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Results of the Randomized Phase IIB ADMIRE Trial of FCR with Or Without Mitoxantrone in Previously Untreated CLL

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Results of the Randomized Phase IIB ADMIRE Trial of FCR with Or Without Mitoxantrone in Previously Untreated CLL Leukemia (2017) 31, 2085–2093 © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 0887-6924/17 www.nature.com/leu ORIGINAL ARTICLE Results of the randomized phase IIB ADMIRE trial of FCR with or without mitoxantrone in previously untreated CLL T Munir1,12, DR Howard2,12, L McParland2, C Pocock3, AC Rawstron4, A Hockaday2, A Varghese1, M Hamblin5, A Bloor6, A Pettitt7, C Fegan8, J Blundell9, JG Gribben10, D Phillips2 and P Hillmen11 ADMIRE was a multicenter, randomized-controlled, open, phase IIB superiority trial in previously untreated chronic lymphocytic leukemia. Conventional front-line 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. Two hundred and fifteen patients were recruited to assess the primary end point of complete remission (CR) rates according to International Workshop on Chronic Lymphocytic Leukemia criteria. Secondary end points 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% confidence interval (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 granulocyte colony-stimulating factor 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 with historical series with intravenous chemotherapy. Leukemia (2017) 31, 2085–2093; doi:10.1038/leu.2017.65 INTRODUCTION been assessed in a phase II clinical trial in which 69 CLL patients Chronic lymphocytic leukemia (CLL) is a lymphoproliferative requiring therapy were given this combination as front-line 6 disorder accounting for 30% of adult leukemia and 25% of non- treatment. This trial reported a complete remission (CR) rate of Hodgkin lymphoma. CLL is the commonest form of leukemia 64% with minimal residual disease (MRD)-negativity rate of 26% above the age of 50 years with a median age of diagnosis of 70 and overall response rate (ORR) of 90%. The same group reported years. The treatment of CLL is tailored around the physical state of the combination of FCM-R in 72 previously untreated patients the patient owing to toxicity associated with the chemotherapy- resulting in an ORR of 93% and a CR rate of 82% of which 46% based treatments. achieved an MRD-negative CR7 that appeared higher than CLL is still an incurable disease, and most patients will expected for FCR. FCM-R has also been reported in patients with eventually become resistant to treatment. For physically fit relapsed/refractory CLL. Two trials involving 60 and 29 patients patients, combination chemoimmunotherapy in the form of with relapsed refractory CLL reported an ORR with FCM of 78% fludarabine, cyclophosphamide and rituximab (FCR) has become and 79%, respectively, with 30 (50%) and 9 (32%) patients, the standard of care based on evidence from large randomized achieving a CR.8,9 We previously reported a randomized phase II controlled and non-randomized trials.1–3 Updated analysis sug- trial of 52 patients with relapsed CLL, with ORR with FCM and gested an improvement in progression-free survival (PFS) and FCM-R of 58% and 65%, respectively,10 and an acceptable toxicity overall survival (OS) in patients treated with FCR over FC.1 Hence, profile. Eight (15.4%) patients in this trial achieved MRD negativity. this combination is considered to be the gold-standard first-line The ADMIRE (Does the ADdition of Mitoxantrone Improve treatment in patients deemed to be suitable for fludarabine-based REsponse to FCR chemotherapy in patients with CLL?) trial was treatment. designed to assess whether the addition of mitoxantone to FCR The addition of mitoxantrone to fludarabine-based therapy has increases the depth of response in previously untreated patients been found to induce high response rates in a variety of with CLL requiring therapy in comparison to the standard FCR lymphoproliferative disorders, including follicular non-Hodgkin treatment. The current literature suggests that patients who lymphoma4 and mantle cell lymphoma.5 The addition of respond to therapy and do not have detectable CLL by extremely mitoxantrone to fludarabine and cyclophosphamide (FCM) has sensitive techniques have a significantly prolonged survival.11–13 1Department of Haematology, St James’s University Hospital, Leeds, UK; 2Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK; 3Haematology, East Kent Hospitals, Canterbury, UK; 4Haematological Malignancy Diagnostic Service, St James’s University Hospital, Leeds, UK; 5Haematology, Colchester Hospital University NHS Foundation Trust, Colchester, UK; 6Haematology, The Christie NHS Foundation Trust, Manchester, UK; 7Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK; 8Haematology, University Hospital of Wales, Cardiff, UK; 9Haematology, Royal Cornwall Hospital, Cornwall, UK; 10Barts and The London NHS Trust, London, UK and 11Section of Experimental Haematology, Leeds Institute of Cancer and Pathology (LICAP), University of Leeds, Leeds, UK. Correspondence: Professor P Hillmen, Section of Experimental Haematology, Leeds Institute of Cancer and Pathology (LICAP), University of Leeds, Leeds, UK. E-mail: peter.hillmen@nhs.net 12These authors contributed equally to this work. Received 30 September 2016; revised 24 November 2016; accepted 29 November 2016; accepted article preview online 20 February 2017; advance online publication, 28 April 2017 ADMIRE: FCR with or without mitoxantrone in CLL T Munir et al 2086 − MRD with a sensitivity of 10 4 has become an important end and acyclovir were given throughout the treatment. Secondary prophylaxis point in the treatment of CLL especially in the era of with granulocyte colony-stimulating factor (G-CSF) was recommended for chemoimmunotherapy. Indeed, attainment of MRD negativity patients experiencing scheduled delays due to neutropenia. Appropriate after therapy is a desirable goal as this results in improvement dose reductions were recommended in patients with therapy-related of PFS and OS.14,15 Therefore, one of the key secondary cytopenias. objectives was to compare MRD negativity within each treatment Participants were assessed for response at 3 months post-treatment and at 12, 18 and 24 months post-randomization in the absence of disease group. progression requiring treatment. Long-term annual follow-up for survival is being performed until death. PATIENTS AND METHODS Trial design End points ADMIRE was a multicenter, randomized, controlled, open-label, parallel- The primary end point was CR rate (including CR with incomplete marrow recovery (CRi)) at 3 months post-treatment. Response was centrally group, phase IIB superiority trial assessing FCR (control) vs FCM-R 16 (experimental) for previously untreated patients with CLL requiring assessed according to IWCLL criteria by two independent, experienced treatment by IWCLL (International Workshop on Chronic Lymphocytic CLL hematologists blinded to treatment allocation. An independent arbiter Leukemia) criteria.16 Patients were randomly allocated via a central reviewed discordant reports. computer-generated minimization programme that incorporated a ran- Secondary end points at 3 months post-treatment included: MRD dom element 1:1 to receive oral fludarabine, cyclophosphamide and negativity assessed in the bone marrow by highly sensitive multiparameter fl o intravenous rituximab with or without intravenous mitoxantrone. Rando- ow cytometry with a level of detection 1 CLL cell in 10 000 13 fi mization was stratified to ensure balance for center, Binet stage leukocytes; ORR de ned as at least partial remission (PR); and safety ⩽ 4 and toxicity as graded by CTCAE (Common Terminology Criteria for (Progressive A or B, C), age group ( 65, 65 years) and sex. 18 The primary objective of the trial was to assess whether the Adverse Events) V3.0. addition of mitoxantrone to FCR improved CR rates in patients with Longer-term secondary end points included PFS, OS and time to MRD previously untreated CLL. The results would be used to determine relapse in participants who became MRD negative. whether a larger randomized phase III trial to formally assess survival was appropriate. Sample size An independent Data Monitoring Committee (DMC) was established The sample size was based on testing the null hypothesis of no difference to review the safety and ethics of the trial. The DMC reviewed in CR rates between the treatment groups. The CR rate with FCR was unblinded safety data on a 6-monthly basis and unblinded safety and estimated to be 50%, with a clinically important improvement considered trial progress reports on an annual basis. The DMC reported to an to be 20%. With a two-sided 5% level of significance and 80% power, 103 established trial steering committee (TSC) that provided general over- participants were required in each group.
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