Jean Oak

All Publications

• B-lymphoblastic leukemia with transient spontaneous remission in the setting of severe group A streptococcus infection. Journal of hematopathology Gilbert, A., Tan, J., Nadimpalli, S., Orkusyan, R., Fernandez, Z. I., Oak, J., Fernandez-Pol, S. 2023; 16 (4): 223-226

  Abstract

  Spontaneous remission of B-lymphoblastic leukemia (B-ALL) in the setting of viral and bacterial infections has been reported. Here, we present a case of B-ALL that showed a complete remission in the setting of group A streptococcal bacteremia. The patient was an 11-year-old boy who presented with a sore throat, right ear pain, and rhinorrhea. Prior to the diagnosis of B-ALL, he was diagnosed with streptococcal pharyngitis and received a single dose of dexamethasone and azithromycin. One day later, he was found to be pancytopenic and an immunophenotypically abnormal B-lymphoblastic population was detected comprising 0.6% and 16.8% of the peripheral blood and bone marrow cells, respectively. Though a diagnosis of B-ALL was highly suspected, blast percentage was <20% and the bone marrow showed relatively unremarkable trilineage hematopoiesis. On close monitoring, the suspected neoplastic population became undetectable by day 17 and the patient's complete blood count (CBC) completely normalized by day 46. On day 82, a peripheral blood smear demonstrated circulating blasts. Flow cytometry of a bone marrow aspirate revealed B-lymphoblastic leukemia accounting for 94% nucleated cells, consistent with the diagnosis of B-lymphoblastic leukemia. This case is of interest as less than 20 examples of spontaneous remission of B-ALL have been reported in the literature. As the case reported here relapsed and previously reported spontaneously remitting cases have uniformly relapsed, cases of B-ALL with spontaneous remission should be followed very closely for recurrence.

  View details for DOI 10.1007/s12308-023-00564-5

  View details for PubMedID 38175433

  View details for PubMedCentralID 3309707

• Antigen density quantification of cell-surface immunotherapy targets by flow cytometry: Multi-antigen assay of neuroblastoma bone marrow metastasis. STAR protocols Radosevich, M. T., Bornheimer, S. J., Mehrpouryan, M., Sahaf, B., Oak, J. S., Mackall, C. L., Heitzeneder, S. 2023; 4 (4): 102709

  Abstract

  The central role of target antigen density on chimeric antigen receptor T cell potency highlights the need for accurate measurement of antigen levels on clinical tumor samples. Here, we present a protocol for quantifying antigen density for six cell-surface antigens on neuroblastoma cells metastatic to bone marrow. We describe steps for patient sample acquisition, flow cytometry panel development, instrument setup, and compensation and detail procedures for running clinical samples and data analysis. For complete details on the use and execution of this protocol, please refer to Heitzeneder et al. (2022).1.

  View details for DOI 10.1016/j.xpro.2023.102709

  View details for PubMedID 37967014

• B-lymphoblastic leukemia with transient spontaneous remission in the setting of severe group A streptococcus infection JOURNAL OF HEMATOPATHOLOGY Gilbert, A., Tan, J., Nadimpalli, S., Orkusyan, R., Fernandez, Z., Oak, J., Fernandez-Pol, S. 2023

  View details for DOI 10.1007/s12308-023-00564-5

  View details for Web of Science ID 001082863900001

• A cell-level discriminative neural network model for diagnosis of blood cancers. Bioinformatics (Oxford, England) Robles, E. E., Jin, Y., Smyth, P., Scheuermann, R. H., Bui, J. D., Wang, H. Y., Oak, J., Qian, Y. 2023

  Abstract

  Precise identification of cancer cells in patient samples is essential for accurate diagnosis and clinical monitoring but has been a significant challenge in machine learning approaches for cancer precision medicine. In most scenarios, training data are only available with disease annotation at the subject or sample level. Traditional approaches separate the classification process into multiple steps that are optimized independently. Recent methods either focus on predicting sample-level diagnosis without identifying individual pathologic cells or are less effective for identifying heterogeneous cancer cell phenotypes.We developed a generalized end-to-end differentiable model, the Cell Scoring Neural Network (CSNN), which takes sample-level training data and predicts the diagnosis of the testing samples and the identity of the diagnostic cells in the sample, simultaneously. The cell-level density differences between samples are linked to the sample diagnosis, which allows the probabilities of individual cells being diagnostic to be calculated using backpropagation. We applied CSNN to two independent clinical flow cytometry datasets for leukemia diagnosis. In both qualitative and quantitative assessments, CSNN outperformed preexisting neural network modeling approaches for both cancer diagnosis and cell-level classification. Post hoc decision trees and 2D dot plots were generated for interpretation of the identified cancer cells, showing that the identified cell phenotypes match the cancer endotypes observed clinically in patient cohorts. Independent data clustering analysis confirmed the identified cancer cell populations.The source code of CSNN and datasets used in the experiments are publicly available on GitHub (http://github.com/erobl/csnn). Raw FCS files can be downloaded from FlowRepository (ID: FR-FCM-Z6YK).Supplementary data are available on GitHub and at Bioinformatics online.

  View details for DOI 10.1093/bioinformatics/btad585

  View details for PubMedID 37756695

• Challenges of detecting measurable/minimal disease in acute leukemia. Seminars in diagnostic pathology Zhang, J., Oak, J. 2023

  Abstract

  Measurable/minimal residual disease (MRD) tracking has emerged as a powerful tool for assessing treatment response and predicting outcomes in acute leukemia. However, the clinical and technological challenges associated with MRD tracking must be addressed to improve its utility in routine patient care. This review article aims to provide a summary of the different MRD methodologies used in acute leukemia. It highlights the strengths, diagnostic pitfalls, and clinical utility associated with MRD tracking in this rapidly evolving field.

  View details for DOI 10.1053/j.semdp.2023.04.004

  View details for PubMedID 37150656

• Role of peripheral blood MRD and 18F-FDG PET in the post-CAR relapse setting: a case study of discordant peripheral blood and bone marrow MRD. Journal for immunotherapy of cancer Schultz, L., Davis, K. L., Walkush, A., Baggott, C., Erickson, C., Ramakrishna, S., Aftandilian, C., Lacayo, N., Nadel, H. R., Oak, J., Mackall, C. L. 2023; 11 (2)

  Abstract

  Chimeric antigen receptor (CAR) T cell therapy is an effective salvage therapy for pediatric relapsed B-cell acute lymphoblastic leukemia (B-ALL), yet is challenged by high rates of post-CAR relapse. Literature describing specific relapse patterns and extramedullary (EM) sites of involvement in the post-CAR setting remains limited, and a clinical standard for post-CAR disease surveillance has yet to be established. We highlight the importance of integrating peripheral blood minimal residual disease (MRD) testing and radiologic imaging into surveillance strategies, to effectively characterize and capture post-CAR relapse.Here, we describe the case of a child with multiply relapsed B-ALL who relapsed in the post-CAR setting with gross non-contiguous medullary and EM disease. Interestingly, her relapse was identified first from peripheral blood flow cytometry MRD surveillance, in context of a negative bone marrow aspirate (MRD <0.01%). Positron emission tomography with 18F-fluorodeoxyglucose revealed diffuse leukemia with innumerable bone and lymph node lesions, interestingly sparing her sacrum, the site of her bone marrow aspirate sampling.We highlight this case as both peripheral blood MRD and 18F-fluorodeoxyglucose positron emission tomography imaging were more sensitive than standard bone marrow aspirate testing in detecting this patient's post-CAR relapse. Clinical/Biologic Insight: In the multiply relapsed B-ALL setting, where relapse patterns may include patchy medullary and/or EM disease, peripheral blood MRD and/or whole body imaging, may carry increased sensitivity at detecting relapse in patient subsets, as compared with standard bone marrow sampling.

  View details for DOI 10.1136/jitc-2022-004851

  View details for PubMedID 36849202

  View details for PubMedCentralID PMC9972424

• Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas. Cancer cell Sworder, B. J., Kurtz, D. M., Alig, S. K., Frank, M. J., Shukla, N., Garofalo, A., Macaulay, C. W., Shahrokh Esfahani, M., Olsen, M. N., Hamilton, J., Hosoya, H., Hamilton, M., Spiegel, J. Y., Baird, J. H., Sugio, T., Carleton, M., Craig, A. F., Younes, S. F., Sahaf, B., Sheybani, N. D., Schroers-Martin, J. G., Liu, C. L., Oak, J. S., Jin, M. C., Beygi, S., Hüttmann, A., Hanoun, C., Dührsen, U., Westin, J. R., Khodadoust, M. S., Natkunam, Y., Majzner, R. G., Mackall, C. L., Diehn, M., Miklos, D. B., Alizadeh, A. A. 2022

  Abstract

  Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches.

  View details for DOI 10.1016/j.ccell.2022.12.005

  View details for PubMedID 36584673

• Determinants of Resistance to Engineered T-Cell Therapies Targeting CD19 in Large B-Cell Lymphomas Sworder, B., Kurtz, D. M., Alig, S. K., Frank, M. J., Shukla, N. D., Garofalo, A., Macaulay, C., Esfahani, M., Olsen, M., Hamilton, J., Hosoya, H., Hamilton, M. P., Spiegel, J. Y., Baird, J. H., Carleton, M., Craig, A. M., Younes, S. F., Sahaf, B., Sheybani, N., Schroers-Martin, J., Liu, C., Oak, J. S., Jin, M. C., Beygi, S., Huttmann, A., Hanoun, C., Duhrsen, U., Westin, J., Khodadoust, M. S., Natkunam, Y., Majzner, R. G., Mackall, C. L., Diehn, M., Miklos, D. B., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022: 1301-1303

  View details for DOI 10.1182/blood-2022-165545

  View details for Web of Science ID 000893223201129

• Correlation of Mutational Profiles and Cytogenetics with Morphologic Dysplasia in Myelodysplastic Syndromes Kumar, J., Khanna, V., Lu, R., Stehr, H., Spinner, M. A., Silva, O., Fernandez-Pol, S., Oak, J. S., Greenberg, P. L., Tan, B. AMER SOC HEMATOLOGY. 2022: 4053-4055

  View details for DOI 10.1182/blood-2022-160237

  View details for Web of Science ID 000893223204027

• Characterization of Clinical, Molecular, and Prognostic Features of the WHO 2022 Classification System for Myelodysplastic Neoplasms (MDS) Khanna, V., Lu, R., Kumar, J., Stehr, H., Spinner, M. A., Silva, O., Fernandez-Pol, S., Oak, J. S., Tan, B., Greenberg, P. L. AMER SOC HEMATOLOGY. 2022: 6955-6957

  View details for DOI 10.1182/blood-2022-165841

  View details for Web of Science ID 000893223206427

• Targeted Mutational Profiling Reveals Clonal Relationships in Metachronous Occurrence of Classic Hodgkin and Mediastinal Large B-Cell Lymphomas. The American journal of surgical pathology Singh, K., Lezama, L. S., Kurzer, J., Oak, J., Schultz, L. M., Walkush, A., Cheng, T. C., Chen, E. H., May, W. A., Chang, C., Link, M. P., Advani, R. H., Suarez, C. J., Natkunam, Y. 2022

  Abstract

  Classic Hodgkin lymphoma (CHL) patients may infrequently present with a prior or recurrent disease with discordant histology resembling non-Hodgkin lymphomas. These include primary mediastinal large B-cell lymphoma (PMBL), diffuse large B-cell lymphoma (DLBCL), or mediastinal gray-zone lymphoma (MGZL). Such patients are often refractory to standard therapy and their diagnosis is hampered by significant morphologic and immunophenotypic overlap and insufficient molecular data. Among 509 CHL patients seen at an academic medical center, 6 patients had a prior or subsequent diagnosis different from CHL. Paired tissue samples were evaluated by targeted mutational analysis using a 164-gene panel. Our findings show multiple shared variants indicative of a clonal relationship between the CHL and the PMBL, DLBCL, or MGZL diagnoses. Most frequent mutated genes included TNFAIP3 (4 of 6, 66.7%), STAT6 (3 or 6, 50%), ARID1A (3 of 6, 50%), and XPO1 (3 of 5, 60%). Three patients showed the same oncogenic variant within the XPO1 gene (E571K), and mutations in TNFAIP3 and B2M were observed in 2 of the 5 patients with shared variants. In addition, differences in the mutation profile between the lymphoma pairs were also observed, which could represent clonal evolution. Mutational profiling could be of benefit in patients with recurrent/refractory disease with discordant histology, where the clonal relationship could be helpful to inform and guide therapeutic decisions. These findings provide further evidence of a true biological continuum surrounding CHL, PMBL, DLBCL, and MGZL and shed light on underlying genetic events and their clinical impact.

  View details for DOI 10.1097/PAS.0000000000001956

  View details for PubMedID 36001451

• CD22-CAR T-Cell Therapy Mediates High Durable Remission Rates in Adults with Large B-Cell Lymphoma Who Have Relapsed after CD19-CAR T-Cell Therapy Frank, M. J., Baird, J. H., Patel, S., Craig, J., Spiegel, J. Y., Ehlinger, Z., Chinnasamy, H., Younes, S. F., Oak, J. S., Natkunam, Y., Reynolds, W. D., Iglesias, M., Crawford, E., Srinagesh, H. K., Egeler, E. L., Arai, S., Johnston, L. J., Lowsky, R., Negrin, R. S., Rezvani, A. R., Shiraz, P., Sidana, S., Weng, W., Schultz, L. M., Ramakrishna, S., Davis, K. L., Sahaf, B., Feldman, S. A., Mackall, C. L., Miklos, D. B., Muffl, L. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-152145

  View details for Web of Science ID 000736398803041

• CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial. Nature medicine Spiegel, J. Y., Patel, S., Muffly, L., Hossain, N. M., Oak, J., Baird, J. H., Frank, M. J., Shiraz, P., Sahaf, B., Craig, J., Iglesias, M., Younes, S., Natkunam, Y., Ozawa, M. G., Yang, E., Tamaresis, J., Chinnasamy, H., Ehlinger, Z., Reynolds, W., Lynn, R., Rotiroti, M. C., Gkitsas, N., Arai, S., Johnston, L., Lowsky, R., Majzner, R. G., Meyer, E., Negrin, R. S., Rezvani, A. R., Sidana, S., Shizuru, J., Weng, W., Mullins, C., Jacob, A., Kirsch, I., Bazzano, M., Zhou, J., Mackay, S., Bornheimer, S. J., Schultz, L., Ramakrishna, S., Davis, K. L., Kong, K. A., Shah, N. N., Qin, H., Fry, T., Feldman, S., Mackall, C. L., Miklos, D. B. 2021

  Abstract

  Despite impressive progress, more than 50% of patients treated with CD19-targeting chimeric antigen receptor T cells (CAR19) experience progressive disease. Ten of 16 patients with large B cell lymphoma (LBCL) with progressive disease after CAR19 treatment had absent or low CD19. Lower surface CD19 density pretreatment was associated with progressive disease. To prevent relapse with CD19- or CD19lo disease, we tested a bispecific CAR targeting CD19 and/or CD22 (CD19-22.BB.z-CAR) in a phase I clinical trial ( NCT03233854 ) of adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) and LBCL. The primary end points were manufacturing feasibility and safety with a secondary efficacy end point. Primary end points were met; 97% of products met protocol-specified dose and no dose-limiting toxicities occurred during dose escalation. In B-ALL (n=17), 100% of patients responded with 88% minimal residual disease-negative complete remission (CR); in LBCL (n=21), 62% of patients responded with 29% CR. Relapses were CD19-/lo in 50% (5 out of 10) of patients with B-ALL and 29% (4 out of 14) of patients with LBCL but were not associated with CD22-/lo disease. CD19/22-CAR products demonstrated reduced cytokine production when stimulated with CD22 versus CD19. Our results further implicate antigen loss as a major cause of CAR T cell resistance, highlight the challenge of engineering multi-specific CAR T cells with equivalent potency across targets and identify cytokine production as an important quality indicator for CAR T cell potency.

  View details for DOI 10.1038/s41591-021-01436-0

  View details for PubMedID 34312556

• Detection of cryptogenic malignancies from metagenomic whole genome sequencing of body fluids. Genome medicine Gu, W., Talevich, E., Hsu, E., Qi, Z., Urisman, A., Federman, S., Gopez, A., Arevalo, S., Gottschall, M., Liao, L., Tung, J., Chen, L., Lim, H., Ho, C., Kasowski, M., Oak, J., Holmes, B. J., Yeh, I., Yu, J., Wang, L., Miller, S., DeRisi, J. L., Prakash, S., Simko, J., Chiu, C. Y. 2021; 13 (1): 98

  Abstract

  BACKGROUND: Metagenomic next-generation sequencing (mNGS) of body fluids is an emerging approach to identify occult pathogens in undiagnosed patients. We hypothesized that metagenomic testing can be simultaneously used to detect malignant neoplasms in addition to infectious pathogens.METHODS: From two independent studies (n = 205), we used human data generated from a metagenomic sequencing pipeline to simultaneously screen for malignancies by copy number variation (CNV) detection. In the first case-control study, we analyzed body fluid samples (n = 124) from patients with a clinical diagnosis of either malignancy (positive cases, n = 65) or infection (negative controls, n = 59). In a second verification cohort, we analyzed a series of consecutive cases (n = 81) sent to cytology for malignancy workup that included malignant positives (n = 32), negatives (n = 18), or cases with an unclear gold standard (n = 31).RESULTS: The overall CNV test sensitivity across all studies was 87% (55 of 63) in patients with malignancies confirmed by conventional cytology and/or flow cytometry testing and 68% (23 of 34) in patients who were ultimately diagnosed with cancer but negative by conventional testing. Specificity was 100% (95% CI 95-100%) with no false positives detected in 77 negative controls. In one example, a patient hospitalized with an unknown pulmonary illness had non-diagnostic lung biopsies, while CNVs implicating a malignancy were detectable from bronchoalveolar fluid.CONCLUSIONS: Metagenomic sequencing of body fluids can be used to identify undetected malignant neoplasms through copy number variation detection. This study illustrates the potential clinical utility of a single metagenomic test to uncover the cause of undiagnosed acute illnesses due to cancer or infection using the same specimen.

  View details for DOI 10.1186/s13073-021-00912-z

  View details for PubMedID 34074327

• Machine Learning Predictability of Clinical Next Generation Sequencing for Hematologic Malignancies to Guide High-Value Precision Medicine. AMIA ... Annual Symposium proceedings. AMIA Symposium Kim, G. Y., Noshad, M., Stehr, H., Rojansky, R., Gratzinger, D., Oak, J., Brar, R., Iberri, D., Kong, C., Zehnder, J., Chen, J. H. 2021; 2021: 641-650

  Abstract

  Advancing diagnostic testing capabilities such as clinical next generation sequencing methods offer the potential to diagnose, risk stratify, and guide specialized treatment, but must be balanced against the escalating costs of healthcare to identify patient cases most likely to benefit from them. Heme-STAMP (Stanford Actionable Mutation Panel for Hematopoietic and Lymphoid Malignancies) is one such next generation sequencing test. Our objective is to assess how well Heme-STAMP pathological variants can be predicted given electronic health records data available at the time of test ordering. The model demonstrated AUROC 0.74 (95% CI: [0.72, 0.76]) with 99% negative predictive value at 6% specificity. A benchmark for comparison is the prevalence of positive results in the dataset at 58.7%. Identifying patients with very low or very high predicted probabilities of finding actionable mutations (positive result) could guide more precise high-value selection of patient cases to test.

  View details for PubMedID 35308914

• In-depth B cell immunophenotyping to monitor response to anti-CD20 therapy in CNS autoimmunity. Multiple sclerosis and related disorders Su, E., Wetzel, N. S., Oak, J., Kipp, L., Han, M. H. 2020; 46: 102594

  View details for DOI 10.1016/j.msard.2020.102594

  View details for PubMedID 33296989

• Two Cases With Features of Lymphocyte Variant Hypereosinophilic Syndrome With STAT3 SH2 Domain Mutations. The American journal of surgical pathology Fernandez-Pol, S., Petersen, B., Murphy, J., Oak, J. S., Wang, E. B., Rieger, K. E., Kim, Y. H., Khodadoust, M. S., Suarez, C. J. 2020

  Abstract

  Lymphocyte variant hypereosinophilic syndrome (LV-HES) is a rare cause of eosinophilia that is due to eosinophilipoietic cytokine production by an immunophenotypically abnormal T-cell clone. The molecular pathogenesis of this disorder is largely unknown and only 1 case of LV-HES with a pathogenic STAT3 mutation has been described thus far. Here we report 2 cases of LV-HES with STAT3 SH2 domain mutations. These cases further support the model that activation of STAT3 signaling through STAT3 SH2 domain mutations is a recurrent event in LV-HES.

  View details for DOI 10.1097/PAS.0000000000001604

  View details for PubMedID 33060403

• Identification of dual positive CD19+/CD3+ T cells in a leukapheresis product undergoing CAR transduction: a case report. Journal for immunotherapy of cancer Schultz, L., Patel, S., Davis, K. L., Ramakrishna, S., Sahaf, B., Bhatia, N., Baggott, C., Erickson, C., Majzner, R. G., Oak, J., Bertaina, A., Mackall, C., Feldman, S. 2020; 8 (2)

  Abstract

  BACKGROUND: Chimeric antigen receptor (CAR) therapy and hematopoietic stem cell transplantation (HSCT) are therapeutics for relapsed acute lymphocytic leukemia (ALL) that are increasingly being used in tandem. We identified a non-physiologic CD19+/CD3+ T-cell population in the leukapheresis product of a patient undergoing CAR T-cell manufacturing who previously received a haploidentical HSCT, followed by infusion of a genetically engineered T-cell addback product. We confirm and report the origin of these CD19+/CD3+ T cells that have not previously been described in context of CAR T-cell manufacturing. We additionally interrogate the fate of these CD19-expressing cells as they undergo transduction to express CD19-specific CARs.MAIN BODY: We describe the case of a preteen male with multiply relapsed B-ALL who was treated with sequential cellular therapies. He received an alphabeta T-cell depleted haploidentical HSCT followed by addback of donor-derived T cells genetically modified with a suicide gene for iCaspase9 and truncated CD19 for cell tracking (RivoCel). He relapsed 6months following HSCT and underwent leukapheresis and CAR T-cell manufacturing. During manufacturing, we identified an aberrant T-cell population dually expressing CD19 and CD3. We hypothesized that these cells were RivoCel cells and confirmed using flow cytometry and PCR that the identified cells were in fact RivoCel cells and were eliminated with iCaspase9 activation. We additionally tracked these cells through CD19-specific CAR transduction and notably did not detect T cells dually positive for CD19 and CD19-directed CARs. The most likely rationale for this is in vitro fratricide of the CD19+ 'artificial' T-cell population by the CD19-specific CAR+ T cells in culture.CONCLUSIONS: We report the identification of CD19+/CD3+ cells in an apheresis product undergoing CAR transduction derived from a patient previously treated with a haploidentical transplant followed by RivoCel addback. We aim to bring attention to this cell phenotype that may be recognized with greater frequency as CAR therapy and engineered alphabetahaplo-HSCT are increasingly coupled. We additionally suggest consideration towards using alternative markers to CD19 as a synthetic identifier for post-transplant addback products, as CD19-expression on effector T cells may complicate subsequent treatment using CD19-directed therapy.

  View details for DOI 10.1136/jitc-2020-001073

  View details for PubMedID 32929049

• Disseminated Pneumocystis jirovecii Infection with Osteomyelitis in a Patient with CTLA-4 Haploinsufficiency. Journal of clinical immunology Siddiqi, A. E., Liu, A. Y., Charville, G. W., Kunder, C. A., Uzel, G. n., Sadighi Akha, A. A., Oak, J. n., Martin, B. n., Sacha, J. n., Lewis, D. B., Gernez, Y. n. 2020

  View details for DOI 10.1007/s10875-020-00748-z

  View details for PubMedID 31955317

• Multiplexed single-cell morphometry for hematopathology diagnostics. Nature medicine Tsai, A. G., Glass, D. R., Juntilla, M. n., Hartmann, F. J., Oak, J. S., Fernandez-Pol, S. n., Ohgami, R. S., Bendall, S. C. 2020; 26 (3): 408–17

  Abstract

  The diagnosis of lymphomas and leukemias requires hematopathologists to integrate microscopically visible cellular morphology with antibody-identified cell surface molecule expression. To merge these into one high-throughput, highly multiplexed, single-cell assay, we quantify cell morphological features by their underlying, antibody-measurable molecular components, which empowers mass cytometers to 'see' like pathologists. When applied to 71 diverse clinical samples, single-cell morphometric profiling reveals robust and distinct patterns of 'morphometric' markers for each major cell type. Individually, lamin B1 highlights acute leukemias, lamin A/C helps distinguish normal from neoplastic mature T cells, and VAMP-7 recapitulates light-cytometric side scatter. Combined with machine learning, morphometric markers form intuitive visualizations of normal and neoplastic cellular distribution and differentiation. When recalibrated for myelomonocytic blast enumeration, this approach is superior to flow cytometry and comparable to expert microscopy, bypassing years of specialized training. The contextualization of traditional surface markers on independent morphometric frameworks permits more sensitive and automated diagnosis of complex hematopoietic diseases.

  View details for DOI 10.1038/s41591-020-0783-x

  View details for PubMedID 32161403

• CD22-Directed CAR T-Cell Therapy Induces Complete Remissions in CD19-Directed CAR-Refractory Large B-Cell Lymphoma. Blood Baird, J. H., Frank, M. J., Craig, J. n., Patel, S. n., Spiegel, J. Y., Sahaf, B. n., Oak, J. S., Younes, S. n., Ozawa, M. n., Yang, E. n., Natkunam, Y. n., Tamaresis, J. S., Ehlinger, Z. n., Reynolds, W. D., Arai, S. n., Johnston, L. n., Lowsky, R. n., Meyer, E. n., Negrin, R. S., Rezvani, A. R., Shiraz, P. n., Sidana, S. n., Weng, W. K., Davis, K. L., Ramakrishna, S. n., Schultz, L. n., Mullins, C. D., Jacob, A. P., Kirsch, I. R., Feldman, S. A., Mackall, C. L., Miklos, D. B., Muffly, L. n. 2020

  Abstract

  The prognosis for patients with large B-cell lymphoma (LBCL) progressing after treatment with chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CAR19) is poor. We report on the first three consecutive patients with autologous CAR19-refractory LBCL treated with a single infusion of autologous 1×106 CAR+ T-cells/kg targeting CD22 (CAR22) as part of a phase I dose escalation study. CAR22 therapy was relatively well tolerated, without any observed non-hematologic adverse events higher than grade 2. Following infusion, all three patients achieved complete remission, with all responses ongoing at the time of last follow up (mean 7.8 months, range 6-9.3). Circulating CAR22 cells demonstrated robust expansion (peak range 85.4-350 cells/µL), and persisted beyond three months in all patients with continued radiographic responses and corresponding decreases in circulating tumor DNA (ctDNA) beyond six months post-infusion. Further accrual at a higher dose level in this phase 1 dose-escalation study is ongoing and will explore the role of this therapy in patients who have failed prior CAR T-cell therapies. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT04088890).

  View details for DOI 10.1182/blood.2020009432

  View details for PubMedID 33512414

• Histology-Independent Signature Distinguishes Kikuchi-Fujimoto Disease/Systemic Lupus Erythematosus-Associated Lymphadenitis From Benign and Malignant Lymphadenopathies. American journal of clinical pathology Scott, G. D., Kumar, J. n., Oak, J. S., Boyd, S. D., Raess, P. W., Gratzinger, D. A. 2020

  Abstract

  Kikuchi-Fujimoto disease (KFD) and systemic lupus erythematosus (SLE) are benign entities with histologic features that raise concern about malignancy and infection. We searched for a histology-independent KFD/SLE signature relying on only immunophenotype and basic clinical characteristics.A histology-independent KFD/SLE signature was generated using 975 excised lymph nodes with flow immunophenotyping, including 16 cases of KFD/SLE. This signature was then evaluated in 1,198 fine-needle aspiration (FNA) specimens.The top flow cytometry discriminant for KFD/SLE was uniform CD38+ expression on CD19+ events. Immunohistochemistry demonstrated nodules of IgD+, IgM- B cells surrounding necrotizing and activated T-cell areas. A signature combining 6 flow cytometry criteria with age and sample site had a positive predictive value of 88% for KFD/SLE, which had a prevalence of 1.6%. All 4 signature-positive FNA cases with follow-up excision were KFD/SLE. At a second institution, 4 of 5 KFD/SLE cases passed the top discriminant.A flow cytometry signature combined with age and biopsy site identifies KFD/SLE independent of histology, suggesting a shared immune composition and independently confirming that KFD/SLE represents a distinct entity. Unexpectedly, an IgD+CD38+ small B-cell population is a distinctive feature of KFD/SLE, suggesting a possible pathologic role for anergic/autoreactive B cells.

  View details for DOI 10.1093/ajcp/aqaa036

  View details for PubMedID 32367142

• Flow Cytometry Signature for Kikuchi-Fujimoto/Lupus Lymphadenitis Derived From 975 Benign and Malignant Lymphadenopathies Kumar, J., Scott, G., Oak, J., Raess, P., Gratzinger, D. OXFORD UNIV PRESS INC. 2019: S105–S106

  View details for DOI 10.1093/ajcp/aqz121.004

  View details for Web of Science ID 000504321700231

• Rationale and Feasibility of Using a Standardized Screening Tube on the FACSCanto II and the FACSLyric Jackson, R., Oak, J., Kurzer, J. NATURE PUBLISHING GROUP. 2019

  View details for Web of Science ID 000478081102317

• Target Antigen Downregulation and Other Mechanisms of Failure after Axicabtagene Ciloleucel (CAR19) Therapy Oak, J., Spiegel, J. Y., Sahaf, B., Natkunam, Y., Long, S. R., Hossain, N., Mackall, C. L., Kong, K. A., Miklos, D. B. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-120206

  View details for Web of Science ID 000454842804282

• Phase I Experience with a Bi-Specific CAR Targeting CD19 and CD22 in Adults with B-Cell Malignancies Hossain, N., Sahaf, B., Abramian, M., Spiegel, J. Y., Kong, K., Kim, S., Mavroukakis, S., Oak, J., Natkunam, Y., Meyer, E. H., Frank, M. J., Feldman, S. A., Long, S. R., Qin, H., Fry, T. J., Muffly, L. S., Mackall, C. L., Miklos, D. B. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-110142

  View details for Web of Science ID 000454837601199

• Elevated Axicabtagene Ciloleucel (CAR-19) Expansion By Immunophenotyping Is Associated with Toxicity in Diffuse Large B-Cell Lymphoma Spiegel, J. Y., Sahaf, B., Hossain, N., Frank, M. J., Claire, G., Abramian, M., Latchford, T., Villa, B., Cancilla, J., Oak, J., Natkunam, Y., Long, S. R., Arai, S., Johnston, L. J., Lowsky, R., Meyer, E. H., Muffly, L. S., Negrin, R. S., Rezvani, A. R., Shizuru, J. A., Weng, W., Kong, K. A., Mackall, C. L., Miklos, D. B. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-113261

  View details for Web of Science ID 000454837601285

• A reevaluation of erythroid predominance in Acute Myeloid Leukemia using the updated WHO 2016 Criteria MODERN PATHOLOGY Margolskee, E., Mikita, G., Rea, B., Bagg, A., Zuo, Z., Sun, Y., Goswami, M., Wang, S. A., Oak, J., Arber, D. A., Allen, M., George, T. I., Rogers, H. J., Hsi, E., Hasserjian, R. P., Orazi, A. 2018; 31 (6): 873–80

  Abstract

  The 2016 WHO update changed the diagnostic criteria for myeloid neoplasms with erythroid predominance, limiting the diagnosis of acute myeloid leukemia to cases with ≥20% blasts in the bone marrow or peripheral blood. Although acute myeloid leukemia with ≥50% erythroid cells has historically been presumed to represent acute myeloid leukemia with myelodysplasia-related changes, this hypothesis has never been systematically examined. We sought to investigate the clinicopathologic, cytogenetic, and molecular features of acute myeloid leukemia with erythroid predominance to subclassify cases as defined by the 2016 WHO. We retrospectively identified patients with ≥50% erythroid precursors and either ≥20% bone marrow blasts or ≥20% peripheral blood blasts at the time of initial diagnosis at seven major academic centers. Laboratory and clinical data were obtained. Patients were then reclassified according to 2016 WHO guidelines. A matched control group was also obtained. We identified 146 patients with acute myeloid leukemia with erythroid predominance (62% M, average age: 62 y, range: 5-93 y). Of these, 91 were acute myeloid leukemia with myelodysplasia-related changes, 20 (14%) were therapy-related myeloid neoplasm, 23 (16%) acute myeloid leukemia, not otherwise specified, and ten acute myeloid leukemia with recurrent cytogenetic/molecular abnormalities. The bone marrow blast count ranged from 9-41%. There was no difference in survival for patients with erythroid predominance compared to patients with acute myeloid leukemia without erythroid proliferations. In a multivariable analysis, cytogenetic risk was the only significant predictor of survival. We find a significantly lower rate of FLT3 and RAS pathway alterations in acute myeloid leukemia with erythroid predominance compared to controls. Our study is one of the first to apply the 2016 WHO guidelines for classification of acute myeloid leukemia. We find acute myeloid leukemia with erythroid predominance is a heterogeneous group and that erythroid richness has no impact on overall survival.

  View details for PubMedID 29403082

• Occult Hemolytic Anemia Due to Anti-Mur in a Patient Receiving Blood from a Region with a Prominent Asian Donor Population Oak, J., Mallari, R., de Asis, M., Shu, E., Hughes, J., Pham, T. WILEY. 2017: 178A

  View details for Web of Science ID 000409065000450

• Myelodysplastic Syndrome, Unclassifiable (MDS-U) With 1% Blasts Is a Distinct Subgroup of MDS-U With a Poor Prognosis AMERICAN JOURNAL OF CLINICAL PATHOLOGY Margolskee, E., Hasserjian, R. P., Hassane, D., Tam, W., Mathew, S., Ok, C., Wang, S. A., Oak, J., Arber, D. A., Orazi, A. 2017; 148 (1): 49–57

  Abstract

  Three situations qualify as myelodysplastic syndrome, unclassifiable (MDS-U): (1) refractory cytopenia with dysplasia and 1% blasts in peripheral blood (BL), (2) pancytopenia with unilineage dysplasia (Pan), and (3) persistent cytopenia, less than 5% bone marrow blasts, and less than 10% dysplastic cells and presence of MDS-defining cytogenetic abnormalities (CG). We compared the clinicopathologic features and mutational profiles for these three groups.MDS-U cases were reviewed at four major academic institutions. Targeted next-generation sequencing for genes implicated in myeloid neoplasms was performed in a subset of cases.Twenty-seven patients were identified (six MDS-U BL, 13 MDS-U Pan, and eight MDS-U CG). Clonal cytogenetic abnormalities were found in six of six, seven of 13, and eight of eight cases in MDS-U BL, Pan, and CG, respectively (P > .05). Overall, four of six patients with MDS-U BL progressed to acute myeloid leukemia; no MDS-U Pan or CG patients did. The rates of progression-free survival and mortality (overall survival) were significantly higher in MDS-U BL compared with Pan and CG (P < .001 for both).We find that MDS-U BL is a distinct subset of MDS-U with a poor prognosis, while MDS-U Pan and CG are relatively indolent. Evaluation of peripheral blood smears in patients with MDS is essential for accurate classification and prognosis.

  View details for PubMedID 28927162

• Oligomonocytic chronic myelomonocytic leukemia (chronic myelomonocytic leukemia without absolute monocytosis) displays a similar clinicopathologic and mutational profile to classical chronic myelomonocytic leukemia. Modern pathology Geyer, J. T., Tam, W., Liu, Y., Chen, Z., Wang, S. A., Bueso-Ramos, C., Oak, J., Arber, D. A., Hsi, E., Rogers, H. J., Levinson, K., Bagg, A., Hassane, D. C., Hasserjian, R. P., Orazi, A. 2017

  Abstract

  Chronic myelomonocytic leukemia is characterized by persistent absolute monocytosis (≥1 × 109/l) in the peripheral blood and dysplasia in ≥1 lineages. In the absence of dysplasia, an acquired clonal genetic abnormality is required or causes for reactive monocytosis have to be excluded. Oligomonocytic chronic myelomonocytic leukemia showing increased monocytes but no absolute monocytosis in the peripheral blood occurs occasionally. These cases are likely classified as myelodysplastic syndrome or myelodysplastic/myeloproliferative neoplasm, unclassifiable. A subset eventually develop overt chronic myelomonocytic leukemia. Better characterization of oligomonocytic chronic myelomonocytic leukemia is essential since the distinction between chronic myelomonocytic leukemia and myelodysplastic syndrome is clinically relevant. We identified 44 cases of oligomonocytic chronic myelomonocytic leukemia (≥10% peripheral blood monocytes with absolute monocyte count of 0.5-1 × 109/l) and 28 consecutive chronic myelomonocytic leukemia controls. Clinicopathologic features were compared and mutation analysis was performed. Oligomonocytic chronic myelomonocytic leukemia patients were significantly younger (median age of 65 vs 72). They had lower WBC and absolute neutrophil count, while the monocyte percentage, hemoglobin and platelet counts were similar in the two groups. The myeloid to erythroid ratio was predominantly decreased or normal, compared with the characteristic increase in chronic myelomonocytic leukemia (P=0.006). 38% of patients progressed to overt chronic myelomonocytic leukemia (median: 12 months). The overall percentage of mutations was significantly lower in oligomonocytic chronic myelomonocytic leukemia. However, the most frequent mutations in both groups were the 'signature' chronic myelomonocytic leukemia mutations in ASXL1, TET2 and SRSF2. Mutations in CBL were found exclusively in overt chronic myelomonocytic leukemia. In conclusion, we demonstrate clinical and genetic similarities between overt chronic myelomonocytic leukemia and oligomonocytic chronic myelomonocytic leukemia. The findings suggest that at least a subset of oligomonocytic chronic myelomonocytic leukemia represents early phase 'dysplastic type' chronic myelomonocytic leukemia.

  View details for DOI 10.1038/modpathol.2017.45

  View details for PubMedID 28548124

• Focusing on frequent ASXL1 mutations in myeloid neoplasms, and considering rarer ASXL2 and ASXL3 mutations. Current medical research and opinion Oak, J. S., Ohgami, R. S. 2017: 1-2

  View details for DOI 10.1080/03007995.2017.1284049

  View details for PubMedID 28097878

• c-Myc Protein Expression Distinguishes Plasma Cell Myeloma from Solitary Plasmacytoma and Is Associated with Aggressive Morphologic Features Oak, J., Raess, P. W., Foley, C., Ohgami, R., Cascio, M. NATURE PUBLISHING GROUP. 2017: 368A

  View details for Web of Science ID 000394467302052

• A Retrospective Study of 305 Cases of Angioimmunoblastic T-Cell Lymphoma with Emphasis on Rare Lymphoplasmacytic and Plasma Cell Proliferations Oak, J., Hoffmann, J. C., Chisholm, K. M., Chen, J., Zehnder, J., Arber, D. A., Natkunam, Y., Warnke, R., Ohgami, R. NATURE PUBLISHING GROUP. 2017: 367A–368A

  View details for Web of Science ID 000393724401748

• Acute Myeloid Leukemia with Erythroid Predominance: Are All Cases MDS-Related? Margolskee, E., Mikita, G., Oak, J., Allen, M. B., Zuo, Z., Wang, S., Arber, D. A., George, T., Hasserjian, R. P., Orazi, A. NATURE PUBLISHING GROUP. 2017: 362A

  View details for Web of Science ID 000394467302031

• Myelodysplastic Syndrome, Unclassifiable (MDS-U) with 1% Blasts Is a Distinct Subgroup of MDS-U with a Poor Prognosis Margolskee, E., Oak, J., Arber, D. A., Hasseijian, R. P., Orazi, A. NATURE PUBLISHING GROUP. 2016: 361A

  View details for Web of Science ID 000370302502434