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Background: Select patients with relapsed/refractory aggressive B cell lymphoma may benefit from bridging radiation (bRT) prior to anti-CD19-directed chimeric antigen receptor T cell therapy (CAR-T). Here, we examined patient and treatment factors associated with outcomes and patterns of failure after bRT and CAR-T., Methods: We retrospectively reviewed adults with diffuse large B-cell lymphoma (DLBCL) who received bRT prior to axicabtagene ciloleucel, tisagenlecleucel, or lisocabtagene maraleucel between 11/2017-4/2023. Clinical/treatment characteristics, response, and toxicity were extracted. Survival was modeled using Kaplan-Meier or Cox regression models for events distributed over time, or binary logistic regression for disease response. Fisher's Exact Test or Mann-Whitney U methods were used., Results: Of 51 patients, 25.5% had bulky disease and 64.7% had Stage III/IV disease at the time of RT. Comprehensive bRT alone to all disease sites was delivered to 51% of patients, and 29.4% were additionally bridged with systemic therapy. Median follow-up was 10.3 months (95% CI: 7.7-16.4). Overall response rate (ORR) was 82.4% at 30 days post-CAR-T infusion. Median overall survival (OS) was 22.1 months (6.6-not reached) and the median progression-free survival (PFS) was 7.4 months (5.5-30). OS/PFS were 80% (66-99)/78% (64-87) at 1-year, and 59% (44-71)/54% (40-67) at 2-years, respectively. Comprehensive RT to all sites of disease correlated with improved PFS and OS, p ≤ 0.04. Additionally, ECOG ≥2 and Stage III/IV disease predicted poor OS ( p ≤ 0.02). Disease bulk, IPI ≥3, and non-GCB histology were poor predictors for disease-specific survival (DSS), p <0.05. The latter two, as well as bRT dose of ≤30 Gy predicted worse PFS ( p <0.05). Among patients with advanced stage disease, comprehensive bRT to all sites of disease ( n =10) was not associated with improved OS and PFS compared to focal bRT ( n =23), p >0.17. No difference was seen in bridging RT vs. chemoRT. Twenty-six patients developed relapse (50.9%), of which 46% was in-field. Risk of in-field relapse correlated with bulky disease (OR=7, 95% CI: 1.2-41, p =0.03) and lack of response at 30 day post-CAR-T evaluation (OR=16.8, 95% CI: 1.6-176, p =0.02), but not with bRT dose ( p =0.27)., Conclusion: bRT and CART is a good treatment strategy for select patients with aggressive B cell lymphoma. Comprehensive bRT including all sites of disease is associated with improved outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Manzar, Pinnix, Dudzinski, Marqueen, Cha, Nasr, Yoder, Rooney, Strati, Ahmed, Nze, Nair, Fayad, Wang, Nastoupil, Westin, Flowers, Neelapu, Gunther, Dabaja, Wu and Fang.)

Purpose: Treatment options for leptomeningeal metastasis (LM) are limited. A recent phase 2 study found that proton craniospinal irradiation (pCSI) was well-tolerated and improved survival. We report our experience with pCSI for solid-tumor LM., Methods and Materials: This is a retrospective review of patients treated with pCSI for solid-tumor LM from December 2020 to January 2024 at our center. Patient characteristics were summarized using descriptive statistics. Median overall survival and median central nervous system progression-free survival from the first day of pCSI were estimated using Kaplan-Meier survival curves., Results: We identified 45 patients who completed pCSI. The median age was 54 years (range, 23-79); 73% were female, and 53% lived more than 100 miles from our center. Breast cancer (53%), lung cancer (20%), and melanoma (9%) were the most common primary cancers; 51% of patients had stable systemic disease at LM diagnosis. All had imaging evidence of LM, and 64% of cases were confirmed using cytologic examination of the cerebrospinal fluid. Eighty percent had symptomatic LM, and the median Karnofsky performance scale at LM diagnosis was 80. The median time from primary cancer diagnosis to LM detection was 23.1 months (range, 0-221.3). Fifty-three percent of patients had active brain metastasis at LM diagnosis; 33% of all patients had received prior intracranial radiation. The median time from simulation to pCSI start was 12 days. At the first visit following pCSI, the median Karnofsky performance scale score was 70. During or right after radiation, 76% of patients reported nausea, 51% headache, and 31% fatigue. Following pCSI, 4% received intrathecal chemotherapy, 67% systemic therapy, and 9% hospice care; 18% were observed and 2% lost to follow-up. Median overall survival was 13.7 months (95% confidence interval [CI], 11.2 to not reached), and median progression-free survival was 6.5 months (95% CI, 4.9-12.8)., Conclusions: The outcomes in our cohort are comparable to those recently reported in a phase 2 trial. Further study is indicated to determine the optimal candidates for pCSI and sequential therapies., (© 2024 The Author(s).)

Purpose: The impact of bridging radiation therapy (bRT) for chimeric antigen receptor (CAR) T-cell therapy on absolute lymphocyte count (ALC) kinetics and treatment outcome is unknown., Methods and Materials: We retrospectively reviewed adults with relapsed/refractory aggressive large B cell lymphoma who received bRT before CD-19 CAR-T between November 2017 and April 2023. The change in ALC (ALC Δ RT) was computed by subtracting ALC pre- and post-bRT. Percent bone marrow (%BM) irradiated was calculated by estimating skeletal BM distribution. Progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS) were modeled via Kaplan-Meier., Results: Fifty-one patients received bRT, of which 13 (25.5%) had bulky disease (≥7.5 cm). The median bRT dose was 30 Gy (range, 4-48 Gy); 26 patients (51%) received ≥30 Gy. Thirty-one patients (61%) received bRT comprehensively to all disease sites. The median cumulative %BM irradiated was 5.05% (range, 0-50%). At a median follow-up of 10.3 months (95% CI, 7.7-16.4), the 1-year OS, PFS, and DSS rates were 80% (95% CI, 66-99), 78% (64-87), and 82% (68-90), respectively. The incidence of grade ≥3 lymphopenia was 33% pre-RT and 68% post-RT, but recovered to 43% at the conditioning chemotherapy timepoint. There was no correlation between post-RT grade ≥3 lymphopenia and the receipt of comprehensive bRT, combined modality bridging, ≥30 Gy bRT, or bRT to ≥15% of BM (all P > .2). Among patients with grade 0-2 lymphopenia pre-RT, increased conversion to grade ≥3 lymphopenia post-RT correlated with comprehensive or ≥30 Gy bRT, but these factors did not impair ALC recovery at conditioning chemotherapy. There was no association between ALC Δ RT or post-RT ALC with 30 or 90 day response (P > .25), DSS, PFS, or OS (P > .3)., Conclusions: Lymphocyte change during bRT is not associated with CAR-T outcomes. Persistent cytopenia risk after bRT is not associated with bRT to ≥30 Gy, ≥15% of BM, or comprehensive coverage. Although bRT can be delivered safely, we urge careful treatment planning when incorporating into pre-CAR-T regimens., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The prognosis of multiple myeloma involving the central nervous system (CNS-MM) is poor. We report outcomes of CNS-MM treated with CNS-directed radiation therapy (RT)., Methods: We retrospectively reviewed patients with CNS-MM treated with CNS-directed RT from 2015 to 2024. CNS-MM was defined as having radiographic leptomeningeal or parenchymal disease, and/or pathologic CSF involvement. Complete response (CR) constituted having no atypical cells in CSF or resolution of radiographic disease. Otherwise, patients were categorized with partial response (PR) based on imaging, or stable disease (SD). The Kaplan-Meier method was used to estimate survival., Results: Of 45 patients with CNS-MM, 28 (62.2%) had high-risk disease. Median overall survival (OS) was 3.7 months (range: 0.4-52.2) postdiagnosis of CNS-MM. Most patients (n = 22, 48.9%) underwent craniospinal irradiation; 9 received whole brain RT (20%), and the others received focal brain or spine RT. The median dose was 20 Gy (2-30 Gy) in 10 fractions (1-15). Due to death or discharge to hospice before further follow-up of treatment efficacy (n = 24), only 21 patients (46.7%) were evaluable post-RT with adequate CSF or radiographic follow-up. For these evaluable patients, post-RT CR occurred in 14 patients (66.7%), PR in 5 (23.8%), and SD in 2 (9.5%). For patients with CR after RT, the median OS was 7.3 months (3-52.2) from CNS-MM diagnosis. Focal brain CNS-MM associated with improved OS and likelihood of attaining long-term survival with CNS CR., Conclusion: Aggressive multimodality therapy including RT may induce durable CNS control in a small subset of patients with CNS-MM, a high-risk population., Competing Interests: Disclosure All reported conflicts are outside the submitted work. GSM reports a patent for induced pluripotent stem cell-derived pancreatic beta cells, previous grants from ReproCell, Inc. and the AAI, and other work is supported by grants from the Radiological Society of North America / Canon Medical Systems (RSNA), an American Society for Radiation Oncology (ASTRO Residents/Fellows in Radiation Oncology Biology Seed Grant), and the American Society of Clinical Oncology (ASCO)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Diffuse large B-cell lymphoma (DLBCL) involving the gastrointestinal (GI) organs is rare, and real-world outcomes after combined modality therapy (CMT) with systemic therapy (ST) and radiotherapy (RT) are not well-characterized, particularly in the contemporary era. We characterized outcomes in a large cohort of GI-DLBCL patients treated with ST alone or CMT., Methods: Patients with GI-DLBCL treated at a single institution were retrospectively reviewed. Kaplan-Meier and Cox regression models estimated survival. Multivariable analyses were conducted using the Cox proportional hazards model., Results: Of 204 patients, gastric involvement was most common (63%). Most presented with early-stage disease (61%). All patients received ST and 65 patients (32%) received RT, 88% as part of first-line CMT. Median dose was 36 Gy (IQR 30.6-39.6) in 18 fractions (IQR 17-22). Median follow-up was 46 months. Five-year overall survival (OS) and progression-free survival (PFS) was 88% and 84%, respectively; complete response (CR) rate was 82%. Improved OS associated with low IPI ( p =0.001), fewer chemotherapy lines ( p <0.001), early stage ( p <0.006), and CR ( p <0.001). Survival did not differ by RT receipt ( p >0.25). Only early stage and CR correlated with improved OS on multivariable analysis. Stomach-directed RT vs. RT to other sites correlated with improved PFS and OS ( p <0.04). Patients with early stage DLBCL treated with CMT in the post-rituximab era had equivalent OS vs. ST alone, even with fewer chemotherapy cycles ( p <0.02; median of 4 with RT vs. 6 cycles without). Fifty patients had bulky disease (≥7.5 cm), of whom 18 (36%) had early stage disease. Among patients with bulky disease, 5 (10%) developed relapse at the initial site of disease bulk. Four of the 5 patients did not receive consolidative radiation. Among these 4 patients, 3 relapsed only in their initial site of bulky disease. Of 191 patients with luminal GI-DLBCL, n =4 (2.1%) developed perforation; only one received RT. Acute Grade 3 toxicities were reported in 41.2% of patients, and 12 (5.8%) patients had late Grade 3 toxicities, 99% attributed to chemotherapy., Conclusion: GI-DLBCL patients have favorable outcomes after CMT with minimal late toxicity. CMT may be offered with abridged systemic regimens with equivalent outcomes. Stomach directed-RT may mitigate relapse risk associated with incomplete disease response or bulky disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Manzar, Cha, Corrigan, Yoder, Schrank, Nasr, Chihara, Castillo, Nair, Jain, Neelapu, Rodriguez, Strati, Nastoupil, Gunther, Dabaja, Pinnix, Wu and Fang.)

Abstract: Inotuzumab ozogamicin (InO) is an antibody-drug conjugate that delivers calicheamicin to CD22-expressing cells. In a retrospective cohort of InO-treated patients with B-cell acute lymphoblastic leukemia, we sought to understand the genomic determinants of the response and resistance to InO. Pre- and post-InO-treated patient samples were analyzed by whole genome, exome, and/or transcriptome sequencing. Acquired CD22 mutations were observed in 11% (3/27) of post-InO-relapsed tumor samples, but not in refractory samples (0/16). There were multiple CD22 mutations per sample and the mechanisms of CD22 escape included epitope loss (protein truncation and destabilization) and epitope alteration. Two CD22 mutant cases were post-InO hyper-mutators resulting from error-prone DNA damage repair (nonhomologous/alternative end-joining repair, or mismatch repair deficiency), suggesting that hypermutation drove escape from CD22-directed therapy. CD22-mutant relapses occurred after InO and subsequent hematopoietic stem cell transplantation (HSCT), suggesting that InO eliminated the predominant clones, leaving subclones with acquired CD22 mutations that conferred resistance to InO and subsequently expanded. Acquired loss-of-function mutations in TP53, ATM, and CDKN2A were observed, consistent with a compromise of the G1/S DNA damage checkpoint as a mechanism for evading InO-induced apoptosis. Genome-wide CRISPR/Cas9 screening of cell lines identified DNTT (terminal deoxynucleotidyl transferase) loss as a marker of InO resistance. In conclusion, genetic alterations modulating CD22 expression and DNA damage response influence InO efficacy. Our findings highlight the importance of defining the basis of CD22 escape and eradication of residual disease before HSCT. The identified mechanisms of escape from CD22-targeted therapy extend beyond antigen loss and provide opportunities to improve therapeutic approaches and overcome resistance. These trials were registered at www.ClinicalTrials.gov as NCT01134575, NCT01371630, and NCT03441061., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Purpose: Azacitidine plus venetoclax is a standard of care for patients with newly diagnosed AML who are unfit for intensive chemotherapy. However, FLT3 mutations are a common mechanism of resistance to this regimen. The addition of gilteritinib, an oral FLT3 inhibitor, to azacitidine and venetoclax may improve outcomes in patients with FLT3 -mutated AML., Methods: This phase I/II study evaluated azacitidine, venetoclax, and gilteritinib in two cohorts: patients with (1) newly diagnosed FLT3 -mutated AML who were unfit for intensive chemotherapy or (2) relapsed/refractory FLT3 -mutated AML (ClinicalTrials.gov identifier: NCT04140487). The primary end points were the maximum tolerated dose of gilteritinib (phase I) and the combined complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate (phase II)., Results: Fifty-two patients were enrolled (frontline [n = 30]; relapsed/refractory [n = 22]). The recommended phase II dose was gilteritinib 80 mg once daily in combination with azacitidine and venetoclax. In the frontline cohort, the median age was 71 years and 73% of patients had an FLT3 -internal tandem duplication (ITD) mutation. The CR/CRi rate was 96% (CR, 90%; CRi, 6%). Sixty-five percent of evaluable patients achieved FLT3 -ITD measurable residual disease <5 × 10 -5 within four cycles. With a median follow-up of 19.3 months, the median relapse-free survival (RFS) and overall survival (OS) have not been reached and the 18-month RFS and OS rates are 71% and 72%, respectively. In the relapsed/refractory cohort, the CR/CRi rate was 27%; nine additional patients (41%) achieved a morphologic leukemia-free state. The most common grade 3 or higher nonhematologic adverse events were infection (62%) and febrile neutropenia (38%), which were more frequent in the relapsed/refractory cohort., Conclusion: The combination of azacitidine, venetoclax, and gilteritinib resulted in high rates of CR/CRi, deep FLT3 molecular responses, and encouraging survival in newly diagnosed FLT3 -mutated AML. Myelosuppression was manageable with mitigative dosing strategies.

Background: Undifferentiated pleomorphic sarcomas (UPSs) are amongst the most common subtypes of soft-tissue sarcomas. Few real-world data on the use of immune checkpoint blockade (ICB) in UPS patients and other high-grade pleomorphic STS patients are available., Purpose: The purpose of our study is to describe the efficacy and toxicity of ICB in patients with advanced UPSs and other high-grade pleomorphic sarcomas treated at our institution., Methods: This is a retrospective, observational study of all patients with metastatic high-grade pleomorphic sarcomas treated with FDA-approved ICB at MD Anderson Cancer Center between 1 January 2015 and 1 January 2023. Patients included in trials for which results are not yet published were excluded., Results: Thirty-six patients with advanced/metastatic pleomorphic sarcomas were included. The median age was 52 years. A total of 26 patients (72%) had UPSs and 10 patients (28%) had other high-grade pleomorphic sarcomas. The median follow-up time was 8.8 months. The median PFS was 2.9 months. The 3-month PFS and 6-month PFS were 46% and 32%, respectively. The median OS was 12.9 months. The 12-month OS and 24-month OS were 53% and 29%, respectively. The best response, previous RT, and type of ICB treatment were significantly and independently associated with shorter PFS ( p = 0.0012, p = 0.0019 and p = 0.036, respectively). No new safety signal was identified, and the toxicity was overall manageable with no toxic deaths and only four patients (11%) stopping treatment due to toxicity., Conclusions: Real-world retrospective data are consistent with the published literature, with a promising 6-month PFS of 32%. Partial or stable responders to ICB treatment have significantly improved PFS compared to progressors.

Background: The combination of low-intensity chemotherapy and inotuzumab ozogamicin (INO), with sequential blinatumomab, is highly effective in older adults with newly diagnosed B-cell acute lymphoblastic leukemia (ALL) and in relapsed or refractory B-cell ALL. Earlier, "dose-dense" administration of blinatumomab could lead to earlier and deeper measurable residual disease (MRD) responses and better outcomes., Patients and Methods: We performed a retrospective analysis of the safety and efficacy of a dose-dense regimen of mini-hyper-CVD (mini-hyperfractionated cyclophosphamide, vincristine, and dexamethasone alternating with mini-methotrexate and cytarabine), INO, and blinatumomab in patients with B-cell ALL., Results: Twenty-one patients were treated (frontline, n = 9; MRD consolidation, n = 4; relapsed/refractory, n = 8). In the frontline cohort, all patients achieved CR/CRi and MRD negativity by flow cytometry at the end of cycle 1. Across the frontline and MRD consolidation cohorts, 10/11 patients (91%) achieved next-generation sequencing MRD negativity at a sensitivity of 10 -6 , including 6/10 evaluable patients (60%) who achieved next-generation sequencing MRD negativity after cycle 1. The CR/CRi rate in the relapsed/refractory cohort was 63%, and all responders achieved MRD negativity by flow cytometry at the end of cycle 1. The 1-year overall survival rate for the combined cohort of the frontline and MRD-positive patients was 83%. No new safety signals were observed with the dose-dense mini-hyper-CVD, INO, and blinatumomab regimen., Conclusion: Dose-dense delivery of mini-hyper-CVD, INO, and blinatumomab was safe and resulted in rapid and deep MRD negativity in patients with B-cell ALL. This regimen is now being prospectively evaluated in both the frontline and relapsed/refractory settings., Competing Interests: Disclosure N.J.S, E.J., and H.K. have received research funding and honoraria from Amgen and Pfizer Inc. The rest of the authors have no relevant conflicts to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Inotuzumab ozogamicin (InO) is an antibody-drug conjugate that delivers calicheamicin to CD22-expressing cells. In a retrospective cohort of InO treated patients with B-cell acute lymphoblastic leukemia, we sought to understand the genomic determinants of response to InO. Acquired CD22 mutations were observed in 11% (3/27) of post-InO relapsed tumor samples. There were multiple CD22 mutations per sample and the mechanisms of CD22 escape included protein truncation, protein destabilization, and epitope alteration. Hypermutation by error-prone DNA damage repair (alternative end-joining, mismatch repair deficiency) drove CD22 escape. Acquired loss-of-function mutations in TP53 , ATM and CDKN2A were observed, suggesting compromise of the G1/S DNA damage checkpoint as a mechanism of evading InO-induced apoptosis. In conclusion, genetic alterations modulating CD22 expression and DNA damage response influence InO efficacy. The escape strategies within and beyond antigen loss to CD22-targeted therapy elucidated in this study provide insights into improving therapeutic approaches and overcoming resistance., Key Points: We identified multiple mechanisms of CD22 antigen escape from inotuzumab ozogamicin, including protein truncation, protein destabilization, and epitope alteration.Hypermutation caused by error-prone DNA damage repair was a driver of CD22 mutation and escape.