Trial Information

Front-line Nilotinib Treatment of BCR-ABL+ Chronic Myeloid Leukaemia in Chronic Phase. An Observational Multicentre Study of the GIMEMA CML WP.

The primary objective of the study is to describe the stability of molecular response with
NIL as frontline therapy in newly diagnosed, unselected, CP CML patients, in an independent,
investigator-initiated observational study. Imatinib mesylate (IM), 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)1,2. Nilotinib (NIL) is a second
generation TKI, effective in IM-resistant and IM-intolerant patients, which demonstrated
superior efficacy to IM in early CP BCR-ABL+ CML patients3. Currently, the most important
target of the treatment of CML with TKIs is the major molecular response (MMR), defined as a
≥ 3 log reduction in BCR-ABL/ABL transcript level, marker of better long-term outcome. With
imatinib therapy, achieving a MMR correlates with an improved probability of a durable
cytogenetic remission30. Results from IRIS suggest that a MMR after 12 months of imatinib
therapy may be a marker of stable response. Further on, the IRIS study showed that patients
with a MMR after 12 months of therapy had a significantly better probability of disease-free
survival compared with those in complete cytogenetic remission, but not in MMR31. Moreover,
obtaining an undetectable BCR-ABL transcript level 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, 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. 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). Standardized molecular monitoring has become widely available
in Europe through the efforts of EUTOS cooperation19 and now allows for the generation of
comparable data on the residual disease using recalculation on the international scale
despite these data being analyzed in many different laboratories. These advances in the
standardization of molecular responses and the improvement of targeted therapy have allowed
for comparable response assessment across Italian Centres and early treatment optimization
of patients.

In summary, 1) monitoring of molecular response and of deep and sustained molecular
response, provides a straightforward opportunity to assess patients' response and possible
prognosis in the use of targeted therapy. 2) Most data on second generation TKIs are from
company-sponsored studies generally implemented in selected referral centres. 3) The
detailed description of the kinetic of the molecular response and, particularly, the rate of
stable MR4, potentially related in turn with a subsequent treatment discontinuation, within
the frame of a long-term post-marketing surveillance observational trial offered to all
eligible patients followed at a nation-wide, independent multicentre group is the core
distinctive feature of this observational trial.