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Mechanism of cont. remission in Patients discont. TKIs

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#1 valiantchong


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Posted 08 September 2011 - 12:31 PM


Mechanisms of continuous remission in patients discontinuing TKI ...

Mechanisms of continuous remission in patients discontinuing TKI
therapy: The STOP study
Chronic myeloid leukemia (CML) is a model disease of cancer as its molecular
pathogenesis is particularly well characterized. The first effective molecularly targeted
treatment of cancer, tyrosine kinase inhibitor imatinib mesylate, induces sustained
cytogenetic remissions in a majority of CML patients in chronic phase. It is currently the
standard first-line treatment in CML.
Despite good clinical efficacy, a small proportion of patients develop resistance to imatinib
therapy. Even in responding patients imatinib is not currently considered as a curative
treatment and therefore the treatment is life-long. However, the long-term effects of
chronic kinase inhibition lasting years or even decades are mostly unknown. Recently,
several significant off-target side-effects have emerged in a proportion of patients (e.g.
cardiotoxicity, effects on bone, hormone and carbohydrate metabolism).
Interferon alpha (IFN) is an immunomodulatory agent and it induces cytogenetic
remissions in a small proportion of CML patients. In a majority of these patients IFN can be
discontinued without clinical relapse of the disease. This has been attributed to the
induction of anti-CML immunity.
Recent reports have indicated that imatinib also has significant immunostimulatory effects,
which might be important in the long-term control of CML. Furthermore, imatinib is an
efficient tool for inducing a state of minimal residual disease, which is one of the
prerequisites for successful cancer immunotherapy. Thus the combination of imatinib and
IFN could be clinically very useful.
The purpose of this academic project is to study the feasibility of drug discontinuation and
examine immune surveillance during and after drug therapy. The study population consists
of CML patients who have achieved an excellent response (major molecular remission)
after 12 months of therapy with either imatinib alone or in combination with IFN. This study
is a part of the NordCML002 study sponsored by the Nordic CML Study Group and is
ongoing in all Nordic countries. The specific aims of the project are
1. Evaluate the feasibility of drug discontinuation in a well-defined cohort of patients
with CML who are on imatinib or imatinib-interferon combination therapy, as a part
of a prospective controlled study
2. Study the cellular and molecular mechanisms underlying restoration of antileukemia
immunity in a proportion of patients
3. Develop sensitive methods for the prediction of the outcome of therapy
discontinuation, i.e., which patients will relapse and which do not.
4. Plan a Phase I study based on results obtained from this study aiming in curative
therapy of CML with the combination of tyrosine kinase inhibitors and
immunomodulation (e.g. vaccines, STAT3-inhibitors, other immunomodulatory
This study aims in answering to one of the key questions of effective molecularly targeted
cancer therapy: can a proportion of patients be cured and what are the mechanisms. Our
clinical, multicenter study on CML patients is an ideal platform for unravelling these
questions and if successful, would have significant implications on cancer therapy.
Safety of drug discontinuation in patients in major molecular remission
Most reported patients, but not all, do rapidly relapse after imatinib discontinuation, but
always re-respond to imatinib. If the patient fulfills the criteria for therapy restart (loss of
major molecular response), the tumor burden is still very low and the patients are
asymptomatic with no changes in, e.g., blood values. There is no clinical or theoretical
evidence that imatinib discontinuation would induce disease progression to advanced
phases of CML. After drug discontinuation, patients will be followed-up very closely for at
least for 12 months (blood tests every 2 weeks, blood MRD measurement by PCR every
month) and if major molecular response (3 log reduction in blood BCR-ABL transcript
level) is lost, imatinib therapy will be immediately restarted.
Study flow-chart
at 12 months
>3 log <3 log
STOP imatinib
Imatinib +
a-IFN Imanib
Restart imatinib therapy on progression
qPCR follow-up
monthly 6 months
qPCR follow-up
monthly 12 months
n=20 n=20
12 months
(imatinib vs. imatinib+ a-IFN)
6 months
6 months
STOP imatinib
6 months
12 months
(>3 log=major molecular response, i.e., >3 log reduction in blood BCR-ABL transcript level)
Patients and methods
Study patients
The study population consists of adult CML patients participating in the NordCML002
study sponsored by the Nordic CML Study Group (NCMLSG) comparing imatinib to
imatinib-IFN combination therapy. The patients will be treated by local CML investigators
and clinical efficacy and safety will be closely monitored as described above. This study
includes CML patients who in the NordCML002 study have achieved an excellent
response (major molecular remission, see flow-chart) after 12 months of therapy with
either imatinib alone or in combination with IFN. This study will be ongoing in all Nordic
Objectives. Cancer immunosurveillance is a multivariable process requiring the actions of
different immune effectors, which may depend on tumor type, mode of transformation,
anatomic location, stromal response, cytokine and chemokine microenvironment, and
mechanism of immunologic recognition. As our current knowledge of mechanisms of antileukemia
immunity are limited, a wide range of both descriptive enumeration assays and
functional assays are required to gain insight to the key objective of the study: why some
patients relapse, while others do not. The analytical lab centers are in Helsinki and Oslo,
where samples will be shipped from clinical centers.
Timeline for sample collection. A total of four samples will be collected from the study
patients according to the following flow-chart. Both bone marrow and peripheral blood
samples will be collected. Material will also be stored for future analyses.
(imatinib vs. imatinib+ a-IFN)
(imatinib vs. imatinib+ a-IFN)
0 12 0 2 4 6 2 4 6 8 10 12 Months
Ima +a-IFN
Continue Continue
STOP ima
STOP ima
STOP Study
Sampling time-points
Immunophenotyping will be done using a large panel of monoclonal antibodies targeted
against various cell surface and intracytoplasmic antigens present in different types of
leukocytes. The analyses will be done at Helsinki and Oslo University Central Hospital
hematology laboratories, which have an extensive expertise both in routine diagnostics
and research.

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