Citations

Abstract Pancreatic ductal adenocarcinoma (PDAC), the most common subtype of pancreatic cancer, is a deadly disease with a complex tumor microenvironment (TME). How chemotherapy alters the TME, and whether these changes drive chemoresistance, is poorly understood. We examined matched pre- and post-treatment tissue specimens and found near-universal enrichment of axonal guidance genes in cancer-associated fibroblasts (CAFs) after treatment. These CAFs were enriched near sites of perineural invasion, coinciding with regions of increased tumor cell proliferation, and were enriched in tumor areas distant from nerves after chemotherapy. Metastatic recurrence lesions had the highest prevalence of these CAFs versus primary tumors and untreated metastasis. These CAFs showed elevated non-canonical Wnt mediators and axonal guidance genes, which complemented matching cognate binding partners in tumor epithelial cells, suggesting a role in tumor-stroma crosstalk. Our findings implicate fibroblast-derived axonal-guidance genes in promoting PDAC invasion and point to a promising target for this disease. Statement of Significance Therapeutic resistance remains a major challenge in pancreatic cancer. Our findings shed light on the changes in the complex tumor microenvironment in response to chemotherapy and identify fibroblasts high in axonal-guidance genes that may drive tumor progression and chemoresistance, thus uncovering a potential avenue for targeting pancreatic cancer.

Abstract Pancreatic cancer, projected to become the second-deadliest malignancy in Western societies by 2030, requires urgent innovations in early detection and risk stratification. Intraductal papillary mucinous neoplasms (IPMNs) represent critical precursor lesions, but current clinical guidelines demonstrate suboptimal accuracy in malignancy prediction, leading to either unnecessary surgeries or missed opportunities for early intervention. In this paper, we present Cyst-X, an artificial intelligence (AI) framework that accurately predicts IPMN malignant transformation using multicenter magnetic resonance imaging (MRI) data. Unlike most previous approaches that rely on computed tomography (CT), our method capitalizes on the superior soft tissue contrast of MRI, allowing for more precise identification of subtle imaging biomarkers. We developed and validated deep learning models on 723 T1-weighted and 738 T2-weighted MRI scans from 764 patients among seven international institutions, demonstrating significantly superior performance (AUC=0.82) compared to current clinical (Kyoto) guidelines (AUC=0.75) and expert radiologists. AI-based imaging features correlate strongly with clinically recognized malignancy markers, providing potential biologically relevant insights. This approach holds promise to significantly refine clinical decision-making, reduce unnecessary surgeries, and better identify high-risk IPMN patients for timely intervention. Our approach integrates a novel pancreas segmentation network with robust classification models that identify subtle imaging biomarkers associated with malignancy risk. Importantly, we demonstrate that these models retain high performance in a privacy-preserving federated learning setting, where institutions collaboratively train AI models without exchanging patient data to address key regulatory and ethical barriers. We publicly release the Cyst-X dataset--the first large-scale, multi-center pancreatic cyst MRI collection--to accelerate research in this field. This study addresses a critical clinical need while establishing technical foundations for privacy-preserving AI in radiology that could transform pancreatic cancer management through earlier intervention and reduced unnecessary procedures. The dataset can be accessed at https://osf.io/74vfs/, and the source code for our deep learning segmentation and classification models is available at https://github.com/NUBagciLab/Cyst-X.

PURPOSE Previous studies suggest that SPOP mutations result in increased sensitivity to androgen receptor pathway inhibitors (ARPIs) but are limited by lack of granular data. We hypothesize that SPOP mutations are associated with improved outcomes across the spectrum of advanced prostate cancer (PC). METHODS Using the real-world clinicogenomic Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort database, we analyzed outcomes based on SPOP mutation status. The primary end point was overall survival (OS) from the diagnosis of metastatic disease. Secondary end points included real-world progression-free survival (PFS) and PSA90 response. RESULTS Among 2,097 patients with metastatic PC, 5.5% (N = 115) had SPOP -mutated tumors. Compared with SPOP wild-type, patients with SPOP mutations were older at diagnosis (median 65 v 63 years; P = .001) and had higher (≥8) Gleason sum (68% v 54%; P = .02), higher incidence of lung metastasis (17% v 6%; P = .001), and increased frequency of intraductal features (13% v 5%; P < .001). SPOP mutations were associated with improved PSA90 response with first ARPI exposure in the castrate-resistant setting (60% v 40.6%; OR, 2.20 [95% CI, 1.15 to 4.19]; P = .02) but not in the castrate-sensitive setting (78.9% v 71.5%; OR, 1.49 [95% CI, 0.66 to 3.37]; P = .43). Median PFS with first ARPI did not differ in SPOP- mutated versus wild-type group in both the castrate-sensitive (24.2 v 19.2 months; hazard ratio [HR], 0.80 [95% CI, 0.49 to 1.32]; P = .39) and castrate-resistant settings (15.0 v 12.4 months; HR, 0.81 [95% CI, 0.58 to 1.12]; P = .20). In multivariable analysis, SPOP mutations were associated with improved OS (HR, 0.65, P = .02). CONCLUSION SPOP mutations were associated with longer OS despite the presence of aggressive clinical features. The distinct clinical and molecular features of SPOP -mutated PC support its consideration as a unique molecular subtype with prognostic implications.

Abstract Systems-based hematology (SBH) is an emerging discipline focused on optimizing care delivery for patients with hematologic disorders within complex health care systems. Despite its growing importance, the field lacks a formal definition, standardized curriculum, and clear career pathway, hindering widespread adoption and training of future SBH experts. We sought to define core principles, competencies, challenges, and future directions of SBH to identify foundational components for a potential educational curriculum. Semistructured interviews were conducted with 8 SBH experts. Expert participants were identified through their committee involvement with the American Society of Hematology. Five overarching themes emerged: (1) The accidental expert: SBH careers have developed organically and reactively in response to pressing institutional needs, not through formal training; (2) Defining the unseen: experts define the field pragmatically by its function and roles; (3) The SBH toolkit: success requires a hybrid skillset combining clinical hematology expertise with health systems science (HSS) principles; (4) The architect's dilemma: the field's growth is hindered by interdependent challenges of building a curriculum, awareness, and securing resources; and (5) Charting the future: the discipline is poised for growth, driven by increasing health care complexity and specialization. SBH represents the nexus of HSS principles and hematology care. Formalizing SBH requires a multipronged approach, including developing a standardized curriculum that equips learners with a hybrid skillset, creating clear value for health systems and patients, and fostering a community of practice through professional societies. These findings provide a foundational framework for developing educational resources and institutional support necessary to continue advancing SBH.

Abstract Wiskott-Aldrich syndrome (WAS), an X-linked disorder characterized by immunodeficiency, thrombocytopenia, autoimmunity, and malignancy, can be effectively treated with allogeneic hematopoietic cell transplantation (HCT). Older age at HCT and mismatched donors are known to affect overall survival (OS). However, the influence of specific clinical manifestations or WAS variant class on OS and factors associated with event-free survival (EFS) remain incompletely defined. We analyzed outcomes of 308 patients with WAS who underwent HCT at 37 institutions of the Primary Immune Deficiency Treatment Consortium from 1990 to 2018. With a median follow-up of 5.3 years, the 5-year OS and EFS were 87.2% and 79.7%, respectively. Age ≥5 years, donor type, and a pre-HCT history of severe infection had a negative impact on OS and EFS, whereas pre-HCT autoimmunity had no impact. Reduced-intensity regimens were associated with lower T-cell and myeloid donor chimerism, particularly when non–busulfan-based regimens were used. Low myeloid donor chimerism was associated with lower platelet counts. Mixed chimerism was not consistently associated with post-HCT autoimmunity. Patients with class I (exon 1-2 missense and intron 5 hot spot variants) and class II variants (all others) had similar pre-HCT clinical symptom severity and no difference in OS, EFS, or platelet recovery post-HCT. In conclusion, our study showed excellent long-term OS and EFS after HCT for WAS, highlighting the importance of early HCT, before the development of severe infections. We confirmed that HCT using busulfan-based conditioning was associated with improved donor chimerism and platelet recovery. This trial was registered at www.clinicaltrials.gov as NCT02064933.

ABSTRACT Enzalutamide and abiraterone are hormonal treatments that improve survival in metastatic castration‐resistant prostate cancer. Identifying genetic variants associated with the clearance of these drugs may aid in improved dosing and outcomes. We performed genetic association studies of enzalutamide and abiraterone oral clearance in the Alliance A031201 clinical trial. Genome‐wide genotyping was performed with the primary analysis limited to European‐descent participants. Pharmacogene metabolic phenotypes were estimated using PyPGx and Stargazer. Associations of metabolic activity groups for CYP3A4 , CYP3A5 , CYP2C19 and SLCO1B1 with enzalutamide clearance ( N = 706) and CYP3A4 , SLCO2B1 and UGT1A4 with abiraterone clearance ( N = 323) were tested by linear regression. Targeted SNP associations were assessed for abiraterone clearance at loci proximal to major metabolizing genes. Full genome‐wide association studies were performed for both sets of clearance values. No significant associations were identified between metabolic phenotypes and enzalutamide or abiraterone oral clearance SNPs in the SULT2A1 5′ flanking region were significantly associated with lower abiraterone clearance, (rs296373, minor allele frequency = 0.15, β = −0.457, p = 3.2E‐06). Liver protein and liver and adrenal gland gene expression QTL databases indicated significantly lower SULT2A1 expression patterns for individuals carrying associated alleles, likely explaining the lower abiraterone oral clearance. CYP2C8*3 was associated with higher enzalutamide clearance ( p = 0.012), but this was not significant after correction for multiple testing. This study is the first to identify the genetic association of SULT2A1, known to be involved in the metabolism of steroids in the liver and adrenal glands, with abiraterone clearance. Genetic variation in SULT2A1 may be useful to inform personalized dosing of abiraterone. ClinicalTrials.gov Identifier: NCT01949337

Abstract Background: IgG4-related disease (IgG4-RD) is a rare, immune-mediated fibroinflammatory condition characterized by tissue infiltration with IgG4-positive plasma cells. While solid organ involvement is well documented, data on hematologic manifestations and associated outcomes remain limited. Understanding hematological burden and real-world treatment patterns is essential to guide comprehensive management. Methods: We conducted a multicenter, retrospective cohort study using the TriNetX Research Network, comprising electronic health records from multiple U.S. healthcare systems. Adults (≥18 years) with a diagnosis of IgG4-RD (ICD-10 codes) were included. Patients with a prior diagnosis of hematologic malignancy were excluded. Demographic characteristics, hematologic manifestations, treatment patterns, and overall mortality were assessed. The median follow-up duration was 519 days. Results: A total of 2,596 patients with IgG4-RD were identified, of whom 554 (21.3%) exhibited at least one hematologic manifestation. The mean age was 58.1 ± 15.9 years; 53% were male (n=1,379), and 57% were White (n=1,492). Hypertension was the most common comorbidity (44%, n=1,136). Among those with hematologic involvement, key manifestations included lymphadenopathy (n=605, 23.3%), hepatomegaly (n=114, 4.4%), splenomegaly (n=73, 2.8%), eosinophilia (n=71, 2.7%), pancytopenia (n=31, 1.2%), hypergammaglobulinemia (n=71, 2.7%), and monoclonal gammopathy (n=86, 3.3%). Regarding outcomes, 127 of 2,596 patients (4.9%) died during the follow-up period. Among those with hematologic manifestations, 36 of 554 (6.5%) died, indicating a numerically higher mortality rate in this subgroup. Treatment data revealed that all patients received corticosteroids as initial therapy. Additionally, 531 patients (20.4%) received steroid-sparing immunosuppressants. The most used agents included rituximab (6%), azathioprine (6%), mycophenolate mofetil (5%), and methotrexate (3%). Conclusion: In this large, real-world cohort of patients with IgG4-RD, hematologic manifestations were observed in over one-fifth of patients and were associated with a numerically higher mortality rate. Lymphadenopathy was the most common hematologic feature. Despite the widespread use of corticosteroids, a substantial proportion of patients required steroid-sparing agents. These findings highlight the hematologic complexity of IgG4-RD and underscore the need for multidisciplinary management and prospective studies focused on hematologic outcomes.

Abstract Introduction: Primary mediastinal B-Cell lymphoma (PMBCL) is a rare form of large B-Cell lymphoma (LBCL) with around 90% of patients (pts) cured with first line (1L) treatment. For pts with relapsed or refractory (RR) PMBCL, the optimal treatment is unclear. Prior retrospective analysis in the rituximab (R) era have shown high response rates to platinum salvage and high-dose chemotherapy followed by autologous stem cell transplant (HDT/ASCT) in second line (2L) RR PMBCL (Bakos et al. ASH 2023 and Dumke et al. ASCO 2024). The pivotal phase III LBCL trials in early relapsing pts that compared CD19 chimeric antigen receptor-T cell (CAR-T) with HDT/ASCT as 2L treatment had few PMBCL pts: none on ZUMA-7 and 17 PMBCL on TRANSFORM, of whom only 8 were randomized to 2L CAR-T. This study aims to evaluate outcomes of 2L therapies for RR PMBCL, including pts treated with 2L CAR-T. Methods: We performed a multicenter retrospective study in pts with RR PMBCL treated between 2001 and 2025. Clinical and pathologic characteristics, treatment regimens, and efficacy outcomes were collected and analyzed. Results: 139 pts were included with 43% male, 69% Caucasian, 7.9% Black, 8.6% Asian and 79% Non-Hispanic. R-EPOCH (64%) and (32%) were the most common 1L treatments and all pts received R. Consolidative radiation was used in 21 pts (15%) as part of 1L therapy, 28% after RCHOP. Primary refractory disease with relapse ≤6 month (mo), or early relapse ≤12 mo, occurred in 83% (N = 115) and 93% (N = 129 pts), respectively. At relapse, median age was 34 years (yrs), 44% had advanced stage disease, 31% had bulky disease (≥ 7.5cm). CNS relapse occurred in 8.6% of pts. Overall and complete response rate (ORR and CR) to any 2L treatment was 44% and 27%, respectively. At median follow-up of 40 months (mo) from the start of 2L treatment, median PFS of the entire cohort was 3.2 mo with a 3 yr OS of 70%. For 2L treatment, N=93 (67%) pts were treated with platinum salvage with intention to proceed with HDT/ASCT. Most commonly used platinum salvage regimens were ICE± R (n= 53, 38%), R-DHAP (n=23, 17%), R-GemOx (n= 5, 3.6%), and GDP ± R (n= 10, 7.2%), and the majority (95%) of pts received R with 2L therapy. ORR and CR to platinum salvage was 46% and 15% respectively. With a median follow up of 30 mo from start of 2L therapy, median PFS was 2.6 mos, and 3 yr PFS and OS was 15% and 64%, respectively. Of the 93 pts treated with platinum salvage, only 25 pts (27%) proceeded with HDT/ASCT- of whom, N = 17 (68%) achieved a CR after ASCT. In patients that proceeded to ASCT, relapses occurred in 10 pts (40%) with a 3 yr PFS and OS 56% and 83%, respectively. CAR-T was used as 2L in 20 pts (14%)- most commonly either axi-cel (N =7) or liso-cel (N = 8). ORR and CR to CART was 89% and 55% respectively, median PFS and OS was NR after CAR-T infusion and 3 yr PFS and OS was 55% and 95%, respectively. Other 2L treatments included pembrolizumab (N =3), brentuximab vedotin (BV) + nivolumab (N= 4) or single agent BV (N=2). Radiation was given as part of 2L treatment in 25.9% of pts. 2L CAR-T therapy was associated with improved ORR (OR 7.60, 95% CI 1.68 – 34.55, p = 0.002), improved CR rate (OR 4.15, 95% CI 1.49 – 11.53, p = 0.008) and improved PFS (HR 0.18, 95% CI 0.06 – 0.57, p = 0.004) compared to pts treated with 2L platinum salvage. There was no difference in OS between pts treated with platinum salvage or 2L CAR-T. A total of 96 patients progressed on 2L therapy, and 92 pts (95.8%) received third-line (3L) treatment. Third line treatments included chemoimmunotherapy +/- HDT/ASCT (N= 23), CD19 CAR-T (N = 35), clinical trial (N=7), check point inhibitor-based regimen (N= 11), BV based regimen (N= 8), allogeneic stem cell transplant (N = 3) or other (N = 5), with 7 pts receiving radiation as part of 3L therapy. Median PFS and OS from start of 3L therapy was 6.7 mo and 6.4 mo, respectively. Conclusions: We report the largest cohort of pts with RR PMBCL treated in the rituximab era and the largest number of PMBCL pts treated with 2L CAR-T. This is the first analysis, to our knowledge, to show a statistically significant benefit in PFS, ORR and CR rate of CAR-T compared to platinum salvage followed by HDT/ASCT as 2L treatment in a study of exclusively RR PMBCL pts. Our dataset was largely (93%) compromised of pts with primary refractory or early relapsing disease and provides support for using CAR-T as 2L treatment in this high-risk subset of RR PMBCL patients.

Abstract Introduction: Older adults (OAs) with classic Hodgkin lymphoma (cHL) have inferior survival compared with younger patients (pts). NAVD has been widely adopted in clinical practice for frontline (1L) treatment of OAs with advanced stage cHL based on the subset analysis of S1826 study (Rutherford et al, JCO 2025) showing a 1-year progression-free survival (PFS) of 93% and 1-year overall survival (OS) of 95% after NAVD (n = 50) which remained durable on longer-term follow up. Another phase 2 study (Torka et al, JCO 2025) showed that NAVD is a highly effective and well-tolerated 1L regimen in OAs with cHL (n=40) across a wide range of geriatric impairments. Adverse events (AEs) and efficacy have not been reported in OAs treated with NAVD outside of a clinical trial. Hence, we sought to evaluate safety profile and efficacy outcomes of OAs with cHL treated with 1L NAVD in a real-world setting (RWS). Methods This is a multicenter retrospective cohort study of adults (≥18 years) with cHL treated with 1L NAVD between 2023 and 2025 at 20 US academic sites. Baseline characteristics and outcomes of pts ≥60 years were evaluated as a pre-planned subset analysis. The safety evaluable cohort received at least 1 cycle of NAVD and included pts who had not yet completed treatment. The efficacy evaluable cohort had completed 6 cycles of treatment including end of treatment (EOT) PET-CT and included pts who intended to complete treatment but died or discontinued due to progressive disease or AEs. The primary endpoint was EOT overall response rate (ORR). Secondary endpoints included EOT complete response rate (CRR), PFS and OS. PFS and OS were analyzed using the Kaplan Meier method. Results Among 311 pts, 81 were OAs (26%). Median age of the OA cohort was 70 (range 60-88) yrs, 65% male, 84% Caucasian, 71% nodular sclerosis subtype, 58% stage 4 disease, 59% B symptoms, 14% bulky disease (&gt;7.5 cm), 69% extranodal sites, 41% EBV positive, 54% hypoalbuminemia, 49% IPS ≥ 4 and10% had an autoimmune disease. G-CSF was given in 81% pts. All 81 pts were evaluable for safety; 74% experienced a grade 3+ (≥G3) AE, 54% had ≥G3 hematological AE, 48% had ≥G3 neutropenia, 17% had febrile neutropenia. Infection rate was 28% with 10% ≥G3, neuropathy rate was 23% with 4% ≥G3. One infusion reaction was noted. Treatment related hospitalizations rate was 23% with median duration of 7 (range 1-16) days. There were 24 immune related AEs (IrAE) (30%) of which 5 were ≥G3. Most common IrAE was hypothyroidism (n=5), followed by inflammatory arthritis (n=4), pneumonitis (n=2, ≥G3, n=1), hepatitis (n=2, both ≥G3), adrenal insufficiency (n=2, ≥G3, n=1), colitis (n=2), and rash (n=2). One patient each had autoimmune neutropenia, sarcoidosis of lung/skin and myocarditis (≥G3). Overall, 15% pts required steroids with resolution of IrAEs in 56% cases, 30% (n=7) pts required continued therapy (levothyroxine in 4 pts, steroids in 3 pts, medical tx for heart failure in 1 pt). Treatment was interrupted in 22%, reduced in 22%, and discontinued in 23% pts. Nivolumab was discontinued in 14% pts. Among all pts (n=81), 81% had an interim PET-CT after 2-4 cycles. The ORR and CR rate at interim PET-CT were 100% and 81%, respectively. In the efficacy evaluable pts (n=52; 24 still on therapy), the EOT ORR and CRR were 93.2% and 84% in OAs compared to 96.8% and 91.7% in pts &lt;60yrs, respectively. At a median follow up of 10.2 mo (range 0.27-28.52), the 1-yr PFS was 90.6% (95% CI: 82.7%-99.3%) in OAs and 95.5% (95% CI: 91.6%- 99.6%) in pts &lt;60 yrs (p=0.044). 1-yr OS was 97.5% (95% CI: 94.1-100%) and not evaluable in pts &lt;60yrs (p=0.017). None of the baseline features were predictive of response, additional analysis to understand impact on AEs and survival is ongoing. Among the 5 pts with progression/relapse, 4 were primary refractory. 4 pts received 2nd line (2L) therapy.79 pts are alive at data cut off, 2 deaths occurred- 1 infection-related and other unknown; both after the 1st cycle. Conclusions In this largest RWS cohort of OAs treated with NAVD we showed comparable response rates, AEs and 1-year survival outcomes to those in the pivotal S1826 trial. Notably, rates of ≥G3 AEs including infections, neuropathy and IrAEs remained low and manageable. Although survival significantly improved with NAVD compared to historical data, outcomes of OAs remained inferior compared to pts &lt;60 yrs. Our data reinforces the use of NAVD as the preferred 1L option for OAs with advanced stage cHL.

Abstract Introduction Ph-like B-ALL is a poor-risk B-ALL subtype defined by gene expression signatures that resemble the BCR::ABL1-associated transcriptional program in the absence of the BCR-ABL1 oncoprotein. Recent studies have demonstrated that up to 80% of Ph-like B-ALLs have recurrent gene fusions involving cytokine receptors or tyrosine kinases that can be identified via cytogenetics, fluorescence in situ hybridization (FISH) or RNA sequencing. However, the inability to rapidly and accurately identify these alterations in the clinical setting is a major impediment to developing therapeutic strategies that may have efficacy in this B-ALL subtype. Here we used 88 patient (pt) samples to validate a rapid, streamlined clinical WGS assay (ChromoSeq) for B-ALL and assessed the diagnostic yield for Ph-like-associated SVs in 136 pts enrolled in the Alliance A041501 clinical trial. Methods ChromoSeq is a clinical WGS assay for hematologic malignancies that uses rapid laboratory workflows and focused analysis methods to identify clinically relevant SVs, copy number alterations and gene-level mutations. We updated the ChromoSeq pipeline for use in B-ALL pts and validated it using 88 retrospective B-ALL samples (80 adult/young adult and 8 pediatric from Washington University School of Medicine and St. Louis Children's Hospital), 54 of which were analyzed via RNAseq for gene fusions and a 6-gene Ph-like B-ALL signature (CA6, SPATS2L, MUC4, JCHAIN, BMPR1B, ADGRF1, NRXN3 and CRLF2). The “ChromoSeqV2” assay was then used to analyze 136 pretreatment blood or bone marrow samples from the Alliance A041501 (trial NCT03150693). These results were compared to data from RNAseq obtained for research purposes (N=35), clinical cytogenetics (N=69) and Ph-like classification via low-density microarray (LDA) card analysis (all pts). Results ChromoSeqV2 was validated in a CLIA-licensed setting using cohort of 88 retrospective B-ALL samples, 45 of which had ICC and WHO class-defining SVs based on G-banded karyotyping, FISH or RNAseq. ChromoSeqV2 detected 100% of the non-Ph-like SVs (37/37), including BCR::ABL1 (N=20), KMT2Ar (N=9), ETV6::RUNX1 (N=3), TCF3::PBX1 (N=1), and rearrangements involving MYC (N=2) or MEF2D (N=2). Fifteen patients met criteria for Ph-like B-ALL via cytogenetics or RNAseq either due to rearrangements of CRLF2 (N=5), JAK2 (N=2) or ABL2 (N=1) or high expression of a 6-gene Ph-like signature (N=7). ChromoSeqV2 detected a Ph-like SV in 93% of these cases (14/15) with 100% specificity in samples negative by RNAseq (N=23). ChromoSeqV2 was then used to profile 136 samples from the Alliance A041501 trial, where it identified ICC and WHO class-defining SVs in 87 pts (64%; 95% CI: 55-72%), including Ph-like SVs (56/136, 41%), KMT2A rearrangements (N=5), TCF3::PBX1 (N=3) and SVs involving MYC (N=3), MEF2D (N=2), DUX4 (N=2), and ZNF384 (N=1). Ph-like SVs were dominated by CRLF2 rearrangements (N=45) and included SVs involving EPOR (N=4), JAK2 (N=3), ABL1/ABL2 (N=2) and PDGFRB (N=1). IGH was the most common CRLF2 partner (N=32), followed by P2RY8::CRLF2 (N=7) and other genes (N=5). Multiple CRLF2 SVs were detected in 4 pts, and 33% (15/45) of pts with a CRLF2 rearrangement had a co-occurring CRLF2 gene mutation. The yield of ChromoSeqV2 for SVs in pts with the Ph-like expression signature via LDA card analysis was 66% (54/82; 95% CI 55%-76%) compared to 24% (11/45; 95% CI 13%-40%) by cytogenetics when these studies were successful and 70% (12/17; 95% CI 44%-90%) vs RNAseq in pts with available data. The sensitivity of ChromoSeqV2 for Ph-like SVs identified by either cytogenetics, FISH or RNAseq was 100% (21/21; 95% CI 84%-100%) and the positive predictive value of Ph-like SVs for the Ph-like expression signature by the LDA card assay was 96% (54/56; 95% CI 88%-99%). Conclusions Genomic assessment of 136 B-ALL pts from the Alliance A041501 trial using the ChromoSeqV2 rapid clinical WGS assay was 100% sensitive for Ph-like SVs identified by other molecular methods and had a 96% PPV for the Ph-like expression signature via LDA card analysis. The diagnostic yield of SV pts with the Ph-like signature was 66% using ChromoSeqV2, which was similar to RNAseq and superior to cytogenetics. These results demonstrate that ChromoSeqV2 is an effective approach for identifying potentially targetable rearrangements in B-ALL pts suspected of having the Ph-like phenotype. Support: U10CA180821, U10CA180882; . Servier; Pfizer.