Active Central Nervous System Involvement Research Articles

Abstract PO-010: Trial in Progress: Phase 1 Study of ARV-393, a PROTAC BCL6 Degrader, in Advanced Non-Hodgkin Lymphoma

Abstract Background: Non-Hodgkin lymphoma (NHL) represents a biologically and clinically diverse group of hematologic malignancies originating from B cells, T cells, and/or natural killer cells, with those of B-cell origin constituting ∼80–85% of all NHL cases. The BCL6 transcription factor is a key oncogenic driver of B-cell lymphomagenesis, and deregulated BCL6 expression is a common feature of diffuse large B-cell lymphoma (DLBCL), the most common type of NHL. BCL6 translocations have been observed in follicular lymphomas, the second most prevalent NHL, with studies suggesting that these translocations may portend a higher risk of transformation into aggressive lymphoma. BCL6 is also a lineage-defining transcription factor of T follicular helper cells, the cell of origin for angioimmunoblastic T-cell lymphoma (AITL). Moreover, BCL6 expression has been identified in biopsies of patients with AITL, and its continued expression was required for tumor growth in a mouse model of AITL, supporting BCL6 as a cancer driver in this type of NHL as well. ARV-393, an orally administered PROteolysis TArgeting Chimera (PROTAC) BCL6 degrader, is a bifunctional small molecule consisting of a BCL6-binding domain attached by a linker to a cereblon E3 ubiquitin ligase–binding domain. ARV-393 induces ubiquitination and subsequent degradation of BCL6 by the proteasome. In preclinical studies, ARV-393 induced rapid and robust degradation (>90%) of BCL6 in NHL cell lines and demonstrated dose-responsive tumor growth inhibition leading to tumor stasis or regression in xenograft models, supporting further investigation in patients with NHL. This multicenter, first-in-human, phase 1 study will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of ARV-393 in patients with advanced B-cell NHL or AITL. Methods: Eligible patients (aged ≥18 years) have relapsed/refractory mature B-cell NHL and ≥2 prior systemic therapies, or histologically confirmed AITL that has recurred or progressed following institutional standard-of-care therapy. Patients must also have ≥1 measurable lesion at study entry, Eastern Cooperative Oncology Group performance status of 0 or 1, freshly biopsied or archival tumor tissue available, adequate organ function, no active central nervous system involvement, and no prior allogeneic stem cell transplant or solid organ transplantation. Autologous stem cell transplant must not have occurred ≤100 days and previous CAR T-cell therapy ≤60 days prior to cycle 1 day 1 of ARV-393 treatment. ARV-393 will be administered orally in 28-day cycles with dose escalation according to a Bayesian optimal interval design. The primary objectives are to evaluate the safety and tolerability of ARV-393, determine maximum tolerated dose if necessary, and identify the recommended phase 2 dose(s) and dosing schedule. Secondary objectives are to characterize the pharmacokinetic profile of ARV-393 and evaluate its preliminary anti-tumor activity. Enrollment for this study will open in 2024. Citation Format: Paolo Caimi, Scott Huntington, Sean Landrette, Sheryl M Gough, Vivian Dai, Bryan Jackson, Juan Chavez, Sarah Tannenbaum-Dvir, Matthew Matasar. Trial in Progress: Phase 1 Study of ARV-393, a PROTAC BCL6 Degrader, in Advanced Non-Hodgkin Lymphoma [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-010.

Open-Label, Randomized, Phase 3 Study of Coformulated Favezelimab and Pembrolizumab Versus Chemotherapy in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma Refractory to Anti-PD-1 Therapy: Keyform-008

Background: The importance of PD-1 therapy in relapsed or refractory (R/R) classical Hodgkin Lymphoma (cHL) is well established, with PD-1 inhibitors such as pembrolizumab being a standard of care option for patients. However, most patients eventually develop progressive disease and optimal therapy after anti-PD-1 failure has not been determined. The inhibitory checkpoint receptor, lymphocyte-activation gene 3 (LAG-3) is expressed in cHL tumor microenvironments and upregulation of LAG-3 is considered to play an important role in anti-PD-1 resistance. Favezelimab (MK-4280) is a humanized immunoglobulin G4 antibody that binds to LAG-3 and blocks interaction with major histocompatibility complex Class II ligands. Results from the ongoing phase 1/2 MK-4280-003 study of the combination of favezelimab and pembrolizumab demonstrated manageable safety and promising antitumor activity in patients with anti-PD-1-refractory R/R cHL. The randomized, open-label, parallel group, active-controlled, phase 3 KEYFORM-008 study (NCT05508867) is designed to evaluate efficacy and safety of the coformulation of favezelimab and pembrolizumab versus physician's choice of chemotherapy in patients with anti-PD-1-refractory R/R cHL. Study Design and Methods: Patients ≥18 years old, with histologically confirmed R/R cHL, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2, and adequate organ function are eligible. Patients must have exhausted all available treatment options with known clinical benefit, including having progressed on anti-PD-1-based therapy and being ineligible for or having failed autologous stem cell transplant (ASCT). In addition, patients should also have been ineligible for brentuximab vedotin (BV), relapsed or failed to respond to BV or discontinued BV due to toxicity. Patients with a history of central nervous system (CNS) metastases or active CNS involvement are excluded. Approximately 360 patients will be enrolled and randomly assigned 1:1 to receive coformulated favezelimab 800 mg and pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) or physician's choice of chemotherapy (gemcitabine 800-1200 mg/m 2 IV on days 1 and 8 of a 21-day cycle or bendamustine 90-120 mg/m 2 IV on days 1 and 2 of either a 21- or 28-day cycle). Randomization will be stratified by prior ASCT (yes vs no) and ECOG PS (0 or 1 vs 2). Treatment will continue for ≤35 cycles for the favezelimab/pembrolizumab coformulation or ≤6 cycles for chemotherapy or until disease progression, unacceptable toxicity, or withdrawal. Patients receiving physician's choice of chemotherapy with progressive disease confirmed by blinded independent central review (BICR) per Lugano criteria may be eligible to cross over to the favezelimab/pembrolizumab coformulation. Response assessments by positron emission tomography (PET) and computed tomography (CT) or magnetic resonance imaging (MRI) will be performed every 12 weeks (Q12W) until disease progression or trial discontinuation. Adverse events will be monitored throughout the study and graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The primary end point is progression-free survival (PFS) per Lugano criteria by BICR. Overall survival (OS) is a key secondary end point. Other secondary end points are objective response rate (ORR), duration of response (DOR) per Lugano criteria by BICR, and safety. Exploratory end points include PFS on subsequent anticancer therapy and health-related quality of life. PFS, OS, and DOR rates in each treatment group will be estimated using the Kaplan-Meier method. The Clopper-Pearson method will be used to estimate ORR with 95% CI. Patient-reported outcomes will be assessed using EORTC Quality Of Life Questionnaire C30 and the EuroQuol 5-dimension, 5-level questionnaire. Enrollment for this study is open in sites in Australia, Belgium, Brazil, Canada, China, Czech Republic, France, Germany, Israel, Poland, Spain, South Korea, Sweden, Switzerland, Turkey, UK, and USA. ©2023 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2023 ASCO Annual Meeting. All rights reserved.

Acrue: A Phase 2, Open-Label Study of Acalabrutinib in Combination with Rituximab in Elderly and/or Frail Patients with Treatment-Naive Diffuse Large B-Cell Lymphoma

Background and Significance: Patients aged ≥80 years with diffuse large B-cell lymphoma (DLBCL) account for approximately 18% of DLBCL cases in the United States (Morrison et al. Future Oncol. 2018). Standard-of-care chemoimmunotherapy (CIT) regimens such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP), including reduced doses of CHOP (R-miniCHOP), are not well tolerated in elderly and/or frail patients, leading to high treatment-related mortality rates (Boslooper et al. Leuk Lymphoma. 2014; Freudenberger et al. Ann Hematol. 2021; Peyrade et al. Lancet Oncol. 2011). Therefore, safe, effective, and convenient treatment alternatives to CIT are needed. Acalabrutinib is a highly selective, second-generation Bruton tyrosine kinase inhibitor approved for the treatment of patients with relapsed/refractory mantle cell lymphoma and in patients with chronic lymphocytic leukemia. Acalabrutinib monotherapy has demonstrated encouraging activity in patients with DLBCL in phase 1b (NCT02112526) and phase 2 (NCT04002947) studies (Strati et al. Haematologica. 2021; Roschewski et al. Blood. 2021). However, neither of these studies were conducted specifically in a population of elderly and/or frail patients. Study Design and Methods: ACRUE (NCT05952024) is a phase 2, open-label, single-arm, global, multicenter study of acalabrutinib plus rituximab in elderly and/or frail patients with treatment-naive (TN) DLBCL who are unable to tolerate standard CIT ( Figure). Eligible patients are aged ≥80 years or aged 65-79 years with impairment in ≥1 activity of daily living (ADL) or instrumental ADL (IADL), or with cardiac/renal/liver function impairment or other comorbidities that render them unable to tolerate CIT. Furthermore, patients must have histologically confirmed CD20-positiveDLBCL (not otherwise specified), according to WHO 2016 classification, an Ann Arbor classification of stage II, III, or IV disease, an Eastern Cooperative Oncology Group performance status of 0-2, and ≥1 measurable lesion. Patients with active central nervous system involvement by lymphoma, leptomeningeal disease, or spinal cord compression, or significant cardiovascular disease within 6 months of screening are excluded. Target enrollment is 80 patients. Patients will receive acalabrutinib plus rituximab combination for 8 cycles (acalabrutinib 100 mg orally twice daily beginning on day 1 of cycles 1-8; rituximab 375 mg/m 2 intravenously on C1D15, then 1400 mg subcutaneously, on day 1 of cycles 2-8; cycles 1-8 are 21 days/cycle), followed by acalabrutinib monotherapy until disease progression, unacceptable toxicity, or 24 months (cycles 9-28 are 28 days/cycle). The primary endpoint is the percentage of patients with grade 3-4 treatment-emergent adverse events. The key secondary endpoint is investigator-assessed objective response rate per Lugano 2014 criteria. Other secondary endpoints include progression-free survival, event-free survival, overall survival, duration of response, and Timed Up and Go test. Exploratory biomarker analyses may include genomic characterization of baseline samples to evaluate predictors of survival, and of progression samples to evaluate genomic resistance mechanisms. Descriptive safety and efficacy data will be summarized. If patients discontinue treatment prior to completing 28 cycles of therapy, they will be followed every 12 weeks after their last treatment dose for up to 2 years. Patients who are still on treatment at the end of the study and are deriving clinical benefit may receive continued treatment, with assessments reverting to standard of care. Enrollment is planned to begin Q4 of 2023 in approximately 40 sites from North and South America and Asia. Summary: This study will help determine if acalabrutinib plus rituximab combination therapy is tolerable and effective in elderly and/or frail patients with TN DLBCL who are unable to tolerate CIT.

A Two-Part Study Evaluating the Combination of Tazemetostat and CPX-351 (Part 1) and Palbociclib with CPX-351 (Part 2) for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia

BACKGROUND AND SIGNIFICANCE Acute myeloid leukemia (AML) is an aggressive cancer of early hematopoietic progenitor cells with only 25-30% of patients (pts) surviving 5 years from diagnosis. For fit pts, conventional chemotherapy with DNA-damaging agents remains the mainstay of treatment. Conventional chemotherapeutic agents cause DNA-damage by targeting cells during DNA replication. Chromatin structure is highly influential in the efficacy of DNA-damaging agents, as areas of compacted chromatin are more resistant to DNA-damaging effects. Areas of DNA marked with histone 3 lysine 27 trimethylation (H3K27me3) are transcriptionally repressed and exhibit reduced accessibility to DNA-damaging agents. Enhancer of Zeste Homolog 2 (EZH2) serves as the catalytic subunit of the polycomb repressive complex 2 which methylates H2K27 to produce a di- or trimethylated state (H3K27me2/3). In preclinical studies, treatment of AML cell lines with the combination of an EZH2 inhibitor (EZH2i) and doxorubicin resulted in an increase in DNA damage and apoptosis compared to those treated with doxorubicin alone. Further, a significant decrease in leukemia burden was seen in mice injected with THP-1 (AML) cells and treated with an EZH2i and doxorubicin and cytarabine compared to doxorubicin and cytarabine alone. This effect was further enhanced by pre-treatment of AML cells with palbociclib (PALB), a CDK4/6 inhibitor, by significantly increasing the number of cells in S phase when exposed to the EZH2i and doxorubicin combination, resulting in an increase in DNA damage and apoptosis compared to cells that were not pre-treated with PALB. These findings were reproduced in in vivo studies with mice injected with the primary AML cells (Porazzi P, et al. Cancer Res., 2021). STUDY DESIGN AND METHODS We will perform a 2-part phase I dose escalation study utilizing EZH2i tazemetostat (TAZ) in combination with CPX-351 induction chemotherapy and of PALB pre-treatment followed by CPX-351 in pts with relapsed or refractory (R/R) AML (NCT05627232). All pts will receive CPX-351 at standard dose on days 1, 3 and 5. Part 1 evaluate the addition of TAZ to CPX-351 via traditional 3+3 design. Pts will be treated with TAZ on days -1 to 6 at a starting dose of 600 mg twice daily to open chromatin concurrent with CPX-351 administration. Part 2 evaluate the pre-treatment with PALB via traditional 3+3 design. Pts will be treated with PALB starting dose of 100 mg daily on days -3 to -1 to induce cell cycle G1. PALB will be held on day 1 to allow cells to then enter S phase prior to administration of CPX-351. ( Figure 1). The study will enroll pts with R/R AML treated at Sidney Kimmel Cancer Center. Pts must be ≥18 years of age with R/R AML (non-acute promyelocytic leukemia) and have received at least 1 prior line of therapy and have adequate performance status and organ function. Pts whose participation would result in a total cumulative dose of daunorubicin greater than 550 mg/m 2 (450 mg/m 2 if they previously received mediastinal radiation) and those with active central nervous system involvement of AML, unstable cardiac disease or other severe concurrent disease will be excluded. The primary endpoints of Parts 1 and 2 will be to determine the maximum tolerated dose of TAZ and of PALB in combination with CPX-351, respectively. Secondary endpoints for Parts 1 and 2 include preliminary assessment of efficacy. Correlative studies to evaluate the on-target effect of TAZ on H3K27me3 and DNA-damage and of PALB on cell cycling will be performed at protocol-specified time points. If these two 2-drug combinations prove to be safe, we will amend the protocol to add Part 3 which will evaluate the safety of the 3-drug combination of pre-treatment with PALB followed by co-treatment with TAZ and CPX-351.

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

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

Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in Secondary Central Nervous System Large B-Cell Lymphoma (SCNSL): A Multicenter Retrospective Analysis

Introduction Secondary central nervous system (CNS) involvement develops in 2-10% of large B-cell lymphoma (LBCL) cases. Current treatment approaches for relapsed or refractory CNS disease generally do not provide durable responses. Limited data suggest efficacy and feasibility of CAR-T therapy in SCNSL. We report here the largest multicenter retrospective analysis of the safety and efficacy of CD19-directed CAR-T therapy in SCNSL patients. Methods This study included SCNSL patients who received commercial CD19-directed CAR-T therapy at 9 academic institutions in the United States between 2016 and 2022. SCNSL was defined as history of parenchymal and/or leptomeningeal/cerebrospinal fluid (CSF) involvement by lymphoma at any time prior to receiving CAR-T therapy. Systemic response was assessed using the Lugano criteria while CNS response was assessed as per International PCNSL Collaborative Group criteria. Kaplan-Meier curves were generated for progression-free survival (PFS) and overall survival (OS) for entire cohort, as well as subsets of patients with and without active CNS disease at the time of CAR-T infusion. Results Ninety patients were included in the analysis, with baseline characteristics shown in Table 1. CAR-T products utilized include axicabtagene ciloleucel (n= 38, 42%), tisagenlecleucel (n=37, 41%) and lisocabtagene maraleucel (n= 15, 14%). Fludarabine/cyclophosphamide was used as lymphodepletion in 84 patients (93%). 28 patients received CNS directed radiation therapy (RT) prior to CAR-T infusion (31%) within a median time of 28.5 days (range 5 - 906) from last day of RT. Amongst all patients at the time of CAR-T infusion 82 (91.1%) had active CNS and/or systemic involvement while 8 (8.9%) had no evidence of disease; 68 (75.5%) had active CNS involvement while 22 (24.5%) had a prior history of CNS involvement but no active at the time of CAR-T infusion. ( Table 1) Median follow up all patients was 0.5 year (range 0.01 - 4.7). 71 patients (79%) developed cytokine release syndrome (CRS; median time to onset 3 days) with 3.3% patients developing Grade 3-4. Immune effector cell-associated neurotoxicity syndrome (ICANS; median time to onset 5 days) was reported in 55 patients (61%), with 28.8% developing Grade 3-4. No patients died due to CRS or ICANS. At 1-month post CAR-T, 80 patients were evaluable for CNS response and 71 patients in the entire cohort were evaluable for systemic response. Similarly, at 3-months these numbers were 66 and 60, respectively. Objective response rates (ORR) were 75% and 80% at 1-month for CNS and systemic disease respectively, while corresponding ORRs at 3-months were 68% and 76.7%. At 1- and 3-months timepoint 36 (45%) and 33 (50%) patients, respectively achieved CNS complete remission (CR), while 44 (62%) and 42 (70%) patients respectively achieved systemic CR. 1- and 2-year PFS for entire cohort were 25% (95%Cl 15% - 34%) and 16% (95%Cl 8.5% - 28%) respectively, while 1- and 2-year OS were 46% (95%Cl 36% - 59%) and 31% (95%Cl 22% - 46%). Non-relapse mortality (NRM) were 4.6% (95%CI, 1.8% -12%) and 7.2% (95%CI 2.9% - 18%) at 1- and 2-year. Cumulative incidence of relapse at 1- and 2-year were 73% (95%Cl 63% - 83%) and 77% (95%Cl 68% - 88%), respectively. ORRs for CNS response in patients with active CNS disease at 1-month and 3-month interval were 71% (n=45) and 60% (n=31). Similarly, ORR for systemic response with active CNS disease at 1-month and 3-month interval were 85% (n=43) and 74.3% (n=32).The 2-year PFS for patients with and without active CNS disease at CAR-T infusion were 12% (95%Cl 5.4% - 27%) and 28% (95%Cl 12% - 65%) respectively, with a corresponding OS of 25% (95%Cl 15% - 41%) and 58% (95%Cl 37% - 91%). ( Figure 1) The 2-year NRM rates for patients with and without active CNS disease at CAR-T infusion were 4.6% (95%Cl 1.5% - 14%) and 14% (95%Cl 3.6% - 53%) respectively, while the cumulative incidence of relapse in similar order were 83% (95%Cl 73% - 95%) and 58% (95%Cl 39% - 88%). Conclusion In this largest known case series to date, CAR-T therapy appeared safe and feasible in patients with SCNSL, but is associated with high rates of treatment failure, particularly in patients with active CNS disease at CAR-T infusion. This warrants further study of optimal CNS-directed treatment strategies prior to CAR-T, development of novel cellular therapy platforms or consideration of post CAR-T maintenance therapy in these high-risk patients.

Traverse: A Phase 2, Open-Label, Randomized Study of Acalabrutinib in Combination with Venetoclax and Rituximab in Patients with Treatment-Naive Mantle Cell Lymphoma

Background and Significance: Despite advances in treatment for mantle cell lymphoma (MCL), no curative option exists. Currently, the majority of patients with treatment-naive (TN) MCL receive chemoimmunotherapy, which can result in prolonged remissions, but is associated with significant toxicity. Almost all patients inevitably relapse, and therefore, frontline chemotherapy-free options are being increasingly explored. Acalabrutinib is a highly selective, second-generation Bruton tyrosine kinase inhibitor (BTKi) approved for the treatment of adult patients with relapsed/refractory (R/R) MCL. In a phase 1b study in patients with TN MCL, acalabrutinib in combination with venetoclax and rituximab (AVR) demonstrated high rates of clinical and molecular response with an acceptable toxicity profile, supporting its continued development as a chemotherapy-free treatment option (Wang et al. Blood. 2021; Wang et al. Blood. 2022). Furthermore, the occurrence of complete responses (CRs) with clearance of minimal residual disease (MRD) in MCL clinical trials suggests that treatment may be stopped in these patients, as observed in patients with chronic lymphocytic leukemia who received combination therapy with venetoclax and rituximab. Study Design and Methods: TrAVeRse (NCT#05951959) is a phase 2, open-label, randomized, multicenter, international study of AVR in patients with TN MCL. Patients aged ≥18 years with an Eastern Cooperative Oncology Group performance status of 0-2 (3 if due to lymphoma), and Ann Arbor stage II, III, or IV disease are eligible. Key exclusion criteria are active central nervous system involvement by lymphoma or leptomeningeal disease, severe/life-threatening illness or medical condition, clinically significant cardiovascular disease, stroke, or intracranial hemorrhage within 6 months of enrollment, and any active uncontrolled infection. Approximately 125 patients will be screened to achieve a study population of 100 patients. During the induction phase, patients will receive oral acalabrutinib 100 mg twice daily (BID) in 28-day cycles for 13 cycles, starting at cycle 1; oral venetoclax once daily, starting at cycle 2 at a dose of 20 mg daily, with ramp-up to a maximum of 400 mg daily over 5 weeks for a total of 12 cycles; and intravenous rituximab 375 mg/m 2 on day 1 of every cycle for 12 cycles, starting at cycle 1. Patients who complete 13 cycles of AVR induction will be centrally tested for MRD status and continue to receive acalabrutinib 100 mg BID for 1 additional cycle (cycle 14) while awaiting disease response assessment and MRD results. Patients who achieve an MRD-negative CR (in peripheral blood at a threshold of 10 -5) at the end of induction will be randomly assigned in a 1:1 ratio to either continue to receive acalabrutinib 100 mg BID or to observation from cycle 15. Randomization will be stratified according to the simplified MCL International Prognostic Index [sMIPI] score (low [score, 0-3] and intermediate risk [4-5] vs high risk [6-11]), histologic features (blastoid or pleomorphic vs classical histology), and TP53 status (mutated vs unmutated). Those with an MRD-positive CR, partial response (PR), or stable disease (SD) at end of induction will continue to receive acalabrutinib 100 mg BID until disease progression, death, or unacceptable toxicity. Patients who progress during observation may be retreated with acalabrutinib 100 mg BID at relapse. The primary endpoint of this study is the MRD-negative CR rate at the end of AVR induction (ie, end of cycle 13). Secondary endpoints include MRD-negative CR rate at any point during the study, objective response rate and CR rate, duration of response, time to next treatment, progression-free survival, event-free survival, overall survival, safety, and tolerability. The study will also assess the feasibility of response-adapted treatment cessation for those who achieve MRD-negative CR after AVR induction and the efficacy of acalabrutinib retreatment in the subgroup of patients randomized to observation who subsequently relapse. Patients will be followed for 36 months post last patient randomized. Enrollment is planned to begin Q3 of 2023 including sites in North America, Australia, and Europe. Summary: This study will evaluate the efficacy of AVR, a chemotherapy-free triplet combination therapy, in patients with TN MCL.

A Phase II Study of Loncastuximab Tesirine As Consolidation Strategy in Patients with LBCL in PR at Day 30 after CAR T-Cell Therapy

Background and Significance. Approximately 30% of patients with large B-cell lymphoma (LBCL) treated with autologous anti-CD19 CAR T-cell therapy (CART) achieve a partial response (PR) on day 30 (D30) assessment. Of those, up to 30% may spontaneously convert to a complete response (CR) during subsequent re-staging. While up to 70% of patients with D30 PR eventually progress, reliable biomarkers that help identify patients at risk are not yet available, and the current standard approach is close monitoring. CD19 expression is retained in most tumors of patients who relapse or progress after CART. Potential reasons for resistance in these tumors include T-cell dysfunction and tumor intrinsic mechanisms that resist T-cell mediated killing. Therefore, targeting such tumors with agents that have an alternative mechanism of action is likely to improve outcomes. To this regard, loncastuximab tesirine (Lonca) is an anti-CD19 antibody conjugated to a cytotoxic pyrrolobenzodiazepine dimer approved by the FDA for LBCL patients who relapse after at least 2 lines of systemic therapy. In the phase 2 LOTIS-2 study, Lonca was associated with an overall response rate of 48% and a CR rate of 24%, and included patients previously treated with CART. Grade 3-4 adverse events were observed in less than one third of patients, and were mainly represented by myelosuppression, skin toxicity and isolated GGT elevation. Study Design and Methods. This is a phase 2 single center study to investigate the safety and efficacy of Lonca as a consolidation strategy for LBCL patients with D30 PR after standard of care CART (NCT05464719). Patients with LBCL, including diffuse large B-cell lymphoma, high grade B-cell lymphoma, primary mediastinal B-cell lymphoma and transformed follicular lymphoma, treated with standard of care CART (in second line and beyond) and with PET-CT evidence of D30 PR are eligible for this study. Patients with absolute neutrophil count < 1000/uL and/or platelet count < 50,000/uL, and those with previous or active central nervous system involvement are excluded. Tissue biopsy for confirmation of PR will be performed; CD19 expression is not required for eligibility. Lonca is administered intravenously, on day 1 of a 21-day cycle, at a dose of 150 mcg/kg for the first 2 cycles, and 75 mcg/kg subsequently, for a total of 6 cycles. Response is assessed by PET-CT, according to 2014 Lugano criteria, after 3 cycles and at the end of treatment. The primary objective is efficacy, measured as conversion from D30 PR to CR. Using a one arm binomial exact test, hypothesizing an increase in conversion rate to CR from 30% to 60%, a sample size of 30 patients has a 90% power to observe a significant difference, with an alpha error of 0.05; a futility analysis, based on efficacy and toxicity, will be performed after the first 10 patients are treated. Secondary objectives are safety and other measurements of efficacy, including duration of CR. Exploratory objectives include identification of biomarkers of response and resistance. Peripheral blood samples will be collected pre-treatment, after 3 cycles, post-treatment and at time of progression, as well as collection of a pre-treatment tissue biopsy and at time of progression. Blood and tissue samples will be analyzed by multi-parameter flow cytometry and hiplex imaging assays (Phenocycler-Fusion/CODEX) to identify immune signatures of response and resistance to Lonca, and to assess CAR T-cell persistence; blood samples will be analyzed by CAPP-Seq to measure minimal residual disease. Finally, total metabolic tumor volume will be assessed on pre-treatment PET-CT scans, and association with response to consolidation therapy will be analyzed.

A Phase 1 Study of PIT565, a First-in-Class, Anti-CD3, Anti-CD19, Anti-CD2 Trispecific Antibody in Patients with Relapsed and/or Refractory B-Cell Malignancies

Background and Significance: There is an unmet therapeutic need for patients with relapsed and/or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) and R/R B-cell acute lymphoblastic leukemia (B-ALL) who have failed multiple lines of therapy. PIT565 is an investigational, first-in-class, immunoglobulin G-like, trispecific antibody that targets CD19 on malignant B cells while engaging CD3 and CD2 (a costimulatory receptor) on T cells, leading to redirected T-cell cytotoxicity toward CD19-positive malignant B cells. CD2 signaling prevents transcriptional changes characteristic of exhaustion during persistent T-cell receptor stimulation of CD8 T cells. Furthermore, the loss of CD2 ligand, CD58, on tumor cells has been shown to mediate resistance to the antitumor activity by T cell-redirecting therapies, confirming the importance of CD2 activation in T cells. Findings from preclinical studies suggest that PIT565 mediates more potent and sustained antitumor T-cell responses compared with CD3 bispecifics (Lu H, ASH 2022). Study Design and Methods: This is an open-label, phase 1, multicenter study of PIT565 in patients with R/R B-NHL and R/R CD19-positive B-ALL who have relapsed/failed to respond to ≥2 lines of prior therapy (including an anti-CD20 monoclonal antibody-containing chemotherapy combination regimen for patients with R/R B-NHL) (NCT05397496). The study is ongoing with plans to enroll approximately 140 patients in Belgium, France, Israel, Italy, Japan, Singapore, Spain, and the USA. Eligible patients are ≥18 years with an Eastern Cooperative Oncology Group performance status ≤2 and have at least one bi-dimensionally measurable nodal lesion or one bi-dimensionally measurable extranodal lesion as measured via positron emission tomography-computed tomography for R/R B-NHL, and/ or morphologic disease in the bone marrow (³5% blasts) for R/R B-ALL. Patients with contraindication to tocilizumab; history of other malignant disease; active central nervous system involvement; autoimmune disease (other than patients with vitiligo, hypothyroidism only requiring hormone replacement, or psoriasis not requiring systemic treatment or conditions not expected to recur); or receiving systemic treatment with any immunosuppressive medication are not eligible. During the dose escalation part of the study, PIT565 is administered to patients with R/R B-NHL (Group A) and patients with R/R B-ALL (Group B). During the dose-expansion part, PIT565 is administered to patients with R/R large B-cell lymphoma (LBCL) who have received CD-19-directed chimeric antigen receptor (CAR)-T therapy (Group A1); patients with R/R LBCL who have not received CAR-T therapy (Group A2); and patients with R/R B-ALL (Group B1). PIT565 is administered either once weekly (Q1W) or once every 2 weeks (Q2W) with and without a priming dosing. Routes of administration (intravenous [IV] or subcutaneous [SC]) are explored in the dose-escalation phase. Patients initially receive PIT565 IV Q1W over a 28-day cycle. Q2W treatment in a 28-day cycle is explored if supported by preliminary pharmacokinetics (PK), pharmacodynamics, efficacy, and safety findings. The primary objective is to assess safety (including dose-limiting toxicities) and tolerability, and to identify the maximum tolerated dose (MTD) and/or recommended dose (RD), schedule, and route of administration for each indication. Secondary objectives include evaluation of preliminary antitumor activity (overall response rate, complete response rate, best overall response, duration of response, overall survival, and progression-free survival for B-NHL or event-free survival for B-ALL), assessment of PK and immunogenicity of PIT565 in R/R B-NHL and R/R B-ALL. The dose escalation phase is guided by an adaptive Bayesian logistic regression model following the escalation with overdose control principle. The MTD and/or RD are further explored during the dose-expansion phase.

A Phase 1 Cohort Dose Escalation and Expansion Trial to Determine the Safety, Tolerance, Maximum Tolerated Dose, and Preliminary Antineoplastic Activity of IKS03 in Patients with Advanced B-Cell Non-Hodgkin Lymphomas (NHL)

Background: IKS03 is an antibody-drug conjugate (ADC) comprising an anti-CD19 antibody conjugated with novel ConjuALL technology to a highly potent proprietary DNA-crosslinking pyrrolobenzodiazepine (PBD) prodrug payload for the treatment of CD19-positive hematologic malignancies. Both the payload and the linker of IKS03 incorporate an innovative tumor-selective chemistry that takes advantage of the overexpression of beta glucuronidase in cancer cells compared to most normal tissues. Payload release and activation require cleavage of glucuronide moieties that are incorporated into the linker payload structure providing improvements in both efficacy and safety compared to traditional ADC formats. This “glucuronide trigger” is stable while in circulation with minimal to no systemic payload release from the ADC. Following binding and internalization of IKS03 into a CD19-positive cancer cell, beta glucuronidase can release the active PBD payload leading to cell death. Normal tissues without CD19 expression and/or with low levels of the beta glucuronidase enzyme have limited ADC uptake, are less able to process IKS03 and are differentially spared. In preclinical studies, IKS03 demonstrated significant in vivo efficacy with complete tumor regressions in CD19-positive diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL) xenograft models at single doses of 0.1 to 1 mg/kg. IKS03 demonstrated greater activity than the clinical benchmark ADC loncastuximab tesirine. IKS03 is also highly effective in patient-derived xenograft models that contain some of the genetic alterations commonly found in relapsed/refractory NHL patients. Results from toxicology studies in cynomologus monkey suggest a manageable safety profile at single doses, well above those required for in vivo activity. Pharmacokinetics are favorable with a mean total ADC half-life of 8 days and undetectable levels of the active PBD payload in circulation confirming targeted delivery of the payload. Study Design and Methods: This Phase 1 multicenter, open label, non-randomized study of IKS03 will consist of two parts: dose-escalation (Part I) and dose-expansion (Part II) together enrolling approximately 140 adult patients with relapsed or refractory B-cell NHL after at least two prior lines of systemic therapy. Patients will receive repeat doses of study drug by IV infusion on Day 1 of each 21-day cycle, until disease progression, unacceptable toxicity, or another withdrawal criterion is met. Key exclusion criteria include: active central nervous system involvement with NHL; clinically significant cardiovascular, pulmonary or hepatic disease; or receipt of other CD19-directed therapy within 3 months. Part I dose escalation will enroll patients with confirmed CD19-positive, measurable or non-measurable advanced B-cell NHL. Eligible subtypes include DLBCL, MCL, FL, high-grade B-cell, and marginal zone lymphoma as per WHO 2016 classification. Patients with Burkitt's lymphoma, Waldenström macroglobulinemia, and chronic lymphocytic leukemia are excluded. In Part 1, the primary objective is establishment of the recommended Phase 2 dose (RP2D) by evaluation of safety, tolerability and the maximum tolerated dose (MTD) of IKS03. Dose escalation will follow a 3+3 design. A two cycle Dose-Limiting Toxicity (DLT) assessment period will be observed, and dose-escalation decisions will be guided by a study safety committee. Dose escalation increments will be adjusted based on occurrence of protocol-specified DLTs as well as overall tolerability. Secondary objectives include characterization of immunogenicity and pharmacokinetic (PK) profile of IKS03. Exploratory objectives include preliminary antineoplastic activity per Lugano criteria (Cheson et al, JCO 2014) and evaluation of pharmacodynamic markers. Part II will further evaluate the antineoplastic activity of IKS03 at the RP2D in expansion cohorts of patients with selected NHL subtypes and with measurable disease. Sample size will be determined for each subtype using a Simon Two-Stage design. Secondary objectives include further evaluation of safety, tolerability, immunogenicity and PK profile of IKS03 as well as confirmation of the RP2D. Clinical trial information: NCT05365659.

Exclusion of Acute Myeloid Leukemia Patients with Central Nervous System Involvement from Clinical Trials: An Analysis of the National Institutes of Health Clinical Trials Registry from 2012 to 2022

Introduction: Central nervous system (CNS) involvement in acute myeloid leukemia (AML) can be successfully treated with intrathecal chemotherapy and carries debatable prognostic impact. However, patients with CNS involvement are commonly excluded from clinical trials at an unknown rate. We systematically evaluated exclusion criteria of AML clinical trials based on CNS involvement and determined associations with clinical trial characteristics. Methods: The National Institutes of Health Clinical Trials Registry was searched for interventional adult AML trials between 2012 and 2022 that were phase 1, 2, or 3 and relevant trial characteristics were extracted. Results: 1,270 trials were included in the analysis with 790 trials (62.1%) explicitly excluding CNS involvement. There was no significant change in rates of CNS exclusion over the past decade. CNS exclusion was higher in trials that included the non-transplant population compared to trials exclusive to the transplant population (66.9% vs. 43.8%, p < 0.01). Non-transplant trials were also more likely to exclude patients with a history of or ambiguous timing of CNS involvement (p < 0.01). Phase 3 trials were associated with more liberal definitions of CNS exclusion (history or ambiguous timing) as compared to phase 1 and 2 trials that had higher rates of excluding patients with only active CNS involvement (p < 0.01). Conclusion: A majority of AML clinical trials, particularly in the non-transplant setting, exclude patients with CNS involvement. Many of these trials, most notably phase 3 trials, exclude patients not only with active but also with any history of CNS involvement. Further research is needed to determine optimal management of these patients in order to increase representation in large clinical trials.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Central nervous system (CNS) involvement in patients with refractory or relapsed large B-cell lymphoma (LBCL) is associated with an extremely poor prognosis. Autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is an approved treatment for patients with refractory or relapsed (R/R) LBCL that has changed the prognosis of patients with chemoresistant LBCL. However, data regarding efficacy and safety of CART cell treatment in patients with active CNS involvement are limited since they are excluded from most of clinical trials. Methods: We retrospectively collected data from 75 patients with LBCL, treated with CART cells from January 2020 to January 2023 in Henri Mondor Hospital. We identified 13 patients with active CNS involvement at the time of CAR-T cell treatment decision: 12/13 had abnormal neurological examination, 8/11 had head and/or medullar MRI abnormalities consistent with lymphoma and 9/10 had detectable lymphoma cells in the cerebrospinal fluid. We compared the characteristics of the 13 patients with CNS involvement (CNS+) with 62 patients without evidence of active CNS disease (CNS-). Median age was 69 and 59 years, respectively (p = 0.05). CNS+ patients received a median of 2 previous lines of treatment versus 3 for CNS- patients (p = 0.34). Performance status prior to CART-cell injection was 2 or more in 9/13 (69%) and 11/62 (18%) p < 0.001, respectively. 5/13 (38%) CNS+ patients had high grade B-cell lymphomas versus 11/62 (18%) CNS- (p = 0.13). CAR-T-cell was axi-cel in 10/13 (77%) CNS+ patients versus 42/62 (68%) CNS– (p = 0.74). It is noteworthy that 7/13 (54%) CNS+ patients had pre-existing low-grade B-cell lymphomas versus 15/62 (24%) CNS- (p = 0.046). Results: The best overall response rate was identical in both groups: 12/13 (92%) in CNS+ patients versus 51/61 (92%) in CNS-, including 11/13 (85%) and 44/61(72%) complete metabolic response. As shown in the figure, median progression free survival and overall survival was 5.5 and 8.4 months, respectively in CNS+ patients versus 11.5 and 21 months in CNS- patients (not significant). Regarding safety, 13/13 (100%) CNS+ patients had a cytokine release syndrome (10 grade 1–2 and 3 grade 3) versus 54/62 (87%) CNS- (49 grade 1–2 and 5 grade 3–4) and 10/13 (77%) experienced ICANS (6 grade 1–2 and 4 grade 3–4) versus 28/62 (45%) CNS- (27 grade 1–2 and 1 grade 3–4) (p = 0.06 and 0.02 for grade 3–4). Transfer into an intensive care unit occurred in 4/13 (31%) CNS+ patients versus 9/62 (15%) CNS- (p = 022). Median time of hospitalization was 37 days for CNS+ patients versus 20 days for CNS- patients (p = 0.007). Six CNS+ patients died from which 5 died of progression and 1 of infection. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cellular therapies, Immunotherapy Conflicts of interests pertinent to the abstract. F. Lemonnier Consultant or advisory role: BMS, Kiowa, Miltenyi Educational grants: Gilead, Janssen, Roche L. Roulin Educational grants: Kite gilead, Novartis, Bristol myers squibb

BELLWAVE-008: A phase 3 study of the efficacy and safety of nemtabrutinib in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) without TP53 aberrations.

TPS7594 Background: Targeting the Bruton’s tyrosine kinase (BTK) pathway has been a revolutionary treatment option for first-line treatment of CLL/SLL. Nemtabrutinib is a noncovalent, reversible, potent BTK inhibitor that targets both wild-type and C481S-mutant BTK. Results of an ongoing phase 1/2 dose-escalation study (BELLWAVE-001) have demonstrated manageable safety and preliminary antitumor activity of nemtabrutinib in pts with CLL/SLL. BELLWAVE-008 is a randomized, open-label, phase 3 study (NCT05624554) designed to evaluate efficacy and safety of nemtabrutinib compared with investigator’s choice of chemoimmunotherapy (FCR or BR) in pts with previously untreated CLL/SLL without TP53 aberrations. Methods: Eligible pts are ≥18 years old with previously untreated CLL/SLL with active disease and without TP53 aberrations (17p deletion and/or TP53 mutation), with ECOG PS of 0-2 and adequate organ function. Pts with Richter transformation or active central nervous system involvement are excluded. Approximately 300 pts will be enrolled and randomly assigned 1:1 to receive nemtabrutinib (65 mg orally once daily until progressive disease, unacceptable toxicity, or discontinuation) or intravenous infusion of the investigator’s choice of chemoimmunotherapy for 6 cycles lasting 28 days each (FCR: fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 on days 1, 2, and 3 of each cycle, plus rituximab 375 mg/m2 initially, followed by 500 mg/m2 on day 1 of each cycle; or BR: bendamustine 70-90 mg/m2 on days 1 and 2 of each cycle plus rituximab 375 mg/m2 initially, followed by 500 mg/m2 on day 1 of each cycle). Randomization will be stratified by risk (high risk: 11q deletion and/or IGHV unmutated vs low risk: absence of high-risk factors) and age ( &lt; 65 years vs ≥65 years). Treatment response (imaging, physical examination, constitutional symptoms, hematologic evaluation, and bone marrow biopsy, as required) will be performed every 12 weeks up to and including cycle 25, and every 24 weeks thereafter. Adverse events (AEs) will be monitored up to 30 days after treatment cessation (90 days for serious AEs) and will be graded per National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0, and hematologic toxicities will be evaluated according to International Workshop on Chronic Lymphocytic Leukemia (iwCLL). Primary end point is progression-free survival per the iwCLL 2018 criteria as assessed by blinded independent central review. Secondary end points include overall survival, objective response rate (ORR), duration of response, and safety. Exploratory efficacy end points include resistance evaluations, ORR including partial response with lymphocytosis as a response category, pharmacokinetics/pharmacodynamics, and health-related quality of life. Enrollment is ongoing. Clinical trial information: NCT05624554 .

CAR T-cell-associated neurotoxicity in central nervous system hematologic disease: Is it still a concern?

Chimeric antigen receptor (CAR) T-cell systemic immunotherapy has revolutionized how clinicians treat several refractory and relapsed hematologic malignancies. Due to its peculiar mechanism of action, CAR T-cell-based therapy has enlarged the spectrum of neurological toxicities. CAR T-cell-associated neurotoxicity-initially defined as CAR T-cell-related encephalopathy syndrome (CRES) and currently coined within the acronym ICANS (immune effector cell-associated neurotoxicity syndrome)-is perhaps the most concerning toxicity of CAR T-cell therapy. Importantly, hematologic malignancies (especially lymphoid malignancies) may originate in or spread to the central nervous system (CNS) in the form of parenchymal and/or meningeal disease. Due to the emergence of deadly and neurological adverse events, such as fatal brain edema in some patients included in early CAR T-cell trials, safety concerns for those with CNS primary or secondary infiltration arose and contributed to the routine exclusion of individuals with pre-existing or active CNS involvement from pivotal trials. However, based primarily on the lack of evidence, it remains unknown whether CNS involvement increases the risk and/or severity of CAR T-cell-related neurotoxicity. Given the limited treatment options available for patients once they relapse with CNS involvement, it is of high interest to explore the role of novel clinical strategies including CAR T cells to treat leukemias/lymphomas and myeloma with CNS involvement. The purpose of this review was to summarize currently available neurological safety data of CAR T-cell-based immunotherapy from the clinical trials and real-world experiences in adult patients with CNS disease due to lymphoma, leukemia, or myeloma. Increasing evidence supports that CNS involvement in hematologic disease should no longer be considered per se as an absolute contraindication to CAR T-cell-based therapy. While the incidence may be high, severity does not appear to be impacted significantly by pre-existing CNS status. Close monitoring by trained neurologists is recommended.

CNCT19 CAR T-Cell Therapy in Relapsed or Refractory B-Cell Lymphoma: Long-Term Results of a Pilot Prospective Clinical Study

Background: Chimeric antigen receptor (CAR) T-cell targeting tumor cells depends on the single chain variable fragment (scFv) against the specific tumor antigen. Most anti-CD19 CAR-T products have the scFv deriving from hybridoma clone FMC63. We developed a new hybridoma clone HI19α which binds to distinct CD19 episodes. CNCT19 was a second-generation CAR T-cell with scFv derived from clone HI19α and 4-1BB/CD3-ζ costimulatory domain. The results of CNCT19 in pediatric and adult patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia had previously been reported [Runxia Gu et al. J Hematol Oncol. 2020 Sep 7;13(1):122]. Herein, we reported the outcome and long-term follow-up of a pilot study administrating CNCT19 in relapsed or refractory B-cell lymphoma. This trial was registered at www.clinicaltrials.gov as NCT03029338. Methods: Patients with R/R CD19-positive B-cell lymphoma were eligible for this study. Subjects with active central nervous system involvement were excluded. Lymphodepleting chemotherapy comprising fludarabine (25~30mg/m2, day -4,-3,-2) and cyclophosphamide (350mg/m2 day -4, -2) was administrated once the CNCT19 product was available. We infused CNCT19 cells in three regimens: three-day split dose (10%-30%-60%, patient (P)1-P10), two-day split dose (40%-60%, P11-P17), and single dose (P18-20). Results: From May 2017 through March 2019, 20 patients were enrolled. Diagnosis of histological subtypes included diffuse large B-cell lymphoma not otherwise specified (DLBCL, NOS) in 14 (70%) patients, DLBCL transformed from chronic lymphocytic leukemia in 1 (5%) patient, follicular lymphoma (FL) grade 3b in 1 (5%) patient, and mantle cell lymphoma (MCL) in 4 (20%) patients. Considering the differences in efficacy and survival between the population with MCL and those with LBCL, we here reported the results of 16 patients who had diseases of DLBCL or FL 3b. The median age was 51 (range 16 to 69), and 62.5% were male. The majority (87.5%) of patients had advanced stage disease, and 11 (68.8%) had non-GCB immunophenotype. Double expressor lymphoma (DEL, cut-off for MYC, >=40%, BCL2, >=50%) was identified in 11 (68.8%) patients, with one of them having MYC and BCL2 rearrangement. TP53 mutation and/or deletion were detected in 5 of 6 (83.3%) patients. The patients had received a median of 3 (range 2 to 7) lines of prior therapy. Thirteen (81.3%) patients had diseases refractory to last-line therapy. The median dose of infused CNCT19 cells was 2.48×106 (range 1.87 to 5.06×106) per kilogram of body weight. Cytokine release syndrome (CRS) occurred in 11 (68.8%) patients, all of whom were grade 1. Only one patient experienced CAR-T-cell-related encephalopathy syndrome (CRES), manifesting as distal muscle weakness of the bilateral upper limb, and he recovered completely after corticosteroids treatment. Twelve (75.0%) patients achieved a response after CNCT19 infusion, with a complete response (CR) rate of 37.5%. The ORR and CR rate at 3 months was 62.5% and 31.3%, respectively. Two patients with ongoing partial remission underwent allogeneic hematopoietic stem-cell transplantation, and both of them died of progressive disease at 6 months and 11 months post CNCT19 infusion, respectively. As of July 5, 2022, the median follow-up from CNCT19 infusion to the data-cutoff date was 44.5 months. The median progression-free survival and overall survival were 6.5 (95% CI 1.0 to NA) months and 12.7 (95% CI 2.9 to NA) months, respectively. Six (37.5%) patients remained alive by data cut-off. Conclusions: CNCT19 cells exhibited comparable efficacy and favorable safety in patients with R/R DLBCL and FL3b. A phase 2 clinical trial (NCT04586478) of administrating CNCT19 in R/R large B-cell lymphoma and high-grade B-cell lymphoma is underway.

ABCL-044 Clinical Outcomes of Commercial CD19-Targeted CAR T-Cell Therapy in Patients With Secondary Central Nervous System Lymphoma

We hypothesized that CD19-targeted chimeric antigen receptor (CAR) T-cell therapy is safe and feasible among high-grade B cell lymphoma (HGBCL) patients with secondary central nervous system (CNS) lymphoma. To evaluate the safety and efficacy of CD19-targeted CAR T-cell therapy in patients with relapsed/refractory HGBCL with secondary CNS lymphoma involvement. Patients who had active CNS involvement at the time of CAR T-cell therapy were identified retrospectively in a single-institution database of 101 consecutive HGBCL patients who received either tisagenlecleucel (tisa-cel) or axicabtagene ciloleucel (axi-cel) between 2017 and 2021. The best overall post-CAR T-cell therapy response was defined as the lowest disease burden measured at any time between post-CAR T-cell therapy and additional salvage therapies. Survival analysis was conducted using the Kaplan-Meier method. Overall, 19 HGBCL patients with active secondary CNS lymphoma (5 parenchymal, 9 leptomeningeal/CSF, 5 parenchymal and leptomeningeal) were identified, with a median age of 59 years (16-79 years) at the time of apheresis. All patients in the cohort received tisa-cel with a pre-conditioning regimen of fludarabine and cyclophosphamide. The median follow-up was 5.2 months (range, 0.8-36.8 months) from the date of CAR T-cell infusion. Ten patients had concurrent systemic involvement at the time of infusion. Seventeen patients received bridging therapy, of whom four received radiation therapy (patients/radiation field: 2/craniospinal, 1/whole brain, 1/skull base). Cytokine release syndrome occurred in 16 patients, among whom no grade 3 or higher event was reported. Neurotoxicity syndrome occurred in 9 patients, one of whom reported a grade 4 event. The best objective CNS response (complete response and partial response) rate post-CAR T infusion as per MRI was 58% (n=11): parenchymal (n=3, 60%), leptomeningeal/CSF (n=5, 56%), parenchymal and leptomeningeal (n=3, 60%). The median overall survival and progression-free survival from the start of CAR T-cell therapy were 12.7 months (95% CI: 5.4 months-not reached) and 3.9 months (95% CI: 0.93 months-not reached), respectively. Our data demonstrate that CD19-targeted CAR T-cell therapy is safe and feasible among HGBCL patients with secondary CNS lymphoma. Prospective cohort studies are required for validation.

P563: A RANDOMIZED, DOUBLE-BLIND, 2-ARM, MULTICENTER, PH3 STUDY OF VENETOCLAX &amp; ORAL AZACITIDINE VS. ORAL AZACITIDINE AS MAINTENANCE THERAPY FOR PTS WITH AML IN FIRST REMISSION AFTER INTENSIVE CHEMOTHERAPHY

Background: Acute myeloid leukemia (AML) is an aggressive, heterogenous hematologic malignancy with poor prognosis. For eligible patients, standard treatment includes intensive chemotherapy during induction, followed by consolidative chemotherapy or stem cell transplantation. Despite current therapies, the prevention of relapse is still a major therapeutic challenge and an unmet need for patients in remission. Venetoclax (Ven) is a selective, potent, oral BCL-2 inhibitor that induces apoptosis in AML cells. Ven in combination with Azacitidine (Aza) leads to prolonged overall survival (OS) and rapid, durable remissions in treatment-naïve AML patients ineligible for intensive chemotherapy. The QUAZAR AML-001 (NCT01757535) trial showed that the median OS in patients receiving maintenance oral Aza was superior to patients receiving placebo following upfront induction and consolidation; this benefit was also observed for patients who achieved either complete remission (CR) or CR with incomplete blood count recovery (CRi). VIALE-M is a randomized, double-blind, two-part study (NCT04102020) to determine the recommended Phase 3 dose (RPTD) of Ven in combination with oral Aza (CC-486) that can be safely administered as maintenance therapy, and to evaluate the safety and efficacy of Ven in combination with oral Aza + BSC compared to placebo and oral Aza + BSC in patients with AML who have achieved CR or CRi after intensive induction and consolidation. Aims: N/A Methods: The study is enrolling patients aged ≥18 years with newly diagnosed AML per WHO 2016 classification, with confirmed CR or CRi following intensive induction and consolidation therapies, from > 200 sites worldwide. Patients must have achieved first CR or CRi (after induction) ≤120 days of first dose of study drug or ≤75 days past last dose of last consolidation cycle, have intermediate or poor risk cytogenetics per NCCN 2016 categorization, ECOG ≤2, and no history of acute promyelocytic leukemia or active central nervous system involvement with AML. For the dose finding part of the study, patients will receive Ven QD for up to 24 cycles and oral Aza QD on D1-14 of each 28-day cycle for up to 24 cycles to determine the RPTD. For safety expansion, patients will receive Ven QD for up to 24 cycles and oral Aza QD on D1-14 of each cycle for up to 24 cycles at the RPTD. For the randomization part, patients will be randomized 1:1 to receive placebo or Ven QD at the RTPD and oral Aza QD on D1-14 of each cycle for 24 cycles. In all parts, treatment may discontinue due to relapse/unacceptable toxicity, or continue beyond 24 cycles under investigator’s discretion. For the randomization portion, the primary endpoint is relapse-free survival; secondary outcomes include OS, minimal residual disease conversion, and improvement in quality of life. Results: N/A Summary/Conclusion: N/A

CD19 CAR T-cells for pediatric relapsed acute lymphoblastic leukemia with active CNS involvement: a retrospective international study

Relapse of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) may occur in the central nervous system (CNS). Most clinical trials of CAR T-cell therapy excluded patients with active CNS leukemia, partially for concerns of neurotoxicity. Here, we report an international study of fifty-five children and adolescents who received CAR T-cell therapy for relapsed BCP-ALL with CNS involvement at the time of referral. All patients received bridging therapy, 16 still having active CNS disease at the time of lymphodepletion. Twelve patients received CD28-based CAR T-cells, 9 being subsequently treated with allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Forty-three patients received 4-1BB-based CAR T-cells. Cytokine-release syndrome (CRS) and neurotoxicity occurred in 65% and 38% of patients, respectively, more frequently following treatment with CD28-based CARs. Fifty-one of 54 evaluable patients (94%) achieved complete response following this therapy. Relapse occurred in 22 patients: 19/43 following 4-1BB-based CARs (12 CNS relapses), and 3/12 after CD28-based CARs with subsequent HSCT (no CNS relapse). Patients treated with tisagenlecleucel for an isolated CNS relapse had a high incidence of a subsequent CNS relapse (6 of 8). CAR T-cells were found to be effective in this cohort, though the risk of CNS relapse was not completely mitigated by this approach.

A Global Phase 2 Study of Valemetostat Tosylate (Valemetostat) in Patients with Relapsed or Refractory (R/R) Peripheral T-Cell Lymphoma (PTCL), Including R/R Adult T-Cell Leukemia/Lymphoma (ATL) - Valentine-PTCL01

A Global Phase 2 Study of Valemetostat Tosylate (Valemetostat) in Patients with Relapsed or Refractory (R/R) Peripheral T-Cell Lymphoma (PTCL), Including R/R Adult T-Cell Leukemia/Lymphoma (ATL) - Valentine-PTCL01

Results from a Phase 1 Study to Evaluate a Memory-Enriched CD19-Specific CAR T Cell Platform in Adult Patients with CD19+ B-Cell Non-Hodgkin Lymphoma (B-NHL)

Results from a Phase 1 Study to Evaluate a Memory-Enriched CD19-Specific CAR T Cell Platform in Adult Patients with CD19+ B-Cell Non-Hodgkin Lymphoma (B-NHL)