Abstract Introduction VAY736 is an afucosylated, human monoclonal antibody engineered to enhance antibody-dependent cellular cytotoxicity that targets BAFF-R+ B cells for elimination. In preclinical CLL models, VAY736 showed antileukemic activity and, when combined with ibrutinib, significantly reduced disease burden, which may allow some pts to discontinue ibrutinib. Methods This Phase Ib dose-escalation (ESC)/-expansion (EXP) trial (NCT03400176) enrolled pts with CLL who did not achieve a complete response (CR) after >1 year of ibrutinib or had developed a resistance mutation to ibrutinib. Pts received IV VAY736 (ESC: 0.3-9 mg/kg; EXP: 3 mg/kg) once every 2 weeks and oral ibrutinib (420 mg) once daily for up to 8 28-day cycles. Pts achieving undetectable MRD (uMRD) at C9D1 could discontinue ibrutinib at investigator discretion. The study aimed to characterize the safety and tolerability of VAY736 + ibrutinib, assess antitumor activity, PK, and characterize PD profiles. Results By Jul 29, 2022, 39 pts were enrolled (ESC: n=15; EXP: n=24). Table 1 shows pt characteristics, safety, and efficacy data. The overall response at C9D1 for 37 evaluable pts was 40.5% CR + CRi and 16.2% PR (1L: 63.6% CR + CRi and 18.2% PR). At C9D1, 17 pts (45.9%) had uMRD in blood or bone marrow (BM). In the 2-year follow-up period, 16 pts discontinued ibrutinib and were off therapy for 4.9-19.8 months. Frequency of peripheral NKp46+ NK cells increased at least 50% after VAY736 in over 50% of pts. Preliminary coverage-based limiting-cell experiment analysis of RNAseq (CLEAR) data from 10 pts supports peripheral NK cell activation with VAY736. Conclusions VAY736 + ibrutinib appears highly active and has an acceptable safety profile. Multiple pts attained uMRD in blood or BM. Biomarker data suggest NK cell activation with VAY736. More pts will be included in the RNAseq analysis at presentation. Future development of VAY736 for CLL is strongly indicated based on these promising data. Table 1. Patient characteristics, safety, and efficacy results. All patients (N=39) Patient demographics and prior treatment Median age, years (range) 65.0 (39-82) ECOG performance status, n (%) 0 36 (92.3) 1 3 (7.7) No prior regimens excluding ibrutinib, n (%) 12 (30.8) Median number of prior regimens, n (range) 1.0 (0.0-14.0) Median duration of ibrutinib, years (range) 2.95 (0.2-8.3) Patient baseline characteristics Dohner risk by FISH,a n (%) 17p deletion 6 (15.4) 11q deletion 9 (23.1) Trisomy 12 3 (7.7) 13q deletion 10 (25.6) IGHV mutant status, n (%) Non-mutant 32 (82.1) Complex karyotype, n (%) Yes 20 (51.3) Safety Dose-limiting toxicities, n (%) 0 Patients with at least one AE, any grade, n (%) 38 (97.4) Patients with at least one Grade ≥3 AE, n (%) 13 (33.3) Most common (occurring in ≥2 patients) Grade ≥3 AEs, n (%) Neutrophil count decreased 5 (12.8) Lymphocyte count decreased 2 (5.1) Hypophosphatemia 2 (5.1) Lipase increased 2 (5.1) Efficacy 1Lb n=11 R/R n=26 Evaluable patients N=37 Overall response at C9D1 or before discontinuation,c n (%) Complete response 6 (54.5) 8 (30.8) 14 (37.8) Complete response with incomplete marrow recovery 1 (9.1) 0 1 (2.7) Partial response 2 (18.2) 4 (15.4) 6 (16.2) Stable disease 2 (18.2) 8 (30.8) 10 (27.0) Progressive disease 0 5 (19.2) 5 (13.5) uMRD response at C9D1 or before discontinuation,c n (%) Bone marrow uMRD 6 (54.5) 6 (23.1) 12 (32.4) Blood uMRD 7 (63.6) 10 (38.5) 17 (45.9) Blood or bone marrow uMRD 7 (63.6) 10 (38.5) 17 (45.9) Patients elected to discontinue ibrutinib after achieving CR or uMRD, n (%) 16 (43.2) aThe categories were: patients with a 17p deletion; patients with an 11q deletion without a 17p deletion; patients with trisomy 12 without a 17p deletion or an 11q deletion; and patients with a 13q deletion without a 17p deletion, trisomy 12, or an 11q deletion; bPatients with no prior therapies excluding ibrutinib; cFor evaluable patients (N=37). 1L, first line; AE, adverse event; CR, complete response; C, cycle; D, day; ECOG, Eastern Cooperative Oncology Group; FISH, fluorescence in situ hybridization; IGHV, immunoglobulin heavy chain variable region; R/R, relapsed/refractory; uMRD, undetectable minimal residual disease. Citation Format: Kerry Anne Rogers, Pearlly Yan, Ian W. Flinn, Deborah M. Stephens, Thomas J. Kipps, Sarah M. Larson, Laura Martz, Xi Chen, Huabao Wang, Ethan Hopping, Ralf Bundschuh, Alexandra Acosta, Daniela Baldoni, Anwesha Chaudhury, Jeanne Whalen, Nadia B. Hassounah, Nina Orwitz, Janghee Woo, John C. Byrd. Assessing clinical and pharmacodynamic (PD) profiles of patients (pts) with chronic lymphocytic leukemia (CLL) on ianalumab (VAY736) + ibrutinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT021.

Little is known about outcomes of patients with chronic lymphocytic leukemia (CLL) with del(17p13.1) karyotype at diagnosis. We reviewed 114 de novo del(17p13.1) CLL patients seen at our institution. Using proportional hazards models to identify pretreatment clinical variables significantly associated with treatment-free survival (TFS) and overall survival (OS), we developed a simplified risk score for de novo del(17p13.1) CLL patients to predict TFS and OS based on these variables. These scores, particularly the very highest, can be utilized to identify high-risk patients for expedient enrollment on clinical trials. Our data support careful observation for low-risk patients, potentially preventing unnecessary use of aggressive therapies.

PURPOSE: Comorbid medical conditions define a subset of patients with chronic lymphocytic leukemia (CLL) with poor outcomes. However, which comorbidities are most predictive remains understudied. EXPERIMENTAL DESIGN: We conducted a retrospective analysis from 10 academic centers to ascertain the relative importance of comorbidities assessed by the cumulative illness rating scale (CIRS). The influence of specific comorbidities on event-free survival (EFS) was assessed in this derivation dataset using random survival forests to construct a CLL-specific comorbidity index (CLL-CI). Cox models were then fit to this dataset and to a single-center, independent validation dataset. RESULTS: The derivation and validation sets comprised 570 patients (59% receiving Bruton tyrosine kinase inhibitor, BTKi) and 167 patients (50% receiving BTKi), respectively. Of the 14 CIRS organ systems, three had a strong and stable influence on EFS: any vascular, moderate/severe endocrine, moderate/severe upper gastrointestinal comorbidity. These were combined to create the CLL-CI score, which was categorized into 3 risk groups. In the derivation dataset, the median EFS values were 58, 33, and 20 months in the low, intermediate, and high-risk groups, correspondingly. Two-year overall survival (OS) rates were 96%, 91%, and 82%. In the validation dataset, median EFS values were 81, 40, and 23 months (two-year OS rates 97%/92%/88%), correspondingly. Adjusting for prognostic factors, CLL-CI was significantly associated with EFS in patients treated with either chemo-immunotherapy or with BTKi in each of our 2 datasets. CONCLUSIONS: The CLL-CI is a simplified, CLL-specific comorbidity index that can be easily applied in clinical practice and correlates with survival in CLL.

Background

Irreversible inhibition of Bruton's tyrosine kinase (BTK) by ibrutinib represents an important therapeutic advance for the treatment of chronic lymphocytic leukemia (CLL). However, ibrutinib also irreversibly inhibits alternative kinase targets, which potentially compromises its therapeutic index. Acalabrutinib (ACP-196) is a more selective, irreversible BTK inhibitor that is specifically designed to improve on the safety and efficacy of first-generation BTK inhibitors.

Methods

In this uncontrolled, phase 1-2, multicenter study, we administered oral acalabrutinib to 61 patients who had relapsed CLL to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of acalabrutinib. Patients were treated with acalabrutinib at a dose of 100 to 400 mg once daily in the dose-escalation (phase 1) portion of the study and 100 mg twice daily in the expansion (phase 2) portion.

Results

The median age of the patients was 62 years, and patients had received a median of three previous therapies for CLL; 31% had chromosome 17p13.1 deletion, and 75% had unmutated immunoglobulin heavy-chain variable genes. No dose-limiting toxic effects occurred during the dose-escalation portion of the study. The most common adverse events observed were headache (in 43% of the patients), diarrhea (in 39%), and increased weight (in 26%). Most adverse events were of grade 1 or 2. At a median follow-up of 14.3 months, the overall response rate was 95%, including 85% with a partial response and 10% with a partial response with lymphocytosis; the remaining 5% of patients had stable disease. Among patients with chromosome 17p13.1 deletion, the overall response rate was 100%. No cases of Richter's transformation (CLL that has evolved into large-cell lymphoma) and only one case of CLL progression have occurred.

Conclusions

In this study, the selective BTK inhibitor acalabrutinib had promising safety and efficacy profiles in patients with relapsed CLL, including those with chromosome 17p13.1 deletion. (Funded by the Acerta Pharma and others; ClinicalTrials.gov number, NCT02029443.).

Checkpoint inhibitor (CPI) therapy with anti-PD-1 antibodies has been associated with mixed outcomes in small cohorts of patients with relapsed aggressive B-cell lymphomas after CAR-T failure. To define CPI therapy efficacy more definitively in this population, we retrospectively evaluated clinical outcomes in a large cohort of 96 patients with aggressive B-cell lymphomas receiving CPI therapy after CAR-T failure across 15 US academic centers. Most patients (53%) had diffuse large B-cell lymphoma, were treated with axicabtagene ciloleucel (53%), relapsed early (≤180 days) after CAR-T (83%), and received pembrolizumab (49%) or nivolumab (43%). CPI therapy was associated with an overall response rate of 19% and a complete response rate of 10%. Median duration of response was 221 days. Median progression-free survival (PFS) and overall survival (OS) were 54 and 159 days, respectively. Outcomes to CPI therapy were significantly improved in patients with primary mediastinal B-cell lymphoma. PFS (128 vs 51 days) and OS (387 vs 131 days) were significantly longer in patients with late (>180 days) vs early (≤180 days) relapse after CAR-T. Grade ≥3 adverse events occurred in 19% of patients treated with CPI. Most patients (83%) died, commonly because of progressive disease. Only 5% had durable responses to CPI therapy. In the largest cohort of patients with aggressive B-cell lymphoma treated with CPI therapy after CAR-T relapse, our results reveal poor outcomes, particularly among those relapsing early after CAR-T. In conclusion, CPI therapy is not an effective salvage strategy for most patients after CAR-T, where alternative approaches are needed to improve post-CAR-T outcomes.