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An expert panel hosted by
Customizing first-line BTK inhibitors for CLL
with Gilles Salles, Paolo Ghia, and Francesc Bosch
Wednesday, October 23, 2024
18:30-19:30 BST
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Last month, on the 20th February 2017, Leukemia published the results of the phase IIB ADMIRE trial by T. Munir from St. James’s University Hospital, Leeds, UK, and colleagues.
This multi-center, randomized-controlled, open, superiority trial (ISRCTN42165735) investigated whether adding mitoxantrone to FCR increases depth of response compared to standard FCR in treatment naïve CLL patients. The primary endpoint was CR (including CRi) at 3 months post-treatment and secondary endpoints were PFS, OS, ORR, MRD negativity, and safety; results would inform whether a larger, randomized, phase III trial would be appropriate. Between July 2009 and April 2012, 215 patients (median age = 62 years [range, 33–77]) were recruited from 29 institutions across the UK.
At the time of analysis, 4 years after randomization of the last participant, 42 (19.5%) patients had died: 24 (22.4%) FCR vs 18 (16.7%) FCM-R. A total of 89 (41.4%) patients had progressed or died: 44 (41.1%) FCR vs 45 (41.7%) FCM-R.
This trial found that adding mitoxantrone to FCR as first-line therapy for CLL did not improve responses, however marginally increased toxicity, and so the authors stated that “FCM-R will not be taken forward into a larger definitive phase III trial.”
Despite this, the trial found that orally administered FCR, at an equivalent dose to IV FCR, resulted in high response rates (versus historical data) and was tolerated well. The authors hypothesized that the higher response rates may be a result of the oral regime lasting 5 days rather than 3 days for IV and “the duration of therapy exposure per cycle may be critical.”
The authors concluded that FCR remains the gold-standard treatment for patients with CLL considered fit for fludarabine-based regimens.
ADMIRE was a multi-center, randomized-controlled, open, phase IIB superiority trial in previously untreated Chronic Lymphocytic Leukemia (CLL). Conventional frontline therapy in fit patients is fludarabine, cyclophosphamide and rituximab (FCR). Initial evidence from non-randomized Phase II trials suggested that the addition of mitoxantrone to FCR (FCM-R) improved remission rates. 215 patients were recruited to assess the primary endpoint of complete remission (CR) rates according to IWCLL criteria. Secondary endpoints were progression-free survival (PFS), overall survival (OS), overall response rate, minimal residual disease (MRD) negativity and safety. At final analysis, CR rates were 69.8% FCR vs 69.3% FCM-R [adjusted odds ratio (OR): 0.97; 95%CI: (0.53-1.79), P=0.932]. MRD-negativity rates were 59.3% FCR vs 50.5% FCM-R [adjusted OR: 0.70; 95% CI: (0.39-1.26), P=0.231]. During treatment, 60.0% (n=129) of participants received G-CSF as secondary prophylaxis for neutropenia, a lower proportion on FCR compared with FCM-R (56.1 vs 63.9%). The toxicity of both regimens was acceptable. There are no significant differences between the treatment groups for PFS and OS. The trial demonstrated that the addition of mitoxantrone to FCR did not increase the depth of response. Oral FCR was well tolerated and resulted in impressive responses in terms of CR rates and MRD negativity compared to historical series with intravenous chemotherapy. Leukemia accepted article preview online, 20 February 2017. doi:10.1038/leu.2017.65.
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