Publications by authors named "Joo Y Song"

58 Publications

EBV-positive HIV-associated diffuse large B cell lymphomas are characterized by JAK/STAT (STAT3) pathway mutations and unique clinicopathologic features.

Br J Haematol 2021 Jul 17. Epub 2021 Jul 17.

Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA.

Even in the era of highly active combination antiretroviral therapy (cART), patients with HIV have a disproportionate risk of developing aggressive lymphomas that are frequently Epstein-Barr virus (EBV)-related. Here, we investigate HIV-associated diffuse large B-cell lymphoma (HIV-DLBCL) and compare EBV-positive and EBV-negative cases. HIV-DLBCL were identified from two academic medical centres and characterised by immunohistochemistry, EBV status, fluorescence in situ hybridisation, cell of origin determination by gene expression profiling, and targeted deep sequencing using a custom mutation panel of 334 genes. We also applied the Lymphgen tool to determine the genetic subtype of each case. Thirty HIV-DLBCL were identified, with a median patient age of 46 years and male predominance (5:1). Thirteen cases (48%) were EBV-positive and 14 (52%) EBV-negative. Nine of the 16 tested cases (56%) had MYC rearrangement, three (19%) had BCL6 (two of which were double hit MYC/BCL6) and none had BCL2 rearrangements. Using the Lymphgen tool, half of the cases (15) were classified as other. All HIV-DLBCL showed mutational abnormalities, the most frequent being TP53 (37%), MYC (30%), STAT3 (27%), HIST1H1E (23%), EP300 (20%), TET2 (20%), SOCS1 (17%) and SGK1 (17%). EBV-negative cases were mostly of germinal centre B-cell (GCB) origin (62%), showed more frequent mutations per case (a median of 13·5/case) and significant enrichment of TP53 (57% vs. 15%; P = 0·046), SGK1 (36% vs. 0%; P = 0·04), EP300 (43% vs. 0%; P = 0·02) and histone-modifying gene (e.g. HIST1H1E, HIST1H1D, 79% vs. 31%; P = 0·02) mutations. EBV-positive cases were mostly of non-GCB origin (70%), with fewer mutations per case (median 8/case; P = 0·007), and these tumours were enriched for STAT3 mutations (P = 0·10). EBV-positive cases had a higher frequency of MYC mutations but the difference was not significant (36% vs. 15%; P = 0·38). EBV-association was more frequent in HIV-DLBCLs, arising in patients with lower CD4 counts at diagnosis (median 46·5 vs. 101, P = 0·018). In the era of cART, approximately half of HIV-DLBCL are EBV-related. HIV-DLBCL are enriched for MYC rearrangements, MYC mutations and generally lack BCL2 rearrangements, regardless of EBV status. Among HIV-DLBCL, tumours that are EBV-negative and EBV-positive appear to have important differences, the latter arising in context of lower CD4 count, showing frequent non-GCB origin, lower mutation burden and recurrent STAT3 mutations.
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http://dx.doi.org/10.1111/bjh.17708DOI Listing
July 2021

First Multimodal, Three-Dimensional, Image-Guided Total Marrow Irradiation Model for Preclinical Bone Marrow Transplantation Studies.

Int J Radiat Oncol Biol Phys 2021 Jun 11. Epub 2021 Jun 11.

Department of Radiation Oncology, City of Hope Medical Center, Duarte, California; Beckman Research Institute of City of Hope, Duarte, California; Department of Radiation Oncology, University of Minnesota, Minneapolis, Minnesota. Electronic address:

Purpose: Total marrow irradiation (TMI) has significantly advanced radiation conditioning for hematopoietic cell transplantation in hematologic malignancies by reducing conditioning-induced toxicities and improving survival outcomes in relapsed/refractory patients. However, the relapse rate remains high, and the lack of a preclinical TMI model has hindered scientific advancements. To accelerate TMI translation to the clinic, we developed a TMI delivery system in preclinical models.

Methods And Materials: A Precision X-RAD SmART irradiator was used for TMI model development. Images acquired with whole-body contrast-enhanced computed tomography (CT) were used to reconstruct and delineate targets and vital organs for each mouse. Multiple beam and CT-guided Monte Carlo-based plans were performed to optimize doses to the targets and to vary doses to the vital organs. Long-term engraftment and reconstitution potential were evaluated by a congenic bone marrow transplantation (BMT) model and serial secondary BMT, respectively. Donor cell engraftment was measured using noninvasive bioluminescence imaging and flow cytometry.

Results: Multimodal imaging enabled identification of targets (skeleton and spleen) and vital organs (eg, lungs, gut, liver). In contrast to total body irradiation (TBI), TMI treatment allowed variation of radiation dose exposure to organs relative to the target dose. Dose reduction mirrored that in clinical TMI studies. Similar to TBI, mice treated with different TMI regimens showed full long-term donor engraftment in primary BMT and second serial BMT. The TBI-treated mice showed acute gut damage, which was minimized in mice treated with TMI.

Conclusions: A novel multimodal image guided preclinical TMI model is reported here. TMI conditioning maintained long-term engraftment with reconstitution potential and reduced organ damage. Therefore, this TMI model provides a unique opportunity to study the therapeutic benefit of reduced organ damage and BM dose escalation to optimize treatment regimens in BMT and hematologic malignancies.
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http://dx.doi.org/10.1016/j.ijrobp.2021.06.001DOI Listing
June 2021

Relative frequency and clinicopathologic characteristics of MYC-rearranged follicular lymphoma.

Hum Pathol 2021 May 5;114:19-27. Epub 2021 May 5.

Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA. Electronic address:

MYC rearrangement is a relatively rare genetic abnormality in follicular lymphoma (FL). In this study, we evaluated the relative frequency of MYC rearrangement in 522 cases of FL and studied their clinicopathologic, cytogenetic, and molecular characteristics. Fluorescence in situ hybridization studies for MYC (break-apart probe), MYC/IGH, IGH/BCL2, and BCL6 rearrangements were performed on tissue microarrays. Immunohistochemical stains for CD10, BCL2, BCL6, and MYC were performed and scored on MYC-rearranged cases. On 4 FL cases, a custom targeted panel of 356 genes was used for mutation analysis. Ten cases (1.9%) were positive for MYC rearrangement. Histologically, 6 of 10 cases were grade 1-2, and 4 cases were grade 3A. By immunohistochemistry, 9 of 9 tested cases were CD10+, all cases were BCL6+, and 9/10 cases were BCL2+. MYC protein staining was low in all cases tested. IGH/BCL2 rearrangement was detected in 5 of 9 cases, whereas BCL6 rearrangement was detected in 3 of 7 tested cases and 4 of 10 cases showed MYC/IGH rearrangement. The most commonly detected mutations in the MYC-positive cases included HLA-B, TNFRSF14, and KMT2D. MYC and/or B2M abnormalities were detected in 2 cases. In conclusion, MYC rearrangement is uncommon in FL and these cases do not appear to have specific histologic characteristics. Molecular analysis showed abnormalities in genes associated with transformation, namely MYC and B2M. Larger studies are needed to evaluate if MYC-rearrangement in FL has prognostic significance.
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http://dx.doi.org/10.1016/j.humpath.2021.04.014DOI Listing
May 2021

MAP-kinase and JAK-STAT pathways dysregulation in plasmablastic lymphoma.

Haematologica 2021 May 6. Epub 2021 May 6.

Hematopathology Unit, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid.

Plasmablastic lymphoma (PBL) is an aggressive B-cell lymphoma with an immunoblastic/large cell morphology and plasmacytic differentiation. The differential diagnosis with Burkitt lymphoma (BL), plasma cell myeloma (PCM) and some variants of diffuse large B-cell lymphoma (DLBCL) may be challenging due to the overlapping morphological, genetic and immunophenotypic features. Furthermore, the genomic landscape in PBL is not well known. To characterize the genetic and molecular heterogeneity of these tumors, we investigated thirty-four PBL using an integrated approach, including fluorescence in situ hybridization, targeted sequencing of 94 B-cell lymphoma related genes, and copy-number arrays. PBL were characterized by high genetic complexity including MYC translocations (87%), gains of 1q21.1-q44, trisomy 7, 8q23.2-q24.21, 11p13-p11.2, 11q14.2-q25, 12p and 19p13.3-p13.13, losses of 1p33, 1p31.1-p22.3, 13q and 17p13.3-p11.2, and recurrent mutations of STAT3 (37%), NRAS and TP53 (33%), MYC and EP300 (19%) and CARD11, SOCS1 and TET2 (11%). Pathway enrichment analysis suggested a cooperative action between MYC alterations and MAPK (49%) and JAK-STAT (40%) signaling pathways. Of note, EBVnegative PBL cases had higher mutational and copy-number load and more frequent TP53, CARD11 and MYC mutations, whereas EBV-positive PBL tended to have more mutations affecting the JAK-STAT pathway. In conclusion, these findings further unravel the distinctive molecular heterogeneity of PBL identifying novel molecular targets and the different genetic profile of these tumors related to EBV infection.
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http://dx.doi.org/10.3324/haematol.2020.271957DOI Listing
May 2021

Fibrin-Associated, EBV-Negative Diffuse Large B-Cell Lymphoma Arising in Atrial Myxoma: Expanding the Spectrum of the Entity.

Int J Surg Pathol 2021 Apr 29:10668969211014959. Epub 2021 Apr 29.

University of Michigan, Ann Arbor, MI, USA.

Fibrin-associated diffuse large B-cell lymphoma (FA-DLBCL) is a provisional entity in the 2017 Revision of the World Health Organization Classification. This indolent entity, which is frequently discovered incidentally, is currently classified under the category of diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI), an aggressive lymphoma with poor survival. Several authors have proposed that it be classified separately since, in contrast to DLBCL-CI, transformation to aggressive lymphoma has rarely been reported and this entity has distinct clinical and histological features. We describe a rare case of a 62-year-old male with FA-DLBCL associated with atrial myxoma, which was incidentally discovered. In contrast to typically described immunophenotypic features of this entity, that is, activated B-cell phenotype (ABC) and Epstein-Barr virus (EBV) positivity, our case showed germinal center B-cell (GCB) phenotype and was EBV negative. Clinical staging revealed no evidence of lymphoma elsewhere in the body, and the patient did not receive adjuvant chemotherapy after surgical excision and remains in remission. This case illustrates that occasionally FA-DLBCL can show GCB phenotype, as opposed to the typical ABC phenotype. Moreover, we propose that the definition of the entity be expanded to include EBV-negative cases.
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http://dx.doi.org/10.1177/10668969211014959DOI Listing
April 2021

Refractory primary autoimmune myelofibrosis treated with ruxolitinib.

Am J Hematol 2021 Aug 11;96(8):E283-E285. Epub 2021 May 11.

Department of Hematology and Hematopoietic Cell Transplantation, Gehr Center for Leukemia Research, City of Hope National Medical Center, California, Duarte, USA.

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http://dx.doi.org/10.1002/ajh.26208DOI Listing
August 2021

Developmental partitioning of SYK and ZAP70 prevents autoimmunity and cancer.

Mol Cell 2021 05 19;81(10):2094-2111.e9. Epub 2021 Apr 19.

Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. Electronic address:

Even though SYK and ZAP70 kinases share high sequence homology and serve analogous functions, their expression in B and T cells is strictly segregated throughout evolution. Here, we identified aberrant ZAP70 expression as a common feature in a broad range of B cell malignancies. We validated SYK as the kinase that sets the thresholds for negative selection of autoreactive and premalignant clones. When aberrantly expressed in B cells, ZAP70 competes with SYK at the BCR signalosome and redirects SYK from negative selection to tonic PI3K signaling, thereby promoting B cell survival. In genetic mouse models for B-ALL and B-CLL, conditional expression of Zap70 accelerated disease onset, while genetic deletion impaired malignant transformation. Inducible activation of Zap70 during B cell development compromised negative selection of autoreactive B cells, resulting in pervasive autoantibody production. Strict segregation of the two kinases is critical for normal B cell selection and represents a central safeguard against the development of autoimmune disease and B cell malignancies.
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http://dx.doi.org/10.1016/j.molcel.2021.03.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239336PMC
May 2021

Cytokine gene polymorphisms are associated with response to blinatumomab in B-cell acute lymphoblastic leukemia.

Eur J Haematol 2021 Jun 24;106(6):851-858. Epub 2021 Mar 24.

Department of Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA.

Blinatumomab is a bispecific T cell-engaging antibody approved for treatment of relapsed/refractory (r/r) ALL, with 40%-50% complete response (CR)/CR with incomplete count recovery (CRi). Cytokine release syndrome (CRS) as a major adverse effect after blinatumomab therapy. Here, we evaluated the possible association between single-nucleotide polymorphisms (SNPs) in cytokine genes, disease response, and CRS in r/r ALL patients who received blinatumomab between 2012 and 2017 at our center (n = 66), using patients' archived DNA samples. With a median duration of 9.5 months (range: 1-37), 37 patients (56.1%) achieved CR/CRi, 54 (81.8%) experienced CRS (G1: n = 35, G2: n = 14, G3: n = 5), and 9 (13.6%) developed neurotoxicity. By multivariable analysis, after adjusting for high disease burden, one SNP on IL2 (rs2069762), odds ratio (OR) = 0.074 (95% CI: NE-0.43, P = .01) and one SNP on IL17A (rs4711998), OR = 0.28 (95% CI: 0.078-0.92, P = .034) were independently associated with CR/CRi. None of the analyzed SNPs were associated with CRS. To our knowledge, this is the first study demonstrating a possible association between treatment response to blinatumomab and SNPs. Our hypothesis-generated data suggest a potential role for IL-17 and IL-2 in blinatumomab response and justify a larger confirmatory study, which may lead to personalized blinatumomab immunotherapy for B-ALL.
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http://dx.doi.org/10.1111/ejh.13622DOI Listing
June 2021

Validation of the Double-Hit Gene Expression Signature (DLBCL90) in an Independent Cohort of Patients with Diffuse Large B-Cell Lymphoma of Germinal Center Origin.

J Mol Diagn 2021 05 23;23(5):658-664. Epub 2021 Feb 23.

Department of Pathology, City of Hope National Medical Center, Duarte, California. Electronic address:

The prognosis of diffuse large B-cell lymphoma (DLBCL) has been associated with clinical parameters, cell of origin, and various genetic aberrations. Recently, a NanoString gene expression assay (DLBCL90) was developed, which identifies DLBCL cases with an outcome similar to those with double- or triple-hit DLBCL with both MYC and BCL2 rearrangements. This study validates the predictive ability of the DLBCL90 assay in an independent cohort of patients with the germinal center B-cell subtype DLBCL. A customized targeted sequencing panel was used to analyze the mutational profile in these patients. Cases with a double or triple hit by conventional fluorescence in situ hybridization cytogenetic analysis are known to have a poor prognosis, and the DLBCL90 gene expression signature identified these cases, as well as additional cases that would have otherwise been missed by fluorescence in situ hybridization analysis. Our findings validate use of the DLBCL90 assay for identifying high-risk patients for new and innovative therapies.
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http://dx.doi.org/10.1016/j.jmoldx.2021.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185969PMC
May 2021

Double-hit Signature with Abnormalities Predicts Poor Survival in Patients with Germinal Center Type Diffuse Large B-cell Lymphoma Treated with R-CHOP.

Clin Cancer Res 2021 Mar 7;27(6):1671-1680. Epub 2021 Jan 7.

Department of Pathology, City of Hope National Medical Center, Duarte, California.

Purpose: We performed detailed genomic analysis on 87 cases of diffuse large B-cell lymphoma of germinal center type (GCB DLBCL) to identify characteristics that are associated with survival in those treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

Experimental Design: The cases were extensively characterized by combining the results of IHC, cell-of-origin gene expression profiling (GEP; NanoString), double-hit GEP (DLBCL90), FISH cytogenetic analysis for double/triple-hit lymphoma, copy-number analysis, and targeted deep sequencing using a custom mutation panel of 334 genes.

Results: We identified four distinct biologic subgroups with different survivals, and with similarities to the genomic classifications from two large retrospective studies of DLBCL. Patients with the double-hit signature, but no abnormalities of , and those lacking mutation and/or translocation, had an excellent prognosis. However, patients with an EZB-like profile had an intermediate prognosis, whereas those with inactivation combined with the double-hit signature had an extremely poor prognosis. This latter finding was validated using two independent cohorts.

Conclusions: We propose a practical schema to use genomic variables to risk-stratify patients with GCB DLBCL. This schema provides a promising new approach to identify high-risk patients for new and innovative therapies.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2378DOI Listing
March 2021

Targeting the alpha subunit of IL-3 receptor (CD123) in patients with acute leukemia.

Hum Vaccin Immunother 2020 10 21;16(10):2341-2348. Epub 2020 Jul 21.

Gehr Family Center for Leukemia Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center , Duarte, CA, USA.

The IL-3 alpha chain receptor (CD123) is a cell surface protein that is widely expressed by various subtypes of acute leukemia, including acute myeloid leukemia (AML), acute lymphoblastic leukemia and blastic plasmacytoid dendritic cell neoplasm. Notably, CD123 is preferentially overexpressed in leukemia stem cells (LSC) in contrast to normal hematopoietic stem cells, and this differential expression allows for the selective eradication of LSC and leukemic blasts through therapeutic targeting of CD123, with less impact on hematopoietic cells. The level of CD123 expression in AML correlates with both treatment response and outcomes. Therefore, targeting CD123 represents a promising universal therapeutic target in advanced acute leukemias irrespective of the individual leukemia phenotype. There are currently 31 ongoing clinical trials examining the utility of CD123-based targeted therapies. Here we focus our review on current efforts to target CD123 in acute leukemia through various therapeutic constructs.
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http://dx.doi.org/10.1080/21645515.2020.1788299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644204PMC
October 2020

Positron Emission Tomography-Directed Therapy for Patients With Limited-Stage Diffuse Large B-Cell Lymphoma: Results of Intergroup National Clinical Trials Network Study S1001.

J Clin Oncol 2020 09 13;38(26):3003-3011. Epub 2020 Jul 13.

Division of Hematology/Oncology, Wilmot Cancer Institute, University of Rochester, Rochester, NY.

Purpose: Diffuse large B-cell lymphoma (DLBCL) presents as a limited-stage disease in 25% to 30% of patients, with better overall survival (OS) than that for advanced-stage disease but with continuous relapse regardless of treatment approach. The preferred treatment is abbreviated rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and radiation therapy. On the basis of promising results of positron emission tomography (PET)-directed treatment approaches, we designed a National Clinical Trials Network (NCTN) study to improve outcomes and decrease toxicity.

Methods: Patients with nonbulky (< 10 cm) stage I/II untreated DLBCL received 3 cycles of standard R-CHOP therapy and underwent a centrally reviewed interim PET/computed tomography scan (iPET). Those with a negative iPET proceeded with 1 additional cycle of R-CHOP, whereas those with a positive iPET received involved field radiation therapy followed by ibritumomab tiuxetan radioimmunotherapy.

Results: Of 158 patients enrolled, 132 were eligible and 128 underwent iPET, which was positive in 14 (11%) of the patients. With a median follow-up of 4.92 years (range, 1.1-7.7 years), only 6 patients progressed and 3 died as a result of lymphoma. Eleven patients died as a result of nonlymphoma causes at a median age of 80 years. The 5-year progression-free survival estimate was 87% (95% CI, 79% to 92%) and the OS estimate was 89% (95% CI, 82% to 94%), with iPET-positive and iPET-negative patients having similar outcomes.

Conclusion: To our knowledge, S1001 is the largest prospective study in the United States of limited-stage DLBCL in the rituximab era, with the best NCTN results in this disease subset. With PET-directed therapy, 89% of the patients with a negative iPET received R-CHOP × 4, and only 11% had a positive iPET and required radiation, with both groups having excellent outcomes. The trial establishes R-CHOP × 4 alone as the new standard approach to limited-stage disease for the absolute majority of patients.
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http://dx.doi.org/10.1200/JCO.20.00999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479758PMC
September 2020

Mimickers of pulmonary lymphoma.

Semin Diagn Pathol 2020 Nov 9;37(6):283-295. Epub 2020 Jun 9.

Department of Pathology, City of Hope, Duarte, CA, USA. Electronic address:

There are multiple entities that involve the lung that have radiographic, clinical, and morphologic overlaps with pulmonary lymphoma. In this review, we will discuss these entities in detail and provide relevant updates.
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http://dx.doi.org/10.1053/j.semdp.2020.05.002DOI Listing
November 2020

Iron Overload Is Associated with Delayed Engraftment and Increased Nonrelapse Mortality in Recipients of Umbilical Cord Blood Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2020 09 11;26(9):1697-1703. Epub 2020 Jun 11.

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.

The negative impact of iron overload (IO) on outcomes of allogeneic hematopoietic cell transplantation (HCT) is well recognized, but its impact on umbilical cord blood (UCB) transplant outcome is unknown. We retrospectively analyzed outcomes of 150 patients who received UCB-HCT at our institution, stratified by pre-HCT serum ferritin (SF) level of 2000 ng/mL. Two-year overall survival rate among patients with SF >2000 and ≤2000 ng/mL was 26.1% (95% CI, 10.6% to 44.7%) and 52.1% (95% CI, 40.1% to 62.8%), respectively; hazard ratio (HR) = 2.26 (95% CI, 1.28 to 4.00, P = .005). Two-year nonrelapse mortality rate was higher among patients with SF >2000 ng/mL (56.5%; 95% CI, 33.3% to 74.4%) compared to SF ≤2000 ng/mL (30.1%; 95% CI, 20.0% to 40.9%); HR = 2.18 (95% CI, 1.10 to 4.31, P = .025). Neutrophil engraftment at 42 days was 78.3% (95% CI, 53.5% to 90.8%) in patients with SF >2000 ng/mL versus 91.8% (95% CI, 82.1% to 96.4%) in patients with SF ≤2000 ng/mL; HR = 0.58 (95% CI, 0.35 to 0.96, P = .034). A significant difference in platelet engraftment at 3 months was also observed: 52.2% (95% CI, 29.4% to 70.8%) for SF >2000 ng/mL versus 80.8% (95% CI, 69.5% to 88.3%) for SF ≤2000 ng/mL; HR = 0.48 (95% CI, 0.23 to 0.98, P = .044). In conclusion, IO defined by SF of 2000 ng/mL is a strong adverse prognostic factor for UCB-HCT and should be considered when UCB is chosen as the graft source for patients without a fully matched donor.
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http://dx.doi.org/10.1016/j.bbmt.2020.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486229PMC
September 2020

Primary Cutaneous CD30+ Lymphoproliferative Disorders: a Comprehensive Review.

Curr Hematol Malig Rep 2020 08;15(4):333-342

City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA, 91010, USA.

Purpose Of Review: Primary cutaneous CD30+ T-cell lymphoproliferative disorders (CD30+ LPDs) are the second most common cutaneous lymphomas after mycosis fungoides and Sezary syndrome. They include primary cutaneous anaplastic large cell lymphoma (pcALCL), lymphomatoid papulosis (LyP), and borderline lesions. The purpose of this literature review is to consolidate the available evidence on the primary cutaneous CD30+ LPD in order to define the tools for correct diagnosis and appropriate treatment.

Recent Findings: The current body of knowledge regarding the clinical features, histopathologic changes, recently described genetic alterations, and therapeutic options will be covered in this comprehensive review. Primary cutaneous CD30+ LPD represent rare cutaneous lymphomas that have significant histologic overlap within the defined group as well as with other neoplastic and reactive entities. The importance of differentiating these entities is crucial, as each one has a different clinical course and prognosis.
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http://dx.doi.org/10.1007/s11899-020-00583-4DOI Listing
August 2020

Follicular lymphoma polygenic risk score is associated with increased disease risk but improved overall survival among women in a population based case-control in Los Angeles County California.

Cancer Epidemiol 2020 04 21;65:101688. Epub 2020 Feb 21.

Division of Health Analytics, Department of Computational and Quantitative Medicine, Beckman Research Institute of City of Hope, Duarte, CA, United States.

Introduction: Although clinical prognostic indicators exist for follicular lymphoma(FL), patient outcomes remain heterogeneous.

Material And Methods: We evaluated the association between survival and a polygenic risk score(PRS) composed of five previously identified FL susceptibility loci(rs12195582, rs13254990, rs17749561, rs4245081, rs4938573) among women who participated in a case-control study of non-Hodgkin lymphoma in Los Angeles County between 2004-2008. Risk associations were estimated through logistic regression, calculating the odds ratios(OR) and 95 % confidence intervals(95 % CI). Survival was estimated under a Cox proportional hazards model and hazard ratios(HR) and 95 % CI were calculated.

Results: Among 437 non-Hispanic White controls and 100 non-Hispanic White FL patients, we confirmed a 2.6-fold increased risk of FL associated with the highest PRS tertile (95 % CI:1.35-4.86). After accounting for clinical indicators, the PRS was associated with improved overall survival in non-Hispanic women (HR:0.31; 95 % CI:0.10-0.96).

Conclusion: PRS was associated with increased risk of FL, but improved overall survival.
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http://dx.doi.org/10.1016/j.canep.2020.101688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7131878PMC
April 2020

Assessing Cancer Treatment Information Using Medicare and Hospital Discharge Data among Women with Non-Hodgkin Lymphoma in a Los Angeles County Case-Control Study.

Cancer Epidemiol Biomarkers Prev 2020 05 17;29(5):936-941. Epub 2020 Feb 17.

Division of Health Analytics, Department of Computational and Quantitative Medicine, City of Hope and the Beckman Research Institute, Duarte, California.

Background: We assessed the ability to supplement existing epidemiologic/etiologic studies with data on treatment and clinical outcomes by linking to publicly available cancer registry and administrative databases.

Methods: Medical records were retrieved and abstracted for cases enrolled in a Los Angeles County case-control study of non-Hodgkin lymphoma (NHL). Cases were linked to the Los Angeles County cancer registry (CSP), the California state hospitalization discharge database (OSHPD), and the SEER-Medicare database. We assessed sensitivity, specificity, and positive predictive value (PPV) of cancer treatment in linked databases, compared with medical record abstraction.

Results: We successfully retrieved medical records for 918 of 1,004 participating NHL cases and abstracted treatment for 698. We linked 59% of cases (96% of cases >65 years old) to SEER-Medicare and 96% to OSHPD. Chemotherapy was the most common treatment and best captured, with the highest sensitivity in SEER-Medicare (80%) and CSP (74%); combining all three data sources together increased sensitivity (92%), at reduced specificity (56%). Sensitivity for radiotherapy was moderate: 77% with aggregated data. Sensitivity of BMT was low in the CSP (42%), but high for the administrative databases, especially OSHPD (98%). Sensitivity for surgery reached 83% when considering all three datasets in aggregate, but PPV was 60%. In general, sensitivity and PPV for chronic lymphocytic leukemia/small lymphocytic lymphoma were low.

Conclusions: Chemotherapy was accurately captured by all data sources. Hospitalization data yielded the highest performance values for BMTs. Performance measures for radiotherapy and surgery were moderate.

Impact: Various administrative databases can supplement epidemiologic studies, depending on treatment type and NHL subtype of interest.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196521PMC
May 2020

Diagnostic utility of STAT6 expression in classical Hodgkin lymphoma and related entities.

Mod Pathol 2020 05 10;33(5):834-845. Epub 2019 Dec 10.

Department of Pathology, The University of Chicago Medicine, Chicago, IL, USA.

Although the distinction of classical Hodgkin lymphoma from nodular lymphocyte predominant Hodgkin lymphoma using morphology and immunostains is straightforward in most instances, occasional cases pose diagnostic challenge. We sought to determine the utility of the novel YE361 STAT6 rabbit monoclonal antibody in Hodgkin lymphoma and diagnostically challenging B- and T-cell non-Hodgkin lymphoma entities with Hodgkin-like features. Cases from seven institutions included: 57 classical Hodgkin lymphomas (31% EBV+), 34 nodular lymphocyte predominant Hodgkin lymphomas, 34 mimicking B- and T-cell non-Hodgkin lymphomas, and 7 reactive lymphoproliferations. After review of histology, STAT6 immunostaining was performed. The intensity and spatial localization of immunopositivity was assessed in neoplastic cells. Additional FISH for programmed death ligand-1 (PD-L1) was performed in one patient in paired treatment-naive and relapse biopsy tissues. Two STAT6 immunopositive cases were examined by whole-exome sequencing after flow sorting to assess mutations in STAT6 pathway genes. Most classical Hodgkin lymphomas showed nuclear staining for STAT6 [46/57 cases (80%)] on Hodgkin cells. Staining was exclusively nuclear in a minority [12/46 (26%)], while dual nuclear and cytoplasmic localization was more common [34/46 (74%)]. In contrast, all nodular lymphocyte predominant Hodgkin lymphomas [0/34 (0%)] were negative for nuclear STAT6 staining on the lymphocyte predominant cells. Within B- and T-cell non-Hodgkin lymphomas, nuclear STAT6 was seen in: B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, and in primary mediastinal large B-cell lymphoma. Strong PD-L1 gene amplification was noted in the paired cHL and relapse B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, although STAT6 was negative in both biopsies. Whole-exome sequencing identified mutations in B2M, XPO1, and ITPKB as well CISHP213L (in the STAT pathway) in one classical Hodgkin lymphoma patient positive for nuclear STAT6 although no underlying STAT6 mutations were observed in either sample examined. STAT6 nuclear staining has 100% positive predictive value and 85.7% negative predictive value in confirming or excluding classical Hodgkin lymphoma diagnosis in the distinction from nodular lymphocyte predominant Hodgkin lymphoma and other benign and malignant entities.
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http://dx.doi.org/10.1038/s41379-019-0428-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191386PMC
May 2020

Inhibition of MDR1 Overcomes Resistance to Brentuximab Vedotin in Hodgkin Lymphoma.

Clin Cancer Res 2020 03 6;26(5):1034-1044. Epub 2019 Dec 6.

Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, California.

Purpose: In classical Hodgkin lymphoma, the malignant Reed-Sternberg cells express the cell surface marker CD30. Brentuximab vedotin is an antibody-drug conjugate (ADC) that selectively delivers a potent cytotoxic agent, monomethyl auristatin E (MMAE), to CD30-positive cells. Although brentuximab vedotin elicits a high response rate (75%) in relapsed/refractory Hodgkin lymphoma, most patients who respond to brentuximab vedotin eventually develop resistance.

Patients And Methods: We developed two brentuximab vedotin-resistant Hodgkin lymphoma cell line models using a pulsatile approach and observed that resistance to brentuximab vedotin is associated with an upregulation of multidrug resistance-1 (MDR1). We then conducted a phase I trial combining brentuximab vedotin and cyclosporine A (CsA) in patients with relapsed/refractory Hodgkin lymphoma.

Results: Here, we show that competitive inhibition of MDR1 restored sensitivity to brentuximab vedotin in our brentuximab vedotin-resistant cell lines by increasing intracellular MMAE levels, and potentiated brentuximab vedotin activity in brentuximab vedotin-resistant Hodgkin lymphoma tumors in a human xenograft mouse model. In our phase I trial, the combination of brentuximab vedotin and CsA was tolerable and produced an overall and complete response rate of 75% and 42% in a population of patients who were nearly all refractory to brentuximab vedotin.

Conclusions: This study may provide a new therapeutic strategy to combat brentuximab vedotin resistance in Hodgkin lymphoma. This is the first study reporting an effect of multidrug resistance modulation on the therapeutic activity of an ADC in humans. The expansion phase of the trial is ongoing and enrolling patients who are refractory to brentuximab vedotin to confirm clinical activity in this population with unmet need.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056527PMC
March 2020

The great masquerader mimicking plasma cell myeloma.

Blood 2019 10;134(17):1481

City of Hope National Medical Center.

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http://dx.doi.org/10.1182/blood.2019002988DOI Listing
October 2019

Phase 1 study of the Aurora kinase A inhibitor alisertib (MLN8237) combined with the histone deacetylase inhibitor vorinostat in lymphoid malignancies.

Leuk Lymphoma 2020 02 16;61(2):309-317. Epub 2019 Oct 16.

Department of Medical Oncology, Division of Molecular Pharmacology, City of Hope, Duarte, CA, USA.

Alisertib, an Aurora kinase A inhibitor, was evaluated in a Phase 1 study in combination with the histone deacetylase inhibitor vorinostat, in patients with relapsed/refractory lymphoid malignancies ( = 34; NCT01567709). Patients received alisertib plus vorinostat in 21-day treatment cycles with escalating doses of alisertib following a continuous or an intermittent schedule. All dose-limiting toxicities (DLTs) were hematologic and there were no study-related deaths. The recommended phase 2 dose (RP2D) of the combination was 20 mg bid of alisertib and 200 mg bid of vorinostat on the intermittent schedule. A 13-patient expansion cohort was treated for a total of 18 patients at the RP2D. There were no DLTs at the RP2D, and toxicities were mainly hematologic. Two patients with DLBCL achieved a durable complete response, and two patients with HL achieved partial response. Alisertib plus vorinostat showed encouraging clinical activity with a manageable safety profile in heavily pretreated patients with advanced disease.
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http://dx.doi.org/10.1080/10428194.2019.1672052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982547PMC
February 2020

CAR T cells targeting BAFF-R can overcome CD19 antigen loss in B cell malignancies.

Sci Transl Med 2019 09;11(511)

Toni Stephenson Lymphoma Center, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.

CAR T cells targeting CD19 provide promising options for treatment of B cell malignancies. However, tumor relapse from antigen loss can limit efficacy. We developed humanized, second-generation CAR T cells against another B cell-specific marker, B cell activating factor receptor (BAFF-R), which demonstrated cytotoxicity against human lymphoma and acute lymphoblastic leukemia (ALL) lines. Adoptively transferred BAFF-R-CAR T cells eradicated 10-day preestablished tumor xenografts after a single treatment and retained efficacy against xenografts deficient in CD19 expression, including CD19-negative variants within a background of CD19-positive lymphoma cells. Four relapsed, primary ALLs with CD19 antigen loss obtained after CD19-directed therapy retained BAFF-R expression and activated BAFF-R-CAR, but not CD19-CAR, T cells. BAFF-R-CAR, but not CD19-CAR, T cells also demonstrated antitumor effects against an additional CD19 antigen loss primary patient-derived xenograft (PDX) in vivo. BAFF-R is amenable to CAR T cell therapy, and its targeting may prevent emergence of CD19 antigen loss variants.
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http://dx.doi.org/10.1126/scitranslmed.aaw9414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015136PMC
September 2019

CAR T cells mimicking an aggressive lymphoma.

Blood 2019 03;133(13):1517

City of Hope National Medical Center.

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http://dx.doi.org/10.1182/blood-2019-01-896753DOI Listing
March 2019

Epidemiology and Pathology of T- and NK-Cell Lymphomas.

Cancer Treat Res 2019;176:1-29

Department of Pathology, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA, 91010, USA.

Purpose: This review will describe and update readers on the recent changes in the 2017 WHO classification regarding peripheral T-cell lymphomas.

Recent Findings: Signficant advances in molecular studies have resulted in revisions to the classification as well as introduction to provisional entities such as breast implant-associated ALCL and nodal PTCL with T-follicular helper phenotype.

Summary: Major advances in molecular and gene expression profiling has expanded our knowledge of these rare and aggressive diseases.
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http://dx.doi.org/10.1007/978-3-319-99716-2_1DOI Listing
July 2019

Molecular classification of primary mediastinal large B-cell lymphoma using routinely available tissue specimens.

Blood 2018 11 26;132(22):2401-2405. Epub 2018 Sep 26.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ.

Primary mediastinal large B-cell lymphoma (PMBCL) is recognized as a distinct entity in the World Health Organization classification. Currently, the diagnosis relies on consensus of histopathology, clinical variables, and presentation, giving rise to diagnostic inaccuracy in routine practice. Previous studies have demonstrated that PMBCL can be distinguished from subtypes of diffuse large B-cell lymphoma (DLBCL) based on gene expression signatures. However, requirement of fresh-frozen biopsy material has precluded the transfer of gene expression-based assays to the clinic. Here, we developed a robust and accurate molecular classification assay (Lymph3Cx) for the distinction of PMBCL from DLBCL subtypes based on gene expression measurements in formalin-fixed, paraffin-embedded tissue. A probabilistic model accounting for classification error, comprising 58 gene features, was trained on 68 cases of PMBCL and DLBCL. Performance of the model was subsequently evaluated in an independent validation cohort of 158 cases and showed high agreement of the Lymph3Cx molecular classification with the clinicopathological diagnosis of an expert panel (frank misclassification rate, 3.8%). Furthermore, we demonstrate reproducibility of the assay with 100% concordance of subtype assignments at 2 independent laboratories. Future studies will determine Lymph3Cx's utility for routine diagnostic purposes and therapeutic decision making.
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http://dx.doi.org/10.1182/blood-2018-05-851154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265647PMC
November 2018

Therapy-related acute lymphoblastic leukemia has distinct clinical and cytogenetic features compared to acute lymphoblastic leukemia, but outcomes are comparable in transplanted patients.

Haematologica 2018 10 14;103(10):1662-1668. Epub 2018 Jun 14.

Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA, USA.

Therapy-related acute lymphoblastic leukemia remains poorly defined due to a lack of large data sets recognizing the defining characteristics of this entity. We reviewed all consecutive cases of adult acute lymphoblastic leukemia treated at our institution between 2000 and 2017 and identified therapy-related cases - defined as acute lymphoblastic leukemia preceded by prior exposure to cytotoxic chemotherapy and/or radiation. Of 1022 patients with acute lymphoblastic leukemia, 93 (9.1%) were classified as therapy-related. The median latency for therapy-related acute lymphoblastic leukemia onset was 6.8 years from original diagnosis, and this was shorter for patients carrying the gene rearrangement compared to those with other cytogenetics. When compared to acute lymphoblastic leukemia, therapy-related patients were older (<0.01), more often female (<0.01), and had more gene rearrangement (<0.0001) and chromosomes 5/7 aberrations (=0.02). Although therapy-related acute lymphoblastic leukemia was associated with inferior 2-year overall survival compared to cases (46.0% 68.1%, =0.001), prior exposure to cytotoxic therapy (therapy-related) did not independently impact survival in multivariate analysis (HR=1.32; 95% CI: 0.97-1.80, =0.08). There was no survival difference (2-year = 53.4% 58.9%, =0.68) between the two groups in patients who received allogenic hematopoietic cell transplantation. In conclusion, therapy-related acute lymphoblastic leukemia represents a significant proportion of adult acute lymphoblastic leukemia diagnoses, and a subset of cases carry clinical and cytogenetic abnormalities similar to therapy-related myeloid neoplasms. Although survival of therapy-related acute lymphoblastic leukemia was inferior to cases, allogeneic hematopoietic cell transplantation outcomes were comparable for the two entities.
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http://dx.doi.org/10.3324/haematol.2018.193599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165794PMC
October 2018

Updates of Peripheral T Cell Lymphomas Based on the 2017 WHO Classification.

Curr Hematol Malig Rep 2018 02;13(1):25-36

Department of Pathology, City of Hope National Medical Center, 1500 E. Duarte Rd., Duarte, CA, 91010, USA.

Purpose Of Review: This review will describe and update the readers on the recent changes of the 2017 WHO classification in regard to peripheral T cell lymphomas.

Recent Findings: Significant advances in molecular studies have resulted in revisions of the classification as well as introduction of provisional entities (such as breast implant-associated ALCL, nodal PTCL with TFH phenotype). Major advances in molecular and gene expression profiling have expanded our knowledge of T cell lymphomas, including updates in the diagnostic criteria and sub-classification which will facilitate in improving patient care and research.
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http://dx.doi.org/10.1007/s11899-018-0429-yDOI Listing
February 2018