Option For Chronic Lymphocytic Leukemia Research Articles

Real-World Patterns of MRD Testing and Impact on Treatment for Chronic Lymphocytic Leukemia Patients

INTRODUCTION Therapeutic options for Chronic Lymphocytic Leukemia (CLL) have advanced significantly over time, resulting in a heterogeneous treatment landscape. Insights into the depth of treatment response can be gained through highly-sensitive detection of residual cancer cells using measurable (also known as minimal) residual disease (MRD) testing. Initially, MRD testing was limited to prognostic use within clinical trials. However, in recent years it has expanded into various clinical settings, although the extent of real-world use is not well established. METHODS 766 individuals with CLL enrolled in the Leukemia and Lymphoma Society (LLS) registry had their medical records collected and data extracted via the Invitae Ciitizen® platform, a patient-centric platform that leverages HIPAA right-of-access to organize clinical data into a standardized, research-ready format, using a combination of machine learning and human clinician review. Proprietary logic-based algorithms were used to characterize lines of therapy (LOTs), MRD testing methods, outcomes and duration of therapy. Descriptive findings are reported below. RESULTS Of the 766 CLL participants, 117 (15%) received a total of 311 MRD tests (mean=3 tests/person, median=2, max=16). 67 individuals had one or more MRD negative results (134 negative results total) and 78 individuals had one or more MRD positive results (177 positive results total). 56/117 (47.9%) patients had one or more MRD tests as part of a clinical trial, for a total of 132/311 (42.2%) MRD tests performed during a trial. Total MRD tests included 260 (83.6%) evaluated by flow cytometry, 8 (2.6%) by next generation sequencing (NGS), with the remainder not having documented methods (43; 13.8%). Since 2014, when MRD testing was integrated as a prognostic indicator in clinical trials, there has been increasing use of MRD testing ( Figure 1) within this cohort, as assessed by percentage of individuals receiving one or more tests per year. Interestingly, there is a peak of percentage tested in a clinical trial setting in 2017, after which a continued increase in those tested outside of a clinical trial setting shifts the overall proportion down. We also note the appearance of NGS testing in 2018. The 117 individuals who were MRD tested received 40 unique LOTs (e.g., “obinutuzumab, venetoclax”). We then quantified the MRD outcomes as either “achieved MRD-negative” or “did not achieve MRD-negative” for the most commonly-used therapies (n≥5) ( Table 1). Ibrutinib and acalabrutinib monotherapies had the lowest proportion of MRD-negative outcomes (1/15 and 0/6, respectively), whereas obinutuzumab-venetoclax +/- ibrutinib combination therapies had the highest proportion of MRD-negative outcomes (4/5 and 17/17, respectively). In order to assess the impact of MRD outcome on treatment patterns, the duration of therapy following a MRD-positive and negative test were evaluated. Therapy continued a mean duration of 691 days (n=126, median=488) after a MRD-positive test and 419 days (n=66, median=230) after a MRD negative test. CONCLUSION In this real-world dataset of 766 individuals with CLL, we detect an increasing rate of MRD testing since 2014. Notably, this usage is not limited to the clinical trial setting, underscoring the growing significance of MRD testing as a more general tool for evaluating disease control. Exploration of which LOTs achieve proportionally more MRD-negative statuses highlights that venetoclax-containing fixed-duration regimens as well as venetoclax monotherapy have higher rates of MRD-negativity. Conversely, BTK monotherapies ibrutinib and acalabrutinib were associated with the lowest percentage of MRD-negative outcomes. Finally, we find that the duration of therapy from the time of MRD testing is shorter when the result is MRD-negative, suggesting that MRD testing as a component of outcomes assessment used in the real-world setting may be useful in deciding when to discontinue therapy. This aligns with ongoing clinical trials investigating fixed duration therapies and the use of MRD-negative status as an outcome measure to assess depth of remission. Future studies on larger datasets will explore how MRD testing is integrated into clinical practice and its impact on treatment decisions.

ONO-7018, a First-in-Class MALT1 Inhibitor, Provides Novel Therapeutic Strategies for B Cell Malignancies: Overcoming BTK Inhibitor Acquired Resistance and Enhancing the Antitumor Effect of BTK Inhibitors

Introduction: B cell receptor (BCR) signaling plays a crucial role in promoting survival and growth in B cell malignancies, and several compounds targeting the signaling pathways have been approved. Bruton's tyrosine kinase (BTK) is a key molecule in BCR signaling pathways and BTK inhibitors are one of the essential treatment options for chronic lymphocytic leukemia (CLL) and certain subtypes of B cell Non-Hodgkin Lymphoma. However, there are issues that acquired resistance mutations in the BTK kinase domain and gain of function mutation of its downstream molecules, which lead to BTK inhibitor resistance and limit its efficacy. For example, BTK C481S mutation is well known as a resistant mutation to covalent BTK inhibitors and several mutations of BTK (such as T474I and L528W mutation) have recently been reported in relapsed or refractory CLL patients with acquired resistance to pirtobrutinib, a non-covalent BTK inhibitor. In addition, there are unmet medical needs to improve the duration of response of current standard therapies including BTK inhibitors for B cell malignancies. Therefore, therapeutic strategies to overcome the BTK inhibitor resistance and novel combination therapies to enhance the efficacy of BTK inhibitors are required. Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is known as a key growth and survival regulator in BCR signaling and an emerging therapeutic target. ONO-7018 (formerly known as CTX-177), a potent and selective MALT1 inhibitor, demonstrated preclinical efficacy in several lymphoma models. Aim: Firstly, to explore the potential of ONO-7018 to overcome BTK inhibitor acquired resistance, we tested the antitumor effects of ONO-7018 on cell lines harboring BTK inhibitor-resistant mutations. Secondly, we examined the combination antitumor efficacy of ONO-7018 and tirabrutinib, a second generation BTK inhibitor in vitro and in vivo. Methods: Diffuse large B-cell lymphoma (DLBCL) cell lines harboring BTK inhibitor-resistant mutations (BTK T474I, C481S, or L528: PLCG2 R665W) were generated by continuous passage with BTK inhibitor or CRISPR-Cas9 gene editing followed by single cell cloning. In in vivo study, human DLBCL cell line, TMD8 cells were subcutaneously implanted in immune deficient mice. ONO-7018 and tirabrutinib were orally administered to the mice twice a day. Results: Anti-proliferative activities of ONO-7018 on these BTK inhibitor resistant cell lines were evaluated in vitro. ONO-7018 inhibited the proliferation of these cells with comparable IC 50 values to the parent cell line. Anti-proliferative activities of ONO-7018 alone or in combination with tirabrutinib on DLBCL and mantle cell lymphoma (MCL) cell lines were evaluated in vitro. ONO-7018 exhibited synergistic effects with tirabrutinib in both DLBCL and MCL cell lines. In addition, combination treatment of ONO-7018 with tirabrutinib strongly inhibited the expression of interferon regulatory factor 4, which is a downstream signal molecule in BCR signaling pathways, compared to their single treatment. We then evaluated the antitumor effects of ONO-7018 in combination with tirabrutinib in the xenograft model. Combination treatment of ONO-7018 with tirabrutinib showed dramatic antitumor effect with tumor regression. These results suggest that ONO-7018 could demonstrate antitumor effect on patients with B cell malignancies harboring BTK inhibitor acquired resistant mutations and synergistic antitumor effect with BTK inhibitors in clinic. Conclusion: ONO-7018 would provide novel therapeutic strategies to overcome the BTK inhibitor acquired resistance and enhance the antitumor effect of BTK inhibitors in clinic. Phase 1 study of ONO-7018 (NCT05515406) is currently ongoing.

Efficacy and Safety of Bruton Tyrosine Kinase Inhibitor Plus Anti-CD20 Antibody Therapy Compared With Chemoimmunotherapy as Front-line Treatment for Chronic Lymphocytic Leukemia: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Treatment with chemoimmunotherapy (CIT) is considered an appropriate front-line treatment option for chronic lymphocytic leukemia (CLL). However, outcomes remain suboptimal. Bruton tyrosine kinase inhibitor (BTKi) combined with anti-CD20 antibody is an effective treatment for treatment-naïve, relapsed/refractory CLL patients. A systematic review and meta-analysis of randomized controlled trials was performed to compare the efficacy and safety of CIT versus BTKi + anti-CD20 antibody as front-line treatment for CLL patients. The endpoints of interest included progression-free survival (PFS), overall survival (OS), overall response rate (ORR), complete response (CR) rate, and safety. Four trials (including 1479 patients) were available as of December 2022 and fulfilled the eligibility criteria. BTKi + anti-CD20 antibody treatment significantly prolonged PFS [hazard ratio (HR), 0.25; 95% confidence interval (CI), 0.15-0.42] compared with CIT, while the combination therapy did not significantly improve OS compared with CIT (HR, 0.73; 95% CI, 0.50-1.06). We observed consistent benefits for PFS among patients with unfavorable features. Although pooled analysis indicated that the addition of BTKi to anti-CD20 antibody led to a higher ORR than CIT [risk ratio (RR), 1.16; 95% CI, 1.13-1.20], there was no difference in CR between the two arms (RR, 1.10; 95% CI, 0.27-4.55). The risk of grade ≥3 adverse effects (AE) was comparable between the two groups (RR, 1.04; 95% CI, 0.92-1.17). The BTKi + anti-CD20 antibody therapy has superior outcomes compared with CIT among patients with treatment-naïve CLL, without excess of toxicity. Future studies should compare next-generation targeted agent combinations versus CIT to determine the optimal management of CLL patients.

Selecting initial therapy in CLL.

Targeted therapy is a powerful treatment option in chronic lymphocytic leukemia (CLL) that has outperformed conventional chemoimmunotherapy in most clinical settings. Except for selected young, fit patients with a mutated immunoglobulin heavy chain variable region gene, most patients benefit from targeted therapy with either a continuous BTK inhibitor or 1-year fixed-duration venetoclax-obinutuzumab as first-line treatment of CLL. Treatment selection is driven by patient-, treatment-, and disease-related factors, encompassing patient preference, concomitant medications, comorbidities, safety profile of the regimen, and TP53 aberration. Clinical trials are actively investigating the simultaneous inhibition of Bruton's tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL-2) proteins with or without a CD20 monoclonal antibody, which can achieve deep response in most patients (52%-89% undetectable minimal residual disease in bone marrow).

A Phase II Clinical Trial of the Pan PI3K Inhibitor, Buparlisib, for the Treatment of Relapsed and Refractory Chronic Lymphocytic Leukemia: Canadian Cancer Trials Group IND.216

Introduction: Inhibition of the phospho-inositol 3 kinase (PI3K) delta isoform is effective in the treatment of relapsed and refractory chronic lymphocytic leukemia (CLL) (Pongas G, et al. Semin Oncol 2016; 43: 647). The efficacy of this class of drugs is limited by the potency of the inhibitor and its toxicity profile. Buparlisib is an orally available pan-Class I PI3K inhibitor which has greater potency than idelalisib in vitro . Low P70S6k and raptor levels, both of which are downstream regulators of the PI3K/mTOR pathway, correlate with sensitivity to PI3K inhibitor activity in CLL lymphocytes in vitro (Amrein L, et al. Int J Cancer 2013; 133: 247-52). The recommended phase II dose of buparlisib is 100 mg daily po and the main toxicities in Phase I were hyperglycemia, hypertension and mood disturbance (Bendell JC, et al. J Clin Oncol. 2012;30:282-90). We conducted a single arm phase II trial of buparlisib in patients with relapsed and refractory CLL (NCT02340780) and attempted to correlate response with P70S6k and raptor levels.Methods: Patients with CLL requiring re-treatment after at least one prior line of therapy were eligible. Buparlisib 100 mg daily was administered continuously on 28-day cycles with dose reductions to 80 mg and 60 mg in the event of toxicity. Mood questionaires (PHQ-9 and GAD-7) were administered at study entry and with each treatment cycle. The primary endpoint was overall response rate, defined according to the Revised International Workship on CLL (Hallek 2008) incorporating updated recommendations for novel targeted agents (Cheson 2012). Additional endpoints included safety, duration of response and progression free survival. Levels of P70S6k and raptor were measured in isolated CLL cells prior to therapy with buparlisib and compared with mean values as per Amrein et al. Int J Cancer 2013;133: 247-52).Results: Between April 2015 and January 2017, fourteen patients were enrolled; Rai stage high (n=7), intermediate (n=6) and low (n=1). Of these, 13 were eligible for toxicity (1 ineligible due to inadequate washout period) and 11 for response assessment (2 did not complete 1 cycle of therapy). The median age was 74 years (61-87), male:female 8:5, ECOG 0-1 and median number of prior therapies 1 (range 1-3). No patients received prior therapy with idelalisib or other PI3K inhibitor; 3 received prior ibrutinib, including the ineligible patient. Six of 13 patients had a partial response (46.2%, 95%, CI: 19.2,74.9%), with a median duration of response of 14.4 months. Five patients with a best response of stable disease all experienced tumor shrinkage (figure). There were no complete responses. Patients received a median of 5 cycles of therapy (range 1 to 20), the dose intensity was 485.6 mg per week and 27.3% received > 90% of planned doses. Ten patients have stopped protocol therapy, 1 for progressive disease and 9 for therapy-related adverse events: hyperglycemia (n=4), mood disorder (n=3), fatigue and generalized muscle weakness (n=1), elevated AST (n=1), hypertension (n=1) and thrombocytopenia (n=1). Mood disorders improved after stopping therapy in all 3 patients. The most common related adverse events (>15%) were diarrhea, nausea, fatigue, anorexia and dysguesia; all were <grade 3 except for fatigue. Hyperglycemia was seen in 9/13 patients. There were no related serious adverse events. Among the 8 patients tested, no correlation was observed between biomarker level and response or progression free survival.Conclusion: The response rates of single-agent idelalisib (Brown JR, et al. JCO ASCO Annual Meeting Abstracts. 2013;31 abstract 7003) and buparlisib are comparable with a different toxicity profile, making buparlisib another potential therapeutic option in CLL. Better mitigation of toxicity is required to make this an acceptable therapy for patients and rational drug combinations are needed to improve the efficacy of this agent. We could not confirm the importance of P70S6K or raptor in this small clinical trial. Validating these biomarkers in a larger cohort may help to predict which CLL patients are most likely to benefit from therapy with a PI3K inhibitor. [Display omitted] DisclosuresAssouline:Bristol Myer Squibb: Speakers Bureau; Novartis Canada Inc.: Honoraria; Pfizer: Speakers Bureau; Paladin: Speakers Bureau; Janssen: Honoraria. Banerji:Roche: Research Funding; Lundbeck: Research Funding; Abbvie: Research Funding; Janssen: Research Funding; Gilead: Research Funding. Caplan:Janssen: Honoraria. Owen:Roche: Consultancy, Honoraria, Research Funding; Lundbeck: Honoraria; Gilead: Honoraria, Research Funding; Janssen: Honoraria; AbbVie: Honoraria; Celgene: Honoraria; AstraZeneca: Honoraria; Pharmacyclics LLC, an AbbVie Company: Research Funding. Robinson:Gilead: Honoraria; Roche: Honoraria; Janssen: Honoraria; Lundbeck: Honoraria; Abbvie: Honoraria. Prica:Celgene: Honoraria; Janssen: Honoraria. Peters:Abbvie: Honoraria; Roche: Honoraria; Lundbeck: Honoraria; Gilead: Honoraria; Janssen: Honoraria. Hay:Roche: Research Funding; Abbvie: Research Funding; Kite: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Novartis: Research Funding.

Phase II/1b Trial of Ibrutinib Plus Prednisone and Rituximab Induction Followed By Venetoclax Plus Ibrutinib Maintenance in Newly Diagnosed High-Risk Chronic Lymphocytic Leukemia

Introduction: Therapy options for chronic lymphocytic leukemia (CLL) are rapidly changing with the approval of ibrutinib, an irreversible Bruton's tyrosine kinase inhibitor, and venetoclax, a Bcl2 inhibitor. In the RESONATE studies, ibrutinib showed significant improvements in overall response rates (ORR), progression-free-survival (PFS), and overall survival (OS). Nonetheless, complete response (CR) rates were only about 4%.During the first few weeks of treatment, ibrutinib will mobilize CLL cells from tissue sites into peripheral blood. Rituximab, a chimeric monoclonal CD20 antibody, when used with ibrutinib, has shown to immediately clear CLL from the blood with durable responses but with CR's of only 8%.Venetoclax is approved for relapsed or refractory CLL with 17p deletion. In a phase 2 study, at a median follow-up of 12.1 months, the ORR was ~79%, but with only 16% CR's. Amongst the 45 patients of whom minimal residual disease (MRD) was assessed, 24 were negative for MRD.In vitro studies have shown that nurse-like cells (NLCs) will protect CLL cells against spontaneous apoptosis by producing chemokines and interleukins such as SDF1, suggestive of a mechanism of ibrutinib resistance. SDF1 was shown to bind to its receptor CXCR4 located on CLL cells and activate a signal transduction pathway that would reduce spontaneous apoptosis. Dexamethasone was found to decrease NLC viability. This suggests that a combined therapy of ibrutinib plus steroids along with rituximab and venetoclax may be necessary to achieve deeper CR's in high-risk CLL.In addition, CLL with overexpression of exosome miR-155 is associated with a poor response to chemoimmunotherapy. In prior preclinical studies, exosome miR-150 and miR-155 have been shown to increase with BCR activation via α-IgM stimulation. We hope that via next generation microRNA sequencing from our patients' CLL plasma cells we will observe a decrease in the levels of exosome miR-150 and miR-155 in response to inhibition of BCR-pathway by ibrutinib as seen in preclinical studies.Methods: Patients with newly diagnosed high-risk CLL per FISH studies will be enrolled. Ibrutinib will be administered orally 420 mg daily, rituximab will be dosed at 375 mg/m2 intravenously on days 1, 8, 15, 22 of cycle 1 and on day 1 for cycle 2-6. Prednisone will be administered as 10 mg one week on, one week off per cycle. Each cycle will last 28 days. After 6 cycles, if patients have MRD, venetoclax will be added in on a weekly schedule with weekly ramp up from 20mg to 50mg, 100mg, and 200mg for a total duration of 6 months plus ibrutinib at 420mg as maintenance until disease progression or drug intolerance. There is the option to reintroduce venetoclax, prednisone, or rituximab if patients progress during maintenance.Results: The primary objectives of this study are to evaluate safety and MRD negative CR rates based on IWG-CLL criteria. For the evaluation of safety, the proportions of the 29 subjects with any adverse events, each specific adverse event, and study-related adverse events will be reported along with the 95% confidence intervals. The proportion of the 29 subjects who demonstrate a MRD negative CR will be reported along with the 95% confidence interval. A sample size of 29 will produce a two-sided 95% confidence interval with a width≤ 0.380.In addition, Kaplan-Meier method will be performed to evaluate time to first MRD negativity (TTMN), time to first relapse (TTFR), PFS and OS, respectively. Based on the Kaplan-Meier curve, the median time to TTMN, TTFR, PFS and OS, respectively, will be reported along with the 95% confidence interval if it exists. Correlation coefficients will be derived to describe the relationship between continuous endpoints and Kendall's tau will be derived to describe the relationship between categorical endpoints.There is no planned interim analysis for the CR rate. However, at any time point if an excessive number of adverse events are observed, the study will be terminated.Conclusion: In this Phase IB/II clinical trial, we seek to observe prolonged response rates of ibrutinib via inhibiting NLC's by adding prednisone. Also, we anticipate that rituximab will further amplify the CR's. For maintenance therapy, we hope that by combining venetoclax with ibrutinib in high-risk CLL patients who were unable to achieve negative MRD's, we will be able to induce deeper remissions. [Display omitted] DisclosuresPersky:Genentech: Consultancy; MorphoSys: Other: Independent Data Monitoring Committee member ; Verastem: Consultancy; Spectrum Pharmaceuticals: Research Funding.

T Cells in Chronic Lymphocytic Leukemia: A Two-Edged Sword.

Chronic lymphocytic leukemia (CLL) is a malignancy of mature, antigen-experienced B lymphocytes. Despite great progress recently achieved in the management of CLL, the disease remains incurable, underscoring the need for further investigation into the underlying pathophysiology. Microenvironmental crosstalk has an established role in CLL pathogenesis and progression. Indeed, the malignant CLL cells are strongly dependent on interactions with other immune and non-immune cell populations that shape a highly orchestrated network, the tumor microenvironment (TME). The composition of the TME, as well as the bidirectional interactions between the malignant clone and the microenvironmental elements have been linked to disease heterogeneity. Mounting evidence implicates T cells present in the TME in the natural history of the CLL as well as in the establishment of certain CLL hallmarks e.g. tumor evasion and immune suppression. CLL is characterized by restrictions in the T cell receptor gene repertoire, T cell oligoclonal expansions, as well as shared T cell receptor clonotypes amongst patients, strongly alluding to selection by restricted antigenic elements of as yet undisclosed identity. Further, the T cells in CLL exhibit a distinctive phenotype with features of “exhaustion” likely as a result of chronic antigenic stimulation. This might be relevant to the fact that, despite increased numbers of oligoclonal T cells in the periphery, these cells are incapable of mounting effective anti-tumor immune responses, a feature perhaps also linked with the elevated numbers of T regulatory subpopulations. Alterations of T cell gene expression profile are associated with defects in both the cytoskeleton and immune synapse formation, and are generally induced by direct contact with the malignant clone. That said, these abnormalities appear to be reversible, which is why therapies targeting the T cell compartment represent a reasonable therapeutic option in CLL. Indeed, novel strategies, including CAR T cell immunotherapy, immune checkpoint blockade and immunomodulation, have come to the spotlight in an attempt to restore the functionality of T cells and enhance targeted cytotoxic activity against the malignant clone.

Improving Outcomes for Patients With Chronic Lymphocytic Leukemia.

Mazyar Shadman, MD, MPH, and Amy Goodrich, CRNP, reviewed data regarding the mechanistic activity, efficacy, and safety of approved and emerging therapeutic options for chronic lymphocytic leukemia (CLL) and strategies for managing adverse events associated with approved therapies for CLL.

Combined chemosensitivity and chromatin profiling prioritizes drug combinations in CLL.

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib has substantially improved therapeutic options for chronic lymphocytic leukemia (CLL). Although ibrutinib is not curative, it has a profound effect on CLL cells and may create new pharmacologically exploitable vulnerabilities. To identify such vulnerabilities, we developed a systematic approach that combines epigenome profiling (charting the gene-regulatory basis of cell state) with single-cell chemosensitivity profiling (quantifying cell-type-specific drug response) and bioinformatic data integration. By applying our method to a cohort of matched patient samples collected before and during ibrutinib therapy, we identified characteristic ibrutinib-induced changes that provide a starting point for the rational design of ibrutinib combination therapies. Specifically, we observed and validated preferential sensitivity to proteasome, PLK1, and mTOR inhibitors during ibrutinib treatment. More generally, our study establishes a broadly applicable method for investigating treatment-specific vulnerabilities by integrating the complementary perspectives of epigenetic cell states and phenotypic drug responses in primary patient samples.

Dual inhibition of MEK1/2 and AKT by binimetinib and MK2206 induces apoptosis of chronic lymphocytic leukemia cells under conditions that mimic the tumor microenvironment

Several key pathways mediate signaling via the B-cell receptor, including the mitogen-activated protein kinase-ERK1/2 pathway. However, inhibition of MEK1/2, a key component of the MAPK-ERK1/2 signaling cascade, results in paradoxical activation of AKT in chronic lymphocytic leukemia (CLL) cells. In the current study we demonstrate synergy between the MEK1/2 inhibitor binimetinib and the AKT inhibitor MK2206, which combined induce apoptosis of primary CLL cells and restrict the cell cycle progression and proliferation of the OSU-CLL cell line. The mechanisms of action of the drug combination involve dual inhibition of MAPK-ERK1/2 and AKT signaling and down-regulation of Mcl-1 expression. Collectively, these data suggest that dual inhibition of MEK1/2 and AKT may represent a therapeutic option for CLL, capable of overcoming the pro-survival effects of the lymph node and bone marrow microenvironments.

Predictors of Patient-Reported Communication with Their Health Care Team about New Treatment Options for Chronic Lymphocytic Leukemia

▪Background: Chronic lymphocytic leukemia (CLL) progresses with time and, as a result, patients can be challenged by considering multiple treatment options. Importantly, over the past decade, an array of new CLL treatments have emerged, including targeted therapy and immunotherapy options. Health care teams, therefore, play an important role in discussing new treatments with patients to ensure shared decision making. A substantial proportion of patients, however, report not discussing newly approved treatment options with clinicians. Our goal was to understand the sociodemographic and clinical factors associated with doctors' likelihood of discussing new treatment options in a national sample of CLL patients.Methods: Using data from the Cancer Support Community's Cancer Experience Registry®, our analytic sample included 187 participants who report CLL as their primary diagnosis. The dependent variable in all analyses was a dichotomous, patient-reported indicator of whether or not their doctor discussed new treatment options (e.g., ibrutinib, idealisib, obinutuzumab) with them. Our independent variables included: 1) sociodemographic characteristics: age, gender, education, urbanicity, and race; 2) clinical factors: genetic risk, treatment status, years since diagnosis, CLL risk (low, intermediate or high; based on patient report of how doctor estimated their CLL may progress over time), and relapse; and 3) patient-clinician communication: patient involvement in treatment decision making, patient's consideration of financial cost of care, discussion of health care team's goals for treatment, and discussion of patient's goals for treatment.Our analyses proceeded in two steps. First, we descriptively compared patients who discuss new treatments with their doctors and those who do not using Student's t-test. Second, multivariate logistic regression models estimated likelihood of doctor discussing new treatment options by sociodemographic, clinical, and patient-provider characteristics. Multiple imputation accounted for missingness in our regression models.Results: Our sample was 48% female, 96% White, and averaged 62 years of age (SD = 10), with a mean time since diagnosis of 7 years (SD = 5). 18% of our sample reported having a deletion 17p, 22% reported having a deletion 13q, 22% were currently receiving chemotherapy, and 16% reported recurrence of their CLL. 58% of our sample reported discussing new treatment options with their doctor. Descriptively, patients who report higher frequencies of cancer recurrence, intermediate or high risk of their CLL, genetic testing results indicative of deletion 17p and deletion 13q, current chemotherapy, greater involvement in treatment decision making, and lower consideration of financial cost of care were significantly more likely to discuss new treatment options with their doctors. In multivariate models, controlling for all sociodemographic, clinical, and patient-clinician characteristics, our results highlight a greater likelihood of discussing new options among patients who have experienced a relapse of their CLL.Conclusion: Nearly half of our CLL patients did not report discussing new treatment options with their clinician, raising concerns about whether shared decision-making is really taking place in the era of novel CLL therapeutics. While those who experience a relapse are significantly more likely to discuss new treatment options, unmet needs remain. As new treatments are incorporated into standard of care, greater efforts are needed to enhance shared decision-making at all points of care. DisclosuresBuzaglo:Vector Oncology: Employment.

Factors That Influence Treatment Decision-Making: Perspectives of 1147 Chronic Lymphocytic Leukemia (CLL) Patients in the United States

Factors That Influence Treatment Decision-Making: Perspectives of 1147 Chronic Lymphocytic Leukemia (CLL) Patients in the United States

Physicians’ documented performance of shared decision-making with chronic lymphocytic leukemia patients.

e18786Background: With expanding treatment options for chronic lymphocytic leukemia (CLL), shared decision-making (SDM) is essential for high-quality care. In a quality improvement program, we eval...

Mechanisms of Resistance to Targeted Therapies in Chronic Lymphocytic Leukemia.

Even if treatment options for Chronic Lymphocytic Leukemia (CLL) patients have changed dramatically in the past few years, with the approval of targeted therapeutic agents, the disease remains incurable. Beside intrinsic genetic features characterizing the leukemic cell, signals coming from the microenvironment have a key role in promoting cell survival and in protecting CLL cells from the action of drugs. Consequently, the identification of previously unrecognized genetic lesions is important in risk-stratification of CLL patients and is progressively becoming a critical tool for choosing the best therapeutic strategy. Significant efforts have also been dedicated to define microenvironment-dependent mechanisms that sustain leukemic cells favoring survival, proliferation, and accumulation of additional genetic lesions. Furthermore, understanding the molecular and biological mechanisms, potentially driving disease progression and chemoresistance, is the first step to design therapies that could be effective in high-risk patients. Significant progress has been made in the identification of the different mechanisms through which patients relapse after "new" and "old" therapies. These studies have led to the development of targeted strategies to overcome, or even prevent, resistance through the design of novel agents or their combination.In this chapter we will give an overview of the main therapeutic options for CLL patients and review the mechanisms of resistance responsible for treatment failure. Potential strategies to overcome or prevent resistance will be also discussed.

Functional and Clinical Significance of the Integrin Alpha Chain CD49d Expression in Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease characterized by the accumulation/expansion of a clonal population of neoplastic cells with the morphological appearance of small mature B lymphocytes in blood, bone marrow, and lymphoid organs. CD49d, the α chain of the α4β1 integrin heterodimer, is one of the main interactors between CLL cells and accessory cells in the microenvironmental sites and one of the main predictors of overall survival. In particular, CD49d is known to play a pivotal role in mediating both cell-cell and cell-matrix interactions in CLL-involved tissues eventually delivering prosurvival signals and protecting CLL cells from drug-induced damages. Treatment strategies targeting the α4β1 integrin could represent an interesting option in CLL. In this context, the recombinant anti-CD49d antibody natalizumab demonstrated the potential to overcome stromal cell-induced resistance of B cell lymphoma cells against cytotoxic drugs and rituximab in vitro. Moreover, a specific interest for the CD49d molecule raises from the clinical activity of the recently proposed inhibitors of kinases downstream the BCR that has been recently related with the inside-out activation of the α4β1 integrin. In the review, we addressed in detail the role of CD49d in CLL cells, including clinical impact, relationship with specific cytogenetic features, and CD49d-dependent interactions in lymph node and bone marrow microenvironment responsible for growth- and survival- supporting signals, eventually influencing CLL prognosis and therapeutic options.

Expanding the armamentarium for chronic lymphocytic leukemia: A review of novel agents in the management of chronic lymphocytic leukemia

Treatment options for chronic lymphocytic leukemia, the most common leukemia in the United States, have expanded rapidly in recent years. While traditional chemoimmunotherapy still remains a mainstay for young, fit patients, a number of novel targeted therapies have emerged that have changed the therapeutic landscape. Two innovative anti-CD20 monoclonal antibodies, obinutuzumab and ofatumomamab, have demonstrated activity in chronic lymphocytic leukemia and represent well-tolerated options in upfront management of elderly patients or in those with significant comorbidities. Agents targeting the B-cell receptor pathway, ibrutinib and idelalisib, have excellent activity in chronic lymphocytic leukemia, particularly in those patients with 17p deletions, in which responses to chemoimmunotherapy are traditionally dismal. Venetoclax (ABT-199), the recently FDA-approved BCL2 inhibitor, as well as several other agents and therapy combinations in the pipeline offer great promise for patients with chronic lymphocytic leukemia, particularly in the relapsed/refractory setting. This article comprehensively reviews the data for novel agents in chronic lymphocytic leukemia, including the pharmacology of therapies, unique toxicities, and other practical management considerations for clinicians.

SYK Is Involved in the CD38 Signal Transduction Pathway in Chronic Lymphocytic Leukemia

B-cell chronic lymphocytic leukemia (CLL) is one of the most prevalent B cell malignancies in adults and characterized by expansion of monoclonal mature B cells. Survival and proliferation of CLL cells depends on microenvironmental contact in lymphoid organs. The transmembrane glycoprotein CD38 acts as an important mediator of survival, proliferation and migration signals for CLL cells, and its expression is associated with poor prognosis. Spleen tyrosine kinase (SYK) is a central element of the B-cell receptor signal transduction pathway and has additionally been shown to be involved in cytokine and integrine signaling. In this study we demonstrate direct involvement of SYK in the CD38 signaling pathway in primary CLL samples.CD38-stimulation of primary CLL cells by its ligand CD31 induced a consistent phosphorylation of the tyrosine residue Y352, the first activation site that releases SYK from its autoinhibitory conformation (p<0.001). SYK downstream targets AKT (p<0.05) and ERK (p<0.05) were subsequently induced and prolonged CD38-stimulation increased MCL-1-expression (p<0.05). Concomitant inhibition of SYK with the SYK inhibitor R406 resulted in inhibition of AKT- and ERK-activation (p<0.05 and p<0.01) and prevented upregulation of MCL-1 (p<0.01). Moreover, we observed SYK-dependent enhancement of BCR-signaling after CD38 ligation. Short-term exposure of CLL cells to CD31 led to an increase of ERK-phosphorylation after BCR-engagement by 41.9% (p<0.05). This effect was completely abolished by concomitant R406-treatment (p<0.05). Additionally, we observed a SYK-dependent increase of Ca2+-flux in response to BCR-stimulation after previous CD38 activation. Moreover, preliminary experiments show that prolonged CD38-stimulation led to a SYK-dependent increase of baseline Ca2+-flux in CLL cells, indicating a potential involvement of CD38 in autonomous BCR-signaling. CD38 acts as an enhancer of migratory stimuli in CLL cells. We therefore analysed, whether SYK is also involved in this interaction process. CXCL12-dependent migration was increased by CD38 stimulation with the agonistic CD38 antibody IB4 by 28.3% (p=0.12). Treatment of CLL cells with R406 completely inhibited IB4-mediated migration (p<0.01). The expression of CD38 is regulated by a variety of mechanisms, including CD40 ligation. SYK is involved in CD40 signaling. We therefore tested, whether SYK-inhibition affects CD38-expression. Stimulation of CLL cells with recombinant CD40L resulted in a significant increase of CD38-expression (p<0.05). This effect was reversed by concomitant SYK-inhibition (p<0.01). In addition, we observed marked down-regulation of CD38 surface-expression (p<0.05) and mRNA-expression (p<0.05) for CLL cells treated with SYK-inhibitors R406 or P505-15 compared to vehicle control. This effect is at least partly based on transcriptional inhibition of CD38-regulators NF-kB (p<0.05) and E2A (p<0.05). Finally, we observed a clear correlation between CD38 expression on CLL cells and SYK-inhibitor efficacy (p<0.01).In conclusion, our data show that SYK acts as a central downstream effector of CD38 signaling regulating survival-, proliferation-, and migration pathways in CLL and also functions as a strong regulator of CD38 expression. The interaction of CD38 and SYK involves the BCR pathways, where CD38 enhances the response to BCR-stimulation and, moreover, may act as an enhancer of autonomous BCR-signaling in CLL. Additionally, the CD38-SYK interaction involves BCR-independent microenvironmental pathways as shown for CD40 and CXCL12. CD38 expression not only serves as a negative prognostic marker but has also been shown to possess biological significance in CLL. We therefore propose that disruption of the CD38-SYK axis may represent a promising therapeutic option in CLL. DisclosuresNo relevant conflicts of interest to declare.

Myeloablative Allogeneic Stem Cell Transplantation in CLL: A Single Centre Retrospective Study

Introduction:Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disorder in the Western world. Despite recent advances in therapy, CLL remains incurable with conventional chemo-immunotherapy. Allogeneic hematopoietic stem cell transplantation (alloSCT) remains the only curative option in CLL. AlloSCT relies on graft-versus-leukemia effect and can achieve the possibility of long-term disease control even in poor prognosis CLL such as chemotherapy refractory or high-risk cytogenetics. Unfortunately, alloSCT is associated with significant morbidity and mortality risks from regimen related toxicity, graft-versus-host disease (GVHD) and infectious complications. In order to reduce the rates of non-relapse mortality (NRM), reduced intensity conditioning regimens have been routinely adopted in most centers. While these newer regimens have shown lower NRM, they result in higher relapse rates compared to traditional myeloablative (MA) regimens. This retrospective analysis describes the outcomes of using contemporary MA conditioning in a consecutive series of patients transplanted for high-risk CLL including patients with relapsed/refractory disease or 17p deletion.Patients & Methods:We retrospectively reviewed CLL patients who underwent alloSCT between February 2000 to July 2012 at a single center using a uniform myeloablative conditioning regimen comprising Fludarabine 250mg/m2, PK targeted Busulfan 12.8mg/kg IV, and Thymoglobulin 4.5mg/kg (FLUBUPATG) with cyclosporine and methotrexate GVHD prophylaxis. Major eligibility criteria were relapsed CLL or del(17p) CLL in adults (18-70yrs) with an available HLA-compatible donor. Cox regression models were used to evaluate the impact of variables on outcomes including OS, PFS, and NRM. Cumulative incidence function (CIF) was used to estimate relapse. Statistical analysis was conducted using SAS (SAS Institute, Cary, NC) version 9.3 software. A p-value <0.05 was used for all statistical significance. Responses were defined according to the iwCLL criteria.Results:Sixty-one patients (46 males, 15 females) with a median age of 53 years (range, 38-65 years) including 21% ≥ 60 years were analyzed. The median time from diagnosis to alloSCT was 48 months (range, 3-236 months). Fifty-six percent of patients were treated with ≥ 2 regimens prior to alloSCT and 74% were fludarabine-refractory. Forty-three percent were considered chemosensitive prior to alloSCT and 5 (8%) were transplanted due to Richter's transformation. Twenty percent had poor-risk cytogenetics including del17p (n=6) and del11q (n=7). Sixty-nine percent were fully HLA matched including a total of 33 (54%) matched related donors and 9 (15%) matched unrelated donors. A total of 19 (31%) patients had a mismatched donor, including 6 (10%) with 2 mismatches. A complete remission (CR) was achieved in 62%, while 16% had partial remission (PR). Twelve (20%) patients relapsed after achieving CR/PR. The 5-year cumulative incidence of relapse was 26%. Fifty-two percent of patients remain alive at a median follow-up of 83 months. The estimated 5-year overall survival (OS) and progression free survival (PFS) were 61% and 47%, respectively. Twenty-nine patients died, 12 from CLL and 17 NRM. The 2-year NRM was 24%. Although 74% of patients had acute GVHD, only 10% had grade III or IV GVHD. Extensive chronic GVHD developed in 49% of patients, of whom 85% required second-line therapy. Only 6 patients (10%) remain on chronic cGVHD treatment and 6 deaths were caused by GVHD. Based upon multivariate analysis, extensive chronic GVHD was associated with improved OS (HR 0.289, [95% CI, 0.136-0.614, p=0.001]) and PFS (HR 0.136, [95% CI, 0.060-0.305, p=0.001]). A mismatched donor was associated with worse OS (HR 2.347, [95% CI, 1.078-5.109, p=0.03]) and the use of a female donor resulted in worse PFS (HR 2.738, [95% CI, 1.290-5.811, p=0.009]).Conclusions:This study illustrates that myeloablative alloSCT in high-risk CLL patients is both feasible and relatively well tolerated, resulting in excellent survival outcomes with comparable NRM to popular reduced intensity regimens. The positive impact of cGVHD confirms a graft versus leukemia effect with this MA regimen. These favorable PFS and OS rates support the value of allogeneic transplantation in the treatment of CLL. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The MEK1/2 inhibitor, MEKi-1, induces cell death in chronic lymphocytic leukemia cells under conditions that mimic the tumor microenvironment and is synergistic with fludarabine

The Raf-1/MEK/ERK1/2 pathway has become a focus for novel cancer therapies. This study sought to investigate whether targeting MEK1/2 may represent a therapeutic option for chronic lymphocytic leukemia (CLL). The MEK1/2 inhibitor, MEKi-1, induced apoptosis of CLL cells and was synergistic with fludarabine under conditions that mimic the tumor microenvironment, irrespective of poor-risk characteristics. MEKi-1 down-regulated the activities of AKT and ERK1/2 and was synergistic with fludarabine through a mechanism that involved potentiation of DNA damage and attenuation of the activity of ERK1/2 and expression of Mcl-1. This study highlights the significant role of the mitogen-activated protein kinase (MAPK)–ERK1/2 pathway in mediating the effects of the CLL tumor microenvironment and suggests that targeting MEK1/2 in CLL cells may impact upon the activity of both ERK1/2 and AKT. Inhibitors of MEK1/2 as single agents or in combination with DNA-damaging agents may represent a novel therapeutic strategy for CLL.

Is Allogeneic Hematopoietic Cell Transplantation Still an Option for Chronic Lymphocytic Leukemia in the Era of BTK Inhibition?

Is Allogeneic Hematopoietic Cell Transplantation Still an Option for Chronic Lymphocytic Leukemia in the Era of BTK Inhibition?