Relapsed/refractory Chronic Lymphocytic Leukemia Research Articles

Multilayer Profiling of MRD in Patients with Relapsed/Refractory CLL Treated with Venetoclax-Based Regimens in a Real-World Setting

Background Clinical trials have shown that patients with relapsed/refractory chronic lymphocytic leukemia (RR-CLL) treated with venetoclax monotherapy (Ven) or venetoclax-rituximab (VenR) often achieve unmeasurable MRD (uMRD) in peripheral blood (57% of VenR-patients achieved uMRD in peripheral blood at the 12 months landmark by FCM and/or ASO-PCR in the RCT MURANO; Kater AP. et al. JCO 2019 1). uMRD is a strong prognostic factor for progression free survival (PFS) in RR-CLL treated with venetoclax, but the rate of uMRD has not been systematically validated in RR-CLL cohorts treated in the real-world setting. Venetoclax imposes a strong selective pressure on the MRD clone, but the magnitude of the genetic drift of MRD persisting under venetoclax has not been quantified or qualified. Resistance to venetoclax can be mediated by selection of BCL2 mutant clones, but it is unknown if they already emerge in persistent cells of the MRD when the disease is in remission. Methods We analyzed peripheral blood of Swiss patients enrolled in the VeRVe study (NCT03342144), a prospective non-interventional observational study assessing effectiveness, safety, and quality of life in real-world patients with RR-CLL treated with Ven or VenR according to local label. MRD was measured by 8-color multi-parametric flow cytometry (FCM) following the European Research Initiative on CLL (ERIC) guidelines (sensitivity 10 -4), by high throughput sequencing (Ig-HTS, clonoSEQ® Assay) on gDNA from PBMCs (sensitivity 10 -6) and by NGS LyV4.0 CAPP-Seq ctDNA Assay on plasma ctDNA (sensitivity 10 -3) at diagnosis and at 12 months of treatment. To overcome the limitations imposed by the small size of MRD under venetoclax treatment, we leveraged ctDNA for clonal evolution profiling and for the detection of BCL2 mutations. Tumor gDNA was extracted from pre-treatment CLL cells purified by flow cytometry. Germline gDNA was extracted from PB leukocytes collected at the time of best MRD remission. Results In total, 28 patients were recruited. At the time of the analysis, 7 patients went off study before the one-year landmark, 4 patients have not yet reached the one-year landmark, resulting in 17 patients (Ven=5, VenR=12) assessable at the one-year landmark [17 analyzed by FCM, 16 by CAPP-seq (1 ongoing) and 12 by Ig-HTS (5 ongoing; 3 could not be evaluated because they failed Ig-HTS QC)]. At the 12 months landmark, uMRD was achieved in 58% of the assessed cases by FCM, 56% by CAPP-seq and 33% by Ig-HTS. FCM and CAPP-seq concordantly defined the MRD status in 76% of cases with κ=0.49 (12% had measurable ctDNA despite uMRD by FCM and 12% lacked ctDNA despite having measurable MRD by FCM). FCM and Ig-HTS concordantly defined the MRD status in 67% of cases with κ=0.40 (33% had measurable MRD by Ig-HTS despite uMRD by FCM). All patients, who had measurable MRD by FCM and/or CAPP-seq, had measurable MRD by Ig-HTS, which instead detected measurable MRD in 11% of patients who scored negative by both FCM and CAPP-seq (κ=0.77). By CAPP-seq of gDNA from purified CLL cells collected before therapy, the most frequently mutated genes were TP53, IGLL5, BRAF, SF3B1, NXF1, and ZMYM3. At baseline the concordance in mutation recovery by CAPP-seq of gDNA from purified CLL and ctDNA from plasma was high (73%). Before therapy, BCL2 mutations were never detected in either gDNA from purified CLL cells, or in ctDNA. To overcome the limitations imposed to genomic profiling by the small size of MRD under Ven or VenR treatment, we leveraged ctDNA for tracking the acquisition of BCL2 mutations. A total of 5 longitudinal, post-treatment timepoints spanning up to two years of therapy were analyzed. No patients who had measurable ctDNA at the one-year landmark (n=16) acquired BCL2 mutations. Conclusions The rate of uMRD achievable by venetoclax-based therapy in RR-CLL as measured in this real-world prospective study is congruent with the rate observed in the randomized clinical study MURANO. Ig-HTS has the best diagnostic performance for MRD detection. BCL2 mutations are not detectable in ctDNA after one year of venetoclax-based treatment, confirming that time limited therapy has low risk of selecting resistance. 1.) Kater AP. et al. Fixed Duration of Venetoclax-Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia Eradicates Minimal Residual Disease and Prolongs Survival: Post-Treatment Follow-Up of the MURANO Phase III Study. JCO 2019, 7(4):269-277

Second Line Treatment with Bruton Tyrosine Kinase Inhibitor (BTKi) or Bcl-2 Inhibitor (Bcl-2i) in Patients with Chronic Lymphocytic Leukemia (CLL): Primary Analysis of the Czech Study Group for CLL (CSCLL)

Introduction: Venetoclax in combination with rituximab (VenR) along with either ibrutinib or acalabrutinib monotherapy represent the most common regimens currently used for the treatment of relapsed/refractory (RR) chronic lymphocytic leukemia (CLL) in the Czech Republic. As all of these regimens are approved for identical indications in RR CLL, the selection of the most appropriate treatment depends on the drug toxicity profile and patient´s comorbidities. Methods: We conducted a retrospective analysis of data from the Czech National Registry of CLL patients (CLLEAR). Patients were treated in one of eight Czech hematological centres between December 2015 and June 2023. Only those who received chemoimmunotherapy in the first-line and Bruton tyrosine kinase inhibitor (BTKi) or Bcl-2 inhibitor (Bcl-2i) in the second-line treatment were included in the study. All patients fulfilled iwCLL diagnostic criteria and had provided informed consent before their data were captured in the CLLEAR. Key CLL-related clinical and laboratory parameters were obtained from the database (Table 1). Ibrutinib and acalabrutinib monotherapy were given at standard doses until disease progression (PD) or unacceptable toxicity. The combination of venetoclax and rituximab (VenR) was administered in the regular dosing schedule for 24 months. Results: Out of 291 patients included in the study, 70.1% (204/291) were treated with ibrutinib, 8.9% (26/291) received acalabrutinib and 20.9% (61/291) VenR. The median age at the start of the second-line treatment was 72.1 and 70.6 years, respectively (BTKi and Bcl-2i). There were no significant differences in sex, clinical stage, CIRS, creatinine clearance and time since diagnosis until the beginning of the second-line treatment. Bendamustine and rituximab followed by fludarabine, cyclophosphamide and rituximab were the most common regimens used in the firs-line treatment. Deletion (del) 17p and/or TP53 mutation, and del 11q were more frequent in the BTKi cohort, while unmutated IGVH gene was detected similarly in both groups (Table 1). Median follow-up was longer in BTKi than in Bcl-2i group (19.2 vs. 11.5 months). The overall response rate (ORR) was evaluated in 191 patients treated with BTKi and in 42 patients treated with Bcl-2i for at least six months. The ORR was comparable between the BTKi and Bcl-2i cohort, 90.6% (173/191) vs. 92.9% (39/42) (p = 0.774). More complete remissions (CR) were seen in Bcl-2i group, 12.0% (23/191) vs. 42.9% (18/42) (p<0.001). Median progression-free survival (mPFS) was 37.4 (31.4 - 43.35) months vs. not reached (BTKi vs Bcl-2i), HR 1.07 (95% CI, 0.59 - 1.94) (p = 0.833, Figure 1). Median overall survival (mOS) was 64.3 (37.2 - 91.5) months vs. not reached (BTKi vs Bcl-2i), HR 1.35 (95% CI 0.70 - 2.63) (p=0.371, Figure 1). Similar results were observed in the subgroup with del17p and/or TP53 mutation (mPFS: 35.6 months vs. not reached, HR 1.80, 95% CI, 0.69 - 4.69), as well as in the subgroup with unmutated IGVH gene (mPFS: 35.6 months vs. not reached, HR 1.36, 95% CI, 0.72 - 2.55). At the time of data analysis, hematological toxicity and infectious complications were premature for comparison (data were assessed in 31.3% of BTKi and 57.4% of Bcl-2i patients). Grade III-IV hypertension and other non-hematological toxicity (excluding infections) prevailed in BTKi cohort (19.2% BTKi, 9.6% Bcl-2i). The median treatment duration of BTKi and Bcl-2i was 14.7 (0.7 - 53.4) and 9.7 (0.3 - 25.8) months, respectively. Early discontinuation was observed more frequently post BTKi compared to post Bcl-2i administration, 43.9% (101/230) vs. 26.2% (16/61) (p<0.001). Except for the progression (24.8% BTKi, 18.8% Bcl-2i), the most common causes leading to premature discontinuation were death (23.8% BTKi, 12.5% Bcl-2i), infection (9.99% BTKi, 37.5% Bcl-2i), and non-hematological toxicity (24.8% BTKi, 6.3% Bcl-2i). Conclusion: In terms of high-risk prognostic markers, a higher prevalence of del 17p and/or TP53 mutation, and del 11q were observed in the BTKi cohort. In contrast, frequency of the unmutated IGVH gene was comparable in both groups. Difference in median PFS and OS was not statistically significant within the current follow-up period. However, premature termination of treatment was more commonly seen in BTKi group. To confirm our primary outcomes, longer follow-up is warranted.

Clinical efficacy and tolerability of venetoclax plus rituximab in patients with relapsed or refractory chronic lymphocytic leukemia—a real-world analysis of the Polish Adult Leukemia Study Group

The results of the MURANO trial showed encouraging progression-free survival (PFS) and overall survival (OS) in relapsed/refractory chronic lymphocytic leukemia (RR-CLL) patients treated with venetoclax-rituximab (VEN-R). A retrospective analysis was performed to evaluate the efficacy and safety of VEN-R within the Polish Adult Leukemia Study Group (PALG) centers. The study group included 117 patients with RR-CLL (with early relapse after immunochemotherapy or bearing TP53 aberrations) treated with VEN-R in 2019–2023 outside clinical trials. Patients were treated with a median of 2 (range 1–9) previous lines of therapy. Twenty-two participants were previously treated with BTKi (18.8% out of 117). The median follow-up was 20.3 months (range 0.27–39.1). The overall response rate (ORR) was 95.3% in the group of patients in whom a response to treatment was assessed and 86.3% for all patients. Twenty patients (17.1% out of 117) achieved a complete response (CR), 81 (69.2%) achieved a partial response (PR), and in 5 patients (4.3%), disease progression was noted (assessed as the best response during treatment). The median PFS in the whole cohort was 36.97 (95% CI 24.5, not reached) months, and the median OS was not reached (95% CI 27.03, not reached). Thirty-six patients died during the follow-up, 10 (8.5%; 27.8% of deaths) due to COVID-19 infection. All grade neutropenia (n = 87/117, 74.4%; grade 3 or higher n = 67/117, 57.3%) was the most common treatment adverse event. Forty-five patients (38.5%) remained on treatment, and twenty-two (18.8%) completed 24 months of therapy, while it was discontinued in fifty cases (42.7%). In this real-world setting of early access in very high-risk RR-CLL patients, the VEN-R regimen was associated with shorter median PFS compared with the results of the MURANO trial. This outcome, however, could be attributed to patients’ exposure to SARS-CoV-2 infection and the aggressive course of the disease as very high-risk patients, after multiple lines of prior therapies, were included in the Polish Ministry of Health reimbursement program.

Real-World Outcomes of Second-Line Chronic Lymphocytic Leukemia Treatments: Retrospective Analysis of the Brazilian Registry of CLL

Introduction: Major advances in the treatment of relapsed-refractory (RR) chronic lymphocytic leukemia (CLL) patients were observed in the last decade with the adoption of targeted agents. While a shift away from chemotherapy is expected, the impact of delayed or unequal access to targeted agents in low- and middle-income countries needs to be uncovered through real-world data. Objective: To assess the clinical outcomes of second-line treatment in RR CLL patients included in the Brazilian Registry of CLL (BRCLL). Patients and Methods: This is an observational study of second-line CLL treatments started between January 2006 and December 2021. BRCLL is a prospective non-interventional data collection tool. All participant centers registered their CLL patients online, after study approval at each center's ethical review board. Diagnosis and staging of included CLL patients were performed in accordance with recommendations from the International Workshop on Chronic Lymphocytic Leukemia (IWCLL). Results: Four hundred and forty-four CLL patients in second-line were included. Median age at start of second-line treatment was 66 years (range: 23-93), and 264 were male (59%). At CLL diagnosis, Binet staging was A in 139 patients (36%), B in 139 (36%), and C in 107 (28%). High beta-2-microglobulin levels at diagnosis were found in 58%, and unmutated IGHV was observed in 61% of patients. At diagnosis, FISH was performed in 166 patients (37%), of which 33 patients had del(17p) (20%). The most commonly prescribed second-line treatments were: FC (+/- R) in 160 patients (36%); chlorambucil (+/- R) in 109 (25%); ibrutinib in 63 (14%); CHOP/CVP (+/- R) in 62 (14%); monoclonal antibodies (+/- steroids) in 33 (7%); allogeneic stem cell transplantation in 9 (2%) and venetoclax in 8 (2%). Forty patients (9%) were treated in clinical trials. Median follow-up after second-line treatment was 34 months (range: 3-176). Median time-to-next treatment (TTNT) was 28 months. TTNT was statistically longer in patients who received second-line with ibrutinib or venetoclax in comparison with FC or chlorambucil +/- anti-CD20 (not reached versus 29 months, p<0.0001) or those who received other regimens (CHOP or CVP +/- anti-CD20, monoclonal antibodies +/- steroids - 12 months, p<0.0001). Higher 3-year treatment-free survival (TFS) was also observed with ibrutinib or venetoclax (69% versus 41% and 23%, respectively, p<0.0001). Among patients included in clinical trials, 3-year TFS was also higher (70% versus 38%, p<0.0001). TFS for patients receiving allogeneic stem cell transplantation was 86% at 3 years. Overall survival (OS) probability at 3 years was 71%. OS was significantly shorter in those who received other regimens (CHOP/CVP-like or monoclonal antibodies +/- steroids - 53%), in comparison with those who received ibrutinib or venetoclax (80%, p<0.0001), or FC/chlorambucil-based chemotherapy (69%, p=0.01). Conclusion: Over the reported period, second-line CLL treatments in Brazil were mostly chemotherapy- or chemoimmunotherapy-based, with unfavorable outcomes associated with CHOP/CVP-like regimens or monoclonal antibodies +/- steroids. While the adoption of targeted therapies was associated with longer TTNT and OS, access to these agents is still very limited in the public setting.

P677: CLINICAL EFFICACY AND TOLERABILITY OF VENETOCLAX PLUS RITUXIMAB IN RELAPSED OR REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA – REAL WORLD ANALYSIS OF POLISH ADULT LEUKEMIA STUDY GROUP

Background: The introduction of venetoclax into clinical practice has improved the outcome of patients with relapsed/refractory chronic lymphocytic leukemia (RR-CLL). The results of the MURANO trial published in March 2018 showed significantly longer progression-free survival (PFS) and overall survival (OS) in RR-CLL patients treated with venetoclax and rituximab (VEN-R) comparing to bendamustine and rituximab (BR) and resulted in the approval of VEN-R in the therapy of RR-CLL in the European Union and the United States. It should be noted that the results of registration studies often do not correspond with the data from real-life observations. Aims: To study the clinical efficacy and safety profile of VEN-R treatment in RR-CLL patients outside clinical trials. Methods: We performed retrospective analysis of RR-CLL patients treated with VEN-R in hematology centers of the Polish Adult Leukemia Study Group (PALG) from 2019 to 2021. Results: Clinical data of 117 RR-CLL patients treated with VEN-R were collected. Median patient age upon initiation of VEN-R therapy was 67 years (range 33 – 84 years). Seventy-two patients (61.5%) were men. Median Cumulative Illness Rating Scale (CIRS) was 6 (range 2 - 16). Patients were treated with a median of 2 (range 1–9) previous lines of therapy, whereas 32 patients (27.4%) had relapsed following the first line of treatment. Overall, 25 patients (21.4%) had 17p deletion, whereas TP53 mutation was identified in 13 patients (11.1%). The median follow-up was 9.96 months (range 0.27 - 29.13). The overall response rate (ORR) was 95.2%. Seventeen patients (14.5%) achieved complete remission (CR), 83 (70.9%) partial remission (PR), while in 5 patients (4.3%) disease progression was noted. In the patients with 17p deletion (n=22) or TP53 mutation (n=11), CR and PR were observed in 4 (12.1%) and 29 (87.9%) patients, respectively. The median PFS in the whole cohort was 20.8 (95% CI 18.43 - not reached) months and the median OS was not reached. In our study none of the analyzed clinico-pathological factors had significant impact on ORR, PFS and OS. During the follow-up time four (3.4%) cases of Richter transformation were diagnosed. There were 18 deaths recorded during the course of observation; 3 (16.7%) due to disease progression and 7 (38.9%) due to COVID-19 infection. The others were due to infections other than SARS-CoV-2 (n=3, 16.7%) and the cause of death could not be specified in five cases (27.8%). Eighty-three patients (70.9%) remain on treatment, while treatment was discontinued in thirty-four cases (29.1%). Reasons for therapy discontinuation included patient’s death (52.9%), treatment-related cytopenias (17.6%), disease progression (14.7%), Richter’s transformation (11.8%), autoimmune hemolytic anemia (5.9%), diarrhea (2.9%) and infections (8.8%). In one case treatment discontinuation was due to consent withdrawal and one patient was lost to follow-up. The following adverse events of VEN-R treatment were reported during the study: all grade neutropenia (71.8% with grade 3/4 in 55.6%), anemia (51.3%), thrombocytopenia (47%), pneumonia (9.4%), neutropenic fever (6.8%), autoimmune hemolytic anemia (4.3%), immune thrombocytopenic purpura (1.7%), diarrhea (4.3%) and in one case exacerbation of heart failure was observed. Summary/Conclusion: In this retrospective analysis the outcomes of treatment with the VEN-R regimen in real-life setting were worse than those reported in the MURANO trial.

Four-year follow-up from a phase 2 study of obinutuzumab, ibrutinib, and venetoclax in CLL.

7540 Background: Targeted agent combinations for chronic lymphocytic leukemia (CLL) have resulted in safe regimens with improved progression-free survival (PFS) compared to chemoimmunotherapy. The optimal regimen and long-term outcomes remain unknown. We conducted a phase 2 study of obinutuzumab (OBIN), ibrutinib (IBR), and venetoclax (VEN) in relapsed/refractory (RR) and treatment-naïve (TN) CLL patients (pts) and report extended follow up on two previously reported cohorts (RR, TN 1) and a new cohort of identically treated TN pts (TN 2). Methods: Pts with TN or RR (≥1 prior treatment) CLL requiring treatment were eligible. Treatment was given for 14 28-day cycles (C). OBIN was started C1, IBR C2, and VEN C3 with standard dose escalation. Response was assessed 2 months (mos) after C14 (EOT) by iwCLL 2008 criteria. Minimal residual disease (MRD) was measured by 10-color flow cytometry with a cutoff of &lt; 1x10-4. The primary endpoint was complete remission (CR) with undetectable MRD (uMRD) in blood and bone marrow at EOT. A sample size of 25 pts per cohort achieves 90% power to test the null hypothesis of 10% against 30% with 1-sided α of 10%. The Kaplan-Meier method was used to estimate PFS and overall survival (OS). Results: 75 pts were treated in 3 cohorts (Table). Data are as of 1/3/2022. In the TN 2 cohort, the overall response rate (ORR) at EOT was 96% (95% CI: 80-100) and CR with uMRD was 20% (95% CI: 7-41). The ORR for TN 1 and TN 2 combined was 90% (95% CI: 78-97) and CR with uMRD was 24% (95% CI: 13-38). Median follow up was 56 (0-65), 57 (7-63), and 30 (24-35) mos, respectively, for RR, TN 1, and TN 2. There were 3 deaths (RR = 1, TN 1 = 1, TN 2 = 1) and 6 disease progressions (RR = 4, TN 1 = 2, TN 2 = 0). Estimated 48-month PFS for TN 1 and RR cohorts were both 96% (95% CI: 72-99) and OS was 85% (95% CI: 60-95) and 100%, respectively. The estimated 24-month PFS and OS for TN 2 were both 96% (95% CI: 75-99). The most frequent adverse events were neutropenia (95%, 73% grade ≥3), leukopenia (95%, 45% grade ≥3), lymphopenia (93%, 40% grade ≥3), and thrombocytopenia (91%, 28% grade ≥3). The only grade ≥3 non-hematologic toxicity occurring at ≥20% was hypertension (85%, 39% grade ≥3). Atrial fibrillation occurred in 11% of pts. Conclusions: At extended follow-up, remissions remain durable after fixed duration OBIN, IBR, and VEN. The efficacy and acceptable safety justify further study and are being compared to IBR and OBIN in 2 phase 3 US cooperative group trials. Clinical trial information: NCT02427451. [Table: see text]

Outcomes with Chimeric Antigen Receptor T-Cell Therapy in Relapsed/Refractory Chronic Lymphocytic Leukemia: A Systematic Review and Meta-Analysis

Background:Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults in the United States. Despite the advancements in the treatment of CLL, relapsed/refractory CLL (RR-CLL) cases are still associated with poor prognosis. Anti-CD19 chimeric antigen receptor T cell (CAR-T) therapy has shown promising initial responses in patients with RR-CLL. We present a systematic review and meta-analysis to investigate the outcomes with CAR-T cell therapy in RR-CLL patients.Methods:Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, 196 articles were searched from 3 databases (PubMed, Cochrane Register of Controlled Trials, and clinicaltrials.gov) using MeSH terms and keywords for “CLL” AND “CAR-T” and “Antigen CD19” OR “adoptive immunotherapy” from the date of inception to March 2021. Studies were screened by title, abstract, and full text. Original studies reporting adult patients with RR-CLL who received CD19 CAR-T therapy as the only intervention were included while reviews, duplicate, and non-relevant articles were excluded. A total of 5 studies (clinical trials) were included and the following outcomes were extracted: complete remission (CR), partial response (PR), overall response rate (ORR), overall survival (OS), progression-free survival (PFS), progressive disease (PD), cytokine release syndrome (CRS) and neurotoxicity (NT). The Joanna Briggs Institute (JBI) critical appraisal checklist for studies reporting prevalence data and randomized control trials was used for quality assessment, and all studies were reported as good. The variance between the studies was calculated using Der Simonian-Laird Estimator. Proportions along with a 95% confidence interval (CI) were extracted to compute pooled analysis using the ‘meta’ package by Schwarzer et al. in the R programming language (version 4.16-2).Results:We included 137 patients from 5 studies. Out of these, a total of 110 patients were evaluated for efficacy and 116 for safety. (Table 1) Median age of the patients was 64 (40-79) years. Seventy-six percent were males as reported by 3 studies. Median number of prior therapies was 4.7 (1-11) and median follow up time was 16 (2-75) months. The pooled analysis showed a CR and PR of 28% (95 % CI 0.19-0.38, I 2=14%, n=110) and 38% (95% CI 0.21-0.57, I 2=72%, n=110) respectively with an ORR of 68% (95% CI 0.51-0.83, I 2=67%, n=110). The pooled prevalence of PD was 21% (95% CI 0.03-0.48, p= <0.01, I 2= 88%, n=110). PFS ranged from 1 month to 40.2 months as reported by 3 studies. OS ranged from 29 months to 64 months as reported by 2 studies. The pooled incidence of Grade I-II and Grade III-IV CRS was 56% (95% CI 0.32-0.79, I 2=80%, n=88) and 14% (95% CI 0.28-0.31, I 2=76%, n=110) respectively. The pooled incidence of grade I-II and grade III-IV NT was 12% (95% CI 0.15-0.29, I 2=72%, n=88) and 17.5% (95% CI 0.98-0.26, I 2=19%, n=110) respectively.Conclusion:CD19 CAR-T cell therapy shows favorable response rates in patients with RR-CLL who have failed multiple prior therapies with an acceptable safety profile. However, it is imperative that large prospective studies should be conducted to confirm these findings. [Display omitted] DisclosuresMcGuirk: Gamida Cell: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Bellicum Pharmaceuticals: Research Funding; Astelllas Pharma: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Pluristem Therapeutics: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding; EcoR1 Capital: Consultancy.

PCN121 A Systematic Literature Review of Pharmacoeconomic Evaluations for Chronic Lymphocytic Leukemia in Europe

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults. This study aims to review pharmacoeconomic evaluations of CLL treatments in Europe. A systematic literature review was conducted using MEDLINE and EMBASE to identify pharmacoeconomic models evaluating CLL treatments. Studies (including conference abstracts) published 2015-2020 in English were included. Data extracted included countries, interventions, data sources, outcomes, and results. A total of 721 publications were reviewed. There were 21 cost-effectiveness/cost-utility analysis studies (10 manuscripts, 11 abstracts) with 49 separate analyses evaluating cost per life-year (LY) (n=21) or quality-adjusted life-year (QALY) (n=47) involving chemotherapies and newer target therapies. The majority (76%) were industry-sponsored, 7 studies were in the United Kingdom, 2 studies in Portugal, 2 studies in Spain and the rest in 10 other European countries. Markov models were utilized in 12 studies, partition-survival models in 7 studies, and decision-analytic models in 3 studies. For model input, clinical data were from trials and network meta-analyses while utility data were sourced from time trade-off studies to clinical trial patient-reported outcomes. Economic and resource utilization data were mostly from government sources. Study population focused on various CLL populations including first-line only (n=2), relapsed-refractory CLL (n=9), and CLL unsuitable/unable to tolerate fludarabine (n=9). ICERs ranged from €9,445 to €83,435 (€/LY) and €1,263 to €130,563 (€/QALY). There were 4 other studies evaluating budget impact (n=2) or cost comparison/minimization (n=2) in Russia, Portugal, and the Czech Republic. Budget impact ranged from €1.1m (year 1) to €7.2m (year 5) for ibrutinib in the Czech Republic and €22,200 (year 1) to €66,900 (year 5) for ibrutinib + obinutuzumab in Russia. Recently published pharmacoeconomic analyses in Europe evaluated various treatments for CLL patient populations across 14 different countries. Future economic analyses on recent CLL treatments in more European countries are warranted.

Final Results of a Phase II Study of Fc Engineered, CD19 Antibody Tafasitamab in Combination with Lenalidomide or Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL)

Final Results of a Phase II Study of Fc Engineered, CD19 Antibody Tafasitamab in Combination with Lenalidomide or Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL)

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

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

Continuous Clinical Remisssion with High MRD Negativity and High PB and BM MRD Concordance during Venetoclax Monotherapy in R/R CLL Patients

Introduction Venetoclax, a novel BCL2 inhibitor, used either as monotherapy or in combinations, induces rapid disease control , with durable clinical remissions, especially in patients with deep responses. In the Venetoclax era, minimal residual disease(MRD) is a new endpoint in CLL studies. MRD negativity is associated with better clinical outcomes (Jain N, et al. ASH 2019, abstract 186, Tam CS, et al. ASH 2019, abstract 642). Aim We present our single-center MRD data from a cohort of patients with relapsed/refractory(RR) CLL, treated with venetoclax monotherapy. Patients and Methods We collected data from 24 R/R CLL patients who have been treated with venetoclax monotherapy until progression, in the context of VENICE-1 study (NCT02756611) in our department between 11/2016 and 1/2018. MRD was locally evaluated with 10-colour flow cytometry(FC) according to ERIC guidelines, with the cut off of &amp;lt;10-4 (&amp;lt;0.01%) as negative, &amp;gt;10-4-&amp;lt;10-2 (&amp;gt;0.01%-&amp;lt;1%) as low-positive and &amp;gt;10-2 (&amp;gt;1%) cut off as high-positive. Peripheral blood(PB) MRD was assessed every 3-6 months. At week48 (1 year), CT scans were performed for response assessment. Bone marrow (BM) biopsy and BM MRD at week48 were also performed in pts with CT confirmed CR. Results Between 11/2016 and 1/2018, 24 patients started treatment with venetoclax monotherapy. Our patients' baseline characteristics are shown in table 1. Disease responses and patients' treatment status as of end-July 2020 are shown in table 2. Progression free survival(PFS) and overall survival at 34 months is estimated 91.6% and 87.5% respectively. Four patients (16.7%) had to reduce their daily Venetoclax dose due to hematological toxicity: 2 to 300mg due to neutropenia and 2 to 200 and 100mg due to thrombocytopenia. MRD results at week 48 are shown in table 3. Sixteen patients have paired PB and BM MRD results (15 at week 48 and 1 at week 24) with 87.5% concordance (14 patients). In seven MRD negative patients MRD conversion (2 consecutive samples) was observed, after a median time of 16 m(6-28): six patients to low-positive and one to high-positive. The high-positive MRD-converted patient presented clinical relapse at the 2nd high-MRD positive sample, according to iwCLL criteria. One of 6 low-positive MRD-converted patients, became MRD negative again at a later time-point. Conclusion Our single-center data from 24 CLL patients enrolled in the Venice-1 study reveal high concordance of PB and BM MRD at week48. Higher PB MRD negativity rate at week 48 is observed (79.2%) in comparison to Venice trial (Kater A, et al. EHA 2020, S156) due to differences in MRD methodology/number of evaluable patients. Our FC MRD data show that MRD conversion from negative to low-positive may be observed during continuous Venetoclax treatment, without clinical disease progression. This observation, along with high PFS at 34 months (91.5%) confirms the importance of continuing Venetoclax therapy in RR CLL patients when given as monotherapy. Disclosures Kyrtsonis: Genesis pharma SA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Panayiotidis:Genesis: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Janssen: Honoraria; Gilead: Honoraria; Takeda: Honoraria; Phizer: Honoraria; ASH: Honoraria.

Clinical activity of cirmtuzumab, an anti-ROR1 antibody, in combination with ibrutinib: Interim results of a phase Ib/II study in mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL).

8036 Background: ROR1 is an onco-embryonic tyrosine kinase receptor that is re-expressed at high levels on many hematologic and solid cancers but not on normal adult tissues. ROR1 binds Wnt5a, resulting in increased tumor growth and survival, cancer cell stemness and epithelial mesenchymal transition. Cirmtuzumab (Cirm) is a humanized monoclonal antibody designed to inhibit the tumor promoting activity of ROR1. In this study, we examined the safety and efficacy of Cirm in combination with ibrutinib (Ibr) in MCL or CLL. Methods: As of Jan 29, 2020, 12 pts with relapsed refractory (RR) MCL were enrolled into Part 1 Dose Escalation (DE). All MCL pts had stage 3/ 4 at original diagnosis, 25% had bulky tumor at study entry, 58% had intermediate/high risk MIPI scores and the majority (83%) had ≥ 2 prior regimens. 34 pts with CLL [12 treatment naïve (TN) and 22 RR pts] enrolled into Part 1 DE (n = 18) or Part 2 Expansion (n = 16). At least 79% of CLL pts were high risk as determined by unmutated IGHV, 17p/p53 loss, and/or del 11q. DE pts received Cirm IV q2wks x 3-5 doses then q4wks plus Ibr (starting D28). Following DE, Cirm 600mg IV q2wks x3 then q4wks plus Ibr (420mg/day CLL or 560mg/day MCL) was chosen for Expansion. Results: Safety : only grade 1/ 2 AEs were reported as possibly related to Cirm alone, whereas the safety profile attributed to Ibr or Ibr / Cirm was similar to published data, with no new or unexpected events. Efficacy for MCL: 83% ORR, 33% (4) CR, 50% (6) PR, 17% (2) SD. CRs were achieved at a median of 3.6 mos in heavily pretreated pts, including 2 with bulky disease &gt; 5cm. Prior therapy of the 4 CR pts: 2 pts failed R-Ibr (7-10 mos) and R-hyperCVAD, 1 pt, auto-SCT and allo-SCT, 1 pt, auto-SCT and CAR-T. Efficacy for CLL : 88% ORR (92% TN, 86% RR), 3% (1) CR, 85% (22) PR/ (7) PR-L, 12% (4) SD. In addition, 3 PR pts with CLL met criteria for “Clinical CR, bone marrow biopsy not performed”. The pt achieving a CR had RR disease with del 11q; this pt remains in remission &gt; 6 mos after stopping all therapy. At a median follow-up of 9.9 mos, 100% of CLL pts are free of disease progression and &gt; 82% remain on study. Conclusions: Cirm in combination with Ibr is a well-tolerated and active regimen for RR MCL and TN or RR CLL. In this evaluation of 46 pts, the ORR and PFS continue to improve with longer follow-up and additional pts, supporting continued investigation of this regimen in ROR1 expressing tumors. This study is ongoing and enrolling an Expansion arm for MCL pts and an open-label randomized Phase 2 in CLL pts comparing Ibr alone to Cirm /Ibr. Clinical trial information: NCT03088878 .

Efficacy and Toxicity of Lenalidomide for Treatment of Chronic Lymphocytic Leukemia: A Systematic Review and Meta-Analysis

Background: During last decade, several therapeutic options have emerged for newly diagnosed (ND) or relapsed / refractory (RR) patients with chronic lymphocytic leukemia (CLL). Lenalidomide (Lena) has immunomodulatory, anti-angiogenic and antitumor activity. Lena is showing antitumor activity against CLL with durable responses.The main aim of our analysis is to study the published literature on the efficacy and safety of Lena based regimens in patients with ND and RR CLL. Methods: We performed the literature search (10/5/2019) using following databases (PubMed, Embase, Cochrane Library, Web of Science, and Clinical trials.gov) identified a total of 4835 articles. Following PRISMA guidelines, we selected twenty articles (Phase I/II/III) with a total of 1309 patients (pts) in which eleven articles (n= 914) were about ND CLL pts and nine articles (n=396) had pts with RR CLL. CMA software v.3 was used for meta-analysis. Results: Lenalidomide based regimens in previously untreated CLL Based on the pooled analysis,(table 1)(an overall response rate (ORR) of 59.9% (95% CI: 55.4-64.2) with complete response (CR) of 17.6% (95% CI: 8.9-31.8) is observed in previously untreated CLL and ORR of 57.6% (95% CI: 50.4-64.4) with a CR of 12.9% (95% CI: 7.7-20.8) in RR CLL were calculated. Most common grade (G) ≥3 adverse events (AE's) based on regimen were calculated using pooled analysis in CLL pts and results are given intable2. Lena in single drug regimen: Three studies (n=445) evaluated the efficacy of Lena as single agent (5mg-25mg). Subgroup pooled analysis showed an ORR of 56.4% (95% CI: 51.6-61) with CR of 7.3% (95% CI: 4.4-11.3). Pooled analysis for safety profile on most common G ≥3 AE's were neutropenia 72.2% (95% CI: 45.1-89.2), thrombocytopenia (tcp) 29.7% (95% CI: 9.1-64), anemia 0.8% (95% CI: 0.1-11.1), fatigue 3% (95% CI: 1.5-5.8) and infections 5% (95% CI: 1.22-18.7). Lena in two drug regimen: One study (n=69) evaluated the efficacy of Lenaas double regimen with ofatumumab. Sub-group pooled analysis showed an ORR of 88% (95% CI: 78-93.8) with CR of 16% (95% CI: 9.1-26.6). Best response was seen when Lena was used with Ofatumumab, with reported ORR of 71%. Pooled analysis for safety profile on most common G ≥3 AE's were neutropenia 58% (95% CI: 46.1-69), anemia 10% (95% CI: 4.8-19.6), tcp 3% (95% CI: 0.8-11) and fatigue 6% (95% CI: 2.3-14.7). Lena in three drug regimen: For six studies (n=375), a pooled analysis on Lena as three drug regimen calculated an ORR of 59.2% (95% CI: 45.2-86) with CR of 24.1% (95% CI: 18.5-30.7). Pooled analysis for safety profile on most common G ≥3 AE's were neutropenia 55% (95% CI: 28.4-79.1), tcp 17.6% (95% CI: 6.1-41.3), anemia 13.9% (95% CI: 4.2-37.5), fatigue 29.1% (95% CI: 0.8-95.6) and infection 10.4% (95% CI: 5.6-18.5). Lena in four drug combination regimen: One study (n=25) evaluated Lena in quadruple regimen (Lena, rituximab, cyclophosphamide and fludarbine) with ORR of 98.1% (95% CI: 75.6-99.9) with CR 75% (95% CI: 54.8-88.1). Pooled analysis for common AE's were neutropenia of 51.6% (95% CI: 37.7-70), tcp of 1.6% (95% CI: 0.1-27), anemia of 1.6% (95% CI: 0-27) and infections of 3% (95% CI: 0.3-23.5) Lena based regimens in Relapsed or Refractory (RR) CLL Nine studies ( n=396)(table 1) evaluated the efficacy of Lena in RR CLL and have given promising results in these pts. Three studies (n=209) evaluated the efficacy of Lena as single agent, pooled analysis (95% CI) on Lena as mono measured an ORR of 32.7% (95% CI: 15.1-57)(fig. 1) with CR of 8.8% (95% CI: 3.1-22.8). Similarly subgroup pooled analysis for double regimen which includes four studies (n=139) measured ORR of 63.2% (95% CI: 54.4- 71.3) with CR of 14% (95% CI: 5.7-30.4). Two studies (n=56) evaluated Lena as triple regimen, an ORR of 52.5% (95% CI: 39.5-65.2) with CR of 21% (95% CI: 10.4-37.8) was calculated. Pooled analysis (95% CI) common G ≥3 AE's are neutropenia 69.9% (62.8-76.2), tcp 26.5% (18.4-36.5), anemia 9.4% (6.4-13.5), infections 29.4% (10.7-59) and fatigue 14.6% (6.2-30.6)(table 2) Conclusion: Lenalidomide is highly efficacious when used for treatment of previously untreated or RR CLL. Regimen efficacy is greater in untreated CLL compared to RR CLL. Four drug Lena based combination regimen showed the best result with an ORR of 98.1% (95%CI: 75.6-99.9). Large prospective studies are required to evaluate efficacy and safety of Lena in newer combination regimens. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Partial Reconstitution of Humoral and Cellular Immunity in Patients with Chronic Lymphocytic Leukemia Treated with Acalabrutinib

IntroductionImmune dysregulation in chronic lymphocytic leukemia (CLL) contributes to a high rate of infections and morbidity. We previously reported that treatment of CLL with ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, leads to partial reconstitution of humoral immunity and fewer infections, especially in patients who achieved a ≥50% increase in serum IgA levels. Acalabrutinib is also an irreversible BTK inhibitor that is more selective than ibrutinib and has demonstrated safety and efficacy in the treatment of relapsed or refractory CLL. It is currently unclear how the increased specificity of acalabrutinib affects immune reconstitution and infection rates. We assessed the immunological impact of acalabrutinib in patients with CLL treated with single-agent acalabrutinib.MethodsSamples originated from a phase 2, single-center trial studying acalabrutinib 100 mg twice daily (BID) or acalabrutinib 200 mg once daily (QD) in patients with relapsed/refractory (RR) CLL or high-risk, treatment naïve (TN) CLL (chromosome 17p deletion or mutation in TP53 or NOTCH1) (NCT02337829). Patients who received at least 6 months of acalabrutinib and had paired longitudinal data available were included in the analyses. Patients receiving IV immunoglobulin replacement were excluded from analysis of IgG levels. Additionally, patients with detectable monoclonal IgG, IgA and/or IgM proteins on serum immunofixation were excluded from analysis of the corresponding immunoglobulin isotype. The analysis of free light chains was stratified based on k or λ restriction of CLL cells determined by flow cytometry. Immunohistochemical staining of bone marrow biopsies was performed: T cell numbers were estimated by CD3 staining and the degree of CD68-positive macrophage extensions in contact with CLL cells were semi-quantitatively assessed on a scale from 0 (no extensions) to 4 (maximum number of extensions). The Wilcoxon signed-rank test and the Mann-Whitney U test were used to compare paired and unpaired data, respectively. Differences in the rate of infection between groups were examined using the Cox regression model for recurrent events.ResultsSerum IgA levels increased as early as 3 months after the initiation of acalabrutinib (median increase 35.7%, P = .0001), with levels sustained up to 24 months (Figure 1), whereas serum IgG and IgM levels were not affected by acalabrutinib. There was no difference (P > .05) in IgA, IgG, IgM trend between TN or RR CLL. Furthermore, there was no difference (P > .05) in IgA, IgG and IgM trends between patients treated with QD compared to BID dosing of acalabrutinib. Among 20 k-restricted and 18 λ-restricted CLL cases, the involved (tumor-derived) free light chain was elevated at baseline and trended toward the normal range after 3 months of acalabrutinib therapy consistent with an anti-tumor effect (k: median decrease 55.4%; P < .0001 and λ: median decrease 49.1%; P = .0003). The uninvolved free light chain did not change (P > .05). Peripheral blood CD3+, CD4+ and CD8+ T cell counts were elevated above the laboratory reference range at baseline and normalized after 6 months (CD4+ median decrease 49.2%; P = .0074 and CD8+ median decrease 54.8%; P = .003). T cell numbers in the bone marrow did not appreciably change. However, treatment-induced changes of the immune microenvironment were apparent in tumor-macrophage interactions. At baseline, macrophages tightly interacted with CLL cells, often with multiple podocytes making contact with CLL cells. On acalabrutinib, we observed a decrease in these macrophage podocyte interactions (P = .0007). At a median follow-up of 20 months, 31 (68.9%) patients developed a total of 68 infections, including 7 (10.3%) grade 3 and 1 (1.5%) grade 4 infections. Patients with superior immune reconstitution, as defined by an increase in serum IgA of ≥ a median of 36% from baseline to 3 months, had a significantly lower rate of infections (risk ratio = 0.52, P = 0.029).ConclusionsThese data indicate that acalabrutinib allows for partial reconstitution of humoral and cell-mediated immunity and disrupts macrophage-CLL cell interaction in the bone marrow microenvironment in patients with CLL. Furthermore, acalabrutinib did not interfere with uninvolved free light chains, suggesting that acalabrutinib selectively inhibits CLL B-cells and does not impair normal B-cell function. [Display omitted] DisclosuresIzumi:Acerta Pharma: Employment, Equity Ownership, Patents & Royalties: Acerta Pharma, various patents for ACP-196. Hamdy:Acerta Pharma: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Acerta Pharma, various patents for ACP-196. Wiestner:Pharmacyclics LLC, an AbbVie Company: Research Funding.

Development of Cirmtuzumab Antibody-Drug Conjugates (ADCs) Targeting Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1)

ROR1 is an onco-embryonic surface antigen expressed on chronic lymphocytic leukemia (CLL) and a variety of other cancers, but not on most normal adult tissues. We generated a humanized IgG1 monoclonal antibody (mAb) cirmtuzumab (formerly UC-961) that binds with high affinity to a specific extracellular epitope of human ROR1 and that can block Wnt5a-induced ROR1 signaling (Yu, J et al, J Clin Invest126:585, 2016; Yu, J et al, Leukemia31:1333, 2017). Preclinical studies found that cirmtuzumab did not react with normal post-partem cells and had a pharmacokinetic (PK) volume distribution in primates consistent with a lack of off-target binding to normal tissues. We evaluated cirmtuzumab in a phase I clinical trial involving patients with relapsed-refractory CLL (Choi MY, et al, Cell Stem Cell22:951, 2018); the drug was well-tolerated at doses ≤20 mg/kg (highest dose tested) without dose-limiting toxicity. PK studies showed cirmtuzumab had a half-life of 32.4 days with no evidence for development of neutralizing antibodies or off-target sequestration of infused antibody. Furthermore, cirmtuzumab effected partial down-modulation of leukemia-cell ROR1 in patients treated with doses ≥2 mg/kg. In vitro confocal microscopy studies showed that this down-modulation was caused by internalization of cirmtuzumab-ROR1 complexes into lysosomal compartments and concomitant steady-state re-expression of nascent surface ROR1. Because of its high specificity, in vivo stability, long serum half-life, and potential capacity to concentrate conjugated drugs into lysosomal compartments, cirmtuzumab appeared ideally suited to serve as the targeting moiety in anti-ROR1 ADCs. We therefore examined cirmtuzumab-based ADCs in collaboration with VelosBio Inc., evaluating multiple linker/payload chemistries, both as single agents and in combinations. We selected for further testing cirmtuzumab-ADC-7, a cirmtuzumab-linker-monomethyl auristatin E (MMAE) ADC that preserves the high-affinity binding specificity of cirmtuzumab and allows for ROR1-targeted intracellular release of MMAE. We found cirmtuzumab-ADC-7 was selectively cytotoxic for ROR1+ CLL and mantle-cell lymphoma (MCL) cell lines at nM concentrations in vitro. Moreover, cirmtuzumab-ADC-7 caused dramatic and sustained in vivo clearance of adoptively-transferred ROR1+ leukemia cells generated from ROR1xTCL1 transgenic mice (Widhopf G, et al, PNAS111:793, 2014), ROR1+ MCL-xenografts, or ROR1+ cancer patient-derived xenografts (PDX). Further, treatment caused dose-dependent and statistically significant decreases in total cancer burden with complete regressions of tumor in multiple animals; no effect on tumor-clearance was observed in mice treated with a control MMAE-ADC of irrelevant specificity. Recently we identified that miR-15a/16-1, which commonly are deleted/downregulated in CLL, target both BCL2 and ROR1, thereby accounting in part for the direct relationship we observed between the levels of BCL2 and levels of surface ROR1 expressed by CLL of different patients (Rassenti, LZ, et al,PNAS114:10731, 2017). Because high level expression of BCL2/ROR1 may mitigate the cytotoxic activity of the BCL2-antagonist venetoclax, but potentially enhance the cytotoxicity of cirmtuzumab-ADC-7, we treated ROR1+ leukemia/lymphoma cell lines with venetoclax and/or cirmtuzumab-ADC-7. Chou-Talalay combination indices were <0.5 in all ROR1+ cell lines tested, indicating strong antitumor synergy with these two agents. Collectively these data support the rationale for clinical development of a cirmtuzumab-based ADC for treatment of patients with ROR1+ malignancies. DisclosuresVo:VelosBio: Employment. Jessen:VelosBio: Employment. Kipps:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Verastem: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Research Funding; Genentech Inc: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Phase 2 Study of Combination Obinutuzumab, Ibrutinib, and Venetoclax in Treatment-Naive and Relapsed/Refractory Chronic Lymphocytic Leukemia

BACKGROUNDDevelopment of targeted therapies for CLL including the anti-CD20 monoclonal antibody obinutuzumab (OBIN), Bruton's tyrosine kinase inhibitor ibrutinib (IBR), and Bcl-2 inhibitor venetoclax (VEN) have demonstrated significant clinical activity in CLL. As they have high response rates as single agents, largely non-overlapping toxicities, and distinct and potentially synergistic mechanisms of action, we designed and initiated a triplet regimen with OBIN, IBR, and VEN for a fixed duration of treatment. The goal of the regimen is to achieve deep remissions and facilitate treatment discontinuation. The previously reported phase 1b cohort on this study established VEN 400 mg daily as the recommended dose for use with the label doses of OBIN and IRB in this combination. To determine response rates, eradication of minimal residual disease (MRD), and progression-free survival (PFS) in relapsed/refractory (RR) and treatment-naïve (TN) CLL with this regimen, two separate cohorts were accrued to a phase 2 trial.METHODSPatients with RR or TN CLL requiring therapy were eligible. Patients were required to have ECOG PS ≤1 and preserved end-organ function, including normal serum creatinine or creatinine clearance ≥50 mL/min/m2. RR patients had to have ≥1 prior CLL therapy. Treatment was given at the doses and schedule established in the preceding phase 1b study (Jones ASH 2016) for 14 cycles (C) of 28 days with OBIN, IBR, and VEN started sequentially over the first 3 cycles. Risk for tumor lysis syndrome (TLS) with VEN was assessed according to US prescribing information with monitoring instituted according to risk. Adverse events (AEs) were assessed and graded using the NCI CTCAE v4.03 except hematologic AEs which were graded according to the IWCLL 2008 guidelines. Response was determined according to IWCLL 2008 criteria after C8 (mid-therapy) and 2 months after completing C14 (EOT). MRD was measured in the bone marrow and peripheral blood by standard 10-color flow cytometry at these time points. The primary endpoint was MRD negative complete response at EOT. For each cohort, 25 patients provided at least 90% power to detect an increase in MRD negative complete response rate from 10% to 30% using a single stage design and constraining type I error rate to 10%. Herein, toxicity and mid-therapy responses are presented.RESULTSThe study enrolled a total of 50 patients with 25 RR and 25 TN in separate cohorts. Baseline characteristics are in Table 1. The adverse event (AE) profile was similar to the phase 1b study and consistent with the known toxicities of the included individual agents. Frequent treatment-related AEs are found in Table 2. Hematologic toxicity was most frequent with the majority of patients experiencing thrombocytopenia (80%) and/or neutropenia (76%). The most frequent non-hematologic toxicities were hypertension (70%), infusion related reactions (66%), bruising (52%), myalgia (50%), and nausea (50%). Grade 3-4 toxicities were largely hematologic with 56% experiencing grade 3-4 neutropenia and 34% grade 3-4 thrombocytopenia. The only frequently occurring non-hematologic grade 3-4 toxicity was hypertension (32%).The median follow-up for the study was 18.0 months (range 0-24.8) for the RR cohort and 20.6 months (range 7.4-23.9) for the TN cohort. At mid-therapy assessment 23/25 of the RR patients remained on study and all had achieved a response. Three patients achieved CR, 3 a CR with incomplete marrow recovery, and 17 a partial remission. The ORR in RR patients at mid-therapy was 92% (95% CI: 74-99%). Twenty-three (92%) RR patients tested for mid-therapy MRD, with 16 (70%) MRD negative in both the blood and marrow. Two patients had MRD in the blood only, 2 in the marrow only, and 3 in both the blood and the marrow. Mid-therapy responses for the TN cohort have previously been reported (Rogers ASH 2017). To date in 21 (84%) TN patients completed treatment through C14 and 23 (92%) RR remain on study with 21 completing treatment. No patients in either cohort had progressive disease. There was one death from neutropenia and colitis in a TN patient.CONCLUSIONSOBIN, IBR, and VEN in combination have a tolerable safety profile in both RR and TN CLL patients with the majority of toxicities being hematologic. This regimen has a high mid-therapy response rate (92%) in RR patients with early MRD negative responses. EOT responses in TN and RR patients will be presented at the meeting. DisclosuresMaddocks:Teva: Honoraria; AstraZeneca: Honoraria; Pharmacyclics/Janssen: Honoraria; Novartis: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; BMS: Research Funding. Jones:Celgene: Employment, Equity Ownership.

Cost of Illness of Japanese Patients with Chronic Lymphocytic Leukemia (CLL), and Budget Impact of the Market Introduction of Ibrutinib.

BackgroundIbrutinib was introduced in Japan in 2016 as a new oral treatment option for patients with relapsed/refractory (RR) chronic lymphocytic leukemia (CLL). There is increasing interest from the Japanese government to assess economic aspects of new medical interventions, especially in the area of oncology.ObjectiveWe describe the treatment patterns of Japanese patients with CLL, estimate the cost of the disease from a health insurance perspective, and predict the budget impact of the introduction of ibrutinib.MethodsA budget impact model was set up and populated with data that were collected from a survey of Japanese hematologists (n = 202) and official statistics. Uncertainty was addressed by one-way sensitivity analysis of several model parameters.ResultsAmong the 2000 Japanese CLL patients, 42.2% have not yet commenced medical treatment, 29.1% were on a treatment break, and 26.8% received medical treatment, mainly rituximab in combination with either fludarabine or bendamustine. Among the patients under medical treatment, 65.7% were receiving first-line treatment and 34.3% were receiving second-line or later treatment. In Japan, the estimated burden of illness for 2015 was ¥1563 million for RR CLL and ¥5471 million for overall CLL. The expected average budget impact of introducing ibrutinib is ¥3077 million per year for the next 5 years.ConclusionDue to low disease prevalence, the burden of illness in Japan is low compared with Western countries.Electronic supplementary materialThe online version of this article (doi:10.1007/s41669-017-0024-5) contains supplementary material, which is available to authorized users.

Updated Analysis of Overall Survival in Randomized Phase III Study of Idelalisib in Combination with Bendamustine and Rituximab in Patients with Relapsed/Refractory CLL

Updated Analysis of Overall Survival in Randomized Phase III Study of Idelalisib in Combination with Bendamustine and Rituximab in Patients with Relapsed/Refractory CLL

A Phase Ib/II Study of Combined Obinutuzumab (Gazyva) and High-Dose Methylprednisolone (HDMP) As Treatment for Patients with Chronic Lymphocytic Leukemia (CLL)

High-dose methylprednisolone (HDMP) and rituximab (R) is an effective non-myelosuppressive treatment regimen for patients (pts) with chronic lymphocytic leukemia (CLL). Also, this combination has shown activity even in pts who have adverse leukemia-cytogenetics, such as del17p. Phase III studies have demonstrated that CLL pts treated with chlorambucil and obinutuzumab-Gazyva (G), another anti-CD20 mAb, had a superior outcome than comparable pts treated with R-chlorambucil. We hypothesized that G-HDMP is well-tolerated and effective in the treatment of pts with CLL. Accordingly, we initiated an open-label phase Ib/II clinical study.A total of 40 pts were enrolled in two cohorts of 20 pts each (previously untreated (PU) and relapsed/refractory (RR) CLL) and treated with HDMP 1 g/m2on Day 1-3 of cycles 1-4 (28 days/cycle) and G administered based on FDA dosing recommendations for 6 cycles.The pts had a median age of 67 years + 9.1 in the RR cohort and 63 years + 8.3 in the PU cohort. The median baseline absolute lymphocyte count was 30.7 + 7.3 x1,000/mm3 for pts in the RR cohort and 47.6 + 19.7 x1,000/mm3for pts in the PU cohort. Pts showed the following cytogenetic abnormalities: del(17p) in 30% RR vs. 0% PU, del(13q) in 60% RR vs. 70% PU, del(11q) in 20% RR vs. 35% PU, and trisomy 12 in 15% RR vs. 20% PU. Most AEs were grade 1-2 (RR=87%; PU=93%) without development of dose-limiting toxicities. Only two pts needed therapy discontinuation. One pt due to pulmonary embolism and the second pt due to asymptomatic gastrointestinal bleeding that required blood transfusion and resolved spontaneously. Grade 1-2 G-infusion-related reactions (IRR) were observed in 40% and 80% of pts in the RR and PU cohorts, respectively. Grade 3-4 IRR were observed in 10% of pts in the PU cohort only.We observed cytopenias (neutropenia grade 3-4: RR=55%, PU=40%; thrombocytopenia grade 3-4: RR=35%, PU=20%; and anemia grade 3-4: RR=0%, PU=0%). There were no cases of febrile neutropenia. Two pts (10%) in the RR cohort and one pt (5%) in the PU cohort developed infection grade 1-2 that was treated with oral antibiotics but did not require study treatment discontinuation. The most frequent non-hematological adverse events (AEs) were transaminitis, hyperglycemia, and electrolyte alterations (grade 1-2). There were no treatment related deaths in either cohort.The response assessment was performed in all 40 pts by iwCLL criteria. The ORR was 100% in the PU cohort and 95% in the RR cohort. 70% of the pts in the PU cohort and 85% of the pts in the RR cohort achieved a PR. CR was observed in 30% and 10% of the pts in the PU and RR cohorts, respectively. One pt (5%) in the RR cohort and four pts (20%) in the PU cohort achieved MRDneg status (<0.01% CLL in the bone marrow by multiparameter flow cytometry). Only one pt in the RR cohort achieved SD.At a median follow-up of 12.2 months, the RR cohort had a median Progression Free Survival (PFS) of 13.6 months and median Treatment Free Survival (TFS) of 14.7 months; the median Overall Survival (OS) has not been reached. In the PU cohort, the median PFS, TFS and OS have not been reached. One pt from the RR cohort and one pt from the PU cohort died during the follow-up period due to disease progression.G-HDMP was well tolerated and all 40 pts showed hematological and clinical responses during the study treatment without development of unexpected AEs. In both cohorts, most of IRR were grade 1-2 and severe IRR (grade 3-4) were much less compared with previously published data (G-chlorambucil / CLL-11 study). Compared to pts in the CLL-11 study, cytopenias appeared to be more frequent, however, the rate of infection and need for IV antibiotics or hospitalizations was lower. Of note, the eligibility criteria allowed pts with severe cytopenias and transfusion requirement to participate in our study. Response in PU pts were higher in terms of ORR, CR and CR-MRDnegativecompared with the data from the CLL-11 study and suggests a possible synergistic activity between G and HDMP.Overall, G-HDMP was well tolerated in the PU and RR CLL pts with a lower rate of IRR making this regimen more manageable in the outpatient setting. Responses were higher than previously reported in PU pts. Responses in RR pts appear to be comparable to our previous studies using R-HDMP. Our data supports G-HDMP as an alternative combination regimen for the treatment of CLL pts. DisclosuresKipps:Celgene: Consultancy, Honoraria, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria.

Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib

AbstractIbrutinib is a Bruton tyrosine kinase inhibitor approved for the treatment of patients with relapsed refractory chronic lymphocytic leukemia (RR-CLL). We describe the characteristics, causes of discontinuation, and outcomes in patients who discontinued treatment with ibrutinib. One hundred twenty-seven patients were enrolled in various clinical trials of ibrutinib, with or without rituximab, at our center. Thirty-three (26%) patients have discontinued ibrutinib to date. The majority of those patients had high-risk features: 94% with unmutated immunoglobulin heavy chain variable gene rearrangement, 58% with del(17p) by fluorescence in situ hybridization, and 54% with a complex karyotype. Causes of discontinuation were disease transformation (7), progressive CLL (7), stem cell transplantation (3), adverse events (11), serious adverse events/deaths (3), and miscellaneous reasons (2). Twenty five patients (76%) died after discontinuing ibrutinib; the median overall survival was 3.1 months after discontinuation. Most patients with RR-CLL who discontinued ibrutinib early were difficult to treat and had poor outcomes.