ALBERT

Description: 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 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 1%, 0.01-1%, or 1% MRD equating to 1% MRD equating to

Description: Introduction Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder. In the last few years several prognostic factors have been shown to identify SMM patients with very high risk of disease progression. Identification of high-risk SMM has assumed greater significance because trials have shown that early therapy can be potentially beneficial to patients. Many risk factors are routinely evaluated in the vast majority of diagnostic centres, such as serum M protein ≥30g/L &/or IgA isotype, immunoparesis, serum involved/uninvolved FLC ratio ≥8 but

Description: Background: Consolidation after high dose therapy and autologous stem cell transplant (ASCT) for multiple myeloma (MM) can improve response depth and prolong progression free survival (PFS), but it is important to ensure good quality of life (QoL) and responsiveness to further salvage therapy. We conducted a single-arm Phase II weekly bortezomib consolidation trial (BCT) to assess outcomes in MM patients receiving upfront ASCT. Methods: Bortezomib-na•ve patients with at least stable disease at 3-4 months post-high dose melphalan 200mg/m2 with ASCT received up to 8 cycles of bortezomib (1.3mg/m2 days 1,8,15,22 in a 4-week cycle), 17 intravenously (IV) and 23 subcutaneously (SC). The primary endpoint was disease response (IMWG) at 6 and 12 months post-ASCT. Other endpoints were MRD by multiparametric flow cytometry (patient 15 onwards) at 6 and 12 months post-ASCT, toxicity, PFS, overall survival, osteoblast function and Qol (EORT-QLQ-C30). Serum basic alkaline phosphatase (bALP) and ostocalcin (OC) were measured by ELISA. Results: The study recruited 40 patients between December 2009 and March 2014 at a median of 3.4 months post-ASCT. The median age was 61 years (range 43-69); 55% male; isotypes were: 22 (59%) IgG, 9 (24%) IgA, 1 (3%) IgD, 5 (14%) light chain only, 1 non-secretory and 2 unknown. Induction regimens pre-ASCT were thalidomide (33, 87%), idarubicin and dexamethasone (5, 13%). and unknown in 2. One patient was withdrawn prior to commencement (unfit for treatment) and 3 patients stopped trial treatment after 1 cycle (2 toxicity, 1 disease progression). Of 36 patients who completed 〉1 cycle of bortezomib, 10 stopped treatment early (5 toxicity, 4 patient choice, 1 disease progression); median number of cycles received was 8. Eleven (28%) patients experienced a total of 15 grade 3 adverse events (AE); 6 (neuropathy, 3 in IV group, 18% cf 3 in SC group, 13%), 4 (infection), 1 (fatigue), 2 (haematological), 2 other. One patient had a grade 4 infection (cycle 1, treatment discontinued) and 1 grade 4 back pain. EORTC-QLQ-C30 scores for global health status and physical, emotional and social functioning did not change significantly throughout treatment. After a median follow up of 44.4 months, 18 (45%) are alive without progression, 20 (50%) are alive with progression and 2 (5%) died after progression. BCT improved response depth in assessable patients who completed 〉1 cycle (n=34). Disease response at trial entry: 4 (12%) sCR/CR, 19 (56%) VGPR, 10 (29%) PR, 1(3%) SD, cf. response at 12 months post-ASCT: 7 (21%) sCR/CR, 22 (65%) VGPR, 4 (12%) PR, 1(3%) PD. Biochemical response depth improved in 12 patients. 19 patients had MRD testing at 3 (where available) or 6 months post-ASCT and again at 12 months, 10 were MRD+ at the earlier time point, of whom 4 converted to MRD- at 12 months. Of the 9 MRD- patients, all remained negative at 12 months. 15 patients (44%) had improvement in biochemical and/or MRD response at 12 months. Median PFS was 38.5 months (95%CI 29.1-47.9)(Figure). Patients who were MRD- at 12 months had median PFS of 49.2 months (95%CI 35.3-63.2) compared with 22.0 months (95%CI 21.5-22.6) in MRD+ patients (p=0.03). Of the 22 patients who relapsed, 12 received bortezomib-based salvage regimens, 5 received carfilzomib-based regimens and 5 have not started second-line therapy. Disease responses in patients receiving bortezomib salvage was 8 (67%) VGPR, 4 (33%) PR. Four patients went on to have a 2nd ASCT. In the 17 patients receiving salvage, median 2nd PFS from start of second line was 14.8 months (95%CI 8.2-18.0). At 3 months post-ASCT, levels of the osteoblast markers bALP and OC were significantly higher in CR/VGPR patients, compared to patients with PR or less (p=0.04 and 0.03, respectively). Neither marker changed significantly following BCT. Conclusions: For patients with MM, consolidation with weekly bortezomib post-ASCT is well tolerated and deepens disease response and MRD negativity without compromising the response to subsequent bortezomib-based salvage therapy. Patients who are MRD- at 12 months enjoy a median PFS of 4 years. This low intensity post-ASCT strategy deserves further study in the context of current and evolving protocols for newly diagnosed patients. Figure Figure. Disclosures Yong: Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: Research Funding.

Description: Introduction. Minimal residual disease (MRD) is a powerful predictor of outcome in multiple myeloma (MM). We have previously demonstrated, in transplant eligible patients, that the level of MRD as a continuous variable independently predicts both PFS and OS, with approximately a one year median OS benefit per log depletion (J Clin Oncol 2013; 31:2540-7 and Blood 2015; 125:1932-5). The impact of MRD also appears to be independent of therapy received. There is more limited data on the applicability of MRD assessment in transplant ineligible patients, largely as a consequence of low rates of CR historically within this patient cohort. Patients and Methods. In this analysis we have assessed the impact of MRD on PFS amongst patients treated within the non-intensive arm of the NCRI Myeloma XI trial. Patients were randomised between thalidomide (CTDa) and lenalidomide (RCDa) based induction therapies with responding patients being subsequently randomised to maintenance with lenalidomide monotherapy, or no further therapy. Bone marrow aspirates were obtained at the end of induction and this analysis represents a subset of 297 patients (median age 74 years). MRD was assessed using flow cytometry (sensitivity 10-4) with a minimum of 500,000 cells evaluated with six-colour antibody combinations including CD138/CD38/CD45/CD19 with CD56/CD27 in all cases and CD81/CD117 in additional cases as required. Results. Overall MRD-negativity was demonstrated in 41/297 (13.8%). When considered according to induction therapy received 25/154 (16.0%) of patients randomized to RCDa were MRD-negative compared to 16/143 (10.8%) of those randomized to CTDa (p=0.24; Fisher's exact test). MRD-negativity was associated with a significant outcome advantage as the median PFS was 34 months versus 18 months for MRD-positive patients (p

Description: Background: A major aim of treatment in CLL is to eradicate detectable minimal residual disease (MRD). Ibrutinib is a major step forward in the treatment of CLL but results in an immediate lymphocytosis that persists in most patients for at least several months. Obinutuzumab is a second generation anti-CD20 monoclonal antibody which appears to be highly effective in CLL resulting in a rapid eradication of peripheral blood lymphocytosis and the eradication of MRD in a proportion of patients. The IcICLLe Extension Study expands on the IcICLLe trial (ISRCTN 12695354) to examine the efficacy and safety of the combination treatment of obinutuzumab and ibrutinib. Patients: The IcICLLetrial recruited 40 participants with CLL requiring treatment (20 treatment-naïve, 20 relapsed/refractory disease) receive continuous ibrutinib therapy until achievement of 20 will have had no prior Ibrutinib treatment (ibrutinib naive), and ≤20 will have received at least 12 months of Ibrutinib monotherapy as part of the IcICLLe trial before enrolling in the Extension Study . Adverse Events (AEs) are collected from registration until 30 days after treatment cessation and reported at 1, 3 and 6 months, and 6-monthly thereafter using the Common Terminology Criteria for Adverse Events v4.0. Results: 17 participants (12 ibrutinib naïve and 5 IcICLLe monotherapy patients) are evaluable for response assessment after one month of combination treatment. In the 12 Ibrutinib-naïve cases, the peripheral CLL counts remained at or below baseline levels in most (9/12) cases from week 1 onwards. After one month of combination therapy the peripheral B-cell count was a median 35% of baseline levels (range

Description: Background: Preliminary results from the UK REMoDL-B trial have shown that circulating neoplastic B-cells and B-lymphopenia are frequently detected by flow cytometry in presenting DLBCL patients. Uncertainty remains about the significance of these findings and how they relate to the course of clinical disease. Aim: The aim of this study was to assess whether numerical and phenotypic peripheral B-cell abnormalities are related to advanced disease and adverse prognosis. Methods: The study was carried out using peripheral blood samples collected from patients prior to first treatment. Peripheral blood was analysed using a panel of antibodies comprising of a CD19 and CD20 backbone, with Kappa, Lambda, CD5, CD45, CD49d, LAIR-1, CXCR5, CD31, CD95, CD38 and CD10, supplemented in some cases by CD81, CD79b, and CD43. Analysis allowed B-cell enumeration, identification of monoclonal populations and phenotypic classification as CLL, germinal centre (GC), non-GC or not otherwise specified (NOS) where the phenotype was indeterminate. In addition, gene expression profiling (GEP) was performed on the diagnostic tissue biopsy (FFPE) using the Illumina WG-DASL assay to classify tumours as GCB-type, ABC-type or unclassified. Results: A total of 845 patients with an average age of 62.7 years (range 20.9-87.8) were included. A monoclonal population was detected in 174/845 (20.5%) of cases; CLL 3%, GC 7.8%, non-GC 7.7% and NOS 2.1%. Numerical abnormalities were also detected; 33% of patients had B-lymphopenia (1 x 109/l). There was minimal overlap between numerical abnormalities and the presence of neoplastic B-cells, with 86% of cases with an abnormal population having a normal B-cell count. Circulating neoplastic cells were present in a small proportion of cases with B-lymphopenia (17/264) and a higher percentage of cases with B-lymphocytosis (8/19), as would be expected. Neoplastic B-cells were detected in 33% of cases an International Prognostic Index (IPI) score of 4-5, compared to 14% of cases with an IPI of 0-2. B-lymphopenia was present in 39% of individuals with an IPI of 4-5 compared to 24% of individuals with an IPI of 0-2. 51% (58/113) of cases with BM involvement had a circulating monoclonal population, compared to 15% (116/732) of cases with no overt marrow disease. Conversely, 66% of cases with circulating neoplastic cells did not have marrow involvement but this may, in part, be a sensitivity issue as staging was based on morphological assessment only. Tumour GEP results were available for 690 individuals; 362 (52%) GCB, 184 (26%) ABC and 144 (21%) unclassified. 86% of populations identified in the ABC subgroup were phenotyped non-GC or NOS. Presence of a GC-population by flow was highly predictive of GCB GEP (88% GC-type populations detected were GCB cases). The number of discordant cases and CLL clones detected approximated to the numbers that would have been expected in a normal age-matched population. Conclusion: Both the presence of circulating monoclonal B-cells and B-lymphopenia showed an association with higher risk disease. In addition, there was strong concordance between clonal phenotypes and the GEP of the underlying tumours. It is likely that in most cases the peripheral clonal populations are circulating tumour cells or a closely related precursor clone. Absolute B-cell counts are known to decline with age but there was no correlation with age in this patient group. Immuosuppression has a role in the pathogenesis of DLBCL in the elderly and the observed B-lymphopenia may be as a result of underlying immune dysfunction. Alternatively it may reflect suppression of normal B-cells by the neoplastic clone. Either way this has implications for the efficacy of immunomodulatory drugs, especially if the T-cell subsets are also affected. Multiparameter flow is highly applicable for diagnostic screening of both numerical and phenotypic B-cell abnormalities and may have a role in the prognostic assessment of DLBCL. Outcome data will be available shortly allowing the impact on progression free overall survival to be assessed. Disclosures Rawstron: Celgene: Honoraria; Abbvie: Honoraria; Pharmacyclics: Research Funding; Gilead: Honoraria, Research Funding; Roche: Honoraria; BD Biosciences: Patents & Royalties. Johnson:Takeda: Honoraria; Pfizer: Honoraria; Janssen: Research Funding. Davies:Seattle Genetics: Research Funding; Takeda: Honoraria. Jack:Jannsen: Research Funding.

Description: 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 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.

Description: Background Proteasome inhibitors (PIs) are central to anti-MM therapy and 3 are currently licensed: bortezomib, carfilzomib and ixazomib, increasing treatment options. Bortezomib (BZ) and carfilzomib (CFZ) have been studied in head-to-head comparison using a CFZ dose of 56mg/m2 in doublet with dexamethasone in relapse (ENDEAVOR), and also at 36mg/m2 in triplet with melphalan and prednisolone in newly diagnosed non-transplant eligible patients. Differing results may relate to dosing and scheduling, as well as to different study populations. There is growing evidence for triplet regimens especially at relapse. Aims The MUK five phase 2 study compared the activity and safety of CFZ and BZ in triplet combination using a CFZ dose of 36mg/m2, with cyclophosphamide and dexamethasone (KCD vs VCD), for patients at first relapse, or refractory to no more than 1 prior line of therapy. Methods The study compares 8 cycles of VCD with 6 cycles of KCD (24 weeks treatment), and also assesses the benefit of maintenance carfilzomib in the KCD arm. Participants were randomised (R1) in a 2:1 ratio in favour of KCD, minimisation factors were β2M, prior bortezomib, prior ASCT and timing of first relapse (〈 or ≥12 months). Participants in the KCD arm with at least stable disease (SD) after 6 cycles of KCD were randomised (R2) 1:1 to receive maintenance carfilzomib or no further treatment. Participants in the VCD arm did not receive maintenance. Inclusion criteria included Hb〉80g/L, neutrophils〉1.0x109/L, platelets 50x109/L and GFR〉30ml/min. KCD therapy was 28 day cycles of biweekly carfilzomib 20/36mg/m2 IV (weeks 1-3) while VCD was 21 day cycles of biweekly bortezomib 1.3mg/m2 SC (weeks 1 and 2), both with cyclophosphamide 500mg orally weekly (weeks 1-3 only for KCD) and dexamethasone 40mg orally weekly. Co-primary endpoints were ≥VGPR rates at 24 weeks post R1 (powered for non-inferiority comparison, deemed non-inferior (NI) if 90% confidence interval (CI) for odds ratio (OR) 〉0.8), and PFS from R2 (superiority). Disease response was assessed according to the Modified IWG Uniform Response Criteria, and minimal residual disease (MRD) by multiparameter flow cytometry (10-4). Results From Feb 2013 to Sept 2016, 300 participants were randomised, 201 to KCD and 99 to VCD. Patient and disease features were balanced between arms, median ages 67 and 69 years, 57.5% and 64.6% male, 93.5% and 94.9% ECOG 0-1 for KCD and VCD respectively. Median time from diagnosis was 32.5 and 36.1 months, 50.0% and 45.5% were ISS 2/3, and 66.2 and 67.7% had had an ASCT. While 81.6% of patients in the KCD arm received all 6 treatment cycles, only 53.5% in the VCD arm received all 8 cycles; reasons for stopping treatment were toxicity (KCD, 7%; VCD, 19.2%), disease progression (6.5%, 6.1%) and withdrawal of consent (2.5%, 11.1%). Dose modifications occurred in 78.6%, and 85.4% of patients in the KCD and VCD arms respectively. A total of 196 and 96 patients were evaluable for efficacy analysis in the KCD and VCD arms. Major response (≥VGPR) at 24 weeks for KCD and VCD was 40.2% and 31.9% respectively (OR 1.48; 90% CI (0.95, 2.31), deemed NI). Overall response (≥PR) was 84.0% and 68.1% (OR 2.72; 90% CI (1.62, 4.55); p=0.0014, deemed superior). MRD negativity (all evaluable patients; n=134 KCD, n=48 VCD) at 24 weeks was 16.4% for KCD and 12.5% for VCD. The safety population was 292 patients (KCD, 196; VCD 96). Treatment emergent neuropathy occurred in 21.4% and 56.3% of patients in the KCD and VCD arm, respectively. The proportion of patients with grade ≥3 neuropathy or grade ≥2 neuropathy with pain (key secondary endpoint) was lower with KCD (1.5%, vs 19.8% with VCD; p