Wu, Qian Vicky

Abstract Introduction: Lisocabtagene maraleucel (liso-cel) was approved in the United States for the treatment of CLL in 3/2024 for patients who have received two prior lines of therapy including a covalent BTK inhibitor and a BCL-2 inhibitor. Data regarding outcomes of liso-cel is limited to reports from the registrational TRANSCEND-CLL 004 clinical trial which had strict inclusion and exclusion criteria. This work investigates the real-world efficacy and safety of liso-cel for patients with CLL and its efficacy in specific sub-populations. Methods: This is a multi-institutional retrospective study (Collaborative Assessment of Real-World Evidence of Lisocabtagene Maraleucel in Patients with Relapsed/Refractory CLL/SLL [CARE CAR-T CLL]) of patients with CLL who received commercial liso-cel in the United States. Patients with Richter transformation were excluded. Response was defined by iwCLL criteria. Patients who did not undergo a marrow biopsy but met other criteria for a complete response (CR) were categorized as unconfirmed CR (CRu). CRS and ICANS were graded per ASTCT criteria. Results: A total of 30 patients were identified with a median age of 67 years (range 44 – 80). Twenty of thirty patients (67%) had either del17p and/or mutated TP53, and 8/30 (27%) had complex karyotype (≥ 3 abnormalities) at time of liso-cel infusion. Patients received a median of 6 prior lines of therapy (range 1 - 12), and 24 (80%) were previously treated with chemotherapy. All patients had previous exposure to a covalent BTK inhibitor and a BCL-2 inhibitor. Twenty-seven (90%) of patients had prior exposure to pirtobrutinib. Twenty-nine patients (96.7%) received bridging treatment that was stopped after leukapheresis with 1 patient in CR and 25 patients in PR at time of liso-cel. Eighteen patients (60%) were treated with pirtobrutinib as the last line of treatment prior to liso-cel. Median length of time on pirtobrutinib prior to liso-cel infusion was 4 months (interquartile range [IQR], 2 – 8 months). Twelve (66.7%) patients stopped pirtobrutinib between leukapheresis and lymphodepletion, and 6 continued after liso-cel. Best CR/CRu rate was 60.0% (CR, n = 17/30; CRu, n = 1/30), and best overall response rate (ORR) was 83.3% (25/30) with median time to best response of 30 days (IQR, 28 – 30 days). Of the 18 patients who received pirtobrutinib as their last line of therapy, 13 (72%) achieved a CR/CRu. Meanwhile, of the 12 patients who did not receive pirtobrutinib as their last line of therapy, only 5 (28%) achieved a CR. Measurable residual disease testing (MRD) by flow cytometry was done in 14/30 patients, and 9 patients (64%) had achieved undetectable MRD (uMRD). MRD by next generation sequencing (NGS) was done in 17 patients, and 7 (41%) patients had uMRD. Twenty-seven of 30 patients (90%) were alive at time of data collection. Median follow-up was 3.3 months (IQR, 1.2 – 8.9 months). Twenty-six patients (87%) experienced any grade cytokine release syndrome (CRS), and 3 patients experienced grade 3 CRS (10%). Twelve patients (40%) experienced any grade immune effector cell-associated neurotoxicity syndrome (ICANS), and 4 patients (13%) experienced grade 3 ICANS. There were no grade 4 or 5 CRS or ICANS. One patient experienced grade 3 immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). At day 30, patients had a median absolute neutrophil count of 1.7K/μL (IQR, 0.8 – 3.6K/μL), hemoglobin of 11.7 g/dL (IQR, 8.6 – 13.1 g/dL), and platelet count of 72K/μL (IQR, 29 – 119K/μL). Conclusion: Real-world analysis of liso-cel for patients with relapsed/refractory CLL showed CR and ORR of 60.0% and 83.3%, respectively. Despite having a heavily pre-treated and chemotherapy-exposed population and with over half the patients having high-risk features, these response rates are higher than what was described in the TRANSCEND-CLL 004 clinical trial. These results are limited by the short follow-up period and the variability in response assessment typical of a retrospective study. As we increase our sample size, we will also be interested if the use of the non-covalent BTK inhibitor pirtobrutinib prior to liso-cel is associated with a higher CR rate, mimicking the findings of the sub-cohort analysis of TRANSCEND-CLL 004 where the concurrent use of ibrutinib led to higher CR rates. Further updates and patients from additional collaborators will be presented at the meeting.

Abstract Introduction CAR T cell treatment is the standard of care for patients (pts) with primary refractory and relapsed large B-cell lymphoma (LBCL) within the first 12 months of chemoimmunotherapy, or for those unfit for autologous stem cell transplant (ASCT) regardless of timing of relapse. Consequently, the role of ASCT is limited to pts with late relapse (>12 months) who achieve a complete or partial response (CR or PR) to salvage therapy and are deemed eligible for ASCT based on comorbidities and performance status. In this report, we evaluated post-ASCT outcomes in this population of pts. Methods We conducted a retrospective cohort study using publicly available data from the Center for International Blood and Marrow Transplant Research (CIBMTR). Adult pts (age ≥18 years) with DLBCL, NOS, and high-grade large B-cell lymphomas (HGBL) who relapsed after having responded to initial treatment and who remained on response for at least 12 months since diagnosis were selected. We considered for this analysis only pts who achieved a CR or PR after salvage treatment at the time of relapse, documented on pre-ASCT CT or PET scan (per the 2014 Lugano definition). CIBMTR databases used for this study included pts who received ASCT from 2013 to 2021. We compared baseline characteristics between ASCT in CR vs PR using the Wilcoxon rank sum test for continuous variables and the Pearson's χ2 test for categorical variables after ignoring missing data. Primary endpoints included Progression-free survival (PFS) and overall survival (OS). Non-relapse mortality (NRM) and relapse rate were among the secondary endpoints. Results 182 were included in the analysis: 100 were in CR and 82 in PR before ASCT. The median age at ASCT was 60 years (range, 26-79). Race distribution was similar across CR and PR pts. Advanced-stage disease at diagnosis (stage III–IV) was seen in 61% of CR pts and 55% of PR pts. High-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements was similar in the CR and PR groups (7% vs 4%). The median number of lines of treatment before ASCT were identical in CR and PR pts (N=2). BEAM was the most frequently used transplant conditioning regimen in both groups (80%). Median follow-up after ASCT was 34 months (range, 1–95): it was 37 months (range 1-95) in the CR group and 26 months (range 1-79) in the PR group For the entire cohort, OS at 3 years was 67.6% and PFS was 50.6%. NRM was 1.7% at 100 days and 3.4% at 1 year. Cumulative incidence of relapse at 3 years was 43.9%. The NRM analysis showed no statistically significant difference between pts in CR and PR. The 3-year OS for CR pts was 73.9%% compared to 59.4% for PR pts (95% CI, 0.334-0.99; p=.044). The 3-year PFS for CR pts was 59.8%, compared to 38.6% for PR pts (95% CI, 0.321-0.784; p=.001). The median PFS for CR pts was 52.01 months, compared to 14.05 months for PR pts. The cumulative incidence of relapse at 3 years in CR and PR pts was 35.2% vs 55.7%, respectively (95% CI, 0.311-0.811; p=.003.). Higher age (HR 1.03; p=.026) and number of previous lines of treatment (HR 1.43; p=.002) were associated with inferior OS. For PFS, no variables showed any significant impact in univariable analysis. The stepwise multivariable analysis showed that only the number of previous treatments had a significant impact on the OS (p=.009), while undergoing ASCT on a PR was the only factor significantly associated with shorter PFS (HR 1.41; 95% CI, 1.09-1.82; p=.029). Conclusion This dataset supports that ASCT provides high efficacy in pts experiencing late relapses (after 12 months) achieving CR following pre-transplant savage and validates the value of achieving CR. Outcomes for PR are inferior, and this analysis provides a benchmark for future investigations. At this time, until convincing on other non-transplant treatment show superior outcomes in this setting, ASCT remains a standard of care for fit pts with chemo-sensitive late relapsed DLBCL. In this group of patients, who have a better prognosis compared to patients who relapse within a year the major hurdle is achieving a remission pre-ASCT.

Abstract Patients with core-binding factor (CBF) acute myeloid leukemia (AML), caused by either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22), have higher complete remission rates and longer survival than patients with other subtypes of AML. However, ∼40% of patients relapse, and the literature suggests that patients with inv(16) fare differently from those with t(8;21). We retrospectively analyzed 537 patients with CBF-AML, focusing on additional cytogenetic aberrations to examine their impact on clinical outcomes. Trisomies of chromosomes 8, 21, or 22 were significantly more common in patients with inv(16)/t(16;16): 16% vs 7%, 6% vs 0%, and 17% vs 0%, respectively. In contrast, del(9q) and loss of a sex chromosome were more frequent in patients with t(8;21): 15% vs 0.4% for del(9q), 37% vs 0% for loss of X in females, and 44% vs 5% for loss of Y in males. Hyperdiploidy was more frequent in patients with inv(16) (25% vs 9%, whereas hypodiploidy was more frequent in patients with t(8;21) (37% vs 3%. In multivariable analyses (adjusted for age, white blood counts at diagnosis, and KIT mutation status), trisomy 8 was associated with improved overall survival (OS) in inv(16), whereas the presence of other chromosomal abnormalities (not trisomy 8) was associated with decreased OS. In patients with t(8;21), hypodiploidy was associated with improved disease-free survival; hyperdiploidy and del(9q) were associated with improved OS. KIT mutation (either positive or not tested, compared with negative) conferred poor prognoses in univariate analysis only in patients with t(8;21).

CD19-targeted chimeric antigen receptor (CAR)-T cell therapy is a novel treatment with promising results for patients with relapsed/refractory lymphoid malignancies. CAR-T cell therapy has known early toxicities of cytokine release syndrome (CRS) and neurotoxicity, but little is known about long-term neuropsychiatric adverse effects. We have utilized patient-reported outcomes (PROs), including PROMIS®measures, to assess outcomes of patients with relapse/refractory chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), and acute lymphoblastic leukemia (ALL) who were treated with CD19-targeted CAR-T cells on a clinical trial in our institution (NCT01865617) and survived at least one year after treatment. Between October 2018 to February 2019, 52 patients (at their 1-5 year anniversary after CAR-T cell therapy) were sent a questionnaire. The questionnaire included the PROMIS Scale v1.2-Global Health and the PROMIS-29 Profile v2.1, as well as 30 additional questions, including questions pertaining to cognitive function. As of February 28, 2019, 40 questionnaires were returned (76.9% response rate) and were included in the analysis. Patients' characteristics are summarized in Table 1. Cognitive function was assessed by asking if patients had experienced difficulties with concentration, finding words, memory, or solving problems since their CAR-T cell therapy; answer "yes" to each of the questions received "1" point to determine the total cognitive difficulty score (0-4). PROMIS measures are standardized to a T-score metric, with a score of 50 representing the general US population mean. Clinically meaningful differences were defined as a 5-point difference in scores (1/2 standard deviation). The cohort's self-reported cognitive difficulties and PROMIS mean T scores are shown in Table 2. Mean T scores of PROMIS domains of Global Mental health, Global Physical Health, Social Function, anxiety, depression, fatigue, pain and sleep disturbance were not clinically meaningfully different from the mean in the general US population. However, 19 participants (47.5%) reported at least one cognitive difficulty and/or clinically meaningful depression and/or anxiety (Figure 1), and 7 participants (17.5%) scored ≤ 40 in Global Mental Health, indicating at least one standard deviation worse than the general population mean. On risk factor analysis, younger age was found to be associated with worse Global Mental Health (p=0.02), anxiety (p=0.01) and depression (p=0.01). Anxiety prior to CAR-T cell therapy was associated with increased likelihood of anxiety after CAR-T cell therapy (p=0.001). Multivariate analysis confirmed association between age and PROMIS Global Mental Health score (p=0.03). 15 participants (37.5%) reported cognitive difficulties post CAR-T cell therapy. On multivariate analysis, depression prior to CAR-T cell therapy was statistically significantly associated with higher likelihood of self-reported cognitive difficulties after CAR-T therapy (p=0.02) and there was a trend for association between acute neurotoxicity after CAR-T cell infusion and self-reported long-term cognitive difficulties (p=0.08). Having more cognitive difficulties was associated with worse Global Mental Health (p=0.0001) and worse Global Physical Health (p= 0.01). Similarly, worse scores for pain interference, sleep disturbance, fatigue, depression, anxiety, physical function, and social function were associated with more long-term self-reported cognitive difficulties (p=0.007,p=0.0003, p=0.00006, p=0.01, p=0.0007, p=0.003, p=0.0004 respectively). Our study demonstrates overall good neuropsychiatric outcomes in 40 long-term survivors after CAR-T cell therapy. However, despite good overall mean scores, nearly 50% of patients in the cohort reported at least one negative neuropsychiatric outcome (anxiety, depression or cognitive difficulty), and almost 20% scored at least one standard deviation lower than the general US population mean in Global Mental Health, indicating that there is a significant number of patients who would likely benefit from mental health services following CAR-T cell therapy. Younger age, anxiety and depression pre-CAR-T cell therapy, and acute neurotoxicity after CAR-T cell infusion may be risk factors for long-term neuropsychiatric problems in this patient population. Larger studies are needed to confirm these findings. Disclosures Shaw: Therakos: Other: Speaker Engagement. Lee:AstraZeneca: Research Funding; Incyte: Research Funding; Syndax: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Kadmon: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Turtle:T-CURX: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Other: Ad hoc advisory board member; Caribou Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Allogene: Other: Ad hoc advisory board member; Humanigen: Other: Ad hoc advisory board member; Juno Therapeutics: Patents & Royalties: Co-inventor with staff from Juno Therapeutics; pending, Research Funding; Nektar Therapeutics: Other: Ad hoc advisory board member, Research Funding; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Ad hoc advisory board member. Maloney:Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; A2 Biotherapeutics: Honoraria, Other: Stock options ; Celgene,Kite Pharma: Honoraria, Research Funding; BioLine RX, Gilead,Genentech,Novartis: Honoraria.