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.
- Patients randomized 1:1; FCR or FCM-R repeated for 28 days, up to six cycles
- Fludarabine 24mg/m 2/day and cyclophosphamide 150mg/m 2/day orally for D1–5 of each cycle
- Rituximab 375mg/m 2IV on D1 of Cycle 1 and 500mg/m 2IV in Cycles 2–6
- Mitoxantrone 6mg/m 2IV on D1
- Patients who received 6 cycles = 82 (76.6%) FCR vs72 (66.7%) FCM-R
- Patients who received ≤3 cycles = 11 (10.3) FCR vs13 (12.0%) FCM-R
- PR = 93/107 (86.9%) FCR vs98/108 (90.7%) FCM-R
- In formal analysis, ORR = 93/96 (96.9%) FCR vs98/101 (97.0%) FCM-R (difference, 0.15%; 95% CI, -4.6 to -5.0%)
- CR = 67/96 pts (69.8%) FCR vs70/101 (69.3%) FCM-R (adjusted OR, 0.97; 95% CI, 0.53–1.79; P= 0.932)
- Pts were significantly more likely to achieve a CR if they received >3 cycles of treatment = 135/183 (73.8%) >3 cycles vs2/14 (14.3%) ≤3 cycles (difference, -59.5%; 95% CI, -78.9 to -40.1%)
- MRD negativity = 54/91 (59.3%) FCR vs47/93 (50.5%) FCM-R (adjusted OR, 0.70; 95% CI, 0.39–1.26; P= 0.231)
- No significant difference between FCR and FCM-R for PFS: mean PFS (up to a restricted time of 72 months post-randomization) = 51.7 vs3 months, respectively (Parameter estimate, 0.48; SE, 3.23; P= 0.8823)
- HR not significant in adjusted Cox regression model for OS (HR, 0.75; 95% CI, 0.41–1.39; P= 0.03596)
- Serious Adverse Events (SAEs) = 41.9% FCR pts vs5% FCM-R pts
- Hospitalization for SAE = 43 (41.0%) FCR vs49 (45.8%) FCM-R
- Serious Adverse Reactions (SARs) = 55 events in 36 (34.3%) FCR pts vs61 events in 40 (37.4%) FCM-R pts
- Grade 3–4 AEs = 15.9% FCR vs2% FCM-R
- TRM mortality reported within 3 months of end of treatment in 1 FCR patient
- Secondary cancer = 19 (18.1%) FCR vs20 (18.7%) FCM-R
- The most common secondary cancers were non-melanoma skin cancers (6.1%; n=13), non-hematological solid tumors (5.7%; n=12)
- Two cases of Myelodysplastic Syndrome, one in each treatment arm
At the time of analysis, 4 years after randomization of the last participant, 42 (19.5%) patients had died: 24 (22.4%) FCR vs18 (16.7%) FCM-R. A total of 89 (41.4%) patients had progressed or died: 44 (41.1%) FCR vs45 (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 ( versushistorical 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.