Introduction BMS-986353 is a CD19 CAR NEX-T cell therapy (Fig 1) that expresses the same CAR as lisocabtagene maraleucel, manufactured via minimally expanded manufacturing process optimized to improve scalability and global patient access. BMS-986353 is being studied in autoimmune indications. Objective Safety and preliminary efficacy of BMS-986353 in multiple severe refractory autoimmune diseases. Methods Two phase 1 studies are evaluating BMS-986353 in severe refractory systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and idiopathic inflammatory myopathy (IIM) (Breakfree-1, NCT05869955), and highly active relapsing multiple sclerosis (haRMS), progressive multiple sclerosis (PMS), and refractory myasthenia gravis (MG; Breakfree-2, NCT06220201).Immunosuppressive therapies (ISTs) were discontinued before lymphodepletion. Patients (pts) received a single BMS-986353 infusion at the recommended phase 2 dose (10 × 106 CAR+ T cells). Primary endpoint: safety. Results As of August 20, 2025, all treated pts (N = 83; SLE, 26; SSc, 25; IIM,14; haRMS, 6; PMS, 9; MG, 3) were safety evaluable. Median follow-up: 92 (range, 2−644) days.Pts had active inflammatory disease: SLE (recent British Isles Lupus Assessment Group Category A), SSc (progressive skin/lung), IIM (severe muscle/skin), haRMS (breakthrough activity), PMS (disability progression), and MG (class II-IV) and highly refractory disease with failed prior ISTs (median): SLE, 7; SSc, 3; IIM, 6; haRMS, 2; PMS, 2.All inflammatory AEs were brief and reversible (Table). Cytokine release syndrome occurred in 59.0% pts; most were grade 1 (Gr; Gr1, 48.2%; Gr2, 8.4%; Gr3, 1.2%), resolving in median 3 days. Immune effector cell-associated neurotoxicity syndrome occurred in 12.0% of pts; most were Gr 1 (Gr1, 7.2%; Gr2, 1.2%; Gr3, 3.6%), resolving in median 3 days. Cytopenias occurred in only 53% of patients and no prolonged high-grade cytopenias were observed.At 6 mo, pts showed median (range) improvement in: SLE, SLE Disease Activity Index 2000 by 10 points (18 to 0); SSc, modified Rodnan skin score (skin thickness) of 8.5 points (-20 to -2) and predicted forced vital capacity by 6.4% (2.9–14.0); and IIM, muscle manual test-8 score (muscle strength) of 27 points (17-42). 91.6% of pts across indications remained off ISTs.All pts achieved complete peripheral B-cell depletion and robust cellular expansion. Median time to B-cell repopulation was 113 days and were predominantly naive (Fig 2). Conclusion CD19 NEX-T CAR T cell therapy demonstrates a manageable safety profile with only transient and reversible CRS and ICANS in the largest dataset in non-malignant indications to date. Preliminary clinical efficacy, robust CAR T cell expansion, complete B-cell depletion, re-emergence of naive B cells, and IST-free responses suggest immune reset potential.

Introduction Vispacabtagene regedleucel (vispa-cel, formerly CB-010) is an allogeneic anti-CD19 CAR-T cell therapy manufactured from healthy donor T cells. The Cas9 chRDNA genome-editing technology is used for three genome edits: (1) KO of TRAC to reduce risk of GvHD, (2) insertion of a CD19-specific CAR (FMC63 scFv, 4-1BB), and (3) KO of PD-1 to prevent premature CAR-T cell exhaustion and potentially enhance antitumor activity. Methods ANTLER is a Phase 1 trial (NCT04637763) with 3+3 dose escalation and expansion to evaluate the safety and efficacy of vispa-cel in patients (pts) with r/r B-NHL and determine the RP2D. All pts received lymphodepletion of sequential cyclophosphamide (60 mg/kg/day x 2 days) then fludarabine (25 mg/m2/day x 5 days) followed by a single infusion of vispa-cel. Three vispa-cel doses (40 million [M], 80M, and 120M cells) were evaluated in dose escalation and dose expansion. 80M cells was selected as the RP2D. Subsequently, a 22-pt 2L LBCL confirmatory cohort prospectively evaluated donor-recipient matching ≥4 HLA alleles. A retrospective analysis was performed and identified LBCL pts treated with vispa-cel manufactured from a young donor (<30 yrs) and ≥2 matched HLA alleles, reported as the optimized cohort (N=35). Results As of Sep 2025, 84 pts received vispa-cel including 67 2L LBCL pts. The median age was 66 years (20-86). Of the 2L LBCL pts, 40 pts (60%) had an aaIPI score of ≥2. Vispa-cel was generally well tolerated; no GvHD was observed. The most common grade (Gr) ≥3 TEAEs were thrombocytopenia (60%), anemia (43%), and neutropenia (36%). By day 60, the neutropenia and thrombocytopenia recovery to Gr ≤2 was 95% and 86%, respectively. CRS occurred in 55% of pts (1% Gr ≥3). ICANS occurred in 14% of pts (5% Gr ≥3). In the 2L confirmatory cohort, ORR was 82% and CR rate was 64%. Median PFS and DOR were not reached (NR) with a 12-month PFS of 51%. Donor age (<30 yrs) and ≥2 matched HLA alleles were identified as covariates associated with improved PFS. In this optimized cohort, ORR was 86% and CR rate was 63%. The median PFS and DOR were NR with a 12-month PFS of 53%. Data from pts treated with vispa-cel from older donor (≥30 yrs) T cells and/or with <2 HLA alleles matched will also be reported.Peak expansion occurred days 7-10 with persistence of up to 30 days post-infusion. Endogenous T and NK cells recovered rapidly in peripheral blood (∼4 weeks) post-infusion, with B cell recovery in all pts by ∼300 days. Conclusions Vispa-cel is an allogeneic CAR-T cell therapy that results in deep and durable responses on par with approved autologous CAR-T cell therapies in 2L LBCL pts with a generally well-tolerated safety profile supporting outpatient administration. Improved PFS was observed in pts treated with vispa-cel manufactured from young donors and ≥2 matched HLA alleles. A randomized controlled pivotal trial in 2L LBCL pts who are ineligible for both autologous CAR-T and transplant is being planned.

7025 Background: CB-010 is an allogeneic anti-CD19 CAR-T cell therapy derived from healthy donor T cells using CRISPR hybrid RNA-DNA (chRDNA) technology. This technology is used to introduce 3 genome edits: (1) knockout of TRACto eliminate TCR expression and reduce risk of GvHD, (2) insertion of a CD19-specific CAR (scFv FMC63) into the TRAC locus, and (3) knockout of PD-1 to prevent premature CAR-T cell exhaustion and potentially enhance antitumor activity. Methods: ANTLER is a Phase 1 clinical trial (NCT04637763) with a 3+3 dose escalation phase and a dose expansion phase designed to evaluate safety, tolerability, and antitumor activity of CB-010 in patients (pts) with r/r B-NHL and determine RP2D. In dose escalation, pts must have received ≥2 prior lines of chemoimmunotherapy or had primary refractory disease to 1L therapy. Pts received lymphodepletion with sequential cyclophosphamide (60 mg/kg/day x 2 days) and fludarabine (25 mg/m2/day x 5 days) followed by a single CB-010 infusion. Results: 16 pts with r/r B-NHL (10 LBCL, 3 MCL, 2 FL with POD24, 1 MZL) received CB-010 at 40 x 106 CAR-T cells (dose level 1; N=8), 80 x 106 CAR-T cells (dose level 2; N=5), or 120 x 106 CAR-T cells (dose level 3; N=3) during dose escalation. Median age was 66 years (range 55-82). Median time since first diagnosis was 2.4 years (range 0.2-16.4). Median prior lines of therapy was 2 (range 1-8). CB-010 was generally well tolerated. No GvHD was seen. CRS occurred in 7/16 (44%) pts (no CRS grade ≥3). Median time to CRS onset was 3.5 days and median duration was 3 days. ICANS occurred in 4/16 (25%) pts (13% grade ≥3). Median time to ICANS onset was 7.5 days and median duration was 2 days. The 3 most common TEAEs grade ≥3 were thrombocytopenia (11/16; 69%), neutropenia (9/16; 56%), and anemia (8/16; 50%). One grade 3 infection (antecubital cellulitis) occurred unrelated to CB-010. After a single CB-010 infusion, 15/16 (94%) pts achieved an overall response, 11/16 (69%) achieved a CR, and 7/16 (44%) achieved a CR at ≥6 months. Median time to CR was 28 days. Among LBCL pts (n=10), 9 (90%) achieved an overall response, 7 (70%) achieved a CR, and 5 (50%) achieved a CR at ≥6 months. To date,2 pts have completed the 24-month study period with ongoing CR. Peak expansion of CB-010 occurred at days 7-10 post-infusion. T and NK cells recovered rapidly in peripheral blood (<3 weeks) after lymphodepletion, and B cells remained below the limit of quantification beyond 3 months, supporting specific targeting of B cells by CB-010. Conclusions: CB-010 showed a manageable safety profile and promising efficacy for treatment of pts with r/r B-NHL, including aggressive subtypes. The dose escalation phase is complete. Enrollment of 2L LBCL pts in dose expansion is ongoing. Initial dose expansion data at the CB-010 RP2D and translational data will be presented for the first time at the meeting. Clinical trial information: NCT04637763 .

Abstract Introduction Splenectomy is utilized in benign and malignant hematologic conditions such as immune thrombocytopenic purpura, autoimmune hemolytic anemia, thalassemia, hereditary spherocytosis, leukemia, lymphoma, and other lymphoproliferative disorders. However, it carries risks like perioperative infections, bleeding, venous thromboembolism (VTE), pulmonary and cardiac events. The introduction of targeted immunomodulatory therapies like Janus kinase inhibitors (2011), Bruton tyrosine kinase inhibitors (2013), and Chimeric antigen receptor T-cell therapy (2017), reduced the use of splenectomy. However, a subset of refractory patients still require it. While splenectomy outcomes are studied, no publicationscompare complication rates in relation to the adoption of immunotherapies. We hypothesize that fewer patients undergo splenectomy for hematologic indications, and that those who do have a splenectomy experience better perioperative outcomes due to improved disease control with immunotherapies. Evaluating these trends can inform modifiable risks. Methods This retrospective cohort study used the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database to review outcomes of splenectomy cases before and after the approval of immunotherapies for hematologic diseases. Group 1 (G1) is pre-immunotherapy data from 1/1/2012-12/31/2014 and Group 2 (G2) is post-immunotherapy data from 1/1/2021-12/31/2023. Adults (age ≥18 years) with a primary diagnosis of a benign or malignant hematologic condition were included. Those with age <18, trauma or non-hematologic primary indications, secondary hematologic diagnoses, preoperative sepsis, and concurrent major surgeries were excluded. Diagnoses were stratified as leukemia, lymphoma, or benign autoimmune conditions. Complication rates between G1 and G2 were compared using chi-square or Fisher’s exact tests. Our primary outcomes are number of splenectomies performed and 30-day mortality. Secondary outcomes are complications categorized as infectious (septic shock, sepsis, urinary tract infection, superficial/deep/organ space surgical site infection), bleeding, VTE (stroke, pulmonary embolism, deep vein thrombosis), pulmonary (pneumonia, intubation/ventilation), cardiac (arrest, myocardial infarction), and return to operating room (OR). Results The cohort included 1551 splenectomy cases (G1: 1067; G2: 484). G1 had 288 malignant (55 leukemia; 233 lymphoma) and 779 autoimmune cases. G2 had 141 malignant (30 leukemia; 111 lymphoma) and 343 autoimmune cases. From G1 to G2, splenectomies decreased by 51.04% for malignancy (leukemia=45.45%; lymphoma=52.36%) and by 55.97% for benign conditions. Infection rates in leukemia cases increased significantly 17.6% (p=0.03) from G1 to G2, while there was no change in bleeding (p=0.09), VTE (p=0.61), pulmonary (p=0.94), or cardiac (p=0.65) events. Lymphoma cases had a significant 10.7% (p=0.04) decrease in bleeding from G1 to G2, while other complication rates were unchanged: infectious (p=0.98), VTE (p=0.35), pulmonary (p=0.11), cardiac (p=0.55). Combined leukemia and lymphoma cases showed 12.2% (p=0.01) reduction in bleeding. Autoimmune cases showed stable complication rates: infectious (p=0.34), bleeding (p=0.09), VTE (p=0.69), pulmonary (p=0.93), and cardiac (p=0.19)). No significant change in rate of return to OR (p= 0.99, 0.18, 0.33) or 30-day mortality (p= 0.66, 0.72, 0.64) was seen in the leukemia, lymphoma, or autoimmune subgroups, respectively. Conclusions Our analysis showed splenectomy rates for hematologic conditions significantly declined over time in G2 due to the FDA approval of immunotherapies. Perioperative bleeding rates decreased for lymphoma cases, while infectious complications increased in leukemia cases. No significant changes were observed in other complications or mortality rates. Although our findings cannot confirm causality, these trends may reflect improved disease control with immunotherapy. We acknowledge the limitation of NSQIP in linking therapy use to individual patient outcomes. G1 and G2 time periods corresponding to therapy availability served as proxy. Nevertheless, findings highlight notable decline in splenectomies for hematologic diseases and suggest immunotherapy may contribute to improved outcomes for those still requiring splenectomy. Future studies focused on patient-level and agent-specific data may better elucidate risk stratification and clinical optimization strategies.

Background: Chimeric antigen receptor (CAR) T-cell therapies have transformed the therapeutic landscape for relapsed or refractory B-cell malignancies in heavily pretreated populations. Six CAR T-cell products have been approved by the U.S. Food and Drug Administration (FDA) to date: tisagenlecleucel (Tisa-cel), axicabtagene ciloleucel (Axi-cel), brexucabtagene autoleucel (Brexu-cel), lisocabtagene maraleucel (Liso-cel), ciltacabtagene autoleucel (Cilta-cel), and idecabtagene vicleucel (Ida-cel), for pediatric and adult B-cell acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), multiple myeloma, follicular lymphoma and mantle cell lymphoma. While clinical trials have established the efficacy and safety of CAR T-cell therapies, long-term real-world data on secondary malignancies and recurrence/relapse patterns are limited. In January 2024, the FDA highlighted the serious risk of T-cell malignancies in the Black Box warning of the products. We conducted a comprehensive FAERS-based analysis to characterize secondary malignancies, recurrent disease, and unique neoplasms reported after CAR T-cell therapy, aiming to identify product-specific patterns that may inform surveillance strategies, regulatory oversight, and risk mitigation. Methods: A retrospective pharmacovigilance analysis was performed using FAERS reports from initial product approval through Q1 2025 for Tisa-cel, Axi-cel, Brexu-cel, and Liso-cel. Data was filtered to capture only post-CAR T-cell events and reports listing “Neoplasms Benign, Malignant and Unspecified” after CAR T-cell therapy were included. Demographics, malignancy subtypes, and serious outcomes were descriptively analyzed. Results: Of 13,685 adverse events reported in the FAERS database, 2,722 (19.9%) were neoplasm-related, including 1,226 linked to Axi-cel (45.1%), 1,169 to Tisa-cel (42.9%), 258 to Brexu-cel (9.5%), and 69 to Liso-cel (2.5%). Males accounted for 55.3% of reports, females 30.5%, and 14.1% were unspecified. The majority of cases occurred in adults aged 18–85, with Tisa-cel being the only product with meaningful pediatric representation. Estimated mean ages were 52.8 years (Axi-cel), 60.0 years (Brexu-cel), 60.7 years (Liso-cel), and 40.6 years (Tisa-cel). Event patterns differed by product.Tisa-cel: Malignant neoplasm progression (n=444, 38.0%), recurrent ALL (n=310, 26.5%), DLBCL (n=239, 20.4%), relapsed/refractory DLBCL (n=201, 17.2%), second primary malignancy (SPM) (n=114, 9.8%), ALL (n=84, 7.2%), and myelodysplastic syndrome (MDS) (n=56, 4.8%).Axi-cel: MDS (n=235, 19.2%), DLBCL (n=234, 19.1%), acute myeloid leukemia (AML) (n=91, 7.4%), recurrent DLBCL (n=62, 5.1%), squamous cell carcinoma of the skin (n=60, 4.9%), lymphoma (n=58, 4.7%), and B-cell lymphoma (n=37, 3.0%).Brexu-cel: MDS (n=41, 15.9%), squamous cell carcinoma of the skin (n=35, 13.6%), basal cell carcinoma (n=30, 11.6%), recurrent mantle cell lymphoma (n=29, 11.2%), mantle cell lymphoma (n=22, 8.5%), AML (n=12, 4.7%), and recurrent ALL (n=12, 4.7%).Liso-cel: Malignant neoplasm progression (n=18, 26.1%), MDS (n=11, 15.9%), tumor pseudoprogression (n=6, 8.7%), DLBCL (n=5, 7.2%), AML (n=5, 7.2%), peripheral T-cell lymphoma, unspecified (n=4, 5.8%), and basal cell carcinoma (n=3, 4.3%). Rare and unique malignancies (≤1.5% per product) were identified across therapies. Tisa-cel was linked to single cases of glioblastoma multiforme, sarcoma, pharyngeal cancer, and pancreatic adenocarcinoma.Axi-celwas associated with 4 cases of Kaposi's sarcoma and single cases of lung carcinoid tumor, leiomyosarcoma, neuroendocrine carcinoma of the skin, and ocular neoplasm. Brexu-cel was linked to alveolar rhabdomyosarcoma (2 cases) and single cases of laryngeal squamous cell carcinoma, glioneuronal tumor, and leukemia cutis. Liso-cel was associated with angiocentric lymphoma, gastric cancer, pancreatic carcinoma, and metastatic adenocarcinoma. Mortality was reported in 41.4% of Tisa-cel, 40.2% of Axi-cel, 36.2% of Liso-cel, and 23.3% of Brexu-cel cases, while hospitalizations ranged from 11.6% to 24.5%, and permanent disability occurred in up to 2.1% of cases. Conclusion: Our FAERS analysis reveals distinct patterns of secondary primary malignancies and relapsed diseases following CAR T-cell therapy in real-world settings. The identification of myelodysplastic syndromes, cutaneous neoplasms, and rare T-cell or solid tumors highlights the need for vigilant post-therapy surveillance.

Abstract: Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, 4-1BB chimeric antigen receptor (CAR) T-cell product approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). We present the OUTREACH primary analysis, evaluating the safety and efficacy of outpatient monitoring after liso-cel treatment at community sites in the United States. Adults with R/R LBCL after ≥2 prior lines of therapy received liso-cel. Outpatient vs inpatient monitoring was per investigator discretion. The primary end points were incidences of grade ≥3 cytokine release syndrome (CRS), neurological events (NEs), prolonged cytopenia, and infections. Efficacy was a secondary end point. Eighty-two patients received liso-cel (outpatient monitored, 70%; inpatient monitored, 30%). The median follow-up was 10.6 months (range, 1.0-24.5). In outpatients and inpatients, grade ≥3 CRS occurred in 0% and 0%, NEs in 12% and 4%, infections in 12% and 8%, and prolonged cytopenia in 33% and 32%, respectively. Among outpatients, 25% were never hospitalized after infusion, and 32% were hospitalized ≤72 hours after the day of infusion; the median time to hospitalization was 5.0 days (range, 2-310). The median initial hospitalization duration after liso-cel was 6.0 days (range, 1-28) for outpatients and 15.0 days (range, 3-31) for inpatients. Objective response rate was 80%, complete response rate was 54%, and the median duration of response was 14.75 months (95% confidence interval, 5.0 to not reached). OUTREACH is, to our knowledge, the first and largest study to prospectively assess CAR T-cell therapy with outpatient monitoring in community-based medical centers. Liso-cel demonstrated meaningful efficacy with favorable safety in patients with R/R LBCL. Data support the feasibility of liso-cel administration at community sites with outpatient monitoring. This trial was registered at www.ClinicalTrials.gov as #NCT03744676.

Introduction: Vitamin B12 and folate deficiencies are common etiologies of macrocytic anemia, mostly encountered with chronic alcohol use, and uncommon for healthy individuals with unremarkable medical history. The pathogenesis of the resulting anemia is described by two possible mechanisms: either ineffective erythropoiesis, driven by vitamin B12 deficiency, or more rarely, via nonimmune intramedullary hemolysis. We present a very rare case of severe vitamin B12 deficiency leading to nonimmune intramedullary hemolysis and highlight the diagnostic evaluation and tailored management. Case Presentation: A 49-year-old female with history of depression, chronic alcohol use and chronic nitrous oxide inhalation, presented with lethargy, hypotension and fevers with visual hallucinations, and was subsequently admitted for acute encephalopathy. Findings on physical examination included diminished proprioception and diminished sensation to fine touch, pinprick and vibration of the lower extremities with distal hyperreflexia of the patellar and Achilles tendon reflexes bilaterally. Lab work was notable for leukopenia and macrocytic anemia with a significant drop in hemoglobin to 9.6 from a baseline of 13.2 within 5 months and MCV of 103. Extensive investigation of encephalopathy was undertaken, of which we note infectious workup, prompted by the septic presentation, which showed Staphylococcus aureus bacteremia. On the other hand, the patient's anemia was concurrently investigated. Hemolysis workup was positive (LDH 394 U/L; direct bilirubin 1.6 mg/dL; haptoglobin<8 mg/dL; reticulocyte count 6.1%); however, schistocytes were low on peripheral smear (Figures 1 and 2). As such, nonimmune intramedullary hemolysis was suspected. Further anemia workup revealed severe vitamin B12 deficiency (75 ng/L), consistent with the physical exam findings, but normal folate levels. Of note, methylmalonic acid levels and homocysteine were also elevated (respectively 4.39 nmol/mL, and 142 umol/L). The constellation of the clinical presentation and all the laboratory findings confirmed a nonimmune intramedullary hemolytic process, elicited by vitamin B12 deficiency. This deficiency was thought to be multifactorial, mainly caused by chronic alcohol abuse, in addition to persistent nitrous oxide use. It was also suggested that hemolysis could be a consequence of drug-induced carboxyhemoglobinemia (level was 9.4%), whereby carboxyhemoglobin can form during the binding and release of nitric oxide from hemoglobin. Treatment was focused on replacing vitamin B12 with 1000 mcg daily intramuscular injections for 7 days, then weekly thereafter for 4 weeks, followed by monthly injections. Improvement of hemoglobin to 11.1 with improvement of neurologic exam findings were noted prior to discharge. Conclusion: Nonimmune hemolytic anemia must be included in the differential diagnosis when evaluating patients with anemia concurrent with vitamin B12 deficiency, mostly encountered with chronic alcohol use. Vitamin B12 supplementation remains the key treatment to correct this rare, but serious outcome of vitamin B12 deficiency.

PURPOSE Gilteritinib is a type 1 FLT3 inhibitor active as monotherapy for relapsed or refractory FLT3-mutated AML. We investigated the safety, tolerability, and efficacy of gilteritinib incorporated into intensive induction and consolidation chemotherapy, and as maintenance therapy for adult patients with newly diagnosed, non–favorable-risk AML. METHODS In this phase IB study (2215-CL-0103; ClinicalTrials.gov identifier: NCT02236013 ), 103 participants were screened and 80 were allocated to treatment. The study was divided into four parts: dose escalation, dose expansion, investigation of alternate anthracycline and gilteritinib schedule, and continuous gilteritinib during consolidation. RESULTS After dose escalation, 120 mg gilteritinib once daily was chosen for further study. There were 58 participants evaluable for response at this dose, 36 of whom harbored FLT3 mutations. For participants with FLT3-mutated AML, the composite complete response (CRc) rate was 89% (83% were conventional complete responses), all achieved after a single induction cycle. The median overall survival time was 46.1 months. Gilteritinib was well-tolerated in this context although the median time to count recovery during induction was approximately 40 days. Longer time-to-count recovery was associated with higher trough levels of gilteritinib, which, in turn, were associated with azole use. The recommended regimen is gilteritinib at a dose of 120 mg once daily from days 4 to 17 or 8 to 21 of a 7 + 3 induction with either idarubicin or daunorubicin and from day 1 continuously with high-dose cytarabine consolidation. Maintenance therapy with gilteritinib was well-tolerated. CONCLUSION These results demonstrated the safety and tolerability of gilteritinib incorporated into an induction and consolidation chemotherapy regimen, and as single-agent maintenance therapy for patients with newly diagnosed FLT3-mutant AML. The data herein provide an important framework for the design of randomized trials comparing gilteritinib with other FLT3 inhibitors.

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare condition characterized by hyperactivation of macrophages and T lymphocytes. While HLH is primarily inherited in a recessive manner among children, in adults, it is more commonly associated with underlying infections, autoimmune disorders, and malignancies. However, the association between HLH and Babesia infection remains exceptionally uncommon, with only a few reported cases in the medical literature. In this report, we present a unique case of HLH in the context of babesiosis, shedding light on the crucial clinical features and risk factors. By raising awareness of this rare differential diagnosis, we aim to contribute to early recognition and timely treatment, potentially reducing mortality from this treatable illness. Case Presentation: A 77-year-old male with history of deep vein thrombosis (DVT), Parkinson's disease, and lumbar radiculopathy on chronic prednisone, presented for progressive generalized weakness, leg pain, and confusion. Initial labs showed normocytic anemia, thrombocytopenia, low fibrinogen and elevated INR and liver enzymes (Table 1). Multiple ischemic signs were noted including acute on chronic DVT, as well as findings of marked splenomegaly with wedge infarcts and periportal lymphadenopathy on abdominal ultrasound and CT (Figure 1). The underlying etiology of these findings was unclear and broad differential work up was pursued. Given the anemia and thrombocytopenia on presentation, the patient received multiple blood products including platelets, red blood cells, fresh frozen plasma and cryoprecipitate, in addition to vitamin K. No schistocytes were seen peripherally, and DIC/TTP workup was negative. Multidisciplinary teams evaluated the risk versus benefit of anticoagulation with heparin drip considering evidence of multi-organ ischemic damage. It was briefly initiated, but later held due to persistent thrombocytopenia and abnormal liver function. Further work up only revealed hemolysis with a low haptoglobin and elevated LDH (Table 1). However, the follow up Coombs test was negative, ruling out immune mediated hemolysis. While symptomatic management continued, blood parasite screen obtained on admission indicated Babesia microti infection. Upon repeat testing, no evidence of babesia was identified on labs or blood smear. However, this finding was skewed by the multiple transfusions the patient received. Unfortunately, the clinical course rapidly declined, and the patient's family elected a transition to comfort care measures whereby the patient expired within two days of presentation. Remaining work up resulted posthumously, with CD25 levels elevated at 38,354.0 pg/mL. Coupled with the previously established splenomegaly, pancytopenia, hypertriglyceridemia, and elevated ferritin, these findings indicate a diagnosis of HLH, likely triggered by Babesia microti infection. Conclusion: HLH should be strongly suspected in patients from endemic regions, especially with additional risk factors such as age, genetics, and immunosuppression. Tools such as the HScore and the HLH-2004 criteria can aid in further patient risk stratification. Urgent treatment with steroids and addressing underlying babesiosis with atovaquone, azithromycin, and potentially red blood cell exchange transfusion, remains crucial for preventing decompensation and improving outcomes.

INTRODUCTION: Luxeptinib (CG-806; LUX) is an orally active noncovalent kinase inhibitor of Bruton's tyrosine kinase (BTK), wild type and mutant forms of Fms-like tyrosine kinase 3 (FLT3) (including the internal tandem duplicates (ITD), tyrosine kinase domain (TKD), and F691L mutant forms), and growth receptors like KIT, CSF1R, PDGFRα, and TRKs. In prior studies, LUX has been shown to suppress aberrant proliferative signaling in B cell malignancies and acute myeloid leukemia (AML) via regulation of BTK, LYN, SYK, AKT, ERK, and MAPK. LUX is cytotoxic to primary AML cells insensitive to other FLT3 inhibitors and to malignant B-cells insensitive to ibrutinib, at pM and nM concentrations, respectively. AIMS: The primary objectives of these studies are to assess the safety, tolerability, and pharmacokinetics (PK) of LUX and determine recommended phase 2 doses for relapsed or refractory (R/R) AML and B cell malignancy patients. METHODS: In two studies (NCT04477291; NCT03893682), LUX (original formulation, G1) was administered continuously as oral capsules BID in 28-day cycles of ascending cohorts (relapsed or refractory de novo, secondary, or therapy-related AML or higher risk myelodysplastic syndrome (MDS), and relapsed and refractory for B cell lymphoma and chronic lymphocytic/small lymphocytic leukemia). A novel generation 3 (G3) formulation of LUX designed to increase bioavailability was tested at a single-dose (sub-study) for relative bioavailability (RBA), followed by continuous dosing in subsequent R/R AML patients. RESULTS: In the B-cell study (as of 15 th May 2023), LUX has been administered to 36 patients at dose levels from 150 mg to 900 mg BID in patients with a median of 3 lines of prior treatment, with 47.2% having received a BTK-inhibitor. Only one (2.8%) patient had a DLT of hypertension and 14 (38.9%) experienced at least one drug related ≥Grade3 treatment emergent adverse event (TEAE). Two patients (900 mg) are currently on study with no DLT and no ≥Grade 3 related TEAEs. A Follicular lymphoma patient is at cycle 28, and achieved a best response as partial response (PR) with a decrease in lesion size of 76.2%; an SLL patient is at cycle 13, and achieved stable disease (SD) showing a decrease in lesion size of 43.1% (Figure A). The overall best response achieved among the 17 patients who have been on treatment for more than 12 weeks are stable disease (SD) (n=11), partial response (PR) (n=3), minor response (n=2) and complete response (CR) (n=1). As of 5 th June 2023, in the AML trial, a total of 40 patients (16 (40%) FLT3-ITD, 21 (52.5%) FLT3-WT, 2 (5.0%) FLT3-TKD, and 1 (2.5%) unknown mutations) with a median of 3 prior treatments (range, 1 - 10) have been treated with LUX G1 formulation at dose levels from 450 mg - 900 mg BID (n=34) or with 50 mg BID of G3 formulation (n=6). Four (10%) experienced drug related SAE and 7 (17.5%) had a drug related grade ≥3 TEAEs. The most common related TEAEs were lymphocyte count decrease, platelet count decrease, and anemia (n=2; 5% patients each). One (2.5%) patient at 450 mg dose, reported complete remission without minimum residual disease (CRmrd) and remained on study for 56 weeks. In the RBA sub-study, G3 (50 mg) produced comparable exposures to G1 (450-900 mg range) (Figure B) and was, therefore, selected as the starting dose for use in the R/R AML study. Six patients were treated with a continuous dosing of 50 mg BID G3; with plasma levels of 274 ng/mL and 195 ng/mL LUX observed by the end of C1D15 and C1D22 respectively. No drug related Grade ≥3 TEAEs or DLTs were observed in 50 mg BID G3 LUX treated patients; with no new safety signals observed for the G3 formulation. Based on these findings and expected exposures for higher dose levels, the cohort safety review committee has approved escalation of G3 dosing to 200 mg BID at which dosing is ongoing. CONCLUSIONS: LUX has a favorable safety profile in patients at all tested dose levels, for multiple cycles, for both studies. Antitumor activity was observed in a heavily pretreated relapsed AML patient and in multiple B-NHL subtypes and CLL/SLL patients including several with prior ibrutinib exposure. Continuous dosing of patients with R/R AML and Higher-Risk MDS with the G3 formulation is ongoing; with updated clinical data (200 mg dose level) to be presented at the meeting.

Gray zone lymphoma is a very rare liquid malignancy that possesses intersecting features between primary mediastinal B-cell lymphoma and classic Hodgkin Lymphoma. In the case presented and accompanying literature review, we will discuss a patient with a chief complaint of shortness of breath and was found to have a mediastinal mass with biopsy consistent with mediastinal gray zone lymphoma. Herein, we explore the historical and recently updated diagnostic criteria of gray zone lymphoma from 2022 as well as the pathophysiology as it pertains to gene expression, while also reviewing the histological findings, epidemiology and treatment modalities.

S514stem cell (HSC) mobilization, neutrophils and platelet engraftment; as well as risk of post-transplant infections.Objective: The present study aims to investigate effect of daratumumab exposure on the HSC collected, neutrophil and platelet engraftment, in addition to the risk of infections post autologous stem cell transplant (ASCT) in patients with MM receiving upfront transplant.Design: This is a single center, retrospective study of MM patients who underwent ASCT between January 2020 and March 2023 at the American University of Beirut Medical Center in Lebanon, and had received proteasome inhibitor, in combination with an immunomodulatory agent, and dexamethasone, with (daratumumab-based) or without addition of daratumumab (triplet group).Outcome Measures: Total stem cells collected, days to neutrophil and platelet engraftment; number and type of post ASCT infection.Data related to patient and disease characteristics were collected, treatment lines, treatment regimens, number of stem cells collected, use of plerixafor, total melphalan dose among others.Results: 56 patients were identified; 24 (42.85%) received daratumumab-based regimen (as quadruplets), as pre-transplant induction.Median age for daratumumab-based group was 54.8, around 70% being older than 50 years.8 patients (33.3%) in daratumumab-based group required addition of plerixafor (for failed or inadequate mobilization), compared to 10 patients (31.3%) in triplet group (p-value 0.039).Median stem cells collected was 3x10 6 /kg in both groups (P-value 0.8).Median days to neutrophil engraftment was 12 days in daratumumab-based group and 11 days in triplet group (P-value 0.07), while median to platelet engraftment was 17 and 18 days respectively (P-value 0.7).Regarding post-transplant infections, 7 patients (29%) had infection within 60 days post-transplant in daratumumab-based group compared to 14 patients (42.85%) in triplet group without statistical significance (P-value 0.18).Conclusions: The use of daratumumab does not seem to significantly affect yield of HSC mobilization, neutrophil or platelet engraftment, with a non-significant decreased risk of posttransplant infections for patients with NDMM.

Background: Liso-cel is an autologous, CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8+ and CD4+ CAR+ T cells that has shown clinical efficacy in patients with R/R LBCL. In TRANSCEND NHL 001 (NCT02631044), patients with third-line or later LBCL treated with liso-cel at academic centers had early, sustained, and clinically meaningful improvements in health-related quality of life (HRQOL) and symptoms that correlated with antitumor activity (Patrick et al. Blood Adv 2021). Here we present patient-reported outcome (PRO)/HRQOL results from the OUTREACH study (NCT03744676), which enrolled patients with R/R LBCL across outpatient and inpatient settings at community sites in the United States. We aimed to assess whether HRQOL among patients treated with liso-cel would, at a minimum, be maintained over the course of the study. Methods: Adults with R/R PET-positive LBCL after ≥ 2 lines of therapy and ECOG PS ≤ 1 were enrolled at community (nontertiary care) sites. Patients with mild to moderate organ function (LVEF ≥ 40%; serum CrCl > 30 mL/min), secondary CNS lymphoma, and prior autologous HSCT were eligible. After leukapheresis and lymphodepleting chemotherapy, patients received liso-cel at a target dose of 100 × 106 CAR+ T cells. Patients completed European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (EORTC QLQ-C30) and EQ-5D-5L (health utility index [HUI] and visual analog scale [VAS]) before treatment (≤ 7 days before lymphodepletion; baseline); before infusion on day of liso-cel infusion (Day 1); and on Days 29, 60, 90, 180, 270, 365, 545, and 730/end of study; and at disease progression. The primary HRQOL domains of interest were the EORTC QLQ-C30 global health status/QOL, physical functioning, role functioning, cognitive functioning, fatigue, and pain. A linear mixed model for repeated measures analysis was performed to assess the least squares (LS) mean change from baseline for visits with ≥ 10 patients. Within-patient meaningful change from baseline was calculated using responder definitions (in points): 5-30 for EORTC QLQ-C30 (based on thresholds set by Cocks and Buchanan [ISOQOL 2015]), 0.08 for EQ-5D-5L HUI, and 7 for EQ-5D-5L VAS. Within-group meaningful change from baseline was defined by the minimally important differences set by Cocks et al (Eur J Cancer 2012). Results: Among the 79 liso-cel‒treated patients, completion rates for the HRQOL assessment were high (≥ 70%) across most visits for all measures. For EORTC QLQ-C30, mean baseline scores were meaningfully worse than in a general noncancer population (difference of ≥ 10 points) for role functioning and fatigue. The overall LS mean change from baseline showed significant and meaningful improvement for the primary domains of EORTC QLQ-C30 global health status/QOL, fatigue, and pain, as well as the EQ-5D-5L VAS (Table). Cognitive functioning and HUI were comparable with the general population at baseline and were maintained over time after liso-cel infusion. In individual assessments across visits, most patients (57%‒100%) experienced either meaningful improvement or no meaningful improvement or deterioration for all domains, and more than half achieved meaningful improvement in global health status/QOL (32.9%‒59.5%), fatigue (27.1%‒65.5%), pain (38.6%‒66.7%), and EQ-5D-5L VAS (27.8%‒71.4%) at most time points, with lowest percentages observed on Day 1. Results comparing PRO/HRQOL data for patients treated in an outpatient versus inpatient setting will be reported in the presentation. Conclusions: In the OUTREACH study, patients had impaired HRQOL at baseline compared with the general noncancer population. HRQOL was either improved or maintained from baseline in most patients with R/R LBCL who received liso-cel as third-line or later treatment in OUTREACH, with the greatest improvements observed in the Global health status/QOL, fatigue, and pain domains. These findings show the importance of PRO/HRQOL assessments as supportive measurements of treatment outcome in patients with R/R LBCL, and they lend support to the use of liso-cel in treating patients with R/R LBCL at community centers and in the outpatient setting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Gilteritinib plus induction and consolidation chemotherapy was well tolerated and resulted in CR, FLT3-ITD clearance, and long-term survival in patients with ND FLT3 AML, supporting ongoing randomized trials testing this approach against current standards.

Background: CAR T cell therapies are generally administered in an inpt setting owing to concerns of AE management. Infusion and monitoring of pts who receive CAR T cell therapy at nonuniversity medical centers (NMC) and in outpt settings have not been studied specifically. Liso-cel is an autologous CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells. In TRANSCEND NHL 001 (NCT02631044) in pts with third- or later-line LBCL, liso-cel treatment showed an ORR of 73% (CR rate, 53%), with grade ≥ 3 cytokine release syndrome (CRS) in 2%, and grade ≥ 3 neurological events (NE) in 10% of pts (Abramson et al. Lancet 2020). We report outcomes of liso-cel in pts with R/R LBCL across inpt and outpt settings at NMCs in the United States treated in the OUTREACH study (NCT03744676).

INTRODUCTION: Luxeptinib (CG-806) is an orally active, non-covalent inhibitor of BTK and FLT3 kinases. It suppresses BCR signaling pathways (LYN, SYK, BTK, AKT, ERK), MAP kinases, and other oncogenic pathways in cell lines and primary leukemic cells. Luxeptinib kills malignant B-cells insensitive to ibrutinib or venetoclax with concentrations in the nanomolar range and shows enhanced activity in combination with venetoclax. Luxeptinib is currently being evaluated in a Phase 1a/b trial in patients with relapsed or refractory B-cell malignancies (NCT03893682). AIMS: Primary objectives are to assess the safety and tolerability of luxeptinib and determine the recommended phase 2 dose for future clinical trials in patients with R/R CLL/SLL or B-NHL. Secondary objectives include elucidation of pharmacokinetics (PK) and evidence of antitumor activity. METHODS: Luxeptinib is administered continuously as oral capsules BID in 28-day cycles, in ascending cohorts of 3 patients. Treatment emergent adverse events (TEAEs) and tumor responses are evaluated per disease specific guidelines. RESULTS: As of June 30, 2022, a total of 35 patients (median age 62 years, 23 male and 12 female, 16 CLL/SLL, 7 follicular lymphoma (FL), 1 Richter's transformation lymphoma, 1 marginal zone lymphoma (MZL), 2 Waldenstrom macroglobulinemia (WM), 4 mantle cell lymphoma (MCL), 4 diffuse large B cell lymphoma (DLBCL)) with a median of 3 prior systemic regimens (range 1 - 13) have been treated with luxeptinib at doses of 150 mg (n=1), 300 mg (n=1), 450 mg (n=10), 600 mg (n=7), 750 mg (n=9), and 900 mg (n=7). Drug related grade ≥ 3 TEAEs include decreased neutrophil count (n=6, 17.1%), decreased white blood cell count, decreased platelet count, diarrhea, anemia, and leukocytosis (n=2, 5.7% each), and increased ALT, headache, neutropenia, hyperhidrosis, hypertension, and neutropenic sepsis (n=1, 2.9% each). One patient experienced a new onset grade 2 hypertension during screening (prior to treatment with luxeptinib) that increased to grade 4 after beginning luxeptinib treatment at 750 mg BID for 5 days. No drug-related hypertension was observed in any other patient treated to date and retrospective analysis of data and patient history suggest the hypertension was not attributable to luxeptinib. PK analysis shows 750 mg BID cohorts have plasma level of luxeptinib > 1µM average steady-state (Cmin) that is sustained over multiple cycles. Response evaluations were available for 20 patients who had at least one imaging study or IgM measurement (WM patients) after starting treatment. Thirteen (3 SLL, 3 FL, 2 CLL, 1 WM, 2 MCL, and 2 DLBCL) out of 20 evaluable patients had various reductions of lesion size or IgM measurements compared to baseline, demonstrating anti-tumor activity. FDG PET-CT scans in 3 FL patients, each treated with at least 2 prior regimens, experienced tumor growth after starting luxeptinib, but demonstrated reductions in lesion size below both peak and pre-treatment baseline tumor sizes after increasing their luxeptinib dose to 600 mg BID. Similarly, additional patients with other NHL (WM, MCL & DLBCL) and SLL/CLL with prior multiple regimens including Ibrutinib, experienced tumor reduction below baseline. Doses levels up to and including 900 mg BID were cleared without additional DLTs. Because increasing the dose to 900 mg BID did not result in substantially greater PK exposure, a novel formulation (G3) of luxeptinib was developed to increase bioavailability. In pre-clinical animal studies this demonstrated 6-30-fold greater exposure compared to the original formulation. Single dose testing in patients produced more rapid and greater per mg exposures than the original formulation. The G3 formulation had 200 times greater exposure/mg at 2 hr when comparing single doses of G3 at 50 mg to 150 mg of the original formulation. Computational modeling of single dose PK data is in progress to inform the potential for continuous dosing with G3 to reduce pill burden and deliver greater exposure and anti-tumor activity. CONCLUSIONS: Luxeptinib has a favorable safety profile in patients treated with 150 mg to 900 mg BID over multiple cycles. Antitumor activity was observed in multiple B-NHL subtypes and CLL/SLL patients post ibrutinib relapse. Enrollment of additional patients at dose level 6 (900 mg) is ongoing while the more bioavailable G3 formulation is being explored. Updated clinical data will be presented at the meeting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

RARA-positive AML is a novel genomically-defined subset with an actionable target for treatment with tamibarotene, an oral and selective RARα agonist (McKeown, Cancer Discovery 2017). Approximately 30% of non-APL AML patients are RARA-positive based on overexpression of the RARA gene in peripheral blood blasts as determined by an RT-PCR based assay (de Botton, ESH 2019). In patients with newly diagnosed (ND) AML ineligible for standard induction chemotherapy, tamibarotene/azacitidine led to a CR/CRi rate of 61% in RARA-positive patients with a rapid onset of response. The combination was well-tolerated with no increase in myelosuppression compared to azacitidine (aza) alone (de Botton, ASH 2020). Responses were observed irrespective of mutations or cytogenetic risk. Approximately one-third of ND AML patients ineligible for standard induction therapy do not respond to venetoclax (ven) and nearly all eventually relapse (DiNardo, NEJM 2020). Translational data suggest that RARA-positive patients are enriched for monocytic features based on a positive Monocytic Expression Score (MES) that may be associated with ven resistance (Fiore, ASH 2020), suggesting that the blood-based RARA biomarker test selects for patients who may respond to tamibarotene and who may also be less likely to respond to ven/aza alone. SELECT-AML-1 (NCT04905407) is a Phase 2, open-label, multi-center study in the US and France comparing the activity of tamibarotene/ven/aza to ven/aza in treatment-naive RARA-positive ND AML patients ineligible for standard induction therapy. The 3-part study includes a safety lead-in of the tamibarotene/ven/aza combination, a randomized efficacy study versus ven/aza, and a salvage arm for ven/aza only patients with primary endpoints of safety, CR/CRi rate, and overall response rate, respectively. Following the safety lead-in, patients will be randomized 1:1 to receive tamibarotene/ven/aza or ven/aza. In the salvage arm, patients randomized to ven/aza only who experience progressive disease, treatment failure, or relapse, will have tamibarotene added to their ven/aza regimen. Patients currently enrolled in the safety lead-in are treated with starting doses of aza at 75 mg/m2 IV/SC daily on Days 1-7, ven on Days 1-28 per the ven USPI/SMPC, followed by tamibarotene at 6 mg twice per day PO on Days 8-28 of each 28-day cycle. Enrollment is ongoing. As of 22 June 2022, six patients have enrolled to date, including four who are response-evaluable. Baseline characteristics of the response-evaluable patients include 75% male; median age 57 (55-74); median bone marrow blasts 55% (39-100%); cytogenetically normal (n=2), inversion 16 (n=1), del 5q and -7 (n=1); and molecular genetic testing normal (n=3), mutations of IDH2, BCOR, SRSF2, CSF3R, RUNX1 (n=1). The MES was high in 3 of 4 (75%) response evaluable patients consistent with a prior report in RARA-positive AML (Fiore, ASH 2020). All 4 response-evaluable patients achieved a best response of CR/CRi (2 CR, 2 CRi). The onset of response was rapid with all patients achieving an initial response after Cycle 1 (2 CR, 1 CRi, 1 MLFS). Median duration of treatment was 68 days (21-110). Two patients discontinued, both in remission, one due to death from neutropenic sepsis and the other by physician decision. The adverse event (AE) profile of the triplet was consistent with reports of ven/aza in AML. AEs experienced by 2 or more patients (all grades/causality) included febrile neutropenia, pneumonia, anxiety, cough, diarrhea, fatigue, decreased appetite, myalgia, decreased neutrophil count, and decreased platelet count. The only serious AE (all causality) occurring in more than one patient was febrile neutropenia. A high response rate was observed in early results of tamibarotene/ven/aza in RARA-positive ND AML patients ineligible for standard induction chemotherapy with 100% (4 of 4) response evaluable patients achieving CR/CRi, 3 of whom may have features of ven-resistance based on high MES. The triplet demonstrated an initial safety profile similar to ven/aza. Data from the safety lead-in will inform triplet dosing for the randomized portion of the study.

INTRODUCTION: Luxeptinib (CG-806) is a potent, non-covalent oral inhibitor of BTK and FLT3. It suppresses BCR signaling pathways (LYN, SYK, BTK, AKT, ERK) and other oncogenic pathways in cell lines and primary CLL cells, kills malignant B-cells insensitive to ibrutinib or venetoclax at low nM concentrations, and shows enhanced activity in combination with venetoclax. Luxeptinib is currently being evaluated in a Phase 1a/b trial in patients with relapsed or refractory B-cell malignancies (NCT03893682).