Chronic Lymphocytic Leukemia/small Lymphocytic Lymphoma Research Articles

BRUIN CLL-322: A phase 3 open-label, randomized study of fixed duration pirtobrutinib plus venetoclax and rituximab versus venetoclax and rituximab in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma.

TPS7583 Background: Covalent (c) Bruton tyrosine kinase inhibitors (BTKi) have reshaped the treatment landscape for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and are now often used as initial therapy. The MURANO study established 2-year fixed duration venetoclax plus rituximab as a standard of care regimen for patients with relapsed or refractory CLL/SLL. However, its efficacy has not been formally assessed in CLL/SLL patients treated with a cBTKi, a common setting where this regimen is used in contemporary practice. Pirtobrutinib, a highly selective, non-covalent (reversible) 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. In the phase 1/2 BRUIN study, pirtobrutinib demonstrated promising durable overall response rates (ORR) and was well tolerated in patients with pre-treated CLL/SLL regardless of prior therapy (including cBTKi), number of prior lines of therapy, BTK C481 mutation status, or reason for prior cBTKi discontinuation. The study's objective is to assess the superiority of adding time-limited pirtobrutinib to the MURANO regimen, hypothesized to prolong disease control in a largely BTKi-pretreated population. Methods: BRUIN CLL-322 (NCT04965493) is a randomized, open-label, global, phase 3 study comparing time-limited pirtobrutinib (200mg QD) plus venetoclax and rituximab versus venetoclax and rituximab in previously treated CLL/SLL patients. Approximately 600 patients, 80% who have been previously treated with cBTKi, will be randomized 1:1 and stratified by del(17p) status (yes/no) and prior BTKi experience (discontinuation due to progressive disease vs due to other reasons vs no prior BTKi exposure). Eligible patients are adults diagnosed with CLL/SLL and require therapy per iwCLL 2018 criteria who have received prior therapy that may or may not include a cBTKi. There are no restrictions on the number of lines of prior therapy. Key exclusion criteria include CNS involvement by CLL/SLL, Richter transformation at any time, prior BCL2 inhibitor or non-covalent BTK inhibitor, or a history of either allogeneic or autologous stem cell transplant, or chimeric antigen receptor T-cell therapy within 60 days prior to randomization. The primary endpoint is progression-free survival (PFS) per iwCLL criteria assessed by an independent review committee. Secondary endpoints include investigator assessed PFS, ORR, overall survival, time to next treatment, event-free survival, safety and tolerability, and patient-reported outcomes. Enrollment is ongoing for patients previously treated with BTKi and completed for BTKi naïve patients. Clinical trial information: NCT04965493 .

BRUIN CLL-314: A phase 3, open-label, randomized study of pirtobrutinib versus ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma.

TPS7584 Background: Covalent (c) Bruton tyrosine kinase inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but these agents are not curative. cBTKi share pharmacologic liabilities such as low oral bioavailability and a short half-life that may lead to suboptimal BTK target coverage, especially in rapidly proliferating tumors with high BTK protein turnover, such as accelerating CLL/SLL, which can manifest as acquired resistance to cBTKi. Novel therapeutic agents addressing both intolerance and resistance while also improving efficacy are needed. Pirtobrutinib, a highly selective, non-covalent (reversible) 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. In the phase 1/2 BRUIN study, pirtobrutinib demonstrated promising durable overall response rates (ORR) and was well tolerated in patients with CLL/SLL irrespective of prior therapy (including cBTKi), number of prior lines of therapy, BTK C481 mutation status, or reason for prior cBTKi discontinuation. The objective of this study is to compare efficacy and tolerability of pirtobrutinib versus ibrutinib in patients with CLL/SLL. Methods: BRUIN CLL-314 (NCT05254743) is a global, phase 3, open-label, randomized study comparing pirtobrutinib with ibrutinib. Approximately 650 BTKi-naïve patients, either treatment-naïve (up to 30%) or previously treated with other non-BTKi agents, will be randomized 1:1 to receive daily 200 mg pirtobrutinib once daily or 420 mg ibrutinib as continuous monotherapy. Randomization will be stratified by del(17p) status (yes/no) and number of prior lines of therapy (0 vs 1 vs ≥2). Enrollment for this study is ongoing. Adults with CLL/SLL who require therapy per iwCLL 2018 criteria are eligible. Key exclusion criteria include prior exposure to any BTKi, use of some concomitant therapies including anticoagulants, such as warfarin and other vitamin K antagonists, significant cardiovascular disease, active infections, and other clinically significant conditions. The primary objective is to establish non-inferiority of pirtobrutinib versus ibrutinib by comparing the ORR per iwCLL guidelines assessed by an independent review committee. Superiority of pirtobrutinib versus ibrutinib in progression-free survival is a key secondary outcome. Other endpoints include duration of response, overall survival, time-to-next treatment, tolerability, and patient-reported outcomes. Trial efficacy and safety will be monitored by an independent data monitoring committee. Clinical trial information: NCT05254743 .

BRUIN CLL-321: A phase 3 open-label, randomized study of pirtobrutinib versus investigator’s choice of idelalisib plus rituximab or bendamustine plus rituximab in BTK inhibitor pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma.

TPS7582 Background: Covalent (c) Bruton tyrosine kinase inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but these agents are not curative. cBTKi share pharmacologic liabilities such as low oral bioavailability and a short half-life that may lead to suboptimal BTK target coverage, especially in rapidly proliferating tumors with high BTK protein turnover, which can manifest as acquired resistance to cBTKi. Novel therapeutic agents addressing both intolerance and resistance while also improving efficacy are needed. Pirtobrutinib, a highly selective, non-covalent (reversible) 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. In the phase 1/2 BRUIN study, pirtobrutinib demonstrated promising durable overall response rates (ORR) and was well tolerated in patients with CLL/SLL regardless of prior therapy (including cBTKi), number of prior lines of therapy, BTK C481 mutation status, or reason for prior cBTKi discontinuation. The objective of this study is to determine whether pirtobrutinib is superior to conventional therapy in patients previously treated with cBTKi. Methods: BRUIN CLL-321 (NCT04666038) is a randomized, open-label, global phase 3 study comparing pirtobrutinib monotherapy (200mg QD) to investigator’s choice of idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR). Approximately 250 CLL/SLL patients previously treated with a covalent BTKi will be randomized 1:1 and stratified by both del(17p) status (yes/no) and prior venetoclax treatment (yes/no). Patients on the control arm can crossover to pirtobrutinib monotherapy if they experience progressive disease per iwCLL 2018 as confirmed by an independent review committee (IRC). Adults with CLL/SLL who require therapy per iwCLL 2018 criteria and have received prior covalent BTKi are eligible. An unlimited number of prior lines of therapy, including venetoclax, are allowed. Key exclusion criteria include CNS involvement by CLL/SLL, a major bleeding event on prior cBTKi, Richter’s Transformation at any time, prior therapy with a non-covalent BTKi, or a history of either allogeneic or autologous stem cell transplant (SCT), or chimeric antigen receptor (CAR) T-cell therapy within 60 days prior to randomization. The primary end point is progression-free survival (PFS) per iwCLL 2018 criteria as assessed by IRC. Secondary endpoints include investigator assessed PFS, overall survival, ORR, duration of response, safety and tolerability, and patient reported outcomes. Enrollment for this study is ongoing. Clinical trial information: NCT04666038 .

Clinical Features and Outcomes of the Patients with B-Cell Chronic Lymphoproliferative Disease in the New Drug Era

To analyze the clinical characteristics of the patients with B-cell chronic lymphoproliferative disease（B-CLPD） in the new drug era and the effect of new drug treatment on efficacy and survival. The clinical and laboratory data of 200 cases B-CLPD patients diagnosed between April 2015 and August 2021 were analyzed retrospectively. The clinical efficacy and survival of the patients under different treatments including Bruton tyrosine kinase（BTK） inhibitors， rituximab， and chemotherapy alone were analyzed. The prognostic factors affecting the survival of patients were analyzed by univarite analysis and multivariate analysis. There were 119 male（59.5％） and 81 female（40.5%） in 200 cases B-CLPD patients， the sex ratio(male/female) was 1.5∶1 with median age of 61（30- 91） years old. The distribution of subtypes were as fallows: 51 cases (25.5%) of chronic lymphocytic leukemia/small lymphocytic lymphoma（CLL/SLL）， 64（32.0%） cases of follicular lymphoma（FL）， 40（20.0%） cases mantle cell lymphoma（MCL）， 30（15.0%） cases of marginal zone lymphoma（MZL）， 10（5%） cases of lymphoplasmacytic lymphoma/waldenstrom macroglobulinemia（LPL/WM）， 5（2.5%） cases of B cell chronic lymphoproliferative disorders unclassified（B-CLPD-U） . The main clinical manifestation of 102 patients was lymph node enlargement, 32 cases were complicated with B symptoms. Among CLL/SLL patients， there were 12（23.5%） cases in Binet A and 39（76.5%） cases in Binet B/C. There were 29 patients（20.9%） in Ann Arbor or Lugano stage I-II and 110 cases（79.1%） in stage III-IV of other subtypes. The complete remission（CR） rate was 43.1%（25/58）， 40.2%（39/97）， 7.1%（1/14）， and overaIl response rate（ORR） was 87.9%（51/58）， 62.9%（61/97）， 28.6%（4/14） in the groups of BTK inhibitors， rituximab-based therapy， and chemotherapy alone. The 3-year OS rate and PFS rate in all patients was 79.2% and 72.4% respectively. The 3-year OS rate of patient with MZL, CLL/SLL, FL,WM was 94.7%, 87.7%, 86.8% and 83.3% respectively, while the 3-year OS rate of MCL was only 40.6%, which was significantly lower than other subtypes. The median OS of patients treated with BTK inhibitors and rituximab-based therapy was 20.5 and 18.5 months respectively， and the 3-year OS rate was 97.4% and 90.7%. However， the median PFS of patients receiving chemotherapy alone was 4 months， and the 1-year OS rate was 52.7%， which was statistically significant compared with the other two groups（P<0.05）. Univarite analysis showed that anemia， elevated lactate dehydrogenase， elevated β2-microglobulin， and splenomegaly were the poor prognostic factors for OS（P<0.05）， elevated lactate dehydrogenase was also poor prognostic factors for PFS（P<0.05）. Multifactor analysis showed that anemia and elevated lactate dehydrogenase were the independent poor prognostic factors for survival（P<0.05）. The clinical features of B-CLPD was various， anemia and elevated lactate dehydrogenase are the prognostic factors for poor survival. BTK inhibitors and new immunotherapy can improve the survival and prognosis of patients in the new drug era.

Association of pharmacist interventions with adherence upon targeted anticancer oral therapy initiation.

7576 Background: Oncology pharmacists (OPs) increasingly play a role in managing cancer patients, with the availability of targeted oral anticancer agents (TOAs). OPs ensure appropriate indications upon initiation; screen for, anticipate, and mitigate potential drug-drug interactions; manage side effects; and promote adherence. The impact of OPs on adherence to TOAs has not been described. Methods: The Veterans Affairs Corporate Data Warehouse and Cancer Registry were used to: 1. identify Veterans with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL), marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (WM), and/or mantle cell lymphoma (MCL) who received single agent TAO for the first time between 2018 and 2021; 2. retrieve patient demographics, disease characteristics, and TAO dispensation information; and 3. identify visits with OPs within a 30-day window of initial dispensation. Dispensation information was used to calculate the proportion of days covered (PDC) during the first 4, 8, and 12 week milestones after initial dispensation. Non-adherence was defined as a PDC &lt; 0.9. A two-sample proportion test and a Wilcoxon rank-sum test were used to compare milestone adherence between patients who visited with an OP at treatment initiation vs those who did not. Results: 1,944 patients were identified, with a median age of 75 years; 98% were male; 1,498 (77%) were white, 244 (13%) were black, and 53 (3%) were Hispanic, rest were other, or unknown. CLL was the most common diagnosis at 1,578 patients (81%), followed by MCL at 162 (8%), WM at 135 (7%), and MZL at 69 (4%). 1,702 patients (88%) received ibrutinib, 110 (6%) venetoclax, 91 (5%) acalabrutinib, and 32 (2%) lenalidomide. Fewer than 5 patients received either idelalisib, zanubrutinib, umbralisib, and/or duvelisib. 1,757 patients had an initial dispensation supply of either &lt; 28 days or 28-30 days and were used to conduct the adherence analysis; of those 702 had met with an OP at therapy initiation. In the 239 patients with a dispensation day supply &lt; 28 days, patients who met with an OP had higher 4, 8, and 12 week adherence rates (97%, 96% and 92%) compared to those who did not (82%, 75%, 72%); odds ratios (OR) 8.8, 7.7 and 4.7 respectively (all with p &lt; 0.01). In the 1,518 patients with a dispensation day supply of 28–30 days, patients who met with an OP also had higher 8-, and 12-week adherence rates (96% and 91%, resp) compared to those that did not (87%, 79%); OR 3.4 and 2.6 resp, both with p &lt; 0.01. Conclusions: Visiting with an OP upon TAO therapy initiation was associated with a clinically and statistically significant increase in adherence at 4, 8, and 12 weeks after first dispensation. To our knowledge, this is the first study to quantify the impact of an OP on non-adherence in a real-world setting. Our findings suggest a critical need to integrate OPs TAO therapy initiation workflows.

NCCN Guidelines Update: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is characterized by the accumulation of abnormal lymphocytes in the blood, bone marrow, and lymphoid tissues, leading to a weakened immune system and an increased risk of infections for patients. The NCCN Guidelines for CLL/SLL underscore the need for a comprehensive evaluation of multiple factors to determine the most appropriate treatment approach for each patient. For frontline therapy, the selection process should consider the patient’s IGHV status, del(17p)/TP53 mutation status, age, and comorbidities. In choosing subsequent therapy, prior therapy, comorbidities, and resistance mutations should be considered. With no clear evidence of a functional cure, it is important to enroll patients in clinical trials when available.

Issue highlights-May 2023.

In the era of personalized medicine, the list of targeted therapeutic drugs has been greatly expanded, many of which are employed to treat hematolymphoid neoplasms. These include drugs specifically targeting immune checkpoint signaling epitopes such as programmed cell death 1 (PD1) and its ligand PDL1 to inhibit T-cell activation. Alternatively, these drugs might target the surface antigens expressed by tumor cells such as CD19 and CD22 in B-cell neoplasms. Of the latter, targeted immunotherapies include monoclonal antibodies with or without drug conjugates, bispecific T-cell engagers, or chimeric antigen receptor (CAR) T-cell therapy. The binding sites of these therapeutic antibodies are often identical or in proximity with the binding sites of the diagnostic antibodies. Therefore, use of these therapies pose great challenges for clinical cytometry labs in the assessment of post-treatment samples, especially in the detection of measurable/minimal residual disease (MRD). In this issue, Chen, Gao, et al. (2023) provided an overview of MRD detection in B-lymphoblastic leukemia/lymphoma in the era of immunotherapy, and Gao et al. (2023) focused their review on the impact of targeted therapy on mature B- and plasma cell neoplasms utilizing flow cytometry assessments. In both reviews, the authors illustrated the challenges, identified the problems, and provided a list of available options and solutions. For each of the above-mentioned disease categories, optimal gating and analysis strategies were illustrated with literature review and inputs from the authors' experience and insights. The utility and interpretation of additional B-cell markers other than CD19 and CD20 for mature or immature B-cell neoplasms such as CD22, CD24, and cCD79a (Mikhailova et al., 2022) were studied as well as VS38, CD229, and CD319 (Pojero et al., 2016; Soh et al., 2021) for plasma cell neoplasms. The authors recommended that the flow cytometry assays in the era of targeted therapies must contain significant redundancy in the antibody panels allowing the detection of the cells of interest and additionally should be ready to utilize several gating strategies for accurate and consistent population identification. Neoplastic mature B-cells often show restricted kappa or lambda light chain expression; however, light chain expression may be absent in around 5%–10% of mature B-cell lymphoma (Li et al., 2002). It is suggested that mature B-cells lacking surface light chain expression can be used as a surrogate marker to diagnose mature B-cell lymphomas. Huang et al. (2023) reported a series of 89 cases of surface light chain negative B-cell lymphoma which consisted primarily of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Interestingly, the authors also reported no detectable light chain expression in normal/reactive mature B cells collected from body fluids and cystic fluids from 14 patients with no clinical and pathological evidence of lymphoma/leukemia. Body fluids are often proteaceous; thus additional washing prior to kappa/lambda staining is often required to obtain adequate light chain staining and caution is needed in the interpretation of light chain expression in B-cells collected from body fluids. It is known that out of the context of chronic myeloid leukemia (CML) (Soma et al., 2016), lymphoblastic crisis is extremely rare in other chronic myeloid neoplasms, such as myelodysplastic syndrome (MDS) (Xie et al., 2019) and Philadelphia negative myeloproliferative neoplasms (MPN). Chan et al. (2023) reported the detection of a low level of abnormal B-lymphoblasts ranging from 0.012% to 3.6% in 9 out of 1262 MDS or Ph-negative MPN. Cell sorting coupled with next-generational sequencing showed that the abnormal B- lymphoblasts in myeloid neoplasms were often, but not always, clonally related to the myeloid compartment, and the molecular genetic findings suggested a mutant multipotent progenitor cell with different lineage output that might be determined by the specific mutations and the particular cell stage where the mutations occurred. Importantly, unlike CML, the presence of abnormal B-lymphoblasts in MDS and Ph-neg MPNs did not necessarily indicate blast crisis, and therapy for the underlying myeloid neoplasms with close monitoring is suggested to be a reasonable approach. The last article in this issue (Chen, Zhang, et al., 2023) studied mucosal-associated invariant T cells (MAIT) (Godfrey et al., 2019) in aplastic anemia (AA), a type of bone marrow failure directly linked to abnormal immune responses. MAIT cells exhibit an effector-memory phenotype and express several NK receptors such as NKG2D and CD161 and play an important role in the development of autoimmune diseases. The authors showed an increased frequency of MAIT cells with an activation and effector function-related cell surface marker profile in patients with aplastic anemia. The specific property of NKG2D expression on MAIT cells suggests that these cells may have a distinct mechanism involved in AA immune pathogenesis.

Abstract CT125: A Phase 1 study to evaluate the safety and tolerability of a combination autologous CD19 CAR T cell therapy (SYNCAR-001) and orthogonal IL-2 (STK-009) in subjects with relapsed or refractory CD19 expressing hematologic malignancies (NCT05665062)

Abstract Background: Chimeric antigen receptor T cell therapy (CAR T) has demonstrated remarkable clinical efficacy in hematological malignancies. However, compromised T cell effector function, proliferation, and persistence can limit CAR T from reaching their full curative potential. Interleukin-2 (IL-2) is a potent stimulator of T cells, however therapeutic use of IL-2 is limited by systemic toxicity due its pleiotropy. Therefore, to provide a selective IL-2 signal to engineered T cells, we have developed a human orthogonal ligand/receptor system consisting of a half-life extended pegylated IL-2 mutein (STK-009) and a mutated IL-2 Receptor Beta (hoRb) that responds to STK-009 but not wild type IL-2. SYNCAR-001 is an autologous CAR T co-expressing a CD19 CAR and hoRb on the T cell surface. In mouse models of refractory lymphoma, STK-009 treatment led to expansion and activation of SYNCAR-001 cells with a maintenance of stem cell memory and effector T cell phenotypes. When added to SYNCAR-001, STK-009 increased complete response rate and durable responses in a dose dependent manner. In non-human primate studies, STK-009 alone demonstrated no significant biological activity in IL-2 sensitive populations (T cells or NK cells) and was tolerable without toxicity. Methods: This is a first-in-human, open-label, dose escalation study of combination SYNCAR-001 + STK-009 in adults with relapsed or refractory (r/r) CD19+ hematologic malignancies. The objectives of this study are to evaluate the safety, preliminary efficacy, pharmacokinetics, immunogenicity, and pharmacodynamics of SYNCAR-001 + STK-009. Dose escalation follows a standard 3+3 design with STK-009 being escalated while SYNCAR-001 is held at a single fixed dose. A dose extension will enroll a cohort of patients treated at a selected dose level and indication based on dose escalation findings. SYNCAR-001 is dosed intravenously (IV) once at Day 0 and STK-009 is dosed subcutaneously (SC) over the course of the study. Participants receive a single safety lead-in dose of STK-009 prior to lymphodepletion and subsequent SYNCAR-001 infusion. After SYNCAR-001 initiation, STK-009 is dosed SC weekly for 12 weeks and then monthly for 3 months. Eligible participants include individuals with r/r chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and selected r/r B-cell non-Hodgkin lymphoma (NHL subtypes of large B cell, mantle cell, and indolent lymphoma). Prior CD19 CAR use is excluded. The primary endpoint of safety includes outcomes such as adverse events and dose-limiting toxicities. Secondary endpoints include assessments of response, pharmacokinetics, and immunogenicity. Exploratory endpoints include assessment of immune cell populations, and relevant gene/protein expression, as well as persistence, phenotype, and functionality of SYNCAR-001 in the peripheral blood and/or bone marrow in response to STK-009. Citation Format: Maria Lia Palomba, Matthew G. Mei, Paolo F. Caimi, Matthew Cortese, Marco Davila, Greg Yadnik, Nestor Huang, David Mou, Martin Oft, Paul-Joseph Aspuria, Anita Mehta-Damani, Navneet Ratti, Naiyer Rizvi, Alex Azrilevich, Ran Reshef. A Phase 1 study to evaluate the safety and tolerability of a combination autologous CD19 CAR T cell therapy (SYNCAR-001) and orthogonal IL-2 (STK-009) in subjects with relapsed or refractory CD19 expressing hematologic malignancies (NCT05665062) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT125.

Progression and transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma and B-cell prolymphocytic leukemia: Report from the 2021 SH/EAHP Workshop.

Session 3 of the 2021 Workshop of the Society for Hematopathology/European Association for Haematopathology examined progression and transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and B-cell prolymphocytic leukemia (B-PLL). Thirty-one cases were reviewed by the panel. Additional studies such as immunohistochemistry and molecular genetic testing, including whole-exome sequencing and expression profiling, were performed in select cases. Session 3 included 27 CLL/SLL cases and miscellaneous associated proliferations, 3 cases of B-PLL, and 1 case of small B-cell lymphoma. The criteria for -accelerated CLL/SLL are established for lymph nodes, but extranodal disease can be diagnostically challenging. Richter transformation (RT) is a broad term and includes true transformation from original CLL/SLL clone(s) and clonally unrelated neoplasms. The morphologic, immunophenotypic, and genetic spectrum is diverse with classical and highly unusual examples. T-cell proliferations can also be encountered in CLL/SLL. B-cell prolymphocytic leukemia is a rare, diagnostically challenging disease due to its overlaps with other lymphoid neoplasms. The workshop highlighted complexity of progression and transformation in CLL/SLL and B-PLL, as well as diagnostic caveats accompanying heterogeneous presentations of RT and other manifestations of disease progression. Molecular genetic studies are pivotal for diagnosis and determination of clonal relationship, and to predict response to treatment and identify resistance to targeted therapy.

A COMPARISON OF BONE MARROW FLOW CYTOMETRY FINDINGS AND BONE MARROW BIOPSY İMMUNOHISTOCHEMICAL FINDINGS IN CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA: A METHODOLOGICAL STUDY

Introduction: The diagnosis of chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL), which also includes atypical forms, can be very difficult. The aim of this study is to compare immunohistochemical (IHC) and flow cytometric (FC) immunophenotyping methods in the CLL/SLL, the most common mature B-cell leukemia/lymphoma of adults, in bone marrow biopsy. In these two methods, it is to determine the minimum panels that can differentiate CLL/SLL from other mature B-cell leukemia/lymphomas. Material and Method: The study included 68 adult patients diagnosed with mature B cell leukemia/lymphoma. Final diagnoses were made on the basis of peripheral smear, bone marrow aspirate, bone marrow biopsy, IHC and FC analysis, clinical and genetic studies. Cell counts, final diagnosis and immunophenotyping were compared with both methods. Cytogenic findings were evaluated. The sensitivity, specificity, positive and negative predictive values of IHC and FC results for CLL/SLL were calculated. Results: CLL/SLL was diagnosed in 64.7% of the cases and non- CLL/SLL in 35.29% of the cases. The median age was 66.50 years, 69.18% male and 30.82% female. The diagnosis compatibility in FC and IHC was found to be highest in hairy cell leukemia/lymphoma with 100%, and in CLL/SLL with 90%. In other lymphomas, a definitive diagnosis could only be made with biopsy. Immunophenotyping made with CD23+CD43+CD5+LEF-1 in the bone marrow biopsy showed a sensitivity of 95.45% (range, 84.53-99.44%) and a specificity of 100.00% (range, 85.75-100.00%) for CLL/SLL. Immunophenotyping made with CD23+CD43+CD5+CD200+ in FC showed a sensitivity of 100.00% (range, 91.96-100.00%) and a specificity of 82.61% (range, 61.22-95.05%) for CLL/SLL. Conclusion: This was the most extensive study to have compared immunophenotyping in IHC and FC in bone marrow biopsies of mature B cell leukemia/lymphoma. The addition of LEF-1 to the CD23(+), CD43(+), CD5(+) panel in IHC and the addition of CD200 to the same panel in FC will be extremely helpful in the differential diagnosis of typical/atypical CLL/SLL from mature B cell leukemia/lymphoma.

Rituximab induced cytokine release with high serum IP-10 (CXCL10) concentrations is associated with infusion reactions

Monoclonal antibody induced infusion reactions (IRs) can be serious and even fatal. We used clinical data and blood samples from 37 treatment naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) initiating therapy for progressive disease with a single 50 mg dose of intravenous (IV) rituximab at 25 mg/h. Twenty-four (65 %) patients had IRs at a median of 78 min (range 35–128) and rituximab dose of 32 mg (range 15–50). IR risk did not correlate with patient or CLL characteristics, CLL counts or CD20 levels, or serum rituximab or complement concentrations. Thirty-five (95 %) patients had cytokine release response with a ≥ 4-fold increase in serum concentration of ≥ 1 inflammatory cytokine. IRs were associated with significantly higher post-infusion serum concentrations of gamma interferon induced cytokines IP-10, IL-6 and IL-8. IP-10 concentrations increased ≥ 4-fold in all patients with an IR and were above the upper limit of detection (40,000 pg/ml) in 17 (71 %). In contrast, to only three (23 %) patients without an IR had an ≥ 4-fold increase in serum concentrations of IP-10 (highest 22,013 pg/ml). Our data suggest that cytokine release could be initiated by activation of effector cells responsible for clearance of circulating CLL cells with IRs occurring in those with higher levels of gamma interferon induced cytokines. These novel insights could inform future research to better understand and manage IRs and understand the role of cytokines in the control of cytotoxic immune responses to mAb.

Outcomes of CD19-Directed Chimeric Antigen Receptor T Cell Therapy for Transformed Nonfollicular Lymphoma

CD19-directed chimeric antigen receptor (CAR) T cell (CAR-T) therapy with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) are approved for the treatment of relapsed or refractory large B cell lymphoma (LBCL), including de novo diffuse LBCL (DLBCL), primary mediastinal B cell lymphoma (PMBCL), and transformed follicular lymphoma (tFL). Transformed nonfollicular lymphomas (tNFLs), including transformed marginal zone lymphoma (tMZL) and transformed chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) were not included in their respective pivotal studies. This study was conducted to evaluate the outcomes of axi-cel and tisa-cel in tNFL patients, including those who received ibrutinib concomitantly through apheresis, lymphodepletion, and CAR-T infusion. This single-center retrospective study included all patients with tCLL/SLL, tMZL, tFL, and DLBCL/PMBCL treated with CAR-T therapy outside of a clinical trial setting from November 2017 to May 2021 at Moffitt Cancer Center, Tampa, Florida. We analyzed and compared outcomes in patients with tCLL/SLL or tMZL and patients with DLBCL/tFL. The study included 134 patients who received a total of 136 CAR-T treatments (111 with axi-cel and 25 with tisa-cel). Ninety patients had de novo DLBCL/PMBCL, 23 had tFL, and 21 had tNFL (12 with tMZL and 9 with tCLL/SLL). The overall response and complete response rates were 66.7% and 55.6%, respectively, for tCLL/SLL and 92.9% and 71.4% for tMZL. The overall response and complete response rates were not different between tNFL and DLBCL/tFL (P=.92 and .81, respectively). At a median follow-up of 21.3 months, the median progression-free survival (PFS) for tCLL/SLL was 5.4 months (95% confidence interval [CI], .8 month to not assessable [NA]); for tMZL, the median PFS was not reached (NR) (95% CI, 2.3 months to NA); and for DLBCL/tFL, the median PFS was 14.3 months (95% CI, 5.6 months to NA) (P=.58). The estimated 1-year PFS rate was 29.6% (95% CI, 5.2% to 60.7%) for tCLL/SLL, 50.0% (95% CI, 22.9% to 72.2%) for tMZL, 42.7% (95% CI, 22.4% to 61.6%) for tNFL, and 53.0% (95% CI, 42.3% to 62.5%) for DLBCL/tFL. The median overall survival was NR (95% CI, 9.2 months to NA) for tCLL/SLL, 27.1 months (95% CI, 8.5 months to NA) for tMZL, and NR (95% CI, 17.4 months to NA) for DLBCL/tFL (P=.79). Compared to the DLBCL/tFL cohort, tNFL patients were more likely to develop immune effector cell-associated neurologic syndrome (ICANS) and to receive tocilizumab (P=.04 and .01, respectively, after controlling for CAR-T product) and with a possibly higher incidence of grade ≥3 cytokine release syndrome (CRS) (P=.07). Two patients in the tNFL cohort died of treatment-related toxicity after receiving axi-cel. Six tNFL patients received ibrutinib concurrently with tisa-cel, with 1 case of grade ≥3 CRS/ICANS that rapidly resolved and no other severe toxicities. Our case series supports the use of CD19 CAR-T therapy in relapsed/refractory tCLL/SLL and tMZL. The concurrent use of ibrutinib and tisa-cel in tNFL was associated with manageable toxicity in tNFL.

Managing Ibrutinib-Intolerant Patients With B-Cell Malignancies.

Ibrutinib is a first-generation inhibitor of Bruton tyrosine kinase (BTK) that is currently approved to treat patients with B-cell malignancies, including Waldenström macroglobulinemia (WM), relapsed/refractory (R/R) mantle cell lymphoma (MCL), R/R marginal zone lymphoma (MZL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Off-target adverse effects, such as atrial fibrillation, hypertension, and bleeding, have been observed and may limit a patient's tolerance for treatment. Currently, there is no well-established treatment regimen for patients who cannot tolerate ibrutinib. Approaches to address such patients include managing ibrutinib side effects with supportive care or dose reductions, switching to an alternative covalent BTK inhibitor, or abandoning covalent BTK inhibitors for alternative forms of treatment. Here we review the literature and provide guidance on treating ibrutinib-intolerant patients with B-cell malignancies.

Clinicopathological Spectrum of B-Cell Non-Hodgkin Lymphoma in Pakistan Population: A Single-Center Study.

Background B-cell non-Hodgkin lymphoma (NHL) is a common malignancy worldwide and in the Pakistani population. In our population, there was limited information regarding the clinicopathological characteristics of B-cell NHL. This study assessed the disease spectrum and most prevalent subtypes of B-cell NHL. Methodology An analysis of 548 cases was conducted in this cross-sectional study between January 2021 and September 2022, using a non-probability consecutive sampling approach. Patient age, gender, site of involvement, and diagnosis were documented according to the 5th edition of the World Health Organization (WHO)Classification of Tumors of Hematopoietic and Lymphoid Tissue, published in 2018. Data were entered and analyzed using Statistical Product and Service Solutions (SPSS) (IBM SPSS Statistics for Windows, Version 26.0, Armonk, NY). Results The mean age of the patients was 47.73±20.44 years. There were 369 males (67.34%) and 179 females (32.66%). The most prevalent type of B-cell NHL was diffuse large B-cell lymphoma (DLBCL) (58.94%), followed by chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (13.14%), Burkitt lymphoma (9.85%), and precursor B-cell lymphoblastic lymphoma (5.11%). In contrast to low-grade B-cell NHL (22.99%), high-grade B-cell NHL was more common (77.01%). Nodal involvement was observed in 62.04% of cases. The cervical region was the most common nodal site of involvement (62.04%), and the gastrointestinal tract (GIT) was the most common extranodal site (48.29%). Conclusion The incidence of B-cell NHL is higher in older age groups. The most common nodal site was the cervical region, whereas the extranodal site was the GIT. The most reported subtype was DLBCL, followed by CLL/SLL, and Burkitt lymphoma. The prevalence of high-grade B-cell NHL is higher than that of low-grade B-cell NHL.

Patterns of bone marrow infiltration in lymphomas- A retrospective descriptive analysis from a tertiary care centre in Southern India

Bone marrow biopsy (BMB) examination is the gold standard for staging of lymphoma which is interpreted along with other clinical, laboratory and radiological investigations. This study aimed to evaluate the various patterns of BMB infiltration by lymphomas which include Hodgkin and Non Hodgkin lymphoma and the usefulness of BMB compared to bone marrow aspiration (BMA). : In a period of three years, there were 212 cases which showed lymphoma infiltration in bone marrow. We assessed the peripheral blood smear (PBS), BMA and BMB slides and concordance between each was evaluated. BMB slides were assessed for the pattern of involvement. The most frequent subtype was chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (21.70%) followed by Hodgkin lymphoma (HL)(12.73%)and follicular lymphoma (FL)(11.32%). Predominant pattern of infiltration showed by CLL/SLL cases was mixed pattern, by FL was paratrabecular pattern, mantle cell lymphoma(MCL) showed either diffuse or nodular, diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma(BL) showed predominantly diffuse pattern. Hairy cell leukemia (HCL) and peripheral T cell lymphoma (PTCL) showed an interstitial pattern. In HL, the pattern was usually focal nodular however diffuse involvement was seen in a few. Of the 212 cases, 50.94% cases had atypical lymphocytes or lymphocytosis in PBS and 81.14% cases showed infiltration in BMA. Atypical lymphoid cells may not be present at times in peripheral blood or bone marrow aspirate in spite of infiltration in the bone marrow. Different lymphomas show characteristic patterns of marrow involvement.

Safety and efficacy of dual PI3K-δ, γ inhibitor, duvelisib in patients with relapsed or refractory lymphoid neoplasms: A systematic review and meta-analysis of prospective clinical trials.

Duvelisib is the first FDA-approved oral dual inhibitor of phosphatidylinositol-3-kinase PI3K-delta (PI3K-δ) and PI3K-gamma (PI3K-γ). Although many clinical studies support the efficacy of duvelisib, the safety of duvelisib remains with great attention. This systematic review and meta-analysis aimed to evaluate the safety and efficacy of duvelisib in treating different relapsed or refractory (RR) lymphoid neoplasm types. We searched prospective clinical trials from PUBMED, EMBASE, Cochrane Library, and ClinicalTrials.gov. For efficacy analysis, Overall response rate (ORR), complete response rate (CR), partial response rate (PR), rate of stable disease (SDR), rate of progressive disease (PDR), median progression-free survival (mPFS), 12-/24-month PFS, and 12-month overall survival (OS) were assessed. For safety analysis, the incidences of any grade and grade ≥3 adverse events (AEs), serious AEs, and treatment-related discontinuation and death were evaluated. Subgroup analysis based on the disease type was performed. We included 11 studies and 683 patients, including 305 chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), 187 B-cell indolent non-Hodgkin lymphoma (iNHL), 39 B-cell aggressive non-Hodgkin lymphoma (aNHL), and 152 T-cell non-Hodgkin lymphoma (T-NHL) patients. The pooled ORR in CLL/SLL, iNHL, aNHL and T-NHL was 70%, 70%, 28% and 47%, respectively. Additionally, the pooled ORR in CLL/SLL patients with or without TP53 mutation/17p-deletion (62% vs. 74%, p=0.45) and in follicular lymphoma (FL) or other iNHL (69% vs. 57%, p=0.38) had no significant differences. Mantle cell lymphoma (MCL) patients had higher pooled ORR than other aNHL (68% vs. 17%, p=0.04). Angioimmunoblastic TCL (AITL) patients had higher pooled ORR than other PTCL patients (67% vs. 42%, p=0.01). The pooled incidence of any grade, grade ≥3, serious AEs, treatment-related discontinuation and death was 99%, 79%, 63%, 33% and 3%, respectively. The most frequent any-grade AEs were diarrhea (47%), ALT/AST increase (39%), and neutropenia (38%). The most frequent grade ≥3 AEs were neutropenia (25%), ALT/AST increased (16%), diarrhea (12%), and anemia (12%). Generally, duvelisib could offer favorable efficacy in patients with RR CLL/SLL, iNHL, MCL, and AITL. Risk and severity in duvelisib treatment may be mitigated through proper identification and management.

A new hope in the management of hematologic malignancy: immunotherapy

In recent years, Hodgkin's and Non-Hodgkin's lymphoma incidence is increasing all over the world. In the United States, lymphomas are the fourth most common malignancies among all. Lymphoid malignancies have a broad spectrum from mild indolent types, such as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL), follicular lymphoma(FL), marginal zone lymphoma, and cutaneous T-cell lymphoma to aggressive types such as diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma, Burkitt's lymphoma, peripheral T-cell lymphoma. With better response rates to chemotherapy, longer disease-free survival and overall survival rates, lymphomas have satisfactory treatment results rather than solid organ tumors for oncologists. Throughout history, conventional chemotherapy agents, radiotherapy and their combinations have been used for the treatment of lymphoma. Especially, in the early stages of Hodgkin's lymphoma, a rate of 85-90% complete remission and high rate long-term remission can be achieved. However, despite this high response rate, 15-30% of patients are resistant to treatment. With current therapiesresponse rate and persistent long-term remission rate in Non-Hodgkin's lymphomas are around 50%. Therefore, new therapeutic approaches such as immunotherapy and the using of cytotoxic properties of T cells against tumor has been developed and used in recent years for the treatment of refractory lymphoma.

Cardiac Involvement in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.

Cardiac involvement of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is recognized extremely rarely. In addition, most CLL/SLL patients with heart infiltration are asymptomatic. In this review, we present the results of a literature search for English language articles concerning CLL/SLL or Richter transformation with symptomatic cardiac involvement. In total, 18 well-described cases with CLL/SLL and heart infiltration were identified. Only three patients were not diagnosed with CLL/SLL before the cardiac manifestation. In other patients, cardiac CLL/SLL was diagnosed between 5 months and 20 years from CLL/SLL diagnosis. All patients in these series had a diagnosis of secondary cardiac CLL/SLL. In addition, we identified four reported cases with Richter transformation in the heart. The treatment of patients with CLL/SLL and cardiac infiltration is variable and depends on the previous history and clinical characteristics of heart infiltration. In addition, no recommendations exist on how to treat patients with CLL/SLL and cardiac involvement.

Incidence of Secondary Hematological Malignancies in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: An Analysis of SEER Database

Background: Patients with Chronic lymphocytic leukemia/ Small lymphocytic lymphoma (CLL/SLL) are at risk of experiencing transformation to aggressive hematological malignancies and can develop second primary malignancies. With a dramatic change in the treatment landscape of CLL/SLL, there is paucity of literature on real-world incidence of second hematological malignancies (SHM) in the era of targeted therapy. We analyzed data obtained from Surveillance, Epidemiology, and End Results (SEER) database to estimate the incidence of SHM in patients with CLL/SLL. Method We used SEER 17 registry to identify adult patients with an index diagnosis of CLL/SLL between January 2000- December 2019, and subsequent diagnosis (>2months after index diagnosis) of any SHM. International Classification of Disease code for Oncology (ICD-O-3) was used to identify codes assigned to CLL/SLL (9823/3) and 11 types of SHM [9650/3: Classical Hodgkin lymphoma(HL), 9673/3: Mantle cell lymphoma(MCL), 9680/3: Diffuse large B-cell lymphoma (DLBCL), 9687/3: Burkitt lymphoma (BL), 9689/3: Splenic marginal zone lymphoma (SMZL), Acute lymphoblastic leukemia/lymphoma (ALL: consisting of 9811/3: B lymphoblastic leukemia/lymphoma, 9728/3: Precursor B-lymphoblastic lymphoma, 9836/3: Precursor B-cell lymphoblastic leukemia and 9837/3: T lymphoblastic leukemia/lymphoma), 9833/3: B-cell prolymphocytic leukemia(B-PLL), 9834/3: T-cell prolymphocytic leukemia(T-PLL), 9861/3: Acute myeloid leukemia (AML), 9863/3: Chronic myeloid leukemia (CML), 9989/3: Myelodysplastic syndrome (MDS)]. We considered SHM as any blood malignancy with diagnosis after treated or untreated CLL/SLL. Patients with CLL/SLL who had unknown survival time or a simultaneous diagnosis of another hematological malignancy were excluded. A data cut-off time point (December, 2019) was used to estimate survival duration (in months) and vital status (dead or alive). Additional data including demographics and treatment details were extracted using SEER Stat v 8.4.0.1 software. Statistical analyses were performed using IBM-SPSS Statistics v 28.0.1.1(15). The reverse Kaplan Meier method was used to calculate median follow-up duration. Chi-squared test was used to calculate difference between categorical variables. Kaplan Meier method and log rank test were used to estimate overall survival (OS). Result 1.8% of adult patients with CLL/SLL (1390 of 78,943) had SHM during the study period. 1255 patients met eligibility criteria (CLL/SLL patients with unknown survival duration (n=3), simultaneous diagnosis of other hematological malignancy (n=3) and a gap of <2months between SHM diagnosis and index diagnosis (n=129) were excluded). Of the 1255 patients, 63.7% (799) were males and 90% (1130) had White race. Median ages at the time of diagnosis of CLL/SLL and SHM were 65 and 70 years respectively. DLBCL (57.2% [n=718]), MCL (10.8% [n=136]), and MDS (8.69% [n= 109]) were the most frequently reported SHMs. Median (95% Confidence Interval) follow-up duration after CLL/SLL and SHM diagnosis were 153 (145.0-160.9) and 58 (53.4-62.6) months respectively. Gender association with SHM was not statistically significant (p =0.146). 394 (31.4%) patients received chemotherapy (CT) for CLL/SLL, while 861 (68.6%) patients either did not receive treatment or status was unknown. OS subsequent to any SHM diagnosis was 12 (95%CI 10.1-13.9) months. OS was lowest for AML [3(1.3-4.6)], and highest for SMZL [113(82.7-143.3)]. Patients who did not receive chemotherapy (for CLL) or details were unknown lived longer subsequent to SHM diagnosis compared to patients who received chemotherapy for CLL/SLL (Median survival months (95%CI): 13(10-16) vs 10(8-12), p =0.034, hazard ratio = 1.159 (95% CI: 1.007-1.334) (Figure). Conclusion SHM were seen in approximately 2% of CLL/SLL patients, predominantly among males and white race. Overall survival after the diagnosis of SHM is around 1 year. Improvement in overall survival with newer targeted therapies for CLL/SLL necessitates robust strategies for surveillance of SHM. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Nemtabrutinib, a Wild-Type and C481S-Mutated Bruton Tyrosine Kinase Inhibitor for B-Cell Malignancies: Updated Analysis of the Open-Label Phase 1/2 Dose-Expansion Bellwave-001 Study

Background: Bruton tyrosine kinase inhibitors (BTKis) have transformed the treatment landscapes of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and certain B-cell neoplasms. However, the most common mechanism of resistance is due to mutations to BTK at the cysteine binding site (C481). Nemtabrutinib (MK-1026, formerly ARQ-531) is a noncovalent, potent inhibitor of both wild-type and ibrutinib-resistant C481S-mutated BTK. Initial results from the phase 1/2 BELLWAVE-001 study (NCT03162536) showed nemtabrutinib had a manageable safety profile and promising antitumor activity in heavily pretreated patients (pts) with relapsed or refractory (R/R) CLL/SLL, including pts whose disease progressed after prior covalent BTKis (Woyach et al. Blood. 2021;138:392). We present updated efficacy for all pts with CLL/SLL treated with nemtabrutinib 65 mg and safety for all pts with hematological malignancies who were treated with nemtabrutinib at the 65-mg dose. Methods: In this open-label, single-arm, phase 1/2 study, 9 expansion cohorts were initiated after determination of the preliminary nemtabrutinib recommended phase 2 dose (RP2D). Eligible pts with CLL/SLL were enrolled in cohort A (R/R CLL/SLL, with ≥2 prior therapies, including covalent BTKis, with documented C481 mutation), cohort B (R/R CLL/SLL with ≥2 prior therapies, intolerant to a BTKi, without C481 mutation), a dose-expansion group, or cohort I (food effect). Primary end points were ORR (per 2018 IWCLL criteria, by investigator), safety, and RP2D for pts with CLL/SLL. Secondary end points were DOR (including partial response [PR] with lymphocytosis), PFS, and safety. Efficacy analysis included CLL/SLL pts treated with nemtabrutinib 65-mg once-daily dose and safety included all pts with hematological malignancies who were treated with the nemtabrutinib 65-mg dose. Results: A total of 112 pts were enrolled and were treated with nemtabrutinib 65 mg once daily: 57 had CLL/SLL, 46 had B-cell non-Hodgkin lymphoma (NHL), 6 had Waldenstrom's macroglobulinemia, and 3 had a diagnosis of "other.” Among the 57 pts with CLL/SLL enrolled and treated with nemtabrutinib 65 mg (cohort A, n = 25; cohort B, n = 10; dose escalation, n = 13; cohort I, n = 9); median age was 66.0 years; 16 pts (28%) were female, and 50 (88%) had ECOG PS ≤1. Median (range) number of prior therapies was 4 (1-18); 54 pts (95%) had prior BTKi therapy; 24 (42%) had prior BTKi and BCL2i therapy. In addition, 36 pts (63%) had C481S-mutated BTK; 18 (32%) had TP53 mutation; 19 (33%) had del(17p); and 30 (53%) had unmutated IGHV. Of pts with CLL/SLL, 39 (68%) discontinued, most commonly because of clinical disease progression [PD] and "other” causes (10 [18%] each); 8 (14%) discontinued owing to adverse events (AEs). Among the 24 pts with CLL/SLL who received prior BTKis and BCL-2is, 19 (33%) discontinued, most commonly because of clinical PD and other causes (6 [11%] each) and AEs (4 [7%]). At data cutoff (April 08, 2022), median (range) follow-up for pts with CLL/SLL was 8.1 months (0.1-38.8); 32 pts had objective response (ORR, 56% [95% CI, 42-69]; complete response, 2; PR, 15; PR with residual lymphocytosis, 15). Among the 32 pts who responded, median DOR was 24.4 months (95% CI, 13.9-not evaluable [NE]); median PFS was 26.3 months (95% CI, 10.1-NE). Efficacy by key subgroups is presented in the table. Among all pts with B-cell malignancies treated with nemtabrutinib at the 65-mg dose (N = 112) included in the safety analysis, 82 (73%) had any-grade treatment-related AEs (TRAEs), most common (≥10%) were dysgeusia (21%); decreased neutrophils (20%); fatigue (13%); nausea and decreased platelets (12%, each); and diarrhea and hypertension (10%, each). Grade 3 or 4 TRAEs occurred in 45 pts (40%); most common (≥5%) were decreased neutrophils (17%) and decreased platelets and lymphocytosis (5%, each). Treatment-related discontinuations occurred in 15 pts (13%). No deaths were attributed to treatment. Conclusion: Nemtabrutinib 65 mg continued to show promising and durable antitumor activity with a manageable safety profile in a highly relapsed/refractory population who had prior therapy with novel agents. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal