Treatment-naive Chronic Lymphocytic Leukemia Research Articles

P66Shc deficiency in CLL cells enhances PD-L1 expression and suppresses immune synapse formation.

Introduction: Escape from immunosurveillance is a hallmark of chronic lymphocytic leukemia (CLL) cells. In the protective niche of lymphoid organs, leukemic cells suppress the ability of T lymphocytes to form the immune synapse (IS), thereby hampering T-cell mediated anti-tumoral activities. By binding its cognate receptor PD-1 at the surface of T lymphocytes, the inhibitory ligand PD-L1, which is overexpressed in CLL cells, mediates the T-cell suppressive activities of CLL cells. However, the molecular mechanism underlying PD-L1 overexpression in CLL cells remains unknown. We have previously reported a defective expression of the pro-apoptotic and pro-oxidant adaptor p66Shc in CLL cells, which is causally related to an impairment in intracellular reactive oxygen species (ROS) production and to the activation of the ROS-sensitive transcription factor NF-κB. The fact that PD-L1 expression is regulated by NF-κB suggests a mechanistic relationship between p66Shc deficiency and PD-L1 overexpression in CLL cells. Methods: 62 treatment-naive CLL patients and 43 healthy donors were included in this study. PD-L1 and p66Shc expression was quantified in B cells by flow cytometry and qRT-PCR. IS architecture and local signaling was assessed by flow cytometry and confocal microscopy. CD8+ cell killing activity was assessed by flow cytometry. Results: Here we show that residual p66Shc expression in leukemic cells isolated both from CLL patients and from the CLL mouse model Eμ-TCL1 inversely correlated with PD-L1 expression. We also show that the PD-L1 increase prevented leukemic cells from forming ISs with T lymphocytes. Reconstitution of p66Shc, but not of a ROS-defective mutant, in both CLL cells and the CLL-derived cell line MEC-1, enhanced intracellular ROS and decreased PD-L1 expression. Similar results were obtained following treatment of CLL cells with H2O2 as exogenous source of ROS, that normalized PD-L1 expression and recovered IS formation. Discussion: Our data provide direct evidence that the p66Shc-deficiency-related ROS depletion in CLL cells concurs to enhance PD-L1 expression and provides a mechanistic basis for the suppression of T cell-mediated anti-tumoral functions in the immunosuppressive lymphoid niche.

Elevate-TN: Impact of First-Year Dose Modifications in Patients with Treatment-Naive Chronic Lymphocytic Leukemia Treated with Acalabrutinib

Background: Acalabrutinib (acala), a second-generation Bruton tyrosine kinase inhibitor (BTKi), with or without obinutuzumab (obin), demonstrated superior progression-free survival (PFS) compared with obin plus chlorambucil in patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL) in the phase 3 ELEVATE-TN (NCT02475681) trial. Despite the long-term benefits observed with acala therapy, data from real-world studies in patients with CLL demonstrate that 22% of patients discontinue acala treatment for any reason in the first year of treatment across therapy lines (Roeker et al. Blood. 2022). To assess the impact on survival outcomes of acala discontinuation and dose modifications occurring in the first year of treatment, we conducted a post hoc analysis in patients treated in the acala-containing arms of ELEVATE-TN. Methods: Patients who received acala 100 mg twice daily with or without obin (fixed duration, up to 6 cycles) with at least 1 year of follow-up were included in this analysis. The impact of dose reductions, treatment breaks, or treatment discontinuations in the first year on overall survival (OS) was assessed. Protocol-specified dose-modification guidelines that included dose reductions, breaks, and discontinuations depending on severity and frequency were applied to patients with apparent treatment-related toxicity. To assess the impact of dose reductions, breaks, or discontinuations, patients were divided into 4 dose-modification subgroups: 1) patients with no dose reductions/breaks >14 days during the first year; 2) patients with dose reductions >14 days, but no breaks >14 days during the first year; 3) patients with breaks >14 days, but who continued treatment in the first year; and 4) patients who discontinued treatment during the first year. Results: With a median follow-up of 60 months, 358 patients (n=179, acala monotherapy; n=179, acala-obin) with ≥1 year of follow-up were included in this analysis. In the first year, 269 (75%) patients had no dose reductions/breaks >14 days, 11 (3%) patients had dose reductions >14 days but no breaks >14 days, 32 (9%) patients had breaks >14 days but continued treatment, and 46 (13%) patients discontinued treatment. Reasons for treatment discontinuation during the first year were adverse events (n=26), disease progression (n=7), physician decision (n=5), consent withdrawn (n=3), death (n=2), loss to follow-up (n=1), and other (n=2). Patients who discontinued treatment within the first year had inferior OS compared with patients who did not require dose reductions or breaks (OS hazard ratio [HR]: 8.39, 95% confidence interval [CI]: 3.96-17.8, P<0.0001; Figure 1). In contrast, patients who had dose reductions or breaks >14 days but did not discontinue treatment had statistically similar OS to patients who did not require dose reductions or breaks. Within the group that had no dose reductions or treatment breaks >14 days, there was no difference in the proportion of patients treated with acala monotherapy (n=133) and acala-obin (n=136). However, OS outcomes in this subgroup of patients with no treatment modifications were superior in patients treated with acala-obin compared with those treated with acala monotherapy (HR: 0.37, 95% CI 0.15-0.87, P=0.0183; Figure 2). Conclusions: This post hoc analysis of acala-treated patients with TN CLL in ELEVATE-TN demonstrated superior OS in patients who did not have dose reductions or breaks compared with patients who discontinued treatment within the first year. OS outcomes in patients who required dose reductions or breaks but did not discontinue treatment in the first year were similar to those in patients who did not require dose modification. Accepting the limitations of retrospective analysis, these data suggest that patients who are unable to tolerate standard-dose acala or who require treatment breaks may benefit from continuing or resuming treatment at a reduced dose rather than stopping treatment altogether. For patients who do not require dose modifications, ongoing follow-up of the ELEVATE-TN trial suggests durable and incrementally improved OS benefit from the addition of obin to acala.

The Impact of Fitness and Dose Intensity on Safety and Efficacy Outcomes after Venetoclax-Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia

Introduction Following the results of two phase-III studies, the CLL14 study, recruiting elderly and unfit patients (pts) with chronic lymphocytic leukemia (CLL), and the CLL13 study, recruiting younger and fit pts, venetoclax-obinutuzumab (Ven-Obi) is a standard of care for pts with treatment-naive CLL. However, it is unclear whether age and/or fitness have an impact on the tolerability and efficacy of Ven-Obi. Furthermore, the impact of dose reductions on response and survival has not been explored yet. Here, we present a pooled analysis detailing the toxicity and efficacy of Ven-Obi in pts treated within the CLL13 and CLL14 studies. Methods Patients randomized to the Ven-Obi arm in CLL14 (2015-2016) and CLL13 (2016-2019) with at least one dose of study drug were considered and categorized as fit or unfit pts (cumulative illness rating scale [CIRS] > 6 and/or creatinine clearance < 70 ml/min). Patients with TP53 aberrations were excluded to ensure balanced features across the CLL13 and CLL14 populations. Correlations regarding minimal residual disease (MRD) in peripheral blood and response (both assessed at the end of treatment [EOT]) were assessed by chi² test. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier methodology and Cox proportional hazard regression modeling. Dose intensity was calculated as the relative fraction within the administered treatment cycles (excluding pts with treatment discontinuation due to PD/death). Adverse events were analyzed up to 28 days after EOT. Results In total, 410 pts were considered for this analysis, 228 from CLL13 and 182 from CLL14. The median observation time was 49 months (interquartile range [IQR] 37.0-65.8 months); for CLL13, median observation time was 38.9 months (IQR 33.8-46.3), and 66.7 months in CLL14 (IQR 64.4-70.8). Median age at enrollment was 67 years (IQR 58-73); 55.7% were grouped as unfit (median age 72), 44.3% as fit (median age 58) ( A). Overall response rate (ORR) was 89.5% in unfit and 96.1% in fit pts (p=0.011), CR rates were 51.8% and 54.1% (p=0.63), respectively. The undetectable MRD (<10 -4) rates were 80.3% in unfit and 85.1% in fit pts (p=0.2). The 3-year-PFS rates were 86.4% in unfit vs 87.5% in fit pts (HR 1.12, 95%-CI 0.70-1.81, p=0.63, B). The 3-year-OS was 91.8% in unfit vs 96.9% in fit pts (HR 2.02, 95% CI 0.90-4.55, p=0.088). Adverse events (any grade) considered of interest included neutropenia, which occurred in 62.7% of unfit and 56.9% of fit pts (febrile neutropenia 4.4% in each group), respectively. Infusion-related-reactions (IRR) occurred in 44.3% of unfit and 56.9% of fit pts. Fatigue was reported in 15.8% of unfit and 35.9% of fit pts; headaches in 9.2% of unfit and 18.2% of fit pts. Infections occurred in 57.5% of unfit and 69.6% of fit pts; in particular, nasopharyngitis was reported for 10.5% of unfit and 24.3% of fit pts. Covid-19 occurred in 3 unfit (3 fatal) and 5 fit (2 fatal) pts. Other common adverse events were balanced between fit and unfit pts. Comparable patterns were also observed when comparing young vs older pts according to exploratory age cut-offs between 65 to 80 years. Early venetoclax discontinuations for reasons other than PD or death (e.g., adverse events, withdrawal) were more common in unfit than in fit pts (15.8% vs 5.0%). Median time to early discontinuation was 6.3 months (3.1-8.7). Patients with early venetoclax discontinuation had a 3-year-PFS from EOT of 71.2%, compared with 83.0% in pts who completed venetoclax as planned (HR 2.25, 95%-CI 1.32-3.83, p=0.003). The 3-year-OS from the EOT was 84.3% and 94.0% (HR 2.48, 95%-CI 1.10-5.59, p=0.029), respectively. Dose reductions <80% (excluding PD/death) occurred in 15.7% of all pts (14.7% unfit, 16.5% fit). ORR in pts with venetoclax dose intensity <80% was 82.5% and 95.9% in pts with dose intensity ≥80% (p<0.001). CR rates were 42.9% and 55.5% (p=0.066), uMRD rates were 76.2% and 85.3% (p=0.073). The 3-year-PFS from the EOT for pts with and without venetoclax dose intensity <80% was 81.0 % and 82.2%, respectively (HR 1.47, 95%-CI 0.84-2.57, p=0.175). Conclusion This analysis confirms the feasibility and efficacy of Ven-Obi for both fit and unfit pts with CLL. The incidence of toxicities was comparable between both patient groups, although IRR and fatigue were more common in fit pts. Reduced venetoclax dose intensity had no impact on PFS, suggesting that dose modifications may have limited impact on long-term clinical outcomes.

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.

Safety and Effectiveness in Treatment Naive CLL Patients with or without High Risk Features Treated with Veno Under Real-World Conditions in Austria, Germany, and Switzerland

Background In chronic lymphocytic leukemia (CLL), the association of genetic markers such as del(17p), TP53 and IGHV status with disease prognosis is well established. In clinical trials, treatment with Venetoclax in combination with Obinutzumab (VenO) has shown promising efficacy and good tolerability in all subgroups 1. However, there is limited real-world data in specific genetic subgroups. Aim Effectiveness and safety data were analyzed for therapy naive patients treated with VenO focusing on CLL patients with or without the genetic risk factors TP53 mut and/or del(17p) as well as IGHV status. Methods VeRVe is a non-interventional, observational, prospective study with 60 study sites in Germany, Austria, and Switzerland. CLL patients treated with VenO according to the local label 2 were included. Study documentation is possible at baseline, weekly during ramp-up, monthly until the end of month 6 and quarterly afterwards up to a maximum of 2 years. Response assessment was documented after ramp-up, 3, 12 and 24 months. Results Until April 12 th, 2023, 101 patients were enrolled and received at least one dose of Venetoclax, 42 % were IGHV unmutated. Baseline characteristics were balanced between the genetic risk groups. Patients with TP53 aberrations were older compared TP53 wildtype patients (71 vs. 66 a). 70% of patients with TP53 aberration, 68% of patients with wt TP53, 74% of patients with IGHVunmutated and 71% of patients with IGHVmut had at least 1 comorbidity. The best overall response rate after 12 months for 88 evaluable patients is shown in the figure. Estimated PFS-rate after 1 year was 93% in the total population, 100% in patients with TP53 aberrations, 91% in patients with wt TP53 95.1% of patients with IGHVunmutated and 82.5% of patients with IGHVmut. Estimated OS -rate after 1 year was identical to the estimated PFS. CTCAE grade AEs 3-5 were reported in 35% of the total population, in 21% in the TP53 aberrant, in 35% in the TP53 wt, in 33% in the IGHVunmutated and 10% in the IGHVmut population. A total of 3 patients had laboratory TLS. No new safety signals were detected. Conclusion In summary, both patients with or without TP53 aberration and with mutated or unmutated IGHV had high rates of best ORR, estimated PFS, and OS. Reassuringly, CR/CRi rates were high in patients with TP53 aberration or IGHV unmutated patients. Treatment was well tolerated. Disclosures DR has received honoraria or research grants from AbbVie, AstraZeneca, Gilead, Janssen, Verastem, Roche, Cellestia. IS has received honoraria from AbbVie, Amgen, AstraZeneca, BeiGene, Janssen, Roche, Servier. HH received speaker or consulting fees from AbbVie, AstraZeneca, Celgene, Janssen, Roche, and Beigene. CL received consulting fees from AbbVie, Amgen. TW received honaria or research funding from Novartis, Celgene, Roche, Bayer, Teva and Abbvie. CL and JH are employees of AbbVie and may own AbbVie stock. BS received speaker or consulting fees from AbbVie, Alexion, Amgen, AstraZeneca, BeiGene, BMS, Hexal, Janssen, Novartis, Pfizer, Sanofi-Aventis and SOBI. PP has received honoraria from Amgen, Gilead, Janssen, Sanofi-Aventis, Takeda. Honorarium paid by AbbVie was not related to authorship of this abstract. No honoraria or payments were made for authorship. AbbVie sponsored this study and contributed to the design, study conduct. AbbVie participated in the interpretation of data, review, and approval of the publication. All authors had access to all relevant data. Statistical support was provided by Daniela Giesder and Anna Eisen of GermanOncology GmbH, which was funded by AbbVie.

Acalabrutinib ± Obinutuzumab Vs Obinutuzumab + Chlorambucil in Treatment-Naive Chronic Lymphocytic Leukemia: 6-Year Follow-up of Elevate-TN

Background: Previous reports of ELEVATE-TN (NCT02475681) at median follow-up of up to 58.2 months (mo) demonstrated superior efficacy of acalabrutinib (A) ± obinutuzumab (O) compared with O + chlorambucil (Clb) in patients (pts) with treatment-naive (TN) chronic lymphocytic leukemia (CLL). Herein, updated results at 74.5 mo of follow-up are reported. Methods: Pts received A monotherapy, A+O, or O+Clb. Pts who progressed on O+Clb could cross over to A monotherapy. Investigator (INV)-assessed progression-free survival (PFS), INV-assessed overall response rate (ORR), overall survival (OS), and safety were evaluated. All analyses are ad-hoc and P-values are descriptive. Results: A total of 535 pts (A, n=179; A+O, n=179; O+Clb, n=177) were randomized: median age was 70 years, 63% had unmutated immunoglobulin heavy chain variable region genes (uIGHV), and 14% had del(17p) and/or TP53 mutation ( TP53m). At a median follow-up of 74.5 mo (range, 0.0-89.0; data cutoff March 3, 2023), median PFS was not reached (NR) for A+O and A vs 27.8 mo for O+Clb (hazard ratio [HR] vs O+Clb: 0.14 and 0.23, respectively; P<0.0001 for both; HR A+O vs A: 0.58; P=0.0229); estimated 72-mo PFS rates were 78%, 62%, and 17%, respectively (Figure 1). For the 79 pts who crossed over from O+Clb to A, median PFS2 (time to second disease progression or death) was NR; estimated 72-mo PFS2 rate was 54%. Median OS was NR in any treatment arm and was significantly longer with A+O vs O+Clb (HR: 0.62; P=0.0349); estimated 72-mo OS rates were 84% for A+O, 76% for A, and 75% for O+Clb ( Figure 2). In 337 pts with uIGHV, median PFS was NR in both the A+O and A arms vs 22.2 mo for O+Clb (HR: 0.08 and 0.12, respectively; P<0.0001 for both), and estimated 72-mo PFS rates were 75%, 60%, and 5%, respectively, with median OS NR in all treatment arms and estimated 72-mo OS rates of 84%, 76%, and 74%, respectively. In 73 pts with del(17p) and/or TP53m, median PFS was 73.1 mo for A+O and NR for A vs 17.5 mo for O+Clb (HR: 0.28 and 0.23, respectively; P≤0.0009 for both), and estimated 72-mo PFS rates were 56%, 56%, and 18%, respectively. Median OS was NR in both the A+O and A arms vs 74.9 mo for O+Clb (HR: 0.53 and 0.46, respectively, neither statistically significant) and estimated 72-mo OS rates were 68%, 72%, and 53%, respectively. ORR was significantly higher with A+O (96%; 95% confidence interval [CI]: 92-98; P<0.0001) and A (90%; 95% CI: 85-94; P=0.0499) vs O+Clb (83%; 95% CI: 77-88). Combined complete response (CR) plus CR with incomplete hematologic recovery rates were higher with A+O (37%) and A (19%) vs O+Clb (14%; P≤0.0499 for both). Median treatment exposure was 74.4 mo and 72.0 mo for A in the A+O and A arms, respectively; 5.5 mo and 5.6 mo for O in the A+O and O+Clb arms, respectively; and 5.5 mo for Clb in O+Clb arm. Adverse events (AEs) for the O+Clb arm have been previously reported. The most common (≥5% of pts) grade ≥3 AEs for A+O and A, respectively, were neutropenia (31% and 12%), thrombocytopenia (8% and 3%), diarrhea (6% and 1%), COVID-19 (9% and 7%), pneumonia (7% and 6%), syncope (5% and 2%), and hypertension (4% and 5%). For events of clinical interest, grade ≥3 atrial fibrillation, hypertension, and secondary primary malignances were reported in 2%, 4%, and 10% of pts treated with A+O and 2%, 5%, and 5% of pts treated with A, respectively. Treatment is ongoing in 54% (A+O; n=96) and 47% (A; n=84) of pts; the most common reasons for treatment discontinuation were AEs, observed in 21% (n=38) of pts treated with A+O and 18% (n=32) of pts treated with A, and progressive disease, observed in 6% (n=10) of pts treated with A+O and 14% (n=25) of pts treated with A. For pts who crossed over from O+Clb to A, 41% (n=32) discontinued A due to AEs in 13% (n=10) of pts and progressive disease in 16% (n=13) of pts. Conclusions: With a median follow-up of 74.5 mo, the efficacy and safety of A+O and A monotherapy were maintained in pts with TN CLL, including in pts with high-risk genetic features. At 6 years of follow-up, PFS was significantly longer in pts treated with A+O vs A. Median OS was NR in any treatment arm and was significantly longer in pts treated with A+O vs O+Clb.

Tislelizumab Plus Zanubrutinib in Patients with Richter Transformation: Primary Endpoint Analysis of the Prospective, Multi-Center, Phase-II RT1 Trial of the German CLL Study Group

Background Richter transformation (RT) describes the development of an aggressive lymphoma, in most cases a diffuse large B cell lymphoma (DLBCL) or Hodgkin's lymphoma (HL), in patients (pts) with chronic lymphocytic leukemia (CLL). Pts with RT have a dismal prognosis with chemoimmunotherapy (CIT) like R-CHOP, with overall response rates (ORR) of <40% and median overall survival (OS) of 6-8 months. Targeted therapies have the potential to improve outcomes, but few prospective studies have been run in this entity. Here we present the first data of the international phase-II RT1 trial, in which the PD1 inhibitor tislelizumab is combined with the next-generation BTK inhibitor zanubrutinib to treat pts with RT. Methods Pts with histologically confirmed RT (DLBCL or HL [HL only when not eligible for standard therapy]) and up to one prior line of RT-directed therapy were eligible. Each cycle (of 21 days) consisted of one infusion of 200 mg tislelizumab at day 1 and 160 mg zanubrutinib twice daily orally. Six cycles of induction were followed by 6 cycles of consolidation; pts with complete response (CR), partial response (PR) or stable disease (SD) continued maintenance until disease progression/non-tolerance. The primary endpoint was ORR after induction therapy for pts receiving ≥ 3 cycles according to the refined Lugano Classification with the aim to test the null hypothesis of ≤0.40. Secondary endpoints include duration of response (DOR), progression-free survival (PFS), OS and time to next treatment (TTNT). Results Of 59 enrolled pts, 48 pts received at least 3 cycles of treatment and comprised the analysis population according to the study protocol. Eleven pts stopped earlier due to withdrawal, death, PD or toxicity. Median observation time was 13.9 months (interquartile range 1.7-35.9). Median age was 67 years (range 45 - 82). 22 (45.8%) pts had ECOG 1 or higher. Median LDH at enrollment was 335 U/l. Sixteen (34.8%) pts had del(17p)/ TP53mut, 29 (70.7%) pts had unmutated IGHV. 25 (64.1%) pts had high or very high-risk CLL according to CLL-IPI, 11 (28.2%) intermediate and 3 (7.7%) low risk. Complex karyotype (≥3 aberrations) was detected in 16 (42.1%) pts. 46 (95.8%) pts had DLBCL-RT and 2 (4.2%) pts had HL-RT. In 26 (54.2%) pts, the RT was reported as clonally related to the CLL (22 [45.8%] unknown). Overall, 36 (75.0%) pts had received prior CLL-directed therapy, including CIT (25 pts) and targeted agents (32 pts) as well as prior allogeneic stem cell transplant (SCT) in 3 pts. 12 (25.0%) pts had treatment-naive CLL. Thirteen pts (27.1%) had received prior RT-directed therapy, including CHOP-like regimens and BTK inhibitors. 35 (72.8%) pts had not received prior RT-directed therapy. Twenty-eight of 48 pts responded to induction therapy resulting in an ORR of 58.3% (95% CI, 0.43-0.72), including 9 (18.8%) CR and 19 (39.6%) PR, meeting the study's primary endpoint (p=0.008) (Fig A). SD was reported in 6 (12.5%) pts, 11 (22.9%) pts had progressive disease (PD), three had missing assessment due to PD. The median DOR was not reached, the 6-month DOR rate was 70.6%. Median PFS was 10 months (95% CI 3.8 -16.3) with a 12-month rate of 46.9% (Fig B). Median OS was not reached (12-month OS rate 74.7%). Median TTNT was not reached (12-month TTNT rate 56.2%). Post-protocol treatment included CIT in 21 cases (48.8%), radiation in 1 case (2.3%), BTK/BCL2 inhibition in 7 (16.3%) cases and 8 (18.6%) allogeneic SCT. SCT was conducted as consolidation in two pts with PR, and as salvage treatment for 5 pts with SD/PD (one missing response). Overall, 606 adverse events (AEs) were reported, of which 173 (28.5%) were ≥ grade 3 and 129 (21.3%) were serious AE. Of the 29 pts who discontinued study treatment, three were due to toxicity, the rest for PD and/or start of next line of therapy. The most frequent AEs were infections and infestations (17.7%), including Covid-19, pneumonia and urinary tract infections, gastrointestinal disorders (12.7%), including diarrhea and nausea, and blood and lymphatic system disorders (11.2%), including anemia, neutropenia and thrombocytopenia. Conclusions Combined checkpoint and BTK inhibition by tislelizumab plus zanubrutinib is an effective and well-tolerated treatment strategy for pts with RT. Responses are durable and overall survival in the RT1 study is encouraging given the otherwise poor prognosis of RT. Translational studies are ongoing to identify predictors of response to checkpoint inhibition in RT.

Real-World Venetoclax-Obinutuzumab in 232 Treatment Naive CLL Patients: Feasibility and Tolerability

Fixed duration venetoclax-obinutuzumab (VO) is approved in treatment naïve (TN) chronic lymphocytic leukemia (CLL), based on CLL14 study addressed to patients (pts) with coexisting conditions. The combinations showed also to be effective and well tolerated in the younger population enrolled in the randomized CLL13 trial. The aim of this retrospective, multicenter Italian study is to evaluate the feasibility and tolerability of this combination in TN CLL in common clinical practice as well as reasons for choosing fixed-duration VO instead of continuous BTKi. Consecutive pts receiving first-line therapy after VO approval/reimbursement in Italy (May 2022) were considered. Reasons for choosing the fixed duration treatment were recorded. The impact of clinical, biological, and demographic characteristics on VO feasibility (definitive treatment discontinuation and/or schedule modifications due to toxicity) and tolerability were analyzed. Debulking (Deb) phase (D1-D56) was separately evaluated to better understand its influence on treatment management. From May 2022 to June 2023, 790 treatment naïve continuous pts were treated with targeted agents in 49 centers. Treatment choice consisted of: continuous BTKi in 558 pts and fixed-duration VO in 232 (the latter representing the population of our analysis). The main reasons given by physicians for choosing VO instead of BTKi were: disease biology 46% (mutated IgHV status), fixed duration 33%, comorbidities 15%, patient choice 6%. Pts' characteristics are shown in Table 1. When considering Deb-phase (232 pts), VO was regularly administered according to the investigator brochure in 150 (64.7%). In 22 cases (9.5%) the schedule was a priori modified by clinicians: 12 pts started with V led-in and postponed O infusion at C2D1; in 10 planned O D8 and D15 infusions were omitted. Overall, 12 pts (5.2%) permanently discontinued VO due to toxicity. 3 of them dying due to: COVID pneumonia, invasive aspergillosis, VO-unrelated cachexia. In the remaining 48 (20.7%) schedule was adjusted due to AEs. Treatment modifications, overlapping in some cases were: 42 extended the Deb-phase (median days to completion 63, range 59-130); 14, never reached the full V dose; 31 did not perform the planned 5 O infusions (median 3 infusions, range 1-4). No age, neither coexisting conditions influenced treatment feasibility. The only parameters having an impact on Deb-phase discontinuation or schedule modifications due to toxicity were: baseline ANC<1500/mmc (OR 3.1, p=.035), hypogammaglobulinemia (OR 2.2, p=.018), concomitant use of anticoagulants (3.13, p=.029). Overall 23 pts (9.9%), including 7 categorized as high risk TLS, were hospitalized for treatment initiation. During Deb-phase grade 3-4 AEs occurred in 69 pts (30%): neutropenia (18%); thrombocytopenia (14%); infections (5%); IRR (5%). Development of any severe AE was influenced by: upper GI disorder, baseline neutropenia or thrombocytopenia. TLS was recorded in 13 pts (6%): 11 O-related and 4 V-related. All 4 clinical TLS were considered as secondary to O. Only high CLL-CI risk was associated with TLS. None of the baseline factors nor type of steroids premedication predicted IRR. At the present follow-up of the 232 pts considered: 142 completed the 6 cycles of combinations treatment, 75 are still ongoing, 15 definitively discontinued treatment for AEs. Overall, 42 pts received VO with an adjusted schedule for toxicities: 22 are receiving V at reduced dose, 39 pts did not complete the planned O infusions (treatment modifications overlapping in some cases). G 3-4 toxicity developed in 78 pts being neutropenia and infections the most common reported. At univariate analysis factors affecting treatment feasibility were: presence of endocrine comorbidity; intermediate/high CLL-CI and hypogammaglobulinemia. To our knowledge this is the first real-world study on clinical factors that may influence VO feasibility. Despite this setting of unselected population, most clinicians were adherent to VO schedule. A low rate of pts permanently discontinued therapy during Deb-phase with no impact of age or comorbidities on feasibility. Furthermore, TLS and IRR were in line with clinical trials. Longer follow-up data will be reported at the meeting allowing by multivariate analysis to better clarify the role of comorbidities on treatment management and the reproducibility of VO tolerability in common clinical practice.

IGLV3-21R110 mutation has prognostic value in patients with treatment-naive chronic lymphocytic leukemia

IGLV3-21R110 mutation has prognostic value in patients with treatment-naive chronic lymphocytic leukemia

Advancements in the Treatment of CLL: The Rise of Zanubrutinib as a Preferred Therapeutic Option.

Ibrutinib, the first-in-class Bruton's tyrosine kinase inhibitor (BTKi), is a commonly deployed therapeutic option for previously untreated and relapsed/refractory (R/R) patients with chronic lymphocytic leukemia (CLL). The use of ibrutinib is, however, partially limited by off-target side effects. Zanubrutinib (zanu) is a second-generation BTKi with enhanced target selectivity and occupancy of the kinase binding site. The SEQUOIA study showed that zanu significantly prolonged progression-free survival (PFS) when compared to bendamustine-rituximab (BR) in treatment-naive CLL patients. More recently, data from the phase III ALPINE trial, which directly compared zanu with ibrutinib, demonstrated that zanu's advantages include an improved safety profile as well as enhanced clinical efficacy. Based on the results of the SEQUOIA and ALPINE pivotal trials, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) licensed zanu for the treatment of patients with CLL or small lymphocytic lymphoma (SLL) in January 2023. The updated (v2.2023) National Comprehensive Cancer Network (NCCN) guidelines and the most recent German CLL algorithm suggest that zanu may replace first-generation BTKis as a preferred therapeutic option for patients with CLL/SLL due to its increased selectivity for the kinase binding site, improved therapeutic efficacy, and favorable toxicity profile. Some drug class-related characteristics such as drug resistance, low complete remission (CR) rates, and indefinite treatment duration still remain with zanu, and the results from recently completed and ongoing fixed-duration clinical trials, combining zanu with an anti-BCL2 agent, are eagerly awaited with the possible promise of a reduced treatment duration and lower financial burden.

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 .

Quality-adjusted survival time without symptoms or toxicity of acalabrutinib with or without obinutuzumab in patients with treatment-naive chronic lymphocytic leukemia

Acalabrutinib monotherapy (A) and acalabrutinib plus obinutuzumab (A + O) demonstrated improved efficacy and safety versus chlorambucil plus obinutuzumab (C + O) among treatment-naive patients with chronic lymphocytic leukaemia (CLL) in the ELEVATE-TN trial. The relative risk-benefit at a median follow-up of 47 months was assessed using Quality-adjusted Time Without Symptoms and Toxicity (Q-TWiST) methodology. Patient data were partitioned into 3 states: time with toxicity (TOX); time without symptoms or toxicity (TWiST); and time after relapse (REL). Mean Q-TWiST was estimated by summing the mean time in each state, multiplied by its respective utility weight. Patients receiving A or A + O experienced significantly longer Q-TWiST versus C + O when toxicity was defined as grade 3–4 adverse events (AEs) (41.79 vs 34.56 months; 42.07 vs 34.56 months) and grade 2–4 AEs (35.07 vs 30.64 months; 34.21 vs 30.64 months). Overall, patients with treatment-naive CLL treated with A or A + O experienced significant gains in Q-TWiST compared with C + O.

Cost-effectiveness of targeted treatment vs chemoimmunotherapy in treatment-naive unfit CLL without TP53 aberrations

AbstractSeveral targeted treatments, such as venetoclax + obinutuzumab (VenO) and ibrutinib, have been developed to treat patients with treatment-naive chronic lymphocytic leukemia (CLL) and have been shown to improve progression-free survival compared with chlorambucil + obinutuzumab (ClbO). However, novel targeted agents are associated with a significant cost investment. The objective of this study was to investigate the cost-effectiveness of VenO compared with ClbO and ibrutinib in treatment-naive CLL without del17p/TP53 mutation in Denmark. We used a decision-analytic modeling approach to simulate hypothetical cohorts of patients with CLL from the initiation of first-line treatment to death, including the full treatment pathway and second-line therapy. VenO, ClbO, or ibrutinib was included as first-line therapy followed by either Ven + rituximab or ibrutinib. Model outcomes were expected quality-adjusted life years (QALYs), life years (LYs), and cost per patient, which were used to calculate incremental cost-effectiveness ratios (ICERs) with a willingness to pay from €23 600 to €35 600 per QALY. Compared with ClbO, VenO was associated with a QALY gain of 1.30 (1.42 LYs) over a lifetime. The incremental cost was €12 360, resulting in an ICER of €9491 per QALY gained, indicating that VenO is cost-effective. Compared with VenO, ibrutinib was associated with a QALY gain of 0.82 (1.74 LYs) but at a substantially increased incremental cost of €247 488 over a lifetime horizon. The ICER was €302 156 per QALY, indicating that ibrutinib in first-line treatment would not be considered cost-effective in Danish health care, compared with VenO. Future analyses in fit patients with CLL are needed to determine the cost-effectiveness of VenO.

Cost-effectiveness of acalabrutinib regimens in treatment-naïve chronic lymphocytic leukemia in the United States

ABSTRACT Background Clinical outcomes in chronic lymphocytic leukemia (CLL) have improved with targeted therapy, including Bruton tyrosine kinase inhibitors such as acalabrutinib. Methods A semi-Markov model with three health states (progression-free, progressed disease, and death) estimated cost per quality-adjusted life-year (QALY) gained for acalabrutinib ± obinutuzumab vs chlorambucil + obinutuzumab in treatment-naive CLL (based on ELEVATE-TN). The model used direct costs and resource utilization from the US Medicare perspective and utility values sourced from literature. Sensitivity analyses tested the robustness of the model. Results Over a 30-year lifetime horizon, the model base case analysis suggested that acalabrutinib monotherapy had an incremental cost of $206,329 and 2.52 QALYs gained versus chlorambucil + obinutuzumab, resulting in an incremental cost-effectiveness ratio (ICER) of $81,960/QALY. Acalabrutinib + obinutuzumab had an incremental cost of $423,747 and 2.79 QALYs gained (ICER: $152,153/QALY). Probabilistic sensitivity analysis showed the probability of acalabrutinib monotherapy being cost-effective as 59% to 73% at a $100,000-to-150,000/QALY willingness-to-pay threshold; the probability of acalabrutinib + obinutuzumab being cost-effective ranged from 34% to 51%. Conclusions Although the analysis is limited by uncertainty in postprogression survival outcomes, acalabrutinib monotherapy is likely cost-effective vs chlorambucil + obinutuzumab in treatment-naive CLL in the US Medicare setting.

EE336 Budget Impact Analysis of Zanubrutinib for Patients With Treatment-Naive Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma in the United States

EE336 Budget Impact Analysis of Zanubrutinib for Patients With Treatment-Naive Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma in the United States

Continuous Venetoclax in Previously Untreated Patients with Chronic Lymphocytic Leukemia and TP53 Abnormalities. a Study of the Italian Campus CLL

BACKGROUNG. Fixed duration venetoclax-based therapy, either in combination with BTK inhibitors or anti-CD20 monoclonal antibody, is a highly active front-line treatment in patients with chronic lymphocytic leukemia (CLL). However, patients with TP53 abnormalities may early relapse after the end of treatment. Continuous treatment with BTK inhibitor is a valid option in TP53 disrupted patients, counteracted by a relatively high rate of discontinuation due to adverse events. In the phase II study investigating venetoclax in TP53-disrupted CLL patients, only 5 patients were treatment naive (TN) and 4/5 were remission-free after a median follow-up of 70months (Stilgenbauer S, EHA2022). AIM. The aim of this retrospective study is to describe the efficacy and discontinuation rate of continuous venetoclax in TN CLL patients with TP53 disruption in the real-life setting. METHODS. Medical charts of CLL patients from 16 centers belonging to the Italian Campus CLL network were retrospectively reviewed to identify CLL with del17p13(cut-off 10%) and/or TP53 mutation (TP53m) treated front-line with continuous venetoclax. The primary endpoint was the rate of treatment discontinuation. Secondary endpoints were overall response rate (ORR), measurable residual disease (MRD) by flow-cytometry, progression-free survival (PFS), overall survival (OS) and comparison with a cohort of 100 TN patients treated with ibrutinib (updated from Visentin A, AJH2022). CLL diagnosis and response assessment were carried out according to the iwCLL2018 guidelines. Adverse events were classified according to the CTCAEv5.0 grading. Statistical analyses were performed with Prism7. RESULTS. Thirty-four TN CLL with TP53 abnormalities were recruited. The median age was 69 years (range 46-84), median CIRS score was 3.5 (range 0-12), 24% had a creatinine clearance <60ml/min. LDH and β2-microglobulin were increased in 38% and 48% of patients. Seventy-one % of patients were IGHV unmutated, 79% harbored del17p13 and 74% TP53m. According to the tumor lysis syndrome (TLS) risk score, 12% were classified at low-risk, 35% intermediate-risk and 53% at high-risk of TLS. Ninety-nine patients were hospitalized during the ramp-up phase while the remaining in the out-patient clinics. No patient developed clinical or biochemical TLS. Eighty-two % of patients were able to reach 400mg of venetoclax. The best ORR was 85%, including 50% complete responses (CR) and 35% partial responses (PR) (Fig. 1). The median time to CR was 14.9 months. MRD was assessed in the peripheral blood of 14 patients, achieving undetectable MRD4 in 6 (43%), detectable MRD4 in 6 (43%) and detectable MRD2 in 2 (14%) patients. After a median follow-up of 20 months, 9 patients decreased the venetoclax dose and 3 discontinued therapy (thrombocytopenia 1 and Richter transformation 2). The median PFS and OS were not reached. The 12 and 24-month PFS were 96% and 83%, respectively (Fig. 1). All patients were alive after 12 months and the estimated 24-month OS was 88%. Regarding safety, we recorded of grade ≥3 (G≥3) adverse events in 23 (67%) patients, including hematological toxicity in 14 (11 neutropenia, 2 anemia, 1 thrombocytopenia), second primary malignancies in 3, diarrhea in 3, infections in 2 and major bleeding in 2. Atrial fibrillation occurred in 2 patients. Compared to patients treated with ibrutinib (n=100 , comparable for age and comorbidities, median follow-up 24months), we observed a higher CR rate (50% vs 9%, p<0.0001), a trend for a longer PFS (p=0.10) and a lower incidence of discontinuation (24-month 14% vs 35%, p=0.0194) in patients receiving venetoclax (Fig. 1). We also observed a higher rate of all G≥3 events (67% vs 22%, p<0.0001) and severe neutropenia in patients treated with venetoclax (32% vs 4%, p<0.0001), but a lower rate of infections (6% vs 22%, p=0.0386) and cardiovascular events (6% vs 14%, p=0.3573). CONCLUSION. To our knowledge, we report the largest real-life study of continuous venetoclax in TN CLL patients with TP53 abnormalities, indicating a high efficacy of venetoclax in this subset of patients, not previously studied systematically in clinical trials. Only one patient discontinued venetoclax due to toxicity. The use of continuous venetoclax in TN CLL patients with TP53 disruption deserve further investigation, as it can be an effective alternative option beside BTK inhibitor. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Final Results of the Phase 1/2 Study of Acalabrutinib Monotherapy in Treatment-Naive Chronic Lymphocytic Leukemia with >6 Years of Follow-up

Background: Acalabrutinib is a next-generation, covalent Bruton tyrosine kinase inhibitor approved for the treatment of patients with treatment-naive (TN) or relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). A previous analysis of the phase 1/2, multicenter ACE-CL-001 study (NCT02029443) demonstrated durable responses and good long-term tolerability of acalabrutinib as first-line therapy in patients with CLL at a median follow-up of 53 months (Byrd et al. Blood. 2021;137:3327-38). Here, we report the final analysis in the TN cohort of that study, the longest running study of acalabrutinib, with over 6 years of follow-up. Methods: Patients included in the study were aged ≥18 years with TN CLL/SLL who met the 2008 iwCLL criteria for treatment, were inappropriate for or declined standard chemotherapy, and had ECOG performance status 0-2. All TN patients were treated in the phase 2 portion of the study and received acalabrutinib 100 mg twice daily (BID) or 200 mg once daily (QD), later switching to 100 mg BID, until progressive disease (PD) or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included investigator-assessed overall response rate (ORR), time to response (TTR), duration of response (DOR), and progression-free survival (PFS), with a post hoc analysis of event-free survival (EFS). Results: Ninety-nine patients (n=62 100 mg BID; n=37 200 mg QD) were treated. The median age was 64 years; 47% of patients had Rai stage 3-4 disease, 10% had del(17p), 14% had TP53 mutation, 17% had del(11q), 62% had unmutated IGHV, and 18% had complex karyotype. At the final data cut-off date of July 15, 2021, the median study follow-up was 73.7 months (range 0.92-82.4), and 70 (71%) patients remain on acalabrutinib treatment. The most common reasons for treatment discontinuation were adverse events (AEs) (10%) and PD (6%). The most common AEs (Table 1) were consistent with those reported in the prior update (53-month median follow-up). The only grade ≥3 AEs with a ≥50% increase in incidence since the prior update were pneumonia (4% [prior update] vs 8%) and syncope (4% [prior update] vs 6%). AEs that led to treatment discontinuation were amyotrophic lateral sclerosis, angiosarcoma, cardiac failure, cerebral hemorrhage, gastric hemorrhage, glioblastoma multiforme, non-cardiac chest pain, prostate cancer, sepsis, small cell lung cancer, and urinary tract infection (in 1 patient each). All-grade and grade ≥3 events of clinical interest included infection (87% and 19%, respectively), bleeding events (74%, 7%), major bleeding events (8%, 7%), and hypertension (29%, 13%). Atrial fibrillation/flutter occurred in 6% of patients (3% grade ≥3). Second primary malignancies excluding non-melanoma skin (all grades) occurred in 14% of patients Two deaths were reported (cardiac failure, n=1; multiple organ dysfunction syndrome, n=1); neither was considered treatment related. ORR was 97% (9% complete response; 88% partial response). Median TTR was 3.7 months (range 1.7-22.1). Median DOR was not reached; the estimated 66-month DOR rate was 89% (95% CI 80-94). ORR of 100% was seen across high-risk groups: del(17p) (9/9), del(11q) (15/15), unmutated IGHV (57/57), and complex karyotype (12/12). Median PFS was not reached; the estimated 72-month PFS rate was 87% (95% CI 77-93; Figure 1). The estimated 72-month EFS was 78% (95% CI 68-85). Reported EFS events overall included AEs (n=10/99, 10%), disease progression (n=9/99, 9%), and new anticancer therapy (n=3/99, 3%). Conclusions: The final data from ACE-CL-001 further support the long-term efficacy and safety of acalabrutinib monotherapy, with high response rates and rapid, durable responses seen in patients with TN CLL regardless of high-risk genomic features. With over 6 years of follow-up, this study firmly establishes the tolerability and safety profile of acalabrutinib seen consistently in subsequent studies, with a low incidence of atrial fibrillation/flutter seen and no new long-term safety issues identified. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Contribution of Obinutuzumab to Acalabrutinib Therapy in Patients with Treatment-Naive Chronic Lymphocytic Leukemia: Analysis of Survival Outcomes By Genomic Features

Contribution of Obinutuzumab to Acalabrutinib Therapy in Patients with Treatment-Naive Chronic Lymphocytic Leukemia: Analysis of Survival Outcomes By Genomic Features

P667: LONG-TERM EFFICACY OF ACALABRUTINIB-BASED REGIMENS IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA AND HIGHER-RISK GENOMIC FEATURES: POOLED ANALYSIS OF CLINICAL TRIAL DATA

Background: Chronic lymphocytic leukemia (CLL) has a highly variable disease course; patients (pts) with higher-risk genomic features typically have poor response to chemoimmunotherapy, and pts with del(17p) also have short, suboptimal response to venetoclax + obinutuzumab. Thus, novel agents such as Bruton tyrosine kinase inhibitors (BTKi), including the highly selective covalent BTKi acalabrutinib (A), are preferred treatments in this higher-risk population based on demonstrated effectiveness in higher-risk subgroups in individual studies. Aims: To assess long-term efficacy of A-based regimens in pts with treatment-naive (TN) or relapsed/refractory (R/R) CLL and higher-risk genomic features. Methods: Data were pooled from CLL pts with higher-risk genomic features treated with A ± obinutuzumab (O) in 3 clinical studies in TN CLL (ELEVATE-TN, CL-001 [TN cohort], CL-003) and 3 in R/R CLL (ASCEND, ELEVATE-RR, CL-001 [R/R cohort]). Higher risk was defined as del(17p) and/or TP53 mutation [del(17p)/TP53m], unmutated IGHV (uIGHV), or complex karyotype (CK, ≥3 chromosomal abnormalities). Efficacy analyses (progression-free survival [PFS], overall survival [OS], response rates) focus on del(17p)/TP53m and uIGHV; safety analyses also include pts with CK. Results: 801 pts (TN 313; R/R 488, median 2 prior therapy lines [range 1–10]) were included; 64 (20%) TN and 219 (45%) R/R pts had del(17p)/TP53m, among whom 44 (69%) and 170 (78%) also had uIGHV. Overall, 288 (92%) TN and 425 (87%) R/R pts had uIGHV and 47 (15%) and 160 (33%) had CK. Median pt age was 68 (TN) and 66 (R/R) y. For A-based regimens combined (A and A+O), overall response rate (ORR) was 91% (n=58/64; complete response [CR]: 20% [n=13/64]) in TN pts with del(17p)/TP53m and 96% (n=276/288; CR 16% [n=47/288) in TN pts with uIGHV. At 47.3 mo median follow-up (range 1.0–82.0), median PFS was not reached (NR) in TN pts with del(17p)/TP53m with A-based regimens; PFS rates at 48 mo suggest similar efficacy with A and A+O in TN pts with del(17p)/TP53m (76% and 77%, respectively) (Fig 1A). Median PFS was NR among TN pts with uIGHV with both A and A+O; PFS rates at 48 mo with A and A+O were 84% and 86%, respectively (Fig 1B). Median OS was NR with A and A+O in TN pts with del(17p)/TP53m or uIGHV; OS rates at 48 mo were similar for A and A+O in pts with del(17p)/TP53m (89% for both) and in pts with uIGHV (92% and 95%). In the R/R cohort (A monotherapy only), ORR was 86% (n=184/214; CR 5% [n=11/214]) in pts with del(17p)/TP53m and 87% (n=356/408; CR 7% [n=29/408]) in pts with uIGHV. At 44.0 mo median follow-up (range 0–88.0), median PFS was 38.6 mo and 46.9 mo and PFS rates at 36 mo were 54% and 65% in pts with del(17p)/TP53m and uIGHV, respectively (Fig 1C). Median OS was 60.6 mo and NR in pts with del(17p)/TP53m and uIGHV, respectively; OS rates at 36 mo were 73% and 82%. Among all higher-risk pts, incidences of grade ≥3 treatment-related AEs were 30% (TN) and 35% (R/R). Discontinuations due to treatment-related AEs occurred in 4% (TN) and 6% (R/R) of pts; 60% and 27%, respectively, remained on treatment at data cutoff. Image:Summary/Conclusion: In this pooled analysis of clinical trial data in 801 CLL pts with higher-risk genomic features, efficacy of A-based regimens led to high PFS and OS rates at a median follow-up of nearly 4 y. The safety profile in this analysis was similar to the overall safety profile of acalabrutinib. Our results demonstrate the long-term benefit of A-based regimens in CLL pts with higher-risk genomic features, regardless of line of therapy.

"Double-Hit" Chronic Lymphocytic Leukemia, Involving the TP53 and MYC Genes.

Although the 17p deletion [del(17p)] is rare in cases of treatment-naive chronic lymphocytic leukemia (CLL), its frequency is higher in refractory/relapsed CLL – particularly in patients undergoing chemo(immuno)therapy. TP53 disruption (deletion and/or mutation) is the strongest prognostic factor for refractoriness to chemotherapy; the use of Bruton tyrosine kinase inhibitors and BCL2 inhibitors is then indicated. Rare cases of CLL can also harbor translocation or gain of the MYC oncogene. “Double-hit CLL” (with del(17p) and MYC gain) is associated with a very poor prognosis. The prognostic impact of TP53 disruption with MYC aberrations in patients receiving targeted therapies must now be evaluated.