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Introduction: Brexucabtagene autoleucel (brexu cel) is a CD19-targeted chimeric antigen receptor (CAR) T cell therapy approved for the treatment of adults with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). Some patients (pts) proceed with a consolidative allogeneic hematopoietic cell transplant (HCT) after breux cel. We do not know which pts can safely avoid a consolidative HCT and its associated morbidity. Methods: We conducted a retrospective cohort study utilizing the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) dataset. ROCCA is a registry of brexu cel pts in 32 centers in North America. We defined complete remission (CR) as < 5% blasts in the bone marrow and no central nervous system (CNS) or extramedullary (EM) disease on or around D28 after brexu cel. We defined measurable residual disease negative (MRD-) CR as CR and no abnormal blasts in the bone marrow by multiparameter flow cytometry, quantitative polymerase chain reaction, ClonoSeq next generation sequencing (NGS), or other sequencing modalities with lower sensitivity. ClonoSeq NGS has a sensitivity of 10-6, while the other modalities have a sensitivity of at least 10-4. We defined progression free survival (PFS) as the time from CAR-T infusion to relapse or death, censored at the date of last follow-up. Statistical analyses were performed in R. Univariable Cox proportional hazards regression analyses were performed to determine the association of pre-specified variables with PFS. Variables known to be associated with CAR T outcomes in ALL were entered into a multivariable model. HCT was incorporated as a time-varying covariate. Results: During the study period, 281 pts were infused with brexu cel. We focused our analysis on 172 (61%) pts with confirmed MRD- CR on D28, as that is the group with clinical equipoise regarding maintenance strategy. 38 (22%) of those pts received a consolidative HCT, 30 (17%) received another form of maintenance therapy (primarily tyrosine kinase inhibitors for Philadelphia (Ph)-chromosome positive ALL), and 104 (60%) pts received no maintenance therapy. Pts who underwent consolidative HCT were younger (median age 35 years) than those who received no maintenance (42y) (p = 0.023) and were less likely to have a history of prior HCT (13% vs. 47%, p < 0.001). No differences were observed with respect to sex, TP53 mutation status, prior inotuzumab (ino) or blinatumomab (blina) exposure, disease burden prior to CAR, or development of any cytokine release syndrome (CRS) or any neurotoxicity with brexu cel. We performed univariable Cox proportional hazard regression analyses among pts in MRD- CR on D28, excluding those who received other maintenance therapy besides HCT; the median follow up was 8.1 months. In univariable analyses, D28 MRD negativity by ClonoSeq NGS (versus MRD negativity by other, less sensitive methods), development of CRS, and pre-CAR BM blasts < 5% were associated with improved PFS; prior ino exposure was negatively associated with PFS (p < 0.05). Age, sex, Ph status, TP53 status, and neurotoxicity development were not associated with PFS. In a multivariable model incorporating ALL type, prior HCT, prior ino/blina, and pre-CAR blast burden, as well as consolidative HCT as a time-varying covariate, only MRD negativity by ClonoSeq NGS with at least 10-6 sensitivity retained statistical significance (PFS hazard ratio 0.34, 95% confidence interval (CI) 0.15-0.77, p = 0.005). Pts who were MRD- by ClonoSeq NGS on D28 and received no maintenance had favorable 6m PFS of 76% (95% CI: 59-98%) and OS of 100% with a median follow up of 6.3 months in this subgroup. Among those in MRD- CR by NGS, HCT as a time-varying covariate was not associated with improved PFS (HR 0.6, p = 0.6). Conclusions: In a large real-world cohort of adults with R/R B-ALL infused with brexu cel, we identified practice variation regarding the use of consolidative HCT. Among brexu cel recipients who entered an MRD- CR, we identified ClonoSeq NGS MRD negativity as a novel predictive factor of favorable oncologic outcomes, even without a consolidative HCT. Similar results have been obtained in pediatric ALL patietns ftreated with 41BB-based tisagenleucleucel (Pulsipher et al., Blood Cancer Discovery 2022). Longer follow-up is needed to validate the safety of omitting consolidative HCT in such pts, but these results encourage the potential for definitive therapy with brexu cel when D28 ClonoSeq NGS MRD is negative.

Background: Hematopoietic stem cell transplant (HSCT) based gene therapies (GT) have successfully demonstrated significant reduction in vasocclusive crises (VOCs) associated with sickle cell disease (SCD). The efficacy and safety of these products is well established across multiple clinical trials (Kanter et al. NEJM 2022, Frangoul et al. NEJM 2024). This led to the Food and Drug Administration (FDA) approval of the lentiviral-based gene addition product (lovotibeglogene autotemcel) and CRISPR-Cas9 based gene editing product (exagamglogene autotemcel) for patients with SCD above 12 years of age. As these therapies have a different logistical process compared to a standard allogeneic HSCT, there is a need to develop a collaborative transition of care plan for these patients and families prior to and long after completion of transformative therapies. Methods: Upper Midwest Sickle Cell Curative Therapies Consortium is a collaborative model including multiple stakeholders between 7 centers across the upper Midwest United States, the regional community-based organization (CBO) and National Marrow Donors Program (NMDP). The structure and workflow for this model was presented previously (Blaylark et al. ASH 2023). With the advent of commercial GTs, we developed a multi-specialty care model in collaboration with community stakeholders to address diverse patient and logistical needs for smoother transition to and from these therapies. Discussion: The initial transition is a period of potential gaps in medical care and often high anxiety for patients and families. Thus, when patients and families are considering GT, our care model engages a multidisciplinary team. As part of the comprehensive evaluation prior to gene therapy, an initial shared collaborative checklist includes an extensive medical history, assessment of treatment plan, an individualized pain plan and adherence, transfusion planning (simple or exchange) with setting of target hemoglobin and hemoglobin S% targets, and coordination of multi-specialty consults including apheresis, fertility preservation, child life, and social work. Additionally, pain, psychology, and integrative medicine specialists address not only ongoing concerns, but also help develop a plan for future transition back to the primary site of SCD care (“re-transition”) after GT. Patients undergo neuropsychological evaluations to establish baseline functioning and the role of chronic pain and fatigue, as GT can significantly impact long term cognitive functioning, emotional coping with transitions, and overall daily functioning. When appropriate and available, warm handoffs are encouraged between centers within each of these specialties. Our team also reviews available resources for education and ongoing support through the process and after from national and regional CBOs. Similarly, the post-GT transition is also a period of potential medical care gaps and high anticipated anxiety and concern, as patients go through significant unfamiliar adverse effects followed by the potential for persistent freedom from VOCs. In the post-GT transition, ongoing psychology, integrative medicine, and pain team support; peer mentoring; and support groups are critical for a smooth re-transition to post-GT care and further successful re-transition back into the community. Using this interdisciplinary approach across GT clinical trials, we successfully weaned opioids in 83% of patients (5/6) by day 60 post-GT infusion and successful re-transition of these patients, further highlighting the role of interdisciplinary care. Our team's collaborative approach to SCD care with sickle cell specialists, transplant team and other care providers and CBO continues into the long term follow up period, including ongoing supportive services for both patients and their families. Conclusion: As newer therapies are developed and approved for transformative SCD care, development of a transitional model with early engagement of an interdisciplinary team is critical for empowering sickle cell warriors and for their successful transition back into the community.

Background Emerging evidence has demonstrated rare subacute to late neurological toxicities (NTs) after BCMA CAR T-cell therapy (CAR-T) in multiple myeloma (MM). These adverse events can be categorized as: 1) Parkinsonism (PD), 2) cranial nerve (CN) palsies, and 3) peripheral neuropathies/Guillan Barré syndrome (GBS). These toxicities can cause significant morbidity, but given their relative rarity in clinical trials, there is limited data regarding evaluation and treatment. To our knowledge, this is the largest and only global registry of delayed NTs after BCMA CAR-T. Methods We retrospectively established a registry of NTs via the Immune Therapy Working Committee of the International Myeloma Working Group (IMWG). We gathered data pertaining to demographics, MM characteristics, MM response, NT signs/symptoms, diagnostic workup, and treatment. Result A total of 52 patients with delayed neurotoxicity were included from 14 institutions and 6 countries; 92% received ciltacel, 4% idecel, and 4% investigational CAR-T. Median age at CAR-T infusion was 65 years; 69% were male and 88% were Caucasian. Median bone marrow plasma cell (PC) burden was 15% prior to CAR-T (range 0-95%). Patients received a median of 4 prior lines of therapy (LOT), with 67% progressing on last LOT. Seventeen percent had pre-existing neurological diagnoses (including stroke, epilepsy, migraines). We identified sixteen cases of PD (94% with movement disorder, 69% with cognitive impairment, 75% with personality changes), occurring at a median of 26 days (range: 15-87) after CAR-T. Ninety four percent had CRS (grade (G)1 50%, G2 38%, G3 6%, G4 0%), while 19% had ICANS (G1 13%, G2 6%, G3-G4 0%). Median peak absolute lymphocyte count (ALC) was 9.5 x 109/L, peak C-reactive protein (CRP) 60.9 mg/L, and peak ferritin 1893.5 ug/L within the first 30 days. Concurrently, 3 upper respiratory infections (URIs) and 2 low-level HHV7 in the cerebrospinal fluid (CSF) were detected. A median of 73% of T-cells in the CSF were CAR-T, based on a flow cytometry assay. Ten patients received steroids (median 19 days after symptoms, 70% partial response, 20% no response, 10% unknown), 2 received intrathecal (IT) methotrexate-based therapy (median 32 days after symptoms, 1 with no response, 1 unknown), 5 received intravenous (IV) cyclophosphamide (median 31 days after symptoms, 40% full response, 20% partial response, 40% no response), 4 received high-dose IVIG ≥1g/kg for one or more dose (50% partial response, 50% no response), and 6 received dopamine agonists. There were 37 CN palsies (76% CN7, 15% CN6, 7% CN5, 2% CN3), occurring at a median of 37.5 days (range: 7-482) after CAR-T. Eighty one percent had CRS (G1 68%, G2 14%, G3-G4 0%); 11% had G1 ICANS (G2-G4 0%). Median peak ALC was 4.1 x 109/L, CRP 25.4 mg/L, and ferritin 543 ug/L within the first 30 days. We identified 2 concurrent URIs, 4 CMV viremia (50% with viral load >1500 IU/mL), 1 HHV6 viremia, and 1 HSV in the CSF. Thirty-two (86%) received steroids for a median duration of 12 days, 50% with full response, 3% with no response, and 47% with partial response (of which 43% had later full recovery without further intervention). One received IT methotrexate and another received IV cyclophosphamide without response. Thirteen (41%) received IVIG, of which 38% was high-dose IVIG. Four patients with CN palsies developed peripheral neuropathy/GBS. Eight patients (15%) in this cohort were not heavily pre-treated (≤1 prior LOT); 7 developed CN palsies (6 after ciltacel, 1 after investigational CAR-T) and 1 PD (after idecel). These patients had median <5% PC; none had extramedullary disease. Median ALC was 4.14 x 109/L, CRP 33 mg/L, and ferritin 448.5 ug/L within the first 30 days. Conclusions Delayed NT requires prompt recognition, evaluation for alternative causes, and treatment. In our cohort, the majority of patients were male and Caucasian, suggesting that sex and race may impact the likelihood of developing NT. Individuals with PDs had greater inflammatory response (CRS, ALC, CRP, ferritin) compared to those with CN palsies. CN palsies responded to steroids and/or IVIG, whereas PD had at best partial response to steroids, prompting additional therapy. These toxicities notably did occur in less heavily pre-treated patients, perhaps driven by immune fitness and greater circulating T-cells rather than MM burden. At the time of the annual meeting, data will be updated with additional NTs from less heavily pre-treated patients.

Background: Daratumumab (DARA) has demonstrated clinical benefit in multiple myeloma (MM) and is approved for the treatment of both newly diagnosed MM (NDMM) and relapsed refractory MM (RRMM). While single-center studies have shown the benefit of DARA retreatment in patients (pts) who are refractory to DARA (D-Ref), there is a lack of real-world data on the characteristics of pts who are retreated with DARA across multiple lines of treatment (LOTs). In this study, we examine DARA retreatment patterns and outcomes among pts who are D-Ref and those who are sensitive to DARA (D-Sens) after the first DARA exposure in the US real-world clinical practice. Methods: This study used the Flatiron MM Core Registry data to identify pts with MM treated with a DARA-containing regimen in ≥2 separate LOTs between November 1, 2015, and March 31, 2024. The first DARA-based LOT was defined as D1, and the second DARA-based LOT was defined as the retreatment LOT (D2). The following criteria, developed by Janssen Scientific Affairs, were used to classify pts as Dara-retreated: 1) pts treated with the same DARA-containing regimens in consecutive LOTs were classified as Dara-retreated if there was a gap of >90 days between D1 and D2, 2) pts treated with different DARA-containing regimens in consecutive LOTs were classified as Dara-retreated, 3) pts treated with DARA-containing regimens had ≥1 LOTs between D1 and D2 they were classified as Dara-retreated, regardless of whether the regimens were the same or different. Derived disease progression reported in the Flatiron data was used for this analysis. If disease progression was reported during D1, or within 60 days of discontinuing D1, the pt was considered as D-Ref, otherwise, the pt was considered as D-Sens. Kaplan-Meier (KM) analyses were conducted to evaluate duration of D2, proportion of pts not receiving subsequent treatment after D2, and progression-free survival (PFS) rates during D2. Results: Data for 201 pts retreated with DARA were identified in this analysis, 150 were D-Sens and 51 were D-Ref. In the D-Sens group, the median age at D2 initiation was 71 years, 44.0% of pts were female, 27.3% were ISS stage II and 16.0% were African American. In the D-Ref group, the median age at D2 initiation was 67 years, 45.1% of pts were female, 21.6% were ISS stage II, and 25.5% were African American. At D2 initiation, 64.7% (D-Sens) and 60.8% (D-Ref) of pts were frail, and 56.0% (D-Sens) and 52.9% (D-Ref) of pts had a Quan-Charlson Comorbidity Index of ≥3, indicating a high burden of comorbidities. About 31% of pts in both groups had high cytogenetic risk abnormalities, and about 20% had a 1q21 gain or amplification. The median time from MM diagnosis to start of D1 and to start of D2 was shorter in the D-Sens group (10.8 and 34.9 months) than in the D-Ref group (18.4 and 44.4 months). D-Sens pts were less likely to receive D1 in the third LOT or later compared to D-Ref pts (30.0% vs 45.1%). The median number of LOTs before D2 was three in both groups. The median gap between D1 and D2 was 9.3 months in D-Sens pts and 9.0 months in D-Ref pts, however, more D-Sens pts received D1 and D2 LOTs consecutively compared to D-Ref pts (62.0% vs 51.0%). The most common regimen used in D1 was DARA + lenalidomide + dexamethasone (dex; 18.7%) and DARA + bortezomib + dex (18.7%) among D-Sens pts, and DARA + pomalidomide + dex (23.5%) among D-Ref pts. The most common regimen used in D2 was DARA mono (31.3%) in D-Sens pts, and DARA mono (17.6%) and DARA + carfilzomib + dex (17.6%) in D-Ref pts. Overall, 32.0% of D-Sens and 35.3% of D-Ref pts received agents from the same drug class in D1 and D2. The KM median duration of D2 was 7.4 months (95% CI: 5.5-9.5) among D-Sens pts and 6.4 months (95% CI: 3.8-23.5) among D-Ref pts. The proportion of pts that had not received subsequent treatment after D2 was 38.7% and 29.5% at 12 months in the D-Sens and D-Ref groups, respectively. PFS rates at 12 months after D2 initiation were 77.1% in the D-Sens group and 49.4% in the D-Ref group. Conclusion: DARA retreatment is utilized frequently and is effective in the real-world, suggesting the ability to use this approach in subsequent LOTs among pts with RRMM. In the absence of other feasible alternatives, this may be a treatment strategy for patient benefit, regardless of whether they are D-Sens or D-Ref. Future studies are needed to definitively investigate the benefit of DARA retreatment in combination with drugs with novel mechanisms of action.

Introduction: Despite advent of multiple tyrosine kinase inhibitors (TKIs) and newer treatment methods for both AML and ALL, the outcomes of patients (pts) with chronic myeloid leukemia in blast phase (CML-BP) remain poor. Consensus guidelines on treatment of CML-BP are scarce. A recent study from the European leukemia network (ELN) blast phase registry reported outcomes of 240 CML-BP pts. They also reported marked heterogeneity in treatment patterns and lack of an accepted standard. Hence, we are undertaking this study through the H Jean Khoury Cure CML Consortium (HJKC3) to study the treatment patterns and outcomes of pts with CML-BP in the US. Methods: This is a multi-institution, retrospective study. IRB approval was obtained at each institution separately and data sharing agreements were executed. All pts diagnosed with CML-BP based on modified MD Anderson Criteria (≥30% blasts in the blood or bone marrow or extramedullary (EM) disease) from 2010 to 2024 were included. Categorical variables were compared using the Chi-square test. Overall survival (OS) was calculated from the time of diagnosis to death from any cause. Survival probabilities were computed using the Kaplan-Meier method and compared with the log-rank test. Results: Of the 72 pts with CML-BP included in this analysis, 29 (40.3%) were female and 43 (59.7%) were males. At the time of diagnosis, 36 (50%) had CML-CP (chronic myeloid leukemia in chronic phase), 11 (15.3%) pts were diagnosed with CML-AP (accelerated phase CML) and 25 (34.7%) pts with de-novo CML-BP. For the 47 pts that were initially diagnosed with CML-CP or CML-AP, the median time to progression to CML-BP was 26 months (1-207 months). Median age at diagnosis of CML-BP was 54 years (range 21-86 years). EM disease was present in 17 (23.6%) pts (7 myeloid sarcoma, 5 central nervous system and 5 skin) with 3 pts presenting with EM disease only. Blasts were of myeloid phenotype in 41 (56.9%), lymphoid in 29 (40.3%) and mixed in 2 (2.8%) pts. The bcr-abl protein was p210 in 59 (81.9%), p190 in 5 (6.9%) and p230 in 1 (1.4%) pt. Four pts had prior allogeneic stem cell transplant (alloSCT) for CML-CP. Of the pts who had an ABL kinase domain mutation tested, 42.9% (18/42) pts were found to have an ABL kinase domain mutation. The most common TKD mutation was T315I (n=6). Next generation sequencing was performed in 32 pts. The most common mutations were ASXL1 (n=10), RUNX1 (n=4), BCOR (n=2), BCORL1 (n=2), DNMT3A (n=2) and 1 each in CSF3R, KMT2A, EZH2, NF1 and TP53. Of the 72 pts, 68 underwent CML-BP directed therapy. While only 9 (13.2%) pts were treated with TKI alone (4 dasatinib, 2 imatinib, 2 ponatinib and 1 asciminib), 54 (79.4%) pts were treated with a combination of chemotherapy with TKI (24 dasatinib, 13 ponatinib, 9 imatinib, 6 nilotinib, 1 bosutinib and 1 asciminib), and 5 (7.4%) pts were treated with chemotherapy alone. The response rate after CML-BP directed therapy was 72.1% (n=49). Best response was return to CML-CP in 17 pts, CHR with PCyR in 1 pt, CCyR in 11 pts, MMR in 5 pts, MR4 in 4 pts, MR4.5 in 5 pts and MR5 in 6 pts. Rate of response with third and second generation TKI was significantly better than first generation TKI (80% and 77.1% vs 36.3%; p=0.02287). 30 (44.1%) pts proceeded to alloSCT. Of the 49 pts that responded, 16 (32.6%) relapsed. The median time to relapse was 5 months (range 1-46 months). At a median follow up of 57 months, the median OS for all pts was 18 months. There was no difference in OS based on blast phenotype (14 months for myeloid, 21 for lymphoid and 7.5 for mixed; p=0.1185), initial diagnosis (38 months CP-CML, 13 for CML-AP and 16 for de-novo BP pts; p=0.6380), or TKI (13 months for first generation, 20 for second and not reached for third generation TKI; p=0.1729). The OS of pts that were treated with a combination of TKI and chemotherapy was significantly longer compared to pts treated with TKI or chemo alone (28 vs 13 or 4.5 months; p=0.0003). Of the 32 pts that responded, OS for pts that underwent alloSCT was significantly longer compared to pts that did not (not reached vs 14 months; p= 0.0022). Conclusion: CML-BP continues to have a dismal prognosis. Treatment is heterogenous involving various combinations of TKI and chemotherapy. In our analysis, treatment with second or third generation TKI led to better responses. In addition, treatment with chemotherapy in combination with TKI and alloSCT led to improved OS. Updated results from further multi-institution analysis will be presented at the meeting.

Introduction: Brexucabtagene Autoleucel (brexu-cel) is the first CD19-targeting chimeric antigen receptor (CD19.CAR) T-cell therapy approved for the treatment of relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) in adult (≥18 yo) patients (pts) based on results from the ZUMA-3 trial. However, data on the safety and efficacy of CAR-T cells in older pts (≥60 yo) remains limited, with only 8 pts >65 yo enrolled in the ZUMA-3 trial. We evaluated the treatment characteristics and outcomes with use of brexu-cel amongst patients ≥60 yo in the Real-World Outcomes Collaborative for CAR-T in ALL (ROCCA) consortium database. Methodology: ROCCA is a consortium of over 30 U.S.-based institutions with a database of adult pts with B-ALL who received brexu-cel as standard of care therapy. We identified pts ≥60 yo and further stratified them into two cohorts: 60-69 yo and ≥70 yo. Outcomes of interest included OS, PFS, ORR, and toxicities (CRS and ICANS). Both OS and PFS were calculated from the day of brexu-cel infusion. Response assessment occurred on day +28, and MRD evaluation was per institutional practices. CRS and ICANS were graded according to the American Society for Transplantation and Cellular Therapy criteria. Results: Of 280 brexu-cel recipients in the ROCCA database, 73 (26%) were ≥60 yo, of which 58 (79%) were between 60-69 yo and 15 (21%) were ≥70 yo. Among pts ≥60 yo, the median age at infusion was 65 (range 60-81). Pts were heavily pretreated with a median of 3 prior lines of therapy (range 2-9). Prior therapies included: allogeneic HSCT (38%), inotuzumab ozogamicin (41%), and blinatumomab (62%). Forty pts (55%) had Ph-negative B-ALL, 24 (33%) had Ph+ B-ALL and 9 (12%) had Ph-like B-ALL. When grouped by HCT-CI equal to 0, 1-2 or ≥3, a higher proportion of pts ≥60 yo had HCT-CI ≥3 (19% vs. 7% in <60 yo; p=0.004). Pre-apheresis, 33 pts (45%) had active disease (>5% marrow blasts or extramedullary disease), 34 (47%) were in CR (of whom 14 were MRD-negative) and 6 had unknown disease status. Following brexu-cel, 43 (59%) achieved MRD-negative CR, 20 (27%) had MRD + or CR with unknown MRD status, 6 (8%) had refractory disease and 5 had no disease evaluation available. The ORR was similar between pts 60-69 and ≥70 yo (MRD-negative CR rate: 58% vs 61%, r/r to brexu-cel: 9% vs 6%) and was comparable to pts <60 yo (MRD-negative CR 66%; r/r disease of 9%). The rate of all grade ICANS was higher in pts ≥70 (77%) than in pts 60-69 (47%) or pts <60 (49%), with grade 1-2 ICANS occurring at a significantly higher rate in pts ≥70 (44% vs. 20% in 60-69 and 20% in <60, p=0.049). Grade 3-4 ICANS were similar between the groups: 33%, 27% and 29% in the ≥70, 60-69, and <60 groups, respectively. Conversely, rates of CRS were similar across age groups (80-84%). There was no statistically significant difference in the rate of grade 3-4 CRS which was 17% in pts ≥70, 4% in pts 60-69, and 11% in pts <60 yo. With a median follow-up of 332 days (range 8-936 days) from infusion, pts ≥60 yo had a median PFS of 395 days compared to 547 days in pts <60 yo. Median PFS was lower in the ³70 yo (231 days) compared to 677 in the 60-69 yo cohort. No statistically significant difference was found between the <60 and ≥60groups in 6- and 12-month PFS rates (6 months PFS: 66% vs 64%, p=0.77 and 12 months PFS: 57% vs 57%, p=1.00). When pts ≥60 yo were stratified by age, pts ≥70 yo had similar 6-month PFS compared to other age groups but significantly lower 12-month PFS (38%; vs. 64% in pts 60-69and 57% in pts <60, p=0.001). Median OS was not reached in any of the age groups, and there was no statistically significant difference in 6-month OS (72% in ≥ 70 vs. 82% in the 60-69 vs. 82% in <60, p=0.14) or 12-months OS (61% in ≥ 70 vs. 69% in 60-69 vs. 73% in <60, p=0.18). Conclusion: This is the largest study to date of older B-ALL pts receiving CAR-T cells. We observed that older pts, particularly those aged 60-69, have similar outcomes to younger pts. However, pts ≥70 yo had lower median and 12-month PFS when compared to younger patients. Additionally, pts ≥70 yo had higher rates of grades 1-2 ICANS. An important limitation of this analysis is the potential selection bias among clinicians when selecting older patients for this treatment. Longer follow-up, including inclusion of additional pts ≥70 yo is needed to confirm these results, and further studies are needed to identify the optimal approach for use of CAR T-cell therapy in patients in this age group.

Fetal hemoglobin (HbF) is anti-sickling and elevated HbF ameliorates sickle cell disease (SCD) manifestations. BEAM-101 is an investigational cell therapy comprised of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) that are base edited ex vivo to introduce naturally occurring A-to-G substitutions into the promoters of the HBG1/2 genes that encode γ-globin to disrupt BCL11A transcriptional repressor binding sites, leading to increased HbF production. We previously demonstrated in pre-clinical studies that base editing potently induced HbF (>60%) and proportionately reduced sickle hemoglobin (HbS) (<40%) without relying on double-stranded DNA breaks. We present initial data from BEACON (NCT05456880), a Phase 1/2, single-arm, open-label study evaluating the safety and efficacy of a single dose of BEAM-101 in patients with SCD with severe vaso-occlusive crises (VOCs). Patients 18-35 years diagnosed with SCD and ≥4 severe VOCs in the 2-year period prior to screening per trial criteria were eligible. After plerixafor mobilization, autologous CD34+ HSPCs were collected by leukapheresis/isolation and genetically modified with an adenine base editor. After myeloablative conditioning with pharmacokinetically adjusted busulfan, patients received a single infusion of BEAM-101 (≥3.0 × 106 viable CD34+ cells/kg) and are monitored for neutrophil and platelet engraftment, adverse events (AEs), total hemoglobin (Hb), Hb fractions, % F-cells, hemolysis markers, peripheral blood editing, and VOCs for 24 months. As of July 2, 2024, >20 patients are enrolled and BEAM-101 has been manufactured for 8 patients, of whom 6 patients have been dosed. One patient not included in this analysis discontinued during the mobilization/collection period prior to BEAM-101 treatment for non-medical reasons. Baseline demographics were as follows: 5/6 patients βS/βS, 1/6 patients βS/β0, all self-reported Black/African American, 50% female, aged 19-27 years. Of the 6 patients, half (n=3) required only a single mobilization cycle and the other half required 2. Patients received a mean BEAM-101 dose of 11.9 × 106 (5.2-23.4) viable CD34+ cells/kg. Excepting safety data that include all patients dosed (n=6), the following data are from patients dosed with ≥1 month of follow up (n=4; 6, 5, 2, and 1 month[s] post-treatment, each). All 4 patients with ≥1 month of follow up achieved neutrophil and platelet engraftment at a median of 17 (15-19) and 20 (11-34) days, respectively. One patient died due to respiratory failure, likely related to busulfan conditioning, 4 months after infusion. In all patients dosed (n=6), there have been no ≥Grade 3 AEs or serious AEs related to BEAM-101. Using the central laboratory data, patients' total Hb increased from baseline (mean 9.3 [7.9-10.9] g/dL) to 17.9, 18.2, 11.0, and 11.8 g/dL at last time point (LTP) available for P1, P2, P3, and P4, respectively. No signs/symptoms or interventions were undertaken for high total Hb. All patients achieved >60% HbF of non-transfused Hb (total Hb − HbA) at Month (M) 1 and sustained this elevation to the LTP available. By M1, HbS% in non-transfused blood dropped to ≤36% in all 4 patients and was sustained through LTP. In total blood, % F-cells were 99.6% in P1 at M6, 94.4% in P2 at M4, 52.0% in P3 at M2, and 13.3% in P4 at M1 with all patients having >19 pg HbF/F-cell at LTP available. Peripheral blood editing in nucleated cells, measured in P1 (at M6) and P2 (at M3), was 69.9% and 76.1%, respectively. Markers of hemolysis (lactate dehydrogenase, indirect bilirubin, haptoglobin, and reticulocyte counts) have normalized or improved for all patients. No VOCs have been reported by investigators following BEAM-101 treatment. These initial data show a safety profile for BEAM-101 consistent with busulfan conditioning and autologous HSCT. Treatment with BEAM-101 resulted in rapid engraftment, improvement in hemolysis markers, and marked improvement of anemia in all 4 dosed patients. We observed rapid and robust HbF induction consistent with pre-clinical data by M1 (>60%) and corresponding HbS reduction (≤36%) in non-transfused blood in all post-treatment assessments. No VOCs were reported by investigators post-treatment. These initial data support base editing of the HBG1/2 promoters as an effective therapeutic modality for the treatment of SCD and will continue to be investigated in the ongoing BEACON study. Updated data to be presented.

Introduction: Multiple myeloma (MM) with t(11;14)(q13;q32), resulting in CCND1;IGH rearrangement, remains the only subset amenable to targeted therapy with the BCL2 inhibitor, Venetoclax. Nevertheless, not all patients with this translocation respond to treatment and some progress early after initial response. The mechanisms behind this clinical heterogeneity are largely unknown. Methods: To investigate mechanisms of heterogeneity in response to Venetoclax, we interrogated 44 whole genome sequencing (WGS) and 24 whole exome sequencing data from a training cohort including 33 patients with t(11;14) MM treated with Venetoclax at the Mayo Clinic. In a validation cohort, we extracted single nucleotide variants (SNV) and indels from 17 MM patients with t(11;14) with available RNAseq data treated with Venetoclax at Emory University. Results: In the training cohort the median number of lines of therapy was 4 and Venetoclax drug regimens included combinations with dexamethasone, proteasome inhibitors, anti-CD38 agents, and immunomodulatory agents. After a median follow up of 30 months, the median progression free survival (PFS) was 9 months, and 13 patients (39%) achieved a complete remission (CR) to therapy, while 9 (27%) were refractory (i.e. no response or progressed within the first 60 days). For our driver discovery analysis, we integrated SNV, indels, copy number variants (CNV) and structural variants (SV). Deletion 17p (del17p) or TP53 mutation, MCL1 gain/amp, and hyper-APOBEC did not correlate with PFS in our cohort (p=0.59, p=0.71, and p=0.05, respectively). In contrast, mutations involving the MAPK pathway (NRAS, KRAS, BRAF, FGFR3) displayed the strongest association with short PFS, which was retained after adjusting for del17p/TP53 mutations, and 1q gain/amp (HR: 4.76, CI: 1.8-12.9, p=0.002). The association between suboptimal response and resistance to Venetoclax in MM patients with MAPK pathway mutations (n=7) was also observed in our validation cohort from Emory University (p=0.046). This is in line with what has been reported in functional studies in acute myeloid leukemia, where RAS pathway promotes MCL1 under the selective pressure of Venetoclax (Zhang et al. Signal Transduct Target Ther 2022). While MAPK mutations explained most cases of refractory patients (86%), the mechanisms through which initially responding patients subsequently progressed remain unclear. To investigate this, we interrogated 10 patients with pre- and post-treatment samples collected at disease progression (PD). We identified genomic events acquired/selected at PD of genes involved in the anti-apoptotic MCL1/BCL2 and MAPK pathways in 6/10 cases. One patient was refractory to Venetoclax and had double minutes involving BCL2, which caused multiple focal amplifications (>30 copies), likely reflecting extrachromosomal DNA. Another patient progressed with an acquired, focal deletion on BCL2L11. In two patients, the progressing clones harbored mutations in MAPK pathways (one BRAF and the other WNK2). Two patients who relapsed after sustained CR had major branching evolution where a previously undetectable focal deletion of PMAIP1 (NOXA) was seen at PD. Importantly, one of these deletions was a biallelic event. Venetoclax sensitivity assays conducted on PMAIP1 knockout in the MM t(11;14) cell line, KMS12PE, demonstrated significantly reduced cell death across all drug concentrations (p<0.05), validating the loss of NOXA as a mechanism of resistance to Venetoclax in MM. Finally, similarly with what was previously reported in chronic lymphocyte leukemia treated with Venetoclax (e.g., Herling et al Nat Comm 2018), CDKN2A/B monoallelic and biallelic focal deletions were selected post-Venetoclax, at PD in 4 patients while TP53 SNV/deletions were selected from subclonal to clonal in 2 patients at PD. Conclusion: In this study, we demonstrate that mutations involving the MAPK pathway identify a population of MM patients with t(11;14)(CCND1;IGH) who are unlikely to respond to Venetoclax. We also show that genomic events involving the MAPK and BCL2/MCL1 pathways are primarily responsible for disease progression after initial response. These findings highlight the critical role of comprehensive genomic profiling through WGS in identifying mechanisms of resistance to targeted therapies in MM, aiding patient selection for Venetoclax, and guiding the development of novel drug combinations.

Background: Multiple myeloma (MM) is an incurable plasma cell malignancy with several recurrent primary cytogenetic abnormalities including t(11,14)(q13;q32), resulting in increased expression of CCND1. Although 40% of patients with t(11;14) MM respond favorably to the BCL-2 inhibitor venetoclax (ven), 60% fail to achieve an objective response. Previous studies have suggested upregulation of PMAIP1, encoding the pro-apoptotic NOXA protein, in association with ven sensitivity (Leblay, Blood, 2024). Here we sought to evaluate the role for NOXA in ven response in t(11;14) MM. Methods: We analyzed whole exome, whole genome and RNA sequencing data of CD138+ tumor cells from 1,359 patients with MM in the CoMMpass and Mayo Clinic cohorts. The histone mark H3K27ac was assessed in t(11;14)+ KMS12PE and U266B1 human myeloma cell lines using ChIP-seq. Gene expression and protein levels of PMAIP1 (NOXA) were also detected by qRT-PCR and Western blot, respectively. Live cell detection was evaluated by Annexin V and PI using flow cytometry and by YoYo3 dye using IncuCyte following treatment with ven. Results: The t(11;14) MM subtype was associated with a 1.6-5.5-fold increased expression of PMAIP1 compared to non-t(11,14) MM in the CoMMpass and Mayo Clinic cohorts (p<0.0001). These findings are consistent with a significant correlation between CCND1 and PMAIP1 expression in both cohorts (p<0.001). To evaluate whether cyclin D1 is directly associated with increasing expression of PMAIP1 in t(11;14) MM, we generated a cyclin D1 knock out (KO) version of the U266B1 line using CRISPR/cas9. Two independent U266B1 KO cell lines showed reduced expression of PMAIP1 and NOXA protein compared to the WT U266B1 consistent with a role for cyclin D1 in regulating PMAIP1 expression. In addition, the KO lines had a 4.8-fold reduced H3K27ac signal at the PMAIP1 locus in comparison to the WT control suggesting a role for cyclin D1 in promoting H3K27ac. We previously observed increased expression of CCND1 in association with the G allele compared to the A allele of rs9344 in both the CoMMpass and Mayo Clinic cohorts (Leukemia, in press). We next asked whether the G risk allele of rs9344 within CCND1 impacted gene expression and H3k27ac levels at the PMAIP1 locus. To study the allele specific effect of CCND1, we used the CRISPR/cas9 edited KMS12PE WT (rs9344 AA) and Knock In (KI) (rs9344 GG) cell lines. In the KI cells, the G allele was accompanied by an ~2-fold increased expression of PMAIP1 and NOXA protein detected by western blot (<0.05). Increased PMAIP1 expression in KI lines was also accompanied by a 2.2-fold increased H3K27ac further suggesting a role for the G allele of rs9344 in promoting H3K27ac and gene expression at the PMAIP1 locus. Finally, we evaluated the consequence of PMAIP1 expression levels in relation to ven response. Increased expression of PMAIP1 and elevated levels of NOXA protein in the KMS12PE KI lines was associated with increased sensitivity to ven resulting in ~50% increase in cell death of KI vs. WT lines (p<0.02). Conclusion: We demonstrate a role for cyclin D1 in regulating PMAIP1 expression through H3K27ac resulting in increased NOXA protein. Levels of NOXA are associated with the G allele of rs9344 and increased venetoclax response.

Background: Multiple Myeloma (MM) is predominantly a disease of older adults. However, older patients vary widely in physiological status and treatment tolerance. The simplified frailty index (Facon 2020) incorporates age, ECOG performance status, and comorbidities (Charleston Comorbidity Index [CCI]) to classify patients as frail or non-frail. While frailty is associated with increased toxicity with conventional systemic therapies, its impact on outcomes of older patients treated with bispecific antibodies (BsAbs) has not been established. Thus, we conducted a retrospective study to evaluate the efficacy and toxicity of BsAbs in older patients based on frailty. Methods: This is a single institution study. We included patients with MM ≥65 years who initiated treatment with a BsAb at Mayo Clinic in Rochester, MN from August, 2018 to January, 2024. Patients who received a BsAb on trial or as standard of care were included. For patients who received 2 different BsAbs at different timepoints, we included the first treatment only. We grouped patients into frail and non-frail based on the simplified frailty index (score ≥2 = frail). We evaluated the overall response (ORR) and ≥very good partial response (VGPR) rates, progression-free (PFS) and overall (OS) survival, early mortality (within 90 days) including early non-relapse mortality (NRM), and toxicities including cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS) and healthcare utilization. P values were insignificant (>0.05) unless otherwise stated. PFS and OS were calculated from the day of BsAb start. Results: A total of 99 patients age 65-89 years were included. The products used were teclistamab (N=43), talquetamab (N=2), and investigational agents (N=54); 67% were ≥70 and 29% were ≥75 years; 39% were female, 95% were non-Hispanic White and 4% were Black/African American. Seventy patients (71%) were considered frail and 29 (29%) were non-frail. At the time of BsAb start, a higher proportion of frail patients had platelets <75 x 10^9/L (30% vs 8%, P=0.04). Otherwise, there was no significant difference between frail and non-frail patients in age (median: 72 vs 70), hemoglobin <8 g/dL (19% vs 12%), absolute neutrophil count <1 x 10^9/L (6% vs 8%), presence of high-risk FISH (70% vs 60%), ISS stage 3 (32% vs 41%), high LDH (58% vs 61%), presence of extramedullary disease (39% vs 25%), serum creatinine ≥2 mg/dL (15% vs 8%), bone marrow plasma cell% (20% in both), triple- (83% vs 90%) and penta-class refractoriness (63% vs 48%), number of prior lines of therapy (median: 6 in both), prior exposure to BCMA-directed therapy (24% vs 21%, P=0.80) and prior autologous stem cell transplant (73% vs 86%). Step-up dosing was used in 81% vs 48% of patients (P=0.001), and treatment was initiated in the outpatient setting in 46% vs 28% (P=0.12) in frail and non-frail patients, respectively. The median follow-up was 1.9 (95%CI: 1.0-2.3) years. There was no significant difference between frail and non-frail patients in ORR (52% vs 62%), ≥VGPR (46% vs 48%), 1-year PFS (36% vs 48%, P=0.26), or 1-year OS (57% vs 61%, P=0.30), respectively. Age and CCI alone were not associated with PFS or OS, but ECOG >1 was associated with decreased PFS (hazard ratio: 3.1, P=0.001) and OS (hazard ratio: 3.1, P<0.001). There was no significant difference between frail vs non-frail patients in grade 3/4 thrombocytopenia (39% vs 17%, P=0.06), grade 3/4 neutropenia (27% vs 35%), total days of hospitalization (median: 8 vs 5, P=0.35), number of unplanned admissions in 6 months (median: 1 in both), or total hospital days for unplanned admissions (1 vs 2 days). There was no significant difference between frail and non-frail patients in early mortality (23% vs 10%, P=0.17), including early NRM (4% in both), CRS (59% vs 66%), grade 3-4 CRS (3% vs 7%), or CRS recurrence (21% vs 10%). ICANS occurred in 5 (9%) frail patients and 1 non-frail patient (grade 2); among frail patients, grades were: 1 in 3 patients, 3 in 1 patient, and 4 in 1 patient. Similarly, there was no significant difference in CRS/ICANS between the 2 groups when patients with and without step-up dosing were analyzed separately. Conclusion: Frailty, defined using the simplified frailty index, was not significantly associated with inferior efficacy or increased toxicity with BsAb therapy among older patients with MM. Poor performance status predicted inferior PFS and OS, while age and comorbidity scores did not.