Sharon, Elad

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but are associated with immune-related adverse events, including ICI–associated acute kidney injury (ICI-AKI). ICI-AKI presents diagnostic and management challenges and can influence decisions regarding immunosuppression and ICI rechallenge, with important implications for both kidney and cancer outcomes. An international, multidisciplinary panel convened at the 34th Acute Disease Quality Initiative (ADQI) consensus conference in September 2024. Systematic literature searches of PubMed were conducted to identify studies on the epidemiology, mechanisms, diagnosis, management, rechallenge, and outcomes of ICI-AKI. The meeting followed the established ADQI process and used a modified Delphi method to achieve consensus. Evidence was reviewed and appraised by workgroups, and consensus statements were developed through structured discussion and voting. Observational data suggest that AKI occurs in up to 20% of patients receiving ICIs, with ICI-AKI accounting for approximately 2%–5% of cases. Acute tubulointerstitial nephritis is the most common lesion, observed in 80%–90% of biopsies, although glomerular diseases are increasingly recognized. No clinical features reliably distinguish ICI-AKI from other causes of AKI, and kidney biopsy remains the diagnostic gold standard. Emerging urinary, circulating, and imaging biomarkers show promise but are not yet ready for routine clinical use. Early glucocorticoid initiation (within 3 days of ICI-AKI diagnosis versus >3 days after diagnosis) is associated with higher rates of kidney recovery, although optimal dosing and duration remain uncertain. Recurrent ICI-AKI occurs in fewer than 20% of patients undergoing ICI rechallenge. Management of high-risk populations, including kidney transplant recipients and patients with autoimmune disease or advanced CKD, requires individualized, multidisciplinary decision-making. ICI-AKI is an important and potentially reversible complication of cancer immunotherapy; these consensus statements provide a framework for diagnosis and management, support cautious ICI rechallenge in selected patients, and identify priorities for future research.

Abstract Purpose: The addition of MEK inhibition (MEKi) to programmed cell death ligand 1 (PD-L1) blockade improves progression-free survival (PFS) in patients with advanced biliary tract cancer. Although MEK inhibitors may increase tumor cell immunogenicity, they can impair T-cell priming/effector function, limiting combination efficacy. We hypothesized that the addition of a CD27 agonist could restore T-cell function and enhance antitumor immunity in this combination. Patients and Methods: We conducted a randomized, phase II trial evaluating atezolizumab (840 mg, intravenously, days 1 and 15) in combination with the CD27 costimulatory monoclonal antibody [CDX-1127/varlilumab (3 mg/kg, intravenously, days 1 and 15)], with/without the addition of an MEK inhibitor [cobimetinib (60 mg, orally, daily, days 1–21, off days 22–28)] in unresectable biliary tract cancer following at least one metastatic therapy. Overall response rate (ORR) and PFS were coprimary endpoints. Treatment-related changes in CD8+ tumor-infiltrating lymphocytes (TIL) were the primary correlative outcomes. Results: The trial was closed early following interim preplanned ORR analysis. At closure, 57 patients had been enrolled [n = 29 in the cobimetinib + atezolizumab + varlilumab (CAV) arm; n = 28 in the atezolizumab + varlilumab (AV) arm]. A majority (67%) had intrahepatic cholangiocarcinoma, and 32% were immunotherapy experienced. Both regimens were well tolerated without new safety signals. Objective responses were rare [0% (CAV); 3.8% (AV)]. The median PFS (mPFS) was 2.40 (CAV) and 1.84 (AV) months [hazard ratio (HR), 0.67; 95% confidence interval (CI), 0.38–1.18]. Among immunotherapy-experienced patients, the mPFS was 3.62 (CAV) and 1.84 (AV) months (HR, 0.54; 95% CI, 0.18–1.62). Treatment with CAV increased intratumoral CD8+ T-cell density compared with treatment with AV. Conclusions: The combinations of atezolizumab and varlilumab with/without cobimetinib were safe, but neither meaningfully improved outcomes in biliary tract cancer treated in the later lines. Correlative tissue studies validated preclinical work that MEKi increases CD8+ TILs.

We previously reported initial results of the pivotal phase II trial of atezolizumab for patients with alveolar soft part sarcoma (ASPS; ClinicalTrials.gov identifier: NCT03141684 ). Here, we report on three additional years of observation. Fifty-three patients with ASPS received atezolizumab. Median duration of response increased to 37.0 months. Objective response rate (ORR) and median progression-free survival (mPFS) remained essentially as previously reported (35.8% [95% CI, 23.1 to 50.2] and 20.8 months [IQR, 7.6-not reached], respectively). ASPSCR1::TFE3 fusion type was determined for 47/53 patients; ORR and mPFS were higher among the 41 patients expressing type 1 (43.9% [95% CI, 28.5 to 60.2] and 28.3 months [IQR, 9.2-not reached], respectively) than the six patients expressing type 2 (0% [95% CI, 0 to 45.9] and 7.5 months [IQR, 3.9-not reached], respectively, PFS HR, 3.2 [95% CI, 1.01 to 10.2]). Eleven patients chose a per-protocol drug holiday (range, 3.5-26.4 months) after ≥2 years of treatment; two experienced disease progression during the holiday. Nine eligible patients elected to receive bevacizumab plus atezolizumab after progressing on monotherapy; ORR was 0% and mPFS was 18.5 months (IQR, 7.9-21.1) in this small cohort. Long-term results support using atezolizumab to treat ASPS, even for several years; a drug holiday with careful monitoring may be an option for some patients.

Abstract Introduction:A comprehensive integration of significantly mutated genes and pathways with molecular subgroups is lacking in adult B-ALL. Furthermore, the genomic drivers underlying each subgroup remain to be identified.We aimed to perform genomic analysis on a large cohort of patients with adult B-ALL, and to correlate genomic markers with achievement of MRD negativity enabling blinatumomab randomization, and with subsequent response to blinatumomab. Methods:For genomic analysis, we studied 569 adults with newly diagnosed B-ALL registered for initial screening on the ECOG-ACRIN-led E1910 trial (NCT02003222), which evaluated the addition of blinatumomab to standard consolidation chemotherapy. The median age was 52 yrs (range 30 to 71 yrs), with 52% males. Analysis was performed on tumor and matched-normal samples using whole transcriptome sequencing (RNA-seq; tumor only; n=569), whole exome sequencing (n=490), whole genome sequencing (n=131), and single nucleotide polymorphism array (n=445). B-ALL cases were classified into 22 molecular groups. Outcome analysis was limited to patients enrolled and treated on E1910 (n=319). Results: Driver genes (n=268) were identified by the mutation-significance detection tool dNdScv or by the presence of pathogenic variants in known cancer genes, with NUP188 identified as a novel driver gene. Recurrently mutated pathways included: B-cell development (46%), cell cycle (44%), epigenetic regulation (30%), other transcriptional regulation (27%), Ras signaling (25%), RNA machinery (17%) and JAK-STAT signaling (8%). A high frequency of high-risk subtypes was observed including BCR::ABL1 (20%), BCR::ABL1-like (18%), low hypodiploid (14%) and KMT2A (12%). Using tSNE analysis, we identified a new cluster of cases (n=20, 3.5%) lacking a known subgroup driver, with overexpression of CEBPA (n=13) or CEBPB (n=7), distinct from CEBPE/ZEB2, termed “CEBP-altered” ALL (CEBPalt). Five of 13 cases with high CEBPA expression harbored an IGH::CEBPA rearrangement and one harbored a RXRA::CEBPA enhancer hijacking alteration. Of the 7 cases with high CEBPB expression, 5 harbored IGH::CEBPB, and two of these had concomitant clonal BCR::ABL1 fusions. To identify additional mechanisms of CEBP deregulation, in situ Hi-C coupled to H3K27 acetylation immunoprecipitation (HiChIP) was performed on 5 cases. Four cases showed evidence of de novo CEBPA enhancer activity. In two cases, we identified novel insertions (12 and 34nt) ~2kb downstream of CEBPA. A novel translocation and enhancer hijacking event between LINC00426 and the 5' UTR of CEBPB was identified in the remaining case. Overall, we confirmed genomic alterations of CEBPA or CEBPB in 16 of 20 cases with available material. Thus, we have identified a new molecular subgroup of adult B-ALL characterized by genomic alterations that drive enhancer hijacking and oncogenic deregulation of CEBPA/CEBPB. Several subgroups were enriched in patients that failed induction chemotherapy (n=62) or were MRD-positive (n=63) compared to those that achieved MRD-negative status (n=194): BCR::ABL1-like (30 vs 14%, p<0.001), KMT2A (18 vs 9%, p=0.03) and BCL2/MYC (5 vs 1%, p=0.06). Conversely, the following subgroups were enriched in patients that achieved MRD-negativity: PAX5alt (6 vs 18%, p=0.002), TCF3::PBX1 (0 vs 5%, p=0.01) and ZNF384 (2 vs 6%, p=0.08) Within each molecular subgroup we compared the survival of patients who achieved MRD-negative status after induction and were randomized to receive blinatumomab plus chemotherapy (n=93) or chemotherapy only (n=91). Although numbers were low, blinatumomab improved relapse-free survival for patients with hyperdiploid, PAX5alt, BCR::ABL1-like and KMT2A ALL compared to chemotherapy alone. Clonal hematopoiesis of indeterminate potential (CHIP)-related gene mutations were identified in 121 of 417 cases analyzed (29% total: somatic 74%, remission 31%, both 5%). TP53 mutations were most frequent (n=65 patients), with the majority identified in patients with low hypodiploid (n=52). Interestingly, patients with CRLF2 rearrangements collectively harbored the highest number of other CHIP gene mutations (n=13), including DNMT3A (n=4), TET2 (n=3) and ASXL1 (n=3). Conclusions:We provide a comprehensive landscape of genomic alterations in adult B-ALL and identify a new group characterized by deregulation of CEBPA/CEBPB (CEBPalt). We also provide insights into the efficacy of blinatumomab in different molecular subgroups of adult B-ALL.

Abstract Background: The addition of the CD19/CD3 bispecific T-cell engager, blinatumomab, to standard consolidation chemotherapy in adults with ALL who achieved a measurable residual disease negative (MRDneg) remission (CR), demonstrated an improvement in 3-year overall survival (OS, 85% vs 68%, HR 0.41, P=0.002) and 3-year relapse-free survival (RFS, 80% vs 64%, HR 0.53) compared to conventional chemotherapy in the ECOG-ACRIN E1910 study (Litzow et al, NEJM 2024). Given the complex therapy in this study, treatment delays and modifications are expected. We herein explored the impact of such delays on patient outcomes. Methods: In the phase 3 ECOG-ACRIN E1910 trial (NCT02003222), adults aged 30-70 years with newly diagnosedALL who had achieved MRDneg CR following induction and intensification were randomized to consolidation chemotherapy with blinatumomab (blina arm) or chemotherapy alone (chemo arm). We examined the association between the timing of the initiation of maintenance therapy and OS and RFS. The expected duration of consolidation was 252 days vs 126 days for patients on the blina and chemo arms, respectively. For this analysis, participants were classified into two groups (no/short delay or long delay) depending on whether they started on time/before or after the median time between the beginning of consolidation and start of maintenance therapy for their treatment group (medians: 335 days, range, 181-457 days vs 176 days, range, 139-265 days for blina and chemo arms, respectively). Multivariate analyses of OS and RFS were performed to examine the effect of no/short delay vs. long delay in starting maintenance. Patients were stratified according to their assigned consolidation treatment arm, and the models were further adjusted for age, sex, white blood cell count, platelets, hemoglobin, peripheral blood blasts, bone marrow blasts, performance status and genetic-genomic risk at diagnosis. Results: Of the 488 patients enrolled, 224 MRDneg patients were randomized to consolidation chemotherapy with or without blinatumomab and 135 of the 224 went on to maintenance therapy on study (N= 66 on blina arm and 69 on chemo arm, respectively). The median follow-up from the time of maintenance registration was 43.4 months. There were no significant differences in baseline characteristics between patients in either arm who experienced no/short delay or long delay. In the blina group, 60 of 66 patients (90.9%) received all 8 cycles of consolidation therapy of which 31 (45.6%) had long delays. Sixty-eight of 69 patients on the chemo arm (98.5%) received all cycles of consolidation therapy, of which 34 (50%) had a long delay. Strikingly, patients who had a long delay before initiation of maintenance had a significant improvement in OS in multivariate analysis compared to patients who had no/short delay (HR 0.31, 95% CI: 0.11-0.91; P =0.03). However, within each treatment group, OS benefit did not reach statistical significance (blina arm: HR 0.04, 95% CI: 0.001-1.64; P =0.09; chemo arm: HR 0.32, 95% CI: 0.08-1.38; P =0.13). Similar results were observed for RFS in multivariate analysis (HR 0.40, 95% CI: 0.16-1.01; P =0.05), though this impact on improved RFS was noted in the chemo arm but not in blinatumomab treated patients (blina arm: HR 0.56, 95% CI: 0.10-3.24; P =0.52; chemo arm: HR 0.19, 95% CI: 0.04-0.83; P=0.03). Additionally, patients who had no/short delay before starting maintenance experienced a longer median duration of maintenance treatment (blina arm, 548 days; chemo arm, 708 days) compared to patients who had a long delay (blina arm 488 days; chemo arm 598 days) before initiation of maintenance (P=0.0008). Conclusion: In the phase 3 randomized ECOG-ACRIN E1910 clinical trial, long delays between initiation of consolidation therapy and start of maintenance therapy were associated with improved OS compared to no/short delays. However, within each treatment group (blina or chemo), no significant difference of OS was observed. We postulate that these longer delays allowed more patients to receive all of the recommended protocol-assigned therapy thereby resulting in improved survival. Furthermore, patients who had no/short delays had a significantly longer duration of maintenance therapy. These data indicate that treatment delays during consolidation do not worsen survival. Further studies are being done to better understand why patients with long delays had better overall survival.

Immune checkpoint inhibitors (ICIs) are an important class of cancer treatment. Endocrine immune-related adverse events (E-irAEs) account for a significant proportion of irAEs in ICI-treated patients. Diagnosing E-irAEs accurately and timely can be challenging in the absence of clear categorization and standardization across oncology, endocrinology and other specialties. While existing guidelines provide some broad directions to diagnosis and management, they lack clarity on irAE-specific symptom evaluation and work-up, as well as assessment of severity. These limitations can then impact triage, time-sensitive management and care escalation to specialists such as oncoendocrinologists. The objective of this study was to develop consensus-based statements on disease definitions for E-irAEs. A core working group of endocrinologists with expertise in the oncoendocrinology field drafted a survey with statements outlining the general approach to E-irAEs, disease definition and management approach of six specific diagnoses: ir-thyroiditis thyrotoxic phase, ir-thyroiditis hypothyroidism, ir-Graves’ disease, ir-hypophysitis, ir-adrenalitis and ir-type 1 diabetes mellitus. Severity grading tables were drafted for three disease categories—“thyroid”, “pituitary and adrenal”, and “diabetes mellitus”. A two-round modified Delphi process, using the RAND/University of California Los Angeles (RAND/UCLA) Appropriateness Method, was employed. In this process, a 25-member voting panel consisting of endocrinologists, oncologists and other specialists and healthcare providers with experience in management of ICI-treated patients and irAEs was recruited. The panel rated anonymously on usability, accuracy, appropriateness or agreement of 41 items on a 9-point scale in Survey 1, after which a meeting was convened. Statements were modified based on voting results from Survey 1 and Meeting 1, and the process was repeated in Survey 2 and Meeting 2. At the end of this process, consensus was achieved for all statements. Our study findings address the gap in standardized nomenclature, clinical, laboratory and radiological evaluations, and management principles of E-irAEs. With consensus achieved from a panel of experts from a variety of disciplines, we anticipate that the statements can form the basis for standardization of the diagnostic process and improvement of patient care.

Importance Immune checkpoint inhibitors (ICIs) are efficacious in many cancer types but can produce immune-related adverse events (irAEs). As such, patients with preexisting autoimmune disorders are often excluded from clinical trials, although subsequent studies have shown that many of these patients have acceptable ICI tolerance. The safety and efficacy of ICIs among patients with preexisting neurologic autoimmune disorders (NAIDs) is not well characterized. Objective To evaluate the safety and clinical outcomes associated with ICI therapy among patients with NAIDs. Design, Setting, and Participants This multicenter retrospective cohort study included patients with cancer who were treated with ICIs between October 2013 and May 2023 and had preexisting multiple sclerosis (MS), myasthenia gravis (MG), Guillain-Barré syndrome (GBS), and other NAIDs as well as a control cohort of patients with Parkinson disease (PD). Exposure ICI therapy. Main Outcomes and Measures Demographic and clinical characteristics (neurologic disability, active or recent immunosuppression), ICI outcomes (response, progression-free survival [PFS], and overall survival [OS]), and safety outcomes (NAID exacerbation, irAEs) were collected. Results A total of 135 patients were included; the median (range) age was 72 (40-88) years, 84 (62%) were men, and 51 (38%) were women. A total of 45 patients had MS; 18, MG; 10, GBS; 5, another NAID; and 57, PD. Exacerbations occurred most frequently in MG (12 of 18 patients [67%]), often resulting in hospitalization (6 [50%]) or death (2 [17%]), with much lower rates in the MS cohort (8 of 45 patients [18%]). Ten patients with a history of GBS tolerated ICI without exacerbations, although 1 developed a fatal case of Lambert Eaton myasthenic syndrome following ICI treatment. No differences in response rate, PFS, or OS were observed between NAID groups. Conclusions and Relevance In this cohort study of ICI use in NAIDs, patients with MG had frequent and more severe exacerbations, while those with MS had few exacerbations. No obvious differences in survival between groups were observed. ICI may be an option for many patients with appropriate oncologic indications and preexisting NAIDs.

TPS2695 Background: The SMARCB1/A4 gene products are core subunits of the SWItch/Sucrose Non Fermentable (SWI/SNF) chromatin remodeling complex. Tumors with defects in SWI/SNF are histologically distinct aggressive cancers occurring in children and young adults. SMARCB1/A4 deficient tumors, particularly malignant rhabdoid tumor (MRT), atypical teratoid rhabdoid tumor (ATRT), poorly differentiated chordoma (PDC), epithelioid sarcoma (ES), and renal medullary carcinoma (RMC), have immune cell infiltrates and programmed death ligand 1 (PD-L1) expression. Responses to immune checkpoint inhibition (CI) have been observed in SMARCB1/A4 deficient tumors; however, responses are not durable. T cell immunoreceptor with Ig and ITIM domains (TIGIT) is a novel inhibitory receptor expressed on multiple immune cells. TIGIT inhibits T and NK cells by binding to its ligand poliovirus receptor (PVR) and Nectin2 on both tumor and antigen-presenting cells. Utilizing RNAseq data, SMARCB1/A4 deficient tumors demonstrate high expression of PVR and Nectin2. Tiragolumab is an antibody to the TIGIT receptor. The combination of tiragolumab and atezolizumab has shown promising activity in early phase studies, and phase 3 studies are ongoing in multiple adult indications. Thus, there is rationale that the addition of tiragolumab to CI may also enhance response rates in patients with SMARCB1/A4 deficient tumors. Methods: This is a phase 1/2 trial of tiragolumab monotherapy (300 mg if ≤ 15 kg; 420 mg if > 15 kg to ≤ 40 kg; 600 mg if > 40 kg or ≥ 18 years) and in combination with atezolizumab (15 mg/kg [max 1200 mg]) if < 18 yrs or 1200 mg if ≥ 18 years) administered IV on Day 1 of 21-day cycles in patients > 12 months of age with SMARCB1/A4 deficient tumors. Part A evaluating the safety of tiragolumab monotherapy in patients < 18 years based on cycle 1 dose limiting toxicities is complete. Part B estimates the antitumor activity of tiragolumab in combination with atezolizumab in 6 histology-specific cohorts (RMC, MRT, ATRT, PDC, ES, and other SMARCB1/A4 deficient tumors) and is now open to all eligible age groups. Each cohort is conducted using a 6+4 Simon’s two stage design. Enrollment for each cohort is as follows: Part A 6/6, Part B RMC 1/6, MRT 1/6, ATRT 4/6, PDC 2/6, ES 3/6, other 6/6. Radiographic imaging central response assessment for the first stage of the “other” cohort is ongoing. Cycle 1 toxicities of the combination therapy are monitored in Part B patients < 12 yrs using a Bayesian Optimal INterval (BOIN) design with a target toxicity of 17%. Secondary objectives are to characterize the pharmacokinetics/anti-drug antibody development and to estimate progression free survival, overall survival, and duration of response. Enrollment is open at all Pediatric Early Phase Clinical Trial Network sites. Data cutoff: Jan 10, 2025. Clinical trial information: NCT05286801 .

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 &gt;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 &lt;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 &gt;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 &gt;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: 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.