Chronic Lymphocytic Leukemia/small Lymphocytic Lymphoma Research Articles

Relevance of Additional Immunohistochemical Markers in the Differential Diagnosis of Small B-Cell Lymphomas: A Case-Control Study

Objective:Clinical and pathological differential diagnosis of small B-cell lymphomas (SBCLs) is still controversial and may be difficult due to their overlapping morphology, phenotype, and differentiation to plasma cells. We aimed to examine the expression of the immune receptor translocation-associated protein 1 (IRTA1), myeloid cell nuclear differentiation antigen (MNDA), lymphoid enhancer-binding factor-1 (LEF1), and stathmin 1 (STMN1) markers in SBCL cases involving different sites that may have plasma cell differentiation.Materials and Methods:We studied 154 tissue samples with lymphoma involvement from 116 patients and evaluated the staining distribution of the markers. Expressions were evaluated in 21 chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), 7 follicular lymphoma (FL), 14 nodal marginal zone lymphoma, 17 extranodal marginal zone lymphoma, 55 splenic marginal zone lymphoma, 22 marginal zone lymphoma-not otherwise specified, and 18 lymphoplasmacytic lymphoma/Waldenström macroglobulinemia cases by immunohistochemistry.Results:The results confirmed that LEF1 was the most sensitive and specific marker for CLL/SLL and STMN1 was the most sensitive and specific marker for FL (p<0.001). MNDA and IRTA1 were useful markers to distinguish marginal zone lymphomas.Conclusion:Our results suggest that LEF1 for CLL/SLL and STMN1 for FL are reliable markers. LEF1, MNDA, STMN1, and IRTA1 are helpful with other routinely used immunohistochemical markers in a diagnostic algorithm considering their limitations.

Zanubrutinib Monotherapy for Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Pooled Analysis of Three Studies.

Zanubrutinib is a highly selective irreversible inhibitor of Bruton tyrosine kinase which has shown significant activity in lymphoid malignancies in early phase studies. We report here the long-term follow-up outcomes of zanubrutinib in various lines of therapy in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). This post hoc analysis pooled patients with treatment-naïve (TN) or relapsed/refractory (R/R) CLL/SLL receiving zanubrutinib monotherapy from three phase 1/2 studies (BGB-3111-1002, BGB-3111-AU-003, BGB-3111-205). A total of 211 patients with CLL/SLL (TN 19, R/R 192) were included. After weighting (TN 19, R/R 24), the overall response rate (ORR) was 95.4% and significantly higher in the TN group than in the R/R group (100 vs. 91.0%, p < 0.0001). ORR was also significantly higher in the TN group than in the one prior line of therapy group (100 vs. 98.9%, p < 0.0001). Among those with R/R disease, the ORR was 97.8% in patients with one prior line of therapy (n = 79) and 90.7% in those with > 1 prior lines of therapy (n = 85; p = 0.080). The median follow-up times were 50.1, 35.7, and 45.9months for TN, R/R and all cohorts, respectively. Progression-free survival and overall survival were significantly longer in the TN group and only one prior line of therapy group compared with the > 1 prior lines of therapy group (all p < 0.05) and were similar in the TN group compared with the one prior line therapy group. Efficacy was similar regardless of the presence of genomic aberrations. Most frequent grade ≥ 3 adverse events were infections (41.7%), neutropenia (34.1%), and thrombocytopenia (9.4%). Atrial fibrillation occurred in only 1.9% of patients. With extended follow-up, zanubrutinib yielded long-term benefits and demonstrated a favorable safety profile for patients with TN or RR CLL/SLL. Earlier utilization of zanubrutinib was associated with better outcomes. Clinical Trials.gov identifiers, NCT03189524, NCT02343120 (retrospectively registered), and NCT03206918 (retrospectively registered).

Use of BTK Inhibitors in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): A Practical Guidance.

The treatment landscape of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has changed significantly since the development of oral Bruton’s tyrosine kinase (BTK) inhibitors. While chemoimmunotherapy was previously the standard of care for first-line treatment, BTK inhibitors have proven to be a highly effective and safe therapeutic option for CLL/SLL, and now constitute one of the preferred first-line options. Ibrutinib, the first approved covalent BTK inhibitor in CLL/SLL, has the most long-term data supporting its efficacy in CLL/SLL treatment although is associated with increased risk of cardiovascular and hemorrhage adverse events due to off-target kinase inhibition. The second-generation covalent BTK inhibitors, including acalabrutinib and zanubrutinib, are more selective to BTK with less off-target effects. Resistance to covalent BTK inhibitors may emerge over time due to mutations in BTK and downstream kinases. Novel non-covalent BTK inhibitors currently being studied are showing promising activities to overcome such resistance. In this review, we discuss the role of BTK inhibitors in treatment of CLL/SLL, review the data that led to approval of BTK inhibitors in CLL/SLL, outline the toxicity profile of each approved BTK inhibitor and management, and give practical guidance on how to select the most appropriate agent for treatment.

P682: NEMTABRUTINIB (MK-1026), A NON-COVALENT INHIBITOR OF WILD-TYPE AND C481S MUTATED BRUTON TYROSINE KINASE FOR B-CELL MALIGNANCIES: EFFICACY AND SAFETY OF THE PHASE 2 DOSE-EXPANSION BELLWAVE-001 STUDY

Background: For patients (pts) with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and certain B-cell neoplasms, resistance to Bruton tyrosine kinase inhibitors (BTKi) develops primarily through mutations at the cysteine binding site (C481) or PLCγ2 mutations. Nemtabrutinib (MK-1026, formerly ARQ-531) is a non-covalent, potent inhibitor of both wild type and C481-mutated BTK. Aims: In the phase 1/2 dose-escalation and dose-expansion BELLWAVE-001 study (NCT03162536), the preliminary recommended phase 2 dose (RP2D) of nemtabrutinib was determined to be 65 mg once daily. The efficacy and safety of nemtabrutinib in patients (pts) with CLL/SLL and B-cell non-Hodgkin lymphoma (NHL) were also evaluated at a higher dose during the dose-expansion phase. Methods: In this open-label, single-arm phase 2 study, 9 expansion cohorts were initiated following determination of preliminary nemtabrutinib RP2D. Approximately 10-25 eligible pts were enrolled into Cohort A (relapsed/refractory (r/r) CLL/SLL, with ≥2 prior therapies including covalent BTKi, with documented C481 mutation), Cohort B (r/r CLL/SLL progressed on/intolerant to a BTKi, with ≥2 prior therapies without C481 mutation), Cohort C (Richter transformation with ≥1 prior therapy), Cohort D-H (follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, high-grade B cell lymphoma with known MYC, BCL-2 or BCL-6 translocations, and Waldenström macroglobulinemia [WM], respectively, who received ≥2 prior therapies), Cohort I (food-effect cohort including pts with B-cell NHL, CLL/SLL, and WM). Primary end point was ORR (per iwCLL criteria, by investigator) for participants with CLL/SLL. Secondary end points included DOR and safety and tolerability. Results: Among 118 pts enrolled, 44 had B-cell NHL, 68 CLL/SLL, and 4 WM. Of these, 94 (79.6%) were treated at the preliminary RP2D, including 51 (54.3%) participants with CLL/SLL. Pts with CLL/SLL had a median (range) number of prior therapies of 4 (1-18), 43 (84%) had prior BTKi therapy, 12 (23%) had del17p, 30 (59%) had IGHV unmutated status, and 32 (63%) had C481S BTK mutation. At data cut-off (April 7, 2021), median (range) follow-up was 4.6 mo (0.1-26.7) for all treated pts. ORR was 57.9% (22/38; 1 CR, 21 PR/PRL) per iwCLL criteria in the efficacy-evaluable population of pts with CLL/SLL treated at preliminary RP2D. Median duration of response was not estimable [NE] (range, 8.3 mo-NE). Among all treated participants, 114 (97%) had a treatment-emergent adverse event (TEAE), with 78 (66%) having a drug-related TEAE, and 9 (8%) having a drug-related TEAE that led to discontinuation. Common TEAEs (≥ 20%) included fatigue (33%), constipation (31%), dysgeusia (28%), cough (25%), nausea (25%), pyrexia (25%), dizziness (23%), hypertension (23%), peripheral edema (22%), diarrhea (21%), and arthralgia (20%). Grade ≥3 TEAEs occurred in 80 (68%) participants. Grade 5 TEAEs occurred in 7 (6%) participants and included death following disease progression 3 (3%), sepsis 1 (1%), dyspnea 1 (1%), and respiratory failure 2 (2%). Common drug-related TEAEs (≥10%) included dysgeusia (15%), nausea (11%), fatigue (11%), and decreased neutrophil count (10%). Grade 3-4 drug-related TEAEs occurred in 31 (26%) participants. No drug-related TEAEs led to death. Summary/Conclusion: Nemtabrutinib has promising antitumor activity with a manageable safety profile in pts with CLL/SLL exposed to multiple lines of therapy, including in those who had progression of disease on prior covalent BTKi. Further evaluation of nemtabrutinib in B-cell malignancies is ongoing.

PB1863: BRUIN CLL-322: A PHASE 3 OPEN-LABEL, RANDOMIZED STUDY OF FIXED DURATION PIRTOBRUTINIB+VENETOCLAX AND RITUXIMAB VS VENETOCLAX AND RITUXIMAB IN PREVIOUSLY TREATED CLL/SLL (TRIAL IN PROGRESS)

Background: Covalent Bruton’s Tyrosine Kinase (BTK) inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but these treatments are not curative and the majority of patients will require additional treatment. The MURANO study established the time-limited combination of 2 years venetoclax plus rituximab as a clinically important regimen for patients with R/R CLL/SLL. However, that trial almost exclusively enrolled patients who were never treated with a covalent BTKi, a population less relevant in the context of today’s standard of care. Aims: Pirtobrutinib is a highly selective, non-covalent BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency. In a phase 1/2 BRUIN trial, pirtobrutinib achieved pharmacokinetic exposures that exceeded its BTK IC96 at trough, was well tolerated, and demonstrated promising efficacy in CLL/SLL patients regardless of prior therapy, number of prior lines of therapy, or BTK C481 mutation status. Therefore, adding fixed duration pirtobrutinib to the time-limited MURANO regimen may allow for even deeper and more prolonged disease control, and generate a clinically relevant dataset in a BTK-pretreated CLL/SLL population. Methods: BRUIN CLL-322 is a randomized, open-label, global phase 3 study comparing fixed duration pirtobrutinib plus venetoclax and rituximab (PVR) versus venetoclax and rituximab (VR) in patients with CLL/SLL who have received prior therapy. To ensure relevance in the modern therapy context, a minimum of 80% of patients must have had a prior covalent BTKi. Approximately 600 patients will be randomized 1:1. Randomization will be stratified by 17p deletion (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 with a diagnosis of CLL/SLL and requirement for therapy per iwCLL 2018 criteria who have received prior therapy that may or may not include a covalent BTKi. Unlimited number of lines of prior therapy are allowed. Key exclusion criteria include CNS involvement by CLL/SLL, Richter transformation at any time pre-enrollment, history of allogeneic stem cell transplant (SCT) or autologous SCT or chimeric antigen receptor (CAR) T-cell therapy within 60 days and prior therapy with a BCL2 inhibitor or non-covalent BTKi. The primary endpoint is progression-free survival (PFS) per iwCLL assessed by an independent review committee. Secondary endpoints include overall response rate (ORR), overall survival (OS), time to next treatment (TTNT), event-free survival (EFS), safety and tolerability, and patient-reported outcomes. This global study is currently enrolling patients (NCT04965493). Results: This study is a Trial in Progress. The results will be presented at a later date. Summary/Conclusion: This study is a Trial in Progress. The conclusions will be presented at a later date.

P687: A PHASE 1 STUDY WITH THE NOVEL B-CELL LYMPHOMA 2 (BCL2) INHIBITOR BGB-11417 AS MONOTHERAPY OR IN COMBINATION WITH ZANUBRUTINIB (ZANU) IN PATIENTS (PTS) WITH B-CELL MALIGNANCIES: PRELIMINARY DATA

Background: BCL2 is aberrantly expressed in many hematologic malignancies and promotes tumorigenesis by enabling cells to evade apoptosis. BCL2 inhibitors have an established role in the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and acute myeloid leukemia. The currently approved BCL2 inhibitor, venetoclax, is associated with mild gastrointestinal toxicities, neutropenia, and the development of BCL2 mutations leading to resistance. BGB-11417 is a highly selective inhibitor of BCL2 with superior potency to venetoclax in human acute lymphoblastic leukemia, mantle cell lymphoma (MCL) cell lines, and xenograft model of diffuse large B-cell lymphoma (DLBCL). BGB-11417 has favorable pharmacokinetics with excellent bioavailability and selectivity for BCL2. Toxicology studies have shown a broad therapeutic index and an improved safety profile. Aims: BGB-11417-101 is an ongoing first-in-human phase 1/1b dose-escalation and expansion study (NCT04277637) evaluating the safety, tolerability, maximum tolerated dose (MTD), and recommended phase 2 dose of oral BGB-11417 as monotherapy or in combination with the BTK inhibitor ZANU, in pts with B-cell malignancies. Methods: In separate monotherapy and combination therapy dose-escalation cohorts, pts with relapsed/refractory (R/R) B-cell malignancies received escalating doses of BGB-11417 (40, 80, 160, 320, or 640 mg once daily [QD]) with a weekly or daily ramp-up to intended target dose. Pts in the combination therapy cohorts received ZANU (320 mg QD or 160 mg twice daily) 8-12 weeks before BGB-11417. Dose-limiting toxicity for each dose cohort was evaluated by a Bayesian logistic regression model during dose ramp-up through day 21 at intended dose. Adverse events (AEs) were reported per Common Terminology Criteria for AEs v5.0. Results: As of 17 Dec 2021, 58 pts received BGB-11417 (32 monotherapy; 26 combination). Of the pts receiving monotherapy, 26 with R/R non-Hodgkin lymphoma (NHL; 17 DLBCL, 6 follicular lymphoma, and 3 marginal zone lymphoma) received BGB-11417 ≤640 mg and 6 with R/R CLL/SLL received ≤160 mg. Of the pts receiving combination treatment, 19 with R/R CLL/SLL received BGB-11417 ≤160 mg and 7 with R/R MCL received ≤80 mg. MTD has not yet been reached. Median follow-up was 3.9 months (range, 0.1-20.4). AEs across all dose levels are listed in the table. Only 2 grade ≥3 AEs (1 neutropenia, 1 autoimmune hemolytic anemia) were reported in combination cohorts. Twenty pts discontinued treatment (17 disease progression; 1 AE; 2 other reasons). One high-risk pt with CLL on monotherapy had laboratory tumor lysis syndrome (TLS) that resolved with no intervention (laboratory TLS <2%). Efficacy data are early: most pts had reduction in sum of product of perpendicular diameters; 2 pts with NHL (monotherapy) achieved responses (1 complete response). Pts with CLL/SLL had notable reductions in absolute lymphocyte count at doses as low as 1 mg; 2 responses (partial response or better) were seen with monotherapy and 12 responses with combination (partial response with lymphocytosis or better). Image:Summary/Conclusion: These preliminary data show promising efficacy for BGB-11417 and an improved safety profile, particularly in combination cohorts. Grade ≥3 neutropenia was uncommon. BGB-11417 is tolerable up to doses of 640 mg as monotherapy and up to 160 mg in combination with ZANU. Dose escalation continues as an MTD has not yet been reached in any dose-escalation cohort. Enrollment continues, with data for Waldenström macroglobulinemia and treatment-naïve CLL/SLL cohorts forthcoming.

P663: HEALTH-RELATED QUALITY OF LIFE OUTCOMES ASSOCIATED WITH ZANUBRUTINIB VS IBRUTINIB MONOTHERAPY IN PATIENTS WITH RELAPSED/REFRACTORY (RR) CLL/SLL: RESULTS FROM THE RANDOMIZED PHASE 3 ALPINE TRIAL

Background: In the phase 3 ALPINE trial (BGB-3111-305; NCT03734016), efficacy and safety of zanubrutinib, a highly selective, next-generation Bruton tyrosine kinase inhibitor (BTKi), were compared with the first-generation BTKi, ibrutinib, in adult patients with RR chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Aims: This abstract, based on the interim analysis of the ALPINE trial, describes the effects of zanubrutinib monotherapy and ibrutinib monotherapy on the health-related quality of life (HRQoL). Methods: Health-related quality of life was examined by patient-reported outcomes (PROs) measures assessed by EORTC QLQ-C30 and EQ-5D-5L at baseline, Cycle 1, and then every 3rd cycle until end of treatment. Key PRO endpoints included global health status (GHS), physical and role functions, and fatigue, pain, diarrhea, and nausea/vomiting. Descriptive analysis on all the scales was conducted as was a mixed model repeated-measure (MMRM) analysis of the longitudinal QLQ-C30 data. Data presented are from key cycles (7 and 13), corresponding to 6 and 12 months of treatment, respectively. Results: In the intent-to-treat population (N=652; zanubrutinib, n=327; ibrutinib, n=325), adjusted completion rates were high (>85%) in both arms at Cycles 7 and 13. On the QLQ-C30, estimated mean treatment differences and 95% CI in key PRO endpoints demonstrated treatment differences, in favor of zanubrutinib, in GHS, physical functioning, and fatigue in Cycle 7, and diarrhea in Cycle 13 (Table). Mean change from baseline (SD) in EQ-5D-5L VAS showed consistently more improvement with zanubrutinib compared with ibrutinib at both Cycle 7 (8.4 [18.2] vs 4.0 [16.6]) and Cycle 13 (6.8 [18.8] vs 5.2 [17.5]). Image:Summary/Conclusion: In the ALPINE trial, patients with RR CLL/SLL who received zanubrutinib monotherapy reported improvements in key HRQoL endpoints compared with patients who received ibrutinib monotherapy.

P649: A FIRST-IN-HUMAN PHASE 1 TRIAL OF NX-2127, A FIRST-IN-CLASS ORAL BTK DEGRADER WITH IMID-LIKE ACTIVITY, IN PATIENTS WITH RELAPSED AND REFRACTORY B-CELL MALIGNANCIES

Background: Bruton’s tyrosine kinase inhibitors (BTKi) have received regulatory approvals and are standard of care for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and WaldenstrÖm macroglobulinemia (WM). However, BTKi-resistant disease remains a clinical challenge with limited options for subsequent therapy. Immunomodulatory drugs (IMiDs, e.g., lenalidomide) are approved as monotherapy for follicular lymphoma (FL), MZL, and MCL, in combination with other therapies for diffuse large B-cell lymphoma (DLBCL) and have shown synergy with BTK-targeted therapy. Dual activity of BTK protein degradation with IMiD-like activity offers a unique approach to overcome known resistance to BTKi. NX-2127 is an oral small molecule that induces BTK degradation via recruitment of cereblon, an adaptor protein of the E3 ubiquitin ligase complex. NX-2127 has shown preclinical activity similar to IMiDs by catalyzing the ubiquitination of Ikaros (IKZF1) and Aiolos (IKZF3), ultimately leading to increased T-cell activation. NX-2127 was shown to degrade both wild-type (WT) and C481-mutated (ibrutinib-resistant) BTK protein in vitro. Robust BTK degradation was also shown in non-human primate studies. Further, NX-2127 demonstrates potent tumor growth inhibition in BTK-dependent mouse xenograft tumor models expressing either WT or ibrutinib-resistant C481S BTK-mutant protein. This dual activity of BTK degradation and IMiD-like activity offers a promising treatment for patients who have failed prior therapy. Aims: The primary objectives are to evaluate safety and tolerability and to determine the maximum tolerated dose (Phase 1a), and to evaluate the early clinical activity of NX-2127 in expansion cohorts (Phase 1b). Methods: NX-2127-001 is a first-in-human, dose escalation (Phase 1a) and cohort expansion (Phase 1b) study designed to evaluate the safety, tolerability, and preliminary efficacy of NX-2127 in adult patients with relapsed/refractory B-cell malignancies with once daily oral dosing. Dose escalation will proceed using a modified Fibonacci design with 1 patient per cohort, proceeding to a standard 3 + 3 design based on protocol specified criteria. There will be up to 5 expansion cohorts in Phase 1b enrolling patients with CLL/SLL, DLBCL, FL, MCL, MZL, and WM. Key eligibility criteria include ≥2 two prior lines of therapy (≥1 prior for WM); measurable disease; and an Eastern Cooperative Oncology Group performance status of 0 or 1. Approximately 130 patients (30 in Phase 1a, 100 in Phase 1b) will be enrolled and treated until disease progression or unacceptable toxicity. The primary endpoint are dose-limiting toxicities and maximum tolerated dose (Phase 1a), objective response (Phase 1b), and safety (Phase 1a and Phase 1b) of NX-1607. Secondary endpoints (Phase 1a and Phase 1b, unless otherwise indicated) include pharmacokinetics, pharmacodynamics, duration of response, progression-free survival, overall survival (Phase 1b), safety (Phase 1b), and complete response rate/complete response rate with incomplete marrow recovery. Results: The Phase 1a part of this study is currently enrolling in the United States. Summary/Conclusion: Accrual is ongoing. Clinical trial information: NCT04830137.

P662: PATIENT-REPORTED OUTCOMES FROM A PHASE 3 RANDOMIZED STUDY OF ZANUBRUTINIB VERSUS BENDAMUSTINE PLUS RITUXIMAB (BR) IN PATIENTS WITH TREATMENT-NAÏVE (TN) CLL/SLL

Background: Zanubrutinib is an oral, highly selective, next-generation Bruton tyrosine kinase (BTK) inhibitor. In cohort 1 of the phase 3 SEQUOIA trial (BGB-3111-304; NCT03336333), efficacy and safety of zanubrutinib and BR were compared in adult patients (pts) with TN chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) without del(17p). Aims: Here, we report the health-related quality of life (HRQoL) outcomes from an interim analysis of the SEQUOIA trial. Methods: Patient-reported outcomes (PROs) were secondary endpoints and assessed using the EORTC QLQ-C30 and EQ-5D-5L VAS. Patients completed these questionnaires at baseline, every 12 weeks for 96 weeks, and then every 24 weeks until disease progression, death, or withdrawal from study. The PRO endpoints included global health status (GHS), physical and role functions, and symptoms of fatigue, pain, diarrhea, and nausea/vomiting, measured by QLQ-C30, with critical clinical cycles of Weeks 12 and 24. Descriptive analyses were performed on all questionnaire responses, and a mixed model for repeated measures was performed on the PRO endpoints at Weeks 12 and 24. Results: Baseline demographics and disease characteristics between the zanubrutinib (n=241) and BR (n=238) arms were similar. Across all pts, adjusted completion rates for PROs (# of pts who completed the questionnaire at each cycle divided by # of pts expected to complete the questionnaires) were high (~80%) at Weeks 12 and 24. Compared with pts who received BR, pts treated with zanubrutinib experienced greater improvements in HRQoL at Weeks 12 and 24 as reported on the QLQ-C30 (Table). By Week 24, significant improvements were observed with zanubrutinib vs BR in GHS, physical functioning, role functioning as well as greater reductions in diarrhea, fatigue, and nausea/vomiting. Per EQ-5D-5L VAS, comparable improvements from baseline between zanubrutinib and BR in the health status were observed at Weeks 12 (4.3 vs 3.5) and 24 (4.5 vs 4.9), respectively. Image:Summary/Conclusion: In the SEQUOIA trial, zanubrutinib was associated with significant improvements in HRQoL in pts with TN CLL/SLL without del(17p), as indicated by the PRO endpoints of the GHS, physical and role functions, and greater reductions in symptoms of fatigue, diarrhea and nausea/vomiting compared with BR.

P1221: DIFFUSE LARGE B-CELL LYMPHOMA RICHTER SYNDROME IN CHRONIC LYMPHOCYTIC LEUKEMIA – A RETROSPECTIVE ANALYSIS OF TREATMENT OUTCOMES IN POLISH ADULT LEUKEMIA STUDY GROUP

Background: Richter syndrome (RS) is a recognized uncommon manifestation and evolution of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with a dismal prognosis. It occurs in 2-10% of CLL patients. It is associated with a clonal evolution and progression, generally with a transformation of the original CLL clone to diffuse large B-cell lymphoma (DLBCL) or, less frequently, to Hodgkin Lymphoma (HL). Despite the advances in understanding pathogenesis of the disease, the DLBCL variant of RS (DLBCL-RS) is associated with a dismal prognosis with a median survival < 1 year. The treatment options and risk factors of worse outcome for RS still need to be further expanded. Aims: To study the characteristic and treatment outcomes of patients with DLBCL-RS. Methods: The retrospective analysis of 99 patients diagnosed with DLBCL-RS treated in hematology centers of the Polish Adult Leukemia Study Group (PALG) between 2011 and 2021. Results: Clinical data of 124 patients with Richter syndrome was collected. Ninety-nine patients were diagnosed with DLBCL-RS (79.8%) and further analyzed. Median time since CLL diagnosis to Richter transformation was 43.0 months (range 0-252.0). At the time of transformation 31.3% patients had CLL Rai stage IV, 74.7% were ECOG< 2, while the median Cumulative Illness Rating Scale (CIRS) was 4 (range 0-16). Thirty-seven patients transformed during CLL treatment, 56.7% of them were receiving novel agents (Brutons tyrosine kinase inhibitor or BCL2 inhibitor). Median time of observation after transformation was 10.7 months (range 0-98.6). Median overall survival (OS) after DLBCL-RS diagnosis was 17.3 months (95% Cl 11.9-46.8) and median progression-free survival (PFS) 13.5 months (95% Cl 9.6-22.7). Seventy-six patients (76.8%) had RS treated with intensive chemotherapy protocols, mainly R-CHOP-like regimens for the first line treatment. Only 42.3% had response to the treatment (25/76 complete responses and 11/76 partial responses). Worth mentioning is that in the group of patients with response two patients had ibrutinib monotherapy and one had rituximab-ibrutinib. In forty patients RS was primarily resistant to administered treatment and 65% of them died due to progression or treatment related complications. In the primary resistant DLBCL-RS p53 pathway aberration was noted in 47.5% of patients (17p deletion in 13 patients or TP53 mutation in 6 patients). Better results were achieved for patients who proceeded to autologous hematopoietic stem cell transplantation (auto-HSCT; n=8) and allogeneic HSCT (allo-HSCT; n=10). The median OS in auto-HSCT recipients was 46.1 months, while in allo-HSCT the median OS reached 18.3 months (3 patients died due to allo-HCST-related complications). Significantly lower OS (3.4 months, 95% Cl 14.13-not reached) was observed for RS in heavily pretreated CLL patients (>3 lines of therapy preceding transformation) compared to those treated with up to 3 lines of therapy (23.7 months) (p=0.0002). Median OS for treatment naïve patients at DLBCL-RS diagnosis was not reached. Other factors identified as predictors of poor OS in univariate analysis were ECOG ≥2 (p=0.0014), hemoglobin level <10 g/dl (p=0.017) and platelet count <100x109/L (p=0.0065). Summary/Conclusion: Our study represents the largest dataset of DLBCL-RS patients in Polish hematology centers and confirms the poor outcomes and prognosis associated with RS. The worst treatment results were observed in RS receiving >3 lines of CLL therapy preceding transformation. Only proceeding to hematopoietic stem cell transplantation may improve the prognosis.

NCCN Guidelines® Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 3.2022.

The treatment landscape of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has significantly evolved in recent years. Targeted therapy with Bruton's tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors has emerged as an effective chemotherapy-free option for patients with previously untreated or relapsed/refractory CLL/SLL. Undetectable minimal residual disease after the end of treatment is emerging as an important predictor of progression-free and overall survival for patients treated with fixed-duration BCL-2 inhibitor-based treatment. These NCCN Guidelines Insights discuss the updates to the NCCN Guidelines for CLL/SLL specific to the use of chemotherapy-free treatment options for patients with treatment-naïve and relapsed/refractory disease.

A first-in-human phase 1 trial of NX-2127, a first-in-class oral BTK degrader with IMiD-like activity, in patients with relapsed and refractory B-cell malignancies.

TPS7581 Background: Bruton’s tyrosine kinase inhibitors (BTKi) have received regulatory approvals and are standard of care for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and WaldenstrÖm macroglobulinemia (WM). However, BTKi-resistant disease remains a clinical challenge with limited options for subsequent therapy. Immunomodulatory drugs (IMiDs, e.g., lenalidomide) are approved as monotherapy for follicular lymphoma (FL), MZL, and MCL, in combination with other therapies for diffuse large B-cell lymphoma (DLBCL) and have shown synergy with BTK-targeted therapy. Dual activity of BTK protein degradation with IMiD-like activity offers a unique approach to overcome known resistance to BTKi. NX-2127 is an oral small molecule that induces BTK degradation via recruitment of cereblon, an adaptor protein of the E3 ubiquitin ligase complex. NX-2127 has shown preclinical activity similar to IMiDs by catalyzing the ubiquitination of Ikaros (IKZF1) and Aiolos (IKZF3), ultimately leading to increased T-cell activation. NX-2127 was shown to degrade both wild-type (WT) and C481-mutated (ibrutinib-resistant) BTK protein in vitro. Robust BTK degradation was also shown in non-human primate studies. Further, NX-2127 demonstrates potent tumor growth inhibition in BTK-dependent mouse xenograft tumor models expressing either WT or ibrutinib-resistant C481S BTK-mutant protein. This dual activity of BTK degradation and IMiD-like activity offers a promising treatment for patients who have failed prior therapy. Methods: NX-2127-001 is a first-in-human, dose escalation (Phase 1a) and cohort expansion (Phase 1b) study designed to evaluate the safety, tolerability, and preliminary efficacy of NX-2127 in adult patients with relapsed/refractory B-cell malignancies with once daily oral dosing. Dose escalation will proceed using a modified Fibonacci design with 1 patient per cohort, proceeding to a standard 3 + 3 design based on protocol specified criteria. There will be up to 5 expansion cohorts in Phase 1b enrolling patients with CLL/SLL, DLBCL, FL, MCL, MZL, and WM. Key eligibility criteria include &gt;2 two prior lines of therapy (&gt;1 prior for WM); measurable disease; and an Eastern Cooperative Oncology Group performance status of 0 or 1. Approximately 130 patients (30 in Phase 1a, 100 in Phase 1b) will be enrolled and treated until disease progression or unacceptable toxicity. The primary objectives are to evaluate safety and tolerability and to determine the maximum tolerated dose (Phase 1a), and to evaluate the early clinical activity of NX-2127 in expansion cohorts (Phase 1b). The Phase 1a part of this study is currently enrolling in the United States. Clinical trial information: NCT04830137.

Are pivotal clinical trials for lymphomas that led to drug approval representative of the population affected by these diseases?

6531 Background: There are significant inequities in cancer care and outcomes in the United States (US) and worldwide. Race, ethnicity, and sex all define sub-groups affected by these inequities. Randomized controlled trials (RCTs) provide new therapies in cancer care. Many new drugs have been recently approved for the management of lymphoma. We examined whether pivotal clinical trials included populations representative of those affected. Methods: Lymphoma clinical trials were collected from the US Food and Drug Administration (FDA) Databases ‘Oncology (cancer)/Hematologic Malignancies approval notifications’ and ‘Novel Drug Approvals’ between 2011 and 2021. Trials were also reviewed for demographic data on ClinicalTrials.gov (CT.gov) and Primary Literature related to the drug approval. Only studies for adult patients were included; one study was excluded due to inconsistencies in the total patients enrolled and the totals by race. Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) RCTs were not included. The burden of diseases based on Surveillance, Epidemiology, and End Results (SEER) data was used as a comparison for US participants. Results: Thirty-three pivotal trials were identified from the FDA databases (2011-2021); 18 (54.5%) had available race data on CT.gov or in Primary Literature. Three trials focused on classical Hodgkin’s Lymphoma (cHL) and 15 on Non-Hodgkin’s Lymphoma (NHL). Two of the three trials for cHL with available data for race reported ethnicity data. Only 10 of 15 NHL trials that reported race demographics had available ethnicity data. Table 1 shows trials that had available data for race and ethnicity along with proportions from the SEER data. There was underrepresentation of Blacks and to some extent Hispanics in both cHL and NHL trials. Females were also underrepresented, particularly in NHL trials. Conclusions: There is racial, ethnic, and sex misrepresentation within clinical trials that led to approval of drugs for lymphomas in the US between 2011 and 2021. In addition, there was significant underreporting of racial and ethnic subgroups noted in the clinical trials.[Table: see text]

CD19/CD20 bispecific chimeric antigen receptor (CAR) in naïve/memory T cells for the treatment of relapsed or refractory non-Hodgkin lymphoma.

2543 Background: Although chimeric antigen receptor (CAR)-T cells produce impressive outcomes in B-cell malignancies, a substantial fraction of patients with relapsed/refractory B-cell leukemia and lymphoma treated with anti-CD19 CAR-T cell therapy (CART19) either do not respond to treatment or relapse, with poor CAR-T cell persistence or CD19 antigen escape being two key factors that limit durability of response. In order to address these factors, we initiated a clinical trial with naïve/memory T (TN/MEM) cells engineered to express bispecific anti-CD19/CD20 CARs (CART19/20) (NCT04007029). Methods: This trial is a Phase 1, first-in-human, dose-escalation trial enrolling patients with relapsed or refractory follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle-cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Following lymphodepletion chemotherapy with fludarabine and cyclophosphamide, patients received CART19/20 cell doses ranging from 50 x 106 to 200 x 106 CAR-positive cells. The primary endpoint was to evaluate the safety of CART19/20 as measured by adverse events and dose limiting toxicities. Secondary endpoints were efficacy as assessed by disease response, progression-free survival (PFS), overall survival (OS), and CAR transgene persistence. Results: As of February 7, 2022, dose-escalation has been completed with 9 patients enrolled and 8 patients infused (3 FL, 4 DLBCL including 2 transformed follicular and 1 primary mediastinal B cell, and 1 MCL). with CART19/20 cells on this study. The median age at the time of CART19/20 infusion was 59 and median prior lines of therapy was 3.5. All patients had stage IV disease and 7 of 9 patients required bridging therapy. Grade-1 cytokine release syndrome (CRS) occurred in 6 of 8 patients, and no patient experienced immune effector cell-associated neurotoxicity syndrome ( ICANS). Among all patients, only one dose of tocilizumab was administered to one subject, and no steroids were given. With a median follow-up of 12 months from time of CART19/20 infusion (range: 4+ to 24+ months), 7 of 8 of patients remain in a complete remission. Median PFS and OS were not reached, and all patients with a complete remission demonstrate ongoing B-cell aplasia. Conclusions: This study demonstrates that CART19/20 cells are safe and effective in patients with relapsed/refractory NHL and potentially obviates the challenges of the commonest causes of relapse after CAR-T cell therapy by means of modifying TN/MEM cells and dual-antigen targeting, respectively. Given the strong safety and response observed, dose escalation was completed with the second dosing level (DL2) of 200 x 106 CAR-positive cells, and DL1 of 50 x 106 CAR-positive cells was chosen as the therapeutic dose for future trial expansion. Clinical trial information: NCT04007029.

Characterization and outcomes of 414 patients with primary SS who developed haematological malignancies.

To characterize 414 patients with primary SS who developed haematological malignancies and to analyse how the main SS- and lymphoma-related features can modify the presentation patterns and outcomes. By January 2021, the Big Data Sjögren Project Consortium database included 11 966 patients fulfilling the 2002/2016 classification criteria. Haematological malignancies diagnosed according to the World Health Organization (WHO) classification were retrospectively identified. There were 414 patients (355 women, mean age 57 years) with haematological malignancies (in 43, malignancy preceded at least one year the SS diagnosis). A total of 376 (91%) patients had mature B-cell malignancy, nearly half had extranodal marginal zone lymphoma (MZL) of mucosa-associated lymphoid tissue (MALT lymphoma) (n = 197), followed by diffuse large B-cell lymphoma (DLBCL) (n = 67), nodal MZL lymphoma (n = 29), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (n = 19) and follicular lymphoma (FL) (n = 17). Rates of complete response, relapses and death were 80%, 34% and 13%, respectively, with a 5-year survival rate of 86.5% after a mean follow-up of 8 years. There were significant differences in age at diagnosis (younger in MALT, older in CLL/SLL), predominant clinical presentation (glandular enlargement in MALT lymphoma, peripheral lymphadenopathy in nodal MZL and FL, constitutional symptoms in DLBCL, incidental diagnosis in CLL/SLL), therapeutic response (higher in MALT lymphoma, lower in DLBCL) and survival (better in MALT, nodal MZL and FL, worse in DLBCL). In the largest reported study of haematological malignancies complicating primary SS, we confirm the overwhelming predominance of B-cell lymphomas, especially MALT, with the salivary glands being the primary site of involvement. This highly-specific histopathological scenario is linked with the overall good prognosis with a 5-year survival rate of nearly 90%.

Herpes Simplex Virus Causing Necrotizing Granulomatous Lymphadenitis

Localized necrotizing granulomatous lymphadenitis (GLA) is a very rare presentation of herpes simplex virus (HSV) infection. We are reporting a case that required multidisciplinary expertise to confirm the diagnosis and effectively treat the patient. Our patient had a recent diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and presented with hematuria and palpable inguinal lymph nodes. Affirmative diagnosis required a core biopsy of the lymph node with immunochemistry staining and polymerase chain reaction (PCR) testing. This case reviews the unusual presentation of an HSV infection and emphasizes the importance of maintaining a high index of suspicion for infection when treating an immunocompromised patient with persistent symptoms.

Biology and Treatment of Richter Transformation.

Richter transformation (RT), defined as the development of an aggressive lymphoma on a background of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), represents a clinical unmet need because of its dismal prognosis. An increasing body of knowledge in the field of RT is arising from the recent development of preclinical models depicting the biology underlying this aggressive disease. Consistently, new therapeutic strategies based on a genetic rationale are exploring actionable pathogenic pathways to improve the outcome of patients in this setting. In this review, we summarize the current understandings on RT biology and the available treatment options.

An unlucky Man with “Lucky” Earlobes: A Case Report of CLL/SLL with Cutaneous Lesions as the Initial Presentation

Introduction: Skin involvement is less common in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) than that of aggressive lymphoma such as diffuse large B cell lymphoma and T cell lymphoma. Cutaneous lesion as an initial presentation of CLL/SLL is even more rarely. While CLL/SLL presenting in the skin has been reported, to our knowledge it has never been described in the context of such as earlobes.

Chronic lymphocytic leukemia (CLL) with Reed\u2013Sternberg-like cells vs Classic Hodgkin lymphoma transformation of CLL: does this distinction matter?

The distinction between chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with isolated Hodgkin/Reed–Sternberg cells (CLL-HRS; background milieu with a paucity of inflammatory cells) and overt transformation to classic Hodgkin lymphoma (CLL-HL; mixed inflammatory background) is incompletely understood. This retrospective study examined the clinicopathologic features of CLL-HRS (n = 15) and CLL-HL (n = 31) patients seen over the past three decades from a single institution. The phenotypic features of Reed–Sternberg cells in both groups were similar, including expression of CD30, CD15, and PAX5, as well as EBV status. However, a spectrum of background CLL/SLL infiltration amongst the HRS cells was noted on pathologic review, and four patients had both diagnoses, either concurrently or in succession. The median overall survival (OS) of patients with CLL-HRS was 17.5 months compared to 33.5 months for patients with CLL-HL (P = 0.24). Among patients with CLL-HRS, those who received Hodgkin-directed therapy had a significantly longer median OS (57 months) compared to those who received CLL-directed therapy (8.4 months, P = 0.02). Our clinical and pathologic findings suggest a biologic continuum between CLL-HRS and CLL-HL and indicate that CLL-HRS patients may benefit from Hodgkin-directed therapy.

Colonic infiltration of chronic lymphocytic leukemia with Hodgkin Reed Sternberg-like cells

A 72-year-old man was diagnosed with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and signet ring cell carcinoma in a gastric biopsy. He underwent a subtotal gastrectomy + lymphadenectomy + chemotherapy + radiotherapy. He did not receive treatment for the lymphoma. Eight years after the diagnosis, he presented with alternating diarrhea and constipation. Physical examination revealed bilateral laterocervical, axillary, and inguinal lymphadenopathies. The laboratory results showed LDH: 286 UI/l and Beta-2-microglobulin: 6.4 mg/L. CT scan showed a mass that seems to involve the cecum and terminal ileum with multiple locoregional, retroperitoneal, and mesenteric lymphadenopathies. He underwent a right hemicolectomy. Macroscopically, we identified an ulcerated mass of approximately 7 x 6 x 5 cm. in the cecum. The microscopic findings were consistent with chronic lymphocytic leukemia (CD20+ and CD5+) with scattered Hodgkin reed Sternberg-like cells CD30 and EBER+ (Epstein-Barr virus-encoded RNA) by in situ hybridization (ISH) positive (Fig. 1). The patient received treatment with mini-CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone) plus rituximab with partial response after the third cycle.