Chronic Lymphocytic Leukemia Registry Research Articles

Real-World Treatment Patterns and Outcomes by Line of Therapy and Race in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Treated in the United States: Results From the Final Analysis of the Prospective, Observational, informCLL Registry

BackgroundinformCLL is the largest US-based prospective, observational registry of patients with chronic lymphocytic leukemia (CLL) initiating FDA-approved treatment in the era of targeted therapy. Patients and MethodsPatients were enrolled between October 2015 and June 2019. Data were collected for baseline characteristics, treatment patterns, outcomes, and safety. ResultsIn total, 1459 eligible patients were enrolled (first line, n = 854; relapsed/refractory, n = 605). The most common index treatments were ibrutinib (first line, 45%; relapsed/refractory, 49%) and chemoimmunotherapy (first line, 43%; relapsed/refractory, 20%). With median follow-up of 31.8 and 30.9 months in first-line and relapsed/refractory cohorts, respectively, median time to next treatment (TTNT) in patients who received any index treatment was not reached (NR) and 48.6 months; estimated proportions without next-line therapy at 48 months were 64% and 50%. Median overall survival (OS) was NR for both cohorts; estimated 48-month OS rates were 81% and 64% in first-line and relapsed/refractory cohorts, respectively. In match-adjusted analyses, TTNT was improved with first-line ibrutinib versus chemoimmunotherapy (median NR vs. 56.5 months; hazard ratio, 0.74; 95% CI, 0.56-0.98). Exposure-adjusted rates of AEs leading to discontinuation and serious AEs were lower with ibrutinib versus chemoimmunotherapy. Estimated 36-month OS rates were similar in Black versus White patients who received any index treatment (first line, 87% vs. 83%; relapsed/refractory, 74% vs. 74%) or ibrutinib (first line, 97% vs. 85%; relapsed/refractory, 81% vs. 77%). ConclusionIn this prospective, large, real-world CLL registry, first-line ibrutinib was associated with longer TTNT than chemoimmunotherapy, with sustained benefit up to 4 years of follow-up.

Identifying CLL Patients at High Risk of Infection on Treatment Using Machine Learning

Background. Targeted therapies, including BTK inhibitors like ibrutinib, have transformed the treatment of patients with chronic lymphocytic leukemia (CLL), improving overall survival and progression-free survival, in particular for patients with the most aggressive CLL disease. However, due to relapse after stopping treatment and the rarity of reaching undetectable minimum residual disease, treatment with ibrutinib requires long-term maintenance therapy. Thus, adverse events (AEs) may have a great impact on the patient's quality of life and overall survival. Several studies have reported higher risk of AEs including severe infections, bleeding, and cardiac events like atrial fibrillation (AF) and hypertension in CLL patients treated with ibrutinib. Identifying patients that might be at a higher risk of developing AEs at the time of treatment initiation could inform individualized treatment and may reduce morbidity and mortality. In this study, we used Machine learning (ML) to predict the risk of developing severe infection (≥ grade 3) after treatment with ibrutinib and/or other standard treatment regimens. Methods. The dataset consisted of 647 patients with CLL that were treated prior to December 2020. Using the Danish CLL registry, the Persimune data warehouse, and Electronic Health Record (EHR) data sources, we extracted baseline features such as age (at the diagnosis and treatment), sex, body mass index (BMI), smoking status, and a range of medical features (with cut-off date set as the date of treatment initiation) including routine laboratory tests, microbiology cultures, known CLL prognostics and historical data on previous infections and type of treatments. The treatment data and AEs were collected by manual review of EHRs as well as through direct data extraction. Features with more than 80% missing values were discarded. For continuous features, missing values were imputed by the mean value of each feature estimated from the training set. Overall, 167 features were used in the modeling. Since some patients received multiple lines of treatment, the dataset consisted of 1400 events of patients receiving treatment. Using an ML algorithm (XGBoost), Cox regression analyses were performed to predict severe infections (≥ Grade 3). Stratified group cross-validation was used to preserve the proportion of samples with severe infection across splits. The contribution of each feature across the study was measured using SHapley Additive exPlanations (SHAP). Results. We identified a high-risk and a low-risk group with 57% and 28% estimated risk of a severe infection within one year of treatment initiation, respectively (Figure 1). The median survival times for the high-risk and low-risk group were 7 (CI%95: 5.0-12.4) and 44 (CI%95: 39.0-56.2) months, respectively. The model could also discriminate the risk of infection within the group of ibrutinib treated and non-ibrutinib treated patients. A c-index of 0.687 (CI%95: 0.649-0.725) for all treatments, 0.672 (CI%95: 0.647-0.696) for ibrutinib, and 0.659 (CI%95: 0.597-0.721) for other treatments (including all treatments except ibrutinib) were achieved using 4-fold cross-validation. To assess impact of different features on the risk of severe treatment related infection, we performed SHAP analysis of feature contribution (Figure 2). The results showed that the targeted therapy (Targeted treatment) and ibrutinib treatment correlated with increased risk of infection. This may in part reflect that targeted therapy was primarily used for patients with aggressive CLL (TP53 aberration and/or relapsed/refractory CLL). In addition, the number of blood cultures drawn prior to treatment correlated with the risk of severe infection. Furthermore, several routine laboratory tests measuring immunoglobulin G, c-reactive protein, and high-density lipoprotein levels were predictive of severe infection. Conclusion. This study confirms the advantage of an ML based approach to stratify patients with CLL prior to initiation of treatment for risk of severe infections within and across treatment regimens. As infections are the main cause of death in CLL, this represents the first steps towards individualized therapy based on risk of AEs. Future work will focus on predicting cardiac events including AF. Validation of the findings in clinical trial populations and other real world data cohorts are awaited before clinical implementation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CENTRAL NERVOUS SYSTEM INFILTRATION IN CHRONIC LYMPHOCYTIC LEUKEMIA: A STUDY ON BEHALF OF THE REGISTRO BRASILEIRO DE LEUCEMIA LINFOCITICA CRONICA

Central nervous system (CNS) infiltration in chronic lymphocytic leukemia (CLL) is a rare presentation of CLL that can potentially have disastrous complications. Reported prognosis is poor. The objective of this study is to report a series of cases of CLL with CNS infiltration. This is a case-series of a Brazilian CLL registry (Registro Brasileiro de Leucemia Linfocitica Cronica). We included patients with CLL and CNS infiltration. This is a descriptive study. A total of 10 (0.28%) in 3610 patients were identified with confirmed (80%) or suspected (20%) CNS infiltration. Median age at CLL diagnosis was 57.5 y/o (range: 50 – 76). Three (30%) patients were diagnosed with CNS infiltration concomitantly with the CLL diagnosis, while others (70%) were diagnosed at a median of 41 months of CLL diagnosis (range: 11 to 119 months). Only three (30%) patients had been previously treated for CLL. Most common symptoms of CNS infiltration were convulsion (30%), altered mental status (30%), headaches (30%), ophthalmologic (30%), and urinary incontinence (20%). Amnesia, asthenia, vomiting, hemiparesis, cervicalgia, and dizziness were also present (one patient each). Of the patients with confirmed CNS infiltration, diagnoses were performed through liquor exam (all patients) and biopsy (one patient). Of the two patients with suspected CNS infiltration, one achieved complete response and the other, partial clinical response, following instituted CLL-directed therapy with (1 patient) or without (1 patient) intrathecal chemotherapy. Of the other 8 patients, 3 achieved complete response, 2 failed treatments, 1 was not evaluated and 2 had missing information. Of all patients, 5 are alive, 3 died of sepsis, multiorgan failure following CNS methotrexate-related toxicity, and COVID, and 2 had missing information. Our results show that the prognosis of CNS infiltration in CLL can be relatively good, with at least 50% of patients alive at 1 year. However, a series of 18 patients published by Strati et al has shown a poorer outcome, with half of the patients dead at 1 year. Although all patients were diagnosed by liquor exam, that same study reported a low specificity for liquor exam in CLL (42%) due to the frequent presence of leukemic cells in the cerebrospinal fluid in other conditions. Establishing CNS CLL as the cause of the symptoms can be difficult, since up to 70% of patients with CLL have CNS infiltration in autopsy studies, and our results may be superestimated. In summary, CNS infiltration in CLL is a rare event, and further studies are needed to address prognosis and management.

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.

Single-Agent Ibrutinib Versus Real-World Treatments for Patients with Treatment-Naïve Chronic Lymphocytic Leukemia: Adjusted Comparison of Resonate-2™ with Real-World Databases

Single-Agent Ibrutinib Versus Real-World Treatments for Patients with Treatment-Naïve Chronic Lymphocytic Leukemia: Adjusted Comparison of Resonate-2™ with Real-World Databases

Bacterial Infections in Patients with Chronic Lymphocytic Leukemia: A Longitudinal Nation-Wide Study

BackgroundBacterial infections remain one of the most important clinical problems in patients with chronic lymphocytic leukemia (CLL) causing significant morbidity and implicated in a third of all deaths among patients with CLL. Identification of bacterial infection by a culture is an important prognostic finding. Several studies have evaluated the incidence and type of bacterial infections in CLL, but often these have only evaluated bacteremia and patients who have been treated in a protocol.AimThe aim of the present study is to estimate incidence rates of- and risk factors for microbiologically verified bacterial infections in a nationwide cohort of treated as well as untreated patients with CLL.MethodsWe used the Danish National CLL registry to identify all patients diagnosed with CLL between 2008 and 2016. From the Danish National Microbiology database and the PERSIMUNE data warehouse we collected data on all microbiologically verified bacterial infections in these patients between January 2010 and April 2017. The study was approved by the Danish data protection agency and the Danish health authorities.ResultsWe identified 3720 CLL patients with 12,833 person-years of follow-up (median 3.1 years). Within our study period 913 patients had received treatment for CLL.A total of 26562 cultures (12,987 blood, 8,607 urine, 658 airway) were collected among 2377 patients during the study period. Of the blood cultures, 755 (5.8 %) were positive and 229 (1.7 %) were defined as possibly contaminated. Among the 755 positive blood cultures the microorganisms identified were Escherichia coli (188, 24.9 %), Enterococcus faecium (81, 10.7 %), Staphylococcus aureus (73, 9.7%), Streptococcus pneumoniae (72, 9.5 %).The rates of positive blood cultures for untreated and treated patients were 0.03 and 0.16 per patient year, respectively.ConclusionWe here report the largest study to date on bacterial infections in a nationwide cohort of consecutive CLL patients. By characterizing type of infection, we will be able to identify different patterns of infections in treated as well as untreated CLL patients and to identify risk factors for specific types of infections. This knowledge should be used to personalize prophylactic interventions as well as the initial treatment of infections in CLL patients. Further, results of this study could be used to guide prophylactic measures for specific subgroups of patients, which should be tested in prospective clinical trials. DisclosuresNiemann:The Danish Cancer Society: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding; Novo Nordisk Foundation: Research Funding; Novartis: Other: Travel grant; Roche: Consultancy, Other: Travel grant.

CLL-395: Real-World Data from the Turkish National Chronic Lymphocytic Leukemia Registry

Objective We have previously established a nationwide registry to obtain real-world data to document the demographics and treatment outcomes of Turkish CLL patients. Patients or other participants Patients who were diagnosed with CLL and over 18 years of age were included in the study. Data were collected starting from January 2017 from 20 centers that were located in different geographic parts of Turkey. Results A total of 652 patients were enrolled in the study. Median age of the patients was 62. Median follow-up time was 25 months; 63.2% of the patients were male, 41.7% of the patients had RAI-0 disease, and only 17.3% had RAI-3 or 4 disease. Twenty-four percent of the patients had a CIRS score of more than 2. Only 23% of the patients required at least one line of treatment. Two percent of the patients died during the follow-up. Median number of lines of treatment was 1 (1–-5): 32% of the patients required two or more lines of treatment, and 50% of the patients received Fludarabin-based chemo-immunotherapy as a frontline treatment option, and this was followed by Bendamustine-based chemo-immuno-therapy in 15% of the patients. The use of novel agents such as BTKi or BCL2i increased by the third line of treatment, in line with the reimbursement policy in Turkey. CR rates declined dramatically with further lines of treatment, starting from 55.5% for the first to 25% for the third line of treatment. None of the patients were able to achieve CR in fourth or fifth line of treatment. Median time to next treatment for the first line was 33.4 months. Conclusions In Turkey, the median age at the time of diagnosis is less when compared with other countries. Even a though a high proportion of the patients weas not able to access modern treatment options such BTKi or BCL2i, the mortality rate was low in this first report. We will be updating the results of this real-world registry on a yearly basis and providing data with a longer follow-up.

Longitudinal health-related quality of life in first-line treated patients with chronic lymphocytic leukemia: Results from the Connect® CLL Registry.

Health‐related quality of life (HRQoL) in patients with chronic lymphocytic leukemia (CLL) is important in guiding treatment decisions. However, the impact of CLL treatment initiation on HRQoL is unclear. We assessed HRQoL using the FACT‐Leu and EQ‐5D‐3L questionnaires in the Connect ® CLL Registry, a large, US‐based, multicenter, prospective observational study of CLL patients enrolled between 2010 and 2014, prior to the introduction of novel therapies. Among 889 patients initiating first‐line therapy with chemoimmunotherapy or rituximab monotherapy, questionnaire completion rates were 95.7% and 95.8% at enrollment, and 70.8% and 69.4% at 12 months, for FACT‐Leu Total and EQ‐5D‐3L, respectively. For 849 patients completing all five FACT‐Leu components, average total scores were 135.7 at enrollment and 141.6 at 12 months. Among 526 patients with FACT‐Leu Total scores at enrollment and 12 months, clinically meaningful (≥11‐point) improvements or reductions were observed in 179 (34.0%) and 88 (16.7%) patients, respectively. Mean EQ‐5D‐3L index scores were 0.87 at enrollment and 12 months. Among 513 patients completing EQ‐5D‐3L at enrollment and 12 months, clinically meaningful (≥0.06‐point) improvements or reductions were observed in 125 (24.4%) and 116 (22.6%) patients, respectively. In the Connect® CLL Registry, HRQoL remained stable or slightly improved after 12 months of follow‐up.

The Connect CLL Registry: final analysis of 1494 patients with chronic lymphocytic leukemia across 199 US sites

Optimal treatment of chronic lymphocytic leukemia (CLL) remains unclear. The Connect CLL Registry, a United States-based multicenter prospective observational cohort study, enrolled 1494 patients between 2010 and 2014 from predominantly community-based settings. Patients were grouped by line of therapy (LOT) at enrollment. With a median follow-up of 46.6 months (range, 0-63.0 months), median overall survival (OS) was not reached in LOT1, 63.0 months (95% confidence interval [CI], 46.0-63.0 months) in LOT2, and 38.0 months (95% CI, 33.0-47.0 months) in LOT≥3. Bendamustine and rituximab (BR; 33.5%); fludarabine, cyclophosphamide, and rituximab (FCR; 21.4%); and rituximab monotherapy (18.5%) were the most common regimens across LOTs. Median event-free survival (EFS) was similar in patients treated with BR (59.0 months) and FCR (55.0 months) in LOT1; median OS was not reached. In multivariable analysis, BR or FCR vs other treatments in LOT1 was associated with improved EFS (hazard ratio [HR], 0.60; P < .0001) and OS (0.67; P = .0162). Using the Kaplan-Meier product limit, ibrutinib vs other treatments improved OS in LOT2 (HR, 0.279; P = .009), LOT3 (0.441; P = .011), and LOT≥4 (0.578; P = .043). Prognostic modeling of death at 2 years postenrollment identified 3 risk groups: low (mortality rate, 6.2%), medium (14.5%), and high (27.4%). The most frequent adverse events across LOTs were pneumonia (11.6%) and febrile neutropenia (6.2%). These data suggest that advantages of LOT1 FCR over BR seen in clinical trials may not translate to community practice, whereas receiving novel LOT2 agents improved outcomes. This trial was registered at www.clinicaltrials.gov as NCT01081015.

IGHV mutational status and outcome for patients with chronic lymphocytic leukemia upon treatment: a Danish nationwide population-based study.

Patients with chronic lymphocytic leukemia and unmutated immunoglobulin heavy-chain variable region gene (IGHV) have inferior survival from time of treatment in clinical studies. We assessed real-world outcomes based on mutational status and treatment regimen in a nationwide population-based cohort, comprising all 4,135 patients from the Danish chronic lymphocytic leukemia registry diagnosed between 2008 and 2017. In total, 850 patients with known mutational status received treatment: 42% of patients received intensive chemoimmunotherapy consisting of fludarabine, cyclophosphamide plus rituximab, or bendamustine plus rituximab; 27% received chlorambucil in combination with anti-CD20 antibodies or as monotherapy, and 31% received other, less common treatments. No difference in overall survival from time of first treatment according to mutational status was observed, while treatment-free survival from start of first treatment was inferior for patients with unmutated IGHV. The median treatment-free survival was 2.5 years for patients treated with chlorambucil plus anti-CD20, and 1 year for those who received chlorambucil monotherapy. The 3-year treatment-free survival rates for patients treated with fludarabine, cyclophosphamide plus rituximab, and bendamustine plus rituximab were 90% and 91% for those with mutated IGHV, and 76% and 53% for those with unmutated IGHV, respectively, and the 3-year overall survival rates were similar for the two regimens (86-88%). Thus, it appears that, in the real-world setting, patients progressing after intensive chemoimmunotherapy as first-line therapy can be rescued by subsequent treatment, without jeopardizing their long overall survival. Intensive chemoimmunotherapy remains a legitimate option alongside targeted agents, and part of a personalized treatment landscape in chronic lymphocytic leukemia, while improved supportive care and treatment options are warranted for unfit patients.

Single-Agent Ibrutinib vs Real-World (RW) Treatments for Patients with Chronic Lymphocytic Leukemia (CLL) and del11q: Adjusted Comparison of RESONATE-2TM and RESONATETM with RW Databases

IntroductionIbrutinib, a first-in-class, oral, covalent inhibitor of Bruton's tyrosine kinase, is approved in many countries for treatment-naïve (TN) and previously treated CLL, supported by improved response rates, progression-free survival (PFS), and overall survival (OS) vs chlorambucil in RESONATE-2™ (NCT01722487; Burger JA, et al. N Engl J Med. 2015;373:2425-2437) and ofatumumab in RESONATE™ (NCT01578707; Byrd JC, et al. N Engl J Med. 2014;371:213-223). We analyzed survival outcomes for ibrutinib vs RW treatments for TN and relapsed/refractory (R/R) CLL by del11q status, an adverse prognostic factor linked with poor patient outcomes despite conventional chemoimmunotherapy. An adjusted comparison restricted to patients with confirmed del11q status was conducted using patient-level data from RESONATE-2™ and RESONATE™ and RW databases from 2 countries.MethodsThe Lyon-Sud RW database holds medical records for CLL patients diagnosed between 1980 and 2017 from the Centre Hospitalier Lyon-Sud, France; the Chronic Lymphocytic Leukemia Registry (CLLEAR) RW database holds medical records for CLL patients diagnosed between 1988 and 2017 from 7 academic centers in the Czech Republic. TN CLL database patients were selected using RESONATE-2™ criteria (which excluded those aged < 65 years or del17p positive). For the R/R group, patients ≥ 18 years of age or those with del17p were allowed per RESONATE™ inclusion criteria. PFS and OS outcomes by del11q status were compared between the ibrutinib arms of RESONATE-2™/RESONATE™ and physicians' choice (PC) treatment in the pooled RW databases (excluding ibrutinib). A multivariate Cox proportional hazards model was fitted on pooled RCT/RW data to estimate adjusted hazard ratios (HRs) for effect of ibrutinib vs RW PC treatment using age, sex, and treatment line as covariates. The unit of observation for the RW databases was the treatment line (rather than patient) number; RW patients receiving multiple lines of therapy contributed to multiple observations, and baseline was defined as the line-specific treatment start date.ResultsFor the RW TN cohort, 466 treatment lines were analyzed; 134 (28.8%) patients were del11q positive. In RESONATE-2™, 29/136 (21.3%) TN patients were del11q positive. The table below shows adjusted HRs for PFS and OS for patients with/without del11q. For the del11q-positive subgroup, adjusted HRs for ibrutinib vs RW PC first-line (1L) therapy were 0.02 (95% confidence interval [CI], 0.00-0.17; p = 0.0002) for PFS and not estimable for OS (no deaths on ibrutinib). For the del11q-negative subgroup, adjusted HRs were 0.34 (95% CI, 0.2-0.57; p < 0.0001) for PFS and 0.74 (95% CI, 0.37-1.49; p = 0.3957) for OS. For second-line (2L) PC treatment in the RW R/R cohort, 385 treatment lines were analyzed; 135 (35.1%) were from del11q positive patients. In RESONATE™, 13 (37.1%) 2L patients were del11q positive. For the del11q-positive subgroup, adjusted HRs for ibrutinib vs RW PC of 2L therapy were 0.03 (0.00-0.21; p = 0.0003) for PFS and 0.08 (0.01-0.46; p = 0.0050) for OS. For the del11q-negative subgroup, adjusted HRs were 0.27 (0.14-0.51; p < 0.0001) for PFS and 0.50 (0.24-1.05; p = 0.0670) for OS. For 2L and beyond (2L+) treatment in the RW R/R cohort, 727 treatment lines were analyzed; 291 (40.0%) were from del11q positive patients. In RESONATE™, 63/195 (32.3%) 2L+ patients were del11q positive. For the del11q-positive subgroup, adjusted HRs (95% CIs) for ibrutinib vs RW PC of 2L+ therapy were 0.13 (0.08-0.20; p < 0.0001) for PFS and 0.15 (0.08-0.26; p < 0.0001) for OS. For the del11q-negative subgroup, adjusted HRs were 0.20 (0.14-0.29; p < 0.0001) for PFS and 0.33 (0.21-0.52; p < 0.0001) for OS.ConclusionsAdjusted comparisons of the registration trial (RESONATE-2™/RESONATE™) and RW patient-level data suggest that OS and PFS improvements with ibrutinib vs PC therapies are pronounced for patients with CLL harboring del11q compared with those who are del11q negative. The findings inform physicians of the comparative effectiveness of ibrutinib in the RW for patients with this high-risk cytogenetic abnormality.Funding Source:This project was sponsored by Janssen Pharmaceutica NV, and Pharmacyclics LLC, an AbbVie Company. The real-world databases are independently owned. Writing assistance was provided by Emma Fulkes of PAREXEL and funded by Janssen Pharmaceutica NV. [Display omitted] DisclosuresSalles:Takeda: Honoraria; Acerta: Honoraria; Epizyme: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Gilead: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Servier: Honoraria; Janssen: Honoraria; Merck: Honoraria; Morphosys: Honoraria. Besson:Janssen Pharmaceutica NV: Employment. Doyle:Janssen Pharmaceutica NV: Employment. Garside:Janssen Pharmaceutica NV: Employment. Spacek:Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Doubek:Novartis: Consultancy; AbbVie: Consultancy, Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Affimed: Research Funding; Gilead: Consultancy, Honoraria, Research Funding.

Risk Factors Associated with Richter's Transformation in Patients with Chronic Lymphocytic Leukemia

Background Richter's transformation (RT) refers to the development of an aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL). Roughly, 2-10 % of patients with CLL develop RT most often as diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma (HL).Aim This study aimed to assess the incidence rate and risk factors for RT for patients with CLL in a nationwide cohort. Furthermore, we want to assess prognostic risk factors for patients with RT.Methods All patients diagnosed with CLL in Denmark between 2008 and 2016 were included in this study. Clinical data was retrieved from the Danish National CLL Registry (DCLLR), whereas all histologically verified DLBCL, HL and/or transformation diagnoses for patients with CLL were retrieved from the Danish National Pathology Registry. Patients were followed from date of CLL diagnosis until date of RT, death or end of follow-up, whichever came first. The time to RT was estimated as cumulative incidence considering death as a competing risk. Stepwise Cox analysis with backward elimination was applied to identify independent risk factors for RT in patients with CLL.Results A total of 3771 CLL patients were identified, and followed for 14165 person-years. With a median follow-up of 4.3 (IQR (2.4;6.6)) years, 120 (3%) CLL patients had a transformation diagnosis, of which 4 patients were excluded due to misdiagnosis. DLBCL accounted for 78/116 (67%) cases, HL for 15/116 (13%) cases and one patient presented with both DLBCL and HL. In the remaining 22/116 (19%) cases the subtype of the transformation was either unspecified or unclassified RT. The median time to RT was 3.4 (IQR (1.8;5.7)) years from CLL diagnosis and the median overall survival (OS) after development of RT was 4.9 (IQR (0.7;8.4)) years. The cumulative incidence of RT, calculated by Aalen-Johansen estimator, at 5 and 8 years post-CLL diagnosis were 3.3% and 7.9% respectively (Figure 1). The annual crude incidence rate of RT was approximately 0.7% per year for all CLL patients. In all, 918 (24%) patients received CLL-related treatment, of whom 59 (6.4%) patients developed RT, resulting in a cumulative incidence of RT of 7% after 5 years and 11% after 8 years. At the time of CLL diagnosis, patients treated for CLL prior to RT diagnosis had a worse median OS (1.49 years) compared to RT patients who were untreated for CLL (6.16 years). In the univariate analysis, RT was significantly associated with male gender, advanced Binet stage (B or C), unmutated IGHV status (CLL-U), elevated beta-2-microglobulin (>3.5 mg/L) and elevated lactate dehydrogenase (>205 U/L). Of cytogenic aberration, deletion 13q (del(13q)) had a protective effect on the risk of RT, whereas deletion 11q (del(11q)) and deletion 17p (del(17p)) increased the risk. In the multivariable model, advanced Binet stage (HR 2.86 (1.82;4.51), p<0.001), del(17p) ((HR 3.74 (2.12;6.61), p<0.001) and CLL-U ((HR 2.30 (1.46;3.63), p<0.001) showed an independent correlation with development of RT. ZAP70 and CD38 were excluded from statistical analyses due to incomplete data and high inter-laboratory variation. Among RT patients, CLL-U, trisomy 12 and del(17p) at CLL diagnosis as well as ECOG Performance Status (PS) (i.e. PS≥1) at time of RT diagnosis correlated with poor OS in univariate analysis. Both del(17p) and PS≥1 were independently associated with an increased risk of death in a multivariable analysis (HR 2.9, (1.1;7.7), p=0.04 and HR 3.0, (1.0;3.1), p=0.05, respectively).Conclusions To the best of our knowledge, we here report the largest study on RT assessing nationwide data of consecutive patients diagnosed with CLL. The incidence of RT in this unselected population was 3.3% after 5 years while the median OS for patients from time of RT was 4.9 years. Advanced Binet stage, del(17p) and CLL-U were significantly and independently associated with an increased risk of RT. Del(17p) at CLL diagnosis and PS≥1 at RT diagnosis were significant predictors for death for patients with RT. For patients diagnosed with RT prior to any CLL treatment, a less severe disease course with a median OS of 6.16 years was demonstrated. Contrary, the median OS for patients receiving prior CLL treatment was 1.49 years. Thus, assessment of different treatment options for patients developing RT based on whether they have received prior CLL treatment or not is warranted. [Display omitted] DisclosuresBen-Dali:Rigshospitalet: Research Funding. Hleuhel:Rigshospitalet: Research Funding. Brieghel:Arvid Nilson's Fund: Research Funding; Rigshospitalet, Denmark: Research Funding. Niemann:Danish Cancer Society: Research Funding; Novo Nordisk Foundation: Research Funding; Janssen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Gilead: Consultancy; AstraZeneca: Consultancy; CSL Behring: Consultancy.

The Risk of Venous Thromboembolism Is High in Chronic Lymphocytic Leukemia Because of Additional Cancers: A Danish National Cohort Study

Background: Venous thromboembolism (VTE) is a frequent yet potentially preventable complication that increases morbidity and mortality among cancer patients. Chronic Lymphocytic Leukemia (CLL) is a heterogeneous hematological cancer. Patient specific factors (age, gender, performance status) and CLL specific markers (e.g. IgHV mutational status, Binet stage, and beta 2-microglobulin (B2M) levels) influence the clinical course of CLL. A considerable proportion of CLL patients are diagnosed with additional cancer after the CLL diagnosis. The risk of VTE in CLL is higher than the background population throughout the clinical course of CLL in contrast to solid tumors where VTE typically develops within the first few months after cancer diagnosis.Aim: To investigate the risk of VTE in CLL patients according to patient specific factors, CLL specific markers, CLL treatment and additional cancer after the CLL diagnosis.Methods: The Danish National CLL Registry provided prospectively collected clinical data from all CLL patients diagnosed in Denmark since 2008. These data were linked at person level by the unique civil registration number to the Danish National Patient Registry for information on VTE and additional cancers, to the Danish National Prescription Database for information on prescribed and reimbursed anticoagulation treatment and to the Danish Civil Registration System for information on vital status and emigration. Study entry was date of CLL diagnosis; subjects were followed until VTE, death, emigration or administrative censoring. Cumulative incidence of VTE according to Binet stage, B2M levels, IgHV mutational status and additional cancers diagnosed later than CLL were calculated. Additional cancer after the CLL diagnosis was defined as a time-varying exposure. Subjects contributed to the number being at risk of VTE in the “no additional cancer” group until the possible date of additional cancer at which they shifted to the “additional cancer after CLL” group. Death and additional cancer were treated as competing risks by use of the Aalen-Johansen estimator. In Cox proportional hazard models, we estimated the hazard ratios (HR) of VTE; WHO-performance score, previous VTE and sex were included in the models as categorical variables, age was included as a continuous variable and anticoagulation treatment and additional cancer were included as time-varying covariates in the appropriate models.Results: From 2008 through 2015, 3609 subjects were diagnosed with CLL, 60.1% were males and the median age at CLL diagnosis was 70.4 years. Median follow-up was 2.6 years. During the study period, 12.7% (461) were diagnosed with an additional cancer and 19.9% (721) died. Anticoagulation treatment was given to 6.3% (227) of the CLL patients in the study period. The majority of the CLL patients had mutated IgHV, and B2M levels below 4mg/L (Table 1). A VTE was registered in 92 CLL patients during the study period. The cumulative incidence of VTE was highest in CLL patients exposed to additional cancer followed by CLL patients with B2M levels above 4 mg/L and unmutated IgHV. (Figure 1). CLL patients with additional cancer after the CLL diagnosis had a 3-4 fold higher risk of VTE compared with CLL patients without additional cancer. Previous VTE increased the risk of VTE after the CLL diagnosis by 5 fold. This was to some extent because a larger proportion of CLL patients with previous VTE were exposed to an additional cancer after the CLL diagnosis (23.9%) compared with the total study population (12.8%). The HR of VTE in case of previous VTE however, remained high after adjustment for additional cancer cancer and other risk factors (Table 1). Unmutated IgHV and B2M level >4 mg/L increased the risk of VTE, these associations persisted after adjustment for additional cancer (Table 1). CLL treatment tended to increase the risk of VTE, patient related factors and CLL specific markers did not affect the association markedly.Conclusion: The risk of VTE was especially high in CLL patients with additional cancer. Previous VTE was also a substantial (expected) risk factor whereas high age and CLL specific markers (B2M level > 4 mg/L, unmutated IgHV) were significant but less strong risk factors of VTE. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prognostic Testing and Treatment Approaches in Patients with Chronic Lymphocytic Leukemia: Clinical Experience from an Interim Analysis of the informCLLTM Real-World Registry

Prognostic Testing and Treatment Approaches in Patients with Chronic Lymphocytic Leukemia: Clinical Experience from an Interim Analysis of the informCLLTM Real-World Registry

Continuous Increasing Prevalence of Chronic Lymphocytic Leukemia (CLL) with an Estimated Future Rise—a Nationwide Population-Based Study from Sweden

RationaleData on the prevalence of chronic lymphocytic leukemia (CLL) are scarce, and reliable population-based data as well as estimates of future changes in prevalence are neededAimsTo investigate previous and current prevalence of CLL in Sweden, the time it takes for new treatments to be implemented in clinical practice and to estimate the future prevalence of CLL.Patients and MethodsIndividuals in Sweden diagnosed with CLL (ICD7 and ICD9 204.1 and ICD10 C91.1) during 1958-2015 were identified through the National Cancer Registry. Background population sizes, prediction of future population sizes, death rates and data on emigration and immigration were obtained from Statistics Sweden. Clinical data on all cases diagnosed 2007-2015 (n=4742), including type of treatment for those requiring therapy (n=1459), were obtained from the Swedish National CLL-registry to which all healthcare units (n=73) diagnosing and treating CLL send reports.The number of prevalent cases at the end of each year was calculated from the total number of individuals diagnosed with CLL still alive and living in Sweden. Future age-specific incidence rates were assumed to be equal to the average age-specific incidence rates in the previous ten years. To estimate the proportion of individuals still alive many years into the future, estimates of relative survival along with expected mortality rates were calculated. These estimates were used in conjunction with predictions of future expected background mortality to predict overall survival among prevalent cases. Using a flexible parametric model (Lambert, Wilkes et al. 2017) with age at diagnosis included as a restricted cubic spline, relative survival was estimated for all ages.To create a “best case” scenario of future prevalence, a sensitivity analysis was performed assuming an increase in survival of newly diagnosed patients based on hazard ratios from randomized trials comparing new treatments with old. From the Swedish National CLL-registry we gathered data on treatments used and made assessments within three age groups (<65 years, 65-79 years and >80 years) on the proportion of patients that would benefit from a change to a more efficient treatment.ResultsIn 2015, the age-standardized incidence of CLL in Sweden was approximately 3/100 000 among males and 1.5-2/100 000 among females. This level had been stable since 1980.During the period 2000 to 2015 there was a continuous improvement in survival. In parallel there was a 42% increase in point prevalence from 33.3/100 000 to 47.4/100 000, corresponding to a 58% increase in the absolute number of prevalent cases from 2954 to 4668 (fig. 1A).Novel treatments were implemented in <5 years in general practice (fig. 1B).Using this information, we calculated a “best-case” scenario, applying survival figures based on recent published studies on novel treatments, and assuming that the maximum proportion of patients receiving the novel drugs would be reached within 5 years.Assuming unchanged relative survival, we estimated a 15% rise in the point prevalence to 54.6/100 000 in 2025 and a 26% rise to 59.5/100 000 in 2035, corresponding to an increase in the absolute number of cases with 28% (n=5980) and 49% (n=6938) during the same period of time.Based on the “best case” scenario, we estimated a 21% rise in the point prevalence to 57.3/100 000 in 2025 and a 45% rise to 68.9/100 000 in 2035. This corresponding to an increase in the absolute number of cases during the same period with 35% (n=6280) and 72% (n=8016), respectively. (fig. 1C)ConclusionUsing data from well-established national, population-based registries in Sweden, focusing on the time period 2000-2015, we found that there has been a continuous increase in the prevalence of CLL from 33.3/100 000 (2000) to 47.4/100 000 (2015). We also describe a fast implementation of new treatments. In parallel we observe a striking increase in survival. Using a model in which we assume further improvements in survival due to the introduction of novel and more efficient treatments, we estimate that the absolute number of cases may increase with as much as 72% in 20 years. These findings have important implications for health economy and planning.AcknowledgmentsThe Swedish Regional Cancer Centers and all hematologists reporting patients to the National CLL Registry. The Swedish CLL-group for their valuable support.FundingThis work was supported by funding from the Swedish CLL-group. [Display omitted] DisclosuresKimby:AbbVie: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Roche: Honoraria.

Venous thromboembolism in chronic lymphocytic leukemia: a Danish nationwide cohort study

AbstractVenous thromboembolism (VTE) is associated with inferior survival in cancer patients. The risk of VTE and its effect on survival in chronic lymphocytic leukemia (CLL) patients remains unclear. The present study investigated the impact of patient-related factors, CLL prognostic markers, and CLL treatment on the risk of VTE and assessed overall survival relative to VTE. All patients in the Danish National CLL Registry (2008-2015) were followed from the date of CLL diagnosis to death, VTE, emigration, or administrative censoring. Hazard ratios (HRs) were estimated using Cox models, and second primary cancers and anticoagulation treatment were included as time-varying exposures. During a median follow-up of 2.6 years, 92 VTEs occurred among 3609 CLL patients, corresponding to a total incidence rate of 8.2 VTEs per 1000 person-years (95% confidence interval [CI], 6.7-10.1). A history of VTE or second primary cancer was associated with HRs of VTE of 5.09 (95% CI, 2.82-9.17) and 3.72 (95% CI, 2.15-6.34), respectively, while β2-microglobulin >4 mg/L, unmutated immunoglobulin HV and unfavorable cytogenetics had lower HRs. CLL patients with VTE had marginally higher mortality, which was most pronounced among patients <60 years of age (HR, 7.74; 95% CI, 2.12-28.29). Our findings suggest that markers of unfavorable CLL prognosis contribute to an increased risk of VTE; however, previous VTE or a second primary cancer is more strongly associated with the risk of VTE than any CLL-specific marker. Focusing attention on this preventable complication may improve survival in young CLL patients.

Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis.

Clinical trials that led to ibrutinib’s approval for the treatment of chronic lymphocytic leukemia showed that its side effects differ from those of traditional chemotherapy. Reasons for discontinuation in clinical practice have not been adequately studied. We conducted a retrospective analysis of chronic lymphocytic leukemia patients treated with ibrutinib either commercially or on clinical trials. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes. This multicenter, retrospective analysis included ibrutinib-treated chronic lymphocytic leukemia patients at nine United States cancer centers or from the Connect® Chronic Lymphocytic Leukemia Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival. Six hundred sixteen ibrutinib-treated patients were identified. A total of 546 (88%) patients were treated with the commercial drug. Clinical trial patients were younger (mean age 58 versus 61 years, P=0.01) and had a similar time from diagnosis to treatment with ibrutinib (mean 85 versus 87 months, P=0.8). With a median follow-up of 17 months, an estimated 41% of patients discontinued ibrutinib (median time to ibrutinib discontinuation was 7 months). Notably, ibrutinib toxicity was the most common reason for discontinuation in all settings. The median progression-free survival and overall survival for the entire cohort were 35 months and not reached (median follow-up 17 months), respectively. In the largest reported series on ibrutinib- treated chronic lymphocytic leukemia patients, we show that 41% of patients discontinued ibrutinib. Intolerance as opposed to chronic lymphocytic leukemia progression was the most common reason for discontinuation. Outcomes remain excellent and were not affected by line of therapy or whether patients were treated on clinical studies or commercially. These data strongly argue in favor of finding strategies to minimize ibrutinib intolerance so that efficacy can be further maximized. Future clinical trials should consider time-limited therapy approaches, particularly in patients achieving a complete response, in order to minimize ibrutinib exposure.

Prognostic Testing Patterns and Outcomes of Chronic Lymphocytic Leukemia Patients Stratified by Fluorescence In Situ Hybridization/Cytogenetics: A Real-world Clinical Experience in the Connect CLL Registry

IntroductionPrognostic genetic testing is recommended for patients with chronic lymphocytic leukemia (CLL) to guide clinical management. Specific abnormalities, such as del(17p), del(11q), and unmutated IgHV, can predict the depth and durability of the response to CLL therapy. Patients and MethodsIn the present analysis of the Connect CLL Registry (ClinicalTrials.gov identifier, NCT01081015), a prospective observational cohort study of patients treated across 199 centers, the patterns of prognostic testing and outcomes of patients with unfavorable-risk genetics were analyzed. From 2010 to 2014, 1494 treated patients were enrolled in the registry by line of therapy (LOT), and stratified by the results of cytogenetic/fluorescence in situ hybridization (FISH) testing into 3 risk levels: unfavorable (presence of del[17p] or del[11q]), favorable (absence of del[17p] and del[11q]), and unknown. ResultsCytogenetic/FISH testing was performed in 861 patients (58%) at enrollment; only 40% of these patients were retested before starting a subsequent LOT. Of those enrolled at the first LOT, unfavorable-risk patients had inferior event-free survival compared with favorable-risk patients (hazard ratio, 1.60; P = .001). Event-free survival was inferior with bendamustine-containing regimens (P < .0001). Event-free survival did not differ significantly between risk groups for patients treated with ibrutinib or idelalisib in the relapse/refractory setting. The predictors of reduced event-free survival included unfavorable-risk genetics, age ≥ 75 years, race, and treatment choice at enrollment. ConclusionThe present study has shown that prognostic cytogenetic/FISH testing is infrequently performed and that patients with unfavorable-risk genetics treated with immunochemotherapy combinations have worse outcomes. This underscores the importance of performing prognostic genetic testing for all CLL patients to guide treatment.

Characterizing and prognosticating chronic lymphocytic leukemia in the elderly: prospective evaluation on 455 patients treated in the United States

BackgroundMedian age at diagnosis of patients with chronic lymphocytic leukemia (CLL) is > 70 years. However, the majority of clinical trials do not reflect the demographics of CLL patients treated in the community. We examined treatment patterns, outcomes, and disease-related mortality in patients ≥ 75 years with CLL (E-CLL) in a real-world setting.MethodsThe Connect® CLL registry is a multicenter, prospective observational cohort study, which enrolled 1494 adult patients between 2010–2014, at 199 US sites. Patients with CLL were enrolled within 2 months of initiating first line of therapy (LOT1) or a subsequent LOT (LOT ≥ 2). Kaplan–Meier methods were used to evaluate overall survival. CLL- and infection-related mortality were assessed using cumulative incidence functions (CIF) and cause-specific hazards. Logistic regression was used to develop a classification model.ResultsA total of 455 E-CLL patients were enrolled; 259 were enrolled in LOT1 and 196 in LOT ≥ 2. E-CLL patients were more likely to receive rituximab monotherapy (19.3 vs. 8.6%; p < 0.0001) and chemotherapy-alone regimens (p < 0.0001) than younger patients. Overall and complete responses were lower in E-CLL patients than younger patients when given similar regimens. With a median follow-up of 3 years, CLL-related deaths were higher in E-CLL patients than younger patients in LOT1 (12.6 vs. 5.1% p = 0.0005) and LOT ≥ 2 (31.3 vs. 21.5%; p = 0.0277). Infection-related deaths were also higher in E-CLL patients than younger patients in LOT1 (7.4 vs. 2.7%; p = 0.0033) and in LOT ≥ 2 (16.2 vs. 11.2%; p = 0.0786). A prognostic score for E-CLL patients was developed: time from diagnosis to treatment < 3 months, enrollment therapy other than bendamustine/rituximab, and anemia, identified patients at higher risk of inferior survival. Furthermore, higher-risk patients experienced an increased risk of CLL- or infection-related death (30.6 vs 10.3%; p = 0.0006).ConclusionCLL- and infection-related mortality are higher in CLL patients aged ≥ 75 years than younger patients, underscoring the urgent need for alternative treatment strategies for these understudied patients.Trial RegistrationThe Connect CLL registry was registered at clinicaltrials.gov: NCT01081015 on March 4, 2010.

Early Progression of Disease (< 2 Years) Is a Negative Predictor of Survival in Patients (Pts) with Chronic Lymphocytic Leukemia (CLL): An Analysis from the Connect® CLL Registry

Introduction: Pre-treatment characteristics of pts with CLL, such as del(17p), are used to identify high-risk populations for enrollment onto clinical trials. Nevertheless, little is known about how to identify high-risk pts who are not captured by conventional prognostic tools, yet may benefit from clinical trials. Studies have shown that first-line chemoimmunotherapy (CIT) provides a therapeutic challenge to CLL and confers a selective pressure favorable to the growth of aggressive clones (Landau et al. Nature 2015;526:525-30). Early progression of disease (POD) may reflect specific aspects of disease biology and serve as a post-treatment prognostic marker that defines high-risk pts. Here we describe the characteristics and survival of pts experiencing early POD within 2 years of treatment initiation. Methods: The Connect CLL Registry (NCT01081015), a multicenter, prospective observational cohort study, enrolled 1,494 CLL pts between 2010-2014 from 179 community, 17 academic, and 3 government sites in the USA. Pts were ≥ 18 years and were enrolled ≤ 2 months of initiating any line of therapy (LOT). Of 889 pts who received first LOT (LOT1), 154 were excluded due to subsequent treatment or death without recorded progression. Pts were stratified by early POD (progression with or without transformation ≤ 2 years of treatment initiation), or late/no POD. A 2-year cutoff was found to approximate median time to POD. Cox regression models were used to identify independent predictors of progression or death. Progression-free survival probabilities were estimated by the Kaplan-Meier method and compared between subgroups using the log-rank test. Results: A total of 735 pts with CLL were included in the analysis. Median age was 67 years (range 22-99), 64% were male, 29% had advanced Rai stage (III/IV), and 14% of those with available FISH data had del(17p). At a median follow-up of 42.5 months, 298 (40.5%) pts had POD. Median time to POD was 20 months. A total of 179 (24.3%) pts experienced early POD (≤ 2 years); the remaining 556 pts experienced late POD (> 2 years; 119 [16.2%]) or no POD (437 [59.4%]). Early and late/no POD subgroups showed similar distribution of sex, race, Rai stage, and Charlson comorbidity index (all P > 0.05). The early POD group had a higher median age (70 vs 67 years; P = 0.025), and more frequently had del(17p) (20 [20%] vs 22 [7%], among pts with available FISH; P = 0.001) than the late/no POD group. Comparison of first-line treatment patterns showed pts with early POD were more likely to receive monotherapy and less likely to receive combination CIT compared to pts in the late/no POD group. The most commonly used monotherapy was rituximab (15.1% in early POD vs 11.8% in late POD vs 9.2% in no POD), followed by chlorambucil, bendamustine, fludarabine, and cyclophosphamide. Overall response rates were lower in the early POD group (54% vs 83%; P Conclusion: Disease progression ≤ 2 years after initiation of frontline therapy is an independent negative predictor of survival in pts with CLL. This trend is observed across different treatment regimens. This clinical risk factor identifies a subgroup of high-risk pts who should be considered for enrollment onto clinical trials. Disclosures Farber: Seattle Genetics: Research Funding. Davids: Pharmacyclics: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Infinity: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity9s Board of Directors or advisory committees, Research Funding; AbbVie, Janssen, Gilead: Consultancy; Celgene Corporation: Consultancy. Grinblatt: Celgene Corporation: Consultancy, Speakers Bureau. Lamanna: Gilead: Research Funding; AbbVie: Research Funding; Genentech: Research Funding; Infinity: Research Funding; Pronai: Research Funding; Celgene Corporation: Research Funding. Mato: Abbvie, Acerta Pharma, Gilead Sciences, ProNAi, TG Therapeutics, Theradex: Research Funding; Abbvie, Gilead Sciences, Pharmacyclics, TG Therapeutics: Consultancy. Nabhan: Celgene, Genentech, Abbvie, Infinity, Cardinal Health: Consultancy; Celgene, Genentech, Seattle Genetics, Astellas: Research Funding. Kiselev: Celgene: Employment, Equity Ownership. Swern: Celgene: Employment, Equity Ownership. Flick: Celgene Corporation: Employment, Equity Ownership. Bhushan: Celgene Corporation: Employment, Equity Ownership. Sullivan: Celgene Corporation: Employment, Equity Ownership. Sharman: Seattle Genetics: Research Funding; Gilead: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; TG Therapeutics: Research Funding. Flowers: Gilead: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Spectrum, Janssen, Infinity, AbbVie, Acerta, Pharmacyclics, TG Therapeutics: Research Funding; Optum Rx, Seattle Genetics, Genentech/Roche: Consultancy; Celgene Corporation: Consultancy, Honoraria.