Chronic Lymphocytic Leukemia Therapy Research Articles

Ublituximab plus ibrutinib versus ibrutinib alone for patients with relapsed or refractory high-risk chronic lymphocytic leukaemia (GENUINE): a phase 3, multicentre, open-label, randomised trial

Patients with chronic lymphocytic leukaemia and high-risk features have poorer outcomes on ibrutinib than those without high-risk features. The aim of this study was to assess the benefit of adding ublituximab, an anti-CD20 monoclonal antibody, to ibrutinib therapy in this population. We did a randomised, phase 3, multicentre study (GENUINE) of patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia with at least one of 17p deletion, 11q deletion, or TP53 mutation, at 119 clinics in the USA and Israel. Eligible patients had received at least one previous chronic lymphocytic leukaemia therapy and had an Eastern Cooperative Oncology Group performance status of 2 or lower. We randomised patients (1:1) using permuted block randomisation with a block size of four and stratified by previous lines of therapy (one vs two or more) to receive ibrutinib alone or ibrutinib in combination with ublituximab. Treatment allocation was not masked to patients or investigators. Ibrutinib was given orally daily at 420 mg for all cycles. Ublituximab was given intravenously in 28-day cycles, with increasing doses during cycle 1 (≤150 mg on day 1, 750 mg on day 2, and 900 mg on days 8 and 15) and continuing at 900 mg on day 1 of cycles 2-6. After cycle 6, ublituximab was given at 900 mg every three cycles. The study was initially designed with co-primary endpoints of progression-free survival and overall response rate but due to protracted patient accrual, the protocol was amended to have a single primary endpoint of independent review committee-assessed overall response rate (defined as the proportion of patients who had a partial response, complete response, or complete response with incomplete marrow recovery according to the 2008 International Workshop on CLL criteria) in the intention-to-treat population. Safety was evaluated in the population of patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02301156, and the final analysis is presented. 224 patients were assessed for eligibility, of whom 126 patients were enrolled and randomly assigned to receive ublituximab plus ibrutinib (n=64) or ibrutinib alone (n=62) between Feb 6, 2015, and Dec 19, 2016. After a median follow-up of 41·6 months (IQR 36·7-47·3), the overall response rate was 53 (83%) of 64 patients in the ublituximab plus ibrutinib group and 40 (65%) of 62 patients in the ibrutinib group (p=0·020). 117 patients, including 59 in the ublituximab plus ibrutinib group and 58 in the ibrutinib group, received at least one dose of treatment and were included in safety analyses. Most adverse events were grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and seven [12%] in the ibrutinib group), anaemia (five [8%] and five [9%]), and diarrhoea (six [10%] and three [5%]). The most common serious adverse events were pneumonia (six [10%] in the ublituximab plus ibrutinib group and four [7%] in the ibrutinib group), atrial fibrillation (four [7%] and one [2%]), sepsis (four [7%] and one [2%]), and febrile neutropenia (three [5%] and one [2%]). Two patients in the ublituximab plus ibrutinib group died due to adverse events (one cardiac arrest and one failure to thrive), neither of which were treatment-related. Five patients in the ibrutinib group died due to adverse events, including one cardiac arrest, one cerebral infarction, one intracranial haemorrhage, one Pneumocystis jirovecii pneumonia infection, and one unexplained death; the death due to cardiac arrest was considered to be treatment-related. The addition of ublituximab to ibrutinib resulted in a statistically higher overall response rate without affecting the safety profile of ibrutinib monotherapy in patients with relapsed or refractory high-risk chronic lymphocytic leukaemia. These findings provide support for the addition of ublituximab to Bruton tyrosine kinase inhibitors for the treatment of these patients. TG Therapeutics.

Prognostic factors and effectiveness of the first-line therapy for chronic lymphocytic leukemia: results of 10-year follow-up

Introduction.The biological heterogeneity of chronic lymphocytic leukemia (CLL) is reflected in the rate of progression, the need for therapy, and the response to treatment. Analysis of prognostic factors contributes to improving the quality of treatment and rational distribution of healthcare resources.Materials and methods.Among 890 patients with documented stage of CLL, 405 (45.5 %) received treatment. As the first-line of treatment, 173 patients received intensive regimens (FCR or BR), 6 – new agents, and 226 – all other regimens. The initial stage of the disease, mutation status of IGHV, del17p with or without complex karyotype were analyzed as prognostic markers.Results.Immunochemotherapeutic regimens were shown to be highly effective in case planned amount of treatment was completed. The combination of such prognostic parameters as the initial stage of the disease, the mutation status of IGHV, and the presence of del17p and/or complex karyotype allows us to clearly identify a group of patients with an unfavorable prognosis, for which it is advisable to use either intensive programs or new agents in the first-line therapy.

Antibody Peptides as Cancer Vaccine-Turning Weapons to Targets.

Stereotyped B-cell receptors (BCR) are frequent in patients with chronic lymphocytic leukemia (CLL). In cell culture and in mouse models of CLL, immunogenic epitopes of these BCRs were shown to trigger specific T-cell responses and to control leukemia development. These results suggest vaccination with autologous BCR-derived peptides as a novel therapy for CLL.See related article by Rovida et al., p. 729.

Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia.

BackgroundSeveral genetic alterations have been identified as driver events in chronic lymphocytic leukemia (CLL) pathogenesis and oncogenic evolution. Concurrent driver alterations usually coexist within the same tumoral clone, but how the cooperation of multiple genomic abnormalities contributes to disease progression remains poorly understood. Specifically, the biological and clinical consequences of concurrent high‐risk alterations such as del(11q)/ATM‐mutations and del(17p)/TP53‐mutations have not been established.MethodsWe integrated next‐generation sequencing (NGS) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 techniques to characterize the in vitro and in vivo effects of concurrent monoallelic or biallelic ATM and/or TP53 alterations in CLL prognosis, clonal evolution, and therapy response.ResultsTargeted sequencing analysis of the co‐occurrence of high‐risk alterations in 271 CLLs revealed that biallelic inactivation of both ATM and TP53 was mutually exclusive, whereas monoallelic del(11q) and TP53 alterations significantly co‐occurred in a subset of CLL patients with a highly adverse clinical outcome. We determined the biological effects of combined del(11q), ATM and/or TP53 mutations in CRISPR/Cas9‐edited CLL cell lines. Our results showed that the combination of monoallelic del(11q) and TP53 mutations in CLL cells led to a clonal advantage in vitro and in in vivo clonal competition experiments, whereas CLL cells harboring biallelic ATM and TP53 loss failed to compete in in vivo xenotransplants. Furthermore, we demonstrated that CLL cell lines harboring del(11q) and TP53 mutations show only partial responses to B cell receptor signaling inhibitors, but may potentially benefit from ATR inhibition.ConclusionsOur work highlights that combined monoallelic del(11q) and TP53 alterations coordinately contribute to clonal advantage and shorter overall survival in CLL.

A Bispecific Single-Domain Antibody Boosts Autologous Vγ9Vδ2-T Cell Responses Toward CD1d in Chronic Lymphocytic Leukemia.

Although considerable progress has been made with autologous T cell-based therapy in B-cell malignancies, application in chronic lymphocytic leukemia (CLL) lags behind due to disappointing response rates as well as substantial toxicity that is of particular concern in the elderly CLL population. Vγ9Vδ2-T cells form a conserved T-cell subset with strong intrinsic immunotherapeutic potential, largely because of their capacity to be triggered by phosphoantigens that can be overproduced by CLL and other malignant cells. Specific activation of Vγ9Vδ2-T cells by a bispecific antibody may improve the efficacy and toxicity of autologous T-cell-based therapy in CLL. We evaluated CD1d expression in a cohort of 78 untreated patients with CLL and generated and functionally characterized a CD1d-specific Vγ9Vδ2-T cell engager based on single-domain antibodies (VHH). CD1d was expressed by CLL in the majority of patients, particularly in patients with advanced disease. The CD1d-specific Vγ9Vδ2-T cell engager induced robust activation and degranulation of Vγ9Vδ2-T cells, enabling Vγ9Vδ2-T cells from patients with CLL to lyse autologous leukemic cells at low effector-to-target ratios. Expression of CD1d on CLL cells is upregulated by all-trans retinoic acid, and sensitizes the malignant cells to bispecific VHH-induced lysis. Furthermore, we provide evidence that the Vγ9Vδ2-T cell receptor retains responsiveness to phosphoantigens when the bispecific VHH is bound, and aminobisphosphonates can therefore enhance bispecific Vγ9Vδ2-T cell engager-mediated tumor-specific killing. Collectively, our data demonstrate the immunotherapeutic potential of this novel CD1d-specific Vγ9Vδ2-T cell engager in CLL.

Overcoming resistance to targeted therapies in chronic lymphocytic leukemia.

Insight into the critical role of B-cell receptor signaling for the pathogenesis of chronic lymphocytic leukemia (CLL) led to the development of targeted therapies directed at key regulators of cell survival. Agents targeting B-cell lymphoma-2 protein, Bruton's tyrosine kinase (BTK), and phosphatidylinositol 3-kinase are approved for treatment of CLL, and have significantly improved the disease management. Nevertheless, acquired resistance to the targeted therapies is a challenge still to be resolved. The mechanisms underlying resistance are becoming clearer, and include secondary mutations within the drug target and activation of bypass pathways. This knowledge has allowed development of strategies to prevent and overcome treatment resistance. Approaches to prevent resistance include targeting bypass mechanisms by combination therapies, temporally sequencing of therapies, improved clinical trial designs, and real-time monitoring of patient response. A rational design of drug sequencing may secure effective treatment options at the relapsed setting. Next-generation inhibitors and bispecific antibodies have the potential to overcome resistance to the BTK inhibitor ibrutinib. Immunotherapy, including chimeric antigen receptor-modified T-cell therapy, is explored for relapsed CLL. Here, recent advances that have contributed to the understanding of resistance to targeted therapies in CLL are discussed. Strategies for managing resistance are reviewed, including translational, real-world, and clinical perspectives.

Impact of Oral Targeted Therapy on the Economic Burden of Chronic Lymphocytic Leukemia in Canada.

Background: Continuous oral targeted therapy (OTT) for chronic lymphocytic leukemia (CLL) represents an effective therapy but also a major economic burden on the healthcare system. This study aimed to estimate future direct costs, along with the prevalence, of CLL in the era of continuous OTT in Canada. Methods: The economic burden of OTT was modelled and compared to chemoimmunotherapy (CIT), for CLL treatment. The burden was assessed/projected from 2011 to 2025. For the OTT scenario, CIT was considered the standard of care before 2015, while OTT was considered standard of care for patients with either unmutated immunoglobulin heavy-chain variable (IGHV) or del(17p)/TP53 mutations starting in 2015 and, from 2020 onwards, for all first-line treatments except for patients with mutated IGHV. A Markov model was developed including four health states: watchful-waiting, first-line treatment, relapse and death. Costs of therapy, follow-up/monitoring and adverse events were included. Key clinical parameters were extracted from pivotal clinical trials. Results: As incidence rates and rate of survival are increasing, the prevalence of CLL in Canada is projected to increase 1.8-fold, from 8301 patients in 2011 to 14,654 by 2025. Correspondingly, the total annual costs of CLL management are predicted to increase 15.7-fold, from $60.8 million to $957.5 million during that same period. Conclusions: Although OTT enhances survival for patients with CLL, it is nonetheless associated with an important economic burden due to the projected vast increase in costs from 2011 to 2025. Changes in clinical strategies, such as implementation of a fixed OTT treatment duration, could help alleviate financial burden.

Ibrutinib as First-Line Therapy in High-Risk Chronic Lymphocytic Leukemia: Case Reports

In the selection of the optimal specific therapy in chronic lymphocytic leukemia (CLL), a crucial role is played by the determination of risk groups. The CLL International Prognostic Index takes account of unfavorable del(17p), del(11q) cytogenetic abnormalities, and/or TP53 gene mutations as well as the mutation status of immunoglobulin heavy chain variable region genes (IGHV). The absence of IGHV gene mutations is often associated with such prognostically unfavorable genetic markers as del(17p), del(11q), trisomy 12, and TP53 mutation. The combinations of this kind affect the prognosis and overall survival rate. Besides, in high-risk CLL the efficacy of therapy is rather low and the development of refractoriness is possible. In such patients the use of Bruton tyrosine kinase inhibitor as first-line therapy considerably increases the probability of long-term remission. The present paper provides the analysis of clinical and hematological efficacy and tolerance of ibrutinib as first-line therapy in highrisk CLL. Ibrutinib shows high efficacy and low toxicity. The use of ibrutinib as first-line therapy effectively reduces the probability of CLL progression, which is especially critical in high-risk patients, i.e., with 17p deletion and TP53 gene mutation.

CAR-T Cells for the Treatment of Chronic Lymphocytic Leukemia: Literature Review

Chronic lymphocytic leukemia (CLL) is the most common adult malignant lymphoid disease. Despite new highly effective targeted drugs, the prognosis of relapsed and resistant form of this disease is poor. CAR-T cell therapy using T-lymphocytes with chimeric antigen receptor (CAR) demonstrated its efficacy in the treatment of such oncohematological diseases as B-cell non-Hodgkin’s lymphomas and acute lymphoblastic leukemia. The present literature review focuses on the experience of using CAR-T cells for CLL therapy. It presents the advantages and drawbacks of this technique as well as the challenging issues to be solved for its implementation into broad clinical practice.

Cladribine with prednisone versus chlorambucil with prednisone as first-line therapy in chronic lymphocytic leukemia: report of a prospective, randomized, multicenter trial

AbstractThe efficacy and toxicity of cladribine (2-CdA) + prednisone (P) versus chlorambucil (Chl) + P were compared in previously untreated patients with progressive or symptomatic chronic lymphocytic leukemia (CLL) in a randomized, multicenter prospective trial. Eligible patients were assigned to either 2-CdA 0.12 mg/kg per day in 2-hour infusions and P 30 mg/m2 per day for 5 consecutive days or Chl 12 mg/m2 per day and P 30 mg/m2 per day for 7 consecutive days. Three courses were administered at 28-day intervals or longer if myelosuppression developed. The therapy was finished if complete response (CR) was achieved. Of 229 available patients 126 received 2-CdA+P and 103 received Chl+P as a first-line treatment. CR and overall response rates were significantly higher in the patients treated with 2-CdA+P (47% and 87%, respectively) than in the patients treated with Chl+P (12% and 57%, respectively) (P = .001). Progression-free survival was significantly longer in the 2-CdA–treated group (P = .01), but event-free survival was not statistically different. Thirteen percent of patients were refractory to 2-CdA+P and 43% to Chl+P (P = .001). Drug-induced neutropenia was more frequently observed during 2-CdA+P (23%) than Chl+P therapy (11%) (P = .02), but thrombocytopenia occurred with similar frequency in both groups (36% and 27%, respectively). Infections were seen more frequently in the 2-CdA+P-treated group (56%) than in the Chl+P-treated group (40%; P = .02). Death rates have so far been similar in patients treated with 2-CdA (20%) and with Chl (17%). The probability of overall survival calculated from Kaplan-Meier curves at 24 months was also similar for both groups (78% and 82%, respectively).

Cladribine with prednisone versus chlorambucil with prednisone as first-line therapy in chronic lymphocytic leukemia: report of a prospective, randomized, multicenter trial

The efficacy and toxicity of cladribine (2-CdA) + prednisone (P) versus chlorambucil (Chl) + P were compared in previously untreated patients with progressive or symptomatic chronic lymphocytic leukemia (CLL) in a randomized, multicenter prospective trial. Eligible patients were assigned to either 2-CdA 0.12 mg/kg per day in 2-hour infusions and P 30 mg/m(2) per day for 5 consecutive days or Chl 12 mg/m(2) per day and P 30 mg/m(2) per day for 7 consecutive days. Three courses were administered at 28-day intervals or longer if myelosuppression developed. The therapy was finished if complete response (CR) was achieved. Of 229 available patients 126 received 2-CdA+P and 103 received Chl+P as a first-line treatment. CR and overall response rates were significantly higher in the patients treated with 2-CdA+P (47% and 87%, respectively) than in the patients treated with Chl+P (12% and 57%, respectively) (P = .001). Progression-free survival was significantly longer in the 2-CdA-treated group (P = .01), but event-free survival was not statistically different. Thirteen percent of patients were refractory to 2-CdA+P and 43% to Chl+P (P = .001). Drug-induced neutropenia was more frequently observed during 2-CdA+P (23%) than Chl+P therapy (11%) (P = .02), but thrombocytopenia occurred with similar frequency in both groups (36% and 27%, respectively). Infections were seen more frequently in the 2-CdA+P-treated group (56%) than in the Chl+P-treated group (40%; P = .02). Death rates have so far been similar in patients treated with 2-CdA (20%) and with Chl (17%). The probability of overall survival calculated from Kaplan-Meier curves at 24 months was also similar for both groups (78% and 82%, respectively). (Blood. 2000;96:2723-2729)

Systems biology drug screening identifies statins as enhancers of current therapies in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a B lymphoid malignancy highly dependent on the microenvironment. Despite new targeted therapies such as ibrutinib and venetoclax, disease progression and relapse remain an issue. CLL cell interactions with the supportive tissue microenvironment play a critical role in disease pathogenesis. We used a platform for drug discovery based on systems biology and artificial intelligence, to identify drugs targeting key proteins described to have a role in the microenvironment. The selected compounds were screened in CLL cell lines in the presence of stromal cells to mimic the microenvironment and validated the best candidates in primary CLL cells. Our results showed that the commercial drug simvastatin was the most effective and selective out of the tested compounds. Simvastatin decreased CLL cell survival and proliferation as well as cell adhesion. Importantly, this drug enhanced the antitumor effect of venetoclax and ibrutinib. We proposed that systems biology approaches combined with pharmacological screening could help to find new drugs for CLL treatment and to predict new combinations with current therapies. Our results highlight the possibility of repurposing widely used drugs such as statins to target the microenvironment and to improve the efficacy of ibrutinib or venetoclax in CLL cells.

Bruton’s Tyrosine Kinase Inhibitors Impair Fcγriia-Mediated Responses of Healthy Donor Platelets and Chronic Lymphocytic Leukaemia Derived Platelets to Bacteria

Platelets play a key role in innate immunity and can interact with bacteria through multiple molecular mechanisms. One key receptor for platelet-bacteria interactions is FcγRIIa, a low affinity IgG immune receptor found on the surface of platelets, which is associated with platelet aggregation, phagocytosis and the release of bactericidal substances and cytokines from alpha and dense granules. The signalling pathways that regulate FcγRIIa mediated platelet responses to bacteria are not fully understood. Downstream of the FcγRIIa receptor is the protein Bruton's tyrosine kinase (Btk) and potentially other Tec family kinases, yet the role of these kinases in platelet-bacteria interactions is unknown. Btk is a therapeutic target in chronic lymphocytic leukaemia (CLL) with inhibitors of Btk (iBtks) including ibrutinib and acalabrutinib. However, iBtks have off-target effects on platelets, inhibiting aggregation with associated haemorrhagic side effects. iBtk treatment is also associated with a higher incidence of infection in CLL patients. The effect of iBtks on platelet immune function has not been evaluated. We hypothesise that Btk has a role in platelet FcγRIIa signalling in response to bacterial agonists, and that iBtks inhibit such responses, contributing towards the increased risk of infection seen with such therapies in CLL. We show that ibrutinib and acalabrutinib inhibit healthy donor FcγRIIa-mediated platelet aggregation, alpha and dense granule release in response to incubation with Staphylococcus aureus and Escherichia coli, and also in response to FcγRIIa crosslinking with the monoclonal antibody IV.3 (anti-FcγRIIa). The observed lack of granule secretion will reduce the bactericidal substances released by the platelet, as well as the amount of cytokine and chemokine secretion limiting cross-talk with other immune cells. Phosphorylation of Btk at tyrosine 223 (a marker of Btk activation) was detected in response to FcγRIIa agonists, and was inhibited by both ibrutinib and acalabrutinib. Little is known about the effect of iBtk treatment on CLL-platelet responses to bacteria. CLL patients tend to be on concurrent medications for comorbid conditions that could alter platelet responses. We show that treatment-naïve and ibrutinib-treated CLL platelets have aggregation and alpha granule release to thrombin receptor activator peptide 6 and ADP comparable to healthy controls, indicating that CLL platelet responses to these FcγRIIa-independent agonists are normal. Moreover, platelets derived from iBtk naïve CLL patients aggregate normally to bacteria in the presence of autologous plasma. However, platelets from ibrutinib-treated CLL patients have significantly inhibited aggregation and alpha granule release in response to S.aureus, E.coli, and IV.3 crosslinking. Moreover, Btk is phosphorylated at Y223 in response to bacterial agonists in treatment-naïve, but not in ibrutinib-treated CLL platelets, highlighting the lack of Btk activation in iBtk-treated patients. An X-linked agammaglobulinaemia (XLA) patient with a known Btk loss of function mutation was examined to investigate if Btk is vital for the FcγRIIa pathway. XLA-derived platelets aggregated normally in response to multiple bacterial species, suggesting Btk is redundant in mediating platelet aggregatory responses to bacteria. These results suggest that other Tec family kinases might have a role in platelet FcγRIIa activation to bacteria, which could be affected by iBtk treatment too. In conclusion, we propose that iBtks impair the FcγRIIa pathway in platelets, reducing platelet-bacteria responses, possibly contributing to the increased risk of infections in observed in CLL. Disclosures No relevant conflicts of interest to declare.

Three Fold Risk of Atrial Fibrillation in Ibrutinib Treated CLL Patients without Increased Risk of Stroke: A SEER-Medicare Database Analysis

INTRODUCTION In February 2014, the Bruton tyrosine kinase inhibitor ibrutinib received FDA approval for treatment of adult Chronic Lymphocytic Leukemia (CLL) patients (pts) treated with at least one prior therapy. Subsequently, ibrutinib was approved for treatment of CLL pts with 17p deletion (July 2014) and then as initial therapy for CLL (March 2017). Although ibrutinib has been shown to have durable responses, it is associated with bleeding complications and an increased risk of atrial fibrillation (Afib) in clinical trials. We present an analysis of Afib and stroke risk associated with ibrutinib in an observational study using real-world cancer registry data. METHODS: We used the SEER-Medicare database to identify adult Medicare beneficiaries (aged 66 years or older) diagnosed with CLL between 2008-2016, who were enrolled in Medicare at least 12 months prior to CLL diagnosis, and received their care through the traditional fee-for-service system (n=4,958). Sociodemographic characteristics, as well as date and cause of death were obtained from the SEER. Comorbidities listed on the Elixhauser comorbidity index were identified from inpatient and outpatient Medicare claims in the year prior to first treatment or first Ibrutinib use. Treatment modalities, including chlorambucil, rituximab, fludarabine, cyclophosphamide, bendamustine, and prescription of ibrutinib (starting in 2014), were identified from Medicare Part B and Part D data. We categorized primary exposure as: 1) pts who did not receive any treatment for CLL; 2) those who were treated but never given ibrutinib; and, 3) those treated with ibrutinib. Our primary outcomes were Afib and stroke. We compared demographic, clinical characteristics and comorbidities, and calculated incidence rates (IR, per 1,000 person-years) across the three treatment groups. Among those who were treated (n=2,789), we used Cox proportional hazards regression with inverse probability weighting (IPW) to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for the association between ibrutinib and other treatment with stroke and Afib, adjusted for age at treatment, sex, race, and Elixhauser comorbidity index. RESULTS: Among 4,958 CLL pts, 2,169 (44%) never received any treatment, 2,490 (50%) were treated but not with ibrutinib, and 299 (6%) received ibrutinib. Baseline characteristics are presented in Table 1. Importantly, pts treated with ibrutinib were younger at diagnosis (medianibrutinib, 75y; mediannon-ibrutinib, 76.5y; mediannot-treated, 80y) and at time of first treatment (medianibrutinib, 77y vs mediannon-ibrutinib, 78y). However, pts initially treated with ibrutinib (n=52) had higher age at first treatment, 77.5y (IQR: 72.5-82). Among pts who were never treated, the stroke incidence was 11.9% after CLL diagnosis (IR: 47.7/1,000 person-years) and Afib incidence was 15.2% (IR: 60.6/1,000 person-years). Among pts who received CLL treatment but not ibrutinib, the IR of stoke and Afib were 54.69/1,000 person-years and 67.2/1,000 person-years, respectively; and CLL pts treated with ibrutinib presented IR of stroke of 72.9/1,000 person-years while IR of Afib was 221.8/1,000 person-years. Among CLL pts who received treatment, after adjusting for potential confounding variables, the risk of Afib for pts treated with ibrutinib was 3-fold times the risk of pts whose treatment did not include ibrutinib (HR: 3.0; 95% CI: 2.1, 4.4). The association between ibrutinib versus other treatment with stroke was not statistically significant (HR: 1.1; 95% CI: 0.48, 2.3). CONCLUSIONS: Our analysis included data of CLL treatment patterns and therapy related toxicities from the initial years after ibrutinib regulatory approval. In alignment with clinical trial results, these early real - world data show ibrutinib pts have a statistically significant risk of Afib. Our analyses did not demonstrate an association between ibrutinib treatment and risk of stroke. We also found that pts prescribed therapy for CLL, including non - ibrutinib treatments, had a higher crude incidence of stroke and Afib than pts who had not initiated treatment. Future analyses will evaluate the risk of these complications in comparison with non CLL pts as well as their correlation with treatment in the setting of widespread use of BTK inhibitors and other targeted agents for treatment of CLL. Disclosures Koroukian: Cleveland Clinic Foundation: Research Funding; Celgene: Research Funding. Caimi:Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; Genentech: Research Funding; ADC Therapeutics: Research Funding.

Assessment of Measurable Residual Disease (MRD) in Chronic Lymphocytic Leukemia (CLL) and Multiple Myeloma (MM) Among U.S. Community Hematologists/ Oncologists (cH/O)

Introduction: In this era of targeted therapy, assessing MRD status is important to guide treatment decision-making in hematologic malignancies. While MRD assessment has long been incorporated the management of patients with acute lymphoblastic leukemia (ALL), there is mounting evidence that MRD-negativity is a critical end point in CLL and MM that correlates well with clinical outcomes. In CLL, undetectable MRD at the end of treatment in peripheral blood or bone marrow is associated with long-term survival (Thompson et al, Leukemia 2018). The international workshop on CLL (iwCLL) guidelines for response assessment in CLL now incorporate MRD assessment (Hallek, et al, Blood 2018). The international myeloma working group (IMWG) and the NCCN now recommend MRD assessment after each phase of MM therapy (induction, stem cell transplant, consolidation and maintenance). Higher rates of durable responses are noted in those with MRD-negativity after induction (Attal et al, NEJM 2017) and associated with favorable survival (Pavia et a, Blood 2008). Based on results from recent studies, MRD negative status can guide clinical decision-making about discontinuation of therapy in CLL (Jain et al, ASH 209 and Tam et al, ASH 2019) and in MM (Costa et al, ASH 2019 and Usmani et al, 2019). A majority of patients with CLL and MM are treated at community practices in the US. but adoption of MRD assessment among cH/O is unclear. We sought to study the self-reported utilization patterns of MRD assessment in CLL and MM, it's use in determining duration of therapy, and the barriers to it's adoption in practice among U.S. cH/O. Methods: U.S.-licensed oncologists and hematologists with broad geographic representation convened at a live meeting in January 2020 to review clinical updates presented at the 2019 ASH Annual Meeting. An electronic pre-meeting survey and live survey were fielded among cH/O meeting attendees. Surveys collected physician perceptions and reported use of MRD assessment for patients with CLL and MM. Responses to questions were summarized using descriptive statistics. Results: A total of 59 cH/O were included who self-identified their specialty as hematology/ oncology (51%) and medical oncology (34%) and reported MM (69%) and CLL (61%) as the two commonest hematologic malignancies treated by them. Excluding those that had not treated MM or CLL in the preceding 3 months, a subset of 46 cH/O were queried on their use and perceptions of MRD assessment in these two diseases. In CLL, 52% of the cH/O do not assess MRD status, and only 17% utilize MRD status in treatment discontinuation decisions. Major reasons for not using MRD status in practice include the perception shared by a majority (52%) of respondents that the evidence does not support its use in CLL at the present time. A minority (9%) utilized MRD assessment when treating younger fit patients with CLL. In MM, 50% do not assess for MRD at any time post-therapy, and 24% utilize MRD status in treatment discontinuation decisions. Major barriers to MRD assessment in MM were the perception that evidence does not support MRD use (59% of the respondents) and lack of payer coverage (11%). Additional details are presented in the Table below. Conclusions: These data from a limited sample of cH/O suggest that adoption of MRD testing among US cH/O is low, despite results from recent trials that highlight the importance of the MRD negativity as an important prognostic factor in both CLL and MM. Half of cH/O do not measure MRD at any point while treating MM and CLL and less than a fifth incorporate MRD data to determine duration of therapy. The greatest barrier to MRD assessment is the impression that there is lack of evidence supporting its utility in practice at the present time. Further education among cH/O is warranted regarding MRD assessment in CLL and MM given that MRD-negative status is associated with favorable prognosis and should be incorporated in treatment decision-making based on updated guidelines in both diseases. Disclosures Gajra: Cardinal Health: Current Employment. Jeune-Smith:Cardinal Health: Current Employment. Klink:Cardinal Health: Current Employment. Feinberg:Cardinal Health: Current Employment.

Comparative Efficacy of First-Line Chemotherapy-Free Combinations in Chronic Lymphocytic Leukemia (CLL): A Network Meta-Analysis

Introduction: Chronic Lymphocytic Leukemia (CLL) is an incurable B-cell malignancy which disproportionately affects the elderly. Although first-line chemoimmunotherapy (CIT) improved CLL clinical outcomes, recent randomized trials revealed superior outcomes with novel chemotherapy-free combinations (CFC) incorporating anti-CD20 monoclonal antibodies and inhibitors of BTK or Bcl-2. So far, these CFC have not been compared head-to-head. We conducted this network meta-analysis to evaluate their relative efficacy to each other. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language; diagnosis of CLL; trials that explored the efficacy of first-line CFC with Obinutuzumab (O), Rituximab (R), Ibrutinib (IB), Acalabrutinib (ACAL), Venetoclax (VEN) compared to standard CIT that included Chlorambucil (CHLOR) with either R or O, Bendamustine+Rituximab, or Fludarabine+ Cyclophosphamide+R; and phase 3 randomized studies reporting responses, progression, death, and adverse (AE) events. A frequentists network meta-analysis was conducted using netmeta package and random-effects model. Results: Five studies comprising a total of 2,272 participants were included. When O-based CFC data was analyzed, only ACAL-O had a significant lower relative risk (RR) of progression and death (P&D). There were no significant differences with respect to overall response rates (ORR), complete remission (CR), minimal residual disease (MRD), or grade >3 adverse events (Grd3+) among O-based CFC. When R-based CFC data was analyzed, IB and IB-R were not different with respect to RR of P&D, ORR, CR, MRD, or Grd3+. When the data was analyzed as CFC versus combined CIT, only ACAL-O was found to be significantly superior to other O- and R-based CFC with respect to RR of P&D. ORR and Grad3+ rates of O- and R-based CFC were not significantly different. While ACAL-O, IB-O, and VEN-O had superior CR and MRD rates compared to other CFC, there were no significant differences among each other. Conclusions: This network meta-analysis is the first to compare and rank first-line CFC therapies in CLL. It indicates that ACAL-O has a superior profile having the lowest RR of P&D without significant difference in Grd3+ among CFC. Disclosures No relevant conflicts of interest to declare.

Pre-Existing T Cell Subsets Determine Anti-PD1 Blockade Response in Richter's Transformation

Pre-Existing T Cell Subsets Determine Anti-PD1 Blockade Response in Richter's Transformation

BRD4 Inhibitors Enhance the Anti-Tumor Activity of Targeted Therapy in Chronic Lymphocytic Leukemia

Background: The development of drugs targeting BTK and BCL2 has dramatically improved the therapeutic landscape in chronic lymphocytic leukemia (CLL). However, resistance to these agents has been reported due to non-recurrent changes in oncogenic pathways and gene expression signatures. The bromodomain and extra terminal (BET) family proteins (BRD2, BRD3, BRD4 and BRDT) are epigenetic reader proteins that recognize acetylated lysine residues in histones. They play a critical role in mediating gene transcription and have been considered as highly promising targets in several diseases including cancer. Of these, the BRD4 protein is highly enriched in super enhancers and regulates transcription of relevant oncogenes such as MYC, CDK genes, cyclin-D1, BCL2 and MCL-1. BRD4 inhibitors (BRD4i) block the transcription of these key oncogenes through the displacement of BRDs and other epigenetic modifiers from chromatin. In this study, we investigated the preclinical activity of two BRD4i, AZD5153 and PLX51107, and their cooperative role with the BCL2 inhibitor venetoclax and BTK inhibitor ibrutinib in CLL. Methods: Primary tumor cells were isolated from 36 CLL patients. Peripheral blood mononuclear cells were isolated via histopaque-1077 (Sigma-Aldrich, St Louis MO) from peripheral blood apheresis samples from consenting adults under RPCCC protocol CIC-01-16. B-cells were then isolated from enriched lymphocytes by MACS separation using a human B-cell Isolation Kit II. CLL cells were seeded at 3 x106/mL in a 384 well tissue culture plates and exposed to different doses of AZD5153 (1-20uM) or PLX51107 (1-20uM) as a single agent or in combination with venetoclax (1-100nM) or ibrutinib (50-1000nM) for 48 and 72hrs (Selleck Chemicals, Houston TX). Cell viability was assessed using Cell Titer-glo (Promega, Madison WI) with all data being normalized to untreated controls. Synergy was calculated using Calcusyn (Cambridge, UK) software to determine Coefficient of Synergy (CI) values. In addition, CLL cells were plated in 6 well plates and exposed to AZD5153 or PLX51107 alone or in combination with either venetoclax or ibrutinib for 24 hrs. Induction of apoptosis and changes in B-cell receptor signaling, BCL2 and NF-kB pathway related proteins were evaluated by flow cytometry or Western blotting respectively. Results: The study included 33 treatment naïve and 3 relapsed/refractory CLL patients. Deletion 11q was detected in 6 patients and del 17p was seen in 1 patient. Both AZD5153 and PLX51107 displayed time and dose dependent induction of apoptosis of CLL cells. Activity was observed in both treatment naïve and relapsed/refractory samples. Moreover, activity was observed in del 17p or ATM deletion samples. Synergistic activity was observed between BRD4is and venetoclax. PLX51107 exhibited synergy with venetoclax in 83% of the samples tested. Similarly, AZD5153 exhibited synergistic effects when combined with venetoclax in 61% of the samples. To a lesser degree, BRD4is exhibited synergistic activity when combined with ibrutinib, (44% with PLX51107 and 39% with AZD5153). Induction of apoptosis was observed in CLL cells exposed to either BRD4i. Morevoer, an increase in the percentage of apoptosis was observed when BRD4i was combined with venetoclax. Western blotting showed a accumulation of p21, reduced levels of C-MYC, as well as modulation of BCL-2 family member proteins such as BCL2, MCL-1 following BRD4i ex vivo exposure. Conclusions: Our data indicate that BRD4 inhibition results in apoptosis of primary tumor cells isolated from patients with various subtypes of CLL. PLX51107 and AZD5153 exhibit synergistic effects when combined with venetoclax and to a lesser degree with ibrutinib. Modulation of BCL-2 family members following BRD4 inibition could play a role in the synergistic activity observed in our studies. A better understanding of the key signaling pathways involved in proliferation and survival of CLL cells impacted by BRD4i in combination with venetoclax and ibrutinib would provide a proof-of-concept rationale for studies validating BRD4i as epigenetic approach to target BCR signaling in CLL. Disclosures Hernandez-Ilizaliturri: Karyopharm: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Gilead: Consultancy; Pharmacyclics: Consultancy; Seattle Genetics: Consultancy; Astra Zeneca: Consultancy; Epyzome: Consultancy.

Real-World Characterization of Ibrutinib Therapy for Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) Patients in British Columbia (BC)

Real-World Characterization of Ibrutinib Therapy for Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) Patients in British Columbia (BC)

Three-Year Follow-up from a Phase 2 Study of Combination Obinutuzumab, Ibrutinib, and Venetoclax in Chronic Lymphocytic Leukemia

Three-Year Follow-up from a Phase 2 Study of Combination Obinutuzumab, Ibrutinib, and Venetoclax in Chronic Lymphocytic Leukemia