315I mutation as the

principle

> mechanism of resistance to dasatinib, but more importantly,

strongly support

> the use for combination kinase inhibitor therapy in CML to

prevent emergence

> of drug resistant clones. A phase I trial to assess the safety of

combining

> imatinib with dasatinib is planned.

>

>

>

>

>