Months Of Ibrutinib Research Articles

An effective treatment and suspicious adverse reaction to Ibrutinib in a patient diagnosed with splenic B-cell lymphoma/leukaemia with prominent nucleoli: A first case report

Rationale: Splenic B-cell lymphoma/leukemia with prominent nucleoli (SBLPN) is a new classification, which is so rare that it lacks clinical data. Patient concerns: An increased proportion of prolymphocytes (84%) in the bone marrow smear. Whole exon sequence analysis revealed a TP53 mutation. Diagnoses: Combining the clinical features with laboratory test results led to a diagnosis of SBLPN which was made according to the 5th edition of the WHO classification of hematolymphoid tumors, although the patient was diagnosed with B-PLL when guided by the 4th edition of the WHO classification. Interventions: The use of Ibrutinib as an effective treatment. Outcomes: The patient was in complete remission after 5 months of Ibrutinib and then died of sudden aortic dissection. Lessons: Ibrutinib was an effective regimen for SBLPN. Aortic dissection might be considered as a suspicious adverse reaction to Ibrutinib.

Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease

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

Toxicity, Progression-Free Survival, and Quality of Life of Patients Treated with Zanubrutinib Versus Ibrutinib: A Q-TWiST Analysis from the ALPINE Study in Relapsed or Refractory Chronic Lymphocytic Leukemia

Introduction: Zanubrutinib is a second-generation Bruton's tyrosine kinase inhibitor (BTKi) with enhanced specificity over the first-generation BTKi ibrutinib. Patients treated with zanubrutinib had a significantly longer progression-free survival (PFS) versus those treated with ibrutinib in the global, phase 3, randomized ALPINE trial in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) (NCT03734016). Quality-adjusted time without symptoms of disease and toxicity (Q-TWiST) is a clinical tool to assess overall benefits and risks of cancer therapies by integrating progression, survival, treatment toxicity, and patient quality of life (QoL) into a single metric. It provides valuable insights into the quality and duration of improved health states. To gain a comprehensive understanding of the benefits and risks associated with zanubrutinib versus ibrutinib in terms of quality-adjusted survival, a Q-TWiST analysis was performed within the ALPINE trial. Methods: Patients in the ALPINE trial were followed for a median duration of 29.6 months. For the Q-TWiST analysis, overall survival (OS) of each patient was partitioned into 3 mutually exclusive health states: TOX (time before disease progression with toxicity after randomization); TWiST (time from randomization to disease progression without toxicity); and REL (time after disease progression until death or censoring). Survival curves corresponding to TOX, PFS, and OS were estimated by Kaplan-Meier method with a monthly cycle. Restricted mean survival time for each health state was derived from the area under the Kaplan-Meier curve (TWiST = PFS - TOX; REL = OS - PFS). Q-TWiST for each treatment was estimated as the mean time spent in each health state weighted by its respective QoL, denoted by health states' utility value (U; 0 [indicates death] to 1.0 [indicates “perfect” health]). Relative Q-TWiST gain was estimated by dividing the absolute Q-TWiST gain by mean OS with ibrutinib. To ensure the comparability of populations and treatments across published Q-TWiST studies, the base-case analysis focused on a high-risk population (i.e., patients with chromosome 17p deletion, TP53 mutation, or both). In the base case, the TOX health state included adverse events (AEs) of grade 2 or higher. Standard utilities were applied, with a value of 0.5 assigned to both TOX and REL and a value of 1.0 assigned to TWiST. A sensitivity analysis was performed in an intent-to-treat population with same-grade AEs considered for TOX and standard utilities. Results:In the base case, the mean durations of TOX, TWiST, and REL health states for zanubrutinib (N = 73) were 11.54 months, 14.45 months, and 1.70 months, respectively. The corresponding durations for ibrutinib (N = 71) were 11.38 months, 11.09 months, and 3.78 months, respectively. The mean difference (95% CI) for zanubrutinib versus ibrutinib was 0.16 months (−0.18, 0.51) for the TOX state, 3.36 months (2.6, 4.2) for the TWiST state, and −2.08 months (−2.6, −1.6) for the REL state. The mean duration of Q-TWiST was 21.07 months for zanubrutinib versus 18.67 months for ibrutinib. The estimated difference in means (95% CI) for Q-TWiST gain was significantly higher for zanubrutinib versus ibrutinib (2.40 months; 1.9, 2.9; P&amp;lt;0.001), and the relative Q-TWiST gain was 9.14% (Figure). In the sensitivity analysis, using the intent-to-treat population, the mean difference (95% CI) for Q-TWiST gain was 1.30 months (1.0, 1.6; P=0.05) for zanubrutinib versus ibrutinib, and the relative Q-TWiST gain was 4.63%. Conclusions: This Q-TWiST analysis demonstrated a statistically significant gain in quality-adjusted survival with zanubrutinib compared with ibrutinib in patients with high-risk R/R CLL. The slightly longer TOX duration in patients receiving zanubrutinib versus those receiving ibrutinib could be explained in part by better treatment adherence. The results of this Q-TWiST analysis, which integrates both the length and quality of survival in addition to efficacy and toxicity, provide valuable insights that may help to inform clinical decision-making in the treatment of patients with R/R CLL.

Real-World Bruton Tyrosine Kinase Inhibitor (BTKi) Treatment Patterns Among Patients with Chronic or Small Lymphocytic Leukemia (CLL/SLL) in US Community Oncology Practices

Background: BTKis have become the standard-of-care therapies for both frontline (1L) and relapsed/refractory (2L) CLL/SLL, and recently the NCCN listed both second-generation BTKis, zanubrutinib and acalabrutinib, as preferred agents over the first-generation BTKi ibrutinib based on toxicity profile. The objective of this study was to assess real-world clinical characteristics, treatment patterns, and adverse events (AEs) among BTKi-treated patients with CLL/SLL. Methods: This was a retrospective observational study of adult patients with CLL/SLL who initiated treatment between 01-Jan-2020 and 28-Feb-2023 in the community oncology setting across the US and were followed up through 31-May-2023. Included patients had to have at least 5 CLL/SLL visits or more CLL/SLL visits than non-CLL/SLL visits; all patients had to have 2 or more evaluation and management visits. The study included structured electronic health data from the Integra Connect-PrecisionQ de-identified real-world database. Descriptive analyses were conducted including all patients who received a BTKi, and a Kaplan-Meier analysis was performed for time-to-event outcomes. Results: A total of 2650 patients who received a BTKi were included in the study (2465: BTKi 1L; 185: BTKi naïve in 1L with use of BTKi in subsequent lines). The median (range) age of patients in the 1L BTKi and BTKi-later line groups was 71 (35-89) and 74 (42-89) years, respectively, and most included patients were male (Table). In 1L, 53.3% (n=1314/2465) were treated with ibrutinib, 43.3% (n=1068/2465) with acalabrutinib, and 3.4% (n=83/2465) with zanubrutinib. Among BTKi-later line patients, similar trends (45.9% [85/185] ibrutinib, 42.7% [79/185] acalabrutinib, 11.4% [21/185] zanubrutinib) were observed in 2L. The rates of cardiovascular AEs within the first 3 and 6 months of BTKi initiation were 10.1% (n=106/1048) and 13.4% (n=123/921) for patients treated with ibrutinib, 7.3% (n=56/767) and 9.8% (n=62/631) for acalabrutinib, and 7.3% (n=5/69) and 7.5% (n=3/40) for zanubrutinib, respectively. More than 10% of ibrutinib-treated patients discontinued therapy and switched to a second-generation BTKi. The median time to treatment discontinuation (95% CI) in the 1L setting was 12.7 (11.7, 15.3) months for ibrutinib, 15.7 (12.0, 20.4) months for acalabrutinib, and 12.9 (10.3, NR) months for zanubrutinib. The proportion of patients continuing treatment at 6 and 12 months was higher with zanubrutinib (72.3% and 61.4%, respectively) compared to acalabrutinib (62.6% and 53.1%) and ibrutinib (62.3% and 51.9%). The median time to next treatment (TTNT) (95% CI) was not reached (NR) (12.6 months, NR) for those who received zanubrutinib in the 1L, while it was 31.3 (26.5, 35.5) months for ibrutinib and 35.8 (31.8, NR) months for acalabrutinib. Conclusions: This study found that cardiovascular AEs at 6 months were higher among patients who received ibrutinib and acalabrutinib compared to zanubrutinib. While the study is limited by the smaller sample size and shorter follow-up period for the zanubrutinib group, the proportions of patients remaining on treatment were higher and the median TTNT was longer for patients who received zanubrutinib.

Molecular Attributes of CAR T Cell Fitness in Patients with Chronic Lymphocytic Leukemia

Chimeric antigen receptor (CAR) T cell therapies have transformed the treatment of hematologic malignancies, leading to FDA approval in B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma, and multiple myeloma. While many patients with previously untreatable disease have achieved excellent responses and long-term remissions, a substantial number do not respond or relapse after months to years. Most prior studies of CAR T cell-intrinsic determinants of response and resistance have focused on infusion products. Functional expansion and persistence of CAR T cells in patients constitute an important feature of treatment success, yet the trajectories of CAR T cells and their molecular underpinnings remain poorly understood due to technical challenges. Here we performed single-cell multiomics with T-cell receptor (TCR) lineage tracing to study the molecular attributes of CAR T cell fitness, which we define as the ability to expand and/or persist to at least 12 months after infusion. We recently published long-term follow-up from a prospective single-center phase 2 clinical trial in which CD19-directed CAR T cells with 4-1BB co-stimulation were administered to patients with relapsed or refractory chronic lymphocytic leukemia (CLL) not in complete remission despite at least 6 months of ibrutinib. In this trial, we found high rates of deep and durable remissions with prolonged persistence of functional CAR T cells determined by flow cytometric detection of CAR T cells with concomitant B-cell aplasia. We obtained CAR T cell infusion products and peripheral blood at day 10 and month 12 from five patients with durable remissions. We then performed single-cell multiomics sequencing to measure gene expression, TCRs, surface proteins, and chromatin accessibility to define the multidimensional phenotypes and clonal trajectories of CAR T cells over time ( Figure). We first evaluated CAR T cell dynamics from infusion product to day 10 and identified clones that expanded using TCR as a molecular barcode. While ~90% of CAR T cells in the infusion product are CD4 +, peak expansion at day 10 is driven by effector CD8 + CAR T cells. Clonally expanded CAR T cells at day 10, compared to non-expanded CAR T cells, showed higher expression of multiple cytotoxicity genes ( GZMH, GZMB, GNLY, PRF1) and co-inhibitory receptors ( LAG3, PDCD1, and KLRB1) and lower expression of memory genes ( SELL, LTB, TCF7). Using TCR lineage tracing and a machine learning classifier, we identified similar markers predictive of clonal expansion from the infusion product, e.g. CD8A, GNLY, KLRG1, KLRK1 among the top positive markers and CD4 and SELL among the top negative markers. Along with clonal expansion, we found that CD8 + CAR T cells undergo significant evolution in their chromatin accessibility landscape from infusion product to day 10. Genomic regions that are more open at infusion are enriched for Fos/Jun (AP-1) and Batf family of transcription factor (TF) motifs, consistent with their function in promoting effector T cell differentiation and proliferation. Genomic regions that are more open at day 10 are enriched for Eomes, T-bet, and other T-box TF motifs, consistent with their roles in regulating T cell cytolytic function, memory formation, and exhaustion. These data provide insights into the regulatory mechanisms of rapid CAR T cell expansion post-infusion in patients which have not yet been reported. We found that most clonally expanded CAR T cells at day 10 contracted or disappeared by month 12. However, a subset of CD8 + CAR T cells in 2 patients that did not undergo early expansion surprisingly demonstrated late clonal expansion and persistence at month 12, coinciding with hyper-expansion (&amp;gt;200 cells per clone) of their TCR clonotypes with or without CAR expression. We then investigated the specificity of TCRs using publicly available databases and found late expansions of clones predicted to bind viral peptides. This observation suggests that the TCR antigen specificity may contribute to the long-term persistence or fitness of CAR T cell clones, in contrast to recent studies of long-lived CAR T cells in a limited number of patients which argue that persistence is driven by specific phenotypes rather than clonotype-specific features. Further validation of this finding is ongoing through flow enrichment of rare persistent CAR T cells for deeper single-cell sequencing and in vitro cellular immunology assays.

Multi-Omics Exploration of Adaptive Mechanism to BTK Inhibition By Ibrutinib in CLL Identified TMBIM6/BI-1 As a Poor Prognosis Variable and Potential Therapeutic Target

Introduction: Ibrutinib is currently part of the therapeutic armamentarium employed in patients with CLL. Despite being an active drug, its usage is not devoid of adverse effects and resistances leading to discontinuation. In addition, current evidence suggests that ibrutinib improves the T cell disfunction associated with CLL progression. The objective of our study was to longitudinally assess the T cell immune profile of ibrutinib-treated CLL patients, and to identify potential adaptive mechanisms to BTK inhibition in B cells in the first 12 months of continuous treatment. Methods: Blood samples from 28 patients from GELLC7 trial (NCT03280160, ibrutinib followed by ofatumumab consolidation) were collected before treatment (BT), and 1, 3, 6 and 12 months on treatment (at least two timepoints). Peripheral blood mononuclear cells and plasma were isolated and stored to perform multi-omics analyses including flow cytometry, RNA sequencing, cytokine determination, migration assays and targeted DNA sequencing. Results: T cell immunophenotyping revealed a decrease of CD4+ and CD8+ T cells expressing PD1 and CD244 and a reduction of regulatory T cells (Tregs) and T follicular helper (Tfh) cells after ibrutinib treatment. In addition, bulk-RNAseq of purified T cells revealed 170 differentially expressed genes (DEG) after 6 months of ibrutinib treatment. These genes participate in pathways related to cell stimulation and regulation of cell activation. Gene set enrichment analysis (GSEA) showed a downregulation of oxidative metabolism, proliferation, and activation pathways, indicating a reduction of the CLL inflammatory burden. Furthermore, there was a significant reduction of several inflammatory/migration chemokines in plasma at 6 months (CCL2/3/4, CXCL10, CXCL12, CXCL13, CCL19). In CLL cells, a decreased expression of adhesion (CD44/CD62L), immunosuppression- (CD200/BTLA), and migration-related markers (CXCR5/CCR7) at 6 months of ibrutinib treatment was observed. However, CXCR4 expression increased upon ibrutinib treatment, and the proliferative CXCR4dimCD5br population was reduced. We investigated CXCR4-mediated migration as a potential mechanism of CLL cell adaptation to ibrutinib in 14 patients at BT and 6 months of BTK inhibition. Reduced CXCR4-migratory capacity was observed, but some cells retained migration under BTK inhibition. Targeted-DNAseq and bulk-RNAseq were performed at BT and 6 months of ibrutinib to characterize CLL cells with retained migratory capacity. There was an alteration of the subclonal composition of CLL cells that retained migratory capacity under BTK inhibition in 7/12 patients with a recurrent enrichment of subclones with mutations in ATM and NFKBIE gene. BTK p.Cys481Ser mutation was acquired in one patient after 6 months of treatment with ibrutinib, while no PLCG2 mutations were detected. GSEA showed an upregulation of mTORC1 and Myc pathways in cells with retained migration. Among the DEG, TMBIM6 was the most significantly upregulated gene. TMBIM6 gene is associated with apoptosis, mTOR-Akt axis and poor prognosis in solid tumors. We evaluated the prognostic impact of TMBIM6 expression using public data from the CLL-map portal (Knisbacher et al. 2022 Nat Genet). TMBIM6 high expression was associated with poor overall survival in both univariate and multivariate analyses including age, gender, IGHV mutation status (Figure 1) and recurrent genetic alterations. When TMBIM6 was targeted with BIA, a TMBIM6 antagonist (Kim et al. 2020 Nat Commun), its effect on CXCR4-mediated migration was limited but it induced CLL cell apoptosis in suspension and co-cultured CLL cells (Figure 2). Moreover, BIA addition to ibrutinib treatment induced synergistic apoptosis. Collectively, these results indicate that TMBIM6 may be a potential novel target for CLL and that combination with ibrutinib could be a valid approach for time-limited therapy. Conclusions: Ibrutinib in T cells reduced the expression of exhaustion markers, Tregs and Tfh cells. In CLL cells, we observed a downregulation of markers related to adhesion, immunosuppression and migration, but an overexpression of TMBIM6 in CLL cells that retained migrative capacity towards CXCL12 under ibrutinib. Finally, we identified TMBIM6 expression as an independent poor prognostic factor and a potential novel target for CLL.

Long-term Outcomes With Ibrutinib Treatment for Patients With Relapsed/Refractory Mantle Cell Lymphoma: A Pooled Analysis of 3 Clinical Trials With Nearly 10 Years of Follow-up.

Long-term Outcomes With Ibrutinib Treatment for Patients With Relapsed/Refractory Mantle Cell Lymphoma: A Pooled Analysis of 3 Clinical Trials With Nearly 10 Years of Follow-up.

Anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia

AbstractIn chronic lymphocytic leukemia (CLL) patients who achieve a complete remission (CR) to anti-CD19 chimeric antigen receptor T cells (CART-19), remissions are remarkably durable. Preclinical data suggesting synergy between CART-19 and the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib prompted us to conduct a prospective single-center phase 2 trial in which we added autologous anti-CD19 humanized binding domain T cells (huCART-19) to ibrutinib in patients with CLL not in CR despite ≥6 months of ibrutinib. The primary endpoints were safety, feasibility, and achievement of a CR within 3 months. Of 20 enrolled patients, 19 received huCART-19. The median follow-up for all infused patients was 41 months (range, 0.25-58 months). Eighteen patients developed cytokine release syndrome (CRS; grade 1-2 in 15 of 18 subjects), and 5 developed neurotoxicity (grade 1-2 in 4 patients, grade 4 in 1 patient). While the 3-month CR rate among International Working Group on CLL (iwCLL)-evaluable patients was 44% (90% confidence interval [CI], 23-67%), at 12 months, 72% of patients tested had no measurable residual disease (MRD). The estimated overall and progression-free survival at 48 months were 84% and 70%, respectively. Of 15 patients with undetectable MRD at 3 or 6 months, 13 remain in ongoing CR at the last follow-up. In patients with CLL not achieving a CR despite ≥6 months of ibrutinib, adding huCART-19 mediated a high rate of deep and durable remissions. ClinicalTrials.gov number, NCT02640209.

Efficacy of Front-Line Ibrutinib Versus Fludarabine, Cyclophosphamide and Rituximab (FCR) in Patients with CLL. a Multicenter “Real-World” Study

Efficacy of Front-Line Ibrutinib Versus Fludarabine, Cyclophosphamide and Rituximab (FCR) in Patients with CLL. a Multicenter “Real-World” Study

CXCL13 (BCA-1) Plasma Levels Are a Useful Biological Marker for Disease Progression in Chronic Lymphocytic Leukemia (CLL) Patients

Background: CXCL13 is a chemokine that is constitutively secreted by follicular dendritic cells (FDC) and T follicular helper (Tfh) cells in secondary lymphoid tissues, where CXCL13 plays an essential role in organizing the micro-architecture of germinal centers (GC). Interactions between CLL cells and the lymph node microenvironment mimic, in several aspects, the normal GC reaction. CXCL13 confers access of CXCR5-expressing CLL cells to the lymph node microenvironment. Interestingly, immunization experiments in mice and man demonstrated CXCL13 to be a reliable blood biomarker for GC activity (PNAS 113:2702, 2016). Therefore, we hypothesized that CXCL13 plasma levels reflect disease activity in CLL.Methods: We measured CXCL13 plasma levels by ELISA in a cohort of 400 CLL patients (329 treatment naïve and 71 previously treated) and correlated CXCL13 levels with prognostic markers, time to first treatment (TTFT), and plasma levels of the BCR signaling-related chemokines CCL3 and CCL4 (MIP-1α and β).Results: CXCL13 plasma concentrations were significantly higher in samples from CLL patients with active disease who progressed to require therapy. Accordingly, advance stage CLL patients had higher CXCL13 plasma concentrations than early stage patients. For example, the median CXCL13 concentration in early stage CLL (Rai stage 0, n=120) was significantly lower (80.6 pg/mL, range: 24.4 - 494.4 pg/mL) than in advanced-stage patients (Rai stage III or IV, n=79), median CXCL13: 202.6 pg/mL (range: 32.8 - 1418.0 pg/mL, n=79, p<0.0001). Similarly, median CXCL13 concentrations were significantly higher in patients with high β2 microglobulin, high plasma CCL3 concentrations, elevated LDH, and high white blood counts (WBC). In contrast, the IGHV mutational status, ZAP70, CD38 expression, CCL4 levels and cytogenetic subgroups had little or no impact on CXCL13 levels. Of the 329 treatment-naïve patients studied, 209 eventually required treatment; the median time from sample collected to first treatment (TTFT) for the entire population was 549 days. Patients were dichotomized in high and low CXCL13 levels, based on the approximate median of 128 pg/mL. Based on this, CLL patients with high CXCL13 levels (n=116) had a significantly shorter median TTFT of only 341 days, when compared to patients with low CXCL13 levels (n=93), in whom the TTFT was 758 days (p=0.0019, see Figure). For validation, we analyzed CXCL13 levels in serial plasma samples from patients treated with ibrutinib (n=30). At baseline, prior to treatment, the median CXCL13 levels was 109.6 pg/mL (range: 23.5 - 403.5 pg/mL), and CXCL13 plasma concentrations significantly decreased during treatment to 58.4 pg/mL after 1 week of ibrutinib therapy (20.8 - 159.3 pg/mL, p<0.001). After at 6 months of ibrutinib, CXCL13 concentrations were 42.3 pg/mL (17.6 - 118.2 pg/mL, p<0.001), and at 12 months 35.6 pg/mL (11.5 - 75.5 pg/mL, p<0.001).Conclusion: These studies demonstrate that CXCL13 serves as a novel plasma biomarker for disease activity and progression in CLL patients. Also, these studies emphasize the importance of CXCL13 as a plasma biomarker for B cell activation and expansion in normal or malignant B cell follicles within secondary lymphatic tissues. [Display omitted] DisclosuresWierda:Genentech/Roche: Consultancy, Honoraria, Research Funding; Karyopharm: Research Funding; Genzyme: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Juno: Research Funding; Kite: Research Funding; Emergent: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Janssen: Research Funding; Sanofi: Consultancy, Honoraria; Acerta: Research Funding; GSK/Novartis: Consultancy, Honoraria, Research Funding; The University of Texas MD Anderson Cancer Center: Employment; Pharmacyclics: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding. Burger:Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding.

International, Practice-Based Recommendations for Prediction of Bleedings and Anti-Platelet/Anti-Coagulant (AP/AC) Co-Medications in CLL Patients Taking Ibrutinib

Introduction: bleeding events (grade 1-2, 50%, grade 3-4 <5%) have been repeatedly reported in patients taking BTK inhibitors, including ibrutinib (IBR) and acalabrutinib. We lack clear recommendations from real-life clinical practice experience, since all existing management decision support systems have been made out from clinical trials (many of which didn't allow the recruitment of patients taking AC). Furthermore in clinical trials, no thorough exploration of platelet aggregation test was available.Methods: we reviewed the in vitro and in vivo evidence collected in 3 different centres from 3 countries (France, Russia, Austria) including: bleeding symptoms with grade, AP/AC co-medications, agonist-induced platelet aggregation tests (ristocetin RIPA, collagen CIPA), platelet counts. In the French series, complete PK evaluation (t0-0.5h-1h-2h-4h-6h) at one month was available for some patients (Cmax, Cmin, AUC).Results: based on our first 121 pts, our aggregation tests monitoring point towards several common considerations:1/ For patients taking IBR alone (without AP/AC):- Half patients' platelets do not demonstrate any collagen-induced platelet aggregation (CIPA) defect with IBR, even sampled at various time points. This 50/50 segregation between IBR-sensitive and IBR-resistant pts is also observed among 47 healthy donors' platelets. Furthermore, acalabrutinib (sparing TEC kinase more than IBR) in vitro induced very similar (in time and size) aggregation defects only in the IBR-sensitive pts, reinforcing the view of a BTK-effect with the two inhibitors.- Among the 50% early bleedings due to ibrutinib, 50% will recover over time (clinical and CIPA test recovery). As a consequence, in our global population 25-30% of patients still present bleeding after 6 months of therapy (100% grade 1-2). No PK parameter was found to explain the discrepancies of bleeding events among patients, suggesting dose reductions of IBR are not mandatory from the start to leverage bleeding risk. The late risk of severe haemorrhage (grade 3-4) seen in 5 patients seems to be linked with AC (not AP) intake.- the CIPA test has a very good sensitivity (85.7%) and a good specificity (62.5%) to discriminate the patients with bleeding diathesis the first 3 months. The specificity (not sensitivity) was however significantly reduced (33.3%) after 3 months, compromising its utility in pts requiring AC therapy while on ibrutinib for >3 months. Yet, the large majority of patients with bleeding syndromes had a weak aggregation response to collagen 3.3 µg/ml. A lower dose of collagen in vitro can be used (2.2 instead of 3.3microg/ml) to increase specificity after 3-6 months of ibrutinib.2/ for patients taking IBR + AP or AC- the percentage of patients with bleeding syndromes before 6 months did not increase significantly compared to patient under IBR treatment alone (the bleeding grade did not increase neither). Conversely, after 6 months, with AP the risk increases a little bit to 40% (all grade 1-2 except 1 grade 3) as compared to 90% bleeding events in the 10 pts with AC (mainly VKA, including 2 grade 3 and 1 grade 4).- the CIPA tests are no longer valid for patients under AP therapy before start of IBR, as their platelet aggregation response is very low, as expected. In vitro, addition of aspirin or clopidogrel to IBR-resistant platelets reduced aggregation to a significantly lesser extent than that observed in IBR-responsive platelets. This is of interest in the investigation of IBR pts requiring a dual AP therapy.- Most patients under AC and IBR with bleedings had also weak CIPA results. This result would suggest that a weak platelet response to collagen could increase the risk of bleeding (inherent to the AC drug), and therefore heparin should be the preferred choice with ibrutinib.- Take home message: our clinical and biological data collectively identify a strong concern with the use of a triplet therapy, IBR+AP+AC, which should be avoided.Conclusion: the monitoring of CIPA testing is not recommended before starting IBR if no AP/AC is added. In clinical situations where AP/AC is mandated, it can predict an “IBR-related” additional risk factor the bleeding risk of the AP drug. Our results are currently being compared with those of RIPA testing (in the Austrian cohort). We will present updated recommendation charts (including direct anticoagulants use) during the meeting. DisclosuresPanteleev:Amgen: Research Funding. Jaeger:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Payrastre:Janssen: Research Funding. Ysebaert:Janssen: Consultancy, Research Funding, Speakers Bureau.

Real-World Treatment Patterns and Associated Adverse Events Among Patients with Mantle Cell Lymphoma (MCL) in the United States

Introduction: MCL is an aggressive lymphoma accounting for 6% of all newly diagnosed non-Hodgkin lymphoma cases in the US. Treatment advances include approval of oral agents such as ibrutinib and lenalidomide in relapsed/refractory MCL. In a study conducted among patients with chronic lymphocytic leukemia, treatment-related toxicity and associated discontinuation rates were higher in a real-world setting compared with clinical trials (Mato et al., Blood, 2016; 128:3222). However, similar real-world data are not available for MCL. Thus, this study aimed to explore and document current treatment patterns and associated adverse events (AEs) for MCL.Methods: In thisretrospective cohort study, we used Truven MarketScan® databases, consisting of claims data relating to medical and drug utilization for more than 60 million unique individuals (in the most recent data year) across the US. Patients were included if they were age ≥18 years, had ≥2 medical claims on separate days with a diagnosis for MCL (ICD-9-CM code: 200.4x or ICD-10-CM code: C83.1x) between July 2012 and June 2015, and were enrolled in medical and drug plans continuously for ≥12 months before the study index date (baseline period), with no evidence of MCL diagnosis or prior MCL treatment in the baseline period. The date of first claim with MCL diagnosis defined the study index date. MCL-directed systemic therapy regimens, stem cell transplantation, and radiation therapy received after the study index date were identified using applicable procedure codes. Treatment regimens were defined as the combination of all treatments on and during the 35 days after the first claim for a systemic therapy agent. End-of-treatment episode was defined as the earliest gap of ≥90 days in treatment or a treatment modification (ie addition/subtraction of agents in the regimen or switch to a different regimen). Treatment patterns (eg duration of treatment, treatment sequencing, adherence to oral therapies) for up to 4 observed treatment episodes were analyzed. Occurrences of potentially treatment-related AEs were determined using AE-specific diagnosis and procedure codes and were stratified by the type of treatment. All analyses were descriptive in nature.Results: A total of 783 patients with MCL met the study selection criteria; median age 65 years (range: 19-99). The median Charlson Comorbidity Index score assessed at baseline was 2.0 (range: 0-13) with a median of 2.0 (range: 0-17) daily oral medicines in the month before MCL diagnosis (Table 1). MCL-directed treatment was recorded for 636 patients (81%); among them, the treatments were chemotherapy (76%), biologic therapy/immunomodulators (64%), radiation therapy (32%), targeted therapy (17%), and stem cell transplantation (11%). Among those receiving systemic therapy at any time during the follow-up (all of above except patients undergoing radiation and stem cell transplantation; n=457), the most common regimens were bendamustine/rituximab (BR; 41%), rituximab/cyclophosphamide/doxorubicin/vincristine (R-CHOP; 27%), rituximab alone (including maintenance therapy; 20%), and ibrutinib alone (14%). Bortezomib- and lenalidomide-based regimens were used in 6% and 5% of patients, respectively. The median (Q1-Q3) duration of treatment in months for ibrutinib, BR, R-CHOP, and rituximab were 6.1 (3.4-9.9), 5.6 (3.2-9.3), 4.3 (3.0-4.9), and 2.4 (1.7-8.8), respectively. The most common hematologic AEs (includes both prevalent and incident cases) across the most common regimens were neutropenia and anemia. Infection, hypertension, dyspnea, and nausea/vomiting were common nonhematologic AEs. Among patients receiving ibrutinib, occurrences of neutropenia (17%) and pyrexia (6%) were less frequent, but atrial fibrillation (20%) and renal failure (14%) were more frequent, as compared with that in patients receiving the common chemoimmunotherapy regimens (BR and R-CHOP).Conclusions: This study identifies the most commonly used MCL-directed treatments in a real-world setting. Chemoimmunotherapy combinations, particularly BR, remain the most common treatment choice for MCL. Ibrutinib is the most common novel agent used for MCL, with few patients receiving lenalidomide- or bortezomib-based therapies. The results indicate that the occurrence of AEs among patients with MCL receiving systemic therapy is substantial and that their frequency varies with treatment regimen. [Display omitted] DisclosuresGoyal:RTI Health Solutions: Research Funding. Karve:AstraZeneca: Employment, Other: Stocks. Nagar:RTI Health Solutions: Research Funding. Kaye:RTI Health Solutions: Research Funding. Mato:Portola: Research Funding; Janssen: Consultancy; AbbVie: Consultancy, Research Funding; Acerta: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy; AstraZeneca: Consultancy; Pharmacyclics: Research Funding; DTRM: Research Funding; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Research Funding.

Efficacy Outcomes of Treatments for Double Relapsed/Refractory Follicular Lymphoma (R/R FL): A Systematic Literature Review

ABSTRACT Introduction: Patients with indolent non-Hodgkin lymphomas (iNHL), including follicular lymphoma (FL), have high response to first-line treatment. However, retreatment is often required when relapses occur, and those with multiple relapses represent a patient population with an unmet need for effective treatment. Clinical data for several treatment options exist for the general relapsed and refractory (R/R) population; however, there are relatively fewer data specific to FL patients with ≥2 lines of prior treatment. This work systematically identified the available efficacy data in the double R/R FL population. Methods: The MEDLINE and EMBASE databases were searched through February 10, 2020. Studies were limited to interventional clinical trials of R/R FL patients (or mixed histologies with a predominance of FL) and articles published in English. Studies also must have reported one or more efficacy measures, such as overall response rate (ORR), complete response (CR), duration of response (DoR), time to next treatment (TTNT), progression-free survival (PFS), and overall survival (OS). Potential interventions of interest were lenalidomide ± rituximab (R), duvelisib, ibrutinib, venetoclax, polatuzumab vedotin + R, obinutuzumab, copanlisib, umbralisib, idelalisib, and tazemetostat. Results: Of 35 publications examining treatment outcomes in R/R FL patients, only 14 (representing 5 unique clinical trials) were specific to the ≥ 2-line population. These trials were: CHRONOS Part B (copanlisib), DAWN (ibrutinib), DELTA (idelalisib), DYNAMO (duvelisib), and Morschhauser et al. 2019 (tazemetostat) and included a total of 605 participants. All studies used similar inclusion criteria, and patients included were similar in age (median 62-65), disease stage (III/IV), and ECOG score (0-2). Patients in the CHRONOS study had a median number of prior treatments of 2, whereas those in the DELTA study had 5. ORR ranged from 21% (ibrutinib) to 59% (copanlisib) (Table). The DoR ranged from 8.3 months in tazemetostat patients with EZH2 gene mutation to 19.4 months for ibrutinib. PFS ranged from 5.7 months in tazemetostat patients with wild-type EZH2 to 11.2 months for copanlisib. Median TTNT was only reported in the DAWN study (16 months). Conclusions: Very few clinical data exist reporting efficacy outcomes specific to the double R/R FL population. The limited data indicate that current treatments do not produce durable responses for most double R/R FL patients, demonstrating an unmet need. Further research is needed to fully understand the efficacy and safety of other potential interventions for this population. Disclosures Kahl: Genentech:Consultancy;Pharmacyclics LLC:Consultancy;AstraZeneca Pharmaceuticals LP:Consultancy, Membership on an entity's Board of Directors or advisory committees;ADC Therapeutics:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Celgene Corporation:Consultancy;AbbVie:Consultancy;Roche Laboratories Inc:Consultancy;BeiGene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Janssen:Consultancy, Membership on an entity's Board of Directors or advisory committees;Acerta:Consultancy, Research Funding.Patel:Kite, a Gilead Company:Current Employment.Zaidi:BMS:Consultancy.Snedecor:Pharmerit - an OPEN Health Company:Other: Employment at consultancy paid by Kite Pharma to conduct this work.Purdum:Kite, a Gilead Company:Current Employment.

Ibrutinib Treatment Mitigates Phenotypic Alterations of Non-Neoplastic Immune Cell Compartments in Chronic Lymphocytic Leukemia

Ibrutinib Treatment Mitigates Phenotypic Alterations of Non-Neoplastic Immune Cell Compartments in Chronic Lymphocytic Leukemia

1719. Incidence and Characterization of Invasive Fungal Infections (IFIs) in Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Ibrutinib (IBR)

BackgroundIBR is a Bruton’s tyrosine kinase inhibitor, and plays a key role in the treatment of CLL. In randomized clinical trials, <1% of IBR-treated CLL patients developed IFIs. However, several IFIs were reported with real-life use of IBR.MethodsThis is a retrospective observational study of all CLL patients (> 18 years) treated with IBR (2/2014–8/2018) at MD Anderson Cancer Center. We excluded patients with active IFI (proven and probable, EORTC/MSG criteria) at the start of IBR and patients with <6 months of follow-up.ResultsOf the 821 CLL IBR-treated patients, 24 developed probable or proven IFI (2.9%). Of these infections, 21 occurred within 30 days (d) of last IBR dose, while 3 IFIs occurred at 94, 135 and 221 d post IBR, respectively. The majority of patients with IFI were male (83%) with a median age of 66 years at IFI diagnosis. The median prior lines of therapy for CLL was 1 (range 0–7), with 29% receiving IBR as frontline treatment. Five patients had evidence of Richter’s transformation at the time of IFI diagnosis, while two patients had prior stem cell transplant. The average time from start of IBR to diagnosis of IFI was 338 d, with only 7 cases of IFI within the first 3 months of IBR. The majority of IFIs were proven/probable aspergillosis (63%), including 9 cases of Aspergillus fumigatus. The remaining infections consisted of Cryptococcus neoformans (21%), Fusarium spp. (8%), with one case each of candidiasis, histoplasmosis, mucormycosis, and Pneumocystis jiroveci pneumonia. Three patients had evidence of poly-fungal IFI. The sites of infection were pulmonary (88%), blood (13%), CNS (13%), and sinus (8%). Five patients were diagnosed with disseminated IFI, including Cryptococcus spp. (2 cases), Rhizopus spp., Aspergillus spp., and Candida spp. The 42-day mortality rate post IFI diagnosis was 25%.ConclusionWe report the largest single-center cohort of CLL patients on IBR to date. The IFI incidence of 2.9% (24/821) is consistent with most previous reports estimating a 0.5–4% incidence. In contrast to published reports, close to 1/3 of our patients with IFI received IBR as frontline therapy and most IFIs (71%) were diagnosed > 3 months after starting IBR. We are currently conducting a case–control comparison with IBR–treated CLL patients with no infection to uncover risk factors associated with IFIs in these patients.DisclosuresSamuel L. Aitken, PharmD, Melinta Therapeutics: Grant/Research Support, Research Grant; Merck, Sharpe, and Dohme: Advisory Board; Shionogi: Advisory Board.

Ibrutinib Treatment Mitigates Phenotypic Alterations of Non-Neoplastic Immune Cell Compartments in Chronic Lymphocytic Leukemia

Ibrutinib Treatment Mitigates Phenotypic Alterations of Non-Neoplastic Immune Cell Compartments in Chronic Lymphocytic Leukemia

Prospective Clinical Trial of Anti-CD19 CAR T Cells in Combination with Ibrutinib for the Treatment of Chronic Lymphocytic Leukemia Shows a High Response Rate

Prospective Clinical Trial of Anti-CD19 CAR T Cells in Combination with Ibrutinib for the Treatment of Chronic Lymphocytic Leukemia Shows a High Response Rate

Real-World Treatment Patterns Among a Contemporary Cohort of Commercially Insured Mantle Cell Lymphoma Patients in the United States

IntroductionMantle cell lymphoma (MCL) is a rare, aggressive non-Hodgkin lymphoma associated with a poor prognosis. The approval of ibrutinib in November 2013 has changed the treatment paradigm for patients with relapsed or refractory MCL. There remains a lack of information on the current treatment patterns used in clinical practice in a contemporary cohort of commercially insured patients. We aimed to identify the treatment patterns for MCL overall and by line of therapy (LOT) and to describe patient demographics and clinical characteristics in a large cohort of commercially insured MCL patients.MethodsA retrospective cohort study was conducted with the IQVIA Real-World Data Adjudicated Claims-US database. Adult patients (≥18 years old) with ≥1 claim for a NCCN-recommended MCL treatment between November 1, 2013 and December 31, 2017 were identified. Index date was the first treatment claim. Patients were also required to have ≥1 diagnosis of MCL during the study period (November 1, 2012 to January 31, 2018), ≥12 months of continuous enrollment prior to index date (pre-index period) and ≥30 days after index date (follow-up period). Patients were excluded if they were ≥65 years at index and not enrolled in Medicare Risk or Medicare Cost, enrolled in a clinical trial during the study period, had evidence of MCL treatment in the pre-index period (except for patients indexed on ibrutinib as it is indicated for MCL patients with ≥1 prior treatment), or had evidence of stem cell transplant (SCT) before index date. The most commonly observed MCL treatment regimens were identified, and demographic and clinical characteristics of patients and treatment durations by regimen were described. Treatment regimen was defined as the combination of all agents observed in the 35-day period after the first MCL treatment claim; treatment duration was defined as the start of treatment until a gap of ≥90 days between end date and next date of treatment or treatment modification. Treatment end date occurred 90 days after the end of the supply for oral medications or 30 days after the last administration for non-oral medications.ResultsThere were 1,785 patients treated with the most commonly observed MCL treatment regimens. The most common regimens, irrespective of LOT, were rituximab monotherapy (including maintenance therapy; n=773, 43.3%), R-CHOP (n=723, 40.5%), B-R (n=436, 24.4%), and ibrutinib monotherapy (n=199, 11.1%). Overall, patients had a median (IQR) age of 57 (52-62) years, and 59.4% were male. Most patients were commercially or self- insured (57.5% and 33.6%, respectively). Patients had a median Charlson Comorbidity Index (CCI) of 0 (IQR 0-1; mean [SD] 0.9 [1.4]), with the most common CCI components being diabetes (15.7%), chronic pulmonary disease (12.8%), and congestive heart failure (9.5%). During the follow-up period (median [IQR] 22.5 [10.5-35.3] months), in addition to the MCL regimen(s), patients received radiation therapy (17.4%), SCT (10.0%), and/or immunotherapy (0.2%). The use of targeted therapies (i.e. lenalidomide, bortezomib) other than ibrutinib was infrequent. When considering treatment lines, R-CHOP was the most commonly observed first regimen, followed by rituximab, B-R, and ibrutinib; for the second and third observed regimens, rituximab was the most common, followed by ibrutinib (Figure 1). The median (IQR) duration for the first observed regimen was 8.1 (3.9-18.0) months for ibrutinib, 5.0 (3.3-5.6) months for B-R, 4.0 (2.5-4.4) months for R-CHOP, and 1.9 (1.7-4.4) months for rituximab; ibrutinib also had the longest duration in the second and third line (median [IQR] 5.5 [2.4-13.5] months and 8.3 [3.9-12.4] months, respectively).ConclusionThis is the largest study of MCL patients describing treatment patterns in current clinical practice among commercially insured patients. MCL patients were most commonly treated with chemoimmunotherapy for all treatment lines while ibrutinib was the second most common LOT2 and LOT3 regimen. As the treatment landscape and clinical practice continues to change with the use of novel agents, future studies are warranted to further study toxicities and outcomes in the real-world setting. DisclosuresKabadi:AstraZeneca: Employment. Burudpakdee:IQVIA received funds from AstraZeneca to conduct the analysis, interpret data, and coauthor the publication.: Consultancy. Near:IQVIA received funds from AstraZeneca to conduct the analysis, interpret data, and coauthor the publication.: Consultancy. Wada:IQVIA received funds from AstraZeneca to conduct the analysis, interpret data, and coauthor the publication.: Consultancy. Mato:TG Therapeutics: Research Funding; Sunesis: Honoraria, Research Funding; Acerta: Research Funding; Janssen: Consultancy, Honoraria; AstraZeneca: Consultancy; Pharmacyclics: Consultancy, Honoraria, Research Funding; Regeneron: Research Funding; Celgene: Consultancy; Prime Oncology: Speakers Bureau; Abbvie: Consultancy.

Economic Evaluation for the US of Ibrutinib Versus Acalabrutinib for Patients with Relapsed or Refractory Mantle Cell Lymphoma

Introduction. Mantle cell lymphoma (MCL) is a rare subtype of Non-Hodgkin lymphoma (NHL) with a poor prognosis. Ibrutinib is an oral Bruton's tyrosine kinase inhibitor (BTKi) approved in the US in 2013 for, among other indications, MCL patients with at least one prior therapy (i.e., relapsed/refractory [R/R] MCL). The BTKi acalabrutinib was approved in late 2017 specifically for this same indication. No studies have assessed the comparative efficacy and cost-effectiveness and cost-utility of both agents in the management of R/R MCL. We performed an indirect comparison of both agents in terms of progression-free survival (PFS) and overall survival (OS) to subsequently evaluate the relative cost-effectiveness and cost-utility of both treatment options of R/R MCL from a USA payer perspective.Methods. A life time horizon Markov model with 3 health states was specified: PFS, progression, and death. Trials to simulate these health outcomes under the respective treatment regimens included Dreyling et al (Lancet 2016) for ibrutinib and Wang et al (Lancet 2018) for acalabrutinib. Kaplan-Meier PFS and OS curves were digitized, PFS and OS data extracted, Weibull distributions fitted to these data, and extrapolations to the life time horizon estimated for both acalabrutinib and ibrutinib to estimate the life time efficacy of each treatment. Naïve patient simulation was performed to indirectly estimate and compare the OS and PFS estimates of the two agents. Wholesale acquisition costs (WAC) were obtained from RedBook (average sales price not yet available for acalabrutinib): $12,180 for ibrutinib and $14,064 for acalabrutinib. Costs of managing side effects and EQ-5D utility values were sourced from published literature. Costs were inflated based on the medical consumer price index to the first quarter of 2018. Disutility values for side effects were assumed the same for both interventions. A discount rate of 3% was applied when survival exceeded one year. The life years (LY) and quality adjusted LY (QALY) for each treatment, the incremental LY and QALY gained with acalabrutinib over ibrutinib, and the incremental cost-effectiveness (ICER) and cost-utility ratios (ICUR) were estimated in both base and probabilistic sensitivity analyses (PSA; 2000 simulations). The cost-effectiveness plane (CEP) and cost-effectiveness acceptability curves (CEAC) were plotted.Results. In the naïve patient simulation median PFS and OS were estimated to be 14.6 months and 25.1 months for ibrutinib, and 27.6 months and 168 months for acalabrutinib. As shown in the table below, in the life time horizon Markov model acalabrutinib showed incremental cost of $259,200/LY (PSA: $258,780/LY) and incremental gains of 0.48 LY (PSA: 0.48 LY) and 0.36 QALY (PSA: 0.36 QALY) over ibrutinib. This yielded an ICER of $540,000 per LY gained (PSA: $539,125 per LY gained) and an ICUR of $720,000 per QALY gained (PSA: $718,833 per QALY gained). In the CEP scatter plot, all estimates were in the upper-right quadrant indicating greater incremental QALY at higher incremental cost. Per the CEAC plot, the probability that acalabrutinib would be considered cost-effective was 50% at a willingness to pay threshold (WTP) of $718,833 per QALY and 70% at a WTP threshold of $748,000 per QALY.Conclusions. Clinically, treating patients with R/R MCL with acalabrutinib was associated with an absolute survival gain of 0.48 years (~6 months) and a quality-adjusted survival gain of 0.36 years (~4 months) over treatment with ibrutinib but at an additional cost of nearly $260,000 per year of treatment. Treating patients with RR/MCL acalabrutinib requires high WTP thresholds to be considered cost-effective to US payers. DisclosuresPersky:Genentech: Honoraria; Spectrum: Research Funding; Merck: Research Funding; Morphosys (IDMC): Consultancy. Abraham:Sandoz: Consultancy.

CD19 CAR-T cells combined with ibrutinib to induce complete remission in CLL.

7509 Background: Immunotherapy with anti-CD19 CART cells induces complete remission (CR) in the minority of patients with CLL, but where CRs occur they tend to be durable. Based on preclinical evidence of synergy, we combined anti-CD19 CAR T cells with ibrutinib to test the hypothesis that pre- and concurrent treatment would enhance the CR rate. Methods: This is a pilot trial of anti-CD19 CAR T cells in adults with CLL/SLL who were not in CR despite at least 6 months of ibrutinib. Pts must have failed at least 1 regimen before ibrutinib, unless they had del(17)(p13.1) or a TP53 mutation. T cells were lentivirally transduced to express a CAR comprising CD3z, 4-1BB, and humanized anti-CD19 scFv (CTL119). Pts were lymphodepleted 1 week before infusion. Ibrutinib was continued throughout the trial. Results: Manufacturing was successful in all pts. Ten pts (9M, 1F; ages 47-77; 0-12 regimens prior to ibrutinib) have been infused. All had abnormalities of TP53 or ATM and two pts had increasing BTK C481S clones. Median marrow CLL burden was 10% (range 10-50%). The median follow-up is 6 months (range 0.5-9). Cytokine release syndrome (CRS) developed in 9 pts; gr1 in 2, gr2 in 6 and gr3 in 1 pt. One pt developed gr4 tumor lysis syndrome. Treatment of CRS with the IL-6 receptor antagonist tocilizumab was not required. At 3 months, 8 evaluable pts had achieved an MRD-ve marrow CR (89%) by 9-color flow, and all remain in marrow CR at last F/U. There was modest residual splenomegaly in 3/5 patients, and adenopathy resolved in 4/6 subjects with progression in 1/6. MRD assessment by deep sequencing will be presented. Conclusions: We observed 89% MRD-ve marrow CR in pts with high-risk CLL using a well-tolerated combination of CART cells and ibrutinib. Longer follow-up will reveal the durability of these results and could support evaluation of a first-line combination approach in an attempt to obviate the need for chronic therapy. Clinical trial information: NCT02640209.