Front-line Treatment of BCR-ABL+ Chronic Myeloid Leukemia (CML) With Dasatinib. An Observational Multicentric Study.
The primary objective is to describe, in the clinical practice, the rate of events leading
to permanent discontinuation after 2 years of treatment with dasatinib as frontline therapy
in newly diagnosed CML patients. Imatinib mesylate, a protein tyrosine kinase inhibitor
(TKI) targeting BCR-ABL, has become in the last decade the standard of care for Chronic
Myeloid Leukaemia (CML) in chronic phase (CP)1-3. Dasatinib is a second generation TKI,
effective in imatinib-resistant and imatinib-intolerant patients, which demonstrated
superior efficacy to imatinib in early CP BCR-ABL+ CML patients 4,6,7. Most data on second
generation TKIs are from company-sponsored studies, generally implemented in selected
referral centres. The long-term outcome is still unknown. The high rate of study
discontinuation observed within the phase 3 study may influence the mid-term and the
long-term data interpretation6,7. A long-term post-marketing surveillance in large
independent trial is extremely important to confirm the feasibility of a frontline treatment
with the second generation TKI dasatinib and to evaluate the efficacy in a nationwide
experience. Moreover, obtaining a deep molecular response is extremely relevant in order to
consider TKIs discontinuation. This condition is known as "Complete Molecular Response"
(CMR) and is further defined according to the sensitivity achieved (for the definition see
the "Criteria of evaluation" section). As far as treatment discontinuation, two experiences
have been published so far, aimed at evaluating the persistence of the CMR after imatinib
discontinuation. The first was a pilot study32 where 12 patients were included. These 12
patients discontinued imatinib after at least 2 years of CMR (median duration of negativity,
32 months). Six patients displayed a molecular relapse with a detectable BCR-ABL transcript
at 1, 2, 3, 4, and 5 months. Imatinib was then reintroduced and led to a novel molecular
response. Six other patients (50%) still have an undetectable level of BCR-ABL transcript
after a median follow-up of 18 months (range, 9-24 months). The results of this pilot trial
have been confirmed and extended in a second trial, the STIM trial33: 100 patients were
enrolled, median follow-up 17 months, 69 patients with at least 12 months follow-up: 42
(61%) of these 69 patients relapsed (40 before 6 months, one patient at month 7, and one at
month 19). At 12 months, the probability of persistent CMR for these 69 patients was 41%
(95% CI 29-52). All patients who relapsed responded to reintroduction of imatinib. An
increase of the CMR rate could possibly translate in a higher proportion of patients
candidate to stopping anti-CML treatment, with higher probability of remaining disease-free
in the long term. Interestingly, dasatinib was able to induce higher 36-month cumulative MR4
and MR4.5 rates than imatinib7. The advantages of this possible future scenario could be:
first, the possibility of treatment discontinuation at least in patients with chronic
clinical adverse events; second, a potential reduction of the costs of TKI treatment (after
the introduction of TKI, the costs of CML treatment is increasing year by year, with the
increasing prevalence of CML patients).
In summary, 1) Most data on second generation TKIs are from company-sponsored studies; 2)
The high rate of study discontinuation observed within the phase III study may influence the
data interpretation; 3) A long-term post-marketing surveillance in large independent trial
is extremely important to confirm the efficacy in a nationwide experience; 4) The
persistence of CMR after TKI discontinuation have been described in selected patients with
"deep" molecular response; 5) A stable CMR is a pre-requisite for treatment discontinuation;
6) A detailed description of the kinetic of the molecular response, potentially related to a
subsequent treatment discontinuation, will be done.
Observational Model: Case-Only, Time Perspective: Prospective
Number of dasatinib permanent discontinuing patients.
The cumulative rate of dasatinib permanent discontinuation by 2 years.
After 2 years from study entry.
Italy: Ethics Committee