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BackgroundThe 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/m2in cycle 1 and 500 mg/m2in 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.ObjectivesTo 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.DesignARCTIC 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.ResultsThe 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.ConclusionsFCM-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 workWe 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 registrationCurrent Controlled Trials ISRCTN16544962.FundingThis project was funded by the NIHR Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 21, No. 28. See the NIHR Journals Library website for further project information.

Introduction FCR improves PFS and OS in CLL. Previous non-randomised Phase II trials suggest adding mitoxantrone to FCR (FCM-R) improves outcomes. The rituximab dose in CLL was inferred from lymphoma but in CLL even low doses of rituximab lead to the loss of CD20 expression (“shaving”) suggesting that low dose rituximab with chemotherapy may be effective. Aims The primary objective was to assess whether the CR rate to FCM-miniR was not inferior to FCR. Secondary objectives were MRD eradication, overall response rates and safety. Late endpoints (not reported) were PFS, OS and MRD relapse. Methods ARCTIC was a phase IIB, randomised, controlled, parallel group trial in previously untreated CLL performed in 34 UK centres. 206 patients were to be randomised to FCR or FCM-miniR with an 80% power to show that FCM-miniR did not lead to 10% worse CR rates compared to FCR. A formal interim analysis on the primary endpoint was planned after 103 patients. The schedule for oral FCR was equivalent to iv FCR with iv rituximab given on Day 1 (375mg/m2 Cycle 1; 500mg/m2 Cycles 2-6), oral fludarabine (24mg/m2/day for 5 days; Days 1-5) and oral cyclophosphamide (150mg/m2/day for 5 days; Days 1-5). FCM-miniR included intravenous mitoxantrone (6mg/m2/day) and 100mg rituximab on Day 1 of 6 cycles given 28 days apart. Patients with neutropenia delaying therapy received G-CSF (lenograstim 263mcg/day; Days 7-13) on all remaining cycles. Prophylaxis with co-trimoxazole and acyclovir was used. Results 200 patients were recruited, 100 to each arm. The interim analysis after 103 patients indicated that although the CR rate to FCM-miniR was similar to predicted it was inferior to FCR. The independent DMC advised that the trial would not show non-inferiority for FCM-miniR and recruitment was stopped. A further 97 patients were recruited up to the interim analysis. 21 patients still receiving FCM-miniR were advised to cross-over to FCR. 100 patients received FCR, 79 FCM-miniR and 21 patients randomised to FCM-miniR crossed over to FCR. The treatment arms were well balanced for the following: median age 63 (36-80) and 20% (n=40) over 70; 67.5% male; 17% prog. stage A, 47% stage B and 35.5% stage C. 33.5% had a creatinine clearance under 70ml/min. 60% (87/146) had unmutated Ig genes; 4% (6/164) 17p deletion; and 15% (26/168) 11q deletion. More 11q del patients were randomised to FCM-miniR (15 vs 7). 29.5% (59/200) discontinued therapy early including 30% (n=30) FCR and 35.4% (n=28) FCM-miniR. 141 (70.5%) completed 6 cycles. 93 (49%) of 189 received G-CSF - more with FCM-miniR compared with FCR (54% vs 44%). 117 (58.5%) patients experienced a dose modification; 57% for FCR and 62% for FCM-miniR; the most common being dose delay in 47% of patients. 181 SAE's were reported from 104 patients; 79 events from 49% (49/100) receiving FCR, 80 from 58% (46/79) receiving FCM-miniR and 47% (9/22) cross-over patients. 62.5% of related SAE's were infectious. 3 patients died due to an SAE, 1 FCR and 2 FCM-miniR. We report only the 179 intention-to-treat patients who did not cross-over. To date 146 of 179 patients (82%) have undergone independent central review. 70% (102/146) achieved a CR or CRi; 78% (62/79) FCR and 60% (40/67) FCM-miniR. 13/22 (59%) patients with a baseline creatinine clearance of Conclusion ARCTIC was stopped prematurely as it was clear that the arm containing mitoxantrone and low dose rituximab would not be non-inferior to FCR. However both FCR and FCM-miniR performed well with CR rates of 78% and 60% respectively. This compares favourably to CR rates of 38% for FC in LRF CLL4 Trial and 44% for FCR in the GCLLSG CLL8 Trial. MRD was undetectable in 55% of patients receiving FCR and 46% for FCM-miniR. Oral FCR in front-line CLL results in extremely high CR rates and the eradication of detectable MRD in the majority. Low dose rituximab (100mg per cycle; 600mg total dose compared to 2875mg/m2 for standard FCR) in combination with FCM appears to be effective although FCM-miniR is inferior to full dose FCR. However there is more toxicity associated with the addition of mitoxantrone confounding the comparison of rituximab doses. Disclosures: Hillmen: Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche Pharmaceuticals: Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Celgene: Honoraria. Off Label Use: The use of ofatumumab in combination with chlorambucil in previously untreated CLL. The reported trial will support the extension of the ofatumumab licence. Schuh:GSK: Honoraria; Celgene: Honoraria; Mundipharma: Honoraria.

Background: The detection of minimal residual disease (MRD) in CLL using a 0.01% cut-off is an independent predictor of progression-free (PFS) and overall survival (OS) after chemo-immunotherapy. There are several new treatments available and using MRD as a trial endpoint could greatly speed up the identification of the best treatment approaches. MRD assessments can be made in the peripheral blood (PB) or bone marrow (BM) but there is substantial variation in the extent to which different treatments deplete disease in the PB, BM, and nodal compartments. Aims: To compare MRD levels in the PB & BM during/after different treatment approaches to determine differential compartment effects and evaluate the impact on predicting PFS/OS. Methods: The level of residual disease was determined using multi-parameter flow cytometry according to ERIC consensus protocols with a limit of quantification of 10-4 / 0.01% or better; "+" and "-" denotes ≥0.01% and Results: The MRD level in PB & BM samples taken at the same time, either during or within 6 months of treatment, was available in 556 cases of which 85 (15%) showed discordant results at the 0.01% threshold. The frequency of discrepant PB & BM MRD levels varied across treatment and patient groups (table 1). In 322 evaluable cases from the ADMIRE/ARCTIC trials at 3 months after the end FCR-based therapy, 66/322 were BM+PB-, representing 54% of the total MRD+ cases. Discrepant results with >1 log difference between PB & BM MRD levels were most common in refractory patients treated with alemtuzumab. There were no discrepant results in patients undergoing idelalisib or ibrutinib monotherapy although all patients have ≥0.01% MRD to date. A small compartment effect was apparent in patients treated with a combination of ibrutinib and obinutuzumab but the relative difference in PB vs. BM disease level appears to be approximately half that of rituximab in combination with chemotherapy. To determine whether the discrepant results affect the ability of MRD status to predict outcome, we compared the PFS according to BM & PB MRD status. In the CLL202 (fludarabine + alemtuzumab) trial the PFS for BM+PB- cases was similar to BM+PB+ cases (median PFS was 1.6 and 6.5 months respectively) and both were substantially shorter than for BM-PB- cases (median PFS 44.7 months, Log-rank P66 months vs. 54 months vs. 33 months for BM-PB- vs. BM+PB- vs. BM+PB+ respectively, Log-rank P1% MRD in the PB also had >1% disease in the BM. Summary/Conclusion: The compartment effect varies greatly according to patient group and treatment. Rituximab typically results in 0.7log lower disease in the PB compared to BM. Patients on BCR-pathway inhibitors have similar levels of disease in PB & BM even in combination with obinutuzumab. This suggests either that BCR-pathway inhibitors counteract the compartment effects of anti-CD20 antibody treatment, or that obinutuzumab is more effective in depleting bone marrow disease than rituximab. Peripheral blood MRD status may be appropriate for predicting outcome in some settings but underestimates MRD level in a substantial proportion of patients. Bone marrow remains the most sensitive and reliable source for MRD detection but is not required if there is >1% MRD in the blood. Evaluating the compartment effect of specific treatment combinations will help to identify approaches to achieve maximal MRD response using peripheral blood monitoring. Table 1 Compartment effect - difference in MRD detection in PB vs. BM samples across different trials. * median log difference only calculated in cases with >0.01% MRD in both PB & BM so may underestimate compartment effect. Table 1. Compartment effect - difference in MRD detection in PB vs. BM samples across different trials. / * median log difference only calculated in cases with >0.01% MRD in both PB & BM so may underestimate compartment effect. Disclosures Rawstron: AbbVie: Honoraria; Roche: Honoraria; Celegene: Honoraria; Janssen: Research Funding; BD Biosciences: Other: Remuneration; Gilead: Consultancy, Honoraria, Research Funding; Genzyme: Honoraria; GlaxoSmithKline: Honoraria. Munir:Alexion pharmaceuticals: Honoraria. Brock:AstraZeneca: Equity Ownership; GlaxoSmithKline: Equity Ownership. Hillmen:Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Research Funding.

BACKGROUND: Minimal residual disease (MRD) in CLL is an independent predictor of progression-free and overall survival after chemo-immunotherapy. Data from the DCLLSG trials indicate that a high, intermediate and low risk of disease progression is seen in patients with >1%, 0.01-1%, or AIM: To apply the ERIC consensus 1-tube multiparameter MRD strategy prospectively in two UK clinical trials of FCR-based treatment (ADMIRE and ARCTIC) to determine the survival benefit per log depletion. METHODS: The level of residual disease was determined using multi-parameter flow cytometry according to the ERIC consensus protocol with a limit of quantification of 10-4 / 0.01% or better on 415 patients at 3 months after end of treatment. RESULTS: The level of MRD at end of treatment was a powerful predictor of PFS and OS independent of age, stage, IWCLL response, FISH and IGHV mutation status. Per log reduction in CLL level, the hazard of disease progression decreased by 33% (95%CI 27-38%) and the hazard of dying decreased by 22% (95%CI 13-29%). Although there were statistically significant improvements per log reduction, the DCLLSG 2-log model showed more meaningful differences in outcome over the period of follow-up. The median PFS for patients with >1% vs. 0.01-1% vs 1% MRD predicts equivalent or worse outcome than a clinical PR. PB MRD analysis at 18 months after randomisation (~1 year after treatment) was also strongly predictive of outcome: 98% of patients with CONCLUSIONS: Prospective enumeration of MRD using the ERIC consensus 1-tube multiparameter protocol confirms that MRD at end of treatment is a powerful independent predictor of progression-free and overall survival. Post-treatment follow-up using peripheral blood MRD could be more informative than clinic assessments because patients with 1% MRD at end of treatment in the peripheral blood have a similar outcome to those with a clinical PR and a bone marrow assessment is not informative in these cases. The level of MRD is highly informative with sequential improvements in outcome per log depletion. The DCLLSG 2-log categorisation (>1%, 0.01-1%, or 6yrs. Figure 1. the level of MRD in the bone marrow at 3 months after treatment is highly predictive of outcome with >1% MRD equating to 5yrs median PFS Figure 1. the level of MRD in the bone marrow at 3 months after treatment is highly predictive of outcome with >1% MRD equating to 5yrs median PFS Figure 2. sequential PB MRD analysis identifies patients with negligible risk of requiring treatment within the following 12 months. Figure 2. sequential PB MRD analysis identifies patients with negligible risk of requiring treatment within the following 12 months. Disclosures Rawstron: BD Biosciences: Patents & Royalties; Roche: Honoraria; Celgene: Honoraria; Abbvie: Honoraria; Gilead: Honoraria, Research Funding; Pharmacyclics: Research Funding. Gregory:Celgene: Honoraria; Janssen: Honoraria. Hillmen:Roche: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Research Funding.

Background: Maximising response in myeloma (MM) patients with effective induction regimens prior to autologous stem cell transplant (ASCT) improves progression-free and overall survival. Triplet regimens combining an immunomodulatory agent (IMiD) and/or proteasome inhibitor (PI) are standard of care, however a more personalised approach is achieved by sequential triplet combinations based on an individual's response. Alternatively, quadruplet regimens may be more effective and new generation PIs such as carfilzomib, with less off-target activity, provide the opportunity to investigate this whilst minimising the risk of increased toxicity. The UK NCRI Myeloma XI trial is a large, phase III study aiming to answer these questions in transplant eligible (TE) patients comparing the quadruplet carfilzomib, cyclophosphamide, lenalidomide and dexamethasone to the sequential strategy of triplet IMiD combinations (with thalidomide or lenalidomide) followed by additional PI triplet therapy for those with a suboptimal response ( Methods: In 2013, the TE pathway was amended to include KCRD: carfilzomib 36mg/m2 IV d1-2,8-9,15-16 (20mg/m2 #1d1-2), cyclophosphamide (cyclo) 500mg PO d1,8, lenalidomide (len) 25mg PO d1-21, dexamethasone (dex) 40mg PO d1-4,8-9,15-16). Patients are randomised to this up-front quadruplet or the sequential strategy of CRD: cyclo 500mg PO d1,8, len 25mg PO d1-21 PO daily, dex 40mg PO d1-4, 12-15 or CTD: cyclo 500mg PO d1,8,15 thalidomide 100-200mg PO daily, dex 40mg PO d1-4,12-15 given to max. response - patients with VGPR/CR proceed straight to ASCT, PR/MR are randomised to sequential CVD: cyclo 500mg d1,8,15, bortezomib 1.3mg/m2 IV/SC d1,4,8,11, dex 20mg PO d1,2,4,5,8,9,11,12 or nothing and SD/PD all receive sequential CVD. All treatments are given to max. response prior to ASCT, after which there is a maintenance randomisation. Patients: 1512 patients entered the TE pathway prior to amendment (756 CRD, 756 CTD). Of these, 201 patients with a suboptimal initial response went on to receive CVD, 142 following randomisation (initial response PR/MR) and 59 with NC/PD. 788 (of target n=1036) patients have been randomised post-amendment to date (394 KCRD, 197 CRD, 197 CTD). Results: TE patients receiving treatment prior to the amendment had response rates ≥VGPR: CRD 58% vs CTD 52%. For patients receiving the sequential triplet CVD due to a suboptimal response this was upgraded to ≥VGPR in 49% of those with initial MR/PR, 27% with NC/PD. This suggests the overall ≥VGPR rate to this treatment approach prior to ASCT would be approx. 75%. This now needs to be compared to the alternative approach of an upfront quadruplet. Comparing patients contemporaneously randomised to initial induction the patients receiving KCRD have completed a median 4 cycles (range 1-7), CRD 5 (range 1-10) and CTD 6 (range 1-9). Dose modifications have been required in 62% of patients receiving KCRD (56% to carfilzomib, 42% to lenalidomide) 44% CRD (40% to lenalidomide) and 65% CTD (59% to thalidomide). Data for study drug related toxicity in patients who have completed at least one cycle of initial induction are shown in table 1. Serious adverse events suspected to be due to trial medications have occurred in 37% on KCRD, 32% CRD and 35% CTD. Updated toxicity and preliminary response analysis on 23/09/15 will be presented at the meeting. This will include a response comparison at the end of initial induction regimen i.e. KCRD vs CRD vs CTD for an anticipated 700 contemporaneous patients who will have completed treatment. Updated response to the sequencing approach (with 250 patients having received sequential CVD) will also be presented and compared. Conclusions: In our study KCRD, an outpatient delivered 4-drug regimen combining second generation IMiD and PI drugs, is well-tolerated in TE NDMM patients, comparable to 3-drug regimens. Data will be presented at the meeting to compare the response rates achieved with the different regimens and treatment approaches. On behalf of the NCRI Haemato-oncology CSG Table 1. Comparative toxicities KCRD n=261 CRD n=143 CTD n=142 % (no. of patients) Peripheral neuropathy Sensory Gr II-IV 1.9 (5) 1.4 (2) 8.5 (12) Motor Gr II-IV 3.1 (8) 1 (1) 5.6 (8) VTE all grades 4.2 (11) 4.9 (7) 5.6 (8) Anaemia Gr III-IV 9.2 (24) 4.2 (6) 5.6 (8) Neutropenia Gr III-IV 14.9 (39) 16.1 (22) 13.3 (19) Thrombocytopenia Gr III-IV 8.4 (22) 1.4 (2) 1.4 (2) Infusion reaction Gr III-IV 0.4 (1) - - Disclosures Pawlyn: Celgene: Honoraria, Other: Travel support; The Institute of Cancer Research: Employment. Off Label Use: Carfilzomib as induction treatment for myeloma Lenalidomide and vorinostat as maintenance treatments for myeloma. Davies:University of Arkansas for Medical Sciences: Employment; Celgene: Honoraria; Onyx-Amgen: Honoraria; Takeda-Milenium: Honoraria. Jones:Celgene: Other: Travel support, Research Funding. Kaiser:Janssen: Honoraria; Chugai: Consultancy; Amgen: Consultancy, Honoraria; BristolMyerSquibb: Consultancy; Celgene: Consultancy, Honoraria, Research Funding. Jenner:Takeda: Honoraria; Amgen: Honoraria. Cook:Jazz Pharma: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Chugai: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Russell:Therakos: Other: shares. Owen:Celgene: Honoraria, Research Funding; Janssen: Honoraria. Gregory:Janssen: Honoraria; Celgene: Honoraria. Jackson:Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Morgan:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; CancerNet: Honoraria; Weisman Institute: Honoraria; MMRF: Honoraria; MMRF: Honoraria; University of Arkansas for Medical Sciences: Employment; Weisman Institute: Honoraria; CancerNet: Honoraria.

e84 In summary, these results indicate that germline mutations in RTKs might be of prognostic relevance in MM.