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

Social deprivation independently impacts clinical outcomes in patients with chronic lymphocytic leukemia

Data from the Surveillance, Epidemiology, and End Results (SEER) database shows that chronic lymphocytic leukemia (CLL) patients with higher social economic status have better outcomes but the reasons underlying this observation remain undetermined.</p

Phase I/II results of ceralasertib as monotherapy or in combination with acalabrutinib in high-risk relapsed/refractory chronic lymphocytic leukemia

Background: Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) have limited treatment options. Ceralasertib, a selective ataxia telangiectasia and Rad-3-related protein (ATR) inhibitor, demonstrated synergistic preclinical activity with a Bruton tyrosine kinase (BTK) inhibitor in TP53- and ATM-defective CLL cells. Acalabrutinib is a selective BTK inhibitor approved for treatment of CLL. Objectives: To evaluate ceralasertib ± acalabrutinib in R/R CLL. Design: Nonrandomized, open-label phase I/II study. Methods: In arm A, patients received ceralasertib monotherapy 160 mg twice daily (BID) continuously (cohort 1) or 2 weeks on/2 weeks off (cohort 2). In arm B, patients received acalabrutinib 100 mg BID continuously (cycle 1), followed by combination treatment with ceralasertib 160 mg BID 1 week on/3 weeks off from cycle 2. Co-primary objectives were safety and pharmacokinetics. Efficacy was a secondary objective. Results: Eleven patients were treated [arm A, n = 8 (cohort 1, n = 5; cohort 2, n = 3); arm B, n = 3 (acalabrutinib plus ceralasertib, n = 2; acalabrutinib only, n = 1)]. Median duration of exposure was 3.5 and 7.2 months for ceralasertib in arms A and B, respectively, and 15.9 months for acalabrutinib in arm B. Most common grade ⩾3 treatment-emergent adverse events (TEAEs) in arm A were anemia (75%) and thrombocytopenia (63%), with four dose-limiting toxicities (DLTs) of grade 4 thrombocytopenia. No grade ⩾3 TEAEs or DLTs occurred in arm B. Ceralasertib plasma concentrations were similar when administered as monotherapy or in combination. At median follow-up of 15.1 months in arm A, no responses were observed, median progression-free survival (PFS) was 3.8 months, and median overall survival (OS) was 16.9 months. At median follow-up of 17.2 months in arm B, overall response rate was 100%, and median PFS and OS were not reached. Conclusion: Ceralasertib alone showed limited clinical benefit. Acalabrutinib plus ceralasertib was tolerable with preliminary activity in patients with R/R CLL, though findings are inconclusive due to small sample size. Registration: NCT0332827

Treatment patterns and outcomes of unfit and elderly patients with Mantle cell lymphoma unfit for standard immunochemotherapy: a UK and Ireland analysis

Mantle cell lymphoma (MCL) presenting in elderly, unfit patients represents a clinical challenge. Front-line ‘attenuated’ or low-intensity immunochemotherapy is often employed, although outcomes are relatively unexplored. We report outcomes of attenuated immunochemotherapy in 95 patients with MCL across 19 centres in the UK and Ireland considered unfit for full-dose rituximab-bendamustine or rituximab-cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP). Regimens examined were rituximab-cyclophosphamide, vincristine, prednisolone (R-CVP) (n = 19), dose-attenuated R-CHOP (n = 22), dose attenuated rituximab-bendamustine (n = 24) and rituximab-chlorambucil (n = 30). The primary outcome was progression-free survival (PFS). The secondary outcomes included overall response, overall survival (OS) and toxicity. The median (range) age was 79 (58–89) years and 50% were aged ≥80 years. The median (range) Cumulative Illness Rating Scale-Geriatric score was 6 (0–24). The median PFS for all patients was 15 months [95% confidence interval (CI) 8·7–21·2) and median OS was 31·4 months (95% CI 19·7–43·2). By multivariable analysis (MVA), the only clinical factor associated with an inferior PFS was blastoid morphology [hazard ratio (HR) 2·90, P = 0·01). Notably, higher treatment intensity (R-CHOP/R-bendamustine composite) provided an independently superior PFS compared with R-CVP/R-chlorambucil (MVA HR 0·49, P = 0·02). Factors associated with inferior OS by MVA were Eastern Cooperative Oncology Group Performance Status (HR 2·14, P = 0·04), blastoid morphology (HR 4·08, P = 0·001) and progression of disease at &lt;24 months status (HR 5·68, P &lt; 0·001). Overall, survival after front-line dose-attenuated immunochemotherapy is unsatisfactory. Clinical trials investigating novel agents such as Bruton tyrosine kinase and B-cell lymphoma 2 inhibitors in this specific clinical setting are warranted

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

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

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