Fludarabine, Cyclophosphamide, Rituximab Research Articles

Abstract 3849: Frontline ibrutinib-based therapy enhances CART cell functions in patients with CLL: Analysis of the phase 3 randomized clinical trial ECOG-ACRIN E1912

Abstract Introduction: Despite the remarkable activity of CD19-directed chimeric antigen receptor T cell therapy (CART19), durable remissions remain low, especially in chronic lymphocytic leukemia (CLL). Ibrutinib is an oral irreversible inhibitor of Bruton’s tyrosine kinase and is a first line therapy for CLL. Preclinical and early clinical data indicate that ibrutinib plus CART19 may be synergistic through inhibition of IL2-inducible T cell kinase. To systematically study the effects of prior ibrutinib treatment on subsequent CART functions, we utilized blood samples from the pivotal clinical trial E1912 (NCT02048813). E1912 was a phase 3 randomized trial comparing treatment with ibrutinib/rituximab (IR) to fludarabine/cyclophosphamide/rituximab (FCR) in previously untreated patients with CLL, which led to the FDA approval of ibrutinib as a first-line therapy in CLL. Methods: We evaluated the ex vivo expansion and effector functions of T cells and CART19 generated from patients (n=12) with CLL progression following treatment with IR or FCR. We generated CART19 from longitudinal samples obtained at baseline (pretreatment), 6 months post-treatment, 12 months post-treatment, and disease progression. Isolated T cells were lentivirally transduced to express CD28- or 41BB-costimulated CAR19. To assess antigen specific killing and proliferation, untransduced T cells or CART19 were co-cultured at a 1:1 ratio with the CD19+ cell line, JeKo-1, as a surrogate for CLL cells. Results: Ex vivo T cell expansion increased from an average of 1.5-fold at baseline to 6.7-fold at 6 months, 11.6-fold at 12 months, and 16.9-fold at progression, following ibrutinib-based therapy (p = 0.02, 0.04, and 0.04, respectively). Improved T cell expansion was independent of disease burden (p = 0.89, 0.73, and 0.54 for expansion vs B cell count at 6 months, 12 months, and progression). T cell expansion significantly worsened following treatment with FCR-based therapy compared to ibrutinib-based therapy (0.6- vs 11.6-fold at 12 months and 0.9- vs 16.9-fold at progression; p = 0.031 and 0.039, respectively). Starting at 6 months post-IR, CART19 demonstrated improved antitumor activity and antigen-specific proliferation against JeKo-1. There was no significant difference in the expansion of 41BB- vs CD28-costimulated CART19 following ibrutinib treatment. However, 41BB-CART19 showed enhanced antigen-specific proliferation upon stimulation with JeKo-1 (p = 0.008, 0.02, and 0.02 at 6 months, 12 months, and progression). Conclusion: Our results indicate significant improvement in T cell expansion and CART19 cell functions in patients with CLL following frontline ibrutinib-based therapy, and worsening T cell functions after FCR treatment. Improvement in T cell functions is independent of malignant B cell eradication and is more significant in 41BB-costimulated CART19. Citation Format: Truc Ngoc Huynh, Victoria Wang, Tait Shanafelt, Elizabeth L. Siegler, Carli M. Stewart, Kun Yun, Long K. Mai, Olivia Sirpilla, James H. Girsch, Claudia Manriquez-Roman, Jennifer M. Feigin, Makena Rodriguez, Brooke L. Kimball, Hong Xia, Reona L. Sakemura, Ismail Can, Omar L. Gutierrez-Ruiz, Ekene J. Ogbodo, Erin E. Tapper, Lionel A. Fonkoua, Mehrdad T. Hefazi, Michael W. Ruff, Sameer Parikh, Neil E. Kay, Saad J. Kenderian. Frontline ibrutinib-based therapy enhances CART cell functions in patients with CLL: Analysis of the phase 3 randomized clinical trial ECOG-ACRIN E1912 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3849.

Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease

BackgroundThe combination of ibrutinib and venetoclax has been shown to improve outcomes in patients with chronic lymphocytic leukemia (CLL) as compared with chemoimmunotherapy. Whether ibrutinib–venetoclax and personalization of treatment duration according to measurable residual disease (MRD) is more effective than fludarabine–cyclophosphamide–rituximab (FCR) is unclear.MethodsIn this phase 3, multicenter, randomized, controlled, open-label platform trial involving patients with untreated CLL, we compared ibrutinib–venetoclax and ibrutinib monotherapy with FCR. In the ibrutinib–venetoclax group, after 2 months of ibrutinib, venetoclax was added for up to 6 years of therapy. The duration of ibrutinib–venetoclax therapy was defined by MRD assessed in peripheral blood and bone marrow and was double the time taken to achieve undetectable MRD. The primary end point was progression-free survival in the ibrutinib–venetoclax group as compared with the FCR group, results that are reported here. Key secondary end points were overall survival, response, MRD, and safety.ResultsA total of 523 patients were randomly assigned to the ibrutinib–venetoclax group or the FCR group. At a median of 43.7 months, disease progression or death had occurred in 12 patients in the ibrutinib–venetoclax group and 75 patients in the FCR group (hazard ratio, 0.13; 95% confidence interval [CI], 0.07 to 0.24; P<0.001). Death occurred in 9 patients in the ibrutinib–venetoclax group and 25 patients in the FCR group (hazard ratio, 0.31; 95% CI, 0.15 to 0.67). At 3 years, 58.0% of the patients in the ibrutinib–venetoclax group had stopped therapy owing to undetectable MRD. After 5 years of ibrutinib–venetoclax therapy, 65.9% of the patients had undetectable MRD in the bone marrow and 92.7% had undetectable MRD in the peripheral blood. The risk of infection was similar in the ibrutinib–venetoclax group and the FCR group. The percentage of patients with cardiac serious adverse events was higher in the ibrutinib–venetoclax group than in the FCR group (10.7% vs. 0.4%).ConclusionsMRD-directed ibrutinib–venetoclax improved progression-free survival as compared with FCR, and results for overall survival also favored ibrutinib–venetoclax. (Funded by Cancer Research UK and others; FLAIR ISRCTN Registry number, ISRCTN01844152; EudraCT number, 2013-001944-76.)

Real-Life Multicentre Study on 547 Patients Affected By Waldenstrom Macroglobulinemia Treated with Chemo-Immunotherapy: Which Is the Best and Most Used First-Line Treatment?

Waldenström Macroglobulinaemia (WM) is an indolent lymphoma still primarily managed with chemo-immunotherapy, which remains a key first-line treatment option, although recently BTKIs have emerged as potential therapies for untreated patients. The aim of our study was to evaluate and compare efficacy and safety of different chemo-immunotherapeutic regimens commonly used in Italy for frontline WM treatment. A retrospective analysis was conducted on 547WM patients enrolled between 2008-2022 from 14 Italian haematological centres. Among them, 245 received the BR scheme (bendamustine-rituximab), 116 were treated with DRC (dexamethasone-rituximab-cyclophosphamide), and 129 were treated with various other regimens including monotherapy with chlorambucil or cyclophosphamide as well as more aggressive combinations, such as Chl-R (chlorambucil-rituximab), FCR (fludarabine-cyclophosphamide-rituximab) or R-CHOP (rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone), 48 patients received rituximab monotherapy for neurological symptoms. The main focus of our analysis was on the two major treatment groups: BR and DRC. There were notable differences between these two groups in terms of age at treatment (69 vs 70 years old, respectively), CIRS (more patients with CIRS&amp;gt;6 in DRC) and revised IPSSWD (higher risk rates in BR). Patients treated with BR tended to be younger, more fit but also had a more aggressive disease. Overall survival (OS) curves did not show significant differences between the two schemes (5-year OS 87.5% for BR and 93.0% for DRC, p=0.42). Similarly, the analysis of progression free survival (PFS) curves demonstrated a better PFS at 5 years for BR (79.2%) compared to DRC (54.5%) (p&amp;lt;0.001; figure 1A). The median PFS was 63.6 months for DRC, while it was not reached for BR. When analysing BR-treated patients separately (standard dose and reduced initial dose) both groups showed better PFS curves than DRC (p&amp;lt;0.001; figure 1B). Multivariate analysis identified the choice of the treatment (BR vs DRC) as the sole significant variable impacting PFS (RR 1.76). Notably, approximately 33% of the patients treated with BR received an initial bendamustine dose lower than the standard dose of 90 mg/m 2 for first-line therapy with 91% of these cases receiving 70 mg/m 2. The two schemes BR and DRC were well tolerated with no significant reduction in administered cycles (16.3% for BR vs 20.7% for DRC). However, dose reduction was more common for BR (14.3%) compared to DRC (6.0%). In conclusion, this large Italian retrospective real-life study showed excellent outcomes for unselected WM patients treated with chemo-immunotherapy. Despite the emergence of new treatment options, chemo-immunotherapy remains a highly effective treatment modality for these patients. The long-term follow-up confirmed better PFS for BR-treated patients, while OS, remained comparable between BR and DRC. Moreover, the BR scheme exhibited excellent PFS even with a reduced initial bendamustine dose.

Fixed-duration venetoclax plus obinutuzumab improves quality of life and geriatric impairments in FCR-unfit patients with CLL

AbstractChronic lymphocytic leukemia (CLL)–related symptoms and morbidity related to the advanced age at diagnosis impairs the well-being of older adult patients. Therefore, it is essential to tailor treatment according to geriatric characteristics and aim for an improvement in health-related quality of life (HRQoL) as a primary treatment goal. In the HOVON139/GiVe trial, 12 cycles of fixed-duration venetoclax plus obinutuzumab (Ven-O) were shown to be effective and tolerable in FCR (fludarabine, cyclophosphamide, rituximab)-unfit patients with CLL (n = 67). However, prolonged venetoclax exposure as consolidation treatment led to increased toxicity with limited effect on minimal residual disease. To assess the impact of geriatric assessment on treatment outcomes and the patients’ HRQoL, patient-reported outcomes (PROs), including function, depression, cognition, nutrition, physical performance, muscle parameters, comorbidities, and the European Organization for Research and Treatment of Cancer C30 and CLL17 questionnaires were assessed. At baseline, geriatric impairments were present in >90% of patients and ≥2 impairments present in 60% of patients predicted grade ≥3 nonhematological toxicity. During treatment, the number of geriatric impairments diminished significantly and clinically relevant improvements in HRQoL subscales were reached for global health status, physical functioning, role functioning, emotional functioning, fatigue, dyspnea, physical condition or fatigue, and worries or fears related to health and functioning. These improvements were comparable for patients receiving venetoclax consolidation and patients in whom treatment could mostly be discontinued. Collectively, frontline fixed-duration Ven-O improves overall PROs in older, unfit patients with CLL with and without geriatric impairments. This study was registered at EudraCT as 2015-004985-27 and the Netherlands Trial Register as NTR6043.

First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia

BackgroundRandomized trials of venetoclax plus anti-CD20 antibodies as first-line treatment in fit patients (i.e., those with a low burden of coexisting conditions) with advanced chronic lymphocytic leukemia (CLL) have been lacking.MethodsIn a phase 3, open-label trial, we randomly assigned, in a 1:1:1:1 ratio, fit patients with CLL who did not have TP53 aberrations to receive six cycles of chemoimmunotherapy (fludarabine–cyclophosphamide–rituximab or bendamustine–rituximab) or 12 cycles of venetoclax–rituximab, venetoclax–obinutuzumab, or venetoclax–obinutuzumab–ibrutinib. Ibrutinib was discontinued after two consecutive measurements of undetectable minimal residual disease or could be extended. The primary end points were undetectable minimal residual disease (sensitivity, <10−4 [i.e., <1 CLL cell in 10,000 leukocytes]) as assessed by flow cytometry in peripheral blood at month 15 and progression-free survival.ResultsA total of 926 patients were assigned to one of the four treatment regimens (229 to chemoimmunotherapy, 237 to venetoclax–rituximab, 229 to venetoclax–obinutuzumab, and 231 to venetoclax–obinutuzumab–ibrutinib). At month 15, the percentage of patients with undetectable minimal residual disease was significantly higher in the venetoclax–obinutuzumab group (86.5%; 97.5% confidence interval [CI], 80.6 to 91.1) and the venetoclax–obinutuzumab–ibrutinib group (92.2%; 97.5% CI, 87.3 to 95.7) than in the chemoimmunotherapy group (52.0%; 97.5% CI, 44.4 to 59.5; P<0.001 for both comparisons), but it was not significantly higher in the venetoclax–rituximab group (57.0%; 97.5% CI, 49.5 to 64.2; P=0.32). Three-year progression-free survival was 90.5% in the venetoclax–obinutuzumab–ibrutinib group and 75.5% in the chemoimmunotherapy group (hazard ratio for disease progression or death, 0.32; 97.5% CI, 0.19 to 0.54; P<0.001). Progression-free survival at 3 years was also higher with venetoclax–obinutuzumab (87.7%; hazard ratio for disease progression or death, 0.42; 97.5% CI, 0.26 to 0.68; P<0.001), but not with venetoclax–rituximab (80.8%; hazard ratio, 0.79; 97.5% CI, 0.53 to 1.18; P=0.18). Grade 3 and grade 4 infections were more common with chemoimmunotherapy (18.5%) and venetoclax–obinutuzumab–ibrutinib (21.2%) than with venetoclax–rituximab (10.5%) or venetoclax–obinutuzumab (13.2%).ConclusionsVenetoclax–obinutuzumab with or without ibrutinib was superior to chemoimmunotherapy as first-line treatment in fit patients with CLL. (Funded by AbbVie and others; GAIA–CLL13 ClinicalTrials.gov number, NCT02950051; EudraCT number, 2015-004936-36.)

Bendamustine-Rituximab in Young CLL: Relevance in the Era of Small Molecule Inhibitors.

Chemo-immunotherapies like Fludarabine-Cyclophosphamide-Rituximab (FCR) are used for treatment of chronic lymphocytic leukemia (CLL) in young and fit patients while Bendamustine-Rituximab (BR) is used in older patients. In a resource constrained setting, managing toxicities of FCR chemotherapy is challenging and this study explores the use of upfront BR treatment in young CLL patients (age < 65). Data of 61 CLL patients treated with the BR regimen between 2016 and 2020 was analysed. Overall-survival and progression-free-survival (OS and PFS) were compared between the two age groups (< / > 65years) and correlated with the fluorescent-in-situ-hybridization (FISH) data, duration of illness and time to initiation of chemotherapy. Out of 61 patients, 34 (85%) were below 65years. Five patients had del 17p and were excluded from the analysis. Forty patients had indications for treatment. Twenty-four (70.5%) of the forty patients achieved overall response; 10 developed progressive disease. The median OS and PFS was 1874days (95%CI 1617-2130days) and 1226days (95% CI 1021-1432days) respectively and were non inferior between the 2 age-groups. There were no correlations with clinical, laboratory or FISH parameters. The OS and PFS were better for patients with longer time to initiation of chemotherapy as compared to those with short duration of illness and short wait-and-watch periods (p < 0.000). Our results show that BR chemotherapy can safely and effectively be used in upfront treatment of young CLL patients and provide durable responses.

MiRNA profile at diagnosis predicts treatment outcome in patients with B-chronic lymphocytic leukemia: A FILO study.

ClinicalTrials.gov, identifier NCT01370772.

Multicenter retrospective analysis of patients with chronic lymphocytic leukemia in Korea.

BackgroundChronic lymphocytic leukemia (CLL) is the most common type of adult leukemia in Western countries but is rare in the East Asian countries. Due to its rarity and the lack of feasible novel agents and laboratory prognostic tools, there are limited data on the clinical outcomes of this disease in Asia. To clarify the current treatment status, we performed a multicenter retrospective analysis of patients with CLL in Korea.MethodsThe medical records of 192 eligible patients between 2008 and 2019 were reviewed for clinical characteristics, treatment courses, and outcomes. The first-line treatment regimens of the patients included in this analysis were as follows fludarabine/cyclophosphamide/rituximab (FCR) (N=117, 52.7%), obinutuzumab plus chlorambucil (GC) (N=30, 13.5%), and chlorambucil monotherapy (N=24, 10.8%).ResultsThe median progression-free survival (PFS) was 55.6 months, and the average 2-year PFS rate was 80.3%. PFS was not significantly different between the patients receiving FCR and those receiving GC; however, chlorambucil treatment was associated with significantly inferior PFS (P<0.001). The median overall survival was 136.3 months, and the average 5- and 10-year OS rates were 82.0% and 57.4%, respectively.ConclusionThis is one of the largest studies involving Korean patients with CLL. Although the patients had been treated with less favored treatment regimens, the outcomes were not different from those reported in Western studies.

Angiogenic factors could help us to define patients obtaining complete response with undetectable minimal residual disease in untreated CLL patients treated by FCR: results from the CLL2010FMP, a FILO study

Angiogenesis is in a constant balance between pro and anti-angiogenic factors. Neoangiogenesis, implicated in metastatic spreading is characterized in solid cancers, but fairly new in chronic lymphocytic leukemia (CLL). We hypothesize that secretion of angiogenic factors could be correlated to the pathogenesis of CLL, and therefore predict the outcome of patients. We investigated concentrations of 22 cytokines and chemokines in 137 non-del 17p B-CLL patients, treated with a fludarabine-cyclophosphamide-rituximab (FCR)-based regimen. We constructed a biomarker index defining different risk groups based on lymphocyte count, the intensity of CD20 antigen on CD19+ cells, Ang-2, and PDGF-BB plasma concentrations at diagnosis. Four groups were defined, exhibiting specific molecular signatures and correlated with progression-free survival of patients. Our results suggest that we can determine at diagnosis of non-del 17p B-CLL patients, those with a very high probability of progression-free survival, independently of IGVH mutational status and residual disease at the end of treatment.

Single-Agent Ibrutinib Versus Real-World (RW) Treatments for Patients with Previously Untreated Chronic Lymphocytic Leukemia (CLL): Adjusted Comparison of Resonate-2™ with the Cllear and Lyon-Sud Rw Databases

IntroductionIbrutinib, a once-daily oral Bruton's tyrosine kinase inhibitor, has shown progression-free survival (PFS) or overall-survival (OS) benefit over chemoimmunotherapy (CIT) in multiple phase 3 studies in previously untreated patients with CLL, and significantly longer time to next treatment compared with CIT in previously untreated high-risk patients in a RW setting. We conducted an adjusted comparison of ibrutinib versus RW treatment for previously untreated CLL using patient-level data from the phase 3 RESONATE-2™ (NCT01722487) trial and RW databases from 2 countries.MethodsPreviously untreated patients with CLL, fulfilling RESONATE-2™ eligibility criteria (age ≥ 65, no del17p) were selected from 2 RW data sources containing electronic medical records for patients with CLL: Centre Hospitalier Lyon-Sud, France; CLLEAR CLL registry from 7 academic centers in the Czech Republic. PFS and OS were compared between patients from the ibrutinib arm of RESONATE-2™ with a median follow-up of 60 months, and those receiving physicians' choice (PC) treatment other than ibrutinib from the RW database, adjusting for differences in baseline characteristics including age, gender, del11q, IGHV status, RAI/BINET disease stage, and Eastern Cooperative Oncology Group (ECOG) score. Hazard ratios (HRs) for ibrutinib versus RW PC treatment were estimated using a multivariable Cox proportional hazards model including available baseline characteristics as covariates, and using an inverse probability weighted (IPW) Cox model with average treatment effect for treatment (ATT) weights derived from propensity scores estimated from a logistic regression including the same covariates.ResultsThe analysis included 136 patients from the RESONATE-2™ study receiving ibrutinib and 920 previously untreated RW patients receiving PC treatment (Lyon-Sud n = 162, CLLEAR n = 758). Baseline characteristics were generally balanced between treatment groups. The most common PC regimens contained CIT and were fludarabine + cyclophosphamide + rituximab (FCR) (n = 227), bendamustine + rituximab (BR) (n = 201), and rituximab + chlorambucil (R + Chlor) (n = 116). Older age, male gender, del11q and advanced disease stage were independent risk factors for PFS and OS. When comparing ibrutinib versus the overall PC cohort, the adjusted HR (95% confidence interval [CI]) was 0.24 (0.16-0.34) for PFS and 0.33 (0.21-0.52) for OS (both p < 0.0001). IPW-based comparative estimates were highly consistent for both PFS (HR = 0.27 [0.18-0.39]) and OS (HR = 0.39 [0.24-0.62]). ATT-weighted survival curves estimating PFS and OS for the RESONATE-2™ population as if treated with PC, showed a median value of 32.1 months and 72.5 months, respectively, while median values for Ibrutinib were not reached. When comparing ibrutinib versus FCR, BR, and R + Chlor, the adjusted HRs (95% CI) were 0.26 (0.17-0.38), 0.27 (0.18-0.41), and 0.27 (0.17-0.42), respectively, for PFS and 0.34 (0.20-0.56), 0.28 (0.16-0.49), and 0.61 (0.32-1.13), respectively, for OS (Figure).ConclusionsAdjusted comparisons of the RESONATE-2™ trial and RW patient-level data demonstrates significantly improved PFS and OS for ibrutinib versus physician's choice treatment (predominantly CIT) in previously untreated patients with CLL. PFS and OS benefit for ibrutinib was consistent across a range of common regimens: FCR, BR, and R + Chlor. These results are consistent with data from phase 3 studies and support the use of ibrutinib for first-line CLL treatment.Funding Source:Sponsored by Janssen Pharmaceutica NV, and Pharmacyclics LLC, an AbbVie Company. The RW databases are independently owned. Writing assistance was provided by Emma Fulkes and Liqing Xiao of Parexel and funded by Janssen Pharmaceutica NV. [Display omitted] DisclosuresDoubek: Janssen-Cilag, AbbVie, AstraZeneca, Amgen, Gilead, Novartis: Honoraria, Research Funding. Smolej: AbbVie, AstraZeneca, Gilead, Janssen-Cilag, and Roche: Consultancy, Honoraria, Other: Travel Grants. Šimkovič: AbbVie, AstraZeneca, Janssen-Cilag, Gilead, Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants. Lysak: Novartis, Janssen-Cilag, AbbVie; AstraZeneca: Honoraria, Research Funding. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Ferrant: AbbVie: Honoraria, Other: Travel, Accommodations, Expenses; AstraZeneca: Honoraria; Janssen: Other: Travel, Accommodations, Expenses. Diels: Janssen: Current Employment. Cabrieto: Janssen: Current Employment. Nielsen: Janssen: Current Employment. Salles: Allogene: Consultancy; Regeneron: Consultancy, Honoraria; Velosbio: Consultancy; Takeda: Consultancy; Rapt: Consultancy; Genentech/Roche: Consultancy; Epizyme: Consultancy, Honoraria; Debiopharm: Consultancy; Genmab: Consultancy; Incyte: Consultancy; Ipsen: Consultancy; Janssen: Consultancy; Kite/Gilead: Consultancy; Loxo: Consultancy; Miltneiy: Consultancy; Morphosys: Consultancy, Honoraria; Novartis: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria.

Ethnic Disparities in Waldenström's Macroglobulinaemia in the United Kingdom - Analysis from the Wmuk Rory Morrison Registry

Introduction: Waldenström's Macroglobulinaemia (WM) is a rare indolent B-cell lymphoma characterised by lymphoplasmacytic infiltrate with an IgM paraproteinaemia. Approximately 400 patients (pts) are diagnosed annually in the United Kingdom (UK). National and regional registries provide important insights on the epidemiology and clinical features of this distinct uncommon disorder. Previous authors from the United States have reported significant differences in age at diagnosis and overall survival (OS) in WM between ethnic groups from Surveillance, Epidemiology and End Results data [1]. We aimed to determine baseline demographics, symptoms and survival outcomes across different ethnic groups in the UK.Methods: We retrospectively reviewed data from the WMUK Rory Morrison Registry, collating descriptive data of WM as well as non-IgM Lymphoplasmacytic lymphoma (LPL) cases from 20 centres across the UK, diagnosed between June 1978 and May 2021. Research ethics approval was obtained.Results: 732 pts with documented ethnicity were included here. Ethnicity was categorised in accordance with the UK National Census. Those other than the White cohort (662/732; 90%) were collectively termed ‘Ethnic Minorities’ (EM) (70/732; 9%): 39/70 (56%) Asian (13 Indian, 6 Chinese, 4 Pakistani, 16 other); 19/70 (27%) Mixed (1 White & Black African, 1 White & Asian, 1 Arab, 16 other); 12/70 (17%) Black (6 Caribbean, 3 African, 3 other).Baseline characteristics are displayed in table 1. EM presented at a significantly younger age compared to White cohort (60 vs 64 years, p=0.01) and had a significantly lower paraprotein at diagnosis (11 vs 18g/L, p=0.05). MYD88 L265P mutation tested in 250 pts (34%): positive in the majority 218/250 (87%) and notably less common in EM (p=0.09), most significantly in the Asian cohort compared to White (67% v 88%, p=0.01). The EM cohort had a smaller proportion of WM diagnoses compared to White cohort (77% vs 93%, p=0.02) with the Asian cohort accounting for the highest proportion of non-IgM LPL (15% vs 4%, p=0.002). Bone marrow trephine infiltration at diagnosis was lower in the EM cohort compared to the White cohort, although not statistically significant (25% vs 37%, respectively; p=0.10). IPSSWM scores were similar throughout.Approximately half of both the White & EM cohorts were asymptomatic at diagnosis. The most common presenting symptoms in EM were anaemia-related (10/34; 29%), B symptoms (6/34; 18%) and fatigue (4/34; 12%). 6/18 (33%) of Asians presented with cryoglobulinaemia, amyloid, nephropathy or acquired von Willebrand's Disease.Of EM, 51/70 (73%) had treatment, 35/51 (69%) within the first year from diagnosis with time to treatment 2 months (range 0-364). Time to next therapy was 14 months. Median lines of therapy were 2 (range 1-8). The most common indication for first line therapy was lymphoma-related (16/39; 41%) followed by paraprotein-related (peripheral neuropathy, hyperviscosity and autoimmune) (13/39; 33%). First line therapies included Bendamustine-Rituximab (BR; 8/49; 16%), Dexamethasone Rituximab Cyclophosphamide (DRC; 7/49; 14%) and R-CHOP (5/49; 10%) with smaller proportions receiving Rituximab monotherapy, Cladribine + Rituximab or Fludarabine + Cyclophosphamide + Rituximab (FCR) (3/49 (6.1% each). Two of 41 (5%) of EM had first treatment as a part of a clinical trial, compared to 16/156 (10%) of the White cohort (p=0.28). Response to first line therapy was similar between the White & EM cohorts (Table 1).For EM, at a median follow up of 7 years, 17 died (1/17; 6% disease related). Median OS was not reached (Figure 1). Estimated 5-year and 10- year OS was 91% (95% CI 96-80%) and 75% (95% CI 85-60%), respectively.Conclusions: This first report on ethnic disparities in WM and non-IgM LPL in the UK identified key differences in presentation of disease. Ethnic minorities present at a younger age, with a lower paraprotein. The Asian cohort had a greater proportion of non-IgM LPL cases and fewer MYD88 mutated cases. A small proportion of Ethnic Minorities have treatment on a clinical trial which may warrant further attention. Further analysis including associations with socioeconomic status, deprivation indices and comorbidities are ongoing.•Ailawadhi, Sikander et al. “Outcome disparities among ethnic subgroups of Waldenström's macroglobulinemia: a population-based study.” Oncology vol. 86,5-6 (2014): 253-62. doi:10.1159/000360992 DisclosuresMcCarthy: Janssen: Honoraria; Astra zenica pharmaceuticals: Honoraria; Amgen: Honoraria. Pratt: Amgen: Consultancy; Binding Site: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy; Janssen: Consultancy; Takeda: Consultancy. El-Sharkawi: AbbVie: Honoraria, Other: Travel Support, Ad boards; AstraZeneca: Honoraria, Other: Ad boards; Janssen: Honoraria, Other: Ad boards; Roche: Honoraria; Takeda: Honoraria; Novartis: Other: Travel Support; ASTEX: Other: Ad boards; Beigene: Other: Ad boards; Kyowa Kirin: Other: Ad boards. Linton: Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aptitude Health: Honoraria; Hartley Taylor: Honoraria; Celgene: Research Funding; BeiGene: Research Funding; University of Manchester: Current Employment. Gatto: Roche: Consultancy. D'Sa: Janssen Cilag: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding; Sanofi: Honoraria.

Frontline Treatment of the Young, Fit Patient with CLL: A Canadian Perspective.

From a Canadian perspective, there has been a limited discussion on the frontline management of young, fit patients with chronic lymphocytic leukemia (CLL). The prevalence of this population ranges between 2 and 22 per 100,000 persons in Canada and varies by region. Until recently, fixed-duration fludarabine-based chemoimmunotherapy (CIT) was the primary treatment option in Canada for this patient population. The ECOG1912 trial has since demonstrated that ibrutinib and rituximab therapy are as effective as fludarabine-cyclophosphamide-rituximab (FCR) in this population. The ALLIANCE trial showed that rituximab added no incremental benefit to ibrutinib. Canadian payors and physicians adopted ibrutinib monotherapy as the CLL standard of care, even in the young, fit population, although frontline ibrutinib therapy is often reimbursed by provincial public drug plans only in patients with high-risk disease or those who are unfit to receive fludarabine. Young, fit patients with CLL and their physicians may now choose between continuous ibrutinib monotherapy and fixed-duration CIT with FCR. Factors affecting this choice include patient preference and the short- and long-term toxicity profiles of both regimens, and a risk-based algorithm is provided. As new continuous-therapy options enter the market, all treatment choices present benefits and risks that must be communicated to the patient.

TP53 Mutations with Low Variant Allele Frequency Predict Short Survival in Chronic Lymphocytic Leukemia.

In chronic lymphocytic leukemia (CLL), TP53 mutations are associated with reduced survival and resistance to standard chemoimmunotherapy (CIT). Nevertheless, the clinical impact of subclonal TP53 mutations below 10% to 15% variant allele frequency (VAF) remains unclear. Using a training/validation approach, we retrospectively analyzed the clinical and biological features of TP53 mutations above (high-VAF) or below (low-VAF) the previously reported 10.0% VAF threshold, as determined by deep next-generation sequencing. Clinical impact of low-VAF TP53 mutations was also confirmed in a cohort (n = 251) of CLL treated with fludarabine-cyclophosphamide-rituximab (FCR) or FCR-like regimens from two UK trials. In the training cohort, 97 of 684 patients bore 152 TP53 mutations, while in the validation cohort, 71 of 536 patients had 109 TP53 mutations. In both cohorts, patients with the TP53 mutation experienced significantly shorter overall survival (OS) than TP53 wild-type patients, regardless of the TP53 mutation VAF. By combining TP53 mutation and 17p13.1 deletion (del17p) data in the total cohort (n = 1,220), 113 cases were TP53 mutated only (73/113 with low-VAF mutations), 55 del17p/TP53 mutated (3/55 with low-VAF mutations), 20 del17p only, and 1,032 (84.6%) TP53 wild-type. A model including low-VAF cases outperformed the canonical model, which considered only high-VAF cases (c-indices 0.643 vs. 0.603, P < 0.0001), and improved the prognostic risk stratification of CLL International Prognostic Index. Clinical results were confirmed in CIT-treated cases (n = 552) from the retrospective cohort, and the UK trials cohort. TP53 mutations affected OS regardless of VAF. This finding can be used to update the definition of TP53 mutated CLL for clinical purposes.

Single-Agent Ibrutinib Vs Chemoimmunotherapy Regimens for Treatment-Naïve Patients with Chronic Lymphocytic Leukemia (CLL): A Cross-Trial Comparison

Single-Agent Ibrutinib Vs Chemoimmunotherapy Regimens for Treatment-Naïve Patients with Chronic Lymphocytic Leukemia (CLL): A Cross-Trial Comparison

BRAF and BIRC3 Mutations Stratify a Poor Prognostic Subgroup in FCR Treated Chronic Lymphocytic Leukemia

Abstract Background. The current shift of therapy of chronic lymphocytic leukemia (CLL) towards novel targeted agents mandates the recognition of molecular predictors to identify patients who can still benefit from chemoimmunotherapy and those who should instead be considered for novel targeted agents upfront. In the case of FCR (fludarabine, cyclophosphamide, rituximab), the IGHV mutation status and FISH karyotype stratify low-risk patients carrying mutated IGHV genes and devoid of both del11q and del17p who maximally benefit from such treatment; intermediate-risk patients harboring unmutated IGHV genes and/or del11q in the absence of del17p are a case mix of good and poor responders to FCR; while high-risk patients harboring del17p are unsuitable for chemoimmunotherapy. This model fails to consider the impact of recurrent CLL mutations of potential prognostic relevance, which may be improved by their inclusion. Purpose. We aimed at refining the genetic-based stratification of FCR-treated CLL patients by integrating the mutational profile in a prognostic model together with the IGHV mutation status and FISH karyotype. Methods. A multicenter cohort of 173 (162 with complete molecular data) untreated CLL receiving first-line therapy with FCR in the real-life clinical practice was evaluated by target resequencing. Tumor genomic DNA collected at the time of treatment was analyzed for mutations in the coding exons plus splice sites of CLL cancer driver genes (n=23). Deep next-generation-sequencing (NGS) of the gene panel was performed on the Illumina MiSeq platform (coverage >2000x in >90% of the target). Non-synonymous mutations represented in >10% of tumor allele were called by using VarScan2, and a stringent bioinformatic pipeline was developed to protect against the false call of polymorphisms and sequencing errors. Medical statistics was performed using SPSS version 24.0 and R version 3.3.2. Results. The cohort characteristics and mutational profile were consistent with those reported in CLL receiving FCR as initial treatment. After a median follow-up of 7.2 years, 114 patients progressed, accounting for a median PFS of 4.5 years. Among patients categorized as low-risk by IGHV and FISH status, gene mutations associated with poor prognosis were virtually absent (Fig. 1A). By univariate analysis, none of the cancer driver gene mutations significantly associated with PFS among low-risk patients. Consistently, by recursive partitioning, the proportion of low-risk patients failing FCR early was not explained by the co-occurrence of a cancer driver gene mutation. Among patients categorized as intermediate-risk by IGHV and FISH status, mutations of BIRC3 (HR: 6.452; 95% CI 2.467-16.875; p Download : Download high-res image (256KB) Download : Download full-size image Disclosures Forconi: AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding; Janssen-Cilag: Speakers Bureau. Zaja: Novartis: Honoraria, Research Funding; Janssem: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Honoraria; Gilead: Honoraria. Rigolin: Celgene: Honoraria, Other: Advisory Board; Mundipharma: Other: Advisory Board; Gilead: Honoraria. Coscia: Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Tedeschi: AbbVie: Consultancy; Gilead: Consultancy, Other: travel expenses; Janssen: Consultancy, Other: travel expenses. Laurenti: Roche: Other: Advisory Board; Gilead: Other: Advisory Board; Janssen: Other: Advisory Board; Abbvie: Other: Advisory Board. Cuneo: Gilead: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Abbvie: Honoraria, Other: Advisory Board; Roche: Honoraria, Other: Advisory Board. Foa: AbbVie: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Sandoz: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau. Gaidano: Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

Real-World Outcomes of Chemoimmunotherapy in Chronic Lymphocytic Leukemia (CLL) Clinical Practice: Results from a Decade of Practice in Helsinki 2005-2015

Introduction: Around 350 new CLL cases are diagnosed annually in Finland, with approximately 1800 individuals living with the disease. However, no comprehensive disease outcome studies from clinical practice have been conducted to-date. In the absence of direct head-to-head trials, robust historical control data have become requisite to complement available clinical trial data and estimate the potential effects of novel therapies in local practice. In addition, patients (pts) in routine clinical care are far more heterogeneous than those included in clinical trials. The Finnish Hematology Registry (FHR) was created to collect real-world practice outcomes in CLL and other hematological malignancies, with Finland's centralized nationwide healthcare system allowing reliable pt identification and complete follow-up. The objective of this registry study is to describe treatment and survival outcomes for CLL pts from routine practice settings.Methods: A non-interventional, retrospective study design was used to collect routine clinical practice data from the FHR. Eligible pts aged ≥18 years diagnosed with CLL and receiving 1 or more treatment lines during 2005-2015 were identified from the FHR, with groupings of pts into those treated in the early (2005-2007), middle (2008-2010) and late (2011-2015) cohort time periods. As the registry had limited CLL pt data at study start, clinical investigators accessed medical records to retrieve and validate data. We report interim results on 66 pts from the Helsinki University Hospital, Helsinki, Finland, a hospital region accounting for 30% of the total national CLL incidence. The completion and validation of the Helsinki cohort (~130 pts) is ongoing and results from the whole dataset will be presented at ASH.Results: Median age at diagnosis was 67 years and 23% had Binet stage C. Longitudinal follow-up was available from 1st to 7th or higher treatment lines. Across all treatment lines, fludarabine-cyclophosphamide-rituximab (FCR) (52%), bendamustine-rituximab (BR) (48%), fludarabine-cyclophosphamide (FC) (27%), and chlorambucil (chl) -based therapies (24%) were the most frequently used treatments. FCR (48%) and FC (27%) were frequently used in the 1st line, whereas BR (34%) was the primary choice in the 2nd line. In later lines a wide array of treatment regimens were used. Only 2 pts received the novel agent ibrutinib as part of a named patient program; no other novel agents were used in this cohort during this period.FC and FCR were initiated in equal yet constantly decreasing proportions through 2008, when FCR became most common (0% FC vs. 40% FCR). A year later in 2009, BR was introduced into clinical practice and its use increased steadily from 14% to 30% through 2014 when its use then declined. The peak year of chl monotherapy or chl-based combinations was in 2006 with 38% of pts receiving chl-based treatment. Since then chl use has decreased dramatically, to 0% in 2015.Median overall survival (OS) from the start of any given 1st line treatment was 81 months (m). Pts receiving FC (p=0,009) and FCR (p<0,001) had significantly longer median OS (79 m and 82 m respectively) compared to bendamustine/BR (62 m) when given in the 1st line. FC and FCR resulted in longer, though not statistically different, time-to-next-treatment (TTNT) compared to bendamustine/BR (77 m vs 44 m). Despite the observed practice changes over the years, there were no detectable outcome differences in 1st and 2nd line median OS between those treated in early, middle and late time periods, possibly due to limited follow-up in the later period (data not shown).Conclusions: We describe real-world treatment trends and outcomes from a decade of practice in the Helsinki region. Our results show that chemoimmunotherapies have been vigorously implemented in clinical practice. However, interim results do not show detectable improvements for OS and TTNT during this decade of treatment in the Helsinki hospital region. In the Nordics, real-world evidence has become essential when introducing novel targeted therapies into clinical practice settings, with comprehensive disease registries expanding to allow for more detailed follow-up. [Display omitted] DisclosuresJarvinen:Janssen-Cilag Oy: Employment. Mehtälä:EPID Research: Employment, Other: EPID Research is a contract research organization that performs commissioned pharmacoepidemiological studies and thus its employees have been and currently are working in collaboration with several pharmaceutical companies.. Khanfir:EPID Research: Employment, Other: EPID Research is a contract research organization that performs commissioned pharmacoepidemiological studies and thus its employees have been and currently are working in collaboration with several pharmaceutical companies.. Juuti:EPID Research: Employment, Other: EPID Research is a contract research organization that performs commissioned pharmacoepidemiological studies and thus its employees have been and currently are working in collaboration with several pharmaceutical companies.. Leval:Janssen-Cilag Ab: Employment.

Clinical, Genomic Profile and Recurrent Somatic Mutations in 205 Chronic Lymphocytic Leukemia Treatment-Naive Patients

BackgroundNext generation sequencing (NGS) approaches have transformed our understanding of the genetic heterogeneity of Chronic lymhocytic leukemia (CLL). However, the detection of somatic mutations and their relative frequencies is variable, which possibly reflects differences in the composition of the cohorts studied worldwide and the time point during the course of the disease when they were tested.Considering the landscape of genomic alterations recently identified in CLL as well as the availability of new targeted therapies, it is warranted to accurately predict outcome at the individual patient level. An international prognostic index (CLL-IPI) and the molecular index (M-IPI) are promising scoring systems to improve the precision of prognostic counseling.AimThe aims of the study were: 1) To characterize CLL patients not previously treated according to their biological profile and their impact on the prognosis; 2) To test the hierarchical of both stratification models in general practice.Patients and methodsWe included 205 patients consecutively diagnosed of CLL between 1986 and 2016 with available DNA at diagnosis. Clinical and biological data were extracted from medical records. IGVH mutational status were identify according to the updated ERIC recommendations. A custom panel designed by Sequencing Multiplex was used to investigate somatic mutations with MiSeq platform. It included the following genes; TP53 (all), BIRC3 (ex 7-9), SF3B1 (ex 14-16), MYD88 (ex 5), and NOTCH1 (ex 34), ATM (all), XPO1 (ex 15-16), EGR2 (ex 2), POT1 (ex 4-9) and NFKBIE (ex 1).Bioinformatics analysis was achieved by Strand-NGS. The statistical analysis was completed with SPSS Version 20.0 and R Version 2.15.1 software. Times to first-treatment (TFT) curves were plotted using the Kaplan-Meier method and compared by the log-rank test.ResultsMedian age was 64 years (range, 32-93) with a 1.2:1 ratio of males to female. The median follow-up was 76 (1-295) months. In our cohort, 166 (83%) patients were in Binet A, and 34 (17%) Binet B-C. Concerning Rai stage 123 (61,5%) were Rai 0 and 77 (38,5%) Rai I-IV. In 118 out of 203 (58,1%) IGVH was germline.The most frequent cytogenetic abnormalities was del(13q) in 61 (32,1%), following +12 in 39 (10,5%), del (17p) in 11 (5,9%) and del(11q) in 8 (4,2%) and 17 missed data.Regarding the molecular data, 61 (29,8%) carried ATM mutation, 30 (14,6%) harbored a TP53 mutation, 26 (12,7%) NOTCH1, 24 (11,7%) NFKBIE, 22 (107 (3,4%) BIRC3, 6 (2,9%) POT1 and 2 (1%) carried a MYD88 hotspot p.L265P mutation. Among the 40 patients with TP53 disruption, 29 had TP53 mutations, 11 had only del(17p) and 6 had both of them. Frequencies and distributions of mutations, genomic aberrations, IGHV status and need of treatment are illustrated in Figure 1.At least 1 mutation was identified in 109 of 171 (63,7%) patients; 60 (35,1%) patients had 1, 34 (19,9%) had 2, 13 (7,6%) had 3, and two cases had 4 and 5 mutations respectively. Cooccurrence of genomic aberrations with mutations for all patients are shown in Figure 2.Most frequent chemotherapy schedules were: Fludarabine-cyclophosphamide-rituximab (FCR) 39 (36,1%), Chlorambucil 36 (33,3%), bendamustine-rituximab 26 (24,1%), Obinutuzumab-Rituximab 4 (2%) and Ibrutinib 3 (1,5%). Five patients transformed into Richter syndrome.Presence of TP53 mutations significantly correlated with unmutated IGVH, increased β2-microglobulin levels, CD38 expression, Richter's Syndrome development and treatment requirement. ATM mutations associated with unmutated IGVH, LDH increased levels and del(11q). Either, IPI-CLL and molecular-IPI identified 4 groups with significantly different outcome in terms of TFT although this difference was marginal in the high and very high categories. The percentage of patients in each group identified by the two scores as well as the TFT is detailed in Figure 3. In our series, IPI-CLL discriminated better than molecular-IPI, (p<0,0001 and 0.011, respectively).ConclusionsIn our cohort, gene mutations frequencies were very similar to those previously described in the literature. Our study highlights that both CLL-IPI and M-IPI are useful tools for real-life practice as both identified four group of patients with significantly different TFT times.Samples provided by INCLIVA Biobank (PT13/0010/0004). Study supported by: FISS PI 10/02095, FISS PI 14/02018, FEHH (Spanish Hematologic Fundation) [Display omitted] DisclosuresSolano:Neovii: Honoraria.

Epidemiology, longitudinal treatment patterns and outcomes of chronic lymphocytic leukemia in Israel

This study aims to describe chronic lymphocytic leukemia (CLL) epidemiology, treatment patterns and outcomes in a 2.3-million-member healthcare provider database (Maccabi Healthcare Services, Israel). Newly-diagnosed CLL patients (1999–2017) were followed through 31/3/2018. A total of 1857 newly-diagnosed CLL patients were included. Annual incidence was 5.82 per 100,000 population. Median overall survival (OS) was 12.7 (95%CI: 11.8–13.5) years since diagnosis. Approximately 1/3 initiated treatment within 5 y. A statistical trend (p = 0.066) for improved OS over time was observed among younger patients (age <70 y) treated in 2009–2017 vs. 1999–2008). Among patients treated since 2009 (n = 411; median age = 68y), fludarabine–cyclophosphamide–rituximab (FCR), bendamustine–rituximab and obinutuzumab ± chlorambucil accounted for 19.5%, 12.2% and 11.4% of first line, respectively. Median (95%CI) time to next treatment and OS were 3.1(2.6–3.6) and 7.0(6.3–7.7) years, respectively. CLL incidence in Israel is comparable to developed countries. Real-world data suggest a trend of improved survival over the last decade among patients treated before age 70.

Evolving Treatment Patterns in Chronic Lymphocytic Leukemia Among Experts and Community Practitioners: Analysis of an Online Decision Support Tool

Evolving Treatment Patterns in Chronic Lymphocytic Leukemia Among Experts and Community Practitioners: Analysis of an Online Decision Support Tool

Prognostic Significance of PET/CT in Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Frontline Chemoimmunotherapy.

The role of positron emission tomography/computed tomography (PET/CT) in identifying Richter Syndrome (RS) is well established, while its impact on the survival of patients with chronic lymphocytic leukemia (CLL) has been less explored. The clinical characteristics and PET/CT data of 40 patients with a biopsy-proven CLL who required frontline chemoimmunotherapy, FCR (fludarabine, cyclophosphamide, rituximab) in 20 patients, BR (bendamustine, rituximab) in 20, were retrospectively analyzed. Standardized uptake volume (SUVmax) values ≥ 5 were observed more frequently in patients with deletion 11q (p = 0.006) and biopsies characterized by a rate of Ki67 positive cells ≥ 30% (p = 0.02). In the multivariate analysis, the presence of large and confluent PCs emerged as the only factor with a negative impact on progression-free survival (PFS), and overall survival (OS). Deletion 11q also revealed a significant and independent effect on PFS. SUVmax values ≥ 5 showed no statistical impact on PFS while in multivariate analysis, they revealed a significant adverse impact on OS (median survival probability not reached vs. 56 months; p = 0.002). Moreover, patients with higher SUVmax values more frequently developed Richter Syndrome (p = 0.015). Our results show that higher SUVmax values identify CLL patients with a pronounced rate of proliferating cells in the lymph-node compartment, inferior survival, and an increased risk of developing RS.