FYI: Matching Patient Response to Optimal Imatinib Dosing

[Guest guest]

Hi all,

I'm posting below a discussion in the wake of the ASH meeting. This is

from a series about CML from ASH that I am privvy to. I'm not posting

them all because there are too many (62 pages in a pdf) but will post

some of them. I have also removed links and references for my

convenience.

Below is the fourth one.

~ G.

www.cmlsupport.com <http://www.cmlsupport.com/>

===================

Matching Patient Response to Optimal Imatinib Dosing

Yang, MD, PhD:

This discussion raises important clinical questions for the community

physician. What is the optimal dose of imatinib? When should a dose

higher than 400 mg be used? Should higher doses be reserved only for

accelerated-phase or blast-crisis CML? Should the dose be increased only

when patients do not achieve molecular milestones, or should dose

increases be based on how patients feel?

Hagop Kantarjian, MD:

I think the general feeling among most of the investigators in this

field is that for most newly diagnosed patients with CML, the standard

dose of 400 mg is enough, whereas higher doses should be used only in

selected instances such as accelerated-phase or blast-crisis CML or for

patients who either failed to achieve an optimal response or have lost

their optimal response. More specifically, high-dose imatinib is

probably warranted when standard therapy has failed to produce a

complete hematologic response at 3 months or a major cytogenetic

response at 12 months, or when either cytogenetic or hematologic

response has been lost. Other than these instances, I think high-dose

imatinib remains investigational and should not be used in community

practice.

O'Brien, MB ChB:

I think that is a fair assessment of when to increase the dose. In

practice, however, it is actually quite difficult to deliver the higher

doses in most of those patients because of both hematologic and

nonhematologic toxicity.

Jane Apperley, MD:

That is a good point. It has been noted that the development of

cytopenias in those first few months is definitively associated with a

poorer outcome.[16] However, we need to ask ourselves whether the poor

outcome is biologically destined in that individual patient or whether

the cytopenias prevent delivery of optimal drug doses.

There is a lack of consensus as to what to do when a patient is clearly

losing response. Although the natural inclination is to increase the

dose, I think it is important to consider why the patient is losing the

response and to consider sending samples to a major center to look for

mutations. Such an analysis could reveal reasons for the loss of

response that could alter the subsequent treatment strategy.

Yang, MD, PhD:

Would you send samples for analysis if the patient has had a molecular

relapse, or would you wait?

Jane Apperley, MD:

I think any major change in a patient's condition, such as a change from

a molecular response to nonmolecular response, the loss of a cytogenetic

response, or the loss of hematological response would be a reason to

send samples for molecular analysis. We are looking quite carefully at

why loss of response occurs, and it is clear from the available data

that some of these mutations are not responsive to the new agents or to

higher doses of existing therapy.

Hagop Kantarjian, MD:

Unfortunately, mutation analysis is not available to the vast majority

of physicians and patients. Furhthermore, the significance of those

mutations remains uncertain, not to mention what is to be done once

those mutations are detected. Several studies have shown that if a

patient has cytogenetic or hematologic relapse, or shows a significant

rise in molecular disease on PCR, then those mutations, if detected,

have clinical relevance.[17-21] They may predict lack of response not

only to imatinib but also to the new kinase inhibitors, necessitating a

major change of therapy.

On the other hand, we may detect mutations that are worrisome but not

necessarily relevant in patients who are responding. We have to monitor

those patients and perhaps stop sending samples from patients who are

responsive. However, we should continue sending samples to detect

mutations in patients who are not responsive by accepted criteria, such

as hematologic relapse, cytogenetic relapse, or a significant rise in

molecular disease. In those instances, if particularly relevant

mutations such as T315I are detected, it may not make sense to give

high-dose imatinib or one of the new kinase inhibitors. Rather, it may

make more sense to take these patients to immediate transplant.

Yang, MD, PhD:

Dr. O'Brien, what do you do if you find a T315I mutation in a sequencing

analysis of BCR-ABL?

O'Brien, MB ChB:

This is an excellent question. Contradictory data were presented at this

meeting about the relevance of that particular mutation. For example,

Dr. Sherbenou and colleagues[20] showed that T315I could be detected,

yet seemed to have no clinically significant effects, in patients with

complete cytogenetic responses. So it does not appear that having T315I

will inevitably lead to clinical problems. I think that monitoring by

PCR and then perhaps performing mutation analysis is an absolutely

cost-effective, reasonably evidence-based approach. Regular PCR

monitoring should trigger a mutation analysis if there is a significant

increase in molecular disease. What is deemed significant can be

debated, but it is usually fairly apparent.

Hagop Kantarjian, MD:

There are many studies on the significance of mutations in the context

of imatinib therapy in CML. The bottom line is that the significance of

any given mutation depends on several factors: the context (eg,

responsive disease vs resistant disease), the kind of mutation (eg,

T315I vs less important mutations), and what to do once the mutation is

detected. Depending on these factors, imatinib therapy may or may not

help. Another important question is when is it necessary to act on those

mutations? The study from Dr. Sherbenou evaluated patients who were in

cytogenetic response. There were 8 patients who had T315I mutations.

Although several of those patients progressed, some patients who had the

mutation did quite well. Importantly, one could not detect any

difference in outcome solely on the basis of whether a patient had

mutations, regardless of if they were P-loop or non-P-loop mutations, or

if there was a T315I mutation. This just proves that studies in

cytogenetically responsive disease may generate misleading data and that

the discovery of mutations in otherwise asymptomatic patients should not

necessarily be interpreted in the same way as mutations found in

resistant disease.

Jane Apperley, MD:

This point about mutations is quite important but needs to be confirmed

by other groups, because mutation analysis is highly dependent on the

detection methods and standards of sensitivity that are employed.