Chronic Lymphocytic Leukemia Pts Research Articles

Abstract CT144: Safety and efficacy of HMPL-523 (Syk inhibitor) in patients with relapsed or refractory lymphoma

Abstract Background: HMPL-523, a selective oral Syk inhibitor, demonstrated encouraging benefit-risk profile in 2 Phase 1 (P1) studies in relapsed/refractory (R/R) lymphoma patients (pts) in USA/Europe (NCT03779113) and China (NCT02857998). In the 16 response-evaluable pts in the dose-escalation portion (Part 1) of study NCT03779113, 4 responses were noted, including complete responses (CRs) in R/R hodgkin lymphoma (HL) and follicular lymphoma (FL) pts (Strati et al. Blood 2021). Here, we report the results from the dose expansion portion (Part 2) of the study NCT03779113. Methods: Safety and efficacy of HMPL-523, at the recommended phase 2 dose (RP2D) of 700 mg QD, was evaluated in lymphoma pts who have exhausted all approved therapy options. Treatment emergent adverse events (TEAEs) were assessed per NCI CTCAE v5.0. Responses were assessed by investigators at weeks 8, 16, and 24, and then every 12 weeks. Results: As of 14 July 2023, 47 pts were enrolled in the Part 2 [25 HL, 9 Peripheral T cell lymphoma (PTCL), 7 Chronic lymphocytic leukemia (CLL), 2 each of FL and Mantle cell lymphoma (MCL), and 1 each with Marginal zone lymphoma (MZL) and Waldenström's macroglobulinemia (WM)]. Median age was 57 (Range:21-93) years, 55% were males, 85% were Caucasian, 47% had ECOG status of 1, 81% were disease stage ≥3 and 17% had B-symptoms at study entry. Median prior lines of therapy was 4 (range 1 - 12); 86% of CLL pts were prior BTK treated and 88% of HL pts had both a PD-1 inhibitor and Brentuximab vedotin. With a median drug exposure of 2.9 months, the overall response rate (ORR) among 41 efficacy evaluable pts was 26.8% and disease control rate (DCR) was 65.9% [4 CR (9.8%), 7 PR (17.1%) and 16 SD (39.0%)]. The median time-to-response was 1.9 months. Among HL pts (N=24), ORR was 25.0% and DCR was 66.7% [2 CR (8.3%), 4 PR (16.7%) and 10 SD (41.7%)]. Among PTCL pts (N=7), ORR and DCR were 42.9% [2 CR (28.6%) and 1 PR (14.3%)]. The median duration of response (DOR) was not reached for HL pts and was 5.7 months (2.0 - NR) in PTCL. Two pts (one each with HL and PTCL) with disease control were taken off treatment to be consolidated with allogenic stem cell transplant. At cut-off, 1 pt each with CLL (N=5 ) and WM (N=1) demonstrated a PR. Serious TEAEs occurred in 18 pts (38.3%), of which 4 (8.5%) were considered treatment-related (TRAE). Grade≥3 TRAEs were noted in 15 pts (31.9%); the most common Grade≥3 TRAEs (>5%) were alanine aminotransferase increase 4 (8.5%) and febrile neutropenia 3 (6.4%). Dose interruption due to TEAEs occurred in 23 pts (48.9%) and dose reduction in 4 pts (8.5%). Two pts (4.3%), 1 each with TEAE of thrombocytopenia and pruritis had drug discontinued. Conclusion: HMPL-523 was well tolerated at the RP2D of 700 mg QD in R/R lymphoma pts. Encouraging proof of activity was demonstrated in heavily pre-treated HL and PTCL pts. Additional studies are needed to evaluate the value of SYK-inhibitor as either monotherapy or combination in these high unmet-need population. Citation Format: Paolo Strati, Eva Gonzalez-Barca, Daniel Morillo, Sairah Ahmed, Dominik Chraniuk, Sirpa Leppa, Fatima de la Cruz Vicente, Piotr Centkowski, Rathi N. Pillai, Shivani Nanda, Alisha Khullar, Marjo Hahka-Kemppinen, Vijayvel Jayaprakash, Giuseppe Gritti. Safety and efficacy of HMPL-523 (Syk inhibitor) in patients with relapsed or refractory lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT144.

Targeted Agents in Chronic Lymphocytic Leukemia (CLL): Advancements in Overall Survival Outcomes?

The impact of targeted agents (TAs) in fully mitigating the detrimental effects of CLL on overall survival (OS) remains uncertain. To address this, we compared the 5-year OS of treatment-naïve CLL pts who received targeted agents (TAs) in phase 3 clinical trials with the 5-year OS of age- and gender-matched general population (AGMGP) in Italy and the US. For this analysis, we included clinical trials that involved elderly or unfit pts (RESONATE2, ILLUMINATE, ALLIANCE, ELEVATE-TN, CLL14, and GLOW). We also considered trials enrolling fit pts eligible for FCR (Fludarabine, Cyclophosphamide, and Rituximab) treatment (ECOG1912, FLAIR, and CLL13). We used the method proposed by Liu et al. [BMC Med Res Methodol 2021;21(1):111] to reconstruct individual patient data (IPD) from published Kaplan-Meier survival curves. The expected OS rate for the control population was calculated using 2019 Italian data from the Istituto Nazionale di Statistica (ISTAT) and the 2019 US database. OS of CLL pts and AGMGP were compared for restricted mean overall survival time (RMOST). The treatment effect on OS was then measured as the difference of RMOST and expressed in months. The elderly CLL trial analysis group (2,222 pts) received TAs (58.1%) or chemo-(immunotherapy)(CT/CIT) (41.8%). TAs included Bruton Kinase inhibitors (BTKis) (i.e., ibrutinib [I] or acalabrutinib [A]) alone or with anti-CD20 (75%) or fixed-duration (FD) venetoclax [V] combos (25%). The control CT/CIT arm mainly consisted of CLB+Obinu (66%). The median age of pts was 70 years (range 47-93). The prevalence of del(17p)/mutated TP53, unmutated IGHV, or CIRS score>6 were 9.1% (0-16%), 62.4% (43-66.5%), and 48.6% (11.7-86.1%), respectively. In the aggregate analysis, the 5-year RMOST of elderly pts treated with CT/CIT (RESONATE2, ILLUMINATE, ALLIANCE, ELEVATE-TN, CLL14, and GLOW) was found to be inferior compared to the 5-year RMOST of Italian [Difference (D), -4.2 months; 95% CI: -5.3 to -3.0; P < 0.0001] and US [D, -3.6 months; 95% CI: -4.7 to -2.4; P < 0.001] AGMGP (Fig 1). The analysis of pts treated with TAs provided conflicting results. In the cross-matched comparison between Italian AGMGP and pts treated with BTKi single-agent or combined with anti-CD20, the 5-year RMOST difference indicates an OS advantage for the former (Fig 1). The same applied in the comparison between pts who received FD V-based therapies and Italian or US AGMGP. Notably, the 5-year RMOST of elderly CLL pts treated with BTKi single-agent (RESONATE2, ALLIANCE, ELEVATE-TN) or combined with anti-CD20 (ILLUMINATE, ALLIANCE, ELEVATE-TN) was similar to the 5-year RMOST of US AGMGP [D, -1.2 mo. (-2.5 to 0.1); P = 0.07 for both](Fig 1). OS comparisons between elderly CLL pts and control populations, although controlled for age and gender, do not account for the interaction between comorbidity burden and OS. The proportion of pts with CIRS score > 6 varied widely across trials: RESONATE2, 31%; ELEVATE-TN, 11.1% in the A-arm and 16.8% in the AO-arm; ILLUMINATE, 32.7%; CLL14, 86.1%; and GLOW, 69.0%. Since CLL pts eligible for FCR enrolled in the ECOG1912, FLAIR, and CLL13 trials typically have fewer comorbidities, they enable a clearer evaluation of the TA's impact on OS. Overall, 1,437 patients (64.5%) received TAs, and 789 (35.4%) received CIT. TAs consisted of I+R (51.5%) or FD V-based combinations (VO, VI, VO+Ibr) (48.5%). The median age of pts was 62 years (range 27-84). The prevalence of ECOG PS 0 and unmutated IGHV were 68% and 56%, respectively. The 5-year RMOST of younger/fit pts treated with FCR was inferior to the 5-year RMOST of Italian AGMGP [D, -1.1 mo; 95% CI: -1.8 to -0.3; P = 0.003] but similar to the 5-year RMOST of US AGMGP [D, -0.4 mo; 95% CI, -1.1 to 0.4; P = 0.28]. Interestingly, no significant difference could be observed between the 5-year RMOST of younger/fit pts treated with TAs (IR or Ven-based) and the 5-year RMOST of Italian or US AGMGP (Fig 2). In conclusion, our results suggest that in comparison to CIT, TAs mitigate but do not fully abrogate the detrimental impact of CLL on OS. The intricate interaction between CLL characteristics and the burden of comorbidities can potentially lead to misleading results in clinical trials of elderly pts. The extent of OS improvement obtained with TAs seems higher in younger/fit CLL pts who have fewer comorbidities. However, longer follow-up is needed to discern the ability of these treatments to mitigate the impact of CLL on OS over longer time intervals.

Assessing Adoption of Standard of Care and Comparing Clinical and Demographic Differences in First-Line (1L) Treatment (Tx) of Chronic Lymphocytic Leukemia (CLL)

Assessing Adoption of Standard of Care and Comparing Clinical and Demographic Differences in First-Line (1L) Treatment (Tx) of Chronic Lymphocytic Leukemia (CLL)

Investigating the Influence of Germline ATM Variants on Susceptibility to Chronic Lymphocytic Leukemia and Other Malignancies

Introduction: Chronic lymphocytic leukemia (CLL) patients (pts) face an increased susceptibility to secondary cancers. Furthermore, the hereditary predisposition to CLL is influenced by factors that have yet to be fully elucidated by GWAS-identified common variants. Among the hereditary cancer risk mutations observed, germline Ataxia-telangiectasia mutated ( ATM) aberrations are among the most prevalent. Rare germline ATM variants are detected in 24% of CLL pts, surpassing the frequency observed in other hematologic neoplasms and the general population. In CLL, loss of ATM via 11q23 deletion is linked to an unfavorable prognosis and a shortened progression-free survival. The extent to which germline ATM variants predispose CLL pts to other malignancies remains unclear; to examine this potential risk we conducted a retrospective study to assess the influence of germline ATM variants on the predisposition to secondary neoplasms in CLL pts and their relatives. Methods: Five hundred and eighty-five pts seen at Dana-Farber Cancer Institute and who had NGS performed to evaluate germline ATM status, either through direct germline sequencing of saliva or by inference according to the hierarchical algorithm we have previously published (Lampson, 2022), were mailed a questionnaire that investigated: demographics; personal and family history of any cancer; non-medical radiation and Agent Orange exposure; and Ataxia-Telangiectasia syndrome (AT). Of these, 333 replied (57%). Information collected from our CLL database included FISH, IGHV status and treatment status. European ancestry was categorized based on the United Nations geoscheme (UNSD, 2019). Pt characteristics are in Table 1. Pts were stratified into 4 groups, based on ATM mutational status and del(11q): Group-1, ATM germline variants alone (N=63); Group-2, ATM germline with somatic ATM mutation and/or del(11q)(N=22); Group-3, ATM somatic aberration alone (including del(11q))(N=41); and Group-4, no ATM aberration (N=207). Results: Of the 333 pts in our cohort, baseline demographic and clinical characteristics among the 4 groups were balanced, except for unmutated IGHV status. Nineteen (86%) and 36 (86%) pts of groups 2 and 3, carrying somatic ATM aberrations, had unmutated IGHV, compared to 21 (33%) and 76 (37%) of groups 1 and 4, without somatic ATM aberrations(p<0.01). Regarding treatment, 60% of our cohort had received at least one line of therapy (median: 1 (1-7)). Among the 164 pts (49%) with history of an additional non-CLL neoplasm, 221 cancers were reported. Excluding pts with only non-melanoma skin cancers, the incidence is reduced to 31% (104 pts). The median number of second cancers per pt is 1 (1-4). Of the 134 pts with available age of onset data for the secondary malignancy, 80 (60%) were diagnosed with the secondary cancer after CLL. Comparing pts with germline ATM variants (N=85) to the ones without germline ATM variants (N=248), no significant difference in the incidence of secondary cancer was found (p=0.73). The median age of secondary cancer onset was also similar between the groups (median: 63 and 64 years in germline ATM present vs absent, p=0.28). Of the whole cohort, 283 pts (85%) reported at least one relative with a cancer history (median 2 relatives affected (1-17)). The incidence of B-cell lymphoproliferative disorders was significantly higher (p=0.02) in pts with germline ATM variants (32%) compared to those without germline ATM variants (21%), including familial CLL (25% vs18%) (p=0.04). Familial CLL was also strongly associated with Ashkenazi Jewish ethnicity (39% incidence in Ashkenazi pts vs 16% in non-Ashkenazi, p=0.004). No difference in the incidence of other hematologic or solid malignancies was found between the relatives in the two groups. No pts reported a familial or personal history of AT. Compared to pts without any ATM aberration, time to first treatment (TTFT) was shorter in pts harboring somatic ATM events, while no difference was observed between pts with germline ATM variants (median TTFT: 82, 59, 52, 90 months for group 1, 2, 3 and 4 respectively, p=0.01) (Figure 1). Conclusions: Our results suggest a higher incidence of B-cell lymphoproliferative disorders, including familial CLL, in the relatives of CLL pts carrying germline ATM variants. The presence of these germline variants did not impact TTFT, compared to pts harboring somatic ATM mutations.

Coronado CLL: A Phase Ib/II Trial of Combination Rp-3500 and Olaparib in DNA Damage Repair Pathway Deficient Relapsed/Refract ory Chronic Lymphocytic Leukemia

Background: Genes within the DNA damage repair ( DDR) pathways are frequently mutated in relapsed/refractory ( R/R) chronic lymphocytic leukemia ( CLL) and clinically correlate with decreased response rates and shortened progression-free ( PFS) and overall survivals ( OS). The most commonly affected DDR genetic aberrations include deletion 17p13 [ del(17p)], deletion 11q22.3 [ del(11q)], and mutations in TP53, ATM, SF3B1, XPO1 and POT1. Due to their poor clinical outcomes, patients (pts) with DDR-deficient CLL remain an area of unmet need and the development of novel drugs and combinations will be critical to improving their prognosis. Mechanistically, CLL cells with DDR genetic alterations lack double-stranded DNA breakage repair and major cell cycle checkpoint pathways. Therefore, R/R CLL cells are dependent on single-stranded DNA breakage ( SSB) repair and alternative DNA replication arrest machinery to ensure DNA integrity, strand repair and cell survival. DNA damage at the replication fork is primarily recognized by ataxia telangiectasia and rad3 ( ATR) protein, which ensures mitotic arrest and recruitment of poly (ADP-ribose) polymerase ( PARP) based SSB repair mechanisms. In germline DDR-deficient breast and ovarian cancers with BRCA1/BRCA2 mutations, the use of both single agent PARP inhibitors ( PARPi) and ATR inhibitors ( ATRi) have led to significant disease response and improved OS. Furthermore, combination PARPi and ATRi have demonstrated synergistic activity in preclinical data producing increased apoptosis and cell death in BRCA2-mutated ovarian cell lines. In DDR-deficient CLL primary cell and murine models, single agent PARPi and ATRi have demonstrated significant cell death as compared to wildtype CLL and healthy donor lymphocytes. RP-3500 is a highly potent ATRi. In preclinical data generated in SUM149PT DDR-deficient breast cancer cell lines, combining RP-3500 with the PARPi, olaparib, substantially reduced tumor volume at lower doses than the previously determined maximum tolerated dose ( MTD) of each drug when used as monotherapy. Furthermore, intermittent dosing of both drugs (3 days per week) demonstrated equal cell apoptosis as continuous dosing. Therefore, we hypothesize that the combination of RP-3500 and olaparib will be a highly efficacious treatment for R/R DDR-deficient CLL pts and that the lower dosages and intermittent dosing schedule required of each drug when administered in combination will improve safety of the treatment. Study Design and Methods: This is a multi-site (University of Utah and the Ohio State University), phase Ib/II investigator-initiated clinical trial using combination RP-3500 and olaparib in R/R CLL pts with DDR pathway deficiencies to determine the safety and efficacy of the drug combination (NCT05405309). Primary objectives include determining the MTD in phase Ib leading to the recommended phase 2 dose ( RP2D), and overall response rate ( ORR) in phase II. Key secondary objectives include safety and tolerability, PFS, OS and duration of response of the combination. Eligibility: Key inclusion criteria include a diagnosis of CLL according to the 2018 iwCLL guidelines, age ≥18 years, ECOG performance status of ≤2, R/R after at least 2 prior lines of therapy. Primary CLL cells must exhibit any one of the following abnormalities: a) somatic mutation(s) in TP53, ATM, SF3B1, XPO1 or POT1, or b) positive FISH for either del(17p) or del(11q). Statistical Methods: Phase Ib: The phase Ib of the trial will utilizea keyboard design, which is a novel Bayesian method that typically underestimates the MTD. The target toxicity is 30% with an equivalence interval between 25-33% of pts. With an anticipated 3 dose levels ( DL) and an option for a DL-1, up to 18 pts may be required to determine the MTD and RP2D. Phase II: Any pt treated at the RP2D within phase Ib will be rolled into the phase II analysis for efficacy. With a planned 24 evaluable pts in phase II, the target ORR will be 60%, which was selected due to a recent phase I/II study of pirtobrutinib enrolling a similar CLL pt population demonstrating an ORR of the drug ~63%. ORR will be summarized by the observed proportion and an exact one-sided 95% confidence interval (Clopper-Pearson method). With 24 evaluable pts, the lower bound of the confidence interval will be approximately 17-20% below the observed proportion for observed ORR near 60%, which is an acceptable level of precision in a dose expansion cohort.

A Long-Term Analysis of Lenalidomide and Rituximab (R 2) for the Treatment of Chronic Lymphocytic Leukemia

Background:Lenalidomide (len) is an immunomodulator that binds cereblon and alters protein degradation of Ikaros and Alios via E3 ligase. The R 2 regimen (len paired with Rituximab (R)) is an effective treatment (tx) for lymphoid malignancies, and its promise in patients (pts) with chronic lymphocytic leukemia (CLL) has been previously reported (James et al, JCO 2014). We performed a long-term, single-center follow-up (f/u) analysis of pts previously enrolled in two phase 2 open-label studies evaluating R 2 in both treatment naïve (TN) and relapsed-refractory (R/R) CLL pts. Methods: The CLL Research Consortium (CRC)-014 trial enrolled TN pts. Pts initiated 2.5 mg of len daily for 21 days (D) out of a 35-day cycle (C) for C1, then 28d cycles for C2-C7. Len was escalated to 10 mg daily as tolerated. R was initiated in a dose-intensive manner: 50 mg/m 2 on C1D29; 325 mg/m 2 on C1D31 and C1D33; 375 mg/m 2 weekly for C2; then 375 mg/m 2 on D1 for C3-C7. R 2 was stopped after 7C. The CRC-022 trial enrolled R/R pts. Pts initiated 5 mg of len daily for 21 days of each 28d cycle, with escalation to 25 mg daily as tolerated. R was initiated weekly at 375 mg/m2 for C1, then 375 mg/m2 on D1 for C2-C6. R/R pts could continue len for up to 6 consolidative cycles after completion of 6C of R 2. Response assessment was performed using iwCLL criteria and minimal residual disease (MRD) was assessed by multi-parametric flow cytometry of the bone marrow with a sensitivity of 10 -4. Time-to-event analyses were performed with the Kaplan-Meier method. Results: We identified 43 TN pts and 25 R/R pts. Notably, 6 pts enrolled in both studies sequentially. The median age for all pts was 62.5 years (range 45-82). Rai staging at time of tx initiation was: 2 38.7%; 3 24.2%; 4: 37.1%. The profile of cytogenetic abnormalities was: 54.8% del(13q); 17.7% del(11q); 16.1% trisomy 12; 9.7% del(17p); 19.4% normal; and 1.6% complex karyotype. 69.4% of pts had unmutated immunoglobulin heavy chain. The median number of prior tx for R/R pts was 2 (range:1-6). The overall response profile was: CR 13.2%; PR 69.1%; SD 2.9%, PD 1.5%. No pts had undetectable MRD. At median f/u time of 129 months (mo), median progression-free survival (PFS) was 15.7 mo in the TN pts and 25.4 mo in the R/R pts (p = 0.11, Figure 1A). The trend towards improvement may reflect len consolidation available to the R/R pts. Median time to next treatment (TTNT) was also not significantly different between the TN pts and the R/R pts (29.5 mo vs. 29.0 mo, p = 0.56). Median OS was significantly higher for the TN pts than the R/R pts (164.8 mo vs. 108.0 mo, p = 0.0001, Figure 1B). This likely reflects heavy pre-treatment in the R/R pts. Across both TN and R/R groups, 21 pts died: 8 deaths (38.1%) were related to CLL, none were related to R 2 treatment, and 13 (61.9%) were related to other causes or unknown. Adverse events included: 30.9% of pts with Grade (Gr) 3-4 neutropenia, 58.8% of pts with Gr ≥2 thrombocytopenia, and 30.9% of pts with Gr ≥2 anemia. During the extended f/u period, 16.2% of pts developed pneumonia and 13.2% developed viral infections. Through the extended f/u, venous thromboembolism (VTE) developed in 9 (14.5%) pts. Only 2 pts developed VTE during active R 2 and both were not taking prophylactic aspirin. Five other pts developed VTE >6 mo after stopping R 2 and had other provoking factors. Four pts (6.5%) developed Richter transformation lymphoma. 43.5% of pts developed cutaneous neoplasms and 12.9% of pts developed non-cutaneous solid neoplasms. No pts developed secondary myeloid neoplasms. Conclusions: In this long-term pooled f/u analysis of CLL pts, we found that R 2 provided high ORR, modest PFS and OS benefit, and tolerable long-term toxicities. The ORR of R 2 in this study (82.3%) compares favorably to ORR of R monotherapy in previous studies (51%, Hainsworth et al, JCO 2003). The absence of secondary myeloid neoplasms suggests that len may not substantially increase cumulative secondary malignancy risk-the cumulative cutaneous neoplasm incidence may reflect elevated baseline risk in CLL pts. Importantly, we found no increased risk in deaths attributed to therapy. The demonstrated activity of R 2 in CLL warrants further investigation of len in combination with other agents. Currently, new immunotherapeutic approaches-such as bispecific antibodies and CAR-T cell therapy-are being investigated in CLL. Given len's immunomodulatory properties, combination approaches with these treatments should be explored in future trials.

Initial Results of a Phase 1 Dose Escalation Study of LP-168, a Novel Covalent and Non-Covalent Next-Generation Inhibitor of Bruton's Tyrosine Kinase

Introduction: Inhibitors of Bruton's Tyrosine Kinase (BTKi) have been transformative therapies in chronic lymphocytic leukemia (CLL) and other lymphoid malignancies. Despite extended remissions, most patients (pts) will relapse. Covalent BTKi (cBTKi) including ibrutinib, acalabrutinib, and zanubrutinib, share a common resistance mechanism, acquisition of a C481 mutation in BTK. Non-covalent BTKi (ncBTKi) can overcome this, however, second-site mutations, notably T474 gatekeeper and kinase-dead mutations, have been observed. LP-168 is a selective next generation inhibitor of BTK that can bind wild-type and C481-mutated BTK covalently and non-covalently, respectively, with preclinical activity in resistant CLL models (submitted to ASH 2023). This dual activity is hypothesized to allow efficacy against cells with wild-type BTK through covalent activity while preventing expansion of the most common resistance mechanisms through non-covalent activity. Here we describe initial results of a phase 1 study of LP-168, with safety evaluation focusing on DLT evaluable pts, and efficacy evaluation focusing on the cohort of pts with CLL. Methods: NCT04775745 is a multicenter phase 1 dose escalation study of LP-168 monotherapy in pts with relapsed/refractory B-cell malignancies. CLL pts must have received ≥2 prior therapies. Dose escalation was performed using 3+3 design with expansion at multiple doses. Treatment emergent adverse events (TEAEs) were assessed per NCI CTCAE v5.0. Responses were evaluated using iwCLL 2018 criteria. Intra-patient dose escalation was permitted when dose levels cleared safety evaluation. Results: From 16 Sep 2021 to 10 Jul 2023, 43 DLT-evaluable pts were enrolled, including 35 with CLL, at doses from 100-300 mg daily as well as 150 mg twice daily. Data for this abstract were locked 10 Jul 2023. CLL pts received a median of 3 prior therapies, with 94% receiving a prior cBTKi and 11% a ncBTKi. 20 pts had alterations in TP53, 21 pts had C481S BTK mutations, 7 pts had gatekeeper mutations at T474 BTK, and 5 pts had mutation in PLCγ2 (Table). 33 pts have response data with median follow-up of 12.6 months (Figure). Overall response rate (ORR) including all dose levels was 54.5% (18/33)-all were partial response (PR) or partial response with lymphocytosis (PR-L). When evaluating only pts at doses of 200 mg or higher, ORR was 66.7% (10/15). In the subgroup of pts who had received only one prior BTKi including all dose levels, ORR was 77.8% (14/18). In the subgroup of pts with both BTK C481 and T474 mutations at doses of 150mg BID or 300mg QD, ORR was 75% (3/4). At the time of this report, only 5 pts with CLL have discontinued the study for progressive disease. At data lock, 43 DLT evaluable pts (with all histologies) were evaluable for safety. No DLT have been observed, and most AE have been low grade. TEAE seen in >20% of pts included diarrhea, fatigue, arthralgia, headache, constipation, cough, and dizziness; of those, grade 3 or higher AE included fatigue and constipation in 1 pt each. Serious AE were seen in 11 pts, of which 1 led to discontinuation (intracranial hemorrhage in a mantle cell lymphoma pt in complete remission). No DLT was identified at doses up to 300 mg daily and 150 mg twice daily. No atrial fibrillation/flutter has been reported. Hypertension grade 3 or higher was seen in 1 pt, and 1 pt experienced high-grade bleeding (as described). AE frequency did not increase with increasing doses. Pharmacokinetics showed plasma exposure increases dose-dependently. Steady state AUC 24h was between 47.1-94.6 ug/mL*h with limited accumulation. Steady state half-life was between 15.3-21.9 hours at all doses and C max was between 3500 and 5600 ng/mL. BTK occupancy is nearly at 100% at dose levels that were tested, with little variability among pts. Collective review demonstrates optimal Cmax to be achieved at either 200 or 300 mg dosed daily. Conclusions: LP-168 has been well tolerated in this study, with no DLTs identified at doses up to 300 mg daily. Preliminary efficacy was observed in high risk CLL pts, including those treated with one or more BTKi. Considering safety, efficacy, and PK/PD, dose expansion will occur at 200 mg and 300 mg daily following the FDA Project Optimus guidelines to determine the recommended phase 2 dose. A separate cohort will enroll pts with gatekeeper mutations to further explore efficacy. Updated biomarker, safety, and efficacy data will be presented at the meeting.

Characterizing ATM Aberrations in Chronic Lymphocytic Leukemia (CLL): Prognostic Implications and Sensitivity to PARP Inhibition

Introduction ATM mutations (muts) frequently occur in CLL, yet their influence on ATM protein function and DNA break repair is poorly elucidated. Our prior study demonstrated functional hypomorphism of the rare germline variant L2307F in ATM and a higher occurrence of 11q deletions (del(11q)) with ATM germline variants in CLL (Lampson et al, JCO 2023). However, the role of other ATM germline variants in association with del(11q) or somatic muts remains unknown. Here, we analyzed the characteristics of CLL patients (pts) with ATM aberrancies and evaluated ATM function in primary CLL cells. Methods We retrospectively analyzed 278 CLL pts with ATM aberrancy, evaluated by clinical targeted sequencing from 2014 to 2019, as per our recent study (Lampson et al, JCO 2023). ATM, KAP1, and H2AX phosphorylation levels were examined after etoposide or irradiation (IR) exposure, by western blot or flow cytometry, in primary CLL cells with or without ATM aberrancy. We assessed the inhibitory effect of talazoparib, a PARP inhibitor, on CLL proliferation over 14 days using flow cytometry and Cell Trace Violet dye. Results We identified 294 ATM variants, 146 unique (germline N=74, somatic N=72). In CLL pts, 58 had dual ATM allele loss (biallelic group), including del(11q) together with only germline ATM variant(s) (N=29), only somatic mut(s) (N=18), or both (N= 11). 168 pts had ATM muts or variants without del(11q), including only germline (N=137), somatic (N=19), or both (N=12) ( ATM group), and 52 pts had del(11q) alone (11q group). Complex karyotype increased with ATM allele deficiency, particularly with 5+ abnormalities (complex karyotype 5+, biallelic vs 11q vs ATM: 22.6% vs 10.6% vs 5.8%, P=0.002). Unmutated IGHV was significantly higher in the groups with del(11q) versus ATM alone (biallelic vs 11q vs ATM: 85.1% vs 87.8% vs 53.9%, p<0.001). Interestingly, when we compared IGHV status in the ATM alone group with or without somatic ATM muts, unmutated IGHV significantly increased in those with somatic muts ( ATM-somatic vs ATM-germline alone, 81.8% vs 43.6%, p<0.001), and karyotypic complexity tended to be higher in the somatic ATM mut group (P=0.077). This might suggest that pts with ATM somatic muts have clinical characteristics and pathogenicity more similar to del(11q) as compared to those with germline muts. SF3B1 muts were more common in those with del(11q) (biallelic vs 11q vs ATM: 20.7% vs 26.9% vs 12.5%, P=0.036). For functional evaluation, we compared the five groups of primary CLL samples: del(11q) with somatic ATM mut with/without germline (11q+ ATM-S), del(11q) alone with no ATM muts (11q), somatic ATM muts without del(11q) with/without germline ( ATM-S), germline ATM muts alone ( ATM-G), and no ATM aberrancies (wild type, WT). Western blot demonstrated significantly lower phosphorylated protein levels (pATM, pKAP1, γH2AX) in response to DNA damage with etoposide in ATM aberrancy groups compared to WT (WT vs 11q, vs ATM-S, vs 11q+ ATM-S, all P<0.001 except for WT vs 11q in γH2AX, P<0.05) (Figure 1A). Flow cytometry also showed significantly lower phosphorylation levels of ATM after IR in 11q, ATM-S and 11q+ ATM-S groups compared to WT, while ATM-G group didn't show significance. To assess ATM deficient cell sensitivity to talazoparib, we compared proliferation inhibition across groups cocultured with talazoparib for 14 days. The 11q+ ATM-S group exhibited significantly greater sensitivity to talazoparib at lower dosage compared to the WT (talazoparib 0.1 μM, P<0.05; 0.5 μM, P=0.098) (Figure 1B). The monoallelic ATM deficient groups (del11q and ATM-G) tended to have lower proliferation, but not significantly. Higher concentrations of talazoparib (2.5μM) strongly inhibited proliferation of all CLLs including WT. Conclusions Pts with ATM somatic aberrancy including del11q had worse associated prognostic factors including unmutated IGHV and complex karyotype. Somatic events showed greater functional impact than some germline variants. CLL cells with ATM aberrancies had ATM pathway dysfunction, and those with biallelic ATM aberrancies were more sensitive to the PARP inhibitor, talazoparib, than WT. This work could potentially lead to additional avenues for treatment based on differential sensitivities of CLLs with ATM aberrancy. Further studies are needed to characterize specific ATM germline variants with or without somatic ATM events.

Genomic Evolution and Resistance during Pirtobrutinib Therapy in Covalent BTK-Inhibitor (cBTKi) Pre-Treated Chronic Lymphocytic Leukemia Patients: Updated Analysis from the BRUIN Study

Background: The majority of patients (pts) discontinue covalent (c) Bruton tyrosine kinase (BTK) inhibitors (BTKi) for either progression or intolerance. BTK Cysteine 481 substitution is known to contribute to cBTKi acquired resistance to ibrutinib, acalabrutinib, and zanubrutinib.Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi has favorable oral pharmacology that enables continuous BTK inhibition throughout the daily dosing interval regardless of intrinsic rate of BTK turnover. Pirtobrutinib has demonstrated broad efficacy in pts with chronic lymphocytic leukemia (CLL) following prior therapy, including those treated with a prior cBTKi, independent of BTK C481 mutational status (Mato et al, NEJM, 2023). Here we report the largest systematic evaluation of genomic evolution in pts with CLL treated with pirtobrutinib conducted to date, using a larger cohort of pts and longer follow-up than previously reported. Methods: Relapsed cBTKi pre-treated CLL pts in the phase 1/2 BRUIN trial (NCT03740529) who subsequently developed disease progression (PD) on pirtobrutinib monotherapy were included. Targeted next-generation sequencing (NGS) was centrally performed on peripheral blood mononuclear cells collected at baseline and within four months of PD . Results: As of May 5, 2023, 86cBTKi pre-treated CLL pts had paired NGS data available at baseline and pirtobrutinib progression. In this group, the median age was 69 years (range, 36-86), median number of prior lines of therapy was 4 (range, 1-10), 74 pts (86%) had discontinued prior cBTKi due to PD and 12 pts (14%) discontinued due to toxicity/other. Pts received one or more of the following prior cBTKi: ibrutinib (n=77, 90%), acalabrutinib (n=15, 17%), or zanubrutinib (n=2, 2%). Median time on pirtobrutinib treatment was 16 months (range, 1.2-39 months). Among these 86 pts who ultimately progressed on pirtobrutinib, the ORR (including partial response with lymphocytosis) was 83% (95%CI, 73-90). The most common baseline alterations were mutations in BTK (53%), TP53 (48%), SF3B1 (35%), ATM (23%), NOTCH1 (20%), XPO1 (16%), PLCG2 (14%), and BCL2 (9%). In 46 pts, 64 BTK mutations were detected at baseline and included C481S (n=45), C481F/R/Y (n=11), T474I/F/S (n=6), A428D (n=1), D149G (n=1). Among 42 pts with C481, BTK C481 VAF decrease or complete clearance was observed at PD in the majority of pts (86%, 36/42, complete clearance = 55%, 23/42). NGS of samples at PD showed 69% (59/86) of pts acquired ≥1 mutation. In 38 (44%) pts, 52 acquired BTK mutations were detected and most commonly included gatekeeper mutations (T474I/F/S/L/Y, n=25 in 22 pts), kinase-impaired (L528W, n=14 in 14 pts), C481S/R/Y (n=6 in 4 pts) and others proximal to the ATP-binding pocket (n=7 in 5 pts), including D539A/G/H (n=3 in 1 pt), V416L (n=2 in 2 pts), Y545N (n=1) and A428D ([n=1] Figure). A total of 83 non-BTK acquired mutations were observed at PD in 45 pts (52%), including 14 TP53 mutations in 12 pts (14%), 6 PLCG2 mutations in 6 pts (7%), 6 PIK3CA mutations in 6 pts (7%) and 3 BCL2 mutations in 3 pts (3%). Conclusions: Despite this cohort representing the first relapsing CLL patients from BRUIN and presenting with frequent baseline BTK mutations, response to pirtobrutinib was high, with an ORR of 83%, and substantial clearance of BTK C481 clones. At progression, the majority of pts (56%) either acquired non-BTK mutations or did not acquire any resistance mutations in this targeted panel, suggesting alternative resistance mechanisms. A smaller group of patients (44%) displayed emergence of non-C481 clones, particularly gatekeeper T474 and kinase-impaired L528W mutations. Whether similar patterns of resistance would manifest if pirtobrutinib was utilized in earlier lines of therapy or prior to cBTKi treatment remains uncertain.

Higher Mutational Burden Is an Independent Predictor of Shorter Time to First Treatment in Untreated Chronic Lymphocytic Leukemia Patients

Background. Recent advancements in next-generation sequencing (NGS) technologies have revolutionized the ability to comprehensively profile chronic lymphocytic leukemia (CLL), unveiling various molecular lesions. Complex mutational landscapes and diverse combinatorial patterns of genetic alterations lead to heterogeneity of clinical course and outcomes. The primary objective of this study was to identify patterns of co-occurrence (CO) and mutual exclusivity (ME) among mutations in CLL and their impact on time to first treatment (TTFT). Methods. The cohort included 795 treatment-naïve (TN) patients (pts) with CLL diagnosed according to iwCLL guidelines. The median follow-up time for the cohort was 3.91 years (range 0 - 42.8). The median time from diagnosis to mutational analysis was 6.6 months (26.50 - 33.27, 95% CI). Mutational screening was performed by a clinical targeted NGS panel, covering all or hotspot exons of 95 genes - the Rapid Heme Panel implemented by BWH (Kluk MJ, et al. J Mol Diagn. 2016;18(4):507-515). Standard protocols were applied to analyze IGHV gene mutational status, chromosomal aberrations by FISH with probes for 11q, 13q, 17p, and trisomy 12, and stimulated karyotype, where complex karyotype (CK) was defined as ≥3 abnormalities. CO and ME patterns were analyzed in pts with a higher mutational burden, determined as ≥2 distinct mutated genes, using Fisher's exact test ( p<.05). Control for false discovery rate was performed using the Benjamini, Krieger and Yekutieli method ( q=20%). TTFT was the time from diagnosis to initial treatment. Results. We detected 1798 mutations in 719 (90.4%) pts. No mutations were detected in 9.6% (n=76) patients, while a single mutated gene was found in 216 (27.2%) pts, 2 mutated genes in 206 (25.9%) pts, and mutations in 3 and ≥4 genes were found in 153 (19.2%) and 144 (18.1%) pts, respectively. The most mutated (≥10%) genes in the cohort were ATM (18.1%), NOTCH1 (17.7%), TP53 (13.2%), SF3B1 (12.3%), TET2 (10.2%), and DNMT3A (10.1%). A higher mutational burden was associated with clinical Rai stages 1-4 [ p=.003]; elevated (>3.5 mg/L) levels of baseline ß-2 microglobulin (B2M) [ p=.036] and established high-risk genomic features: del(17p) [ p<.001], del(11q) [ p=.021], CK [ p=.009], unfavorable ZAP70 [ p=.027] and unmutated IGHV (UM- IGHV) [ p<.001] (incidence of UM- IGHV cases is 48.4% (n=359) in cohort). At the same time, cases with 0-1 mutation were more likely to have del(13q) [ p=.006]. Sex and age >65 years at diagnosis were not associated with mutational burden. Otherwise, lack of any mutations was associated with absence of del(17p) (0% vs 11.1% [ p=.002]), lower rates of B2M >3.5 mg/L (3.9% vs 21.7% [ p<.001]), less frequent UM- IGHV (25.4% vs 50.9% [p<.001]), lower ratio of CK (7.0% vs 17.5% [p=.024] and age >65 years at diagnosis (21.1% vs 35.1% [ p=.014]). After controlling for multiple comparisons, no genes showed significant mutational co-occurrence. UM- IGHV cases were enriched in mutated ATM [ p=.003], NOTCH1 [ p<.00001], SF3B1 [ p=.0012] and XPO1 [ p<.00001]. Mutated NOTCH1 [ p<.00001], as well as KRAS [ p=.0012], occurred along with tri12. In contrast, UM- IGHV did not co-occur with mutations in MYD88 [ p<.00001], as previously reported. Del(13q) did not co-occur with mutated BRAF [ p=.0006] or BCOR [ p=.006]. Mutated TP53 [ p=.008] and SF3B1 [ p=.0013] were absent in tri12 positive cases. Increased mutational burden in ≥2 distinct mutated genes predicted a shorter TTFT than 0 or 1 mutated gene (HR 2.16; 95%CI 1.57 - 2.97; p<.001). Factors including Rai stages 1-4 (HR 2.63; 95%CI 1.88 - 3.7; p<0.001), UM- IGHV (HR 2.4; 95%CI 1.74 - 3.3; p<.001), CK (HR 1.47; 95%CI 1.07 - 2.0; p=.018), mutational burden in ≥2 genes (HR 1.57; 95%CI 1.14 - 2.2; p=.006) and del(17p) /TP53mut (HR 1.79; 95%CI 1.15 - 2.8; p=.01) were independently associated with worsened TTFT ( Figure 1). Neither mutated TP53 without del(17p) (HR 1.47; 95%CI 0.92 - 2.3; p=.104), or wild-type TP53 with del(17p) (HR 1.03; 95%CI 0.51 - 2.1; p=.932) were significant predictors of TTFT. Conclusions: Higher mutational burden is associated with worsened TTFT in CLL pts independently of other genomic events. In this cohort we did not see co-occurrence of specific mutations.

First Results from a Phase 1, First-in-Human Study of the Bruton's Tyrosine Kinase (BTK) Degrader Bgb-16673 in Patients (Pts) with Relapsed or Refractory (R/R) B-Cell Malignancies (BGB-16673-101)

Introduction: BTK inhibitors (BTKis) are approved for chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). Disease that progresses on BTKis often has BTK mutations that lead to treatment (tx) resistance; novel BTK-targeting agents that overcome BTKi resistance are needed. BGB-16673 is a heterobifunctional small molecule that binds to BTK and E3 ligase, resulting in BTK degradation via ubiquitination. In preclinical models, BGB-16673 degraded wild-type (WT) BTK and known covalent and noncovalent BTKi-resistant mutant proteins, leading to tumor suppression. Methods: Pts with R/R CLL, WM, MCL, MZL, non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), or Richter transformation (RT) were eligible for this open-label, first-in-human, phase 1 trial (BGB-16673-101; NCT05006716). Pts must have received ≥2 prior therapies (≥1 for RT) and have an ECOG performance status of 0-2 and adequate end-organ function. In the US and Australia, pts must have received a covalent BTKi (cBTKi) if approved for their disease. BGB-16673 was dosed daily by mouth in 28-day cycles. Escalation using a Bayesian optimal interval design with 6 dose levels (50-600 mg once daily) is planned. Primary objectives are to assess safety/tolerability and establish the maximum tolerated dose (MTD) and recommended phase 2 dose. Key secondary objectives are to assess pharmacokinetics, pharmacodynamics (PD), and preliminary antitumor activity. Safety was assessed according to CTCAE v5.0 (all pts) and iwCLL hematologic toxicity criteria (pts with CLL). Dose-limiting toxicities (DLTs) were assessed in the first 4 weeks. Response was assessed per Lugano criteria for all except CLL (iwCLL 2018 criteria) and WM (iwWM-6 criteria). Results: As of May 26, 2023, 26 pts (10 CLL, 4 MCL, 2 MZL, 4 WM, 4 FL, 1 DLBCL, 1 RT) were enrolled at 5 dose levels (50 mg, 4; 100 mg, 9; 200 mg, 9; 350 mg, 3; 500 mg, 1). Median age was 70.5 y (range, 25-83). Median number of prior therapies was 3.5 (range, 2-9), including cBTKis (n=21; 10 CLL, 4 WM, 4 MCL, 1 MZL, 1 RT, 1 DLBCL), BCL2 inhibitors (n=12; 9 CLL, 2 WM, 1 RT), and noncovalent BTKis (ncBTKis; n=4; 2 CLL, 1 WM, 1 FL). In CLL, del17p/ TP53 mutation (n=8) and unmutated IGHV (n=7) were frequent. Median follow-up was 3.5 mo (range, 0.2-13.9). MTD was not reached. Treatment-emergent AEs (TEAEs) were reported by 88.5% of pts (grade [gr] ≥3, 46.2%; serious, 38.5%). The most common TEAEs were contusion (30.8%; no gr ≥3), pyrexia (23.1%; no gr ≥3), neutropenia/neutrophil count decreased (23.1%; gr ≥3, 15.4%), and lipase increased (23.1%; gr ≥3, 3.8%; all transient and asymptomatic). No hypertension or atrial fibrillation was observed. One pt died from sepsis with possible disease progression. No discontinuations due to AEs occurred. Two pts had dose reductions due to TEAEs (gr 3 hematuria with urinary tract infection and recurrent urothelial carcinoma and gr 2 arthralgia). One DLT occurred in 1 pt at 200 mg (gr 3 maculopapular rash on day 27; after 5-day dose hold, assigned dose was recommenced with persistent gr 1 rash). BGB-16673 exposure increased in a dose-dependent manner. At steady state with doses ≥50 mg daily, BGB-16673 exposure exceeded the calculated half maximal degradation concentration for WT and cysteine 481-mutated BTK for the dosing interval. Preliminary PD data showed deep, sustained reductions in BTK protein levels in peripheral blood and tumor tissue, even at the lowest dose. Most CLL pts experienced lymphocytosis during the first 3 cycles of tx. Twenty of 26 pts (77%) remain on therapy (discontinuation: 4 progressive disease, 2 withdrawal). Of 18 response-evaluable pts, 12 (67%) responded (5/6 CLL, 1/3 MCL, 2/2 MZL, 3/4 WM, 1/2 FL, 0/1 DLBCL; 1 CR in MCL, all others had PR; Figure), including pts who received a cBTKi (n=10) and an ncBTKi (n=2). Responses started at the lowest dose level. All responders remain in response, the longest responder remaining on tx for 60 weeks. Conclusions: Preliminary data from this ongoing, first-in-human study of the novel BTK degrader BGB-16673 demonstrate a tolerable safety profile and clinical responses in heavily pretreated pts with B-cell malignancies, including those with BTKi-resistant disease. Substantial reductions in BTK protein levels in peripheral blood and tumor tissue were also observed, demonstrating proof-of-concept of a strong, on-target effect.

Time-Limited Bendamustine, Rituximab, and Venetoclax (BR-VR) in Untreated Chronic Lymphocytic Leukemia (CLL): High Rates of Undetectable Minimal Residual Disease Remissions

Background: Despite the efficacy of venetoclax (VEN) in frontline CLL, optimal combination regimens and duration of treatment remain unclear. We hypothesized that cytoreduction with bendamustine/rituximab (BR) induction followed by venetoclax/rituximab (VR) consolidation for a fixed 1-year duration would be associated with an increased rate of undetectable minimal residual disease (uMRD) compared to historical controls and a reduction in the risk of tumor lysis syndrome (TLS). Here we report updated data from a fully-enrolled ongoing phase 2 multicenter, US, single-arm, open-label study (NCT03609593) designed to assess the safety and efficacy of BR-VR in previously untreated CLL patients (pts). Methods: Previously untreated CLL/SLL pts ≥ 18 years requiring therapy per iwCLL criteria initially received 3 cycles of bendamustine 50-90 mg/m 2 daily for 2 days and rituximab 375 mg/m 2 every 28 days for 3 cycles. Following BR, VEN was initiated with a standard dose escalation from 20 mg to 400 mg daily over 5 weeks. This was followed by 6 cycles of VR with rituximab given monthly and 5 cycles of VEN alone (12 cycles of VEN in total). Additional eligibility included: ECOG PS ≤ 2, hemoglobin ≥8g/dL, ANC ≥1000/mm 3, and platelets ≥50,000/mm 3. Response was assessed by 2018 iwCLL criteria with uMRD testing by central flow cytometry at a level of <10 -4 in peripheral blood (PB) and bone marrow (BM). The primary endpoint was objective response rate (ORR). Secondary endpoints included uMRD rate, time to uMRD, and adverse events (AEs) assessed by CTCAE v 5.0. Results: As of data cutoff on 15 July 2023, 42 pts were accrued. Baseline demographics were as follows: male/female (29/13), median age 61.5 yrs (range 38-84). Baseline prognostic studies showed unmutated IGHV in 22 (52%) pts, TP53 aberrant (either del(17p) and/or TP53 mutation) in 2 (5%) pt, del(11q) in 3 (7%) pts, and complex karyotype in 11 (26%) pts. TLS risk among 24 evaluable pts at baseline was high (H) in 9 (21%), medium (M) in 22 (52%), and low (L) in 6 (26%). At a median follow-up of 16.6 mo. (range, 3-40), 37 pts remain on study. Of 29 pts with at least 15 mo. follow-up (completing all therapy), the ORR was 100% (79% CR/CRi, 21% PR [due to small residual nodes]). 3 pts died on study (2 due to COVID-19 and 1 developed newly metastatic squamous cell carcinoma and taken off study after achieving a CR post-VEN ramp-up). 1 pt was lost to follow-up while in a CR. Bendamustine was administered at doses of 50 mg/m 2 in 11%, 70 mg/m 2 in 13%, and 90mg/m 2 in 76% of pts. In 38 evaluable pts, response assessments after cytoreduction with BR demonstrated 16% of pts achieved CR/CRi and 84% achieved PR. For evaluable pts at 16 mo., uMRD (<0.01%) in the PB and BM was observed in 80% (20/25) and 78% (18/23) of pts, respectively. MRD was intermediate (0.01% - <1.0%) in 17% (4 patients) in BM (Figure 1 ORR and MRD). Median time to uMRD was 11 mo. (range 3-15) in PB and 10 mo. (range 2.6-15) in BM. The most common treatment-emergent AEs during BR induction were (any grade/grade ≥3) anemia in 15/4 (36%/10%) pts, nausea in 9/0 (21%/0%), neutropenia in 12/8 (29%/19%), rash in 12/1 (29%/2%), constipation 7/0 (17%/0%), and infusion reactions in 7/1 (17%/2%). 2 pts (5%) developed febrile neutropenia during BR. Emergent AEs during VEN treatment included neutropenia in 21/13 (50%/31%), diarrhea in 18/0 (43%/0%) pts, leukopenia in 14/4 (24%/10%), and nausea in 11/0 (26%/0%). TLS risk was substantially reduced after BR lead-in. Of 9 H-risk pts at baseline, 1 remained H-risk after BR; of 16 M-risk pts, 5 remained M-risk, with the remainder at L-risk (89% reduction in H-risk TLS). Conclusions: BR-VR is a safe and well-tolerated regimen in untreated CLL pts. BR debulking substantially reduces TLS risk, and this sequential strategy achieves high rates of PB and BM uMRD across all prognostic risk groups.

Extended Follow-up and Resistance Mutations in CLL Patients Treated with Acalabrutinib

Background: Covalent Bruton tyrosine kinase inhibitor (cBTKi) is a standard treatment for chronic lymphocytic leukemia (CLL). Understanding of acquired resistance to cBTKi therapy has largely come from data on patients (pts) treated with the first-in-class cBTKi ibrutinib. Mutations in BTK C481 and to a lesser extent PLCG2 are frequently detected in ibrutinib-treated pts at the time of progressive disease (PD). In contrast, much less is known about genetic mechanisms of drug resistance in pts treated with next generation cBTKi acalabrutinib and zanubrutinib. A recent study identified 3 pts with BTK C481 mutations and no pts with PLCG2 mutations among 8 acalabrutinib-treated pts with progressive disease (PD) (Black, et al. Blood 2022). A second study found a kinase-dead BTK L528W mutation in 7/13 zanubrutinib-treated pts (Blombery, et al. Blood Adv 2022). Although cBTKi share the same mechanism of action by binding to BTK C481, the latter report discloses differences in clonal selection and underscores the need for further investigation in pts treated with next generation cBTKi. In a phase 2 study of acalabrutinib in pts with treatment naïve (TN) CLL or small lymphocytic lymphoma (SLL) with 17p deletion, or TP53 or NOTCH1 mutation, or relapsed/refractory (R/R) CLL/SLL regardless of cytogenetics or somatic mutations (Sun, et al. Blood 2020), we sought to understand clonal evolution during treatment. Methods: Peripheral blood mononuclear cells (PBMCs) were collected from 48 pts at baseline, after 6 months, then annually on treatment until PD. Current analysis includes 14 PD pts [excluding 3 Richter transformation (RT) pts] comprising 10 R/R and 4 TN CLL pts. Additionally, paired baseline and PD bone marrow (BM) from 6 pts and lymph node (LN) samples from 2 pts were included. Targeted next-generation sequencing of ~700 recurrently mutated genes in hematological malignancies (Collins, et al. Leuk Lymphoma. 2021) was performed using DNA isolated from CD19 + enriched cryopreserved PBMCs and BM aspirates, as well as fresh-frozen core LN biopsies. Filtered variants in putative CLL driver genes (Knisbacher, et al. Nat Genet. 2022) with variant allele frequencies (VAF) ≥1% for BTK and PLCG2, ≥5% for variants with known oncological significance, and ≥7.5% for all other variants were included in downstream analysis. Results: After a median follow-up of 6.5 years (IQR 2.9-6.3), 23/48 (48%) pts developed PD (20 CLL, 3 RT). PD occurred in 17/32 (53%) R/R pts and 6/16 (38%) TN pts. Median progression-free survival was reached at 6.0 years. Best response was complete remission in 2/20 (10%) pts and partial remission in 18/20 (90%) pts with CLL PD. IGHV was unmutated in all but one PD patient. At baseline, 34 CLL driver genes were mutated in 41/45 pts (91%; excluding 3 RT pts) with most mutations in NOTCH1, TP53, ATM, SF3B1, BIRC3, and NFKBIE. During acalabrutinib treatment but before PD, 14/45 pts (31%; 8 R/R and 6 TN) acquired mutations in 11 driver genes, most commonly in BRAF (n=4), CREBBP (n=4), and KMT2D (n=2). At the time of PD, 11/14 pts (79%) had newly acquired mutations in 4 genes, predominantly BTK (n=6) and PLCG2 (n=4). BTK C481 mutations (VAF 2-42%) were detected in 6/14 (43%; 4 R/R and 2 TN) pts and T474I mutation (VAF 4-46%) in 3/14 (21%; 1 R/R and 2 TN) pts. Paired BM samples in 2 pts and LN samples in 2 pts showed the same BTK mutations as PBMCs with similar VAFs. PLCG2 mutations (VAF 1-8%) were found in 4/14 (29%; 2 R/R and 2 TN) pts. BTK C481 co-occurred with BTK T474I in 3 pts, but on different sequencing reads suggesting independent subclones, and with a PLCG2 mutation in 1 pt. There have been no pts with BTK L528 mutations. In conclusion, mutations in BTK and PLCG2 are the predominant resistance mechanism to acalabrutinib. Among BTK mutations, C481 was the most common. All T474I mutations co-occurred with C481.

Cumulative Review of Hypertension in Patients with Chronic Lymphocytic Leukemia (CLL) and Other Hematologic Malignancies Treated with Acalabrutinib

Background: Patients (pts) with CLL have a high rate of comorbidities, including cardiovascular disease (CVD). Comorbid CVD is correlated with higher mortality in this pt population. Hypertension (HTN) is the most common concurrent CVD in pts with CLL and is associated with development of complications such as stroke and heart failure. The incidence of new or worsening HTN in treatment-naive CLL pts receiving placebo within the CLL12 trial was 8.3% over a 69.3-month observation period (Langerbeins et al. Hematol Oncol. 2023). New and/or worsening HTN has been observed in pts with CLL treated with Bruton tyrosine kinase inhibitor (BTKi) therapy. Studies have shown new or worsening HTN with ibrutinib (7−30%) and zanubrutinib (11−20%) (Christensen et al. Expert Rev Hematol. 2022). Acalabrutinib (acala), a selective, second-generation BTKi, demonstrated a lower rate of HTN (8.6%) vs ibrutinib (22.8%) in the head-to-head ELEVATE-RR study at a median follow-up of 40.9 months (Byrd et al. J Clin Oncol. 2021). Here, we performed a cumulative analysis of new or worsening HTN from the acala global development program and compared these data against real-world prevalence and incidence of HTN for pts with CLL prior to treatment initiation using claims data. Methods: Safety reports of new or worsening HTN were obtained from 11 clinical trials with acala (the safety database analysis comprised 2034 pts from studies in CLL [86.3%] and mantle cell lymphoma [6.1%], with the remainder from other B-cell malignancies). The clinical trials analyzed included therapy with acala (monotherapy or in combination with obinutuzumab) and active comparator groups (described in Table 1). Using the narrow Standardized MedDRA Query and the related MedDRA preferred terms for “HTN,” exposure-adjusted incidence rates in events/100 person-years were determined, and as a comparison, HTN prevalence was assessed at median treatment exposure for acala monotherapy. HTN prevalence (proportion of pts with HTN 6 months before treatment initiation) and incidence rates (number of new cases of HTN per 100 person-years during the 5 years before any treatment initiation) were also assessed based on ICD-10 codes from 3 adjudicated closed claims databases (Optum, MarketScan, and IQVIA). Results: In the claims database analysis, prevalence of HTN ranged from 47.3% to 66.1% in pts with TN CLL prior to treatment initiation. HTN prevalence with acala monotherapy at median treatment exposure (45.5 months) was 55.7%. Exposure-adjusted incidence rates of HTN were analyzed from 11 clinical trials; 1225 pts received acala monotherapy (947 pts with CLL), 223 pts received acala + obinutuzumab (all pts with CLL), 264 pts received ibrutinib as a comparator (all pts with CLL), and 322 pts received other comparators (all pts with CLL). Among the 1225 pts treated with acala monotherapy, 165 pts (147 with CLL) experienced a treatment-emergent adverse event of HTN (median age 66 years; 66.1% [n=109] male; 59.4% [n=98] with history of HTN at baseline). The exposure-adjusted incidence rates of HTN with acala monotherapy (3.844) and acala + obinutuzumab (3.926) were similar to that of other comparators (4.788 [excluding ibrutinib]) ( Table 1). In the ELEVATE-RR study specifically (subgroup of the current analysis), the exposure-adjusted incidence rate of HTN with acala (3.053) was approximately one-third that of ibrutinib (8.590). The exposure-adjusted incidence rate of HTN in pts treated with acala monotherapy without history of HTN was 3.239. Conclusions: Our data showed that HTN is a common comorbidity in pts with CLL as demonstrated in the claims database and clinical trial database analyses where 59.4% of pts who experienced HTN with acala monotherapy had history of HTN at baseline. The incidence rates of new or worsening HTN with acala monotherapy and acala + obinutuzumab were low (3.844 and 3.926, respectively). This is supported by similar incidence proportion of new or worsening HTN in pts receiving placebo (8.3%) from CLL12 (median follow-up 69.3 months) and acala monotherapy (8.9%) from ELEVATE-TN (median follow-up 58.2 months; Sharman et al. EHA. 2022), and similar HTN prevalence at median treatment exposure vs before treatment initiation in claims databases. Our analysis, conducted predominantly in patients with CLL, suggests that acala monotherapy did not worsen pre-existing HTN or increase the risk of new-onset HTN.

Impact of Baseline Comorbidities and Treatment on Cardiovascular (CV) Outcomes in Patients with Chronic Lymphocytic Leukemia (CLL): Results of a Systematic Literature Review (SLR) of Interventional Trials and a Targeted Literature Review (TLR) of Real-World Observational Studies in CLL

Background: Ibrutinib, the first Bruton tyrosine kinase inhibitor (BTKi) indicated for CLL, has been associated with a higher risk of CV events, including atrial fibrillation (AF) and hypertension, vs non-BTKi active comparators and placebo. In a phase 3 clinical trial of patients (pts) with CLL comparing ibrutinib with acalabrutinib-a more selective, second-generation BTKi-CV event incidence was numerically higher with ibrutinib and the incidence and cumulative risk of AF were significantly higher with ibrutinib (Byrd JC et al. J Clin Oncol. 2021;39:3441-52). Ibrutinib's toxicity profile prompted changes to its prescribing information and lowered its recommendation status in current CLL guidelines. We conducted an SLR of interventional trials in CLL followed by a supplemental TLR of observational studies in CLL to explore the extent to which CV outcomes of pts with CLL are driven by their baseline comorbidities or treatments. Methods: Embase and MEDLINE were searched to identify evidence in peer-reviewed journals (cutoff date: June 23, 2023). For the SLR, limits were English articles published in 2012 or later, and inclusion criteria specified phase 2/3 interventional trials in adults aged ≥18 y with treatment-naive or relapsed/refractory CLL. Treatments included BTKis, BCL-2 inhibitors, and chemoimmunotherapy. CV outcomes were arrhythmia, heart failure, major adverse CV events, major bleeding, myocardial infarction, stroke, sudden cardiac death, and venous thromboembolism. For the TLR, language and time limits were analogous to the SLR. Additional limits were observational studies with >70% CLL pts receiving any or no treatment. The TLR assessed baseline CV events/risk, including arrhythmia, heart failure, major adverse CV events, major bleeding, myocardial infarction, stroke, sudden cardiac death, and venous thromboembolism. Results: The SLR yielded 55 studies. Among the phase 3 randomized controlled trials, incidence ranges were 0%-16% for AF/atrial flutter, 0%-6.9% for heart failure, and 0%-11% for major bleeding; rates were generally higher with BTKis, among which ibrutinib appeared to be associated with the highest rates ( Figure 1). CV data from the SLR were sparse and heterogeneous, primarily due to limited baseline CV risk reporting and substantial variability in CV adverse event reporting. To clarify relationships of CV risk with treatment, we performed the TLR, which yielded 24 studies. Analysis of baseline CV risk reported in the observational studies yielded several key findings ( Figure 2): 1) in pts with CLL, the risk of CV events, including AF, increased with age; in pts aged 65−74 y and ≥65 y, the reported risk of AF was 2.4-fold and 2.8-fold higher, respectively, than that of pts aged <65 y (Shanafelt TD et al. Leuk Lymphoma. 2017;58:1630-9; Visentin A et al. Hematol Oncol. 2019;37:508-12); 2) baseline CV risk was similarly high in pts with CLL and matched non-CLL comparators (Larsson K et al. Am J Hematol. 2022;97:E255-7); 3) ibrutinib was associated with a higher risk of CV disease relative to chemotherapy, even when prior AF, age, and anticoagulant exposure were controlled for (Abdel-Qadir H et al. J Clin Oncol. 2021;39:3453-62). In ibrutinib-treated pts with a B-cell malignancy followed in cardio-oncology clinics (N=53; n=38 CLL), median time to new onset of ibrutinib-related AF was 5.5 mo; AF incidence was 15-fold higher in ibrutinib-treated pts overall vs that expected in an age- and sex-comparable general population and in ibrutinib-treated pts with CLL vs that expected in pts with CLL and no ibrutinib treatment (Baptiste F et al. Open Heart. 2019;6:e001049). Conclusions: CLL primarily affects the elderly, who are at higher risk of CV events vs a younger demographic. Results suggest that some pts with CLL have an increased risk of adverse CV outcomes; thus, it would be inaccurate to attribute the higher rates of CV events observed in pts with CLL solely to their treatment as it is plausible that pts with CLL already have an elevated CV risk contributing to such outcomes. However, our findings suggest that the first-generation BTKi (ibrutinib) may impact CV outcomes in these pts; data examining the CV risk of second-generation BTKis and other novel therapies (eg, venetoclax) are limited. Future research that consistently estimates baseline CV risk and closely monitors CV parameters in pts with CLL is required to ascertain the true risk of CV disease due to CLL treatment.

Real-world (RW) dosing patterns and outcomes among chronic lymphocytic leukemia (CLL) patients (pts) with or without an ibrutinib (IBR) dose adjustment (DA) in first-line (1L).

7537 Background: Pts treated for CLL with IBR, a once-daily Bruton’s tyrosine kinase inhibitor with dosing flexibility options, may adjust their daily dose to help prevent recurrence or worsening of adverse events, while preserving efficacy. This RW study describes outcomes for CLL pts treated with 1L IBR who did or did not have a DA. Methods: Electronic medical records from the Acentrus database (1/1/2016-4/30/2022) were used to identify CLL pts initiated on 1L IBR (index date). The first 6 months post-index were used to identify pts who remained on a starting dose of 420mg/day or with a DA (reducing to a dose lower than 420mg/day; reasons for DA not available). Treatment adherence (measured by proportion of days covered [PDC] and medication possession ratio [MPR]) and time to next treatment (TTNT) were described for patients with and without a DA. Descriptive analyses are reported for all pts and among a subgroup of pts with high cardiovascular (CV) risk, defined as having a pre-existing CV comorbidity or a high CV risk score (CV subgroup). Results: 1,171 CLL patients were initiated on 1L IBR at the recommended dose of 420mg/day (Table). Of those, 1,038 (88.6%) remained on 420 mg for ≥6 months (mean age=70.2 years, 33.6% female, median follow-up: 30.5 months); 229 (19.6%) had a DA at any time post-index (median time to DA: 5.5 months) and 126 had the DA during the first 6 months (mean age=72.2 years, 42.9% female, median follow-up: 35.1 months). Mean PDC and MPR were descriptively higher in pts with a DA (overall: PDC=0.81, MPR=0.84; CV subgroup: PDC=0.78, MPR=0.81) relative to pts with no DA (overall: PDC=0.70, MPR=0.73; CV subgroup: PDC=0.69, MPR=0.72). Median TTNT was not reached for pts with or without a DA; 12-month Kaplan-Meier (KM) rates were similar for pts with a DA (overall: 89.1%; CV subgroup: 92.7%) and with no DA (overall: 92.5%; CV subgroup: 92.0%). Conclusions: Among CLL pts initiating 1L with standard-of-care IBR, 19.6% had a DA. Those with a DA had descriptively higher treatment adherence with no detriment to TTNT, relative to those who maintained 420mg/day starting dose, regardless of baseline CV risk. These findings are consistent with other RW studies and suggest that IBR DA can be an effective treatment strategy that does not negatively affect efficacy while being well-tolerated outside of clinical trials. [Table: see text]

Results of a phase 3 study of IVO vs IO for previously untreated older patients (pts) with chronic lymphocytic leukemia (CLL) and impact of COVID-19 (Alliance).

7500 Background: The Bruton’s tyrosine kinase inhibitor (BTKi) ibrutinib +/- anti-CD20 antibody obinutuzumab (IO) is a standard frontline regimen for older adults with CLL. BTKi alone do not often lead to complete response (CR) or undetectable minimal residual disease (uMRD), thus are given indefinitely. Smaller trials showed that IO plus venetoclax (IVO) can induce uMRD CRs which may allow successful discontinuation. Methods: Alliance for Clinical Trials in Oncology A041702 is a multicenter trial designed to evaluate if IVO with response-guided discontinuation of I improves progression free survival (PFS) versus IO with indefinite I in treatment-naïve, older CLL pts. IO is given in standard fashion, and in the IVO arm V is added at C3D1 and continued until C14D28. After 14 cycles, pts undergo response evaluation including CT scans and bone marrow biopsy with central MRD assessment by flow cytometry. Pts in IVO arm with uMRD CR discontinue I; all others continue I until progression or unacceptable toxicity. Eligible pts were age ≥70 years (amended to ≥65). Pts had CrCl ≥ 40 mL/min, bilirubin ≤ 1.5 x ULN, and no other life-limiting intercurrent illness. Pts were stratified based on Rai stage and +/- del17p13.1 by FISH, and randomized 1:1 to IO:IVO. With 431 evaluable pts, the trial had 90% power to detect significant improvement in PFS using a one-sided log-rank test with one-sided type 1 error rate of 2.5%. The Alliance DSMB approved release of data on Nov 4, 2022 after meeting the protocol defined futility threshold at the second planned event-driven interim analysis. Data were locked on December 15, 2022. Results: Between January 4, 2019 and July 15, 2022, 465 pts were registered (IO:232, IVO:233). Median age was 74; 67% of pts were men. Rai stage 3-4 was seen in 55% and del17p in 13%. With median follow-up of 14 months, PFS of IO was 87.5% compared to 85% on IVO. Events were observed in 29 pts on IO (4 progressions, 23 deaths, 2 pts started other therapy) and 35 on IVO (7 progressions, 28 deaths). The predefined futility boundary was crossed, with a hazard ratio (HR) of 1.20 (95% CI: 0.73-1.97) in favor of IO. COVID-19 was the leading cause of death in both arms, (11 COVID-19 deaths on IO, 19 on IVO), with 13 and 11 additional deaths from other causes, respectively. Censoring pts with COVID-19 related deaths, PFS HR is 0.82 (95% CI: 0.44-1.53) in favor of IVO. Grade 3+ toxicity and discontinuation in year 1 of therapy were similar between arms. Conclusions: This study demonstrates that PFS for IVO is not superior to IO for treatment-naive older CLL pts in the setting of the COVID-19 pandemic. Study treatment is ongoing, and long-term follow-up will determine if there are advantages to IVO, with special attention to MRD and therapy discontinuation. Support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org . Clinical trial information: NCT03737981 .

GENOMIC EVOLUTION AND RESISTANCE TO PIRTOBRUTINIB IN COVALENT BTK‐INHIBITOR PRE‐TREATED CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS: RESULTS FROM THE PHASE I/II BRUIN STUDY

GENOMIC EVOLUTION AND RESISTANCE TO PIRTOBRUTINIB IN COVALENT BTK‐INHIBITOR PRE‐TREATED CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS: RESULTS FROM THE PHASE I/II BRUIN STUDY

Five-year follow-up update of defined-composition CD19 CAR T-cell therapy for relapsed/refractory CLL.

7511 Background: We have described high response rates in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) treated with CD19-targeted CAR T cells. We now report comprehensive analyses of factors associated with duration of response (DOR) with a 68-month median follow-up. Methods: We included 49 pts with R/R CLL and/or Richter’s transformation (n = 10) treated on a phase I/II clinical trial of defined-composition CD19 CAR T-cell therapy (1:1 ratio of CD8+:CD4+). Response rates were investigator-assessed by 2018 iwCLL criteria. Measurable residual disease (MRD) in bone marrow (BM) was evaluated by multiparameter flow cytometry (MFC) and IGH next-generation sequencing (NGS; clonoSEQ assay). CAR T-cell enumeration was assessed by MFC. Serum cytokine concentrations (20 analytes) were measured by Luminex assay. Univariate associations between duration of response (DOR) and patient, disease, CAR T-cell manufacturing, and treatment-related variables were estimated using Cox regression (50+ variables). Association between CAR T-cell in vivo persistence and DOR was modeled with a time-dependent Cox model including blood CAR transgene levels (copies/µg genomic DNA). Results: Median age was 61 years (IQR, 55-67). Forty-six pts (94%) had complex karyotype and/or 17p deletion; 46 (94%) received cyclophosphamide/fludarabine lymphodepletion. In the response-evaluable cohort (n = 47), median follow-up was 68.3 months (IQR, 54.3-81.6). Overall and complete response rates at day+28 were 70% and 17%, respectively, and the median DOR was 22.2 months (95% CI, 10.7-not reached [NR]). MRD-negativity at day+28 by MFC occurred in 33/47 (70%). In pts with MRD-negativity by MFC and available data, MRD negativity by NGS was seen in 18/29 (62%). In NGS MRD-negative responders, the median DOR was 56.8 months (95% CI, 39.5-NR). In all evaluable patients, the 5-year OS and PFS were 35.5% (95% CI, 24.0%-52.5%) and 21.5% (95% CI, 12.0%-38.5%), respectively. In univariate Cox regression, day+28 MRD-negativity by MFC (HR = 0.03, 95% CI, 0.01-0.18, p < 0.001), day+28 MRD-negativity by NGS (HR = 0.21, 95% CI, 0.07-0.61, p = 0.004), peak CD8+ CAR T-cell expansion (HR = 0.49, 95% CI, 0.24-1.00, p = 0.05), CAR T-cell persistence (HR = 0.71, 95% CI, 0.54-0.91, p = 0.01), and lower peak MIP-1β (HR = 3.12, 95% CI, 1.13-8.65, p = 0.03) were associated with longer DOR. Peak MIP-1β remained associated with DOR (HR = 3.83, 95% CI, 1.35-10.9, p = 0.012) in a multivariable model including pre-LD CLL cells in BM, tumor cross-sectional area, peak CD8+ CAR T-cell expansion, and day+28 MRD by MFC. Conclusions: CD19 CAR T-cell therapy achieved durable remissions in R/R CLL pts. Day+28 MRD, CAR T-cell peak expansion, and CAR T-cell persistence were strongly associated with DOR. Lower peak serum levels of MIP-1β, a cytokine known to be produced by CLL cells upon BCR activation, was strongly and independently associated with DOR. Clinical trial information: NCT01865617 .

Outcomes of Therapies and Resistance Mutations Following Non-Covalent Bruton's Tyrosine Kinase Inhibitor Treatment for Patients with Chronic Lymphocytic Leukemia and Richter Transformation

Background: Non-covalent Bruton's Tyrosine Kinase inhibitors (ncBTKi) have shown excellent clinical activity for patients (pts) with relapsed and/or refractory chronic lymphocytic leukemia (CLL) and Richter Transformation (RT). However, some pts treated with ncBTKi develop progressive disease (PD). In addition, acquired BTK mutations (mut) at the time of PD on ncBTKi were recently described, although the frequency at which these mut occur has not been reported. Currently, data regarding treatment sequencing post ncBTKi are lacking but are critical to guide further treatment selection. Methods: We conducted a retrospective, multicenter study of pts treated with any ncBTKi for CLL or RT who have discontinued ncBTKi for any reason. Using a standardized template we collected: pt and disease characteristics (including prior therapies, cytogenetic/molecular characteristics), demographics, clinical response to ncBTKi and subsequent therapies, and survival. Data on 2 lines of therapies (LOT) following ncBTKi were collected for each pt. Primary endpoint was overall response rate (ORR) for therapies following ncBTKi. Progression free survival (PFS) was estimated using the Kaplan Meier method. We also collected next generation sequencing (NGS) data for CLL pts who discontinued ncBTKi. Analyses were performed using STATA 17.0. Results: We identified 63 pts (48 CLL, 15 RT) treated with who then discontinued ncBTKi. Baseline characteristics at ncBTKi start are presented in Table 1. Median number of prior therapies was 4 (1-10), and most pts received prior covalent BTKi (93.7%) and venetoclax (57.1%). At ncBTKi start, 84.8% of patients had unmutated IGHV, 48.8% had a TP53 mut and 37.0% had a complex karyotype. ORR to ncBTKi was 58.8% for the CLL cohort (PR 54.4%, PR-L 4.4%) and 46.7% for the RT cohort (CR 6.7%, PR 40%). Median duration of ncBTKi exposure prior to discontinuation was 9 (1-27) and 4 (1-12) months for CLL and RT, respectively. Overall, 73.7% of the combined cohort progressed on ncBTKi. Specific reasons for ncBTKi discontinuation included: CLL PD (n=26, 41.2%), PD of existing RT (n=7), death not secondary to PD or toxicity (n=6), other reason (n=6), stem cell transplant (SCT, n=5), toxicity (n=4), PD of CLL to RT (n=4), MD/pt preference (n=2), CAR T (n=2), and sudden death on therapy (n=1). Following ncBTKi, 76.2% of pts (n=48) received another LOT. Therapies and responses are presented in Table 1. Common treatment strategies were: chemo+/-immunotherapy (CIT) (n=16, ORR 18.8%), CD19-directed CAR T-cell therapy (n=7, ORR 85.7%), allogeneic SCT (n=6, ORR 83.3%), and venetoclax-based therapy (n=10, ORR 70.0%). 27.3% of therapies administered post ncBTKi were administered on a clinical trial. For CLL pts, median PFS for first LOT following ncBTKi was 14 months (n=25 pts, Figure 1). For the RT cohort, the median PFS for the first LOT following ncBTKi discontinuation was 6 months (median follow-up 2.5 months). Importantly, median PFS for venetoclax following ncBTKi discontinuation for CLL pts was 14 months (8 pts, 87.5% venetoclax-naive, median follow-up 10.5 months). 49.2% of the overall cohort has died, with 58.6% of deaths due to CLL or RT (n=17 of 29 pts with available data). 15 CLL pts who discontinued ncBTKi for PD had end of treatment NGS data available. For these pts, at the start of ncBTKi, BTKC481 mut and PLCG2 mut were present in 38.5% and 33%, respectively. At end of ncBTKi treatment, novel (not C481) BTK mut were identified in 9 of 15 pts (60.0%). These included mut in BTKL528W (n=6), BTKV416L (n=2) and BTKT474I (n=2); 1 pt had mut in both BTKT474I and BTKL528W. Additionally, 4 pts had pre-existing mut in PLCG2 that persisted at PD. Overall, 11 of 15 (73.3%) of CLL pts had a novel BTK mut and/or a persistent PLCG2 mut at PD on ncBTKi. Conclusions: We report results from the first series of CLL and RT pts following ncBTKi discontinuation. CIT for RT and CLL yielded poor outcomes, while CAR T-cell therapy and allogeneic SCT had high ORR warranting further investigation. Most importantly, venetoclax has clinical activity (high ORR, durable PFS) for CLL pts following ncBTKi discontinuation suggesting CLL pts can stay within the BTKi class prior to switching to venetoclax. In addition, at PD 73% of pts had a novel BTK mut and/or the persistence of a PLCG2 mut conferring resistance to ncBTKis. Overall, these results highlight an unmet need for novel therapeutic strategies for pts who require treatment following ncBTKi. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal