GRAVITAS-119 (NCT03320642), a single-arm, open-label, phase 1, proof-of-concept study, assessed addition of itacitinib to standard-of-care graft-versus-host disease (GVHD) prophylaxis regimens in reduced-intensity conditioning peripheral blood allogeneic hematopoietic stem cell transplant. Day 28 hematologic recovery (percentage of patients demonstrating neutrophil recovery and platelet recovery) was the primary endpoint. Of 84 enrolled patients, 41 received itacitinib plus tacrolimus/methotrexate (nine with antithymocyte globulin [ATG]), 24 received itacitinib plus cyclosporine A/mycophenolate mofetil (16 with ATG), and 19 received itacitinib plus post-transplant cyclophosphamide/tacrolimus. Hematologic recovery was achieved by 51/55 (92.7%) evaluable patients (neutrophil recovery, 98.7%; platelet recovery, 94.6%). Estimated 1-year GVHD-free, relapse-free survival was 39.7%; estimated 1-year overall survival was 78.3%. Cumulative incidences for grade 2-4 and grade 3-4 acute GVHD at Day 180 were 13.2% and 4.8%, respectively; cumulative incidence of chronic GVHD at 1 year was 37.8%. Most common grade ≥ 3 adverse events were cytopenias; grade ≥ 3 infections occurred in 23 (27.4%) patients. Most patients receiving itacitinib plus standard-of-care GVHD prophylaxis achieved hematologic recovery, with any-grade GVHD and infection rates similar to previous reports with standard-of-care prophylaxis. Addition of itacitinib to GVHD prophylaxis permits timely hematologic recovery and does not increase GVHD or infection rates, although unmet need still remains for improved regimens.

Introduction Omidubicel (Omi) is an ex vivo expanded product derived from a single umbilical cord blood (UCB) unit. In the Phase III trial (P3) comparing Omi transplant (HCT) to standard UCB transplant, overall aGVHD and cGVHD rates were similar, though a subgroup analysis of Omi HCT revealed a higher incidence of grade II-IV aGVHD in those receiving total body irradiation (TBI). Objective Here, we characterize rates of GVHD in Omi HCT with chemo-only myeloablative conditioning (MAC) at Loyola University Medical Center (LUMC). Methods We included Omi HCT at LUMC through participation in the P3 (PMID:34157093), the Expanded Access Protocol (EAP) (PMID:40204073), or as commercially available therapy between 12/2/17 and 7/1/24. All patients received conditioning with thiotepa, busulfan, and fludarabine and prophylaxis with tacrolimus and mycophenolate. None received TBI or anti-thymocyte globulin. Data was collected retrospectively. Descriptive statistics were reported around variables of interest. Results Eighteen patients underwent Omi HCT at LUMC. Descriptive statistics and outcomes are listed in Figure 1, and were comparable to P3 and EAP outcomes. Six patients (33%) developed aGVHD within 100 days of transplant, with 4 (22%) grade 3-4. Day 100 aGVHD was 56% with 14% Grade 3-4 in the P3, and 63% with 19% Grade 3-4 in the EAP (Figure 2). There was no difference comparing aGVHD+ vs aGVHD- with respect to age, mean age of donor cord blood (DCB) unit, mean DCB CD34+ cell dose, mean total nucleated cell (TNC) dose, and degree of HLA matching (Figure 3).Five patients (28%) developed cGVHD, 4 within 1 year of HCT (3 mild, 1 moderate, 1 severe). By comparison, the P3 reported 35% 1-year cGVHD with 27% moderate-severe, and the EAP 9% cGVHD; all mild (Figure 2). Notably, mean age of DCB unit was younger for those with cGVHD: 4.2 years in cGVHD+ vs 7.9 in cGVHD-. There did not appear to be a difference comparing cGVHD+ vs cGVHD- with respect to mean DCB CD34+ cell dose, mean TNC dose, and degree of HLA match. Donor-recipient CMV status was mismatched in 4/5 (80%) patients with cGVHD versus in 5/13 (38%) without (Figure 3).One-year GVHD-free relapse-free survival (GRFS) was 33% (vs 36% in P3 and 48% in EAP) and cGVHD-free relapse-free survival (cGRFS)was 50% (vs 40% in P3 and 66% in EAP), rates affected by relapse in high-risk disease in this cohort. (Figure 2). Conclusion Omi HCT with chemo-only conditioning showed comparable outcomes with the pivotal P3 and with the EAP. However, rates of aGVHD appeared lower, and cGVHD was comparable to the lower rates seen in the EAP, compared to the P3, in which 31/62 (50%) of patients in the Omi group received TBI. Our findings support use of a chemo-only MAC prior to HCT with Omi.

Introduction QT interval prolongation increases risk of sudden cardiac death from Torsades de Pointes (TdP), though rates are 0.0025% - 0.16% for hospitalized patients. There has been increased emphasis on QTc monitoring during hematopoietic stem cell transplantation (HSCT) due to increased use of QTc-prolonging medications. Limited data exist on QTc prolongation during HSCT. Objectives To assess rates and risk factors for QTc prolongation, cardiac complications, and sudden cardiac death in allogenic-HSCT patients treated from earlier time points versus recently. Methods This single-center, retrospective study compared patients hospitalized for allogeneic-HSCT between 2005-2015 (Cohort 1) and 2020-2023 (Cohort 2). We collected demographic and lab data, medical history, pre-admit and post-transplant EKGs, and QTc-prolonging medication use before and during HSCT. Summary statistics were computed and survival analyses performed. Demographic and clinical variables were compared between cohorts. Normal QTc was defined as ≤ 459 msec, abnormal ≥ 460 msec. Results There were 617 patients in Cohort 1, 116 in Cohort 2. Cohort 2 was older (55.70 vs 52.97 years, p=0.008) and had more coronary artery disease (14.66% vs 5.51%, p=0.000), cardiac stenting or bypass (7.76% vs 3.40%, p=0.039), and myocardial infarction (6.90% vs 1.78%, p=0.005). There were no significant differences in gender or performance status. While Cohort 2 received more QTc-prolonging medications prior to (p=0.001) and during HSCT (p=0.023), intake QTc and QTc changes during HSCT were not significantly different between cohorts. Cohort 1 patients with normal intake QTc (n=512) had median maximal repeat QTc of 458 (IQR 440-488), while those with an abnormal intake QTc (n=105) had median of 496 (IQR 468-528). Cohort 2 patients with normal intake QTc (n= 82) had median maximal repeat QTc of 462 (IQR 443-489), while those with an abnormal intake QTc (n= 34) had median of 493 (IQR 449-514). There were no cases of TdP. Two-year OS for normal and abnormal intake QTc patients was 51.96% vs 50.39%, respectively (p=0.208). Conclusion Despite greater age, medical complexity, and increased use of QTc-prolonging drugs in Cohort 2, there was no significant increase in QTc prolongation or rate of adverse cardiac events. Patients with normal intake QTc tended to remain below the clinically significant 500 msec, whereas patients with abnormal intake QTc tended to remain prolonged with some exceeding 500 msec, despite similar QTc-prolonging drug use. This suggests patients with normal intake QTc may not need stringent monitoring of QTc during hospitalization for HSCT. Given the rarity of cardiac complications and no survival difference at 2 years despite prolonged QTc at entry, withholding potential life-saving medications for fear of further prolonging the QTc may not be necessary and prospective data are needed.

6578 Background: Relapse is a major cause of death after allogeneic stem cell transplant (allo-SCT) in patients with high-risk myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). Chemotherapy maintenance to prevent relapse has had limited success to date, with a phase 3 hypomethylating agent (HMA) study showing no improvement in relapse rate or survival (Oran et al.). A subgroup analysis, however, showed that high-risk patients may indeed benefit (Pasvolsky et al.). We tested a combination of an HMA [azacitidine (AZA)] and a histone deacetylase (HDAC) inhibitor [valproic acid (VPA)] as a novel maintenance following allo-SCT for high-risk AML and MDS patients based on previously reported in vitro synergism between these agents. Methods: This investigator-initiated, single-center, phase II trial included only patients with high-risk MDS and AML who were enrolled following day+40 of allo-SCT to receive AZA and VPA for 4, 28 day cycles. Exclusions included no grade 3-4 acute GVHD, active infection, low risk AML in CR1, a neutrophil count < 1500/µl, or platelets < 50 000/µl. Risk was assessed via DRI at time of transplant. AZA was administered at 40 mg/m2 daily for 5 days SQ with daily oral VPA starting at 15 mg/kg and dose-adjusted to achieve a trough level of bound VPA of 100 µg/mL. Tacrolimus and methotrexate were used as GVHD prophylaxis. The primary endpoints were 1-year relapse rate, overall (OS), and progression-free (PFS) survival. Results: Fifty patients were enrolled. The median age was 52 with 28 (56%) male. The median hematopoietic cell transplantation-specific comorbidity index was 2. Graft types: 21 (42%) matched related, 21 (42%) matched unrelated, and 8 (12%) cord blood. Thirty grafts were from peripheral blood and 12 marrow. Myeloablative conditioning was used in 36 (72%) and reduced intensity conditioning in 14 (28%). At time of transplant for AML patients, 21 (46%) were in CR1, 5 (11%) in CR2, 2 (4%) in CRi, and 18 (39%) were relapsed/refractory. Four had high grade MDS. Baseline DRI: 42 (84%) were very high risk or high risk and 8 (16%) were intermediate risk. Eight (16%) patients did not receive all four cycles: 5 (10%) due to progression of disease, 1 (2%) due to acute GVHD, 1 each (2%) due to fatigue and cytopenias. One-year PFS and OS were 80% and 86% and 5-year PFS and OS were 47% and 61%, respectively. The one-year relapse rate was 18%. Most toxicities were grade I or II: fatigue, cytopenias, and acute kidney injury. Conclusions: The co-administration of AZA and VPA as a short-term maintenance strategy following allo-SCT in patients with high risk MDS and AML is safe and feasible. While a comparative trial is warranted, the use of this HMA+HDAC regimen seems to validate prior data that HMA-based maintenance may improve the outcomes of high-risk MDS and AML patients. Clinical trial information: NCT02124174 .

Omidubicel-onlv is an FDA-approved, nicotinamide-modified, allogeneic hematopoietic progenitor cell therapy derived from umbilical cord blood (UCB). A phase 3 study demonstrated improved hematopoietic recovery and decreased infections with omidubicel compared with UCB allogeneic transplantation. We report results of an Expanded Access Program evaluating clinical outcomes in patients with hematologic malignancies following transplantation with omidubicel. Between August 2020 and May 2023, 29 patients were transplanted at 5 US sites. Patients received myeloablative conditioning, prophylactic and therapeutic medications, and supportive care per institutional guidelines, and were monitored for engraftment, infections, and graft-versus-host-disease (GVHD) for up to 2 years post-transplant. Results were compared with previously reported phase 3 outcomes. Omidubicel recipients had a median age of 39 (range 20-73, 62% male); 45% were non-White and 65.5% had acute leukemia. Median follow-up was 11.8 (range: .3-27.7) months. Median neutrophil and platelet engraftment times were 12 and 33.5 days, respectively. Acute GVHD (grade 3-4) at day 100 occurred in 19% of patients, with chronic GVHD at 1 year in 9% of patients, all of which were mild. First grade 2 to 3 bacterial infections through 100 days post-transplant and first grade 3 viral infection 1 year post-transplant occurred in 18% and 12% of patients, respectively. One-year disease-free survival and overall survival rates were 76% and 87%, respectively. This real-world study of omidubicel transplantation for hematologic malignancies finds that this graft source is commonly used for non-White allogeneic transplant recipients. The rapid engraftment kinetics observed following transplantation with omidubicel appears to have addressed excessive nonrelapse mortality that has been previously observed following myeloablative umbilical cord blood transplantation.

Despite the increasing number of novel therapies to treat newly diagnosed multiple myeloma (NDMM), preventing skeletal-related events (SREs) remains a challenge. This review summarizes the mechanistic causes of myeloma bone disease, data supporting the use of bisphosphonates and RANKL inhibitors, and the optimal management of preventing SREs in NDMM patients. Both zoledronic acid (ZA) and denosumab are acceptable treatment options with comparable safety and efficacy profiles. However, in patients who are candidates for autologous stem cell transplant (ASCT), denosumab may be preferred over ZA due to a progression-free survival (PFS) benefit observed in post hoc analyses when used with proteasome inhibitor-based regimens. The optimal duration of bone-directed therapy is unclear, but it is typically given for two years. Supportive care should include dental evaluation at baseline, annually, and if symptoms appear, given the risk for jaw osteonecrosis with both ZA and denosumab. Both drugs should be held in the setting of dental work. Patients should receive adequate calcium and vitamin D supplementation. Supportive procedures such as cement augmentation, radiation, and orthopedic surgery can also help treat compression fractures, uncontrolled pain, cord compression, and pathologic fractures. We conclude with our approach for managing SREs and a review of novel therapies and targets.

Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 CAR T-cell therapy approved in the US to treat adults aged ≥18 years (≥26 years in the EU) with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). Brexu-cel showed an overall complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate of 73% (CR rate 60%) and median overall survival (OS) of 25.4 months in 78 patients with R/R B-ALL after 2 years in ZUMA-3. Here, we report updated outcomes after >3 years median follow-up. As of July 23, 2022, median follow-up in all patients (N = 78) was 41.6 months. Median OS (95% CI) was 25.6 months (1.2-47.0; N = 78) and was 38.9 months (25.4–not estimable) for responders (n = 58), with 9 patients in ongoing remission without subsequent therapies. Five deaths (none deemed brexu-cel–related) occurred since prior data cut. Benefits from brexu-cel were maintained regardless of age, prior therapies, and subsequent allogeneic stem cell transplantation (alloSCT). Subsequent alloSCT was not associated with survival benefit among responders versus responders without subsequent alloSCT. No secondary T-cell malignancies were reported in ZUMA-3 with long-term follow-up.

To improve outcomes in relapsed or refractory activated B-cell type Diffuse Large B-cell Lymphoma (ABC-DLBCL), we launched a randomized phase 3 trial evaluating 2-year progression free survival (2yPFS) with the addition of ibrutinib to autologous transplant. Patients received ibrutinib 560 mg or placebo with conditioning and for 12 additional cycles. Accrual was adversely affected by implementation of the ABC classifier in this setting and the changing treatment landscape of DLBCL. In all, 39 patients on ibrutinib and 38 on placebo were evaluable. 2yPFS was 57.6% on ibrutinib versus 40.8% on placebo (p = 0.09). We observed a higher incidence of grade ≥3 sepsis (10% vs 5%) and mucositis (13% vs. 3%) on ibrutinib but similar rates of atrial fibrillation. There were 4 fatalad verse events in the ibrutinib arm due to infection. Ibrutinib added to transplant may improve 2yPFS in relapsed/refractory ABC-DLBCL but future clinical trials should incorporate more efficient patient selection.

CAR-T cell therapies have risen to prominence over the last decade, and their indications are increasing with several products approved as early as second line in Large B Cell non-Hodgkin Lymphomas. Their major toxicities are the cytokine release syndrome (CRS) and the Immune-effector Cell Associated Neurotoxicity Syndrome (ICANS). These entities involve a hyperinflammatory cascade which is amplified through the mononuclear phagocytic system (MPS). Herein, we review the immune mediated adverse events related to CAR therapy, including their pathophysiologies, and current therapies. In particular, we discuss the emerging role of the MPS in both the toxicity and efficacy of CAR-T therapy, and possible avenues for the modulation of the MPS to optimize efficacy while minimizing toxicity.

Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of

CD19-specific chimeric antigen receptor (CAR) T cells have demonstrated impressive responses in patients with relapsed and refractory B cell malignancies. However, many patients relapse or fail to respond to CD19 CAR T cells, demonstrating the need to improve its efficacy and durability. Current protocols for generating CAR T cells involve T cell activation through CD3 stimulation to facilitate efficient CAR transfer followed by ex vivo expansion with exogenous cytokines to obtain adequate cell numbers for treatment. Both T cell activation and expansion inevitably lead to terminal differentiation and replicative senescence, which are suboptimal for therapy. Interleukin-7 (IL-7) was previously shown to allow for lentiviral transduction of T cells in the absence of activation. In these studies, we used IL-7 to generate CD19 CAR T cells without stimulating CD3. Nonactivated and IL-7 cultured (NICE) CD19 CAR T cells were enriched with the T memory stem cell population, retained novel markers of stemness, had lower expression of exhaustion markers, and increased proliferative potential. Furthermore, our findings are consistent with engraftment of NICE CD19 CAR T cells and demonstrate a superior therapeutic response in both intraperitoneal and subcutaneous in vivo B cell lymphoma models. These results suggest that NICE CD19 CAR T cells may improve outcomes for B cell malignancies and warrant clinical evaluation.

Background Most older patients with relapsed or refractory acute myeloid leukemia (R/R AML) are ineligible for curative allogeneic hematopoietic cell transplant (alloHCT) due to intolerance to intensive therapies. Iomab-B (131I-apamistamab) delivers high-dose targeted radiation to CD45-expressing cells, producing antileukemic effect and myeloablation while limiting off-target toxicity. In SIERRA, Iomab-B-led alloHCT improved outcomes in active R/R AML patients (shown at June 2022 data cutoff). We report a subsequent analysis of efficacy after longer follow-up (as of January 2024). Methods SIERRA (NCT02665065) was a multicenter, randomized, controlled phase 3 study of Iomab-B-led alloHCT compared with the physician's choice of conventional care (CC) in patients ≥55 years with active, R/R AML. Patients were randomized (1:1, N=153) to CC or Iomab-B with fludarabine and total body irradiation (2 Gy) followed by alloHCT (CC, n=77; Iomab-B, n=76). Primary endpoint was durable CR (dCR), defined as a remission lasting ≥180 days from initial CR/CRp. Results Baseline patient characteristics were balanced between arms. All 66 patients who received a therapeutic dose of Iomab-B underwent alloHCT vs 14 CC patients (18.2%). Of evaluable patients (Iomab-B: 59; CC: 64), 44 (74.6%) Iomab-B pts achieved initial CR/CRp versus 4 (6.3%) CC patients; dCR rates were 22% vs 0% (95% CI, 12.29-34.73; P<0.0001), respectively. Median follow-up was 36.6 mos (95% CI, 24.8-49.4) and 43.6 mos (95% CI, 35.1-60.9) at primary and subsequent cutoffs. Median overall survival (OS) was 6.3 mos (95% CI, 5.1-7.9) for Iomab-B and 4.0 months (95% CI, 3.0-5.1) for CC pts (HR 0.69 [95% CI, 0.49-0.97]; P=0.0314) at the January 2024 data cutoff. Of the 13 dCR patients in the Iomab-B arm, 92.3% were alive at 12 mos and 69.2% at 24 mos. Iomab-B was well tolerated, with lower sepsis and mucositis rates than standard alloHCT patients. Conclusion The primary endpoint of dCR was improved in patients ≥55 y with active R/R AML receiving Iomab-B-led alloHCT versus CC. Most patients achieving dCR are long-term survivors. Improved outcomes in Iomab-B-treated patients persisted at longer follow-up. The Iomab-B-led regimen was well-tolerated and provided access to potentially curative alloHCT in a patient population traditionally considered ineligible for transplant.

The standard of care for fit, newly diagnosed multiple myeloma patients includes induction therapy followed by consolidative high-dose chemotherapy with melphalan and autologous stem cell transplant (AHSCT). Intensified preparative regimens, such as busulfan and melphalan (BuMel), have shown promise to lengthen progression-free survival (PFS). We previously reported that the addition of bortezomib to BuMel improved PFS compared to melphalan alone in CIBMTR-matched controls. We now integrate the second-generation protease inhibitor, carfilzomib, before and after BuMel (BuMelCar) in a phase I/II trial with carfilzomib. Patients with NDMM, relapsed/refractory MM (RRMM) and those failing prior AHSCT were eligible. Primary end-points were safety and tolerability. Secondary end-points included minimal residual disease negativity rates, PFS and OS. The study enrolled 19 patients. 73% were high risk either due to R-ISS III status, adverse genetics or relapsed after prior AHSCT. The maximum tolerated dose (MTD) of carfilzomib was determined to be 36 mg/m2. Noted grade 3 toxicities were febrile neutropenia (79%), mucositis (21%) and diarrhoea (16%). The 2-year PFS for the whole cohort and MTD was 89% and 100% respectively. 80% of all patients and 82% of patients in the MTD cohort achieved MRD negativity. Further studies regarding this regimen are planned.

ZUMA-1 safety management cohort 6 investigated the impact of prophylactic corticosteroids and earlier corticosteroids and/or tocilizumab on the incidence and severity of cytokine release syndrome (CRS) and neurologic events (NEs) following axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory large B-cell lymphoma (R/R LBCL). Prior analyses of cohort 6 with limited follow-up demonstrated no Grade ≥3 CRS, a low rate of NEs, and high response rates, without negatively impacting axi-cel pharmacokinetics. Herein, long-term outcomes of cohort 6 (N = 40) are reported (median follow-up, 26.9 months). Since the 1-year analysis (Oluwole, et al. Blood. 2022;138[suppl 1]:2832), no new CRS was reported. Two new NEs occurred in two patients (Grade 2 dementia unrelated to axi-cel; Grade 5 axi-cel–related leukoencephalopathy). Six new infections and eight deaths (five progressive disease; one leukoencephalopathy; two COVID-19) occurred. Objective and complete response rates remained at 95% and 80%, respectively. Median duration of response and progression-free survival were reached at 25.9 and 26.8 months, respectively. Median overall survival has not yet been reached. Eighteen patients (45%) remained in ongoing response at data cutoff. With ≥2 years of follow-up, prophylactic corticosteroids and earlier corticosteroids and/or tocilizumab continued to demonstrate CRS improvement without compromising efficacy outcomes, which remained high and durable.

BackgroundOlder patients (pts) with relapsed or refractory acute myeloid leukemia (AML) have poor outcomes which have not improved over time. Only about 30% of AML pts aged 65 and older are offered treatment and the vast majority are not eligible for curative allogeneic hematopoietic cell transplant (HCT). Age as an independent risk factor for non-relapse mortality (NRM) exists in a continuum. 131I-apamistamab (Iomab-B), an anti-CD45 radioimmunoconjugate, safely delivers targeted radiation, allowing for myeloablation and eradication of leukemic cells. Iomab-B based conditioning can provide pts ≥65 years with access to HCT. Here we present the outcome analysis for pts ≥65 years old receiving Iomab-B led HCT.MethodsSIERRA (NCT02665065) was a multi-center, randomized, controlled phase 3 study comparing the efficacy of Iomab-B based conditioning versus physician's choice of Conventional Care (CC) in pts ≥55 years of age with active, r/r AML. Pts were randomized (1:1, N=153) to CC or Iomab-B with fludarabine and total body irradiation (2 Gy) followed by HCT. Primary endpoint was durable complete remission (dCR), defined as CR/CRp ≥6 mos. Pts not achieving CR/CRp in the CC arm could crossover (CO) to Iomab-B.ResultsA total of 153 pts were randomized (CC, n=77; Iomab-B, n=76). Forty-five pts ≥65 years received Iomab-B led HCT (Iomab-B=28; CO=17) while 9 pts ≥65 years in the CC arm received standard HCT. Baseline characteristics are shown in Table 1. Iomab-B pts ≥65 years represented a very high-risk population. 73.3% were primary induction failure, more than 90% in the intermediate or adverse cytogenetic risk group and nearly 70% having failed prior targeted therapy, 45% of which with a BCL2 inhibitor. 22% were TP53 positive. The CR/CRp rate of 62.2% and the dCR rate of 13.3% were markedly better in the Iomab-B pts compared to a CR/CRp rate of 33.3% and the dCR rate of 0% in the CC pts. These rates were also similar to the overall SIERRA population. Pts receiving Iomab-B based treatment were able to achieve a notably higher 1-year survival rate of 20.1% (95% CI: 9.7, 33.1) compared to 0% for CC pts (Figure 1). Safety was similar to the overall SIERRA population.ConclusionPatients 65 years and older presented with multiple high-risk features such as primary induction failure (PIF), venetoclax failure and TP53 positivity which independently portend dismal outcomes. Both PIF and TP53 for Iomab B pts were double in frequency compared to the CC patients. Iomab-B was effective in improving outcomes despite advancing age and presence of these very high-risk features. In these pts, Iomab-B produced response rates and survival that were markedly better than the CC pts and approached that of historically comparable high risk AML subjects in remission. Iomab-B based conditioning was well-tolerated and provided access to HCT with curative potential in pts irrespective of advancing age and high-risk features.

Ovarian cancer is usually detected in the advanced stages. Existing treatments for high grade serous ovarian cancer (HGSOC) are not adequate and approximately fifty percent of patients succumb to this disease and die within five years after diagnosis. We conducted pre-clinical studies in a mouse model of ovarian cancer to evaluate disease outcome in response to treatment with the multi-kinase inhibitor cabozantinib. Cabozantinib is a receptor tyrosine kinase inhibitor with multiple targets including vascular endothelial growth factor receptor-2 (VEGFR-2), associated with immune suppression in ovarian cancer. Mice (C57BL/6) were injected with ID8-RFP ovarian tumor cells and treated with cabozantinib. Studies investigated ascites development, tumor burden and regulation of anti-tumor immunity with treatment. Mice treated with cabozantinib had significantly decreased solid tumor burden and decreased malignant ascites as compared to untreated controls. Improved outcome in cabozantinib treated mice was associated with a significantly higher percentage of CD69 early activated T cells, a higher percentage of granzyme B secreting CD8 T cells, the enhanced release of cytokines and chemokines known to recruit CD8 T cells and amplify T cell function, as well as reduced VEGFR-2. Findings suggest that cabozantinib is an important clinical agent capable of improving ovarian cancer in mice potentially in part by priming the autologous immune system to promote anti-tumor immunity.

6531 Background: Brexu-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for pts ≥18 y with R/R B-ALL in the US (≥26 y in the EU). In the 3-y follow-up of ZUMA-3, median overall survival (OS) was 25.6 mo (N=78). Survival benefit was seen regardless of age, prior treatment, or subsequent allogeneic stem cell transplant (sub alloSCT) status (Shah et al. ASCO 2023. #7023). Here we report 4-y survival outcomes for ZUMA-3. Methods: Eligible pts (≥18 y) had R/R B-ALL and received brexu-cel (1×106 CAR T cells/kg) after leukapheresis and lymphodepleting chemotherapy. The primary endpoint was overall complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate per independent review with OS as a key secondary endpoint. Descriptive statistics are reported for post hoc exploratory subgroup analyses. Results: As of July 23, 2023, median follow-up time in Phase 1 and 2 pts who received the pivotal dose of brexu-cel (N=78) was 53.6 mo (range 44.7-82.3). Median OS (95% CI) was 25.6 mo (16.2-60.4) in all treated pts and 47.0 mo (23.2-not estimable [NE]) in pts with CR/CRi (n=57). In pts <26 y (n=15), median OS (95% CI) was 23.2 mo (9.0-NE) and was 26.0 mo (15.9-NE) in pts ≥26 y (n=63). Median OS (95% CI) in pts with 1 prior therapy (n=15) was 60.4 mo (7.6-NE) and was 25.4 mo (15.9-47.0) in pts with ≥2 prior therapies (n=63). Medians for OS (95% CI) in pts with (n=38) and without (n=40) prior blinatumomab (blina) were 15.9 (8.3-26.0) and 60.4 mo (18.6-NE), respectively. Median OS (95% CI) was 36.3 mo (10.2-NE) in responders who went on to sub alloSCT (n=14) and 60.4 mo (23.2-NE) in those who did not (n=43). The 48-mo OS rate was 40% (95% CI, 28-52) in all pts but appeared lower in pts with prior blina (24%; Table). No new adverse events or deaths occurred since the prior analysis. Grade ≥3 infection rates since the start of study appeared higher in pts <26 y and in pts with prior blina (Table). Rates of non-relapse mortality (NRM) and relapse-related mortality (95% CI) at 48 mo were 25% (15-37) and 34% (24-45; N=78), respectively. Of note, 6/17 NRM events (35%) occurred in pts with sub alloSCT. Conclusions: After >4 y follow-up, pts in ZUMA-3 continued to experience OS benefit regardless of age, prior therapy, or sub alloSCT status, though pts with prior blina had a numerically lower 48-mo OS rate. Small subgroups and unbalanced pt characteristics limit interpretation of these results. No new safety signals were observed. Further studies are needed to fully assess the impact of age, prior therapies, and sub alloSCT on outcomes after brexu-cel. Clinical trial information: NCT02614066 . [Table: see text]

BackgroundMost older patients (pts) with relapsed or refractory (r/r) AML cannot tolerate intensive treatment and are not eligible for curative allogeneic hematopoietic cell transplant (HCT). Iomab-B (131I-apamistamab), an anti-CD45 radioimmunoconjugate, safely delivers targeted radiation to hematopoietic cells, allowing for myeloablation and eradication of leukemic cells. Iomab-B based induction and conditioning can provide these pts with access to HCT.MethodsSIERRA (NCT02665065) was a multi-center, randomized, controlled phase 3 study comparing the efficacy of Iomab-B based conditioning vs physician's choice of Conventional Care (CC) in pts ≥55 years of age with active, r/r AML. Pts were randomized (1:1, N=153) to CC or Iomab-B with fludarabine and total body irradiation (2 Gy) followed by HCT. Primary endpoint was durable CR (dCR), defined as CR/CRp ≥6 mos. CR/CRp assessment was 28-56 days post HCT on the Iomab-B arm or 28-42 days post start of CC. Pts not achieving CR/CRp could crossover (CO) to Iomab-B. We analyzed time to neutrophil and platelet engraftment, and complete donor chimerism (defined as >95% donor cells detected in bone marrow or blood) rates in each transplanted group (Iomab-B, CO and CC).ResultsA total of 153 pts were enrolled in the SIERRA trial, 76 in the Iomab-B arm and 77 in the CC arm. Baseline characteristics were well balanced between both arms (Table 1). The primary endpoint of dCR at 6 mos strongly favored Iomab-B with 22% dCR vs. 0% for CC (p<0.0001). Of the 106 pts who received a therapeutic dose (TD) of Iomab-B (Iomab-B=66, CO=40), 100% underwent HCT vs. 14 (18.2%) on the CC arm. The median radiation dose to marrow was 16 Gy (range: 4.6-44.6 Gy), 100% engraftment was achieved without any graft rejection. Median times to neutrophil and platelet engraftment were 14 days (range 9-31) and 19 days (range 10-40) for Iomab-B arm; 13 days (range 10-35) and 18.5 days (range 12-38) for CO pts; 16 days (range 13-83) and 15 days (range 8-35) for the CC+HCT arm respectively (Table 2). Ninety of the 106 pts that received Iomab-B+HCT were evaluable for chimerism by day +90 with 79% (71/90) having complete donor chimerism and 21% mixed chimerism which was due to persistent AML. Cumulative incidence of grade III-IV acute graft-versus-host-disease (GvHD) for pts receiving Iomab-B was 9.4% vs. 14.3% for those on CC+HCT arm. The cumulative incidence of chronic GvHD at 12 mos was 16.9% and 13.5% for Iomab-B and CO pts respectively; no pts on the CC+HCT arm were evaluable for chronic GvHD at one year due to death or relapse.ConclusionDespite receiving a very high dose of targeted radiation to the marrow, having a high leukemia burden and being heavily pre-treated, all pts undergoing HCT using the Iomab-B led regimen achieved engraftment that was robust and comparable to those in the CC arm who received standard of care conditioning. Iomab-B pts had overall low rates of chronic and acute grade III-IV GvHD.