Chronic lymphocytic leukemia therapy guided by measurable residual disease

Background:Ibrutinib (I) and venetoclax (V) improve chronic lymphocytic leukemia (CLL) outcomes compared to chemo-immunotherapy. We hypothesized I+V is more effective than fludarabine-cyclophosphamide-rituximab (FCR), and personalizing treatment duration, using measurable residual disease (MRD), would optimize outcomes.Methods:FLAIR, a phase III, multicenter, randomized, controlled, open-label platform trial for untreated CLL, compared I+V and I, to FCR. In I+V, after 2m I, V was added for up to 6y of therapy. The duration of I+V was defined by MRD assessed in peripheral blood (PB) and bone marrow (BM) and was double the time to undetectable MRD (uMRD). The primary endpoint was progression-free survival for I+V vs FCR, reported herein. Key secondary endpoints were overall survival, response, MRD and safety. Results:523 participants were randomized to FCR or I+V. At median 43.7m, there were 87 progressions (75 FCR, 12 I+V). The hazard ratio (HR) for progression-free survival for I+V vs FCR is 0.13 (95% confidence interval [CI], 0.07-0.24; P&lt;0.0001). There were 34 deaths (25 FCR, 9 I+V). The HR for overall survival for I+V vs FCR is 0.31 (95%CI, 0.15-0.67). At 3y, 58.0% I+V participants stopped therapy due to uMRD. After 5y of I+V, 65.9% and 92.7% participants were BM and PB uMRD, respectively. Infection rates were similar. There were more cardiovascular events with I+V (10.7%) vs FCR (0.4%). Conclusion:MRD-directed I+V improved progression-free survival and favored overall survival compared to FCR. (Funded by Cancer Research UK and others; Trial Registration number: ISRCTN01844152 and EudraCT, 2013-001944-76.) <br/

Ibrutinib Plus Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia: The CLARITY Study.

PURPOSE:The treatment of chronic lymphocytic leukemia (CLL) has been revolutionized by targeted therapies that either inhibit proliferation (ibrutinib) or reactivate apoptosis (venetoclax). Both significantly improve survival in CLL and replace chemoimmunotherapy for many patients. However, individually, they rarely lead to eradication of measurable residual disease (MRD) and usually are taken indefinitely or until progression. We present the CLARITY trial that combined ibrutinib with venetoclax to eradicate detectable CLL with the intention of stopping therapy. PATIENTS AND METHODS:CLARITY is a phase II trial that combined ibrutinib with venetoclax in patients with relapsed or refractory CLL. The primary end point was eradication of MRD after 12 months of combined therapy. Key secondary end points were response by International Workshop on CLL criteria, safety, and progression-free and overall survival. RESULTS:In 53 patients after 12 months of ibrutinib plus venetoclax, MRD negativity (fewer than one CLL cell in 10,000 leukocytes) was achieved in the blood of 28 (53%) and the marrow of 19 (36%). Forty-seven patients (89%) responded, and 27 (51%) achieved a complete remission. After a median follow-up of 21.1 months, one patient progressed, and all patients were alive. A single case of biochemical tumor lysis syndrome was observed. Other adverse effects were mild and/or manageable and most commonly were neutropenia or GI events. CONCLUSION:The combination of ibrutinib plus venetoclax was well tolerated in patients with relapsed or refractory CLL. There was a high rate of MRD eradication that led to the cessation of therapy in some patients. The progression-free and overall survival rates are encouraging for relapsed and refractory CLL

Venetoclax ramp-up strategies for chronic lymphocytic leukaemia in the United Kingdom: a real world multicentre retrospective study

This retrospective, observational study evaluated patterns of inpatient versus outpatient tumour lysis syndrome (TLS) monitoring during venetoclax ramp-up in 170 patients with chronic lymphocytic leukaemia. The primary outcome was clinical/biochemical TLS. Two clinical and four biochemical TLS occurred (4.1%). Five of the six events occurred in high-risk patients, four occurred at 20 mg dose and three at the 6-h time-point. Inpatient versus outpatient TLS rates within the high-risk subgroup were 15% and 8%. Risk category was the only predictor of TLS events in multivariate analysis. Outpatient escalation did not associate with clinically meaningful TLS events, suggesting outpatient escalation has manageable associated TLS risks, including in high-risk cohorts. These observations require confirmation in larger studies

Torque Teno Virus 10 Isolated by Genome Amplification Techniques from a Patient with Concomitant Chronic Lymphocytic Leukemia and Polycythemia Vera

An infectious etiology has been proposed for many human cancers, but rarely have specific agents been identified. One difficulty has been the need to propagate cancer cells in vitro to produce the infectious agent in detectable quantity. We hypothesized that genome amplification from small numbers of cells could be adapted to circumvent this difficulty. A patient with concomitant chronic lymphocytic leukemia (CLL) and polycythemia vera (PV) requiring therapeutic phlebotomy donated a large amount of phlebotomized blood to test this possibility. Using genome amplification methods, we identified a new isolate (BIS8-17) of torque teno virus (TTV) 10. The presence of blood isolate sequence 8-17 (BIS8-17) in the original plasma was confirmed by polymerase chain reaction (PCR), validating the approach, since TTV is a known plasma virus. Subsequent PCR testing of plasmas from additional patients showed that BIS8-17 had a similar incidence (~20%) in CLL (n = 48) or PV (n = 10) compared with healthy controls (n = 52). CLL cells do not harbor BIS8-17; PCR did not detect it in CLL peripheral blood genomic deoxyribonucleic acid (DNA) (n = 20). CLL patient clinical outcome or prognostic markers (immunoglobulin heavy chain variable region [IGHV ] mutation, CD38 or zeta-chain associated protein kinase 70kDa [ZAP-70]) did not correlate with BIS8-17 infection. Although not causative to our knowledge, this is the first reported isolation and detection of TTV in either CLL or PV. TTV could serve as a covirus with another infectious agent or TTV variant with rearranged genetic components that contribute to disease pathogenesis. These results prove that this method identifies infectious agents and provides an experimental methodology to test correlation with disease

Venetoclax ramp-up strategies for chronic lymphocytic leukaemia in the United Kingdom: a real world multicentre retrospective study

This retrospective, observational study evaluated patterns of inpatient versus outpatient tumour lysis syndrome (TLS) monitoring during venetoclax ramp-up in 170 patients with chronic lymphocytic leukaemia. The primary outcome was clinical/biochemical TLS. Two clinical and four biochemical TLS occurred (4.1%). Five of the six events occurred in high-risk patients, four occurred at 20 mg dose and three at the 6-h time-point. Inpatient versus outpatient TLS rates within the high-risk subgroup were 15% and 8%. Risk category was the only predictor of TLS events in multivariate analysis. Outpatient escalation did not associate with clinically meaningful TLS events, suggesting outpatient escalation has manageable associated TLS risks, including in high-risk cohorts. These observations require confirmation in larger studies

Efficacy of venetoclax monotherapy in patients with relapsed chronic lymphocytic leukaemia in the post-BCR inhibitor setting: a UK wide analysis.

Venetoclax is a BCL2 inhibitor with activity in relapsed/refractory (R/R) chronic lymphocytic leukaemia (CLL). We conducted a multi-centre retrospective analysis of 105 R/R CLL patients who received venetoclax pre-National Health Service commissioning. The median age was 67 years and median prior lines was 3 (range: 1-15). 48% had TP53 disruption. At ≥2 lines, 60% received a Bruton Tyrosine Kinase inhibitor (BTKi) and no prior phosphoinositide 3-kinase inhibitor (Pi3Ki), 25% received a Pi3Ki and no prior BTKi, and 10% received both. Patients discontinued B cell receptor inhibitor (BCRi) because of toxicity in 44% and progression in 54%. Tumour lysis syndrome risk was low, intermediate or high in 27%, 25%, and 48% respectively. Overall response was 88% (30% complete response [CR]). The overall response rate was 85% (CR 23%) in BTKi-exposed patients, 92% (CR 38%) in Pi3Ki-exposed patients and 80% (CR 20%) in both (P = 0·59). With a median follow-up of 15·6 months, 1-year progression-free survival was 65·0% and 1-year overall survival was 75·1%. Dose reduction or temporary interruption did not result in an inferior progression-free or discontinuation-free survival. Risk of progression or death after stopping a prior BCRi for progression was double compared to those stopping for other reasons (predominantly toxicity) (Hazard Ratio 2·01 P = 0·05). Venetoclax is active and well tolerated in R/R CLL post ≥1 BCRi. Reason(s) for stopping BCRi influences venetoclax outcomes

Ibrutinib and rituximab versus fludarabine, cyclophosphamide, and rituximab for patients with previously untreated chronic lymphocytic leukaemia (FLAIR): interim analysis of a multicentre, open-label, randomised, phase 3 trial

Background: The approval of Bruton tyrosine kinase (BTK) inhibitors in patients with previously untreated chronic lymphocytic leukaemia (CLL) was based on trials which compared ibrutinib with alkylating agents in patients considered unfit for fludarabine, cyclophosphamide, and rituximab, the most effective chemoimmunotherapy in CLL. We aimed to assess whether ibrutinib and rituximab is superior to fludarabine, cyclophosphamide, and rituximab in terms of progression-free survival. Methods: This study is an interim analysis of FLAIR, which is an open-label, randomised, controlled, phase 3 trial in patients with previously untreated CLL done at 101 UK National Health Service hospitals. Eligible patients were between 18 and 75 years of age with a WHO performance status of 2 or less and disease status requiring treatment according to International Workshop on CLL criteria. Patients with greater than 20% of their CLL cells having the chromosome 17p deletion were excluded. Patients were randomly assigned (1:1) by means of minimisation (Binet stage, age, sex, and centre) with a random element in a web-based system to ibrutinib and rituximab (ibrutinib administered orally at 420 mg/day for up to 6 years; rituximab administered intravenously at 375 mg/m2 on day 1 of cycle 1 and at 500 mg/m2 on day 1 of cycles 2–6 of a 28-day cycle) or fludarabine, cyclophosphamide, and rituximab (fludarabine 24 mg/m2 per day orally on day 1–5, cyclophosphamide 150 mg/m2 per day orally on days 1–5; rituximab as above for up to 6 cycles). The primary endpoint was progression-free survival, analysed by intention to treat. Safety analysis was per protocol. This study is registered with ISRCTN, ISRCTN01844152, and EudraCT, 2013-001944-76, and recruiting is complete. Findings: Between Sept 19, 2014, and July 19, 2018, of 1924 patients assessed for eligibility, 771 were randomly assigned with median age 62 years (IQR 56–67), 565 (73%) were male, 206 (27%) were female and 507 (66%) had a WHO performance status of 0. 385 patients were assigned to fludarabine, cyclophosphamide, and rituximab and 386 patients to ibrutinib and rituximab. After a median follow-up of 53 months (IQR 41–61) and at prespecified interim analysis, median progression-free survival was not reached (NR) with ibrutinib and rituximab and was 67 months (95% CI 63–NR) with fludarabine, cyclophosphamide, and rituximab (hazard ratio 0·44 [95% CI 0·32–0·60]; p<0·0001). The most common grade 3 or 4 adverse event was leukopenia (203 [54%] patients in the fludarabine, cyclophosphamide, and rituximab group and 55 [14%] patients in the ibrutinib and rituximab group. Serious adverse events were reported in 205 (53%) of 384 patients receiving ibrutinib and rituximab compared with 203 (54%) of 378 patients receiving fludarabine, cyclophosphamide, and rituximab. Two deaths in the fludarabine, cyclophosphamide, and rituximab group and three deaths in the ibrutinib and rituximab group were deemed to be probably related to treatment. There were eight sudden unexplained or cardiac deaths in the ibrutinib and rituximab group and two in the fludarabine, cyclophosphamide, and rituximab group. Interpretation: Front line treatment with ibrutinib and rituximab significantly improved progression-free survival compared with fludarabine, cyclophosphamide, and rituximab but did not improve overall survival. A small number of sudden unexplained or cardiac deaths in the ibrutinib and rituximab group were observed largely among patients with existing hypertension or history of cardiac disorder. Funding: Cancer Research UK and Janssen

Ibrutinib Plus Venetoclax with MRD-Directed Duration of Treatment Is Superior to FCR and Is a New Standard of Care for Previously Untreated CLL: Report of the Phase III UK NCRI FLAIR Study

Introduction: Ibrutinib (I), an irreversible Btk inhibitor, and venetoclax (V), a Bcl-2 inhibitor, improve CLL outcomes in trials compared to chemoimmunotherapy. I and V target two key pathophysiological pathways in CLL and should be synergistic. This is supported both by in vitro studies and Phase II trials in which I+V results in high proportions of measurable residual disease (MRD) negativity. A Phase III trial comparing I+V (15 months [mo]) with chlorambucil-obinutuzumab led to the approval of I+V. However, mathematical disease modelling and Phase II studies favor defining duration of I+V according to individual patient sensitivity. We hypothesized that I+V is more effective than FCR in CLL and that treatment duration personalised using MRD response would optimize outcome.Methods: FLAIR (ISRCTN01844152) is a phase III, multicentre, randomised, controlled, open, parallel group trial for untreated CLL. Patients (pts) with >20% 17p deleted cells were excluded. FLAIR was adapted in 2017 to add 2 arms, I alone and I+V compared to FCR. Here we report the planned analysis of I+V vs FCR. In I+V after 2 mo I, V was added with a 4-week dose escalation to 400mg/day and then I+V for up to 6 years with duration of I+V defined by MRD (65yo) and 40.9 % Binet Stage C. IGHV unmutated (≥98% homology to germline) in 56.9%, 37.6% IGHV mutated and 5.5% Subset 2. Hierarchical FISH: 20.6% 11q del, 20.1% trisomy 12, 27.8% normal and 31.4% 13q del. At 2 yrs 111/260 (42.7%) and 3 yrs 135/232 (58.1%) pts stopped I+V according to the MRD stopping rules. At a median 43.7 months there were 87 progressions - 75 FCR and 12 I+V. The hazard ratio (HR) for PFS for I+V vs FCR is 0.13 (95% CI: [0.07, 0.24]; p<0.0001; Fig). This result was consistent for gender, age or stage. At 3 yrs 2.8% had progressed on I+V compared to 23.2% on FCR. There have been 34 deaths (25 FCR and 9 I+V) resulting in improved overall survival for I+V vs FCR: HR 0.31 (95% CI: [0.15, 0.67]; p=0.0029; Fig). At 3 years 2.0% of I+V pts had died compared to 7.0% for FCR. At 9 months (3 mo post-FCR) 48.3% FCR pts became MRD neg in BM compared to 41.5% for I+V. However, with continued I+V more pts became MRD neg: the odds of MRD negativity at any time for I+V vs FCR were 2.03 (95% CI: [1.43, 2.89]; P<0.001) in BM and 3.91 (95% CI: [2.55, 6.00]; P<0.001) in PB. 90.6% pts achieved PB MRD negativity at up to 5 yrs I+V and 88% of these were BM MRD negative 6 mo after their first PB MRD neg result. At 9 months a higher proportion achieved CR and overall response for I+V; CR - FCR 49.0% (95% CI: [42.9%, 55.3%]), I+V 59.2% (53%, 65.3%); ORR - FCR 76.4% (70.8%, 81.4%); I+V 86.5% (81.8%, 90.4%). This difference was greater for best response at any time: ORR 83.7% (78.6%, 87.9%) for FCR vs 95.4% (92.1%, 97.6%) for I+V; CR 71.5% (65.6%, 76.9%) for FCR vs 92.3% (88.4%, 95.2%) for I+V. The odds ratios estimate to achieve CR with I+V vs FCR is 1.51 (95% CI: [1.07, 2.14]; p<0.05). Responses and outcomes by FISH and IGHV will be presented. SAEs were reported in 252 (51.3%) pts (129 FCR vs 123 I+V). Notable SAEs by organ class for FCR vs I+V were: infections 18.8% of FCR pts vs 22.2% for I+V; blood and lymphatic 31% vs 5%; and cardiac in 0.4% vs 10.7%. 4 pts had sudden or cardiac deaths - 2 FCR and 2 I+V. 69 other cancers were diagnosed (45 in FCR, 24 in I+V) in 51 pts (34 FCR, 17 I+V). The incidence of other cancers per 100 pt-years was greater for FCR than I+V; 5.4 (95% CI: [5.11, 5.68]) vs. 2.6 (2.40, 2.79). There were 7 cases of MDS/AML with FCR and 1 with I+V.Conclusion: Ibrutinib plus venetoclax significantly improved progression-free and overall survival compared to FCR in untreated CLL. Using MRD to direct the duration of I+V maximizes outcome with 97.2% progression free survival at 3 years The efficacy seen in FLAIR is superior to previous Phase III CLL trials indicating that I+V with duration guided by MRD is a new gold standard for CLL treatment