Advani, Anjali S.

Abstract Introduction: While newly diagnosed patients (pts) with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy have prolonged survival outcomes with venetoclax plus azacitidine (VEN+AZA) over AZA alone (2-year overall survival rate: 37.5% vs 16.9%), more can be done to further enhance outcomes (Pratz et al., 2024). CD123 is overexpressed on AML blasts and leukemia stem cells in AML. Pivekimab sunirine (PVEK) is a first-in-class antibody-drug conjugate comprised of a high-affinity anti-CD123 antibody, a cleavable linker, and an indolinobenzodiazepine pseudodimer payload. Previously, in pts with CD123-positive AML, PVEK combined with VEN+AZA demonstrated robust response rates with a manageable safety profile (Daver et al., 2023). Here we report a subgroup analysis from a preliminary cohort of frontline (1L)-treated pts with AML. Methods: Data are from the dose expansion phase of an ongoing, open-label, multicenter, fully enrolled, Phase 1b/2 study of PVEK+VEN+AZA in adults with 1L unfit AML deemed CD123-positive by investigator. Unfit pts were aged ≥75 years (yr), or aged <75 yr with Eastern Cooperative Oncology Group performance status (ECOG PS) score 2–3, or ≥1 defined comorbidity. Pts received PVEK (0.045 mg/kg, intravenous [IV]) on Day (D) 7 plus VEN (400 mg equivalent, oral) daily in a 28-D cycle (cohort 1 received ≥14 D of VEN; cohort 2 received 28 D of VEN) plus AZA (up to 75 mg/m2, subcutaneous or IV) on D1–7. Bone marrow assessments were performed by D12–14 (cohort 1) or D18–21 (cohort 2) to determine VEN duration in cycle 1 and at the end of every subsequent cycle to assess responses and myelosuppression. The primary endpoint was antileukemia activity (complete remission [CR] rate) and measurable residual disease (MRD) assessments. Responses were determined using the modified European LeukemiaNet 2017 criteria (plus CR + partial hematologic recovery [CRh]). MRD-negativity was defined centrally as <0.1% using multiparameter flow cytometry. Safety was assessed as a secondary endpoint. Results: Among 1L unfit pts with CD123-positive AML (n=49), the median (range) age was 77 (58–85) yr, with most pts aged ≥75 yr (n=36 [74%]). Forty-two (86%) pts reported an ECOG PS ≤1, 14% (n=7) had secondary AML, and 20% (n=10) and 51% (n=25) had intermediate or adverse cytogenetic risk, respectively; 65% (n=32) and 35% (n=17) were reported as TP53wt or TP53mut, respectively. Eight (16%) pts bridged to stem cell transplant. The median (range) number of treatment cycles and duration of treatment were 4 (1–20) and 5.5 (0.7–22.7) months (mo), respectively, for PVEK; 4 (1–20) and 5.1 (0.9–22.9) mo for VEN; and 4 (1–21) and 5.7 (0.9–23.4) mo for AZA. For cohort 1 (n=10), the median (range) duration of VEN was 4.5 (2.1–22.9) mo, and for cohort 2 (n=39), the median (range) duration of VEN was 5.7 (0.9–15.2) mo. With a median (range) follow-up of 10 (1.2–26.7) mo, 63.3% (95% CI: 48.3%–76.6%) of pts achieved CR, 79.6% (95% CI: 65.7%–89.8%) achieved CR/CR with incomplete hematologic recovery (CRi), and 73.5% (95% CI: 58.9%–85.1%) achieved CR/CRh; morphologic leukemia free state was achieved in 4% (n=2) of pts. Of pts who achieved CR or CR/CRi with a MRD-evaluable sample, 92% (23/25) and 90% (27/30) achieved flow cytometry MRD-negativity (<0.1%) respectively. The most common (≥50% of pts) any grade treatment-emergent adverse events (AEs) were neutropenia/neutrophil count decreased and thrombocytopenia/platelet count decreased (both 69%); constipation (61%); and peripheral edema (51%). Three pts (6%) experienced AEs leading to discontinuation (myocardial infarction/soft tissue infection/thrombocytopenia) and 2 pts had AEs leading to death (respiratory failure/pancytopenia). Conclusions: Unfit pts with newly diagnosed CD123-postive AML demonstrated high CR rates with PVEK+VEN+AZA. These robust response rates were observed across the select mutational profiles tested. Follow up with duration of response and survival estimates among all pts, by molecular subgroups and MRD negativity status, are being evaluated. Triplet therapy in unfit 1L pts with CD-123–positive AML was well-tolerated, and no new safety signals were observed. These data highlight the need to further evaluate this regimen in a randomized trial.

Abstract Introduction: Leukemogenesis is driven by nucleophosmin 1 mutations(NPM1-m) or lysine methyltransferase 2A rearrangements(KMT2A-r) in ~35–40% of acute myeloid leukemia (AML) cases. Nearly half of AML patients will develop relapsed/refractory (R/R) disease within a year, with <20% expected response rate following venetoclax/azacitidine (Ven/Aza) and progressively poorer outcomes with each subsequent line of therapy. Ziftomenib–a potent, highly selective, oral, investigational menin inhibitor–has demonstrated clinical activity as both monotherapy and in combination for adults with R/R NPM1-m or KMT2A-r AML. KOMET-007 (NCT05735184) is an ongoing, open-label, ph1a/b study of ziftomenib in combination with standard chemotherapies in adults with newly diagnosed and R/R NPM1-m or KMT2A-r AML. Here we present updated safety and clinical activity in patients with R/R AML treated with the recommended ph2 dose (RP2D) of ziftomenib 600 mg in combination with Ven/Aza across ph1a/b. Methods: Adults (≥18y) with R/R NPM1-m or KMT2A-r AML enrolled independently into separate arms; patients in dose escalation (ph1a) and expansion (ph1b) were treated with oral ziftomenib 600 mg once daily (QD; continuously from C1D8 onward) plus standard doses of Ven/Aza. Primary endpoints: AEs, complete remission (CR; ELN 2022), dose limiting toxicities (DLT; ph1a only). Key secondary endpoints: composite CR (CRc; CR with full, partial or incomplete hematologic recovery), overall response, duration of response. Results: As of June 25, 2025, 80 patients (51 NPM1-m, 29 KMT2A-r) with R/R AML were enrolled (20 ph1a; 60 ph1b) and treated with ziftomenib 600 mg QD + Ven/Aza. Median age was 63y (range 19–85), 50% were female, 74% had ECOG PS 0–1; 22 (28%) had FLT3 co-mutations and 7 (9%) had IDH co-mutations. Median number of prior therapies was 1 (range 1–6); 18% (14/80) had prior stem cell transplant; 25 (49%) NPM1-m and 19 (66%) KMT2A-r patients had prior Ven exposure. 71 patients (89%) had Gr ≥3 treatment-emergent AEs, most commonly (≥20% of patients) febrile neutropenia (31%), decreased platelet count (28%), decreased white blood cell count (26%) and decreased neutrophil count (23%). Gr ≥3 ziftomenib-related AEs occurred in 30 patients (38%), most commonly febrile neutropenia (9%) and anemia (8%). 6% of patients discontinued ziftomenib treatment due to AEs. Differentiation syndrome (DS) occurred in 1 (1%) NPM1-m patient (Gr 3), which lasted 1d and successfully resolved with protocol-specified DS mitigation. No ziftomenib-related QTc prolongation was reported with the combination, and no DLTs were observed in ph1a. 70 patients (43 NPM1-m; 27 KMT2A-r) were response-evaluable (≥1 response assessment or death). Median follow-up was 18.0 wks for NPM1-m and 16.4 wks for KMT2A-r. Overall response rates (ORRs) were 65% (28/43) for NPM1-m and 33% (9/27) for KMT2A-r. CRc rates were 49% (21/43) for NPM1-m and 22% (6/27) for KMT2A-r after median time to first CRc of 4.9 wks (range 2.7–15.6) and 5.5 wks (range 2.6–18.9), respectively; measurable residual disease (MRD)-negativity rates (local) among tested CRc responders were 50% (9/18) for NPM1-m and 60% (3/5) for KMT2A-r after median time to first MRD-negativity of 5.9 wks (range 2.9–15.6) and 8.1 wks (range 7.7–18.9), respectively. During continuous ziftomenib administration in patients who achieved CRc, median time to neutrophil recovery (≥1×109/L) was 43d overall (43d for NPM1-m; 71d for KMT2A-r), and median time to platelet recovery (≥100×109/L) was 27d overall (27d for NPM1-m; 23d for KMT2A-r). As of the data cutoff, overall median duration of CRc was not estimable; median overall survival was not estimable for NPM1-m and 21.1 wks for KMT2A-r. In Ven-naive patients, CRc rates were 71% (15/21) for NPM1-m and 33% (3/9) for KMT2A-r; CR rates were 48% (10/21) and 11% (1/9); and ORRs were 81% (17/21) and 56% (5/9), respectively. The study is ongoing with 44% (19/43) of NPM1-m and 11% (3/27) of KMT2A-r patients still on treatment, with responses continuing to evolve.Updated data to be presented.Conclusions: In the ongoing KOMET-007 study, ziftomenib RP2D of 600 mg QD + Ven/Aza was well tolerated with robust clinical activity in patients with R/R NPM1-mor KMT2A-rAML. No ziftomenib-related QTc prolongation was reported. One case of DS (NPM1-m, Gr 3) successfully resolved with protocol-specified mitigation. These data support further investigation of ziftomenib-based combinations in R/R NPM1-mand KMT2A-rAML.

Abstract Chimeric antigen receptor (CAR) T-cell (CAR-T) treatment for B-cell acute lymphoblastic leukemia (ALL) induces high initial response rates, but most patients relapse. Low disease burden (often defined as <5% blasts in the bone marrow) is associated with better outcomes. CAR HEMATOTOX (HT) is a score using prelymphodepletion hematologic and inflammatory parameters to predict outcomes in lymphoma. Here, we assess its prognostic utility in a large multicenter adult B-cell ALL cohort. Patients who received brexucabtagene autoleucel across 33 centers in North America were included as part of the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) consortium. An independent cohort of 61 patients with ALL treated with an investigational CD19 CAR-T therapy at 1 center was also described. Among 199 ROCCA consortium patients, 43 (22%) patients with HTlow scores had lower rates of delayed neutrophil recovery than those with HThigh scores (26% vs 52%, P = .002) and fewer severe infections (2.5% vs 18.8%, P = .011). They also had higher response rates, overall survival (OS), and event-free survival (EFS), as well as lower nonrelapse mortality and cumulative incidence of relapse. The survival differences remained significant after multivariable adjustment for disease burden and other covariates. In the investigational cohort of 61 patients, patients with HTlow scores had improved OS and EFS, as well as higher peak CAR-T expansion. In summary, CAR HT score is a prognostic factor independent of disease burden in adult ALL. HTlow score is associated with superior outcomes after CD19 CAR-Ts and higher CAR-T expansion in a single-center cohort. These trials were registered at www.clinicaltrials.gov as #NCT01044069 and #NCT01860937.

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 While central nervous system (CNS) disease is found in minority of patients (pts) at diagnosis of Ph+ ALL, later relapses can occur in pts despite adequate CNS prophylaxis. CNS disease can be managed with varying combinations of systemic, radiation, and intrathecal (IT) therapy and can be associated with significant toxicity, especially in older pts. While there are more durable systemic responses with 2nd or 3rd generation tyrosine kinase inhibitors (TKIs) based combinations, CNS penetration can vary by TKI. In this large multi-center study, we analyze the incidence of CNS disease in Ph+ ALL in the context of induction therapies and survival post relapse. Methods We conducted a multicenter observational study in collaboration with 10 U.S. academic centers under the COMMAND consortium and reviewed the incidence of CNS relapse in 505 Ph+ ALL pts. We evaluated baseline characteristics, treatment given prior to CNS relapse, and outcome post relapse. Results Baseline characteristics, initial treatment and outcome prior to CNS relapse Eighteen (3.56%) pts were identified to have CNS disease at relapse. Median age of the pts in years (yrs) was 51 (range [R], 22-75), median white blood cell (WBC) was 33.3 x 10(9)/L (R, 2.1-200) and 6 (33%) pts had additional cytogenetic abnormalities at diagnosis. Sixty-one percent (n= 11) of pts received intensive chemotherapy (IC) during induction; 2 (11%), 14 (78%) and 2(11%) of pts received 1st, 2nd or 3rd generation TKI-based combination during induction, respectively. All of pts achieved complete remission (CR), 45.5% achieved complete molecular remission (CMR) at 3 months from the time of diagnosis. Five (28%) pts received allogeneic stem cell transplantation (allo-HCT) as a consolidation therapy. Treatment received at CNS relapse and response The median time to CNS relapse after induction was 10.8 months (mo) (R, 2-79). All pts except 1 had isolated CNS relapse after CR1, 4/18 (22%) pts had T315I mutation at relapse. Twelve (67%) and 6 (33%) pts received intrathecal chemotherapy (IT) with TKI and systemic chemotherapy + TKI in addition to IT, respectively. Eleven (61%) pts received dasatinib, 5 (28%) pts received ponatinib and one (6%) pts each received bosutinib and imatinib at relapse. Ninety-three percent of pts achieved CR (n=3, not evaluable). Six (33%) pts underwent allo-HCT after CNS relapse, one of these transplanted pts had second allo-HCT. Survival after CNS relapse The median relapse free survival (RFS) and overall survival (OS) after CNS relapse was 9.8 (95% CI: 3.80-15.76) and 13.87 (95% CI: 4.08-23.65) mo, respectively. In subset analysis, we compared survival outcome among pts who had relapse without CNS involvement (n= 160/505 [32%]). The median RFS (9.9 vs 9.8, p= 0.88) and OS (31.53 vs 28.80, p= 0.57) after relapse was not significantly different among pts who had relapse with or without CNS involvement, respectively. We also compared OS among pts without relapse to those with relapse. The median OS was not reached (NR; 73% alive at 5 years), 28.80 and 31.53 months (p= <0.001) among pts with no relapse, relapse with CNS and without CNS involvement, respectively. Conclusion Our retrospective analysis from a large database showed that CNS relapses were uncommon (3.56%) in adult pts with Ph+ ALL. A majority of pts (89%) received a 2nd or a 3rd generation TKI during induction. Approximately one quarter of pts with CNS relapse had emergence of T315I mutation. While almost all pts achieved CR, the RFS was relatively short. We did not see significant differences in survival among pts who had relapse with or without CNS involvement.

Introduction E1910 randomized pts with ALL aged 30-70 years who were measurable residual disease negative (MRD-) by multi-color flow cytometry (FC) after intensification to conventional chemotherapy (chemo) with or without blinatumomab (blina). The addition of blina resulted in improved overall survival (OS) (Litzow, NEJM 2024) and led to a new standard of care. Older ALL pts have inferior outcomes when compared to younger pts in part due to increased treatment toxicity. In E1910, exposure to dexamethasone and pegasparagase was reduced for older pts (age >55 years). We present results of subgroup analyses describing outcomes of older pts enrolled in E1910. Methods Details of the E1910 protocol remission induction (step 1), high dose methotrexate with pegaspargase intensification (step 2), blina randomization (step 3), and maintenance (step 4) or allogeneic hematopoietic stem cell transplant (HCT) were previously presented (Litzow, NEJM 2024). MRD status was determined after step 2 centrally with 6-color FC with MRD- defined as <0.01% in the bone marrow (BM). Following approval of blina in the US for MRD positive (MRD+) disease in 2018, MRD+ pts were assigned to the blina arm and no longer randomized. The primary objective was to compare the OS and relapse free survival (RFS) among older pts aged >55 years (pre-specified stratification factor) who received chemo + blina to that of pts who received chemo alone (step 3 treatment). Estimates of OS and RFS were calculated using the Kaplan-Meier method. Comparison of OS and RFS between treatment arms was conducted using the two-sided stratified log-rank test and Cox model with CD20 status, rituximab use, and whether pts intended to receive HCT or not as stratification factors. Stratified Multivariate Cox models of OS and RFS were used to further evaluate the effect of step 3 treatment, adjusted by gender, white blood cell count (WBC), platelets, hemoglobin, peripheral blood blasts, BM blasts, performance status and combined molecular risk category. Results Among the 488 enrolled pts, 211 were ≥55 years old with median age of 61 (range 55-70). Among older pts, 49.3% were female and 83.4% were white, 17 (8.1%) pts had WBC >30.000/uL at the time of diagnosis. 156 (73.9%) pts had CD10+ early B-ALL and 46 (21.8%) had CD10- B-ALL immunophenotype. The most common genetic subgroups were low hypodiploid (n=58, 27.5%), BCR::ABL1-like (n=34, 16.1%) and KMT2A rearranged (n=26, 12.3%). 8.1% of pts had low, 9.0% intermediate, 63.5% high combined molecular risk disease and in 19.4% of pts risk could not be assigned. Baseline characteristics were not significantly different in chemo + blina and chemo only pts. The median follow-up for this analysis from step 1 registration was 54.6 months. Complete response with (CR) or without (CRi) count recovery after induction was observed in 174 (82.5%) pts (167 CR, 7 CRi). 93 (44%) pts were MRD-. 32 (15.1%) pts received HCT on study and 24 (11.4%) pts received it off study. Among MRD- pts (n=93), 46 were randomized to and 45 received blina: 6 (13.3%) pts had 1, 14 (31.1%) had 2, 2 (4.4%) had 3 and 23 (51.1%) had 4 cycles. 3-year OS were 71% and 67% for the blina and the chemo only arm (univariate model: HR 0.75, 95% CI: 0.37-1.50; multivariate model: HR 0.56, 95% CI: 0.25-1.27). 3-year RFS were 69% and 59% for the blina and the chemo only arm (univariate model: HR 0.75, 95% CI: 0.39-1.45; multivariate model: HR 0.67, 95% CI: 0.32-1.42). Among MRD+ pts (n=25), 14 were randomized to and 11 received blina: 7 (63.6%) pts had 2, and 4 (36.4%) had 4 cycles. 3-year OS were 66% and 44% for the blina vs the chemo only arm (univariate model: HR 0.66, 95% CI: 0.12-3.64). 3-year RFS were 64% and 31% for the blina vs the chemo only arm (univariate model: HR 0.64, 95% CI: 0.15-2.74). Frequency of treatment-related toxicities among older pts during different study phases and treatment assignments will be presented. Conclusion Despite evidence of improved outcomes in the whole study cohort, the addition of blina to consolidation chemo for older pts with ALL was not associated with statistically significant improvement of OS or RFS in this exploratory analysis not powered to detect the difference in subgroups. This is possibly due to sample size but may be due to biologic differences in the older adult population. Further studies are needed to definitively determine tolerance and benefit of blina addition to consolidation for older pts with ALL.

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.

Introduction: Based on a donor versus no-donor analysis, UKALLXII/E2993 showed a survival benefit for adults with acute lymphoblastic leukemia (ALL) who underwent allogeneic hematopoietic cell transplantation (alloHCT) in first complete remission (CR1) compared to consolidation/maintenance chemotherapy alone. The follow-up phase 3 E1910 trial (NCT02003222) randomized BCR::ABL1-negative B-lineage ALL patients (pts) aged 30-70 years in measurable residual disease (MRD)-negative CR1 after intensification to conventional chemotherapy (CC) +/- blinatumomab (blin) and demonstrated significantly improved overall survival (OS) with blin (Litzow, NEJM 2024). The current exploratory subgroup analysis evaluates outcomes of MRD-negative pts randomized on E1910 who underwent alloHCT on trial. Methods: Among pts enrolled on E1910, pts in MRD-negative CR1 by 6-color flow cytometry after intensification who were randomized to CC +/- blin and subsequently underwent alloHCT were identified. We compared baseline characteristics, MRD status post induction, relapse-free survival (RFS) and OS using the Kaplan-Meier method and the two-sided log-rank test and Cox model. A multivariable analysis was performed with alloHCT included as a time-varying covariate as well as a landmark analysis comparing the outcome of pts with unfavorable risk on the CC + blin arm who underwent alloHCT versus those who did not. Results: Of 224 MRD-negative randomized pts, 44 underwent alloHCT on trial: 22 in each arm. The median time from randomization to transplant was 3.2 months (mos). The median follow-up from initial registration was 57.8 mos. Baseline demographics including age (median 55 years), gender (53% male), race (89% white) and ethnicity (89% non-Hispanic/Latino) were equally distributed. Compared to CC + blin, the median peripheral blood white cell (WBC) count and blast percentage at diagnosis were higher in the CC arm at 6,640 vs 3,740/uL and 55 vs 9%, respectively, while median marrow blast percentage and overall unfavorable risk as defined in E1910 (55% vs 64%) were similar. Of the 44 MRD-negative pts who proceeded to alloHCT on study, 77% in the CC arm and 64% in the CC+ blin arm were MRD-negative after induction. Myeloablative conditioning was given to the majority of pts (68% CC arm and 73% CC+blin arm) and the most common graft versus host disease prophylaxis was tacrolimus-based on both arms. Among the 44 pts who underwent alloHCT, the observed hazard ratio (HR) comparing relative risk of death between pts randomized to CC+blin or CC only was 0.59 (95% CI: 0.12-2.11) with a 3-year OS rate of 82% versus 71% and the HR comparing relative risk of relapse/death was 0.52 (CI: 0.15-1.79) with a 3-year RFS rate of 82% versus 67%. For patients with unfavorable risk, 3-year OS and 3-year RFS in each treatment arm were both 71% versus 65%. Among 50 pts with unfavorable risk in MRD-negative CR after intensification who were randomized to CC + blin, a landmark analysis performed at 5 mos post randomization showed 3-year OS and RFS rates of 71% versus 90% and 71% versus 86% between the 14 pts who underwent alloHCT and those who did not, respectively. Receipt of alloHCT was a time-varying covariate in a multivariable analysis with gender, WBC count, platelets, hemoglobin, peripheral blood blasts, bone marrow blasts, performance status, and combined molecular risk category. Age, CD20 status, rituximab use, and intention to receive alloHCT were used as stratification factors. In the entire cohort of MRD-negative pts who were randomized, there was a significant association between improved OS and the receipt of CC+blin vs CC alone (HR 0.46, 95% CI: 0.26 - 0.82; p=0.009), better performance status of 0-1 vs ≥2 and favorable vs unfavorable risk ALL. In contrast, the receipt of alloHCT had no significant effect on OS (HR 1.00, 95% CI: 0.49 - 2.01). Conclusions: Within the constraints of small numbers, this exploratory subgroup analysis demonstrates that in pts with newly diagnosed BCR::ABL1-negative B-ALL treated on E1910 who achieved MRD-negativity after intensification, alloHCT outcomes did not appear to be different with or without blin in consolidation. In a multivariate analysis of all MRD-negative pts, receipt of blin but not alloHCT was associated with improved OS. Further investigation is warranted to characterize the relative benefit of blinatumomab in pts receiving alloHCT in frontline consolidation.

Introduction: Inotuzumab ozogamicin (INO) is an antibody targeting CD22 conjugated with a cytotoxic antitumor antibiotic (calicheamicin) approved for treatment of relapsed/refractory CD22 positive B-cell acute lymphoblastic leukemia (ALL) (Kantarjian et al. NEJM 2017). CD22 is expressed on the surface of lymphoblasts in ALL (~95%). Young adult patients (pts) 18-39 years (yrs) treated on the pediatric regimen CALGB 10403 resulted in a 3-yr event-free survival (EFS) of 59% (95% CI: 52-67%) and an estimated 3-yr overall survival (OS) of 73% (95% CI: 68-78%) (Stock et al. Blood 2019). Alliance A041501(NCT03150693), a phase 3 NCTN sponsored cooperative group trial was conducted to determine if the addition of INO to the CALGB 10403 pediatric regimen would significantly improve EFS. Methods: Eligibility included pts 18-39 years with newly diagnosed CD22 positive ALL, defined as baseline expression in > 20% of lymphoblasts by local institution. Pts with Burkitt-type ALL, BCR::ABL1 positive ALL, or Down syndrome were excluded. Eligible pts received the CALGB 10403 regimen modified to omit extended induction, include dexamethasone as opposed to prednisone as steroid backbone, cap the pegaspargase dose to 3750 units, and adding rituximab for pts with CD20 expression (> 20%). An amendment added blinatumomab for minimal residual disease (MRD) positivity. Pts achieving a complete remission (CR/CRi) or partial remission (PR) were eligible for randomization. Following a 6 pt safety run-in with INO, pts were randomized 1:1 to receive INO or continue CALGB 10403 backbone. Two cycles of INO (1.5 mg/m2/cycle) were administered following induction in the experimental arm. Pts were stratified by age, disease status post induction (M0/M1 vs M2), CD20 status, and LDA Card, which tests for the Ph-like status. The primary endpoint was to determine if the addition of INO would improve the EFS of the pediatric regimen CALGB 10403 without censoring for stem cell transplant (SCT). Key secondary endpoints included the impact of INO on disease-free survival (DFS), OS, and MRD. The Alliance Data and Safety Monitoring Board halted enrollment after 273 out of a planned 341 pts were registered because of increased grade (gr) 5 events in the INO arm compared with the control arm. Results: 273 pts were enrolled between 6/15/2018, and 5/24/2022. Median age was 27.0 yrs, 65.2% were White, 30.4% were Hispanic, and 63.4% were male. Baseline CSF analysis revealed 14% with CNS-2/3 disease. The overall CR rate was 86.8% (82.8-90.8%). 46 pts were not randomized due to death (5), withdrawal (6), ineligibility (3), toxicity (5), receipt of non-protocol therapy (8), progression (5), and other (14). 227 eligible pts were randomized 1:1 to receive INO (N=111) or not (N=116)). For randomized pts, 92.5% achieved M0/M1 marrow status, 48.9% had a positive LDA Card defining Ph-like ALL, 50.7% were CD20 positive. Only 36 pts (13%) received a SCT. With a median follow up of 28.3 months for randomized pts, 3-yr EFS was 69.0% (59.1-80.5%) for the INO arm and 66.7% (57.1-78.1%) for the control (HR=0.97; 0.58-1.63). Similarly, the 3-yr OS was 79.4% (71.0-88.7%) for the INO arm and 80.3% (71.9-89.6%) for the control (HR=1.05; 0.55-2.01). The MRD undetectable rate at Course II Day 56 was 80.6% in the INO arm and 74.2% in the control arm. Univariate analysis suggests improved EFS with INO in pts with a positive LDA card (Ph-like ALL) and of Hispanic ethnicity. There were 22 gr 5 events, 7 occurred prior to randomization. Of the 15 gr 5 events on the randomized cohort, 12 were reported in the INO arm and 3 in the control arm. Of the 12 gr 5 events in the INO arm, all occurred during intensive consolidation courses complicated by prolonged pancytopenia infection/sepsis (8), hepato-biliary in setting of infection (2), multi-organ failure (1), or post-surgical complication (1). These events occurred after INO during Course II (3), Course III (5), or Course IV (4). Conclusions: Although this trial did not meet the primary EFS endpoint for the addition of INO to the pediatric regimen CALGB 10403, these data provide compelling evidence for continued use of pediatric regimens in young adults with ALL as the EFS and OS compares favorably with prior published results. INO may still be efficacious if late toxicity can be mitigated. A pilot study is planned that will decrease INO dose, add 2 cycles of blinatumomab and strict infectious prophylaxis guidelines. Support: U10CA180821, U10CA180882

PURPOSE On the basis of the results of the ZUMA-3 trial, brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor T-cell therapy, gained US Food and Drug Administration approval in October 2021 for adults with relapsed/refractory (R/R) B-cell ALL (B-ALL). We report outcomes of patients treated with brexu-cel as a standard therapy. METHODS We developed a collaboration across 31 US centers to study adults with B-ALL who received brexu-cel outside the context of a clinical trial. Data were collected retrospectively from October 2021 to October 2023. Toxicities were graded per American Society for Transplantation and Cellular Therapy guidelines for cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). RESULTS At the time of data lock, 204 patients had undergone apheresis and 189 were infused. Median follow-up time was 11.4 months. Forty-two percent of patients received brexu-cel in morphologic remission and would have been ineligible for participation in ZUMA-3. After brexu-cel, 151 achieved complete remission (CR), of which 79% were measurable residual disease (MRD) negative remissions. Median progression-free survival (PFS) was 9.5 months and median overall survival was not reached. Grade 3-4 CRS or ICANS occurred in 11% and 31%, respectively. In multivariable analysis, patients receiving consolidative hematopoietic cell transplantation (HCT; hazard ratio, 0.34 [95% CI, 0.14 to 0.85]) after brexu-cel had superior PFS compared with those who did not receive any consolidation or maintenance therapy. CONCLUSION Similar to ZUMA-3, high rates of MRD-negative CR were observed after brexu-cel treatment for R/R B-ALL. The use of HCT as consolidation after brexu-cel resulted in improved PFS.