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ImportanceEarly anhydramnios during pregnancy, resulting from fetal bilateral renal agenesis, causes lethal pulmonary hypoplasia in neonates. Restoring amniotic fluid via serial amnioinfusions may promote lung development, enabling survival.ObjectiveTo assess neonatal outcomes of serial amnioinfusions initiated before 26 weeks’ gestation to mitigate lethal pulmonary hypoplasia.Design, Setting, and ParticipantsProspective, nonrandomized clinical trial conducted at 9 US fetal therapy centers between December 2018 and July 2022. Outcomes are reported for 21 maternal-fetal pairs with confirmed anhydramnios due to isolated fetal bilateral renal agenesis without other identified congenital anomalies.ExposureEnrolled participants initiated ultrasound-guided percutaneous amnioinfusions of isotonic fluid before 26 weeks’ gestation, with frequency of infusions individualized to maintain normal amniotic fluid levels for gestational age.Main Outcomes and MeasuresThe primary end point was postnatal infant survival to 14 days of life or longer with dialysis access placement.ResultsThe trial was stopped early based on an interim analysis of 18 maternal-fetal pairs given concern about neonatal morbidity and mortality beyond the primary end point despite demonstration of the efficacy of the intervention. There were 17 live births (94%), with a median gestational age at delivery of 32 weeks, 4 days (IQR, 32-34 weeks). All participants delivered prior to 37 weeks’ gestation. The primary outcome was achieved in 14 (82%) of 17 live-born infants (95% CI, 44%-99%). Factors associated with survival to the primary outcome included a higher number of amnioinfusions (P = .01), gestational age greater than 32 weeks (P = .005), and higher birth weight (P = .03). Only 6 (35%) of the 17 neonates born alive survived to hospital discharge while receiving peritoneal dialysis at a median age of 24 weeks of life (range, 12-32 weeks).Conclusions and RelevanceSerial amnioinfusions mitigated lethal pulmonary hypoplasia but were associated with preterm delivery. The lower rate of survival to discharge highlights the additional mortality burden independent of lung function. Additional long-term data are needed to fully characterize the outcomes in surviving neonates and assess the morbidity and mortality burden.Trial RegistrationClinicalTrials.gov Identifier: NCT03101891

BACKGROUND AND OBJECTIVES: Adult spinal deformity (ASD) with fixed sagittal malalignment (FSM) may require a pedicle subtraction osteotomy (PSO) for greater focal lordosis and restoration of global alignment. Despite growing trends in minimizing PSOs given their associated high risks, a considerable portion of patients with ASD still require a lumbar PSO most commonly because of iatrogenic flat back deformity. The purpose of this article is to describe a modified extended PSO technique with additional anterior column support coined the “sandwich” extended PSO (SE-PSO) to promote arthrodesis and report the outcomes in a consecutive case series. METHODS: Patients with ASD treated with a lumbar SE-PSO at a single institution from 2015 to 2020 were analyzed. Complications, radiographic data, and patient-reported outcomes were compared preoperatively, at immediate postoperative follow-up, and at a 2-year postoperative follow-up (FU). RESULTS: Fourteen patients who underwent revision operations for FSM were included. Improvements in segmental lordosis across the PSO site (14.8 ± 6.8 vs 39.9 ± 7.1, P < .0001), overall lumbar lordosis (14.6 ± 15.4 vs 44.6 ± 12.1, P < .0001), sacral slope (21.0 ± 10.5 31.1 ± 10.7, P = .0150), C7 sagittal vertical axis (140.1 ± 59.0 mm vs 35.9 ± 28.5, P < .0001), and spinopelvic mismatch (52.5 ± 21.3 vs 18.6 ± 14.1, P = .0001) were obtained in all patients. Eight patients experienced perioperative complications, with intraoperative durotomy being the most common (n = 7). Eight patients had a 2-year FU and demonstrated improvements in their segmental lordosis across the PSO site (14.3 ± 7.0 vs 41.3 ± 7.3, P = .0003), overall lumbar lordosis (8.7 ± 17.8 vs 46.1 ± 14.2, P = .0014), sacral slope (19.1 ± 12.8 vs 32.3 ± 12.5, P = .0479), C7 sagittal vertical axis (173.6 ± 54.4 mm vs 35.8 ± 30.0, P < .0001), and spinopelvic mismatch (63.0 ± 19.7 vs 21.1 ± 18.3, P < .0001), all of which were maintained at final FU ( P > .05). At 2 years, a significant increase in Scoliosis Research Society-22r total score (2.5 ± 0.8 vs 3.6 ± 0.7, P = .0023 was reported. There were no reports of symptomatic pseudarthrosis or mechanical complications. CONCLUSION: SE-PSO is an effective technique to correct FSM and is associated with low complications, improved patient-reported outcomes, and spinopelvic parameters that are maintained at 2 years.

Cellular Immunotherapies: Late Phase and Commercially Available Therapies The Impact of Inotuzumab Ozogamicin (InO) Treatment on Brexucabtagene Autoleucel (Brexu-cel) Outcomes in Adults with Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia (B-ALL) Introduction: Brexu-cel is the first approved CD19-directed chimeric antigen receptor (CAR) T-cell therapy for adult patients (pts) with relapsed/refractory (r/r) B-ALL. InO, an anti-CD22 antibody drug conjugate, is also approved for the same indication. With the accessibility to several targeted therapies in r/r B-ALL, the optimal sequence remains uncertain. The effect of prior treatment with InO on brexu-cel outcomes remains underreported, especially as a bridging therapy, as well as the effect of previous response to InO on post brexu-cel outcomes. Methods: This is a retrospective multicenter analysis from 25 U.S. institutions of adults (≥18 years) with r/r B-ALL treated with commercial brexu-cel from 2021 to 2023 post FDA approval. Methodologies for assessing minimal residual disease (MRD) (minimal threshold of 10 -4) included flow cytometry, NGS, or qPCR depending on institutional practice. Progression-free survival (PFS) and overall survival (OS) were calculated from day of brexu-cel infusion and were not censored for hematopoietic cell transplant (HCT) or maintenance. All living patients were censored at the time of last follow-up prior to data lock, which occurred on June 30, 2023. Results: Among 152 infused, 83 (54.6%) had pre-CAR InO therapy (InO-exposed), with a median of 3 administered doses (range: 1-22). Within the InO-exposed cohort, 23 (28%) pts received InO as a CAR T-cell bridging therapy (ie, between apheresis and lymphodepletion) with or without pre-apheresis and 60 (72%) pts received InO only during pre-apheresis. Baseline characteristics for InO exposed and InO-naïve pts are shown in Table 1. InO-exposed pts had higher median prior lines of therapies (4 vs. 3; p= 0.05), more frequently had active disease (≥5% marrow blasts) at the time of apheresis (67% vs. 44%, p= 0.02), and had lower incidence of Ph+ disease (19% vs. 45%, p=0.003), compared to InO-naïve pts, respectively. The incidences of cytokine release syndrome (CRS) (85% vs. 85%, p= 0.26) and ICANS (58% vs. 57%, p= 0.36) post infusion were similar, and post-infusion death in remission occurred in 17% and 12% among InO-exposed and InO-naïve pts, respectively. Morphological complete remission (CR) and MRD- rates following brexu-cel infusion were 89% and 77% for InO-exposed pts, and 92% and 70% for InO-naive pts, respectively. Post CAR therapy, more InO-naïve pts underwent consolidation/maintenance therapy (transplant, chemotherapy, or TKIs) compared to InO-exposed pts (41% vs. 19%, p= 0.004). The median follow-up after brexu-cel was 8.4 (range) months. Median OS (not reached (NR) vs. 12 months; p= 0.033) and median PFS (NR vs. 7 months; p= 0.029) were superior in InO-naïve pts compared to InO-exposed pts, respectively. However, after adjusting for pre-apheresis disease burden and post-CAR maintenance therapy, there were no longer significant differences in OS (HR= 1.25;95%CI: 0.62-2.53; p= 0.53) or PFS (HR= 1.24;95%CI:0.71-2.16, p=0.45) based on pre-CAR InO exposure. When InO-exposed pts were stratified based on prior InO-response (CR vs. no response), InO-responsive pts had superior estimated 12-month OS (64%) and PFS (38%) relative to InO-refractory pts (OS: 33%; PFS: 34%), but inferior to InO-naïve pts (OS: 75%; PFS 56%), with p-values of 0.0001 and 0.021 for OS and PFS, respectively (Figure 1). The timing of pre-CAR InO therapy did not impact brexu-cel survival outcomes, with comparable estimated 12-month OS (43% vs. 58%, p= 0.35) and PFS (46% vs. 38%, p= 0.57) for InO-exposed pts during bridging therapy and patients who received InO as a therapy prior to apheresis. Conclusion: After adjusting for pre-CAR disease burden and post-CAR consolidation/maintenance, we found that prior InO exposure does not significantly associate with PFS or OS following brexu-cel. However, relative to InO-responsive patients, patients who were InO-refractory appear to have worse post-CAR survival outcomes. Finally, timing of InO administration (ie as a prior line of therapy or as CAR bridging) did not influence outcomes brexu-cel outcomes.