FYI: Residual Disease Reduction With Longer-Term Imatinib Treatment (IRIS)

[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 second one.

~ G.

www.cmlsupport.com

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Residual Disease Reduction With Longer-Term Imatinib Treatment (IRIS)

Yang, MD, PhD:

In another follow-up presentation of IRIS data, Dr. Goldman and

colleagues[6] evaluated levels of cytogenetic response, including major

molecular response, at 4 years (Capsule Summary). As part of a subset

analysis of 124 patients who had achieved complete cytogenetic remission

at 1 year and had tissue samples available for polymerase chain reaction

(PCR) analysis at 4 years, the investigators reported a significant

increase in the reduction of molecular disease over time. The results

show that as patients continue imatinib therapy, the amount of minimal

residual molecular disease continues to decrease, rather than plateau or

increase (paired t test: P < .0001), with a mean log reduction of 3.14

and 3.54 at 1 and 4 years, respectively, and a median log reduction of

3.08 and 3.78 at 1 and 4 years. Furthermore, the proportion of these 124

patients with more than a 4 log10 reduction in BCR-ABL transcripts

increased from 22%-41% over that same time period. These data suggest

that continuous therapy is important and may be one of the reasons for

the reduction in the annual rate of transformation to accelerated-phase

or blast-crisis CML.

Jane Apperley, MD:

I think we should be careful about the interpretation of these data,

which encompass only a subset of the 397 patients in IRIS who remain on

first-line imatinib. I would like to know what is happening to the

patients who were not included in this analysis.

Yang, MD, PhD:

I think that the important point about this abstract is that after 4

years, patients were still converting from being PCR positive to being

PCR negative. Based on these findings, how should a community physician

treat patients who after 2 or 3 years still have not achieved a

complete, major molecular response by PCR? Should they continue

treatment? Should they consider additional therapies?

Hagop Kantarjian, MD:

Actually, most experts are cautious about the interpretation of PCR

results from commercial laboratories. Rather than discussing PCR

negativity, I think it is better to talk about a reduction in molecular

disease of 4 logs or more, which goes beyond the minimum requirement for

major molecular response. However, detecting this level of disease can

result in significant amounts of false-positive and false-negative

results. Notwithstanding, investigators are reporting increasing rates

of disease reduction by 4 logs or more. For example, in the article

published by , the Australians showed that more than 50% of

patients achieved a cumulative log reduction rate of 4 or more at 5

years, which is an incredible percentage.[3] How should we interpret

this? If, after many years, a patient does not have at least a 3 log10

reduction in the amount of disease, should we intervene? From a clinical

point of view, the vast majority of these patients are asymptomatic.

From the scientific and research point of view, these patients might be

ideal candidates for interventions, such as vaccines or nonspecific

immune therapy, like interferon, that stimulate the immune system. It is

also possible that some of the new kinase inhibitors may be useful in

this setting.

O'Brien, MB ChB:

I concur. PCR is not yet so robust or standardized that we can depend on

it as a completely reliable tool for disease monitoring. We are

confident that achieving a 3 log10 reduction or a major molecular

response is an important endpoint, but failure to achieve that endpoint

does not necessarily indicate failure of therapy. I think it is

premature to say that anyone who does not achieve a 3 log10 reduction

after 2 years should change treatment or increase their dose of

imatinib, especially since we are now seeing improved responses after

several years in some of these patients.

Jane Apperley, MD:

It is true that the Europeans have been very enthusiastic about

monitoring response by PCR, whereas clinicians in the United States have

typically monitored their patients with fluorescence in situ

hybridization (FISH). Previously, I supported the European view

regarding PCR monitoring, but now, after reading Dr. Simonsson's results

from his long-term IRIS study follow-up, I wonder whether the

achievement of complete cytogenetic response is actually good enough. It

is obviously important to know when a patient is " failing " therapy,

however failure may be defined, as long as there is some alternative

therapy to offer. In the case of young patients with potential donors

for transplant, monitoring should be performed very carefully in order

to identify failure as early as possible. For older patients who are not

candidates for transplant, failure to respond might justify switching

them to one of the new tyrosine kinase inhibitors. Although long-term

durability has not yet been proven in this situation, studies we will

discuss today suggest that the next generation of tyrosine kinase

inhibitors is quite effective in the short term.[7-9]

Yang, MD, PhD:

Do you still perform PCR for your patients who are not transplant

candidates?

Jane Apperley, MD:

Yes. We monitor PCR to identify the patient who is doing poorly.