Agents In Chronic Lymphocytic Leukemia Research Articles

Targeted Agents in Chronic Lymphocytic Leukemia (CLL): Advancements in Overall Survival Outcomes?

The impact of targeted agents (TAs) in fully mitigating the detrimental effects of CLL on overall survival (OS) remains uncertain. To address this, we compared the 5-year OS of treatment-naïve CLL pts who received targeted agents (TAs) in phase 3 clinical trials with the 5-year OS of age- and gender-matched general population (AGMGP) in Italy and the US. For this analysis, we included clinical trials that involved elderly or unfit pts (RESONATE2, ILLUMINATE, ALLIANCE, ELEVATE-TN, CLL14, and GLOW). We also considered trials enrolling fit pts eligible for FCR (Fludarabine, Cyclophosphamide, and Rituximab) treatment (ECOG1912, FLAIR, and CLL13). We used the method proposed by Liu et al. [BMC Med Res Methodol 2021;21(1):111] to reconstruct individual patient data (IPD) from published Kaplan-Meier survival curves. The expected OS rate for the control population was calculated using 2019 Italian data from the Istituto Nazionale di Statistica (ISTAT) and the 2019 US database. OS of CLL pts and AGMGP were compared for restricted mean overall survival time (RMOST). The treatment effect on OS was then measured as the difference of RMOST and expressed in months. The elderly CLL trial analysis group (2,222 pts) received TAs (58.1%) or chemo-(immunotherapy)(CT/CIT) (41.8%). TAs included Bruton Kinase inhibitors (BTKis) (i.e., ibrutinib [I] or acalabrutinib [A]) alone or with anti-CD20 (75%) or fixed-duration (FD) venetoclax [V] combos (25%). The control CT/CIT arm mainly consisted of CLB+Obinu (66%). The median age of pts was 70 years (range 47-93). The prevalence of del(17p)/mutated TP53, unmutated IGHV, or CIRS score>6 were 9.1% (0-16%), 62.4% (43-66.5%), and 48.6% (11.7-86.1%), respectively. In the aggregate analysis, the 5-year RMOST of elderly pts treated with CT/CIT (RESONATE2, ILLUMINATE, ALLIANCE, ELEVATE-TN, CLL14, and GLOW) was found to be inferior compared to the 5-year RMOST of Italian [Difference (D), -4.2 months; 95% CI: -5.3 to -3.0; P < 0.0001] and US [D, -3.6 months; 95% CI: -4.7 to -2.4; P < 0.001] AGMGP (Fig 1). The analysis of pts treated with TAs provided conflicting results. In the cross-matched comparison between Italian AGMGP and pts treated with BTKi single-agent or combined with anti-CD20, the 5-year RMOST difference indicates an OS advantage for the former (Fig 1). The same applied in the comparison between pts who received FD V-based therapies and Italian or US AGMGP. Notably, the 5-year RMOST of elderly CLL pts treated with BTKi single-agent (RESONATE2, ALLIANCE, ELEVATE-TN) or combined with anti-CD20 (ILLUMINATE, ALLIANCE, ELEVATE-TN) was similar to the 5-year RMOST of US AGMGP [D, -1.2 mo. (-2.5 to 0.1); P = 0.07 for both](Fig 1). OS comparisons between elderly CLL pts and control populations, although controlled for age and gender, do not account for the interaction between comorbidity burden and OS. The proportion of pts with CIRS score > 6 varied widely across trials: RESONATE2, 31%; ELEVATE-TN, 11.1% in the A-arm and 16.8% in the AO-arm; ILLUMINATE, 32.7%; CLL14, 86.1%; and GLOW, 69.0%. Since CLL pts eligible for FCR enrolled in the ECOG1912, FLAIR, and CLL13 trials typically have fewer comorbidities, they enable a clearer evaluation of the TA's impact on OS. Overall, 1,437 patients (64.5%) received TAs, and 789 (35.4%) received CIT. TAs consisted of I+R (51.5%) or FD V-based combinations (VO, VI, VO+Ibr) (48.5%). The median age of pts was 62 years (range 27-84). The prevalence of ECOG PS 0 and unmutated IGHV were 68% and 56%, respectively. The 5-year RMOST of younger/fit pts treated with FCR was inferior to the 5-year RMOST of Italian AGMGP [D, -1.1 mo; 95% CI: -1.8 to -0.3; P = 0.003] but similar to the 5-year RMOST of US AGMGP [D, -0.4 mo; 95% CI, -1.1 to 0.4; P = 0.28]. Interestingly, no significant difference could be observed between the 5-year RMOST of younger/fit pts treated with TAs (IR or Ven-based) and the 5-year RMOST of Italian or US AGMGP (Fig 2). In conclusion, our results suggest that in comparison to CIT, TAs mitigate but do not fully abrogate the detrimental impact of CLL on OS. The intricate interaction between CLL characteristics and the burden of comorbidities can potentially lead to misleading results in clinical trials of elderly pts. The extent of OS improvement obtained with TAs seems higher in younger/fit CLL pts who have fewer comorbidities. However, longer follow-up is needed to discern the ability of these treatments to mitigate the impact of CLL on OS over longer time intervals.

Patient and Physician Preferences for Fixed-Duration Vs Treatment to Progression Chronic Lymphocytic Leukemia (CLL) Treatments: Results from a Multi-Country Discrete Choice Experiment

Background Novel agents in chronic lymphocytic leukemia (CLL) have demonstrated improved outcomes while resulting in more complex treatment decision making. Agents vary in efficacy, tolerability, and duration of therapy, including fixed-duration (FD) therapy and treatment to progression (TTP) regimens, resulting in the need to make trade-offs in the selection of treatment. In the absence of mature overall survival data that clearly demonstrates long-term advantages of each regimen, it is important to understand the treatment preferences of patients and oncologists in the first line CLL setting. Aims We aimed to examine and quantify the preferences for key treatment attributes, including duration of therapy, of first line CLL therapies among oncologists and CLL patients. Methods Oncologists and CLL patients in the US, UK, Germany, France, and Australia were recruited into the study. They were asked to complete an online survey including a discrete choice experiment (DCE) where, in 12 tasks, participants were asked to choose between two hypothetical first-line therapies with levels that varied across five attributes: progression-free survival (PFS); risk of an adverse event (such as headache, muscle pain, or diarrhea); risk of treatment discontinuation due to side effect; FD intravenous (IV) regimens; FD and TTP oral regimens. The percentages of time each level was chosen when it appeared in a profile was reported. Bayesian models were used to estimate attribute level preference weights and attribute relative importance (RI) estimates, which capture how influential changes in an attribute are in treatment choice. Results In total, 259 oncologists (74% male, mean age: 50 + 8 years, mean years of practice: 17 + 6) and 192 patients (mean age 63 + 11 years; time since diagnosis 8 + 7 years; 69% treatment experienced) participated. Patients selected ‘daily oral medication taken indefinitely’ 40% of the time, which was significantly lower than the percentage of times they selected ‘daily oral medication taken for 24 months’ (53% of the time) and ‘daily oral medication taken for 12 months’ (54% of the time) (p<0.001). Conversely, there was no significant difference in the proportions of time that FD and continuous oral medications were selected by oncologists. Efficacy was the most important attribute for both patients and physicians, although more important for physicians than for patients (p<0.001), followed by reducing the risks of the two side effect attributes, which were similar in importance. Mode of administration attributes were not as important as efficacy and safety: changes in the oral regimens (FD therapy and TTP) was the fourth most important attribute, with patients placing a greater importance on this attribute compared to physicians (p<0.001); changes among the FD therapy IV regimens was least important. Changes in the oral and IV regimens were more important for patients than for physicians (p<0.001, Table). Patients with experience with FD therapies (n=101) had a higher preference for the 12-month FD oral regimens compared to those without FD therapy experience. Those with TTP regimen experience (n=73) had a higher preference for the TTP oral regimens compared to those without prior TTP therapy experience. There was no significant difference in attribute importance according to patient's treatment history (currently treated, previously treated but off treatment now, never treated). Conclusions In contrast to oncologists, patients preferred FD oral therapy over TTP regimens. Efficacy and safety of the medications were important to both patients and oncologists, and both were willing to make trade-offs in relation to duration of therapy if efficacy and safety were established. Our results suggest that patients may be more sensitive to type of regimen, whether it is FD or TTP than oncologists. Understanding factors that affect the preferences and perceptions of patients is important and may lead to improved treatment outcomes and better management of adverse events, leading to greater patient satisfaction. Further work is required to explore the determinants/drivers of these preferences.

Anti-tumor activity of selinexor in combination with antineoplastic agents in chronic lymphocytic leukemia

Despite recent relevant therapeutic progresses, chronic lymphocytic leukemia (CLL) remains an incurable disease. Selinexor, an oral inhibitor of the nuclear export protein XPO1, is active as single agent in different hematologic malignancies, including CLL. The purpose of this study was to evaluate the anti-tumor effects of selinexor, used in combination with chemotherapy drugs (i.e. fludarabine and bendamustine) or with the PI3Kδ inhibitor idelalisib in CLL. Our results showed a significant decrease in CLL cell viability after treatment with selinexor-containing drug combinations compared to each single compound, with demonstration of synergistic cytotoxic effects. Interestingly, this drug synergism was exerted also in the presence of the protective effect of stromal cells. From the molecular standpoint, the synergistic cytotoxic activity of selinexor plus idelalisib was associated with increased regulatory effects of this drug combination on the tumor suppressors FOXO3A and IkBα compared to each single compound. Finally, selinexor was also effective in potentiating the in vivo anti-tumor effects of the PI3Kδ inhibitor in mice treated with the drug combination compared to single agents. Our data provide preclinical evidence of the synergism and potential efficacy of a combination treatment targeting XPO1 and PI3Kδ in CLL.

EE141 Cost-Effectiveness of TP53 and IGHV Biomarker Testing Prior to First-Line Treatment With Novel Agents for Chronic Lymphocytic Leukemia

Patients with chronic lymphocytic leukemia (CLL) harboring TP53 aberrations (including del[17p] and mutations) and/or unmutated IGHV (IGHV-U) have inferior survival to standard first-line chemoimmunotherapies and should be considered for novel agents, such as ibrutinib. This study aims to evaluate the cost-effectiveness of predictive biomarker testing for first-line treatment in patients with CLL from an Australian healthcare system perspective.

Clinicobiological characteristics and treatment efficacy of novel agents in chronic lymphocytic leukemia with IGLV3-21R110

Clinicobiological characteristics and treatment efficacy of novel agents in chronic lymphocytic leukemia with IGLV3-21R110

Exploring a peptide nucleic acid-based antisense approach for CD5 targeting in chronic lymphocytic leukemia

We herein report an innovative antisense approach based on Peptide Nucleic Acids (PNAs) to down-modulate CD5 expression levels in chronic lymphocytic leukemia (CLL). Using bioinformatics tools, we selected a 12-mer tract of the CD5 mRNA as the molecular target and synthesized the complementary and control PNA strands bearing a serine phosphate dipeptide tail to enhance their water solubility and bioavailability. The specific recognition of the 12-mer DNA strand, corresponding to the target mRNA sequence by the complementary PNA strand, was confirmed by non-denaturing polyacrylamide gel electrophoresis, thermal difference spectroscopy, circular dichroism (CD), and CD melting studies. Cytofluorimetric assays and real-time PCR analysis demonstrated the downregulation of CD5 expression due to incubation with the anti-CD5 PNA at RNA and protein levels in Jurkat cell line and peripheral blood mononuclear cells from B-CLL patients. Interestingly, we also observed that transfection with the anti-CD5 PNA increases apoptotic response induced by fludarabine in B-CLL cells. The herein reported results suggest that PNAs could represent a potential candidate for the development of antisense therapeutic agents in CLL.

Abstract 2990: In vitro drug sensitivity screening platform for primary chronic lymphocytic leukemia (CLL) patient samples

Abstract Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. It is characterized by proliferation and accumulation of monoclonal, small, mature CD5+ B-cells in peripheral blood, bone marrow and secondary lymphoid organs. The current treatment regimens have improved overall survival but CLL patients will eventually experience relapse. The disease is still incurable making it a necessity to discover and screen for new drugs. Patient derived CLL specimens undergo spontaneous apoptosis when grown in culture and is a major limitation to screening for new therapeutic drugs. We have established an in vitro culture conditions which supports growth and proliferation of patient derived primary CLL cells. Champions has a bank of primary CLL patient samples across different Rai stage, genetic mutations and relapsed and refractory cases. We tested nine CLL samples (models) for proliferation. All nine models proliferated 1.5 to 9.6-fold in the optimized media in 6 days, as measured using CellTiter-Glo. Flow cytometric analysis showed that the CLL cells mostly retained the primary phenotypic characteristic CD5+CD10-Cd19+CD20+ even after being in the culture for 6 days. Next, we screened for sensitivity of primary CLL patient samples (N=9) against known standard of care (SOC) drugs venetoclax, ibrutinib, idelalisib, chlorambucil and cytarabine. Primary PBMC patient samples were seeded in 96 well plates in the enriched media and treated with respective drugs over a concentration range over 5 logs. Drug sensitivity was assessed using CellTiter-Glo® luminescent cell viability assay on day 6. Our in vitro assay indicated varied sensitivity of patient samples to approved standard of care drugs. A relapsed bendamustine pre-treated patient sample was sensitive to all the SOC drugs tested. In addition to drug response, whole exome sequencing and RNAseq are being conducted on these samples, to compare mutational analyses with drug responsiveness. With clinically annotated patient-derived CLL samples, WES and RNAseq plus drug response to standard of care provides a comprehensive ex vivo platform for the preclinical testing of drug candidates, which may not only provide information on agent efficacy, but that can permit potential biomarker mining and exploration of patient selection criteria for investigational new agents in CLL. Citation Format: Bandana Ajay Vishwakarma, Amy Wesa. In vitro drug sensitivity screening platform for primary chronic lymphocytic leukemia (CLL) patient samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2990.

Incidence of Atrial Fibrillation and Bleeding in CLL Patients Treated with Ibrutinib: Evidence from the Veterans Health Administration

Background: Chronic Lymphocytic Leukemia (CLL) is the second most common type of leukemia in adults, with an estimated 62,130 new cases expected to be diagnosed in 2017 (Siegel, Miller, and Jemal 2017). The introduction of novel oral agents in CLL, starting with ibrutinib (IB) in 2013, has revolutionized the therapeutic landscape, with efficacy and safety that compare favorably overall with prior mainstays of treatment such as chemoimmunotherapy. However, novel agents are associated with specific toxicities that may limit their utility. Several clinical trials have suggested that there is an association between IB and the risk of bleeding-related adverse events and atrial fibrillation (Afib) in CLL patients (Leong et al. 2016; McMullen et al. 2014; Lipsky et al. 2015). The risk of bleeding and Afib in CLL patients treated with IB in a real-world clinical setting is unknown.Aims: This study examines the real-world incidence of bleeding and Afib in CLL patients receiving IBR in the Veterans Health Administration (VHA). We also report the utilization of anticoagulant and antiplatelet medications following treatment with IB. For comparison, the incidence of bleeding and Afib and use of anticoagulant and antiplatelet medications during treatment in a cohort of CLL patients treated with bendamustine and rituximab (BR) is also reported.Methods: Patients who were diagnosed and treated for CLL at the VHA from 2010-2014 were identified through the VA Clinical Cancer Registry (VACCR). Patients were excluded if they had a prior malignancy. Patients were followed until the end of study observation period, death, or lack of utilization of hematology/oncology services for 18 months, or incidence of another cancer. For the IB cohort, patients were indexed at the time of the first dispensation of IB. Comorbidities and medications that could influence incidence of bleeding or Afib were extracted in the six months prior to the index date while the incidence of bleeding and Afib was extracted in the six months following the index date. Charlson Comorbidity Index (CCI),(Deyo 1992; D'Hoore, Bouckaert, and Tilquin 1996) liver disease (cirrhosis, alcoholic liver disease, HCV infection)(Kramer et al., n.d.), and diabetes (controlled and uncontrolled) were examined (Guzman et al. 2014). Treatments dispensed, evidence of VHA system use, bleeding events, and Afib were determined from the administrative records, lab records, pharmacy dispensation records, and clinical notes in the electronic medical record. Descriptive statistics were used to report estimates.Results: From 2010-2014, 2,796 patients were diagnosed and received care for their CLL within the VHA. We identified 172 patients receiving IB and 291 patients receiving BR (table 1).Of the BR patients, 282 (97%) were male. Similarly, 167 (97%) of IB patients were male. The median age at diagnosis was 67 years for BR patients and 69 years for IB patients. The CCI, liver disease and end-stage liver disease comorbidities were higher in patients receiving BR than IB, however, there were significantly more patients with diabetes (both controlled and uncontrolled) who received IB (24%) compared to those who received BR (8%). The use of anticoagulants following induction therapy did not differ between BR and IB patients (9% v 8%), nor did the use of antiplatelets (6% v 2%). Incidence of anticoagulants and antiplatelet usage prior to BR or IB induction therapy was minimal (fewer than 10 patients) and is therefore not reported. Of the 291 patients that received BR, 12 (4%) developed a bleeding event compared to 20 (12%) of the 172 patients that received IB. Additionally, 13 (8%) of IB patients developed Afib compared to only 3% of BR patients.Conclusions: Real-world evidence from a nationwide cohort of CLL patients suggest that while IB is associated with increased bleeding-related adverse events and Afib it is comparable to those reported in previous clinical trials (Leong et al. 2016; Lipsky et al. 2015). Additionally, these findings suggest that patients in real-world clinical care settings with higher levels of comorbidities may be at an increased risk for bleeding events and Afib. [Display omitted] DisclosuresHalwani:Kyowa Hikko Kirin: Research Funding; Bristol Myers Squib: Research Funding; Seattle Genetics: Research Funding; Roche/Genentech Inc.: Research Funding; Genetech Inc.: Research Funding; Takeda: Research Funding; Pharmacyclics: Research Funding; Amgen: Research Funding; AbbVie: Research Funding; Immune Design: Research Funding; Miragen: Research Funding. Sauer:AbbVie: Research Funding; Genentech Inc.: Research Funding; Pharmacyclics: Research Funding; Amgen: Research Funding.

The evolving role of Bruton's tyrosine kinase inhibitors in chronic lymphocytic leukemia.

Ibrutinib, the first in class of the oral covalent Bruton tyrosine kinase (BTK) inhibitors, has profoundly changed the treatment landscape of chronic lymphocytic leukemia (CLL). The phase III RESONATE and RESONATE-2 trials first demonstrated the superiority of ibrutinib over ofatumumab in the relapsed/refractory setting and over chlorambucil in older patients with de novo disease. The phase III ECOG–ACRIN trial extended these results to young, fit patients, demonstrating a significant survival advantage to ibrutinib plus rituximab over fludarabine, cyclophosphamide, and rituximab. Similarly, the Alliance trial demonstrated the superiority of ibrutinib over bendamustine with rituximab as frontline in elderly patients. Challenges with ibrutinib include toxicity, development of resistance, and need for indefinite therapy. The second generation BTK inhibitor acalabrutinib may cause less off-target toxicity. The ELEVATE TN trial demonstrated the superiority of acalabrutinib with or without obinutuzumab over chlorambucil and obinutuzumab as frontline therapy for elderly or comorbid patients. Promising early results from the phase II CAPTIVATE and CLARITY trials, which combined ibrutinib with venetoclax, suggest a future role for minimal residual disease (MRD) testing to determine treatment duration. The ongoing phase III GAIA/CLL13, ECOG EA9161, Alliance A041702, CLL17, and [ClinicalTrials.gov identifier: NCT03836261] trials will assess various combinations of ibrutinib/acalabrutinib, venetoclax, and anti-CD20 antibodies. These trials will answer key questions in the treatment of CLL: should novel agents in CLL be used in combination or sequentially? What is the best frontline agent? Can treatment be safely stopped with BTK inhibitors? Can undetectable MRD be used to determine treatment duration? In this review, we will discuss these and other aspects of the evolving role of BTK inhibition in CLL.

Establishment ofin VitroDrug Sensitivity Screening Assay for Chronic Lymphocytic Leukemia (CLL) Primary Patient Samples

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. CLL is characterized by proliferation and accumulation of monoclonal, small, mature CD5+ B-cells in peripheral blood, bone marrow and secondary lymphoid organs. The current treatment regimens have improved overall survival but CLL patients will eventually experience relapse. The disease is still incurable making it a necessity to discover and screen for new drugs. Patient derived CLL specimens undergo spontaneous apoptosis when grown in culture and is a major limitation to screening for new therapeutic drugs. We have established anin vitroculture conditions which supports growth and proliferation of patient derived primary CLL cells. Champions has a bank of primary CLL patient samples across different Rai stage, genetic mutations and relapsed and refractory cases. Using the optimizedin vitroculture conditions, we tested three CLL human primary samples (models) for proliferation . All three models proliferated 1.5 to to 2-fold in the optimized media in 6 days, as measured using CellTiter-Glo®. We also examined the phenotypic changes in the cells after growing them in the established media. Flow cytometric analysis showed that the CLL cells mostly retained the primary phenotypic characteristic CD5+CD10-Cd19+CD20+ even after being in the culture for 6 days. Next, we screened for sensitivity of primary CLL patient samples (N=10) against known standard of care (SOC) drugs venetoclax, ibrutinib, idelasib, chlorambucil and cytarabine. Primary patient samples derived from peripheral blood mononuclear cells (PBMC) were cultured in 96 well plates in the enriched media and treated with respective drugs over a concentration range over 5 logs. Drug sensitivity was assessed using CellTiter-Glo® luminescent cell viability assay on day 3. Ourin vitroassay indicated that some, but not all patient samples were sensitive to approved standard of care drugs. A relapsed bendamustine pre-treated patient sample was sensitive to all the SOC drugs tested. In addition to drug response, whole exome sequencing and RNAseq are being conducted on these samples, to compare mutational analyses with drug responsiveness. With clinically annotated patient-derived CLL samples, WES and RNAseq plus drug response to standard of care provides a comprehensiveex vivoplatform for the preclinical testing of drug candidates, which may not only provide information on agent efficacy, but that can permit potential biomarker mining and exploration of patient selection criteria for investigational new agents in CLL. Disclosures No relevant conflicts of interest to declare.

How Do Progression-Free Survival and Toxicity Risks Influence Oncologist and Patient Preferences for Novel Agents in Chronic Lymphocytic Leukemia?

Introduction: Treatment for chronic lymphocytic leukemia (CLL) has changed with the approval of novel agents, which have different toxicity profiles. The aim of the current analysis was to determine how incremental changes in efficacy and toxicity profile impact treatment selection among patients with CLL and oncologists. Methods: In this US-based study, oncologists and CLL patients completed an online survey that included a discrete choice experiment (DCE) to quantify preferences for first line (1L) treatment with novel agents. Self-reported data on oncologist and patient characteristics were also collected. In the DCE, respondents selected between hypothetical treatment profiles consisting of 8 attributes with varying levels. The attributes were selected based on the findings of qualitative interviews assessing treatment priorities among oncologists and patients. The attribute levels were abstracted from clinical trials and published literature (Table 1). Hierarchical Bayesian regression models were used to estimate preference weights for each attribute level. The preference weights were used to generate a base case hypothetical treatment profile, against which other hypothetical profiles varying in adverse event (AE) risk and 2-year progression-free survival (PFS) were evaluated to understand which attributes and levels drive treatment selection. The overall mean summed preference weight for the collective set of alternative profiles was then compared with the base case, with higher positive values indicating the more preferred profile. Results: Oncologists (N=151) reported a mean of 16.3±7.0 years in practice (Table 2). Most practiced in a community setting (72%) and in a major metropolitan/urban area (64%). Among patients (N=220), median age was 56.0 years, with a mean disease duration of 2.0±3.1 years at time of study (Table 2). Most patients were in or had completed at least 1L therapy (68%). Figure 1 illustrates the impact of changing various attribute levels on the overall preference of an alternative profile, relative to a base case profile. Decreasing 2-year PFS from 95% to 75% (Profile A) and reducing the risks of atrial fibrillation (A-fib) from 20% to 5% (Profile B) and infection from 30% to 7% (Profile C) had the greatest influence on treatment preferences for oncologists when holding all other attribute levels constant. Oncologists preferred the profile with reduced 2-year PFS and reduced risk of AEs (Profile G) to the base case profile, corresponding to a 45% difference in preference share. Similarly, for patients, reducing 2-year PFS from 95% to 75% (Profile A) and reducing the risks of infection from 30% to 7% (Profile C) and A-fib from 20% to 5% (Profile B) were most influential in treatment choice when all other attribute levels were held constant (Figure 1). However, patients preferred the base case profile with higher PFS and higher risk of AEs to Profile G, corresponding to a 38% difference in preference share. Conclusions: For oncologists and patients, decreasing 2-year PFS and reducing the risks of either A-fib or infection had the most influence on 1L treatment preference, relative to the base case in which 2-year PFS was the highest and the AE risks were set to the worst levels reported in literature for novel therapies. The pattern and direction of treatment preferences were generally consistent among oncologists and patients, relative to the base case, across all alternative profiles when individually examined. However, for patients, the positive impact of reducing the risk of AEs was outweighed by the negative impact of reducing PFS. Consequently, all other things being equal, patients preferred a 1L profile with higher PFS even if it came with higher AE risks. In contrast, oncologists were willing to accept a treatment with less efficacy in exchange for the most favorable safety profile. This difference may be due to a patient's lack of understanding of the potential severity of AEs or a physician's lack of awareness of the patient's treatment priorities. This is an area for future research and highlights the importance of oncologists explicitly communicating the known efficacy benefits and AE risks associated with each treatment option because these factors may influence patients' treatment choice in a way that differs from their own. Disclosures Ryan: AstraZeneca: Current Employment, Current equity holder in private company. Le:AstraZeneca: Current Employment, Current equity holder in private company. Wahlstrom:AstraZeneca: Current Employment, Current equity holder in private company. Beusterien:Kantar: Other: Employee of Kantar, which received funding from AstraZeneca to conduct this study. Will:Kantar: Other: Employee of Kantar, which received funding from AstraZeneca to conduct this study. Maculaitis:Kantar: Other: Employee of Kantar, which received funding from AstraZeneca to conduct this study. Leblanc:UpToDate: Patents & Royalties: Royalties; Agios, AbbVie, and Bristol Myers Squibb/Celgene: Speakers Bureau; AstraZeneca: Research Funding; AbbVie, Agios, Amgen, AstraZeneca, CareVive, BMS/Celgene, Daiichi-Sankyo, Flatiron, Helsinn, Heron, Otsuka, Medtronic, Pfizer, Seattle Genetics, Welvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; American Cancer Society, BMS, Duke University, NINR/NIH, Jazz Pharmaceuticals, Seattle Genetics: Research Funding.

Patient and physician decision-making on the use of novel agents in chronic lymphocytic leukemia (CLL): What drives preferences?

148 Background: CLL treatment has changed dramatically with the approval of novel agents, but data to guide treatment decisions are still lacking. How patients (PTs) and oncologists (ONCs) prioritize treatment attributes is unknown. Methods: ONCs and PTs completed an online survey to quantify preferences for first-line (1L) CLL treatment with novel agents via a discrete choice experiment; ONCs and PTs chose between hypothetical treatment profiles with varying attribute levels taken from product labels, registrational trials, and real-world studies. Hierarchical Bayes models were used to estimate attribute level preference weights, which were used to compute relative importance (RI), a measure of how influential an attribute is in treatment choice out of a total of 100%. Results: For ONCs (N=151), 72% were in community practice. PTs (N=220) had a median age of 56 years; 32% were in active surveillance, 36% were in/had completed 1L treatment, and 32% were relapsed/refractory. Increasing 2-year progression-free survival (PFS) from 75% to 95% had the greatest impact on preferences, with a mean RI of 40% for PTs and 30% for ONCs (Table). When assessing trade-offs between 2-year PFS and other attributes, ONCs required the largest increase in PFS (11%) to compensate for an increased risk of atrial fibrillation (AF) from 5% to 20%. PTs required the largest increase in PFS (6%) to compensate for an increased risk of infection from 7% to 20%. ONCs (vs PTs) required 2–4-times higher increases in PFS to accept an increased risk of AF, discontinuation due to adverse events (AEs), bleeding, tumor lysis syndrome (TLS), and arthralgia/myalgia. Conclusions: ONCs and PTs valued PFS most when selecting a novel CLL agent. While both groups accepted potential risks in exchange for increased PFS, ONCs were less likely to accept a higher risk of AEs. ONCs and PTs may perceive the risks and benefits of novel agents differently. ONC–PT communication may be improved by a more focused discussion on the risks of AEs, relative to treatment outcomes, with patient goals in mind. [Table: see text]

Utilizing Real-World Evidence (RWE) to Improve Care in Chronic Lymphocytic Leukemia: Challenges and Opportunities.

This review discusses important findings from real-world evidence (RWE) studies impacting the field of chronic lymphocytic leukemia (CLL), from prognostication to long-term management and sequencing of novel agents. RWE data, which represents a heterogeneous cohort of patients treated at non-academic centers and off-clinical trial, demonstrate several key differences between findings in randomized controlled trials (RCT) of novel agents in CLL. While toxicity and discontinuation rates are higher, survival outcomes are encouraging in clinical practice, with often equivalent outcomes from reduced-dose or time-limited therapy of drug. Though sequencing of novel agents lacks robust RCT data, RWE data provide important guidance for selection and sequencing of novel agents. RWE has critically informed our practice by providing diverse patient data and real-time analysis for important clinical questions outpacing the rapidly growing field of CLL.

Promises and pitfalls of targeted agents in chronic lymphocytic leukemia.

Targeted agents have significantly improved outcomes for patients with chronic lymphocytic leukemia, particularly high-risk subgroups for whom chemoimmunotherapy previously offered limited efficacy. Two classes of agent in particular, the Bruton tyrosine kinase inhibitors (e.g., ibrutinib) and the B-cell lymphoma 2 inhibitor, venetoclax, induce high response rates and durable remissions in the relapsed/refractory and frontline settings. However, maturing clinical data have revealed promises and pitfalls for both agents. These drugs induce remissions and disease control in the majority of patients, often in situations where modest efficacy would be expected with traditional chemoimmunotherapy approaches. Unfortunately, in the relapsed and refractory setting, both agents appear to be associated with an inevitable risk of disease relapse and progression. Emerging patterns of resistance are being described for both agents but a common theme appears to be multiple sub-clonal drivers of disease progression. Understanding these mechanisms and developing effective and safe methods to circumvent the emergence of resistance will determine the longer-term utility of these agents to improve patients’ quality and length of life. Rational drug combinations, optimised scheduling and sequencing of therapy will likely hold the key to achieving these important goals.

Understanding Clinician and Patient Preferences about Novel Agents in Chronic Lymphocytic Leukemia

Understanding Clinician and Patient Preferences about Novel Agents in Chronic Lymphocytic Leukemia

Fungal Infections in Chronic Lymphocytic Leukemia before and after Treatment

Background : Patients with Chronic Lymphocytic Leukemia (CLL) are susceptible to infections due to impaired immunity, from both complications of disease and treatments. Specific treatments such as fludarabine or rituximab are incorporated in chemotherapy regimens for CLL and cause lymphocyte depletion and impaired humoral immunity, resulting in increased risk of fungal infections. The aim of this study is to explore the incidence rates of fungal infections in patients before and after treatment for CLL. Methods : We identified patients diagnosed with CLL using ICD9 code 204.1X within the Veterans Health Affairs (VHA) between 1999 and 2013, before the availability of novel agents for CLL. Pharmacy records were used to identify treatment of CLL (alemtuzumab, bendamustine, chlorambucil, fludarabine, ofatumumab, pentostatin, and rituximab) as well as anti-fungal agents (amphotericin, caspofungin,fluconazole, flucytosine, itraconazole, ketoconazole, micafungin, posaconazole, and voriconazole). Fungal infections were identified with two strategies, using ICD9 codes alone (candida 112.X; pneumocystis 136.3; coccidiomycosis 114.x; histoplasmosis 115.X; blastomycosis 116.X; aspergillus 117.3; cryptococcus 117.5; opportunistic mycoses 118.X) as well as using ICD9 codes combined with evidence of treatment with an anti-fungal (ICD9+antifungal). Number of infections and incidence rates were categorized as occurring in patients prior to first treatment (pre-treat), or after first treatment (post-treat), or in patients who had never received treatment within the VHA (no-treat). Incidence rate ratio between pre- and post-treatment period was calculated to quantify the magnitude of risk increase in patients who received CLL treatment. Results : A cohort of 20,023 patients were identified with CLL and followed for a mean of 5.33 years for a total surveillance of 106,772 person-years. Of these patients, 3,726 (18.6%) received treatment for CLL within the VHA. Using ICD9 codes alone, 970 fungal infections were identified and with ICD9+anti-fungal, 415 patients had an infection. With ICD9, the most common infection was candida with 765 infections, followed by aspergillus with 58 and pneumocystis with 39 infections. Rates of infections based on ICD9 were highest in the post-treat group with 2.98 infections per 100 person-years, followed by 1.08 infections per 100 person-years in the pre-treat group and 0.58 infections per 100 person-years in the no-treat group. The most common first treatment was rituximab alone, used in 35.9% of patients, followed by chlorambucil in 31.9%, fludarabine in 20.4%, and bendamustine in 9.9%. In comparison to pre-treat patients, post-treat patients had 2.91 times increased risk of fungal infection (95% confidence interval (CI) 2.24-3.81) determined by ICD9 code and 4.74 times increased risk (95% CI 3.09-7.57) determined by ICD9+antifungal. The rate of candida infection increased 2.9 fold (95% CI 2.24-3.81) with ICD9 and 4.7 fold (95% CI 3.09-7.57) with ICD9+antifungal while aspergillus infections increased 8.7 fold (95% CI 3.01-35.4) with ICD9 and 10.2 fold (95% CI 2.88-63.1) with ICD9+antifungal between post-treat and pre-treat groups. Conclusions: In this retrospective analysis of CLL patients, treatment for CLL significantly increased the rate of fungal infections, primarily candida and aspergillus. Further study is needed to understand the effect of modern treatments on fungal infections in CLL. Disclosures Schoen: Pharmacyclics: Research Funding. Georgantopoulos:Pharmacyclics: Research Funding. Bennett:Pharmacyclics: Research Funding.

Discontinuation Patterns in Patients Receiving Novel Oral Agents for Chronic Lymphocytic Leukemia in the Veterans Health Administration

Introduction Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults, accounting for 25-30% of all leukemias in the United States. During the past decade, there has been a paradigm shift in CLL treatment, with increasing adoption of novel oral agents (NOAs) such as acalabrutinib (ACALA), duvelisib (DUV), ibrutinib (IBR), idelalisib (IDELA), and venetoclax (VEN) instead of traditional chemoimmunotherapy (CIT). Unlike CIT, most NOAs are given daily for an indefinite period of time and are self-administered at home, raising concerns about adherence and discontinuation. The discontinuation patterns of NOAs in a real-world population of CLL patients is currently unknown. Methods Using the Veterans Administration (VA) Cancer Registry System and electronic healthcare records, we identified patients treated for CLL with NOAs in the VA from November 1, 2013 to November 30, 2018. Patients were followed from the first NOA dispensation until death or the end of the study observation (May 31, 2019). NOAs were selected in accordance with the National Comprehensive Cancer Network (NCCN) guidelinesfor CLL and were extracted using pharmacy dispensation records. Discontinuation was defined as the absence of NOA dispensation within 60 days of estimated exhaustion of patient's NOA supply from the last recorded dispensation. A discontinuation event for each NOA treatment episode in each patient was classified as either 1) a drug holiday, if there was evidence of resumption of the same treatment without any other treatment interventions after the first discontinuation; or 2) permanent discontinuation, in which the treatment ceased without evidence of resumption for 60 days or there was evidence of new treatment initiation after the discontinuation of previous treatment. We report the proportion of discontinuation and exposure-adjusted discontinuation rates (e-AR), which were calculated using the length of NOA duration in person-time. Results We identified 1,196 CLL patients treated with NOAs from November 1, 2013 to November 30, 2018. The mean age at NOA initiation was 70.7 years; 96.7% of patients were male. The median time from diagnosis to NOA initiation was 56.5 months (0-189.5 months). Of the 1,196 patients treated with NOAs, 1,172 received IBR, 53 received IDELA, and 106 received VEN. There were few patients (<10)treated with ACALA and DUV, therefore these patientswere omitted from the final analyses. During a median follow-up of 18.9 months (0-65.3 months), 48.2% NOA treatment courses were followed by a discontinuation event. The proportions of patients who discontinued for IBR, IDELA, and VEN were 47.5%, 77.4%, and 41.5%. The e-AR of IBR, IDELA, and VEN are reported in Table 2. At the end of the study observation (May 2019), 52.6% of IBR, 22.6% of IDELA, and 58.3% of VEN treatment courses were still being administered. In first-line (L1) IBR, the median NOA treatment duration until the first discontinuation was 10.7 months (0.8-55.8 months), 12.6 months (0.5-62.0 months) in second-line (L2) IBR, and 12.2 months (0.78-57.8 months) in third-line or subsequent lines (L3+) IBR. In IDELA treatment courses, the median treatment duration until the first discontinuation was 17.8 months (1.9-41.6 months) in L2 and 4.3 months (1.7-26.2 months) in L3+. In VEN, the median treatment duration until the first discontinuation was 8.4 months (3.1-26.0 months) in L2 and 7.4 months (1.7-18.5 months) in L3+. Of 532 L1 IBR treatment courses with >1 dispensation, 96 (18%) were associated with a drug holiday and 97 (18%) with permanent discontinuation. These numbers were 64 (27%) and 50 (21%) for L2 IBR courses, and 90 (28%) and 76 (24%) for L3+ IBR courses. Similarly, 24 (67%) of L3 IDELA treatment courses with >1 dispensation were associated with permanent discontinuation. Among 63 L3+ VEN courses with >1 dispensation, 6 (10%) were associated with a drug holiday and 14 (22%) with permanent discontinuation. Conclusions To our knowledge, this study is the first to report on the NOA discontinuation in a nationwide VA cohort of CLL patients treated in a real-world setting. Our results suggest there is a substantial proportion of drug holidays and permanent discontinuation among commonly used NOAs. Further efforts will focus on understanding factors leading to discontinuation and the impact of discontinuation/drug holidays on clinical outcomes. Disclosures Biondo: Genentech, Inc.: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership. Halloran:Roche: Equity Ownership; Genentech, Inc.: Employment. Shapouri:Roche: Equity Ownership; Genentech, Inc.: Employment. Wu:Genentech, Inc.: Employment. Sauer:University of Utah and SLC VA Medical Center: Employment. Halwani:Miragen: Research Funding; Kyowa Hakko Kirin: Research Funding; Pharmacyclics: Research Funding; Amgen: Research Funding; Seattle Genetics: Research Funding; Genentech, Inc.: Research Funding; AbbVie: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Immune Design: Research Funding.

Evolution in Practice Patterns and Differences Among Experts and Community Healthcare Providers in the Treatment of Patients with Chronic Lymphocytic Leukemia

Evolution in Practice Patterns and Differences Among Experts and Community Healthcare Providers in the Treatment of Patients with Chronic Lymphocytic Leukemia

Resistance Mechanisms to Targeted Agents in Chronic Lymphocytic Leukemia.

Agents that specifically target pathologic mechanisms of survival have now been approved for the treatment of chronic lymphocytic leukemia in both the treatment-naive and relapsed/refractory settings. These 4 agents include the Bruton tyrosine kinase inhibitor ibrutinib, the B-cell leukemia/lymphoma-2 inhibitor venetoclax, and the phosphatidylinositol-3 kinase inhibitors idelalisib and duvelisib. Although clinical outcomes are improved with all of these inhibitors, acquired resistance does occur and leads to progression of disease. Resistance to targeted therapy can occur through direct mutations of the target or through the overexpression of alternative cell survival pathways not affected by the specific inhibitor. Determining which patients will develop resistance, why resistance occurs, how to overcome resistance, and when to test for resistance are all subjects of ongoing research. In this review, we describe the current data relative to the development of resistance to targeted therapies in CLL.

Sequential and combination treatments with novel agents in chronic lymphocytic leukemia.

Chemoimmunotherapy has been the standard of care for patients with chronic lymphocytic leukemia for a long time. However, over the last few years, novel agents have produced unprecedented outcomes in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia. With the advent of these targeted agents, treatment options have diversified very considerably and new questions have emerged. For example, it is unclear whether these novel agents should be used as sequential monotherapies until disease progression or whether they should preferably be combined in time-limited treatment regimens aimed at achieving deep and durable remissions. While both approaches yield high response rates and long progression-free and overall survival, it remains challenging to identify patients individually for the optimal concept. This review provides guidance in this decision process by presenting evidence on sequential and combined use of novel agents and discussing the advantages and drawbacks of these two approaches.