Chronic Lymphocytic Leukemia/small Lymphocytic Lymphoma Research Articles

Hepatocellular Carcinoma With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma in the Absence of Cirrhosis

ABSTRACT This report describes a rare case of hepatocellular carcinoma (HCC) concurrent with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) without traditional risk factors, such as hepatic fibrosis or chronic hepatitis. Initially presenting with hematuria, incidental imaging revealed a liver lesion, later diagnosed as moderately differentiated HCC. Notably, the patient had no history of well-established risk factors of HCC including viral hepatitis or liver cirrhosis. CLL/SLL was unexpectedly discovered in the surgical specimen during the hepatectomy. This case challenges traditional perceptions of HCC etiology, suggesting a potential link between HCC and CLL/SLL even without established risk factors.

Real-world patterns and sequences of targeted therapy use in chronic lymphocytic leukemia and small lymphocytic lymphoma in the United States: a longitudinal study

With increasing focus on novel targeted therapies for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), this longitudinal claims-based study evaluated real-world CLL/SLL treatment sequences, particularly sequential targeted therapy. Among patients with first-line (1 L) treatment in 2014-2017 (N = 2,612; median follow-up = 3 years), the most common 1 L treatment was chemoimmunotherapy (CIT; 44.6%), followed by CD20 (25.2%) and Bruton’s tyrosine kinase inhibitors (BTKi; 21.7%). Among those with 1 L in 2018-2021 (N = 4,534; median follow-up = 1 year), these were BTKi (45.5%), CD20 (20.4%), CIT (17.5%), and B-cell lymphoma 2 inhibitor (8.3%). In 2014-2017, the proportion of patients receiving sequential targeted therapy in the first 2 LOTs was 11.2% (80.2% was BTKi→BTKi); in 2018-2021, this proportion was 34.3% (66.4% was BTKi→BTKi). Over time, there was a substantial increase in targeted therapy use in 1 L and sequential targeted therapy, particularly with BTKi→BTKi. Future studies should assess clinical outcomes to determine optimal sequences for CLL/SLL and reasons for restarting BTKi.

Long-term follow up of the combination of ofatumumab, high-dose methylprednisolone, and lenalidomide for untreated chronic lymphocytic leukemia with biomarker analysis

BackgroundAdvancements in frontline therapy and chemotherapy-sparing treatments in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have altered the treatment algorithms of this disease. We present a frontline alternative for treatment- naïve (TN) CLL/SLL patients. MethodsThis was a single-center, phase 2 study of high-dose methylprednisolone (HDMP) and ofatumumab with lenalidomide and ofatumumab consolidative therapy for all comers with TN CLL/SLL. Treatment was continued until disease progression or intolerable side effects. Patients were assessed for response per iwCLL 2008 criteria after completing cycles 3 and 12. ResultsForty-five patients were enrolled (median age, 62.6 years). High-risk features included del17p (18%), Del11q (22%), and unmutated IGHV gene (76%). Median treatment duration was 32·2 (2·7-75·9) months. Thirty-six patients discontinued treatment due to disease progression (22%), adverse events (40%), allogeneic hematopoietic cell transplantation (allo-HCT) (7%), consent withdrawal (4%), and secondary malignancies (7%). The best overall and complete response rates were 96& and 29% respectively. At median follow-up of 61·7 (5·6-84·9) months, 9 patients remained on treatment. Median progression-free survival was 54·4 (2·9-77·6) months. Three patients underwent allo-HCT after a median of 3 (3-4) treatment cycles. Treatment was well tolerated, with a grade 3/4 infusion reaction in one patient. The most common grade 3/4 hematological adverse event was neutropenia (69%). Four patients had grade 3/4 infections. No grade 3/4 tumor flares, tumor lysis syndrome, or thrombosis were observed. ConclusionThe combination of ofatumumab, HDMP, and lenalidomide was effective and relatively well tolerated in treatment-naive CLL/SLL. Its role in the frontline setting remains unclear given the current available and effective treatment options. FundingThe funders had no role in the study.

Venetoclax plus dose-adjusted R-EPOCH (VR-DA-EPOCH) or G-EPOCH bridging to subsequent cellular therapy for the patients with transformed lymphoma a single center clinical experience

Indolent lymphoma, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma (FL), can undergo histological transformation into an aggressive subtype, typically diffuse large B-cell lymphoma (DLBCL). The prognosis of transformed lymphoma is poor. In this study, we reported the efficacy and toxicity of a combination of venetoclax, dose-adjusted rituximab or obinutuzumab, etoposide, prednisone, vincristine, doxorubicin, and cyclophosphamide (VR-DA-EPOCH or VG-DA-EPOCH) in 11 patients with biopsy-proven histology transformation into DLBCL, including 8 patients with RT and 3 with transformed FL (tFL). The study was conducted between October 2019 and March 2023 at our single center. The median age of participants at enrolment was 53 years. Six patients (85.7%, 6/7) achieved complete remission (CR) at the end of treatment. The best overall response rate (ORR) and CR rate were both 72.7%, respectively. Two patients received autologous hemopoietic stem cell transplant (ASCT) while two patients received ASCT concurrently with CAR-T therapy for consolidation. With a median follow-up of 13.5 (range, 2.4–29.8) months after enrollment, the median event-free survival, progression-free survival, and overall survival were 9.4, 11.5, and 17.5 months, respectively. Hematologic toxicities of grade ≥3 consisted of neutropenia (90.9%, 10/11), thrombocytopenia (63.6%, 7/11), and febrile neutropenia (54.5%, 6/11). In conclusion, VR-DA-EPOCH or VG-DA-EPOCH was a promising strategy to achieve an early remission, bridging to cellular therapy within this population.

Patient perspectives on treatment for mantle cell lymphoma and chronic lymphocytic leukemia in Japan.

The increasing number of treatment options for patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in Japan underscores the critical need to comprehend their treatment preferences. In this study, individual semi-structured interviews with 20 Japanese patients with diagnosis of MCL or CLL/SLL were conducted and qualitatively analyzed to elicit concepts important for patients regarding treatment selection. Although effectiveness and safety were imperative for treatment selection, convenience and quality of life were also reported as important attributes. Over the course of their disease journey, patients reported diverse and changing preferences in terms of treatment characteristics. Additionally, there was a discrepancy between their desired and actual levels of involvement in shared decision-making with physicians about treatment choices. Optimal personalized care for better outcomes of patients with MCL and CLL/SLL hinges on healthcare professionals acknowledging individual patient needs and preferences within their cultural, societal and personal context.

CO102 Physician Reported Treatment Attributes Considered in First-Line and Perceptions Around Bruton Tyrosine Kinase Inhibitor (BTKi) Treatments in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) in the US

CO102 Physician Reported Treatment Attributes Considered in First-Line and Perceptions Around Bruton Tyrosine Kinase Inhibitor (BTKi) Treatments in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) in the US

HSD114 Treatment Patterns and Adverse Events (AEs) in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) in France, Italy, and the United Kingdom (UK)

HSD114 Treatment Patterns and Adverse Events (AEs) in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) in France, Italy, and the United Kingdom (UK)

Outcomes of Patients with Richter Transformation without Prior Chemoimmunotherapy for CLL/SLL: An International Multicenter Retrospective Study

Background: Richter Transformation (RT) refers to the development of an aggressive lymphoma in the setting of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Small molecule inhibitors (SMI), such as the Bruton tyrosine kinase inhibitors (BTKi) and BCL2 inhibitors (BCL2i), have revolutionized the treatment of CLL/SLL. Prior studies evaluated outcomes of patients (pts) with RT in an era where chemoimmunotherapy (CIT) was typically used to treat CLL/SLL. Now that SMI are standard of care, fewer pts with CLL/SLL receive CIT, therefore we sought to determine which variables predict survival in pts who developed RT without prior CIT exposure for CLL/SLL. Methods: We conducted an international multicenter retrospective study of pts from 11 academic centers. Pts with RT occurring as large B-cell lymphoma who did not previously receive CIT (e.g., fludarabine, cyclophosphamide, bendamustine, chlorambucil) for their CLL/SLL were included. We collected pt, disease, and treatment (tx) characteristics. RT was categorized into 3 groups: “Concurrent RT,” defined as RT and CLL/SLL diagnosed simultaneously (within 3 months [mos]); “RT w/o prior CLL/SLL tx,” defined as RT and CLL/SLL diagnosed >3 mos apart with the CLL/SLL never treated; and “RT with prior non-CIT tx for CLL/SLL” defined as having received prior CLL/SLL tx. Overall survival (OS) was measured from RT diagnosis (Dx) and estimated using the Kaplan-Meier method. Cox regression model was used to identify prognostic factors associated with OS. Results: 242 pts were identified. At CLL/SLL Dx, 66% of pts had unmutated IGHV, 37% had del17p/ TP53 disruption, and 20% had trisomy 12. At RT Dx, 56% of the RT with prior non-CIT tx for CLL/SLL group had a del17p/ TP53 disruption versus 27% for the concurrent RT group and 18% for the RT w/o prior CLL/SLL tx groups. Median time from CLL/SLL Dx to RT Dx was 47 mos (range 3-394) for RT w/o prior CLL/SLL tx and 46 mos (range 4-218) for RT with prior non-CIT tx for CLL/SLL. Pts with prior non-CIT tx for CLL/SLL received a median of 1 (range 1-5) prior tx. 86% of pts previously received a BTKi or a BCL2i for tx of CLL/SLL (54% BTKi only, 5% BCL2i only, 27% both). The remaining 14% had been treated with an anti-CD20 monoclonal antibody (MoAb), steroids, lenalidomide, radiation, or alemtuzumab. 85% of pts developed RT while on active tx with SMI. Median age at RT Dx was 69 years (range 37-92). At RT Dx, 38% and 21% of pts had del17p/ TP53 disruption, and trisomy 12 in CLL/SLL tissue, respectively. At RT Dx, there was no difference in highest SUV on PET (median 16, range 2.9-65.6), LDH (median 325, range 103-8162, ULN range 180-271), largest lymph node in diameter (median 4.9 cm, range 0-17.1), Ki-67 (median 80%, range 5%-100%), rate of GCB subtype (27%), presence of MYC translocation (20%), or CLL/SLL and RT clonal relationship (81%) for those pts tested amongst the 3 groups ( Table). The most common 1 st line tx for RT was CIT with or w/o radiation and/or steroids (76%), followed by CIT plus SMI (13%), SMI single agent or combination (7%), and other (4%, which includes anti-CD20 MoAb). Median follow-up from RT Dx was 42.3 mos; the median OS for the entire cohort was 25.8 mos (95% CI: 16.8-49.1). Pts with RT after non-CIT tx for CLL/SLL had a significantly worse OS (median 8.2 mos [95% CI: 5.6-14.3]) than pts with concurrent RT (median 46.3 mos [95% CI: 23.8-96.9]) and RT w/o prior CLL/SLL tx (median 63.5 mos [95% CI: 28.3-70.3]) ( Figure). From an exploratory univariable analysis, we found RT after non-CIT tx for CLL/SLL compared to concurrent RT (HR 2.32 [95% CI: 1.55-3.46]), RT Dx age (HR for 5-year increase 1.14 [95% CI: 1.05-1.23]), del17p/ TP53 disruption (HR 2.27 [95% CI: 1.45-3.56]), and LDH (HR for 2-fold increase 1.37 [95% CI: 1.20-1.58]) were prognostic for worse OS. Conclusions: This is the largest cohort of pts who developed RT having received only SMI with no CIT for their CLL reported, thus reflecting the current treatment landscape. Despite being CIT-naïve, pts in our series who received tx for their CLL/SLL and then developed RT had a short OS, underscoring the need to develop better therapies for these pts. In contrast, as in other published analyses (Wang Haematologica 2020), pts w/o prior tx for CLL/SLL had more favorable outcomes, with a median OS of approximately 5 years. Further analysis to determine PFS and OS by tx for RT for pts who have been treated with SMI for their CLL/SLL is ongoing.

Patient-Reported Outcomes (PROs) Among Patients with Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Receiving Pirtobrutinib: Analysis from the BRUIN Phase 1/2 Study

Background PROs including health-related quality of life (HRQoL) and symptom burden can provide helpful information to support benefit-risk assessment of a new treatment. Pirtobrutinib, a highly selective, non-covalent (reversible) Bruton tyrosine kinase inhibitor (BTKi), inhibits both wildtype and C481-mutant BTK with equal low nM potency, and has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval regardless of intrinsic rate of BTK turnover. Pirtobrutinib recently received regulatory approval in the US for the treatment of patients with relapsed or refractory mantle cell lymphoma after two or more lines of systemic therapy, including a covalent BTKi (cBTKi). BRUIN (NCT03740529) is an ongoing, open-label, multi-center phase 1/2 study investigating the safety and efficacy of pirtobrutinib for the treatment of B-cell malignancies, including CLL/SLL. This current analysis reports PROs among patients enrolled in the BRUIN study with relapsed or refractory (R/R) CLL/SLL treated with prior cBTKi-containing regimens. Methods Pretreated patients with R/R CLL/SLL in the BRUIN study completed PRO assessments at each clinic visit. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ-C30) was used to measure physical function (PF) and HRQoL via PF and Global Health Status/QoL subscales. Patient-reported CLL/SLL symptoms and fatigue were assessed using 13 and 6 EORTC Item Library (IL) items, respectively. All subscales are scored 0-100. Higher scores represent better PF and HRQoL; and higher scores represent worse CLL/SLL symptoms and fatigue. Pre-specified clinically meaningful within patient change (MWPC) thresholds of at least 10-point changes in each PRO score were used to categorize patients based on their individual change from Cycle 1 Day 1 (i.e., baseline). Mean changes from baseline and proportions of patients with improved, stable, and worsened PROs from baseline were summarized by treatment cycle. PRO data were presented from Cycle 1 to 24 (a 28-day cycle) since the study median progression-free survival by investigator assessment was 19.6 months. The data cutoff date was 22 July 2022. Results There were 263 patients with CLL/SLL at the time of analysis; median (Quartile 1 and 3) age was 69 (62, 74) years and the majority were male (68%). All patients had received prior cBTKi; 21% received 2 or more prior cBTKi lines and 20% discontinued from their most recent cBTKi treatment due to toxicity. The mean overall completion rate of PRO instruments was 83% at baseline. 76% of all patients in the analysis completed at least one subsequent PRO assessment. Baseline mean (±SD [standard deviation]) score was 80.8 (±19.5) for PF, 61.6 (±23.2) for QoL, 24.8 (±18.4) for CLL/SLL symptoms, and 33.5 (±24.7) for fatigue. The majority of patients reported stable or clinically improved outcomes from baseline at each of the post-baseline visits (through Cycle 24) for PF (proportion of stable/improved ranged from 72.5% to 95.5%), QoL (range 80.4% to 95.0%), CLL/SLL symptoms (range 77.8% to 96.3%), and fatigue (range 77.3% to 89.9%). Conclusion Overall, consistent with the favorable safety profile of pirtobrutinib, HRQoL and symptoms were stable or improved for over 70% of patients with pretreated R/R CLL/SLL throughout the first 24 cycles of pirtobrutinib treatment. These PRO data should be interpreted with caution due to single arm trial design and small numbers of patients available for assessment in later cycles.

Pirtobrutinib in Post-cBTKi CLL/SLL: ~30 Months Follow-up and Subgroup Analysis With/Without Prior BCL2i from the Phase 1/2 BRUIN Study

Background: The treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has benefited from covalent (c) Bruton tyrosine kinase inhibitors (BTKi), however, therapy can fail due to progression or intolerance. Sequential treatment with B-cell lymphoma 2 protein inhibitor (BCL2i) venetoclax, either as monotherapy or combined with an anti-CD20 monoclonal antibody, has been the primary treatment option for CLL/SLL patients (pts) whose disease has progressed on cBTKi. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that demonstrated promising efficacy in patients with relapsed or refractory CLL/SLL (Mato et al, NEJM, 2023). Here, we report on the efficacy of pirtobrutinib treatment in CLL/SLL in the post-cBTKi setting, including subgroups with or without prior BCL2i, using data from the BRUIN study (NCT03740529) with more than 2 years follow-up. Methods: Pts with previously treated CLL/SLL were eligible for treatment with pirtobrutinib in the multicenter Phase 1/2 BRUIN study. Key endpoints included ORR (including partial response with lymphocytosis; PR-L) as assessed by an independent review committee per 2018 iwCLL response criteria, DoR, PFS, OS, and safety. A data cut of 05MAY2023 was utilized. Results: In total, 282 pts with CLL/SLL who received prior cBTKi were included in this analysis. Median age was 69 years (range, 36-88), 68% were male, and median number of prior therapies was 4 (range, 1-11). Of 282 pts, 154 (55%) had not received prior-BCL2i therapy (Naïve; BCL2i-N) and 128 (45%) had (Exposed; BCL2i-E). BCL2i-N pts were exposed to fewer prior therapies than BCL2i-E pts (median prior therapies 3 and 5, respectively), including anti-CD20 antibody (83% and 97%), chemotherapy (74% and 89%), PI3K inhibitor (11% and 42%), CAR-T cell therapy (1% and 12%), and hematopoietic cell transplantation (1% and 6%). The ORR for all post-cBTKi pts was 72% (95% CI, 66.4-77.1), and ORR including PR-L was 82% (95% CI, 76.5-85.9). Post-cBTKi pts included a subgroup of 19 pts with one prior line of cBTKi-containing therapy and second line therapy of pirtobrutinib, who had ORR including PR-L of 89.5% (CI 95%, 66.9-98.7). The ORR including PR-L was 83.1% (95% CI, 76.2-88.7) for BCL2i-N pts, and 79.7% (95% CI, 71.7-86.3) for BCL2i-E pts. Median DoR was 18.4 months (95% CI, 15.3-20.4) for all cBTKi pre-treated pts, 24.9 months (95% CI, 18.4-32.0) for BCL2i-N, and 14.8 months (95% CI, 12.0-17.4) for BCL2i-E. With a median follow up of 27.5 months, the median PFS was 19.4 months (95% CI, 16.6-22.1) among all cBTKi pre-treated pts, 23.0 months (95% CI, 19.6-28.4) for BCL2i-N, and 15.9 months (95% CI, 13.6-17.5) for BCL2i-E (Figure). With a median follow up of 29.3 months, the median OS was not estimable for all cBTKi pre-treated pts, BCL2i-N, and BCL2i-E; the 24-month OS rates were 73.2% (95% CI, 67.4-78.2), 83.1% (95% CI,75.9-88.2), 60.6% (50.9-68.9), respectively. In the CLL/SLL cohort (N=282), the most frequent treatment-emergent adverse events (TEAE), regardless of attribution, were fatigue (36.9%), diarrhea (28.4%), cough (27.3%) and contusion (26.2%). The most frequent Grade ≥3 TEAE was neutropenia/neutrophil count decreased (28.4%). Grade ≥3 TEAEs of hypertension (4.3%) and atrial fibrillation/flutter (1.8%) were infrequent. The AE profile of BCL2i-N and BCL2i-E pts was overall similar. Though Grade ≥3 neutropenia/neutrophil count decreased was higher in BCL2i-E pts (36.7% and 21.4%), this may have been attributed to the higher frequency of baseline neutropenia in BCL2i-E pts (27.3% and 11.0%). In total, 7 (2.5%; 4 BCL2i-N, 3 BCL2i-E) pts had treatment-related AE leading to pirtobrutinib discontinuation. Conclusion: Pirtobrutinib continues to demonstrate promising and durable efficacy in pts with post-cBTKi heavily pretreated CLL/SLL. ORR was high regardless of prior BCL2i status. Longer PFS was observed in BCL2i-N pts than BCL2i-E pts, likely due to the more heavily pretreated status of the BCL2i-E population which can be associated with poorer prognosis. Pirtobrutinib was well-tolerated with low-rates of discontinuation due to drug-related toxicity among both BTKi-N and BTKi-E pts. These results suggest that continuation of BTK pathway inhibition following a cBTKi may be an important sequencing approach to consider in the treatment of CLL/SLL.

Real-World Patterns of Targeted Therapy Use in Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma in the United States: A Longitudinal Study

Introduction: Clinical guidelines and practice have shifted toward increasing use of novel Bruton's tyrosine kinase inhibitors (BTKi) or B-cell lymphoma 2 inhibitor (BCL2i) for treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). To highlight recent changes in clinical practice, this study evaluated real-world treatment sequences, with a focus on sequential novel targeted therapy, among patients with CLL/SLL in the US over time. Methods: Adult patients with ≥2 medical claims for CLL/SLL diagnosis on distinct days and ≥1 claim for CLL/SLL therapy were identified in the Optum Clinformatics DataMart database (2014-2021). The index date was the date of initiation of the first observed line of therapy (LOT) following the first observed CLL/SLL diagnosis. The observation period spanned from index to the earliest of end of eligibility, data availability, or death. LOTs were identified using a claims-based algorithm adapted from published literature during the observation period. Each LOT spanned from the initiation of a new agent to discontinuation of all agents in the LOT (i.e., 90-day gap without any dispensing), a switch to another agent, or the addition of a new agent. The proportion of patients receiving sequential targeted therapy in the first 2 LOTs (i.e., BTKi/BCL2i as first-line [1L] and second-line [2L] treatments in any order) was described. For sequential BTKi in 1L and 2L, treatments were also described by agent (i.e., ibrutinib, acalabrutinib, zanubrutinib, and combinations thereof). To assess longitudinal patterns, Sankey plots were created for 2 temporal data cohorts: patients with a 1L in 2014-2017 and patients with a 1L in 2018-2021. Results: We identified 7,146 eligible patients, 40.6% female, median age 73 years, with a median follow-up of 2 years after 1L initiation. The most common 1L treatment was BTKi (36.8%), then chemoimmunotherapy (CIT; 27.4%), CD20 (22.2%), chemotherapy (7.6%), and BCL2i (5.4%). In the first 2 LOTs, 22.3% of patients had sequential targeted therapy, comprising 70.0% BTKi→BTKi (i.e., BTKi retreated), 23.8% BTKi→BCL2i, 3.6% BCL2i→BCL2i, and 2.6% BCL2i→BTKi. The most common BTKi sequences by agent were ibrutinib→ibrutinib (61.6%) and ibrutinib→acalabrutinib (28.4%). Among patients with a 1L in 2014-2017 (N=2,612; median follow-up=3 years; Figure A), the most common 1L treatment class was CIT (44.6%), followed by CD20 (25.2%), BTKi (21.7%), chemotherapy (7.6%), and BCL2i (0.3%). For those receiving a 2L treatment (N=905), the 3 most common treatment classes were BTKi (37.6%), CD20 (30.2%), and CIT (17.2%). The proportion of patients receiving sequential targeted therapy in the first 2 LOTs was 11.2%; among these patients, 80.2% had BTKi→BTKi; 17.8% had BTKi→BCL2i; 2.0% had BCL2i→BCL2i; and 0% had BCL2i→BTKi. The most common BTKi sequences by agent were ibrutinib→ibrutinib (81.5%) and ibrutinib→acalabrutinib (17.3%). Among patients with a 1L in 2018-2021 (N=4,534; median follow-up=1 year; Figure B), the most common 1L treatment class was BTKi (45.5%), followed by CD20 (20.4%), CIT (17.5%), BCL2i (8.3%), and chemotherapy (7.6%). For 2L (N=833), the 3 most common treatment classes were BTKi (40.9%), CD20 (24.4%), and BCL2i (14.9%). The proportion of patients receiving sequential targeted therapy in the first 2 LOTs was 34.3%, comprising 66.4% BTKi→BTKi; 25.9% BTKi→BCL2i; 4.2% BCL2i→BCL2i; and 3.5% BCL2i→BTKi). Among those receiving sequential BTKi, the most common sequences by agent were ibrutinib→ibrutinib (53.2%), ibrutinib→acalabrutinib (33.2%), and acalabrutinib→acalabrutinib (5.3%). Conclusions: This longitudinal real-world study found a substantial increase in patients with CLL/SLL receiving targeted therapies in 1L over time. In particular, the proportion receiving BTKi in 1L doubled in 2018-2021 relative to 2014-2017 and accounted for almost half of the recent 1L CLL/SLL initiations. A third of patients with 1L observed in 2018-2021 also received a targeted agent in 2L, relative to about 1 in 10 patients in 2014-2017, with BTKi→BTKi being the most common sequence. Surprisingly, patients who received a BTKi in 1L were more likely to receive a BTKi in 2L than they were to switch to a BCL2i. Future studies should assess clinical outcomes to determine optimal sequences for CLL/SLL as well as the reasons for re-treatment with BTKi.

Clinical Characteristics, Treatment Patterns, and Outcomes of Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Refractory to Covalent Bruton's Tyrosine Kinase Inhibitor (BTKi) and Exposed to B-Cell Lymphoma 2 Inhibitor (BCL2i)

Introduction: CLL/SLL patients who failed BTKi and are treated with BCL2i represent a growing population with few standard-of-care treatment options after discontinuing both therapies. Patients who fail both BTKi and BCL2i have poor prognosis, with a median overall survival (OS) of 3.6 months (Lew et al., Blood Advances, 2021). However, real-world evidence for these patients is limited. This study described the characteristics, treatment patterns, and outcomes of CLL/SLL patients who were relapsed or were resistant/refractory/intolerant (R/R/R/I) to BTKi and who were exposed to BCL2i. Among patients who discontinued BCL2i, responses to the treatment immediately after BCL2i were reported. Methods: This retrospective chart review study evaluated Dana-Farber Cancer Institute patients with CLL/SLL (≥18 years old) who were R/R/R/I to BTKi and received BCL2i (in any order). Abstraction took place from 12/2021 to 07/2023. Patients were required to have records available from 6 months before to 12 months after first BTKi initiation. Patients who received non-hormonal antineoplastic therapy for other primary malignancies in the period between CLL/SLL diagnosis and receipt of their first BTKi treatment were excluded. Demographic and clinical characteristics at or before BCL2i initiation were described. Lines of treatment (LOTs) and responses to BCL2i were summarized. Time to treatment discontinuation, real-world PFS (rwPFS) and OS were estimated by Kaplan-Meier analysis. Patients were considered doubly refractory if they were R/R/R/I to BTKi and BCL2i. Overall response rate to first treatment after BTKi and BCL2i was summarized among doubly refractory patients. Results: Among 104 patients who were R/R/R/I to BTKi, 61 (58.7%) received a BCL2i. The patients exposed to both BTKi and BCL2i were observed for a median (interquartile range [IQR]) time of 2.6 (1.1,4.4) years after BCL2i initiation. 57 (93.4%) patients received BCL2i after BTKi and 4 (6.6%) received BCL2i before BTKi. BCL2i was most commonly (23 [37.7%] patients exposed to BCL2i) received in the fourth LOT and all patients received their first BCL2i after their first LOT. Median (IQR) age at BCL2i initiation was 68.4 (63.3-74.4) years. Among patients who were assessed for cytogenetic abnormalities (n=58), the most common abnormalities were del(13q) (55.2%) and del(17p) (36.2%). 36 (61.0%) patients had TP53 mutation. 45 (73.8%) patients discontinued their first BCL2i treatment. IGHV mutation was assessed for 49 patients and 8 (16.3%) had mutation rates ≥ 2%. Median (IQR) time to BCL2i discontinuation for patients receiving BCL2i was 1.5 (0.4, 3.1) years. 40 (76.9%) of the 52 patients with a known first response to BCL2i achieved clinician-assessed complete (CR) or partial response (PR) at first assessment. 25 (41.0%) patients were R/R/R/I to BCL2i at the time of abstraction. Of them, 21 (84.0%) progressed, 7 (28.0%) developed Richter transformation (RT) and 11 (44.0%) died. Primary cause of death was available for 8 (72.7%) patients and, of these, 5 (62.5%) died due to disease progression, 2 (25.0%) died due to a secondary malignancy, and 1 (12.5%) died from unspecified causes. Among doubly refractory patients, median (95% CI) rwPFS was 1.6 (0.7, 2.4) years and median OS was 3.8 (2.3, not reached) years from the initiation of the latter of BTKi and BCL2i treatment. Among doubly refractory patients, 18 (72.0%) received an additional LOT after the latter of BTKi and BCL2i. The therapies received in the first line after BTKi and BCL2i were allogeneic HSCT (4 patients), duvelisib (3 patients), oral CDK9i (2 patients), and 1 patient each with CAR-T, anti-CD20 bispecific antibody, alemtuzumab, vecabrutinib, zanubrutinib; and for patients with RT: venetoclax plus rituximab with anthracycline chemotherapy (2 patients), PI3Ki/PD-1 (1 patient), duvelisib (1 patient) ( Figure 1). Response to the additional LOT was known for 17 patients and unknown for 1 patient. Clinician-assessed CR or PR to treatment immediately after BCL2i and BTKi was achieved for 4 (23.5%) of these patients at first assessment. Conclusions: Patients with CLL/SLL who were failed by BTKi and BCL2i treatment have poor prognosis. Overall response rates to treatment immediately after BTKi and BCL2i treatment are low among doubly refractory patients. More effective treatments are needed to address the unmet therapeutic needs of CLL/SLL patients who are refractory to both BTKi and BCL2i.

Loss of DDX3X Function Promotes CLL Progression By Facilitating NOTCH1 mRNA Translation

A variety of driver genes are present in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and those with high mutation frequencies include SF3B1, NOTCH1, and TP53, which are involved in the development of CLL/SLL and are associated with poor prognosis. The biological significance of some driver genes, such as DDX3X, has not yet been elucidated. DDX3X is located on the X chromosome. As one of the members of the DEAD-box helicase family, it is expressed ubiquitously in human tissues and participates in many biological processes. Here, we described the mapping of the DDX3X abnormalities and demonstrated its clinical significance in CLL/SLL. We also explored the effect and mechanism of DDX3X dysregulation on tumorigenesis and development of CLL by in vitro experiments. To examine the mutational landscape of DDX3X, we performed next-generation sequencing on 402 CLL/SLL patients, and 17 patients (4.2%) had DDX3X mutations. Six patients were frameshift mutations and 2 were nonsense mutation, which caused truncation of DDX3X. Among the 7 cases of missense mutations, 4 cases involved the ATP-binding or C-terminal domain, which may affect the function of DDX3X. The remaining two cases are deletion mutation and splicing mutation. Next, we evaluated the clinical significance and prognostic role of DDX3X mutation. The patients with DDX3X mutations are mostly male (94.1% vs 66.5%, P=0.017), and had more adverse prognostic indicators: unmutated IGHV (88.2% vs 48.6%, P=0.002), 17p deletion (42.9% vs 11.4%, P=0.041), and 11q deletion (46.7% vs 15.7%, P=0.006). DDX3X mutation was an independent risk factor for disease specific survival of CLL/SLL in the competing-risk regression. Also, we found all (14/14) the mutated patients and 15.2% (5/33) of the non-mutated patients had low expression of DDX3X in bone marrow samples by immunohistochemistry. Overall, these results indicates that dysregulation of DDX3X are common in CLL/SLL and may contribute to its progression. To delineate the functional consequences of DDX3X loss in CLL, we used CRISPR/cas9 system to construct stable DDX3X knockout (DDX3X-KO) MEC-1 and JVM-3 cells. DDX3X-KO cells showed significantly increased proliferation and reduced spontaneous apoptosis compared to vector control. Additionally, DDX3X-KO cells showed higher rates of cell viability and reduced apoptosis after treatment of ibrutinib or venetoclax. We further found that DDX3X-KO cells had higher expression level of phosphorylated BTK and MCL-1, which may explain the resistance to ibrutinib and venetoclax, respectively. Moreover, DDX3X-KO cells showed increased expression level of CXCR4 and enhanced chemotaxis in response to CXCL-12. In summary, loss of DDX3X function promotes progression of CLL by mediating more invasive biological behaviors of CLL cells. To evaluate the mechanisms by which DDX3X deletion affects CLL, we detected key signaling pathways in the tumorigenesis and development of CLL in DDX3X-KO and control cells. We found increased expression of NOTCH1 and its downstream target proteins in DDX3X-KO cells (Figure 1), indicating that loss of DDX3X activated the NOTCH1 pathway. Considering that DDX3X is an RNA-binding protein and mainly regulates translation, we speculated that DDX3X may regulate the translation of NOTCH1. We performed RNA binding protein immunoprecipitation assay and found that DDX3X directly interacted with NOTCH1 mRNA (Figure 2A, B). Dual-luciferase reporter assay showed enhanced activity of NOTCH1 5‘ UTR in DDX3X-KO cells (Figure 2C), further suggesting that DDX3X may regulate translation of NOTCH1 mRNA through binding to the 5‘ UTR. Finally, polysome profiling demonstrated that DDX3X knockout resulted in increased NOTCH1 mRNAs in polysome fractions (Figure 2D), confirming that loss of DDX3X function facilitates NOTCH1 mRNA translation. In conclusion, DDX3X abnormalities are common in CLL and associated with poor prognosis. DDX3X dysregulation is involved in the progression of CLL by facilitating NOTCH1 mRNA translation through binding to the 5' UTR.

Correlation between Real-World Progression-Free Survival (rwPFS) and Overall Survival (OS) in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Who Relapsed or Are Refractory, Intolerant, Resistant to Treatment with a Bruton's Tyrosine Kinase Inhibitor (BTKi)

Introduction: Given the long maturation time of OS, PFS is often used in oncology and hematology as a surrogate for OS. However, the association between the two endpoints varies across cancer types. In CLL clinical trial populations, PFS and OS were shown to be strongly correlated in patients receiving at least two lines of therapy (LOT). The present study used real-world individual patient data to evaluate the strength of correlation between real-world PFS (rwPFS) and OS in CLL/SLL patients who relapsed or were resistant/refractory/intolerant to treatment with a covalent BTKi. Methods: A retrospective chart review was conducted of adult CLL/SLL patients at Dana-Farber Cancer Institute who were treated with at least one covalent BTKi and relapsed or were resistant/refractory/intolerant to the treatment and have discontinued BTKi. Patients were included if they had records available from 6 months before to 12 months after initiation of the first observed (index) BTKi, and were excluded if they were treated with a non-hormonal antineoplastic agent for other primary malignancies in the period between CLL/SLL diagnosis and receipt of their first BTKi. Demographic and clinical variables, oncologic and medical histories, treatments, and clinical outcomes were abstracted from patients' medical charts. Time to event endpoints were described using Kaplan-Meier curves. Time to progression (TTP) was defined as time from index to progression. OS was defined as time from index to death; patients were censored at the last visit if they did not die. rwPFS was defined as the time to progression or death; patients who did not progress or die were censored at index BTKi treatment discontinuation. Fleischer's method was used to estimate the individual-level Pearson correlation coefficient between rwPFS and OS among patients treated with BTKi in any line of treatment. Confidence intervals (CIs) were calculated by bootstrapping (1000 replicates). Results: A total of 104 patients who initiated treatment with the index BTKi from 07/2011 to 09/2019 and relapsed or were resistant/refractory/intolerant to the treatment were included in the analysis. Median (interquartile range [IQR]) age at BTKi initiation was 66.7 (60.3-73.0) years, median (IQR) time from index BTKi initiation to last clinical visit or death was 5.7 (3.3-7.0) years. Among patients with a known index BTKi LOT (N=102 [98%]), 28% received the index BTKi in first line, 32% in second line, 23% in third line, 12% in fourth line, and 6% in or after the fifth line. An assessment date for response to the index BTKi and for whether a patient had progressed was available for 95 patients (91%) ( Table 1). Among these patients, progression after index BTKi treatment was observed for 48 (51%) patients. Median (95% CI) time from BTKi initiation to progression was 3.7 (2.6, 4.1) years. More than one-third of patients (35%) died and median (95% CI) OS was 8.9 (6.7, not reached) years. 7 patients died without progressing and cause of death was available for 5 of these patients: 3 died because of an infection, 1 because of a secondary malignancy, and 1 because of other unspecified causes. 58% patients progressed or died and median (95% CI) rwPFS was 3.2 (2.6, 3.9) years. The correlation (95% CI) between rwPFS and OS was 0.79 (0.63, 0.94). Conclusions: This analysis found a strong, positive, and significant correlation between rwPFS and OS in patients with CLL/SLL who received treatment with a covalent BTKi and relapsed on or were resistant/refractory/intolerant to the treatment. These findings reinforce the hypothesis that rwPFS may be a useful early endpoint for evaluating the effectiveness of BTKi treatment outside of clinical trials among the patient population of CLL/SLL patients who relapsed or were refractory/resistant/intolerant to BTKi, at time points when OS is not mature. However, further analysis of the change in rwPFS that predicts an improvement in OS (surrogate threshold effect) is required to establish rwPFS as a valid surrogate for OS.

Comparative Analysis of Patient Characteristics, BTK Treatment, and Treatment Outcomes in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): A Cross-National Study between the United States and China

Background: Bruton's tyrosine kinase (BTK) inhibitors have transformed the treatment landscape for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Real-world data can provide insights into factors influencing BTK inhibitor initiation and switching, enabling a comprehensive understanding of treatment patterns. This study aimed to evaluate these factors in CLL/SLL patients in the United States and Tianjin, China, and compare overall survival outcomes among patients using different BTK inhibitor types. Methods: We conducted a comparative analysis utilizing real-world data from two sources: the Flatiron Database in the US and Tianjin Regional Healthcare Data in China. Data from both databases were analyzed to identify factors associated with BTK inhibitor initiation and switching in CLL/SLL patients. Additionally, overall survival outcomes were assessed among patients using various types of BTK inhibitors, including ibrutinib, acalabrutinib, and zanubrutinib. Results: Our analysis revealed key differences in patient characteristics. Median age of US BTK users was 66 years (IQR: 58-73) vs. 61 years (IQR: 59-69) in China. Notably, the US exhibited higher rates of hypertension (40.3% vs. 9.6%), diabetes (12.4% vs, 9.1%) and infections (22.1% vs. 8.1%). BTK treatment utilization differed between the US and China: Ibrutinib 82.3% vs. 81.6%; Zanubrutinib 0.2% vs. 17.2%; and Acalabrutinib 17.5% vs. 0%. A higher proportion of US BTK users were exposed to immunochemotherapy (50.8% vs. 19.1%). Overall survival rates at 1-year and 3-years from 1 st BTK were comparable (US 95.2% vs. China 96.4%; US 90.2% vs. China 92.3%); and from 2 nd BTK (US 98.6% vs. China 100%, US 96.4% vs. China 100%). Conclusion: This study contributes to a comprehensive understanding of real-world BTK inhibitor initiation and switching in CLL/SLL patients from the United States and Tianjin, China. Additionally, the 1-year and 3-year OS rates from both 1st and 2nd BTK treatments were generally favorable in both regions, suggesting the effectiveness of BTK therapies in B-cell malignancies. These findings have implications for treatment decision-making and optimizing patient care in CLL/SLL.

Impact of Psychological Distress on Immune Phenotype in CLL/SLL Patients Managed By Active Observation

Introduction: Asymptomatic patients with a new diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) are usually managed by active observation; however, many patients report elevated levels of distress and worry during the ‘watchful waiting’ phase. Psychological distress may have clinical implications given that natural killer [NK] and T cells are not only sensitive to distress, but also critical in controlling disease progression. Thus, the purpose of this study was to examine associations of psychological functioning and quality of life (QOL) with biomarker expression and functional activity of immune cells from peripheral blood of CLL/SLL patients being managed with surveillance. Methods: We conducted a multisite, prospective study in patients with indolent B-cell neoplasms who were managed with surveillance. Participants completed measures of perceived stress (Perceived Stress Scale), anxiety and depressive symptoms (Hospital Anxiety and Depression Scale) and quality of life (FACT-G) at study entry and then every 6 months for up to 2 years or disease progression (whichever occurred first). Blood samples were collected at study entry and every 6 months for immune phenotyping using multiparametric flow cytometry (up to 13-color). Biomarkers of activation, viability, proliferation, exhaustion, and receptor expression were assessed on subsets of T, NK, and myeloid cells, and mean fluorescence intensity or percentage of cells staining were determined. Results: Between April 2016 and November 2020, 233 patients were enrolled at two academic institutions in Philadelphia, including 111 with a diagnosis of CLL/SLL. Of these, 76 patients also had viable samples for immune phenotyping. Participants were predominantly male (60.5%) with a mean age of 63.7 years (SD=9.1 years). Approximately 5% self-reported their race as Black or African American and 4% were of Hispanic ethnicity. At enrollment, the median time since diagnosis was 10.6 months (median follow-up time = 23.6 months). Multivariable regression analyses revealed that increased depressive symptoms were associated with a significant shift from lower percentages of non-classical monocytes (NCM) to higher percentages of classical monocytes (CM; see Figure 1). Similar significant population shifts from reduced NCM toward increased CM were also observed with increased levels of stress and anxiety. These results suggest that patients reporting increased stress, anxiety, and depressive symptoms have fewer of the “patrolling” NCM and increased “sensing” CM in peripheral blood. We also assessed expression of numerous innate immune receptors, including DNAM-1, which can stimulate responses by NK and T cells toward tumors. We observed lower expression of DNAM-1 on CD4 + helper T cells and CD8 + cytotoxic T cells in patients with increased depressive symptoms (p< 0.05). Similarly, patients reporting lower QOL also expressed lower levels of DNAM-1 on CD4 + and CD8 + T cells, as well as cytotoxic CD56 dim NK cells (p<0.05). As DNAM-1 is important for antitumor responses, our data suggest that patients with higher depressive symptoms have T and NK cells with reduced capacity to respond to CLL/SLL tumor cells. NKp30, another activating receptor on NK and CD8+ T cells promoting cytotoxicity, was also expressed at lower levels on CD56 dim NK cells and T cells in the peripheral blood of patients reporting depressive symptoms. Patients who reported higher levels of depressive symptoms had lower levels of expression of the activation marker CD69 on CD4+ and CD8+ T cells. Finally, longitudinal analyses revealed that higher levels of depressive symptoms predicted lower levels of PD-L1 on CD56 dim NK cells over time ( p = 0.04). Conclusion: In CLL/SLL patients, psychological functioning is associated with differential patterns of monocyte distribution. Greater depressive symptoms and lower quality of life predicted lower expression of innate immune receptors, such as DNAM-1 on CD4 + helper T cells and CD8 + cytotoxic T cells. Future directions will investigate whether these measures are associated with disease progression or the occurrence of second primary cancers, given the importance of DNAM-1 and NKp30 in immune surveillance for cancers and reactivation of latent viruses. These findings may have direct translational relevance and enable the early identification of patients at-risk for poor outcomes.

Effectivness and Safety of Orelabrutinib in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Retrospective, Real-World Study in China

Introduction: Orelabrutinib is a second-generation Bruton tyrosine kinase inhibitor (BTKi) with high kinase selectivity. Clinical studies have demonstrated that orelabrutinib achieved a high complete response rate of 26.3% in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), showing promising efficacy and acceptable safety profile. However, the real-world data of Orelabrutinib are not available. This study aimed to evaluate the effectiveness and safety of orelabrutinib-containing regimens for the treatment of patients (pts) with CLL/SLL in a real-world setting. Methods: This was a retrospective, multi-center, real-world study conducted. Pts (aged 18 years or older) with CLL/SLL who received at least 3 months of orelabrutinib-containing regimens between December 2020 and March 2023 were analyzed. Efficacy was evaluated by hematologic response rate (HRR), defined as the proportion of pts who met at least 1 of the following hematologic response criteria: hemoglobin response (pts having a recovery of hemoglobin value or ≥50% increase from baseline), platelet response (pts having a recovery of platelet count or ≥50% increase from baseline), or lymphocyte response (pts having a recovery of lymphocyte count or ≥50% reduction from baseline). Safety was assessed by adverse events (AEs) as per NCI-CTCAE 5.0. Results: 24 pts with CLL/SLL (12 males; 22 CLL) were included, with a median age of 62.5 years (range: 38-82). Most pts had an Eastern Cooperative Oncology Group score of 0-1 (17/24, 70.8%) and Rai stage III or IV disease (16/18, 88.9%). 7 pts with hypertension, of which 2 with very high-risk hypertension. 3 pts have previously received other BTKi. A total of 9 pts(37.5%) performed del(17p), TP53, or IGHV testing. Among them, pts received orelabrutinib 100 mg (2/24,) or 150 mg (22/24,) once daily. As of the cut-off date (July 13, 2023), the median follow-up was 10.67 (range, 2.73-25.77) months. 18 pts (16 CLL, 2 SLL) with abnormal hemoglobin value, platelet count, or lymphocyte count at baseline were evaluable for hematologic response. Hematologic response was achieved in 11 (61.1%) of 18 evaluable pts. Pts aged <65 years had a higher HRR versus pts aged ≥65 years (87.5% vs. 40.0%, p=0.040). HRR was 56.3% in CLL versus 100.0% in SLL pts, and 60.0% in pts with hypertension versus 61.5% without hypertension . Four of 11 responders had a hematologic response in at least two criteria (CLL, n=3; SLL, n=1), of which 3 pts had a hemoglobin response (Figure 1). The most commonly reported AEs included hemoglobin decreased (16.7%) and platelet count decreased (16.7%). Grade ≥3 AEs were white blood cell count decreased (4.2%), platelet count decreased (4.2%), and lymphocyte count decreased (4.2%). No pts experienced severe AEs. No cardiovascular AEs were reported during treatment in 7 pts with hypertension at baseline. Conclusions: This real-world study assessed the preliminary characteristics and clinical outcome of patients receiving orelabrutinib-containing regimens under routine clinical practice conditions in China. The orelabrutinib-containing regimens in this study furnished beneficial evidence for the treatment of CLL/SLL and is essential for determining the best treatment option, future data with a larger sample and longer follow-up will be updated.

Real-World Use and Outcomes of Therapies, Including Venetoclax-Based Treatments, after Discontinuation of a Covalent BTK Inhibitor in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Background Current treatment guidelines for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) support the use of covalent BTK inhibitor (cBTKi)-based regimens in the front-line setting. Optimal treatment sequencing following the discontinuation of cBTKi therapy, however, remains unknown. Venetoclax-based regimens, such as the combination of venetoclax plus rituximab, are commonly employed in the treatment of relapsed/refractory CLL/SLL; however, published clinical trial evidence is limited in the post-cBTKi setting due to the small numbers of patients treated with venetoclax-based therapies after cBTKi. This real-world study evaluated patient characteristics, treatment patterns, and clinical outcomes associated with immediate subsequent treatment, including the use of venetoclax-based treatment, after initial cBTKi discontinuation among US patients with CLL/SLL. Methods This descriptive, retrospective observational study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. Patients with CLL/SLL aged 18 years or older were included who received at least one cBTKi (ibrutinib, zanubrutinib, or acalabrutinib) and at least one additional line of treatment immediately after their initial cBTKi treatment discontinuation from December 01, 2011, through March 31, 2022. Initial cBTKi treatment could be first line or second or later line of therapy. Patient characteristics and outcomes (time to treatment discontinuation or death [TTD-D], time to next treatment or death [TTNT-D], and overall survival [OS]) were reported. Kaplan Meier method was used for time-to-event outcomes, which were measured from the start of the post-cBTKi treatment. Results In this study, n=1,243 patients were analyzed with a median age of 72 years (range, 37-86) at post-cBTKi treatment initiation (Table 1). Most patients received their immediate post-cBTKi treatment in the second (61%) or third line (28%) setting. Twenty-three percent (n=288) of patients received venetoclax-containing regimens as the immediate post-cBTKi therapy, with 10% (n=120) who received venetoclax monotherapy (VenMono), 5% (n=63) venetoclax plus rituximab (VenR), and 8% (n=105) venetoclax plus other (e.g., chemoimmunotherapy, obinutuzumab). In the entire post-cBTKi cohort, the median TTD-D and TTNT-D were 6.5 (95% CI, 5.8-7.5) and 18.8 (95% CI, 16.1-21.7) months, respectively (Table 2). The median TTD-D and TTNT-D in the cohort that included all venetoclax-containing treatments were 12.9 (95% CI, 10.6-16.5) and 30.1 (95% CI, 23.8-39.4) months, respectively. For patients who received VenMono or VenR, the median TTD-D was 10.6 (95% CI, 7.5-16.0) months and median TTNT-D was 29.5 (95% CI, 18.6-39.4) months. Median OS was not reached for any of the cohorts investigated. Conclusions The findings of this study suggest that the outcomes observed in clinical trials of venetoclax-containing regimens, where patient populations may differ, may not be routinely extrapolated to patients who received a prior cBTKi. In addition, outcomes for patients treated in the post-cBTKi setting appear to be suboptimal overall. These data suggest the need for additional treatment options and sequencing data to determine the best treatment strategy following the discontinuation of initial cBTKi therapy.

Zanubrutinib and Venetoclax As Initial Therapy for CLL/SLL with Obinutuzumab Triplet Consolidation in Patients with Minimal Residual Disease Positivity (BruVenG)

Background: Bruton's tyrosine kinase inhibitors (BTKi), anti-CD20 antibodies, and B cell lymphoma 2 inhibitors (BCL-2i) are essential therapeutic drug classes in the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Clinical synergy of BTKi and BCL-2i combinations have been observed, which allow for an oral regimen, that can be safely administered in a clinic setting for most patients (Tam et al., 2022; Wierda et al., 2021). Still, it remains uncertain if anti-CD20 antibodies meaningfully add to the effectiveness of oral combination therapy. Recent reports of triplet regimens demonstrate modest improvement in minimal residual disease (MRD) negativity with similar response rates when compared to oral doublets (Davids et al., 2021; Soumerai et al., 2021; Wierda et al., 2021). Additionally, anti-CD20 antibody use causes significant B cell depletion resulting in prolonged immune suppression. Recent reports suggest BTKi use may in fact impair clinical activity of anti-CD20 antibodies, which can be mitigated by using selective BTKi and incorporating anti-CD20 later in the treatment course when lower disease burden is present (Da Roit et al., 2015; Flinsenberg et al., 2020; Pavlasova et al., 2016; Rawstron et al., 2018). Therefore, anti-CD20 therapy may not be required for all patients and could be optimized within a response-adapted strategy. This trial has been developed to assess efficacy and safety of a response adapted consolidative treatment approach utilizing obinutuzumab triplet consolidation in CLL/SLL patients who remain MRD positive after an oral doublet fixed duration treatment with zanubrutinib and venetoclax. This approach looks to maximize MRD negative remissions, spare toxicity by limiting anti-CD20 exposure, and provide a finite therapy. This study will utilize once daily zanubrutinib for which there is limited data in regard to safety and efficacy particularly in combination with venetoclax. Study Design and Endpoints: This is a single center, open label, phase II, investigator initiated clinical trial enrolling 50 subjects evaluating the efficacy and safety of zanubrutinib and venetoclax with obinutuzumab triplet consolidation in subjects who remain MRD positive (BruVenG). Eligible patients must have treatment naïve CLL/SLL and treatment indications per the International Workshop on CLL 2018 guidelines. Subjects with Richter's transformation are excluded. Treatment will consist of lead-in, combination, and consolidation phases. All subjects will be treated with a 3-cycle lead-in of 320mg oral, once daily zanubrutinib monotherapy. Venetoclax will be incorporated at cycle 4, per the standard prescriber insert ramp-up schedule. A final dose of 400mg oral, once daily venetoclax, in combination with 320mg oral, once daily zanubrutinib will be used in all subsequent cycles after ramp-up. At cycle 16, MRD will be assessed in the peripheral blood (PB) and bone marrow (BM) via clonoSEQ (Adaptive Biotechnologies). Subjects who are MRD negative (<1x10 -4 ) in both compartments will stop therapy. Subjects who are MRD positive in PB or BM will continue zanubrutinib and venetoclax for an additional 6 cycles. Obinutuzumab will be added to the oral doublet starting at cycle 17. Standard intravenous obinutuzumab lead-in will occur during cycle 17, followed by standard monthly intravenous dosing of 1000mg through cycle 22. Depending on MRD status, subjects will be treated for 16 or 22 cycles. All subjects who receive consolidation will stop treatment at cycle 23 regardless of end of treatment MRD status. The primary endpoint is cycle 16 PB and BM MRD negativity rates. A co-primary endpoint will be cycle 23 PB and BM MRD negativity rates in subjects who were MRD positive at C16 and who went on to receive at least 1 dose of obinutuzumab. Key secondary endpoints will include cycle 16 overall response rate, 36-month progression free survival, 36-month overall survival, 36-month time to next treatment, 24- and 36-month PB MRD negativity rates, tumor lysis risk reduction rates, and safety. Exploratory endpoints will assess the positive predicative value of the ∆400 biomarker (Soumerai et al., 2021) on MRD negativity at cycle 16. This biomarker will be assessed between cycle 4 and 6. The MRD negative rates at cycle 16 and cycle 23 will be estimated with a 90% confidence interval using the Clopper-Pearson method based on exact binomial distribution.

Bellwave-010: Phase 3, Open-Label, Randomized Study of Nemtabrutinib Plus Venetoclax Versus Venetoclax Plus Rituximab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Following at Least One Prior Therapy

Background: Venetoclax + rituximab (VR) is a standard therapy among patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who have relapsed after at least 1 line of prior therapy. However, there is an unmet need for more effective treatments. Bruton's tyrosine kinase (BTK) is a critical signaling molecule in the pathogenesis of CLL, and inhibitors of BTK have resulted in significant improvements in survival for patients with CLL. Nemtabrutinib is a noncovalent, reversible, competitive inhibitor of BTK that does not require the C481 residue of BTK for binding and inhibition of kinase activity. As a result, nemtabrutinib can target both wild-type and C481-mutant forms of BTK. Results from the ongoing BELLWAVE-001 study have demonstrated manageable safety and durable antitumor activity of nemtabrutinib in patients with CLL/SLL with and without C481 mutations. The randomized, active-controlled, open-label, phase 3 BELLWAVE-010 study (NCT05947851) is designed to investigate the efficacy and safety of nemtabrutinib + venetoclax versus VR as second-line (2L) or later treatment for patients with relapsed/refractory (R/R) CLL/SLL. Study Design and Methods: Patients aged ≥18 years with active CLL/SLL that is relapsed/refractory to at least 1 prior therapy per the iwCLL 2018 criteria, an ECOG performance status of 0-2, and adequate organ function are eligible. Patients with Richter transformation, active central nervous system involvement, or severe bleeding disorder are excluded. Approximately 720 patients will be enrolled in 2 parts: an open-label, nonrandomized dose escalation and confirmation phase (part 1) to evaluate safety and determine the optimal dose of nemtabrutinib in combination with venetoclax and an open-label, parallel-group, randomized phase (part 2) comparing the efficacy and safety of nemtabrutinib + venetoclax with VR. In part 1, 30 patients will be enrolled to establish the dose of nemtabrutinib using a modified toxicity probability interval design. Patients will receive nemtabrutinib at 2 dose levels (45 mg PO QD starting dose, escalating to 65 mg PO QD) for 28 days followed by the combination of nemtabrutinib + venetoclax (20-400 mg PO QD ramp up over 4 weeks). In part 2, approximately 690 patients will be randomly assigned 1:1 to receive either nemtabrutinib at the recommended dose for 28 days followed by the combination of nemtabrutinib + venetoclax (20-400 mg PO QD ramp up over 4 weeks) or venetoclax (20-400 mg PO QD ramp up over 4 weeks) + rituximab (or rituximab biosimilar; 375 mg/m 2 at week 6 followed by 500 mg/m 2 Q4W starting at week 10 until week 26 [total 6 doses]). Patients will receive study treatment for ~2 years or until unacceptable toxicity, disease progression, or other discontinuation criteria are met. Randomization will be stratified by BTK-C481 mutation status (detected vs not detected; determined by droplet digital PCR with a limit of detection of approximately 0.01%-0.1%), geographic region (US/Canada vs Europe vs rest of world) and risk (high risk [del(17p) and/or TP53-mutated and/or IGHV-unmutated] vs low risk [absence of high-risk factors]). Response will be assessed (including imaging, physical examination, constitutional symptoms, hematological evaluations, and bone marrow biopsy as required) every 12 weeks up to week 97 and every 24 weeks thereafter or more frequently if clinically indicated. Adverse events will be monitored up to 30 days after treatment cessation (90 days for serious adverse events) and will be graded per NCI CTCAE, version 5.0. Hematologic toxicities will be evaluated according to iwCLL 2018 criteria. Patient-reported outcomes will be assessed using the EORTC QLQ-C30, EORTC QLQ-CLL17, and EQ-5D-5L questionnaires. The primary end points for part 1 are safety and tolerability, including dose-limiting toxicities, and to establish the recommended dose of nemtabrutinib in combination with venetoclax. The primary end point for part 2 is PFS as assessed per iwCLL 2018 criteria by blinded independent central review (BICR). Secondary end points for part 2 include undetectable minimal residual disease in bone marrow at month 14 as assessed by central laboratory, ORR, and DOR per iwCLL 2018 criteria by BICR, OS, and safety. Exploratory end points include ORR including partial response with lymphocytosis, pharmacokinetics, and health-related quality of life.