RE: From ASH - Interview with Dr. Goldman

[Guest guest]

Thanks Zavie, but what I am taking note of is this apparent

contradiction. Huh??

" Medscape: If a patient achieves a molecular response, is it safe to

discontinue therapy?

Dr. Goldman: <snip> The answer is yes, it is safe -- but the disease

will come back fairly rapidly in most cases. <snip> as the disease comes

back and the quantity of disease in the body increases, the probability

of

disease progression (advanced phase or blastic transformation) will also

probably increase. "

In other words, yeah, it's safe to stop taking it if you don't mind

dying? Many of you will recall my personal experience with stopping

treatment. I don't get Goldman's self-contradictory statements here.

G.

www.upstairswindow.org

[ ] From ASH - Interview with Dr. Goldman

Take note of his recommendations for monitoring CML.

Zavie

Long-term Results for Imatinib-Treated Patients With CML: An Interview

With Professor Goldman

Disclosures

Sally Church, PhD

Editor's Note:

Approximately 20,000 people suffer from chronic myeloid leukemia (CML)

in the United States, and approximately 4500 new cases are diagnosed

each year.[1] The International Randomized Interferon vs STI 571 (IRIS)

trial[2] initially randomized newly diagnosed patients in the chronic

phase of the disease to either the standard of care at the time,

interferon + ara-C, or vs imatinib. When treatment with imatinib showed

a clear survival advantage and received approval from the US Food and

Drug Administration (FDA), most of the patients on interferon chose to

switch to imatinib, and now, essentially, only the imatinib arm has been

followed long-term.

This year, the updated long-term survival data[3] in these patients were

eagerly awaited at the American Society of Hematology (ASH) annual

meeting. Medscape sat down with Professor Goldman, Fogarty Scholar

at the National Institutes of Health, Bethesda, land, who presented

the data, to discuss long-term follow-up in these patients. Dr. Goldman

emphasized the importance of regular monitoring, even in patients who

are well controlled on therapy.

Medscape: The updated IRIS data[3] are now available; can you tell us

how the patients are doing over the long term?

Dr. Goldman: The answer is that they are continuing to look very good.

About 550 patients with newly diagnosed chronic-phase CML were

randomized to receive imatinib as a single agent 400 mg/daily in the

year 2000. Four years later, which is the date of the most recent

analysis, the majority of those patients are alive, still in complete

chromosomal remission, and really doing very, very well.

The most fascinating data as of right now are from 125 of the patients

who had molecular monitoring and were found to have a considerable

degree of reduction of minimal residual disease by transcript numbers,

namely a 3.2 median log reduction of transcript numbers at 1 year. At 4

years -- that is, 3 years later -- those continuing imatinib have gone

on to 3.9 log reduction. That means that during the 3 years on imatinib

during which they continued in complete chromosomal remission, the level

of disease continued to fall (as measured by molecular technology known

as reverse transcriptase polymerase chain reaction [RT-PCR]). Because we

think the level of residual disease correlates with the probability of

disease progression -- in other words, the lower the level of residual

disease, the lower the probability of disease progression -- we believe

that these patients are going to have very substantial prolongation of

life compared with those who received previous therapies. This is very

good news for a subset of patients treated with imatinib. It does not,

however, apply to every single patient treated with imatinib -- this

result particularly applies to the 20% of patients we have been able to

analyze at 4 years, but it probably applies to more than that.

Medscape: If a patient achieves a molecular response, is it safe to

discontinue therapy?

Dr. Goldman: A major molecular response (MMR) is a 3-log reduction from

a standardized baseline, so having reached an MMR, would it be safe to

discontinue therapy? The answer is yes, it is safe -- but the disease

will come back fairly rapidly in most cases. In other words, the level

of residual disease will rise, and if you wait long enough, the patient

will develop leucocytosis and clinical features of chronic-phase CML.

The other point to keep in mind is that as the disease comes back and

the quantity of disease in the body increases, the probability of

disease progression (advanced phase or blastic transformation) will also

probably increase.

So, one has to say at the present time, the best advice must be to

continue imatinib forever. That is a little bit of an exaggeration, but

certainly imatinib treatment should be continued for a very long time.

We are nowhere near the situation where one would recommend stopping

treatment, no matter how well the patient is doing, as measured by

molecular criteria.

Medscape: What are the main reasons for regular monitoring in CML, and

how does that assist in evaluating how a therapy is performing?

Dr. Goldman: Why should you monitor patients on a regular basis, even if

they are responding well to a tyrosine kinase inhibitor? Well, the

answer is because a small proportion of patients either lose their

response to the particular tyrosine kinase inhibitor or show early signs

of progression. And I think in both cases, you should contemplate a

change of therapy. One of the most important considerations for change

of therapy is the availability of allogeneic stem cell transplant, if

there is a donor, or other alternatives such as chemotherapy,

immunotherapy, or even a clinical trial with other tyrosine kinase

inhibitors. So, ensuring that the patient who has responded well

continues to maintain a really good response is important, because if he

or she loses a really good response, one has to consider alternative and

fundamentally different forms of therapy.

In terms of what you should do, the first thing is to sit down and think

very hard: (a) has this person really lost response, or ( could you

continue imatinib, for example, at a higher dose and gain some benefit?

If the answer is potentially yes, maybe you could continue imatinib. But

assuming that you have decided that imatinib is really not working at

the highest possible dose, what else can you do? Regarding alternative

tyrosine kinase inhibitors, there are a number currently undergoing

clinical trials[4-6] and there will certainly be others within the next

12 months.

In addition to allogeneic transplant, autologous transplant is another

option that certainly needs to be considered in appropriate patients.

Cytotoxic drugs such as cytosine arabinocide (Ara-C), daunorubicin,

homoharringtonine, arsenic compounds, and decitabine are all options,

especially in advanced disease. They are all worth considering, although

none is clearly established in this situation. There is also the

possibility of introducing an immunotherapeutic approach (with

interferon-alpha), which is very interesting indeed in terms of dealing

with minimal residual disease.

Medscape: How often would you recommend monitoring to optimize therapy,

and what options are available?

Dr. Goldman: The actual recommendations for monitoring disease are still

very much under discussion. My colleague, Michele Baccarani, from

Bologna in Italy, is preparing what were originally meant to be

guidelines, but I think we now call them recommendations, for

monitoring.

Quite simply, at the time of diagnosis, I think it is clear a patient

should have a full blood count, conventional examination of the bone

marrow, examination of the bone marrow for metaphase cytogenetics, and a

baseline real-time quantitative reverse transcriptase polymerase chain

reaction (RQ-PCR). I do think those are all really mandatory today, and

I recommend a bone marrow examination again at 3 months after starting

imatinib. I would also suggest that a patient has molecular monitoring

with RQ-PCR transcript numbers on peripheral blood at every clinic

visit. It really is my recommendation -- but if not that often, at no

less frequent intervals than every 3 months -- because as that patient

achieves complete chromosomal remission, the way to continue monitoring

is with RQ-PCR.

You can also use FISH (fluorescence in situ hybridization) for BCR-ABL

fusion gene at diagnosis, to exclude the possibility of

Philadelphia-negative, BCR-ABL-positive disease and to look for a 9Q+

deletion. You can certainly use FISH sequentially thereafter, as the

patient responds to therapy, but in my opinion it should not be the

criterion by which you judge the quality and the durability of response

to therapy. The standard should be RQ-PCR for BCR-ABL transcripts, which

is probably 2 or 3 orders of magnitude more sensitive than the best

FISH. FISH has been associated with considerable false positive rates,

and it is unreliable in some labs. It is only a secondary adjunct to

RQ-PCR for the responding patient, so it is not the ideal approach. I am

sure new technologies will become available to further increase the

sensitivity of RQ-PCR, but that is for the future.

References

American Cancer Society. Cancer Facts & Figures 2005. Available at:

http://www.cancer.org/downloads/STT/CAFF2005f4PWSecured.pdf. Accessed

December 19, 2005.

O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with

interferon and low-dose cytarabine for newly diagnosed chronic-phase

chronic myeloid leukemia. N Engl J Med. 2003;348:994-1004.

Goldman JM, T, Radich J, et al. Continuing reduction in level of

residual disease after 4 years in patients with CML in chronic phase

responding to first-line imatinib in the IRIS study. Blood.

2005;106:51a. Abstract 163.

Kantarjian HM, Ottman O, Cortes J, et al. AMN107, a novel

aminopyrimidine inhibitor of bcr-abl, has significant activity in

imatinib-resistant chronic myeloid leukemia (CML) or

Philadelphia-chromosome positive acute lymphoid leukemia (Ph + ALL).

Blood. 2005;106:15a. Abstract 37.

Sawyers CL, Kantarjian H, Shah N, et al. Dasatinib (BMS-354825) in

patients with chronic myeloid leukemia (CML) and Philadelphia-chromosome

positive acute lymphoblastic leukemia (Ph+ALL) who are resistant or

intolerant to imatinib: update of a phase I study. Blood. 2005;106:16a.

Abstract 38.

Hochhaus A, Baccarani M, Sawyers C, et al. Efficacy of dasatinib in

patients with chronic phase Philadelphia chromosome-positive CML

resistant or intolerant to imatinib: first results of the CA180013

'START-C' phase II study. Blood. 2005;106:17a. Abstract 41.

[Guest guest]

Hi ,

I get the impression that he may be using sarcasm to make his point. He

does state elsewhere " We are nowhere near the situation where one would

recommend stopping treatment, no matter how well the patient is doing,

as measured by molecular criteria. "

You might remember what happened when Giora went off Gleevec. At the

time he had the deepest molecular remission of anyone and the disease

came back.

There have been several documented cases where a patient has gone off

Gleevec and they still remain in PCRU even after 15 months off Gleevec.

Zavie

[ ] From ASH - Interview with Dr. Goldman

Take note of his recommendations for monitoring CML.

Zavie

Long-term Results for Imatinib-Treated Patients With CML: An Interview

With Professor Goldman

Disclosures

Sally Church, PhD

Editor's Note:

Approximately 20,000 people suffer from chronic myeloid leukemia (CML)

in the United States, and approximately 4500 new cases are diagnosed

each year.[1] The International Randomized Interferon vs STI 571 (IRIS)

trial[2] initially randomized newly diagnosed patients in the chronic

phase of the disease to either the standard of care at the time,

interferon + ara-C, or vs imatinib. When treatment with imatinib showed

a clear survival advantage and received approval from the US Food and

Drug Administration (FDA), most of the patients on interferon chose to

switch to imatinib, and now, essentially, only the imatinib arm has been

followed long-term.

This year, the updated long-term survival data[3] in these patients were

eagerly awaited at the American Society of Hematology (ASH) annual

meeting. Medscape sat down with Professor Goldman, Fogarty Scholar

at the National Institutes of Health, Bethesda, land, who presented

the data, to discuss long-term follow-up in these patients. Dr. Goldman

emphasized the importance of regular monitoring, even in patients who

are well controlled on therapy.

Medscape: The updated IRIS data[3] are now available; can you tell us

how the patients are doing over the long term?

Dr. Goldman: The answer is that they are continuing to look very good.

About 550 patients with newly diagnosed chronic-phase CML were

randomized to receive imatinib as a single agent 400 mg/daily in the

year 2000. Four years later, which is the date of the most recent

analysis, the majority of those patients are alive, still in complete

chromosomal remission, and really doing very, very well.

The most fascinating data as of right now are from 125 of the patients

who had molecular monitoring and were found to have a considerable

degree of reduction of minimal residual disease by transcript numbers,

namely a 3.2 median log reduction of transcript numbers at 1 year. At 4

years -- that is, 3 years later -- those continuing imatinib have gone

on to 3.9 log reduction. That means that during the 3 years on imatinib

during which they continued in complete chromosomal remission, the level

of disease continued to fall (as measured by molecular technology known

as reverse transcriptase polymerase chain reaction [RT-PCR]). Because we

think the level of residual disease correlates with the probability of

disease progression -- in other words, the lower the level of residual

disease, the lower the probability of disease progression -- we believe

that these patients are going to have very substantial prolongation of

life compared with those who received previous therapies. This is very

good news for a subset of patients treated with imatinib. It does not,

however, apply to every single patient treated with imatinib -- this

result particularly applies to the 20% of patients we have been able to

analyze at 4 years, but it probably applies to more than that.

Medscape: If a patient achieves a molecular response, is it safe to

discontinue therapy?

Dr. Goldman: A major molecular response (MMR) is a 3-log reduction from

a standardized baseline, so having reached an MMR, would it be safe to

discontinue therapy? The answer is yes, it is safe -- but the disease

will come back fairly rapidly in most cases. In other words, the level

of residual disease will rise, and if you wait long enough, the patient

will develop leucocytosis and clinical features of chronic-phase CML.

The other point to keep in mind is that as the disease comes back and

the quantity of disease in the body increases, the probability of

disease progression (advanced phase or blastic transformation) will also

probably increase.

So, one has to say at the present time, the best advice must be to

continue imatinib forever. That is a little bit of an exaggeration, but

certainly imatinib treatment should be continued for a very long time.

We are nowhere near the situation where one would recommend stopping

treatment, no matter how well the patient is doing, as measured by

molecular criteria.

Medscape: What are the main reasons for regular monitoring in CML, and

how does that assist in evaluating how a therapy is performing?

Dr. Goldman: Why should you monitor patients on a regular basis, even if

they are responding well to a tyrosine kinase inhibitor? Well, the

answer is because a small proportion of patients either lose their

response to the particular tyrosine kinase inhibitor or show early signs

of progression. And I think in both cases, you should contemplate a

change of therapy. One of the most important considerations for change

of therapy is the availability of allogeneic stem cell transplant, if

there is a donor, or other alternatives such as chemotherapy,

immunotherapy, or even a clinical trial with other tyrosine kinase

inhibitors. So, ensuring that the patient who has responded well

continues to maintain a really good response is important, because if he

or she loses a really good response, one has to consider alternative and

fundamentally different forms of therapy.

In terms of what you should do, the first thing is to sit down and think

very hard: (a) has this person really lost response, or ( could you

continue imatinib, for example, at a higher dose and gain some benefit?

If the answer is potentially yes, maybe you could continue imatinib. But

assuming that you have decided that imatinib is really not working at

the highest possible dose, what else can you do? Regarding alternative

tyrosine kinase inhibitors, there are a number currently undergoing

clinical trials[4-6] and there will certainly be others within the next

12 months.

In addition to allogeneic transplant, autologous transplant is another

option that certainly needs to be considered in appropriate patients.

Cytotoxic drugs such as cytosine arabinocide (Ara-C), daunorubicin,

homoharringtonine, arsenic compounds, and decitabine are all options,

especially in advanced disease. They are all worth considering, although

none is clearly established in this situation. There is also the

possibility of introducing an immunotherapeutic approach (with

interferon-alpha), which is very interesting indeed in terms of dealing

with minimal residual disease.

Medscape: How often would you recommend monitoring to optimize therapy,

and what options are available?

Dr. Goldman: The actual recommendations for monitoring disease are still

very much under discussion. My colleague, Michele Baccarani, from

Bologna in Italy, is preparing what were originally meant to be

guidelines, but I think we now call them recommendations, for

monitoring.

Quite simply, at the time of diagnosis, I think it is clear a patient

should have a full blood count, conventional examination of the bone

marrow, examination of the bone marrow for metaphase cytogenetics, and a

baseline real-time quantitative reverse transcriptase polymerase chain

reaction (RQ-PCR). I do think those are all really mandatory today, and

I recommend a bone marrow examination again at 3 months after starting

imatinib. I would also suggest that a patient has molecular monitoring

with RQ-PCR transcript numbers on peripheral blood at every clinic

visit. It really is my recommendation -- but if not that often, at no

less frequent intervals than every 3 months -- because as that patient

achieves complete chromosomal remission, the way to continue monitoring

is with RQ-PCR.

You can also use FISH (fluorescence in situ hybridization) for BCR-ABL

fusion gene at diagnosis, to exclude the possibility of

Philadelphia-negative, BCR-ABL-positive disease and to look for a 9Q+

deletion. You can certainly use FISH sequentially thereafter, as the

patient responds to therapy, but in my opinion it should not be the

criterion by which you judge the quality and the durability of response

to therapy. The standard should be RQ-PCR for BCR-ABL transcripts, which

is probably 2 or 3 orders of magnitude more sensitive than the best

FISH. FISH has been associated with considerable false positive rates,

and it is unreliable in some labs. It is only a secondary adjunct to

RQ-PCR for the responding patient, so it is not the ideal approach. I am

sure new technologies will become available to further increase the

sensitivity of RQ-PCR, but that is for the future.

References

American Cancer Society. Cancer Facts & Figures 2005. Available at:

http://www.cancer.org/downloads/STT/CAFF2005f4PWSecured.pdf. Accessed

December 19, 2005.

O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with

interferon and low-dose cytarabine for newly diagnosed chronic-phase

chronic myeloid leukemia. N Engl J Med. 2003;348:994-1004.

Goldman JM, T, Radich J, et al. Continuing reduction in level of

residual disease after 4 years in patients with CML in chronic phase

responding to first-line imatinib in the IRIS study. Blood.

2005;106:51a. Abstract 163.

Kantarjian HM, Ottman O, Cortes J, et al. AMN107, a novel

aminopyrimidine inhibitor of bcr-abl, has significant activity in

imatinib-resistant chronic myeloid leukemia (CML) or

Philadelphia-chromosome positive acute lymphoid leukemia (Ph + ALL).

Blood. 2005;106:15a. Abstract 37.

Sawyers CL, Kantarjian H, Shah N, et al. Dasatinib (BMS-354825) in

patients with chronic myeloid leukemia (CML) and Philadelphia-chromosome

positive acute lymphoblastic leukemia (Ph+ALL) who are resistant or

intolerant to imatinib: update of a phase I study. Blood. 2005;106:16a.

Abstract 38.

Hochhaus A, Baccarani M, Sawyers C, et al. Efficacy of dasatinib in

patients with chronic phase Philadelphia chromosome-positive CML

resistant or intolerant to imatinib: first results of the CA180013

'START-C' phase II study. Blood. 2005;106:17a. Abstract 41.