MULTICENTER TRIAL ESTIMATING THE PERSISTANCE OF MOLECULAR REMISSION IN CHRONIC MYELOID LEUKAEMIA AFTER STOPPING TKI

Before the imatinib era, the FI-LMC group published data on the possibility of
stopping IFNα after CCyR achievement in 15 patients in CP or AP at diagnosis
(Mahon et al. 2002). Without treatment 7 (47%) of 15 patients remained in CCyR
after a median observation time of 36 months (6-105). Persistant CCyR rate
without treatment was clearly higher in case of CCyR for at least 2 years
before stopping IFN-alpha. Formerly, RTQPCR technics were not available, so it
was impossible to know if patients were in MMR or CMR as defined today.
Some clinical cases of patients in CMR (old/own definition) who stopped
imatinib on their own decision were published.
In three small studies (Cortes et al. 2004; Mauro et al. 2004; Merante et al.
2005), 9 patients stopped imatinib after IFN-alpha failure or after first line.
Six relapsed either cytogenetically or molecular. All responded to imatinib
after relapse with at least a CCyR. Three were still in remission at last
observation. Kim et al. stopped imatinib for 23 CML-CP patients, accelerated or
blastic, or from failure after HSC transplant. All of them were in CCyR after
median duration of 13 months, but only 9 were in complete molecular remission
(Kim et al. 2004). 20 patients had a cytogenetic relapse and 5 of them resumed
treatment with success. It is quite difficult to draw conclusions from these
limited experiences. However, all patients who relapsed after stopping imatinib
were again sensitive to the imatinib.

The FI-LMC group reported results of a pilot study in 12 patients with stable
CMR for at least 2 years under treatment (Rousselot et al. 2007) who
discontinued imatinib treatment. Six of them relapsed during the first 6 months
and 6 are still in CMR with median follow up of 42 months (36 to 49 months).
All of these patients were previously treated with IFNα.
The multicenter STIM study was started to confirm these promising results in a
prospective study and to select patients under imatinib for at least 3 years
and with stable CMR for at least 2 years. 100 patients were enrolled between
2007 and 2009. In the preliminary analysis the median follow-up was 17 months
(range 1-30), and 69 patients had at least 12 months follow-up (median 24
months, range 13-30). 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: 16 of the 42
patients who relapsed showed decreases in their BCR-ABL levels, and 26 achieved
CMR that was sustained after imatinib restart (Mahon et al. 2010).

A more recent analysis was performed on 100 pts (48 men, 52 women) and the
median follow up was 30 months (range 9-45) with a mean of 30 months. After
imatinib was discontinued, a molecular relapse occurred in 61 pts with 58
relapses occurring during the first 7 months and 3 late relapses at month 19,
20 and 22, respectively. The overall probability of maintenance of CMR at 24
and 36 months was 39% (95% CI 29-48). We confirmed that all patients were
sensitive to an imatinib re-challenge. Among the 11 pts with high sokal score
10 relapsed. The probability to be in stable CMR after discontinuation was
significantly better for the low risk group (55% at 24 months, p<0.001) as
compared to intermediate and high risk group. Using multivariate analysis, we
confirmed that Sokal risk score (low vs intermediate vs high; p=0.0009) and
Imatinib therapy duration (<60 months vs >=60 months p=0.0183) were 2
independent prognostic factors for prediction of molecular relapse after
imatinib cessation. Taking into account the cost of imatinib and the number of
months without treatment in the total study population, the savings within the
STIM trial were estimated at 4 millions Euros.

There are a lot of open questions which should/will be answered with the curent
EUROSKI study. The identification of patients who would benefit most from
discontinuation of imatinib remains a key issue. So far, only limited
experience is available with nilotinib or dasatinib (Rea et al. 2011).
Recently it has been demonstrated that second generation TKI may be safely
discontinued in CML patients with a stable CMR. (Rea et al. 2011) In a
preliminary study 12 patients (7 women / 5 male ) with a minimum follow-up 6
months (median 12 months , range, 7-18) were reported (dasatinib n=8, nilotinib
n=4 for imatinib intolerance). The median duration of therapy was 50 months
(range, 3-92). 4/12 of patients lost MMR by 6 monthsFour among the 12 patients
lost MMR by 6 months. (MMR was rapidly regained upon early 2G-TKI
re-introduction). Treatment was also re-started in one patient with CMR loss
(on 2 consecutive assessments). 7pts remained off therapy at the last follow-up
after a median of 11 months (range, 7-18), with either a stable CMR or weakly
detectable BCR-ABL transcripts on one or more occasions.

A longer follow-up and higher number of such patients will be required to
ascertain whether CML will recur and but it seems that the loss of MMR is a
most accurate and robust criteria for restarting imatinib after imatinib
discontinuation

Evaluation of molecular relapse-free survival after stopping TKI (survival
without molecular relapse defined by BCR-ABL1 > 0.1% on the IS at one time
point (loss of major molecular response, MMR))

Multicenter study, prospective, open label, uncontrolled

no risks. Burden in ther first year: once a month: hospital visit and
bloodcollection