Assessment of ibrutinib plus rituximab in front-line CLL (FLAIR trial): study protocol for a phase III randomised controlled trial.

BACKGROUND: Treatment of chronic lymphocytic leukaemia (CLL) has seen a substantial improvement over the last few years. Combination immunochemotherapy, such as fludarabine, cyclophosphamide and rituximab (FCR), is now standard first-line therapy. However, the majority of patients relapse and require further therapy, and so new, effective, targeted therapies that improve remission rates, reduce relapses, and have fewer side effects, are required. The FLAIR trial will assess whether ibrutinib plus rituximab (IR) is superior to FCR in terms of progression-free survival (PFS). METHODS/DESIGN: FLAIR is a phase III, multicentre, randomised, controlled, open, parallel-group trial in patients with previously untreated CLL. A total of 754 participants will be randomised on a 1:1 basis to receive standard therapy with FCR or IR. Participants randomised to FCR will receive a maximum of six 28-day treatment cycles. Participants randomised to IR will receive six 28-day cycles of rituximab, and ibrutinib taken daily for 6 years until minimal residual disease (MRD) negativity has been recorded for the same amount of time as it took to become MRD negative, or until disease progression. The primary endpoint is PFS according to the International Workshop on CLL (IWCLL) criteria. Secondary endpoints include: overall survival; proportion of participants with undetectable MRD; response to therapy by IWCLL criteria; safety and toxicity; health-related quality of life (QoL); and cost-effectiveness. DISCUSSION: The trial aims to provide evidence for the future first-line treatment of CLL patients by assessing whether IR is superior to FCR in terms of PFS, and whether toxicity rates are favourable. TRIAL REGISTRATION: ISRCTN01844152 . Registered on 8 August 2014, EudraCT number 2013-001944-76 . Registered on 26 April 2013.

Clinical effectiveness and cost-effectiveness results from the randomised, Phase IIB trial in previously untreated patients with chronic lymphocytic leukaemia to compare fludarabine, cyclophosphamide and rituximab with fludarabine, cyclophosphamide, mitoxantrone and low-dose rituximab: the Attenuated dose Rituximab with ChemoTherapy In Chronic lymphocytic leukaemia (ARCTIC) trial.

BACKGROUND: The conventional frontline therapy for fit patients with chronic lymphocytic leukaemia (CLL) is fludarabine, cyclophosphamide and rituximab (FCR). Rituximab (Mabthera®, Roche Products Ltd) targets the CD20 antigen, which is expressed at low levels in CLL. The standard dose of rituximab in CLL (375 mg/m2 in cycle 1 and 500 mg/m2 in cycles 2-6) was selected based on toxicity data only. Small doses of rituximab (as low as 20 mg) have biological activity in CLL, with an immediate reduction in circulating CLL cells and down-regulation of CD20. Phase II trials had suggested improved efficacy with the addition of mitoxantrone to FCR. The key assumption for the Attenuated dose Rituximab with ChemoTherapy In CLL (ARCTIC) trial was that the addition of mitoxantrone to fludarabine, cyclophosphamide and low-dose rituximab would be more effective than conventional FCR. OBJECTIVES: To assess whether fludarabine, cyclophosphamide, mitoxantrone and low-dose rituximab (FCM-miniR) (100 mg of rituximab per cycle) was non-inferior to FCR in frontline CLL. Complete response (CR) rate was the primary end point, with the secondary end points being progression-free survival (PFS), overall survival (OS), overall response rate, eradication of minimal residual disease (MRD), safety and cost-effectiveness. DESIGN: ARCTIC was a UK multicentre, randomised, controlled, open, Phase IIB non-inferiority trial in previously untreated CLL. A total of 206 patients with previously untreated CLL who required treatment, according to the International Workshop on Chronic Lymphocytic Leukaemia criteria, were to be randomised to FCR or FCM-miniR. There was an independent Data Monitoring and Ethics Committee (DMEC) with a pre-planned interim efficacy assessment on 103 participants. RESULTS: The DMEC's interim analysis led to early trial closure. Although the response rates in both arms were higher than anticipated, FCM-miniR had a lower CR rate than FCR. This was partly attributable to the higher toxicity associated with mitoxantrone. A total of 100 participants completed FCR, 79 completed FCM-miniR and 21 commenced FCM-miniR but switched to FCR following DMEC recommendations. The CR rate for participants receiving FCR was 76%, compared with 55% for FCM-miniR (adjusted odds ratio 0.37; 95% confidence interval 0.19 to 0.73). Key secondary end points also showed that FCR was superior, with more participants achieving MRD negativity (57% for FCR vs. 46% for FCM-miniR). More participants experienced a serious adverse reaction with FCM-miniR compared with FCR (50% vs. 41%). At a median of 37.3 months' follow-up, the PFS and OS rates are good compared with previous studies, with no significant difference between the treatment arms. The economic analysis indicates that because FCM-miniR is less effective than FCR, FCM-miniR is not expected to be cost-effective over a lifetime horizon, producing a mean cost-saving of -£7723, a quality-adjusted life-year loss of -0.73 and a resulting incremental net monetary loss of -£6780. CONCLUSIONS: FCM-miniR is less well tolerated, with poorer response rates, than FCR, partly owing to the additional toxicity associated with mitoxantrone. In view of this, FCM-miniR will not be taken forward into a larger definitive Phase III trial. The trial demonstrated that oral FCR yields extremely high response rates compared with historical series with intravenous chemotherapy. FUTURE WORK: We shall compare the results of ARCTIC with those of the ADMIRE (Does the ADdition of Mitoxantrone Improve Response to FCR chemotherapy in patients with CLL?) trial, which compared FCR with FCM-R to assess the efficacy of low- versus standard-dose rituximab, allowing for the toxicity associated with mitoxantrone. TRIAL REGISTRATION: Current Controlled Trials ISRCTN16544962. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 28. See the NIHR Journals Library website for further project information.

Assessment of minimal residual disease in myeloma and the need for a consensus approach.

Treatment options for myeloma continue to develop at a rapid pace, and it is becoming increasingly challenging to determine the optimal therapeutic approaches because demonstrating a clear survival benefit now requires many years of follow-up. The detection of minimal residual disease (MRD) is recognized as a sensitive and rapid approach to evaluate treatment efficacy that predicts progression-free and overall survival independent of categorical response assessment and patients' biology. The benefit of MRD analysis is reflected in the many different techniques (multiparameter flow cytometry, quantitative polymerase chain reaction, and high-throughput sequencing) and collaborative groups (including EMN, ESCCA, ICCS, EuroFlow, and EuroMRD) that have performed collaborative projects to harmonize quantitative MRD detection. The time has come to adopt a consensus approach, and this report reviews the benefits and disadvantages of different strategies for MRD detection in myeloma and highlights the requirements for a sensitive, reproducible, and clinically meaningful cellular analytical approach.

Response assessment in Waldenström macroglobulinaemia: update from the VIth International Workshop.

This report represents a further update of the consensus panel criteria for the assessment of clinical response in patients with Waldenström macroglobulinaemia (WM). These criteria have been updated in light of further data demonstrating an improvement in categorical responses with new drug regimens as well as acknowledgement of the fact that such responses are predictive of overall outcome. A number of key changes are proposed but challenges do however remain and these include the variability in kinetics of immunoglobulin M (IgM) reduction with different treatment modalities and the apparent discrepancy between IgM and bone marrow/tissue response noted with some regimens. Planned sequential bone marrow assessments are encouraged in clinical trials.

Assessment of bone marrow response in Waldenström's macroglobulinemia.

In this study we used bone marrow flow cytometry and immunohistochemistry to evaluate response to fludarabine therapy in patients with Waldenström's macroglobulinemia (WM)/lymphoplasmacytic lymphoma. Responses in serum M protein were typically delayed with a median time to maximum response of 6 months following the completion of therapy (range, 0-18 months). In contrast, bone marrow responses occurred promptly in responding patients such that there were no detectable clonal B cells at the end of therapy in 55% of patients assessed. Persistent monoclonal plasma cells were, however, readily identified by CD138 immunohistochemistry, explaining the persistence of serum M protein in these patients. This simple observation has significant implications for the assessment of responses in WM as well as the design of future therapeutic strategies.

Minimal residual disease assessment in chronic lymphocytic leukaemia.

The concept of minimal residual disease (MRD) eradication in chronic lymphocytic leukaemia (CLL) is a relatively new one, as conventional therapy with alkylating agents is relatively ineffective and responding patients almost always have a significant tumour burden remaining at the end of treatment. However, a variety of novel therapies is now yielding higher response rates, and responses of better quality are now routinely achieved. This progress in therapy has been paralleled by an improvement in laboratory assays, allowing detection of CLL cells to levels as low as ten CLL cells in a million leukocytes. In this chapter we briefly review the existing methods for MRD assessment, the clinical relevance of MRD eradication in CLL, and the therapies available to attain this endpoint.

CD52 expression in Waldenstrom's macroglobulinemia: implications for alemtuzumab therapy and response assessment.

The efficacy of monoclonal antibody therapy is determined, at least in part, by the extent to which the target antigen is expressed. This is a complex issue in Waldenstrom's macroglobulinemia (WM) as it is a disorder characterized by plasma cell differentiation and therefore target antigen expression may differ between the B-cell and plasma cell compartments of the disease. In order to assess this in the context of alemtuzumab therapy, the authors used multiparameter flow cytometry to determine CD52 expression in the B-cells and plasma cells of patients with WM. CD52 expression was demonstrable in the B-cells of all cases, with a median of 99% of cells (range, 81%-100%) expressing the antigen compared with the isotype control (n = 47). Antigen density was very similar to that seen in chronic lymphocytic leukemia (median mean fluorescence intensity [MFI], 1249; range, 175-3170). Antigen expression was, however, significantly lower in the plasma cells (median MFI, 235; range, 31-1814) in all but 1 of the cases assessed (n = 21). The clinical significance of this was assessed by examining serial bone marrow samples from patients receiving alemtuzumab as part of an ongoing clinical trial. In 4 of 5 patients, alemtuzumab therapy successfully eradicated clonal B-cells from the bone marrow, but residual plasma cells remained evident in 2 of these patients. The implications of these findings for monoclonal antibody therapy in WM are discussed.