William George Wierda

Patients in the lisocabtagene maraleucel (liso-cel) plus ibrutinib cohort of the phase 1/2, open-label TRANSCEND CLL 004 study had relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and received liso-cel (50 × 106 [dose level 1 (DL1)] or 100 × 106 [DL2] chimeric antigen receptor–positive T cells) with concurrent ibrutinib from enrollment through 90 days after liso-cel infusion or longer per investigator discretion. Primary end point was complete response/remission (CR)/CR with incomplete marrow recovery (CRi) by investigator assessment. Among 56 patients who received ibrutinib plus liso-cel (DL1, n = 5; DL2, n = 51), median age was 64.5 years (range, 44-77), 98% had high-risk cytogenetics, and median number of prior therapies was 5 (range, 1-13). Median follow-up was 24.8 months (range, 3.1-51.8). At DL2, CR/CRi rate was 45% (95% confidence interval [CI], 31-60), and overall response rate was 86% (95% CI, 74-94). Median duration of response was not reached (NR; 95% CI, 28.7 to NR) for patients with CR/CRi. Median progression-free survival was 31.4 months (95% CI, 20.1 to NR). In DL1 plus DL2, the most common grade ≥3 treatment-emergent adverse events (TEAEs) were neutropenia (52%) and anemia (41%). Cytokine release syndrome was reported in 80% of the patients (grade 3, 4%; no grade 4/5), and neurological events were reported in 41% (grade 3/4, 11%; no grade 5). Ibrutinib-related TEAEs were reported in 68% of the patients (grade 3/4, 43%; no grade 5). Liso-cel plus ibrutinib demonstrated notable efficacy in patients with R/R CLL/SLL with predictable and manageable safety. This trial was registered at www.clinicaltrials.gov as NCT03331198 and NCT03435796.

The receptor tyrosine kinase‑like orphan receptor (ROR1) is aberrantly expressed on chronic lymphocytic leukemia (CLL) cells and promotes survival signaling through NF‑κB, ERK1/2, and mTORC1. Zilovertamab is a humanized monoclonal antibody targeting ROR1. We conducted a multicenter phase 1b/2 study of zilovertamab plus ibrutinib (Z + I) in relapsed/refractory CLL. Phase 1b/2a ( N = 34) established a recommended zilovertamab dose based on safety, pharmacokinetics, and ROR1 occupancy. In phase 2b, patients were randomized to zilovertamab plus ibrutinib ( N = 18) or ibrutinib alone (I; N = 10); the primary endpoint was complete response (CR) per iwCLL, with progression‑free survival (PFS) and safety as secondary endpoints. Z + I was well tolerated, with no dose‑limiting toxicities and safety profile consistent with BTK inhibition. CR rates, overall response, and PFS were similar between randomized arms. In a post hoc subset of 10 patients with del(17p), Z + I was associated with prolonged disease control relative to historical BTK inhibitor experience; this hypothesis-generating observation requires prospective confirmation. Zilovertamab achieved ROR1 occupancy and attenuated NF‑κB, ERK1/2, and mTORC1 signaling in CLL cells, supporting further exploration of ROR1‑targeted strategies in biologically high‑risk CLL. The study was registered at ClinicalTrials.gov (NCT03088878).

Remarkable progress in the understanding of disease pathogenesis and treatment across hematologic malignancies has been achieved in the past 2 decades. Nevertheless, the reliable elimination of disease remains elusive for many cancers. Chronic lymphocytic leukemia (CLL) exemplifies the needs that must be addressed to close the gap between discovery science and the remaining clinical challenges. In CLL, targeted therapies have substantially prolonged survival and enabled long-term disease control for many patients. However, curative outcomes remain exceptional, particularly in high-risk groups such as those with TP53 disruption, dual resistance to Bruton tyrosine kinase and B-cell lymphoma 2 inhibitors, or transformation to aggressive lymphoma. Recent insights into the interconnection between cancer and immunity have positioned CLL as a model example of cancer-associated immunodeficiency, a realization brought into sharp focus by the severe acute respiratory syndrome coronavirus 2 pandemic during which patients with CLL were at extremely high-risk for infection and poor outcomes. Therefore, complications related to infections, autoimmunity, and secondary cancers continue to contribute substantially to morbidity and mortality, underscoring the need for research on immune dysfunction in CLL. Furthermore, pronounced heterogeneity in disease progression and therapeutic resistance highlight the need for mechanistic studies to clarify these distinct biological patterns. Advances in these areas not only hold the promise of curative therapy for broader patient subgroups in CLL but will also inform innovation in research on other cancers, particularly in establishing a molecular definition of disease and defining those interactions with the underlying and resultant immune deficiencies.

We performed next-generation sequencing (NGS)-based measurable residual disease (MRD) assessment in 17 patients with chronic lymphocytic leukemia (CLL) in

Supplementary Appendix: Inclusion Criteria, Exclusion Criteria

Table S1a: Representativeness of study participants. Table S1b: Response and MRD rates at 12 and 24 cycles of combination treatment in intention-to-treat population (N=79). Table S2: Response and MRD rates at 12 and 24 cycles of combination treatment in evaluable patients. Table S3a: Univariate analysis of factors associated with CR/CRi at the end of treatment. Table S3b: Multivariate analysis of factors associated with CR/CRi at the end of treatment. Table S3c: Univariate analysis of factors associated with the best CR/CRi response. Table S3d: Multivariate analysis of factors associated with the best CR/CRi response. Table S4a: Univariate analysis of factors associated with marrow UMRD4 at the end of treatment. Table S4b: Multivariate analysis of factors associated with marrow UMRD4 at the end of treatment. Table S4c: Univariate analysis of factors associated with the best marrow UMRD4 response. Table S4d: Multivariate analysis of factors associated with the best marrow UMRD4 response. Table S5a: Univariate analysis of factors associated with progression-free survival. Table S5b: Multivariate analysis of factors associated with progression-free survival. Table S6: Summary of dose modifications. Table S7: The common reasons for dose reductions and dose interruptions. Table S8a: Summary of patients with U-MRD4 at EOT who had CLL progression. Table S8b: Summary of patients with MRD at EOT who had CLL progression.

Figures S1a: Response rates at serial time points in evaluable patients. Histogram showing iwCLL 2018 response at serial study time points in evaluable patients. CR/CRi rate was 64% at the end of cycle 12 and 77% at the end of cycle 24 of combination therapy. The best CR/CRi rate was 71% at anytime during the study treatment Figure S1b: Marrow UMRD4 rates in evaluable patients. Histogram showing bone marrow UMRD4 rates at serial study time points in evaluable patients. Bone marrow UMRD4 rate was 48% at the end of cycle 12 and 71% at the end of cycle 24 of combination therapy. The best bone marrow UMRD4 rate was 64% at anytime during the study treatment. Figure S2: Time to First Bone Marrow UMRD4. Reversed Kaplan-Meier survival estimate curve for time to first bone marrow UMRD4. The analysis included all patients who had MRD assessments after 3 months of combination therapy. Figure S3: Progression-free survival and overall survival stratified by IGHV mutation status (n=76). Kaplan-Meier progression-free and overall survival estimate curves stratified by IGHV mutation status. Log-rank test was used to compare between IGHV mutated and unmutated subgroups. Figure S4: Progression-free survival and overall survival in stratified by prior chemoimmunotherapy treatment. Kaplan-Meier progression-free and overall survival estimate curves stratified by prior chemoimmunotherapy treatment status. Log-rank test was used to compare between the two subgroups. Figure S5a: Time to treatment discontinuation in all patients. Kaplan-Meier survival estimate curve for time to treatment discontinuation. Figure S5b: Time to treatment discontinuation, stratified by IGHV status. Kaplan-Meier survival estimate curve for time to treatment discontinuation stratified by IGHV mutation status. Log-rank test was used to compare between the two subgroups. Figure S5c: Time to treatment discontinuation, stratified by TP53 aberration. Kaplan-Meier survival estimate curve for time to treatment discontinuation stratified by TP53 aberration status. Log-rank test was used to compare between the two subgroups. Figure S5d: Time to treatment discontinuation, stratified by prior chemoimmunotherapy treatment. Kaplan-Meier survival estimate curve for time to treatment discontinuation stratified by prior chemoimmunotherapy treatment status. Log-rank test was used to compare between the two subgroups. Figure S6: Patient Disposition. Flowchart showing patient disposition. Figure S7: Time to MRD recurrence in peripheral blood. Reversed Kaplan-Meier survival estimate curve for time to MRD recurrence in peripheral blood. Figure S8: Time to next treatment. Kaplan-Meier survival estimate curve for time to next treatment.

Acalabrutinib is a selective, covalent Bruton tyrosine kinase inhibitor approved for marketing in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). We report final, long-term phase 1/2 study results in 99 patients with treatment-naive (TN) and 134 with relapsed/refractory (R/R) CLL/SLL. At final data cutoff, 71% and 31% of patients in the TN and R/R cohorts, respectively, remained on acalabrutinib treatment (median follow-up of 73.7 and 52.6 months). Among the events of clinical interest (any grade) in the TN and R/R cohorts, atrial fibrillation was reported in 6.1% and 9.0%, hypertension in 29.3% and 23.1%, other malignancies (excluding nonmelanoma skin cancer) in 14.1% and 17.2%, and major bleeding in 8.1% and 8.2% of patients, respectively. The incidence of the most common adverse events decreased over time. Overall response rates were 97.0% and 94.8% in the TN and R/R cohorts, respectively, with similar response findings among patients with standard and high-risk genomic features. In the TN cohort, median progression-free survival (PFS) was not reached and the 72-month PFS rate was 86.7% (95% confidence interval [CI], 77.0-92.5). For the R/R cohort, median PFS was 66.1 months (range, 0.4-87.8) and the 72-month PFS rate was 45.1% (95% CI, 35.6-54.1). This final analysis extends the duration of benefit observed with acalabrutinib, demonstrates that no new safety signals are apparent with longer follow-up, and confirms the safety and tolerability of acalabrutinib monotherapy for patients with CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02029443.