SUSTRENIM - GIMEMA CML1415 / HOVON 142 CML

The most important aim of any new clinical trial on tyrosine kinase inhibitor
(TKI) treatment of CML should be the achievement of a condition now called
treatment-free remission (TFR), defined as a sustained leukemic mass reduction
induced by therapy followed by treatment discontinuation without a loss of the
response. Indeed, several important, but small and uncontrolled, studies have
provided the proof-of-principle that TKI treatment can result into a TFR, and
that a deep molecular response (DMR) is required to achieve that condition. It
is not currently clear whether TFR corresponds to the eradication of leukemia
cells or, alternatively, to a functional balance between their growth potential
and the host anti leukemic control. In this context, the traditional and more
conservative endpoint of all cancer treatment protocols, that is overall
survival, may be no longer sufficient to evaluate the outcome of treatment.
Indeed, after the introduction of Imatinib (IM), the first TKI, and of the
other second-generation TKIs, life expectancy of CML patients has become very
close, and maybe even overlapping, to that of non-leukemic subjects. The
impressive impact on overall survival probability has been observed with all
TKIs used as first line treatment; therefore, it is difficult now to design a
clinical trial aimed to improve overall survival or to demonstrate any
superiority of a TKI over the other TKIs using this end-point. Furthermore, the
continuous, lifelong treatment required to treat CML has a number of important
implications: physical, i.e. the off-target side effects and the toxicity of
the chronic treatment, social and psychological, i.e. family planning, work
planning, anxiety and depression caused by living with leukemia. Even financial
implications should be considered, since TKI treatment is expensive and the
number of CML patients is progressively growing.
This investigator-sponsored study is the first that is designed to compare
prospectively a policy of CML treatment based on a second-generation TKI (NIL)
first line versus a policy of first-line IM, with a switch to NIL only in the
patients who do not achieve an optimal response to IM. One of the two principal
aims of the present study is to evaluate the rates of TFR after 1-year TKI
discontinuation following a four year of TKI treatment in a randomized
comparison between patients treated frontline with NIL 300mg BID versus those
treated with IM 400mg OD, with a switch to NIL 300mg BID in case of absence of
optimal response according to the ELN2013 recommendations (>10% BCR/BL levels
at 3 months, >1% at 6 months and >0.1% at 12months). The risk of molecular
relapse during TFR varies from 40 to 60%, occurring most frequently within the
first year after discontinuation. Recent evidences suggest that the loss of
MR3.0 can be safely considered as a trigger to restart treatment, leading to
more prolonged TFR.The second main aim of the study is the evaluation of the
MR4.5 rates at 24 months in the two treatment arms (NIL 300mg BID vs IM 400mg
OD with switch to NIL for treatment optimization) as co-primary endpoint, since
the rates of DMR are strictly dependent on the kinetics of residual disease
during the first years of treatment. In addition, the MR4.5 rates at 24months
represent an immediate and clean end-point for the comparison of the two
policies of front-line treatment, i.e. NIL 300mg BID versus IM 400mg OD, with a
switch to NIL 300mg BID for treatment optimization.
Therefore, this study will provide a long-term post-marketing surveillance in a
large independent study of the comparison of two different strategies for
frontline treatment of CML that is extremely relevant to explore, using
clinically relevant end-points, the potential superiority of second generation
TKIs as initial treatment of CP CML. In this protocol, only NIL has been
selected as second generation TKI, because Dasatinib, the other new generation
TKI already registered for frontline therapy of CML, is under investigation in
an independent clinical trial currently running in UK. The final aim is to
establish the most suitable options for the first-line therapy of CML in terms
of efficacy, of tolerability, of quality of life.

This study has been transitioned to CTIS with ID 2023-510434-83-00 check the CTIS register for the current data.

The study will investigate in newly diagnosed CP-CML patients the efficacy of
NIL frontline therapy vs IM followed by switch to NIL in the case of absence of
optimal response as defined by the ELN criteria

A prospective, interventional, randomized, two arms study

Patients are either randomized for treatment with imatinib or randomized for
treatment with nilotinib.

Participation in this study might be associated with extra investigations,
which might require the patient to visit the hospital more often.
In addition to the routine blood and bone marrow samples there will be taken
extra blood and bone marrow during regular sampling.
Patients might experience adverse events due to the received treatment.
Patients will be requested to participate in Quality of Life studies.